WORKBOOK FOR INVESTIGATORS - WHO · WORKBOOK FOR INVESTIGATORS. WORKBOOK FOR INVESTIGATORS...

UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases

(TDR)

WORKBOOK FORINVESTIGATORS

WORKBOOK FOR

INVESTIGATORS

UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases

(TDR)

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TDR/PRD/GCP/02.1b

This document is not a formal publication of the World Health Organization (WHO), and all rights

are reserved by the Organization. The document may, however, be freely reviewed, abstracted,

reproduced or translated, in part or in whole, but not for sale or for use in conjunction with

commercial purposes.

The views expressed in documents by named authors are solely the responsibility of those authors.

© TDR, 2002

Concept and design: Lisa Schwarb

Layout: Transfotexte SA

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Workbook for investigators • III

All clinical studies supported by theUNDP/World Bank/WHO SpecialProgramme for Research and Training inTropical Diseases (TDR) must be carriedout according to InternationalConference on Harmonization (ICH)/WHO good clinical practice standards,regulatory authorities’ requirements,ethical requirements, and TDR standardoperating procedures (SOPs).

This booklet is intended for clinicalinvestigators who are conducting clini-cal trials sponsored or co-sponsored byTDR Product Research and Development(TDR/PRD). Its aim is to provide a regu-latory framework within which clinicaltrials should be conducted to ensureaccordance with international standards.Relevant TDR/PRD working documentsare also presented.

The booklet is divided into two sec-tions.

In Section one, relevant ICH guidelinesare presented, together with theOperational guidelines for ethics com-mittees that review biomedical researchand the two latest versions of theDeclaration of Helsinki. These docu-ments represent the minimum interna-tional requirements when conducting aclinical trial. They do not represent anexhaustive list of all legal and regula-tory requirements, and considerationshould also be given to other relevantinternational and local requirements.

Section two consists of the TDR/PRDstandard operating procedures (SOPs)and guidelines. These must be compliedwith when conducting clinical trialssupported by TDR/PRD, and are subjectto update by TDR.

Comments and suggestions on allaspects of this booklet are most wel-come, and will be taken into considera-tion for future revisions.

Foreword

Dr Juntra KarbwangClinical Coordinator,

Product Research and Development

UNDP/World Bank/WHO SpecialProgramme for Research and Training

in Tropical Diseases (TDR),World Health Organization

1211 Geneva 27SWITZERLAND

Tel: +41 22 791 3867Fax: +41 22 791 4854E-mail: [email protected]

Web: www.who.int/tdr

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Workbook for investigators • V

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Table of contents

Guidelines and Recommendations

ICH GUIDELINES*– Clinical Safety Data Management: Definitions and

Standards for Expedited Reporting (E2A) . . . . . . . . . . . . . . . . . 1– Structure and Content of Clinical Study Reports (E3) . . . 13– Guideline for Good Clinical Practice (E6) . . . . . . . . . . . . . . . . . 61– Statistical Principles for Clinical trials (E9) . . . . . . . . . . . . . . 119

DECLARATION OF HELSINKI– South Africa version / Oct 1996 . . . . . . . . . . . . . . . . . . . . . . . . . . . 163– Scotland version / Oct 2000 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167

Operational Guidelines for Ethics Committees thatReview Biomedical Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173

TDR/PRD Standard Operating Procedures(SOPs) and guidelines– CT 05 Investigator’s Responsibilities . . . . . . . . . . . . . . . . . . . . . . 197– CT 06 Breaking Code . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 257– Manual for Completing the SAE Reporting Form . . . . . . . . . 261– Good Clinical Practice Laboratory for Clinical Trials . . . . . 268

*All the ICH Guidelines are available on the official website of the International Conference on Harmonisation: www.ich.org

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ICH Guidelines • Clinical Safety Data Management (E2A) • 1

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N 1INTERNATIONAL CONFERENCE ON HARMONISATION OF

TECHNICAL REQUIREMENTS FOR REGISTRATION OF PHARMACEUTICALSFOR HUMAN USE

ICH Harmonised Tripartite Guideline

CLINICAL SAFETY DATA MANAGEMENT:DEFINITIONS AND STANDARDS FOR

EXPEDITED REPORTING

Recommended for Adoptionat Step 4 of the ICH Process

on 27 October 1994by the ICH Steering Committee

This Guideline has been developed by the appropriate ICH Expert Working Group andhas been subject to consultation by the regulatory parties, in accordance with theICH Process. At Step 4 of the Process the final draft is recommended for adoptionto the regulatory bodies of the European Union, Japan and USA.

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CLINICAL SAFETY DATA MANAGEMENT:DEFINITIONS AND STANDARDS FOR EXPEDITED REPORTING

ICH Harmonised Tripartite GuidelineHaving reached Step 4 of the ICH Process at the

ICH Steering Committee meeting on 27 October 1994, this guideline is recommended for adoption

to the three regulatory parties to ICH

I. INTRODUCTIONIt is important to harmonize the way to gather and, if necessary, to take action onimportant clinical safety information arising during clinical development. Thus,agreed definitions and terminology, as well as procedures, will ensure uniform GoodClinical Practice standards in this area. The initiatives already undertaken for mar-keted medicines through the CIOMS-1 and CIOMS-2 Working Groups on expedited(alert) reports and periodic safety update reporting, respectively, are importantprecedents and models. However, there are special circumstances involving medi-cinal products under development, especially in the early stages and before anymarketing experience is available. Conversely, it must be recognized that a medi-cinal product will be under various stages of development and/or marketing indifferent countries, and safety data from marketing experience will ordinarily be of interest to regulators in countries where the medicinal product is still underinvestigational-only (Phase 1, 2, or 3) status. For this reason, it is both practicaland well-advised to regard pre-marketing and post-marketing clinical safety report-ing concepts and practices as interdependent, while recognizing that responsibilityfor clinical safety within regulatory bodies and companies may reside with differentdepartments, depending on the status of the product (investigational vs. marketed).

There are two issues within the broad subject of clinical safety data managementthat are appropriate for harmonization at this time:

(1) the development of standard definitions and terminology for key aspects ofclinical safety reporting, and

(2) the appropriate mechanism for handling expedited (rapid) reporting, in theinvestigational (i.e. pre-approval) phase.

The provisions of this guideline should be used in conjunction with other ICH GoodClinical Practice guidelines.

II. DEFINITIONS AND TERMINOLOGY ASSOCIATED WITH CLINICAL SAFETY EXPERIENCE

A. Basic TermsDefinitions for the terms adverse event (or experience), adverse reaction, and unex-pected adverse reaction have previously been agreed to by consensus of the morethan 30 Collaborating Centres of the WHO International Drug Monitoring Centre

2 • ICH Guidelines • Clinical Safety Data Management (E2A)

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N 1(Uppsala, Sweden). [Edwards, I.R., et al, Harmonization in Pharmacovigilance. Drug

Safety 10(2): 93-102, 1994.] Although those definitions can pertain to situationsinvolving clinical investigations, some minor modifications are necessary, especiallyto accommodate the pre-approval, development environment.

The following definitions, with input from the WHO Collaborative Centre, have beenagreed:

1. ADVERSE EVENT (OR ADVERSE EXPERIENCE)

Any untoward medical occurrence in a patient or clinical investigation subjectadministered a pharmaceutical product and which does not necessarily have tohave a causal relationship with this treatment.

An adverse event (AE) can therefore be any unfavourable and unintended sign(including an abnormal laboratory finding, for example), symptom, or disease tem-porally associated with the use of a medicinal product, whether or not consideredrelated to the medicinal product.

2. ADVERSE DRUG REACTION (ADR)

In the pre-approval clinical experience with a new medicinal product or its newusages, particularly as the therapeutic dose(s) may not be established:

all noxious and unintended responses to a medicinal product related to any doseshould be considered adverse drug reactions.

The phrase “responses to a medicinal products” means that a causal relationshipbetween a medicinal product and an adverse event is at least a reasonable possi-bility, i.e. the relationship cannot be ruled out.

Regarding marketed medicinal products, a well-accepted definition of an adversedrug reaction in the post-marketing setting is found in WHO Technical Report 498[1972] and reads as follows:

A response to a drug which is noxious and unintended and which occurs at dosesnormally used in man for prophylaxis, diagnosis, or therapy of disease or formodification of physiological function.

The old term “side effect” has been used in various ways in the past, usually todescribe negative (unfavourable) effects, but also positive (favourable) effects. Itis recommended that this term no longer be used and particularly should not beregarded as synonymous with adverse event or adverse reaction.

3. UNEXPECTED ADVERSE DRUG REACTION

An adverse reaction, the nature or severity of which is not consistent with theapplicable product information (e.g. Investigator’s Brochure for an unapprovedinvestigational medicinal product). (See section III.C.)

B. Serious Adverse Event or Adverse Drug ReactionDuring clinical investigations, adverse events may occur which, if suspected to bemedicinal product-related (adverse drug reactions), might be significant enough to

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lead to important changes in the way the medicinal product is developed (e.g.change in dose, population, needed monitoring, consent forms). This is particularlytrue for reactions which, in their most severe forms, threaten life or function. Suchreactions should be reported promptly to regulators.

Therefore, special medical or administrative criteria are needed to define reactionsthat, either due to their nature (“serious”) or due to the significant, unexpectedinformation they provide, justify expedited reporting.

To ensure no confusion or misunderstanding of the difference between the terms“serious” and “severe”, which are not synonymous, the following note of clarifica-tion is provided:

The term “severe” is often used to describe the intensity (severity) of a specificevent (as in mild, moderate, or severe myocardial infarction); the event itself, how-ever, may be of relatively minor medical significance (such as severe headache).This is not the same as “serious”, which is based on patient/event outcome oraction criteria usually associated with events that pose a threat to a patient’s lifeor functioning. Seriousness (not severity) serves as a guide for defining regulatoryreporting obligations.

After reviewing the various regulatory and other definitions in use or under discus-sion elsewhere, the following definition is believed to encompass the spirit andmeaning of them all:

A serious adverse event (experience) or reaction is any untoward medical occur-rence that at any dose:

– results in death,

– is life-threatening,

NOTE: The term “life-threatening” in the definition of “serious” refers to anevent in which the patient was at risk of death at the time of the event; it doesnot refer to an event which hypothetically might have caused death if it weremore severe.

– requires inpatient hospitalisation or prolongation of existing hospitalisation,

– results in persistent or significant disability/incapacity, or

– is a congenital anomaly/birth defect.

Medical and scientific judgement should be exercised in deciding whether expeditedreporting is appropriate in other situations, such as important medical events thatmay not be immediately life-threatening or result in death or hospitalization butmay jeopardise the patient or may require intervention to prevent one of the otheroutcomes listed in the definition above. These should also usually be consideredserious.

Examples of such events are intensive treatment in an emergency room or at homefor allergic bronchospasm; blood dyscrasias or convulsions that do not result in hos-pitalization; or development of drug dependency or drug abuse.


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N 1C. Expectedness of an Adverse Drug Reaction

The purpose of expedited reporting is to make regulators, investigators, and otherappropriate people aware of new, important information on serious reactions.Therefore, such reporting will generally involve events previously unobserved orundocumented, and a guideline is needed on how to define an event as “un-expected” or “expected” (expected/unexpected from the perspective of previouslyobserved, not on the basis of what might be anticipated from the pharmacologicalproperties of a medicinal product).

As stated in the definition (II.A.3.), an “unexpected” adverse reaction is one, thenature or severity of which is not consistent with information in the relevant sourcedocument(s). Until source documents are amended, expedited reporting is requiredfor additional occurrences of the reaction.

The following documents or circumstances will be used to determine whether anadverse event/reaction is expected:

1. For a medicinal product not yet approved for marketing in a country, a com-pany’s Investigator’s Brochure will serve as the source document in thatcountry. (See section III.F. and ICH Guideline for the Investigator’s Brochure.)

2. Reports which add significant information on specificity or severity of a known,already documented serious ADR constitute unexpected events. For example, an event more specific or more severe than described in the Investiga-tor’s Brochure would be considered “unexpected”. Specific examples would be(a) acute renal failure as a labeled ADR with a subsequent new report of inter-stitial nephritis and (b) hepatitis with a first report of fulminant hepatitis.

III. STANDARDS FOR EXPEDITED REPORTING

A. What Should be Reported?

1. SINGLE CASES OF SERIOUS, UNEXPECTED ADRS

All adverse drug reactions (ADRs) that are both serious and unexpected are subjectto expedited reporting. This applies to reports from spontaneous sources and fromany type of clinical or epidemiological investigation, independent of design or pur-pose. It also applies to cases not reported directly to a sponsor or manufacturer (forexample, those found in regulatory authority-generated ADR registries or in publi-cations). The source of a report (investigation, spontaneous, other) should alwaysbe specified.

Expedited reporting of reactions which are serious but expected will ordinarily beinappropriate. Expedited reporting is also inappropriate for serious events fromclinical investigations that are considered not related to study product, whether theevent is expected or not. Similarly, non-serious adverse reactions, whether expectedor not, will ordinarily not be subject to expedited reporting.

Information obtained by a sponsor or manufacturer on serious, unexpected reportsfrom any source should be submitted on an expedited basis to appropriate regu-

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latory authorities if the minimum criteria for expedited reporting can be met. Seesection III.B.

Causality assessment is required for clinical investigation cases. All cases judged byeither the reporting health care professional or the sponsor as having a reasonablesuspected causal relationship to the medicinal product qualify as ADRs. For pur-poses of reporting, adverse event reports associated with marketed drugs (sponta-neous reports) usually imply causality.

Many terms and scales are in use to describe the degree of causality (attributability)between a medicinal product and an event, such as certainly, definitely, probably,possibly or likely related or not related. Phrases such as “plausible relationship”,“suspected causality”, or “causal relationship cannot be ruled out” are also invokedto describe cause and effect. However, there is currently no standard internationalnomenclature. The expression “reasonable causal relationship” is meant to conveyin general that there are facts (evidence) or arguments to suggest a causal rela-tionship.

2. OTHER OBSERVATIONS

There are situations in addition to single case reports of “serious” adverse eventsor reactions that may necessitate rapid communication to regulatory authorities;appropriate medical and scientific judgement should be applied for each situation.In general, information that might materially influence the benefit-risk assessmentof a medicinal product or that would be sufficient to consider changes in medicinalproduct administration or in the overall conduct of a clinical investigation repre-sents such situations. Examples include:

a. For an “expected”, serious ADR, an increase in the rate of occurrence which isjudged to be clinically important.

b. A significant hazard to the patient population, such as lack of efficacy with amedicinal product used in treating life-threatening disease.

c. A major safety finding from a newly completed animal study (such as carcino-genicity).

B. Reporting Time Frames

1. FATAL OR LIFE-THREATENING UNEXPECTED ADRs

Certain ADRs may be sufficiently alarming so as to require very rapid notification toregulators in countries where the medicinal product or indication, formulation, orpopulation for the medicinal product are still not approved for marketing, becausesuch reports may lead to consideration of suspension of, or other limitations to, aclinical investigations program. Fatal or life-threatening, unexpected ADRs occur-ring in clinical investigations qualify for very rapid reporting. Regulatory agenciesshould be notified (e.g. by telephone, facsimile transmission, or in writing) as soonas possible but no later than 7 calendar days after first knowledge by the sponsorthat a case qualifies, followed by as complete a report as possible within 8 addi-tional calendar days. This report must include an assessment of the importance and


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N 1implication of the findings, including relevant previous experience with the same or

similar medicinal products.

2. ALL OTHER SERIOUS, UNEXPECTED ADRs

Serious, unexpected reactions (ADRs) that are not fatal or life-threatening must befiled as soon as possible but no later than 15 calendar days after first knowledgeby the sponsor that the case meets the minimum criteria for expedited reporting.

3. MINIMUM CRITERIA FOR REPORTING

Information for final description and evaluation of a case report may not be avail-able within the required time frames for reporting outlined above. Nevertheless, forregulatory purposes, initial reports should be submitted within the prescribed timeas long as the following minimum criteria are met: an identifiable patient; a sus-pect medicinal product; an identifiable reporting source; and an event or outcomethat can be identified as serious and unexpected, and for which, in clinical inves-tigation cases, there is a reasonable suspected causal relationship. Follow-up infor-mation should be actively sought and submitted as it becomes available.

C. How to ReportThe CIOMS-I form has been a widely accepted standard for expedited adverse eventreporting. However, no matter what the form or format used, it is important thatcertain basic information/data elements, when available, be included with anyexpedited report, whether in a tabular or narrative presentation. The listing inAttachment 1 addresses those data elements regarded as desirable; if all are notavailable at the time of expedited reporting, efforts should be made to obtain them.(See section III.B.)

All reports must be sent to those regulators or other official parties requiring them(as appropriate for the local situation) in countries where the drug is under de-velopment.

D. Managing Blinded Therapy CasesWhen the sponsor and investigator are blinded to individual patient treatment (asin a double-blind study), the occurrence of a serious event requires a decision onwhether to open (break) the code for the specific patient. If the investigator breaksthe blind, then it is assumed the sponsor will also know the assigned treatment forthat patient. Although it is advantageous to retain the blind for all patients priorto final study analysis, when a serious adverse reaction is judged reportable on anexpedited basis, it is recommended that the blind be broken only for that specificpatient by the sponsor even if the investigator has not broken the blind. It is alsorecommended that, when possible and appropriate, the blind be maintained forthose persons, such as biometrics personnel, responsible for analysis and interpre-tation of results at the study’s conclusion.

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There are several disadvantages to maintaining the blind under the circumstancesdescribed which outweigh the advantages. By retaining the blind, placebo and com-parator (usually a marketed product) cases are filed unnecessarily. When the blindis eventually opened, which may be many weeks or months after reporting to regu-lators, it must be ensured that company and regulatory data bases are revised. Ifthe event is serious, new, and possibly related to the medicinal product, then if the Investigator’s Brochure is updated, notifying relevant parties of the new infor-mation in a blinded fashion is inappropriate and possibly misleading. Moreover,breaking the blind for a single patient usually has little or no significant implica-tions for the conduct of the clinical investigation or on the analysis of the finalclinical investigation data.

However, when a fatal or other “serious” outcome is the primary efficacy endpointin a clinical investigation, the integrity of the clinical investigation may be com-promised if the blind is broken. Under these and similar circumstances, it may beappropriate to reach agreement with regulatory authorities in advance concerningserious events that would be treated as disease-related and not subject to routineexpedited reporting.

E. Miscellaneous Issues

1. REACTIONS ASSOCIATED WITH ACTIVE COMPARATOR OR PLACEBO TREATMENT

It is the sponsor’s responsibility to decide whether active comparator drug reactionsshould be reported to the other manufacturer and/or directly to appropriate regu-latory agencies. Sponsors must report such events to either the manufacturer of theactive control or to appropriate regulatory agencies. Events associated with placebowill usually not satisfy the criteria for an ADR and, therefore, for expeditedreporting.

2. PRODUCTS WITH MORE THAN ONE PRESENTATION OR USE

To avoid ambiguities and uncertainties, an ADR that qualifies for expedited report-ing with one presentation of a product (e.g. a dosage form, formulation, deliverysystem) or product use (e.g. for an indication or population), should be reported orreferenced to regulatory filings across other product presentations and uses.

It is not uncommon that more than one dosage form, formulation, or deliverysystem (oral, IM, IV, topical, etc.) of the pharmacologically active compound(s) isunder study or marketed; for these different presentations there may be somemarked differences in the clinical safety profile. The same may apply for a givenproduct used in different indications or populations (single dose vs. chronic admin-istration, for example). Thus, “expectedness” may be product or product-use spe-cific, and separate Investigator’s Brochures may be used accordingly. However, suchdocuments are expected to cover ADR information that applies to all affectedproduct presentations and uses. When relevant, separate discussions of pertinentproduct-specific or use-specific safety information will also be included.

It is recommended that any adverse drug reactions that qualify for expeditedreporting observed with one product dosage form or use be cross referenced to regu-


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N 1latory records for all other dosage forms and uses for that product. This may result

in a certain amount of overreporting or unnecessary reporting in obvious situations(for example, a report of phlebitis on IV injection sent to authorities in a countrywhere only an oral dosage form is studied or marketed). However, underreporting iscompletely avoided.

3. POST-STUDY EVENTS

Although such information is not routinely sought or collected by the sponsor,serious adverse events that occurred after the patient had completed a clinicalstudy (including any protocol-required post-treatment follow-up) will possibly bereported by an investigator to the sponsor. Such cases should be regarded for ex-pedited reporting purposes as though they were study reports. Therefore, a causalityassessment and determination of expectedness are needed for a decision onwhether or not expedited reporting is required.

F. Informing Investigators and Ethics Committees/Institutional ReviewBoards of New Safety Information

International standards regarding such communication are discussed within the ICH GCP Guidelines, including the addendum on “Guideline for the Investigator’sBrochure”. In general, the sponsor of a study should amend the Investigator’sBrochure as needed, and in accord with any local regulatory requirements, so as tokeep the description of safety information updated.

Attachment 1

KEY DATA ELEMENTS FOR INCLUSION IN EXPEDITEDREPORTS OF SERIOUS ADVERSE DRUG REACTIONS

The following list of items has its foundation in several established precedents,including those of CIOMS-I, the WHO International Drug Monitoring Centre, and var-ious regulatory authority forms and guidelines. Some items may not be relevantdepending on the circumstances. The minimum information required for expeditedreporting purposes is: an identifiable patient, the name of a suspect medicinalproduct, an identifiable reporting source, and an event or outcome that can be iden-tified as serious and unexpected and for which, in clinical investigation cases, thereis a reasonable suspected causal relationship. Attempts should be made to obtainfollow-up information on as many other listed items pertinent to the case.

1. Patient Details

• Initials

• Other relevant identifier (clinical investigation number, for example)

• Gender

• Age and/or date of birth

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• Weight

• Height

2. Suspected Medicinal Product(s)

• Brand name as reported

• International Non-Proprietary Name (INN)

• Batch number

• Indication(s) for which suspect medicinal product was prescribed or tested

• Dosage form and strength

• Daily dose and regimen (specify units – e.g., mg, ml, mg/kg)

• Route of administration

• Starting date and time of day

• Stopping date and time, or duration of treatment

3. Other Treatment(s)

For concomitant medicinal products (including non-prescription/OTC medicinalproducts) and non-medicinal product therapies, provide the same information as forthe suspected product.

4. Details of Suspected Adverse Drug Reaction(s)

Full description of reaction(s) including body site and severity, as well as the cri-terion (or criteria) for regarding the report as serious should be given. In additionto a description of the reported signs and symptoms, whenever possible, attemptsshould be made to establish a specific diagnosis for the reaction.

• Start date (and time) of onset of reaction

• Stop date (and time) or duration of reaction

• Dechallenge and rechallenge information

• Setting (e.g. hospital, out-patient clinic, home, nursing home)

Outcome: information on recovery and any sequelae; what specific tests and/ortreatment may have been required and their results; for a fatal outcome, cause ofdeath and a comment on its possible relationship to the suspected reaction shouldbe provided. Any autopsy or other post-mortem findings (including a coroner’sreport) should also be provided when available. Other information: anything relevantto facilitate assessment of the case, such as medical history including allergy, drugor alcohol abuse; family history; findings from special investigations.

5. Details on Reporter of Event (Suspected ADR)

• Name

• Address

• Telephone number

• Profession (speciality)


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N 16. Administrative and Sponsor/Company Details

Source of report: was it spontaneous, from a clinical investigation (provide details),from the literature (provide copy), other?

• Date event report was first received by sponsor/manufacturer

• Country in which event occurred

• Type of report filed to authorities: initial or follow-up (first, second, etc.)

• Name and address of sponsor/manufacturer/company

• Name, address, telephone number, and FAX number of contact person in reportingcompany or institution

• Identifying regulatory code or number for marketing authorization dossier orclinical investigation process for the suspected product (for example IND or CTXnumber, NDA number)

• Sponsor/manufacturer’s identification number for the case (this number must bethe same for the initial and follow-up reports on the same case).

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ICH Guidelines • Structure and Content of Clinical Study Reports (E3) • 13

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INTERNATIONAL CONFERENCE ON HARMONISATION OF TECHNICAL REQUIREMENTS FOR REGISTRATION OF PHARMACEUTICALS

FOR HUMAN USE


STRUCTURE AND CONTENT OF CLINICAL STUDY REPORTS


on 30 November 1995by the ICH Steering Committee


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14 • ICH Guidelines • Structure and Content of Clinical Study Reports (E3)

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ICH Steering Committee meeting on 30 November 1995, this guideline is recommended for adoption


TABLE OF CONTENTS

Introduction to the guideline . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181. Title Page . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 202. Synopsis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203. Table of contents for the individual Clinical Study Report . . . . . . . . . . . 214. List of Abbreviations and Definition of Terms . . . . . . . . . . . . . . . . . . . . . . . . . 215. Ethics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21

5.1 Independent Ethics Committee (IEC) or InstitutionalReview Board (IRB) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21

5.2 Ethical Conduct of the Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 215.3 Patient Information and Consent . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21

6. Investigators and Study Administrative Structure . . . . . . . . . . . . . . . . . . . . . 217. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 228. Study Objectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 229. Investigational Plan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22

9.1 Overall Study Design and Plan – Description . . . . . . . . . . . . . . . . . . . . . . 229.2 Discussion of Study Design, including the Choice of

Control Groups . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 239.3 Selection of Study Population . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24

9.3.1 Inclusion Criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249.3.2 Exclusion Criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249.3.3 Removal of Patients from Therapy or Assessment . . . . . . 24

9.4 Treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 259.4.1 Treatments Administered . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 259.4.2 Identity of Investigational Product(S) . . . . . . . . . . . . . . . . . . 259.4.3 Method of Assigning Patients to Treatment Groups . . . . 259.4.4 Selection of Doses in the Study . . . . . . . . . . . . . . . . . . . . . . . . . 259.4.5 Selection and Timing of Dose for Each Patient . . . . . . . . . 269.4.6 Blinding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 269.4.7 Prior and Concomitant Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . 269.4.8 Treatment Compliance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27

9.5 Efficacy and Safety Variables . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27

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9.5.1 Efficacy and Safety Measurements Assessed and Flow Chart . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27

9.5.2 Appropriateness of Measurements . . . . . . . . . . . . . . . . . . . . . . . 289.5.3 Primary Efficacy Variable(s) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 289.5.4 Drug Concentration Measurements . . . . . . . . . . . . . . . . . . . . . . . 28

9.6 Data Quality Assurance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 289.7 Statistical Methods Planned in the Protocol and Determination

of Sample Size . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 299.7.1 Statistical and Analytical Plans . . . . . . . . . . . . . . . . . . . . . . . . . . 299.7.2 Determination of Sample Size . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29

9.8 Changes in the Conduct of the Study or Planned Analyses . . . . . . . 30

10. Study Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3010.1 Disposition of Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3010.2 Protocol Deviations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30

11. Efficacy Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3111.1 Data Sets Analysed . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3111.2 Demographic and Other Baseline Characteristics . . . . . . . . . . . . . . . . . . 3111.3 Measurements of Treatment Compliance . . . . . . . . . . . . . . . . . . . . . . . . . . . 3211.4 Efficacy Results and Tabulations of Individual Patient Data . . . . . 32

11.4.1 Analysis of Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3211.4.2 Statistical/Analytical Issues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33

11.4.2.1 Adjustments for Covariates . . . . . . . . . . . . . . . . . . . 3411.4.2.2 Handling of Dropouts or Missing Data . . . . . . 3411.4.2.3 Interim Analyses and Data Monitoring . . . . . . 3411.4.2.4 Multicentre Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . 3511.4.2.5 Multiple Comparison/Multiplicity . . . . . . . . . . . . 3511.4.2.6 Use of an “Efficacy Subset” of Patients . . . . . 3511.4.2.7 Active-Control Studies Intended to

Show Equivalence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3511.4.2.8 Examination of Subgroups . . . . . . . . . . . . . . . . . . . 36

11.4.3 Tabulation of Individual Response Data . . . . . . . . . . . . . . . . . 3611.4.4 Drug Dose, Drug Concentration, and Relationships to

Response . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3711.4.5 Drug-Drug and Drug-Disease Interactions . . . . . . . . . . . . . . . 3711.4.6 By-Patient Displays . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3711.4.7 Efficacy Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37

12. Safety Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3712.1 Extent of Exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3812.2 Adverse Events (AEs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39

12.2.1 Brief Summary of Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . 3912.2.2 Display of Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3912.2.3 Analysis of Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4012.2.4 Listing of Adverse Events by Patient . . . . . . . . . . . . . . . . . . . . 41

12.3 Deaths, Other Serious Adverse Events, and Other Significant Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41

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12.3.1 Listing of Deaths, Other Serious Adverse Events and Other Significant Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . 4112.3.1.1 Deaths . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4112.3.1.2 Other Serious Adverse Events . . . . . . . . . . . . . . . . 4212.3.1.3 Other Significant Adverse Events . . . . . . . . . . . . 42

12.3.2 Narratives of Deaths, Other Serious Adverse Events and Certain Other Significant Adverse Events . . . . . . . . . . . . . . . 42

12.3.3 Analysis and Discussion of Deaths, Other Serious Adverse Events and Other Significant Adverse Events . . 43

12.4 Clinical Laboratory Evaluation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4312.4.1 Listing of Individual Laboratory Measurements by

Patient (16.2.8) and Each Abnormal Laboratory Value(14.3.4) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43

12.4.2 Evaluation of Each Laboratory Parameter . . . . . . . . . . . . . . . 4412.4.2.1 Laboratory Values over Time . . . . . . . . . . . . . . . . . 4412.4.2.2 Individual Patient Changes . . . . . . . . . . . . . . . . . . . 4412.4.2.3 Individual Clinically Significant

Abnormalities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4512.5 Vital Signs, Physical Findings and Other Observations Related to

Safety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4512.6 Safety Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45

13. Discussion and Overall Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4514. Tables, Figures and Graphs Referred to but not included in

the Text . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4614.1 Demographic Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4614.2 Efficacy Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4614.3 Safety Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46

14.3.1 Displays of Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4614.3.2 Listings of Deaths, Other Serious and Significant

Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4614.3.3 Narratives of Deaths, Other Serious and Certain Other

Significant Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4614.3.4 Abnormal Laboratory Value Listing (each patient) . . . . . 46

15. Reference List . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4616. Appendices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46

16.1 Study Information . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4716.1.1 Protocol and protocol amendments . . . . . . . . . . . . . . . . . . . . . . 4716.1.2 Sample case report form (unique pages only) . . . . . . . . . . 4716.1.3 List of IECs or IRBs (plus the name of the committee

Chair if required by the regulatory authority) – Representative written information for patient and sample consent forms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47

16.1.4 List and description of investigators and other impor-tant participants in the study, including brief (1 page) CVs or equivalent summaries of training and experience relevant to the performance of the clinical study . . . . . . 47

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16.1.5 Signatures of principal or coordinating investigator(s) or sponsor’s responsible medical officer depending on the regulatory authority’s requirement . . . . . . . . . . . . . . . . . . 47

16.1.6 Listing of patients receiving test drug(s)/investiga-tional product(s) from specific batches where more than one batch was used . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47

16.1.7 Randomization scheme and codes (patient identifi-cation and treatment assigned) . . . . . . . . . . . . . . . . . . . . . . . . . . 47

16.1.8 Audit certificates (if available) . . . . . . . . . . . . . . . . . . . . . . . . . . 4716.1.9 Documentation of statistical methods . . . . . . . . . . . . . . . . . . . 4716.1.10 Documentation of inter-laboratory standardization

methods and quality assurance procedures if used . . . . . 4716.1.11 Publications based on the study . . . . . . . . . . . . . . . . . . . . . . . . . 4716.1.12 Important publications referenced in the report . . . . . . . 47

16.2 Patient Data Listings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4716.2.1 Discontinued patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4716.2.2 Protocol deviations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4716.2.3 Patients excluded from the efficacy analysis . . . . . . . . . . . . 4716.2.4 Demographic data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4716.2.5 Compliance and/or drug concentration data

(if available) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4716.2.6 Individual efficacy response data . . . . . . . . . . . . . . . . . . . . . . . . 4716.2.7 Adverse event listings (each patient) . . . . . . . . . . . . . . . . . . . 4716.2.8 Listing of individual laboratory measurements by

patient, when required by regulatory authorities . . . . . . . 4716.3 Case Report Forms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47

16.3.1 CRFs for deaths, other serious adverse events and withdrawals for AE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47

16.3.2 Other CRFs submitted . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4716.4 Individual Patient Data Listings (US Archival Listings) . . . . . . . . . . . 47

Annex I Synopsis (Example) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48Annex II Principal or Coordinating Investigator(s) Signature(s) or

Sponsor’s Responsible Medical Officer (Example) . . . . . . . . . . . . . . . . 50Annex III a Study Design and Schedule of Assessments (Example) . . . . . . . . . . 51Annex III b Study Design and Schedule of Assessments (Example) . . . . . . . . . . 52Annex IV a Disposition of Patients (Example) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53Annex IV b Disposition of Patients (Example) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54Annex V Listing of Patients Who Discontinued Therapy (Example) . . . . . . . 55Annex VI Listing of Patients and Observations Excluded from

Efficacy Analysis (Example) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56Annex VII Number of Patients Excluded from Efficacy Analysis (Example) . 57Annex VIII Guidance for Section 11.4.2 – Statistical/Analytical Issues and

Appendix 16.1.9 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58

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INTRODUCTION TO THE GUIDELINE

The objective of this guideline is to allow the compilation of a single-core clinicalstudy report acceptable to all regulatory authorities of the ICH regions. The regula-tory authority specific additions will consist of modules to be considered as appen-dices, available upon request according to regional regulatory requirements.

The clinical study report described in this guideline is an “integrated” full report ofan individual study of any therapeutic, prophylactic or diagnostic agent (referred toherein as drug or treatment) conducted in patients, in which the clinical and sta-tistical description, presentations, and analyses are integrated into a single report,incorporating tables and figures into the main text of the report, or at the end ofthe text, and with appendices containing the protocol, sample case report forms,investigator related information, information related to the test drugs/investiga-tional products including active control/comparators, technical statistical docu-mentation, related publications, patient data listings, and technical statisticaldetails such as derivations, computations, analyses, and computer output etc. Theintegrated full report of a study should not be derived by simply joining a separateclinical and statistical report. Although this guideline is mainly aimed at efficacyand safety trials, the basic principles and structure described can be applied toother kinds of trials, such as clinical pharmacology studies. Depending on thenature and importance of such studies, a less detailed report might be appropriate.

The guideline is intended to assist sponsors in the development of a report that iscomplete, free from ambiguity, well organized and easy to review. The report shouldprovide a clear explanation of how the critical design features of the study werechosen and enough information on the plan, methods and conduct of the study sothat there is no ambiguity in how the study was carried out. The report with itsappendices should also provide enough individual patient data, including the demo-graphic and baseline data, and details of analytical methods, to allow replication ofthe critical analyses when authorities wish to do so. It is also particularly impor-tant that all analyses, tables, and figures carry, in text or as part of the table, clearidentification of the set of patients from which they were generated.

Depending on the regulatory authority’s review policy, abbreviated reports usingsummarized data or with some sections deleted, may be acceptable for uncontrolledstudies or other studies not designed to establish efficacy (but a controlled safetystudy should be reported in full), for seriously flawed or aborted studies, or for con-trolled studies that examine conditions clearly unrelated to those for which a claimis made. However, a full description of safety aspects should be included in thesecases. If an abbreviated report is submitted, there should be enough detail ofdesign and results to allow the regulatory authority to determine whether a fullreport is needed. If there is any question regarding whether the reports are needed,it may be useful to consult the regulatory authority.

In presenting the detailed description of how the study was carried out, it may bepossible simply to restate the description in the initial protocol. Often, however, it

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is possible to present the methodology of the study more concisely in a separatedocument. In each section describing the design and conduct of the study, it is par-ticularly important to clarify features of the study that are not well-described in theprotocol and identify ways in which the study as conducted differed from the pro-tocol, and to discuss the statistical methods and analyses used to account for thesedeviations from the planned protocol.

The full integrated report of the individual study should include the most detaileddiscussion of individual adverse events or laboratory abnormalities, but theseshould usually be reexamined as part of an overall safety analysis of all availabledata in any application.

The report should describe demographic and other potentially predictive character-istics of the study population and, where the study is large enough to permit this,present data for demographic (e.g. age, sex, race, weight) and other (e.g. renal orhepatic function) subgroups so that possible differences in efficacy or safety canbe identified. Usually, however, subgroup responses should be examined in thelarger database used in the overall analysis.

The data listings requested as part of the report (usually in an appendix) are thoseneeded to support critical analyses. Data listings that are part of the report shouldbe readily usable by the reviewer. Thus, although it may be desirable to includemany variables in a single listing to limit size, this should not be at the expense ofclarity. An excess of data should not be allowed to lead to overuse of symbolsinstead of words or easily understood abbreviations or to too small displays etc. Inthis case, it is preferable to produce several listings.

Data should be presented in the report at different levels of detail: overall summaryfigures and tables for important demographic, efficacy and safety variables may beplaced in the text to illustrate important points; other summary figures, tables andlistings for demographic, efficacy and safety variables should be provided in sec-tion 14; individual patient data for specified groups of patients should be providedas listings in Appendix 16.2; and all individual patient data (archival listingsrequested only in the US) should be provided in Appendix 16.4.

In any table, figure or data listing, estimated or derived values, if used, should beidentified in a conspicuous fashion. Detailed explanations should be provided as tohow such values were estimated or derived and what underlying assumptions weremade.

The guidance provided below is detailed and is intended to notify the applicant ofvirtually all of the information that should routinely be provided so that post-submission requests for further data clarification and analyses can be reduced as much as possible. Nonetheless, specific requirements for data presentation and/ or analysis may depend on specific situations, may evolve over time, may vary fromdrug class to drug class, may differ among regions and cannot be described in gen-eral terms; it is therefore important to refer to specific clinical guidelines and todiscuss data presentation and analyses with the reviewing authority, whenever pos-sible. Detailed written guidance on statistical approaches is available from someauthorities.

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Each report should consider all of the topics described (unless clearly not relevant)although the specific sequence and grouping of topics may be changed if alterna-tives are more logical for a particular study. Some data in the appendices are spe-cific requirements of individual regulatory authorities and should be submitted asappropriate. The numbering should then be adapted accordingly.

In the case of very large trials, some of the provisions of this guideline may beimpractical or inappropriate. When planning and when reporting such trials, contactwith regulatory authorities to discuss an appropriate report format is encouraged.

The provisions of this guideline should be used in conjunction with other ICH guide-lines.


1. TITLE PAGEThe title page should contain the following information:

– study title

– name of test drug/investigation product

– indication studied

– if not apparent from the title, a brief (1 to 2 sentences) description giving design(parallel, cross-over, blinding, randomized) comparison (placebo, active, dose/response), duration, dose, and patient population

– name of the sponsor

– protocol identification (code or number)

– development phase of study

– study initiation date (first patient enrolled, or any other verifiable definition)

– date of early study termination, if any

– study completion date (last patient completed)

– name and affiliation of principal or coordinating investigator(s) or sponsor’sresponsible medical officer

– name of company/sponsor signatory (the person responsible for the study reportwithin the company/sponsor. The name, telephone number and fax number of thecompany/sponsor contact persons for questions arising during review of thestudy report should be indicated on this page or in the letter of application.)

– statement indicating whether the study was performed in compliance with GoodClinical Practices (GCP), including the archiving of essential documents

– date of the report (identify any earlier reports from the same study by title anddate).

2. SYNOPSISA brief synopsis (usually limited to 3 pages) that summarizes the study should beprovided (see Annex I of the guideline for an example of a synopsis format used inEurope). The synopsis should include numerical data to illustrate results, not justtext or p-values.

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3. TABLE OF CONTENTS FOR THE INDIVIDUAL CLINICAL STUDY REPORT

The table of contents should include:

– the page number or other locating information of each section, including sum-mary tables, figures and graphs,

– a list and the locations of appendices, tabulations and any case report formsprovided.

4. LIST OF ABBREVIATIONS AND DEFINITION OF TERMSA list of the abbreviations, and lists and definitions of specialized or unusual termsor measurements units used in the report should be provided. Abbreviated termsshould be spelled out and the abbreviation indicated in parentheses at first appear-ance in the text.

5. ETHICS5.1 Independent Ethics Committee (IEC) or Institutional Review Board

(IRB)It should be confirmed that the study and any amendments were reviewed by anIndependent Ethics Committee or Institutional Review Board. A list of all IECs orIRBs consulted should be given in appendix 16.1.3 and, if required by the regula-tory authority, the name of the committee Chair should be provided.

5.2 Ethical Conduct of the StudyIt should be confirmed that the study was conducted in accordance with the ethi-cal principles that have their origins in the Declaration of Helsinki.

5.3 Patient Information and ConsentHow and when informed consent was obtained in relation to patient enrolment (e.g. at allocation, pre-screening) should be described.

Representative written information for the patient (if any) and a sample patientconsent form should be provided in appendix 16.1.3.

6. INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTUREThe administrative structure of the study (e.g. principal investigator, coordinatinginvestigator, steering committee, administration, monitoring and evaluation com-mittees, institutions, statistician, central laboratory facilities, contract researchorganisation (C.R.O.), clinical trial supply management) should be described brieflyin the body of the report.

There should be provided in appendix 16.1.4 a list of the investigators with theiraffiliations, their role in the study and their qualifications (curriculum vitae orequivalent). A similar list for other persons whose participation materially affectedthe conduct of the study should also be provided in appendix 16.1.4. In the caseof large trials with many investigators the above requirements may be abbreviated

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to consist of general statements of qualifications for persons carrying out particularroles in the study with only the name, degree and institutional affiliation and rolesof each investigator or other participant.

The listing should include:

a) Investigators

b) Any other person carrying out observations of primary or other major efficacyvariables, such as a nurse, physician’s assistant, clinical psychologist, clinicalpharmacist, or house staff physician. It is not necessary to include in this lista person with only an occasional role, e.g. an on-call physician who dealt witha possible adverse effect or a temporary substitute for any of the above

c) The author(s) of the report, including the responsible biostatistician(s).

Where signatures of the principal or coordinating investigators are required by regu-latory authorities, these should be included in appendix 16.1.5 (see Annex II for asample form). Where these are not required, the signature of the sponsor’s respon-sible medical officer should be provided in appendix 16.1.5.

7. INTRODUCTIONThe introduction should contain a brief statement (maximum: 1 page) placing thestudy in the context of the development of the test drug/investigational product,relating the critical features of the study (e.g. rationale and aims, target popula-tion, treatment, duration, primary endpoints) to that development. Any guidelinesthat were followed in the development of the protocol or any other agreements/meetings between the sponsor/company and regulatory authorities that are rele-vant to the particular study, should be identified or described.

8. STUDY OBJECTIVESA statement describing the overall purpose(s) of the study should be provided.

9. INVESTIGATIONAL PLAN

9.1 Overall Study Design and Plan – DescriptionThe overall study plan and design (configuration) of the study (e.g. parallel, cross-over) should be described briefly but clearly, using charts and diagrams as needed.If other studies used a very similar protocol, it may be useful to note this anddescribe any important differences. The actual protocol and any changes should beincluded as appendix 16.1.1 and a sample case report form (unique pages only; i.e.it is not necessary to include identical pages from forms for different evaluations orvisits) as appendix 16.1.2. If any of the information in this section comes fromsources other than the protocol, these should be identified.

The information provided should include:

– treatments studied (specific drugs, doses and procedures)

– patient population studied and the number of patients to be included

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– level and method of blinding/masking (e.g. open, double-blind, single-blind,blinded evaluators and unblinded patients and/or investigators)

– kind of control(s) (e.g. placebo, no treatment, active drug, dose-response, his-torical) and study configuration (parallel, cross-over)

– method of assignment to treatment (randomization, stratification)

– sequence and duration of all study periods, including pre-randomization andpost-treatment periods, therapy withdrawal periods and single- and double-blindtreatment periods. When patients are randomized should be specified. It is usu-ally helpful to display the design graphically with a flow chart which includestiming of assessments (see Annexes IIIa and IIIb for an example)

– any safety, data monitoring or special steering or evaluation committees

– any interim analyses.

9.2 Discussion of Study Design, including the Choice of Control GroupsThe specific control chosen and the study design used should be discussed, asnecessary. Examples of design issues meriting discussion follow.

Generally, the control (comparison) groups that are recognized are placebo concur-rent control, no treatment concurrent control, active treatment concurrent control,dose comparison concurrent control, and historical control. In addition to the typeof control, other critical design features that may need discussion are use of across-over design and selection of patients with particular prior history, such asresponse or non-response to a specific drug or member of a drug class. If random-ization was not used, it is important to explain how other techniques, if any,guarded against systematic selection bias.

Known or potential problems associated with the study design or control groupchosen, should be discussed in light of the specific disease and therapies beingstudied. For a cross-over design, for example, there should be consideration, amongother things, of the likelihood of spontaneous change in the disease and of carry-over effects of treatment during the study.

If efficacy was to be demonstrated by showing equivalence, i.e. the absence of aspecified degree of inferiority of the new treatment compared to an establishedtreatment, problems associated with such study designs should be addressed.Specifically there should be provided a basis for considering the study capable ofdistinguishing active from inactive therapy. Support may be provided by an analysisof previous studies similar to the present study with respect to important designcharacteristics (patient selection, study endpoints, duration, dose of active control,concomitant therapy etc.) showing a consistent ability to demonstrate superiorityof the active control to placebo. How to assess the ability of the present study to distinguish effective from ineffective therapy should also be discussed. Forexample, it may be possible to identify a treatment response (based on paststudies) that would clearly distinguish between the treated population and anuntreated group. Such a response could be the change of a measure from baselineor some other specified outcome like healing rate or survival rate. Attainment ofsuch a response would support the expectation that the study could have distin-

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guished the active drug from an inactive drug. There should also be a discussion ofthe degree of inferiority of the therapy (often referred to as the delta value) thestudy was intended to show was not exceeded.

The limitations of historical controls are well known (difficulty of assuring compara-bility of treated groups, inability to blind investigators to treatment, change in the-rapy/disease, difference due to placebo effect etc.) and deserve particular attention.

Other specific features of the design may also deserve discussion, including pres-ence or absence of washout periods and the duration of the treatment period, espe-cially for a chronic illness. The rationale for dose and dose-interval selection shouldbe explained, if it is not obvious. For example, once daily dosing with a short half-life drug whose effect is closely related in time to blood level is not usually effec-tive; if the study design uses such dosing, this should be explained, e.g. by pointingto pharmacodynamic evidence that effect is prolonged compared to blood levels.The procedures used to seek evidence of “escape” from drug effect at the end of the dose-interval, such as measurements of effect just prior to dosing, should bedescribed. Similarly, in a parallel design dose-response study, the choice of dosesshould be explained.

9.3 Selection of Study Population

9.3.1 INCLUSION CRITERIA

The patient population and the selection criteria used to enter the patients into thestudy should be described, and the suitability of the population for the purposes ofthe study discussed. Specific diagnostic criteria used, as well as specific diseaserequirements (e.g. disease of a particular severity or duration, results of a par-ticular test or rating scale(s) or physical examination, particular features of clinicalhistory, such as failure or success on prior therapy, or other potential prognosticfactors and any age, sex or ethnic factors) should be presented.

Screening criteria and any additional criteria for randomization or entry into thetest drug/investigational product treatment part of the trial should be described. Ifthere is reason to believe that there were additional entry criteria, not defined inthe protocol, the implications of these should be discussed. For example, someinvestigators may have excluded, or entered into other studies, patients who wereparticularly ill or who had particular baseline characteristics.

9.3.2 EXCLUSION CRITERIA

The criteria for exclusion at entry into the study should be specified and the ratio-nale (e.g. safety concerns, administrative reasons or lack of suitability for the trial)provided. The impact of exclusions on the generalizability of the study should bediscussed in section 13 of the study report, or in an overview of safety and efficacy.

9.3.3 REMOVAL OF PATIENTS FROM THERAPY OR ASSESSMENT

The predetermined reasons for removing patients from therapy or assessment obser-vation, if any, should be described, as should the nature and duration of anyplanned follow-up observations in those patients.

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9.4 Treatments

9.4.1 TREATMENTS ADMINISTERED

The precise treatments or diagnostic agents to be administered in each arm of thestudy, and for each period of the study, should be described including route andmode of administration, dose and dosage schedule.

9.4.2 IDENTITY OF INVESTIGATIONAL PRODUCT(S)

In the text of the report, a brief description of the test drug(s)/investigationalproduct(s) (formulation, strength, batch number(s)) should be given. If more thanone batch of test drug/investigational product was used, patients receiving eachbatch should be identified in appendix 16.1.6.

The source of placebos and active control/comparator product(s) should be pro-vided. Any modification of comparator product(s) from their usual commercial stateshould be noted, and the steps taken to assure that their bioavailability was un-altered should be described.

For long-duration trials of investigational products with limited shelf-lives orincomplete stability data, the logistics of resupply of the materials should bedescribed. Any use of test materials past their expiry date should be noted, andpatients receiving them identified. If there were specific storage requirements,these should also be described.

9.4.3 METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUPS

The specific methods used to assign patients to treatment groups, e.g. centralizedallocation, allocation within sites, adaptive allocation (that is, assignment on thebasis of earlier assignment or outcome) should be described in the text of thereport, including any stratification or blocking procedures. Any unusual featuresshould be explained.

A detailed description of the randomization method, including how it was executed,should be given in appendix 16.1.7 with references cited if necessary. A tableexhibiting the randomization codes, patient identifier, and treatment assignedshould also be presented in the appendix. For a multicentre study, the informationshould be given by centre. The method of generating random numbers should beexplained.

For a historically controlled trial, it is important to explain how the particular con-trol was selected and what other historical experiences were examined, if any, andhow their results compared to the control used.

9.4.4 SELECTION OF DOSES IN THE STUDY

The doses or dose ranges used in the study should be given for all treatments andthe basis for choosing them described (e.g. prior experience in humans, animaldata).

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9.4.5 SELECTION AND TIMING OF DOSE FOR EACH PATIENT

Procedures for selecting each patient’s dose of test drug/investigational productand active control/comparator should be described. These procedures can vary fromsimple random assignment to a selected fixed drug/dose regimen, to some speci-fied titration procedure, to more elaborate response-determined selection pro-cedures, e.g. where dose is titrated upward at intervals until intolerance or somespecified endpoint is achieved. Procedures for back-titration, if any, should also bedescribed.

The timing (time of day, interval) of dosing and the relation of dosing to mealsshould be described, and if it was not specified, this should be noted.

Any specific instructions to patients about when or how to take the dose(s) shouldbe described.

9.4.6 BLINDING

A description of the specific procedures used to carry out blinding should be pro-vided (e.g. how bottles were labelled, labels that reveal blind-breakage, sealed codelist/envelopes, double dummy techniques), including the circumstances in whichthe blind would be broken for an individual or for all patients, e.g. for seriousadverse events, the procedures used and who had access to patient codes. If thestudy allowed for some investigators to remain unblinded (e.g. to allow them toadjust medication), the means of shielding other investigators should be explained.Measures taken to ensure that test drug/investigational product and placebo wereindistinguishable and evidence that they were indistinguishable, should be de-scribed, as should the appearance, shape, smell, and taste of the test material.Measures to prevent unblinding by laboratory measurements, if used, should bedescribed. If there was a data monitoring committee with access to unblinded data,procedures to ensure maintenance of overall study blinding should be described. Theprocedure to maintain the blinding when interim analyses are performed should alsobe explained.

If blinding was considered unnecessary to reduce bias for some or all of the obser-vations, this should be explained; e.g. use of a random-zero sphygmomanometereliminates possible observer bias in reading blood pressure and Holter tapes areoften read by automated systems that are presumably immune to observer bias. Ifblinding was considered desirable but not feasible, the reasons and implicationsshould be discussed. Sometimes blinding is attempted but is known to be imper-fect because of obvious drug effects in at least some patients (dry mouth, brady-cardia, fever, injection site reactions, changes in laboratory data). Such problemsor potential problems should be identified and if there were any attempts to assessthe magnitude of the problem or manage it (e.g. by having some endpoint mea-surements carried out by people shielded from information that might reveal treat-ment assignment), they should be described.

9.4.7 PRIOR AND CONCOMITANT THERAPY

Which drugs or procedures were allowed before and during the study, whether andhow their use was recorded, and any other specific rules and procedures related to

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permitted or forbidden concomitant therapy should be described. How allowed con-comitant therapy might affect the outcome due either to drug-drug interaction orto direct effects on the study endpoints should be discussed, and how the inde-pendent effects of concomitant and study therapies could be ascertained should beexplained.

9.4.8 TREATMENT COMPLIANCE

The measures taken to ensure and document treatment compliance should bedescribed, e.g. drug accountability, diary cards, blood, urine or other body fluiddrug level measurements, or medication event monitoring.

9.5 Efficacy and Safety Variables

9.5.1 EFFICACY AND SAFETY MEASUREMENTS ASSESSED AND FLOW CHART

The specific efficacy and safety variables to be assessed and laboratory tests to beconducted, their schedule (days of study, time of day, relation to meals, and thetiming of critical measures in relation to test drug administration, e.g. just prior tonext dose, two hours after dose), the methods for measuring them, and the personsresponsible for the measurements should be described. If there were changes in per-sonnel carrying out critical measurements, these should be reported.

It is usually helpful to display graphically in a flow chart (see Annex III of theguideline) the frequency and timing of efficacy and safety measurements; visit num-bers and times should be shown, or, alternatively, times alone can be used (visitnumbers alone are more difficult to interpret). Any specific instructions (e.g. guid-ance or use of a diary) to the patients should also be noted.

Any definitions used to characterize outcome (e.g. criteria for determining occur-rence of acute myocardial infarction, designation of the location of the infarction,characterization of a stroke as thrombotic or haemorrhagic, distinction between TIAand stroke, assignment of cause of death) should be explained in full. Any tech-niques used to standardize or compare results of laboratory tests or other clinicalmeasurements (e.g. ECG, chest X-ray) should also be described. This is particularlyimportant in multicentre studies.

If anyone other than the investigator was responsible for evaluation of clinical out-comes (e.g. the sponsor or an external committee to review X-rays or ECGs or todetermine whether the patient had a stroke, acute infarction, or sudden death) theperson or group should be identified. The procedures, including means of main-taining blindness, and centralizing readings and measurements, should be describedfully.

The means of obtaining adverse event data should be described (volunteered,checklist, or, questioning), as should any specific rating scale(s) used and anyspecifically planned follow-up procedures for adverse events or any planned rechal-lenge procedure.

Any rating of adverse events by the investigator, sponsor or external group (e.g.rating by severity, or, likelihood of drug causation) should be described. The criteriafor such ratings, if any, should be given and the parties responsible for the ratings

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should be clearly identified. If efficacy or safety was to be assessed in terms ofcategorical ratings, numerical scores etc., the criteria used for point assignment(e.g. definitions of point scores) should be provided. For multicentre studies, indi-cate how methods were standardized.

9.5.2 APPROPRIATENESS OF MEASUREMENTS

If any of the efficacy or safety assessments was not standard, i.e. widely used andgenerally recognized as reliable, accurate, and relevant (able to discriminatebetween effective and ineffective agents), its reliability, accuracy and relevanceshould be documented. It may be helpful to describe alternatives considered butrejected.

If a surrogate endpoint (a laboratory measurement or physical measurement or signthat is not a direct measure of clinical benefit) was used as a study endpoint, thisshould be justified e.g. by reference to clinical data, publications, guidelines or pre-vious actions by regulatory authorities.

9.5.3 PRIMARY EFFICACY VARIABLE(S)

The primary measurements and endpoints used to determine efficacy should beclearly specified. Although the critical efficacy measurements may seem obvious,when there are multiple variables, or when variables are measured repeatedly, theprotocol should identify the primary ones, with an explanation of why they werechosen, or designate the pattern of significant findings or other method of com-bining information that would be interpreted as supporting efficacy. If the protocoldid not identify the primary variables, the study report should explain how thesecritical variables were selected (e.g. by reference to publications, guidelines or pre-vious actions by regulatory authorities) and when they were identified (i.e. beforeor after the study was completed and unblinded). If an efficacy threshold wasdefined in the protocol, this should be described.

9.5.4 DRUG CONCENTRATION MEASUREMENTS

Any drug concentrations to be measured, and the sample collection times andperiods in relation to the timing of drug administration, should be described. Anyrelation of drug administration and sampling to ingestion of food, posture and thepossible effects of concomitant medication/alcohol/caffeine/nicotine should alsobe addressed. The biological sample measured, the handling of samples and themethod of measurement used should be described, referring to published and/orinternal assay validation documentation for methodological details. Where otherfactors are believed important in assessing pharmacokinetics (e.g. soluble circu-lating receptors, renal or hepatic function), the timing and plans to measure thesefactors should also be specified.

9.6 Data Quality Assurance The quality assurance and quality control systems implemented to assure the qualityof the data should be described in brief. If none were used, this should be stated.

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Documentation of inter-laboratory standardization methods and quality assuranceprocedures, if used, should be provided under appendix 16.1.10.

Any steps taken at the investigation site or centrally to ensure the use of standardterminology and the collection of accurate, consistent, complete, and reliable data,such as training sessions, monitoring of investigators by sponsor personnel, instruc-tion manuals, data verification, cross-checking, use of a central laboratory for cer-tain tests, centralized ECG reading, or data audits, should be described. It shouldbe noted whether investigator meetings or other steps were taken to prepare inves-tigators and standardize performance.

If the sponsor used an independent internal or external auditing procedure, itshould be mentioned here and described in appendix 16.1.8; and audit certificates,if available, should be provided in the same appendix.

9.7 Statistical Methods Planned in the Protocol and Determination ofSample Size

9.7.1 STATISTICAL AND ANALYTICAL PLANS

The statistical analyses planned in the protocol and any changes made before out-come results were available should be described. In this section emphasis shouldbe on which analyses, comparisons and statistical tests were planned, not on whichones were actually used. If critical measurements were made more than once, theparticular measurements (e.g. average of several measurements over the entirestudy, values at particular times, values only from study completers, or last on-therapy value) planned as the basis for comparison of test drug/investigationalproduct and control should be specified. Similarly, if more than one analyticalapproach is plausible, e.g. changes from baseline response, slope analysis, life tableanalysis, the planned approach should be identified. Also, whether the primaryanalysis is to include adjustment for covariates should be specified.

If there were any planned reasons for excluding from analysis patients for whomdata are available, these should be described. If there were any subgroups whoseresults were to be examined separately, these should be identified. If categoricalresponses (global scales, severity scores, responses of a certain size) were to beused in analysing responses, they should be clearly defined.

Planned monitoring of the results of the study should be described. If there was adata monitoring committee, either within or outside the sponsor’s control, its com-position and operating procedures should be described and procedures to maintainstudy blinding should be given. The frequency and nature of any planned interimanalysis, any specified circumstances in which the study would be terminated, andany statistical adjustments to be employed because of interim analyses should bedescribed.

9.7.2 DETERMINATION OF SAMPLE SIZE

The planned sample size and the basis for it, such as statistical considerations orpractical limitations, should be provided. Methods for sample size calculationshould be given together with their derivations or source of reference. Estimates

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used in the calculations should be given and explanations provided as to how theywere obtained. For a study intended to show a difference between treatments, thedifference the study is designed to detect should be specified. For a positive con-trol study intended to show that a new therapy is at least as effective as the stan-dard therapy, the sample size determination should specify the difference betweentreatments that would be considered unacceptably large and therefore the differ-ence the study is designed to be able to exclude.

9.8 Changes in the Conduct of the Study or Planned AnalysesAny change in the conduct of the study or planned analyses (e.g. dropping a treat-ment group, changing the entry criteria or drug dosages, adjusting the sample sizeetc.) instituted after the start of the study should be described. The time(s) andreason(s) for the change(s), the procedure used to decide on the change(s), theperson(s) or group(s) responsible for the change(s) and the nature and content ofthe data available (and to whom they were available) when the change was madeshould also be described, whether the change was documented as a formal protocolamendment or not (personnel changes need not be included). Any possible impli-cations of the change(s) for the interpretation of the study should be discussedbriefly in this section and more fully in other appropriate sections of the report. Inevery section of the report, a clear distinction between conditions (procedures)planned in the protocol and amendments or additions should be made. In general,changes in planned analyses made prior to breaking the blind have limited impli-cations for study interpretation. It is therefore particularly critical that the timingof changes relative to blind breaking and availability of outcome results be wellcharacterized.

10. STUDY PATIENTS10.1 Disposition of PatientsThere should be a clear accounting of all patients who entered the study, using figures or tables in the text of the report. The numbers of patients who wererandomized, and who entered and completed each phase of the study (or eachweek/month of the study) should be provided, as well as the reasons for all post-randomization discontinuations, grouped by treatment and by major reason (lost tofollow-up, adverse event, poor compliance etc.). It may also be relevant to providethe number of patients screened for inclusion and a breakdown of the reasons forexcluding patients during screening, if this could help clarify the appropriatepatient population for eventual drug use. A flow chart is often helpful (see AnnexesIVa and IVb of the guideline for example). Whether patients are followed for theduration of the study, even if drug is discontinued, should be made clear.

In appendix 16.2.1, there should also be a listing of all patients discontinued fromthe study after enrolment, broken down by centre and treatment group, giving apatient identifier, the specific reason for discontinuation, the treatment (drug anddose), cumulative dose (where appropriate), and the duration of treatment beforediscontinuation. Whether or not the blind for the patient was broken at the time of

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discontinuation should be noted. It may also be useful to include other informa-tion, such as critical demographic data (e.g. age, sex, race), concomitant medica-tion, and the major response variable(s) at termination. See Annex V for an exampleof such a listing.

10.2 Protocol DeviationsAll important deviations related to study inclusion or exclusion criteria, conduct ofthe trial, patient management or patient assessment should be described.

In the body of the text, protocol deviations should be appropriately summarized bycentre and grouped into different categories, such as:

– those who entered the study even though they did not satisfy the entry criteria

– those who developed withdrawal criteria during the study but were not with-drawn

– those who received the wrong treatment or incorrect dose

– those who received an excluded concomitant treatment.

In appendix 16.2.2, individual patients with these protocol deviations should belisted, broken down by centre for multicentre studies.

11. EFFICACY EVALUATION11.1 Data Sets AnalysedExactly which patients were included in each efficacy analysis should be preciselydefined, e.g. all patients receiving any test drugs/investigational products, allpatients with any efficacy observation or with a certain minimum number of obser-vations, only patients completing the trial, all patients with an observation duringa particular time window, only patients with a specified degree of compliance etc.It should be clear, if not defined in the study protocol, when (relative to studyunblinding), and how inclusion/exclusion criteria for the data sets analysed weredeveloped. Generally, even if the applicant’s proposed primary analysis is based ona reduced subset of the patients with data, there should also be for any trialintended to establish efficacy an additional analysis using all randomized (or other-wise entered) patients with any on-treatment data.

There should be a tabular listing of all patients, visits and observations excludedfrom the efficacy analysis provided in appendix 16.2.3 (see Annex VI of the guide-line for an example). The reasons for exclusions should also be analysed for thewhole treatment group over time (see Annex VII of the guideline for an example).

11.2 Demographic and Other Baseline CharacteristicsGroup data for the critical demographic and baseline characteristics of the patients,as well as other factors arising during the study that could affect response, shouldbe presented in this section and comparability of the treatment groups for all rele-vant characteristics should be displayed by use of tables or graphs in section 14.1.The data for the patient sample included in the “all patients with data” analysisshould be given first. This can then be followed by data on other groups used in

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principal analyses, such as the “per-protocol” analysis or other analyses, e.g. groupsdefined by compliance, concomitant disease/therapy, or demographic/baselinecharacteristics. When such groups are used, data for the complementary excludedgroup should also be shown. In a multicentre study where appropriate, compara-bility should be assessed by centre, and centres should be compared.

A diagram showing the relationship between the entire sample and any otheranalysis groups should be provided.

The critical variables will depend on the specific nature of the disease and on theprotocol but will usually include:

• demographic variables– age– sex– race

• disease factors – specific entry criteria (if not uniform), duration, stage and severity of disease

and other clinical classifications and sub-groupings in common usage or ofknown prognostic significance

– baseline values for critical clinical measurements carried out during the studyor identified as important indicators of prognosis or response to therapy

– concomitant illness at trial initiation, such as renal disease, diabetes, heartfailure

– relevant previous illness– relevant previous treatment for illness treated in the study – concomitant treatment maintained, even if the dose was changed during the

study, including oral contraceptive and hormone replacement therapy; treat-ments stopped at entry into the study period (or changed at study initiation)

• other factors that might affect response to therapy (e.g. weight, renin status,antibody levels, metabolic status)

• other possibly relevant variables (e.g. smoking, alcohol intake, special diets)and, for women, menstrual status and date of last menstrual period, if pertinentfor the study.

In addition to tables and graphs giving group data for these baseline variables,relevant individual patient demographic and baseline data, including laboratoryvalues, and all concomitant medication for all individual patients randomized(broken down by treatment and by centre for multicentre studies) should be pre-sented in by-patient tabular listings in appendix 16.2.4. Although some regulatoryauthorities will require all baseline data to be presented elsewhere in tabular list-ings, the appendix to the study report should be limited to only the most relevantdata, generally the variables listed above.

11.3 Measurements of Treatment ComplianceAny measurements of compliance of individual patients with the treatment regimenunder study and drug concentrations in body fluids should be summarized, analysedby treatment group and time interval, and tabulated in appendix 16.2.5.

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11.4 Efficacy Results and Tabulations of Individual Patient Data

11.4.1 ANALYSIS OF EFFICACY

Treatment groups should be compared for all critical measures of efficacy (primaryand secondary endpoints; any pharmacodynamic endpoints studied), as well asbenefit/risk assessment(s) in each patient where these are utilized. In general, theresults of all analyses contemplated in the protocol and an analysis including allpatients with on-study data should be performed in studies intended to establishefficacy. The analysis should show the size (point estimate) of the differencebetween the treatments, the associated confidence interval and, where utilized, theresults of hypothesis testing.

Analyses based on continuous variables (e.g. mean blood pressure or depressionscale score) and categorical responses (e.g. cure of an infection) can be equallyvalid; ordinarily both should be presented if both were planned and are available.If categories are newly created (i.e. not in the statistical plan) the basis for themshould be explained. Even if one variable receives primary attention (e.g. in a bloodpressure study, supine blood pressure at week x), other reasonable measures (e.g.standing blood pressure and blood pressures at other particular times) should be assessed, at least briefly. In addition, the time course of response should bedescribed, if possible. For a multicentre study, where appropriate, data display andanalysis of individual centres should be included for critical variables to give a clearpicture of the results at each site, especially the larger sites.

If any critical measurements or assessments of efficacy or safety outcomes weremade by more than one party (e.g. both the investigator and an expert committeemay offer an opinion on whether a patient had an acute infarction), overall differ-ences between the ratings should be shown, and each patient having disparateassessments should be identified. The assessments used should be clear in allanalyses.

In many cases, efficacy and safety endpoints are difficult to distinguish, (e.g.deaths in a fatal disease study). Many of the principles addressed below should beadopted for critical safety measures as well.

11.4.2 STATISTICAL/ANALYTICAL ISSUES

The statistical analysis used should be described for clinical and statisticalreviewers in the text of the report, with detailed documentation of statisticalmethods (see section Annex IX) presented in appendix 16.1.9. Important featuresof the analysis including the particular methods used, adjustments made for demo-graphic or baseline measurements or concomitant therapy, handling of drop-outsand missing data, adjustments for multiple comparisons, special analyses of multi-centre studies, and adjustments for interim analyses, should be discussed. Anychanges in the analysis made after blind-breaking should be identified.

In addition to the general discussion the following specific issues should beaddressed (unless not applicable):

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11.4.2.1 Adjustments for Covariates

Selection of, and adjustments for, demographic or baseline measurements, con-comitant therapy, or any other covariate or prognostic factor should be explainedin the report, and methods of adjustment, results of analyses, and supportive infor-mation (e.g. ANCOVA or Cox regression output) should be included in the detaileddocumentation of statistical methods. If the covariates or methods used in theseanalyses differed from those planned in the protocol, the differences should beexplained and where possible and relevant, the results of planned analyses shouldalso be presented. Although not part of the individual study report, comparisons ofcovariate adjustments and prognostic factors across individual studies may be aninformative analysis in a summary of clinical efficacy data.

11.4.2.2 Handling of Dropouts or Missing Data

There are several factors that may affect dropout rates. These include the durationof the study, the nature of the disease, the efficacy and toxicity of the drug understudy, and other factors that are not therapy related. Ignoring the patients whodropped out of the study and drawing conclusions based only on patients who com-pleted the study can be misleading. A large number of dropouts, however, even ifincluded in an analysis, may introduce bias, particularly if there are more earlydropouts in one treatment group or the reasons for dropping out are treatment oroutcome related. Although the effects of early dropouts, and sometimes even thedirection of bias, can be difficult to determine, possible effects should be exploredas fully as possible. It may be helpful to examine the observed cases at various timepoints or, if dropouts were very frequent, to concentrate on analyses at time pointswhen most of the patients were still under observation and when the full effect ofthe drug was realized. It may also be helpful to examine modelling approaches tothe evaluation of such incomplete data sets.

The results of a clinical trial should be assessed not only for the subset of patientswho completed the study, but also for the entire patient population as randomizedor at least for all those with any on-study measurements. Several factors need tobe considered and compared for the treatment groups in analysing the effects ofdropouts: the reasons for the dropouts, the time to dropout, and the proportion ofdropouts among treatment groups at various time points.

Procedures for dealing with missing data, e.g. use of estimated or derived data,should be described. Detailed explanation should be provided as to how such esti-mations or derivations were done and what underlying assumptions were made.

11.4.2.3 Interim Analyses and Data Monitoring

The process of examining and analysing data accumulating in a clinical trial, eitherformally or informally, can introduce bias and/or increase type I error. Therefore, allinterim analyses, formal or informal, pre-planned or ad hoc, by any study partici-pant, sponsor staff member, or data monitoring group should be described in full,even if the treatment groups were not identified. The need for statistical adjust-ment because of such analyses should be addressed. Any operating instructions orprocedures used for such analyses should be described. The minutes of meetings of

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any data monitoring group and any data reports reviewed at those meetings, par-ticularly a meeting that led to a change in the protocol or early termination of thestudy, may be helpful and should be provided in appendix 16.1.9. Data monitoringwithout code-breaking should also be described, even if this kind of monitoring isconsidered to cause no increase in type I error.

11.4.2.4 Multicentre Studies

A multicentre study is a single study under a common protocol, involving severalcentres (e.g. clinics, practices, hospitals) where the data collected are intended tobe analysed as a whole (as opposed to a post-hoc decision to combine data orresults from separate studies). Individual centre results should be presented, how-ever, where appropriate, e.g. when the centres have sufficient numbers of patientsto make such analysis potentially valuable, the possibility of qualitative or quanti-tative treatment-by-centre interaction should be explored. Any extreme or oppositeresults among centres should be noted and discussed, considering such possibilitiesas differences in study conduct, patient characteristics, or clinical settings. Treat-ment comparison should include analyses that allow for centre differences withrespect to response. If appropriate, demographic, baseline, and post-baseline data,as well as efficacy data, should be presented by centre, even though the combinedanalysis is the primary one.

11.4.2.5 Multiple Comparison/Multiplicity

False positive findings increase in number as the number of significance tests(number of comparisons) performed increases. If there was more than one primaryendpoint (outcome variable), more than one analysis of particular endpoint, or ifthere were multiple treatment groups, or subsets of the patient population beingexamined, the statistical analysis should reflect awareness of this and either explainthe statistical adjustment used for type I error criteria or give reasons why it wasconsidered unnecessary.

11.4.2.6 Use of an “Efficacy Subset” of Patients

Particular attention should be devoted to the effects of dropping patients withavailable data from analyses because of poor compliance, missed visits, ineligibility,or any other reason. As noted above, an analysis using all available data should becarried out for all studies intended to establish efficacy, even if it is not theanalysis proposed as the primary analysis by the applicant. In general, it is advan-tageous to demonstrate robustness of the principal trial conclusions with respect toalternative choices of patient populations for analysis. Any substantial differencesresulting from the choice of patient population for analysis should be the subjectof explicit discussion.

11.4.2.7 Active-Control Studies Intended to Show Equivalence

If an active control study is intended to show equivalence (i.e. lack of a differencegreater than a specified size) between the test drug/investigational product andthe active control/comparator, the analysis should show the confidence interval forthe comparison between the two agents for critical end points and the relation of

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that interval to the prespecified degree of inferiority that would be consideredunacceptable. (See 9.2, for important considerations when using the active controlequivalence design.)

11.4.2.8 Examination of Subgroups

If the size of the study permits, important demographic or baseline value-definedsubgroups should be examined for unusually large or small responses and the resultspresented, e.g. comparison of effects by age, sex, or race, by severity or prognosticgroups, by history of prior treatment with a drug of the same class etc. If theseanalyses were not carried out because the study was too small it should be noted.These analyses are not intended to “salvage” an otherwise non-supportive study butmay suggest hypotheses worth examining in other studies or be helpful in refininglabelling information, patient selection, dose selection etc. Where there is a priorhypothesis of a differential effect in a particular subgroup, this hypothesis and itsassessment should be part of the planned statistical analysis.

11.4.3 TABULATION OF INDIVIDUAL RESPONSE DATA

In addition to tables and graphs representing group data, individual response dataand other relevant study information should be presented in tables. Some regula-tory authorities may require all individual data in archival case report tabulations.What needs to be included in the report will vary from study to study and from onedrug class to another and the applicant must decide, if possible after consultationwith the regulatory authority, what to include in appendix to the study report. Thestudy report should indicate what material is included as an appendix, what is inthe more extensive archival case report tabulations, if required by the regulatoryauthority, and what is available on request.

For a controlled study in which critical efficacy measurements or assessments (e.g.blood or urine cultures, pulmonary function tests, angina frequency, or global eval-uations) are repeated at intervals, the data listings accompanying the report shouldinclude, for each patient, a patient identifier, all measured or observed values ofcritical measurements, including baseline measurements, with notation of the timeduring the study (e.g. days on therapy and time of day, if relevant) when the mea-surements were made, the drug/dose at the time (if useful, given as mg/kg), anymeasurements of compliance, and any concomitant medications at the time of, orclose to the time of, measurement or assessment. If, aside from repeated assess-ments, the study included some overall responder vs. non-responder evaluation(s)(bacteriologic cure or failure), it should also be included. In addition to criticalmeasurements, the tabulation should note whether the patient was included in theefficacy evaluation (and which evaluation, if more than one), provide patient com-pliance information, if collected, and a reference to the location of the case reportform, if included. Critical baseline information such as age, sex, weight, diseasebeing treated (if more than one in study), and disease stage or severity, is alsohelpful. The baseline values for critical measurements would ordinarily be includedas zero time values for each efficacy measurement.

The tabulation described should usually be included in appendix 16.2.6 of the studyreport, rather than in the more extensive case report tabulations required by some

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regulatory authorities, because it represents the basic efficacy data supporting sum-mary tables. Such a thorough tabulation can be unwieldy for review purposes, how-ever, and it is expected that more targeted displays will be developed as well. Forexample, if there are many measurements reported, tabulations of the most criticalmeasurements for each patient (e.g. the blood pressure value at certain visits mightbe more important than others) will be useful in providing an overview of each indi-vidual’s results in a study, with each patient’s response summarized on a single lineor small number of lines.

11.4.4 DRUG DOSE, DRUG CONCENTRATION, AND RELATIONSHIPS TO RESPONSE

When the dose in each patient can vary, the actual doses received by patientsshould be shown and individual patient’s doses should be tabulated. Althoughstudies not designed as dose-response studies may have limited ability to con-tribute dose-response information, the available data should be examined for what-ever information they can yield. In examining the dose response, it may be helpfulto calculate dose as mg/kg body weight or mg/m2 body surface.

Drug concentration information, if available, should also be tabulated (appendix16.2.5), analysed in pharmacokinetic terms and, if possible, related to response.

Further guidance on the design and analysis of studies exploring dose-response or concentration response can be found in the ICH Guideline “Dose-ResponseInformation to Support Drug Registration”.

11.4.5 DRUG-DRUG AND DRUG-DISEASE INTERACTIONS

Any apparent relationship between response and concomitant therapy and betweenresponse and past and/or concurrent illness should be described.

11.4.6 BY-PATIENT DISPLAYS

While individual patient data ordinarily can be displayed in tabular listings, it hason occasion been helpful to construct individual patient profiles in other formats,such as graphic displays. These might, for example, show the value of (a) particularparameter(s) over time, the drug dose over the same period, and the times of par-ticular events (e.g. an adverse event or change in concomitant therapy). Wheregroup mean data represent the principal analyses, this kind of “case report extract”may offer little advantage; it may be helpful, however, if overall evaluation of indi-vidual responses is a critical part of the analysis.

11.4.7 EFFICACY CONCLUSIONS

The important conclusions concerning efficacy should be concisely described, con-sidering primary and secondary endpoints, pre-specified and alternative statisticalapproaches and results of exploratory analyses.

12. SAFETY EVALUATIONAnalysis of safety-related data can be considered at three levels. First, the extentof exposure (dose, duration, number of patients) should be examined to determine

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the degree to which safety can be assessed from the study. Second, the morecommon adverse events, laboratory test changes etc. should be identified, classi-fied in some reasonable way, compared for treatment groups, and analysed, asappropriate, for factors that may affect the frequency of adverse reactions/events,such as time dependence, relation to demographic characteristics, relation to doseor drug concentration etc. Finally, serious adverse events and other significantadverse events should be identified, usually by close examination of patients wholeft the study prematurely because of an adverse event, whether or not identifiedas drug related, or who died.

The ICH Guideline on Clinical Safety Data Management, Definitions and Standardsfor Expedited Reporting defines serious adverse events as follows: a “seriousadverse event” (experience) or reaction is any untoward medical occurrence that atany dose: results in death, is life-threatening, requires inpatient hospitalization orprolongation of existing hospitalization, results in persistent or significant dis-ability/incapacity, or is a congenital anomaly/birth defect.

For the purpose of this guideline, “other significant adverse events” are markedhaematological and other laboratory abnormalities and any adverse events that ledto an intervention, including withdrawal of drug treatment, dose reduction or sig-nificant additional concomitant therapy.

In the following sections, three kinds of analysis and display are called for:

1) summarized data, often using tables and graphical presentations presented inthe main body of the report

2) listings of individual patient data, and

3) narrative statements of events of particular interest.

In all tabulations and analyses, events associated with both test drug and controltreatment should be displayed.

12.1 Extent of ExposureThe extent of exposure to test drugs/investigational products (and to active con-trol and placebo) should be characterized according to the number of patientsexposed, the duration of exposure, and the dose to which they were exposed.

• Duration: Duration of exposure to any dose can be expressed as a median ormean, but it is also helpful to describe the number of patients exposed for speci-fied periods of time, such as for one day or less, 2 days to one week, more thanone week to one month, more than one month to 6 months etc. The numbersexposed to test drug(s)/investigational product(s) for the various durationsshould also be broken down into age, sex, and racial subgroups, and any otherpertinent subgroups, such as disease (if more than one is represented), diseaseseverity, concurrent illness.

• Dose: The mean or median dose used and the number of patients exposed tospecified daily dose levels should be given; the daily dose levels used could bethe maximum dose for each patient, the dose with longest exposure for eachpatient, or the mean daily dose. It is often useful to provide combined dose-dura-tion information, such as the numbers exposed for a given duration (e.g. at least

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one month) to the most common dose, the highest dose, the maximum recom-mended dose etc. In some cases, cumulative dose might be pertinent. Dosagemay be given as the actual daily dose or on a mg/kg or mg/m2 basis as appro-priate. The numbers of patients exposed to various doses should be broken downinto age, sex, and racial subgroups, and any other pertinent subgroups.

• Drug concentration: If available, drug concentration data (e.g. concentration atthe time of an event, maximum plasma concentration, area under curve) may behelpful in individual patients for correlation with adverse events or changes inlaboratory variables. (Appendix 16.2.5.)

It is assumed that all patients entered into treatment who received at least onedose of the treatment are included in the safety analysis; if that is not so, anexplanation should be provided.

12.2 Adverse Events (AEs)

12.2.1 BRIEF SUMMARY OF ADVERSE EVENTS

The overall adverse event experience in the study should be described in a brief nar-rative, supported by the following more detailed tabulations and analyses. In thesetabulations and analyses, events associated with both the test drug and controltreatment should be displayed.

12.2.2 DISPLAY OF ADVERSE EVENTS

All adverse events occurring after initiation of study treatments (including eventslikely to be related to the underlying disease or likely to represent concomitant ill-ness, unless there is a prior agreement with the regulatory authority to considerspecified events as disease related) should be displayed in summary tables (section14.3.1). The tables should include changes in vital signs and any laboratory changesthat were considered serious adverse events or other significant adverse events.

In most cases, it will also be useful to identify in such tables “treatment emergentsigns and symptoms” (TESS; those not seen at baseline and those that worsenedeven if present at baseline).

The tables should list each adverse event, the number of patients in each treatmentgroup in whom the event occurred, and the rate of occurrence. When treatments arecyclical, e.g. cancer chemotherapy, it may also be helpful to list results separatelyfor each cycle. Adverse events should be grouped by body system. Each event maythen be divided into defined severity categories (e.g. mild, moderate, severe) ifthese were used. The tables may also divide the adverse events into those consid-ered at least possibly related to drug use and those considered not related, or usesome other causality scheme (e.g. unrelated or possibly, probably, or definitelyrelated). Even when such a causality assessment is used, the tables should includeall adverse events, whether or not considered drug related, including eventsthought to represent intercurrent illnesses. Subsequent analyses of the study or ofthe overall safety data base may help to distinguish between adverse events thatare, or are not, considered drug related. So that it is possible to analyse and eval-

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In addition to these complete tables provided in 14.3.1, an additional summarytable comparing treatment and control groups, without the patient identifying num-bers limited to relatively common adverse events (e.g. those in at least 1% of thetreated group), should be provided in the body of the report.

In presenting adverse events, it is important both to display the original terms usedby the investigator and to attempt to group related events (i.e. events that prob-ably represent the same phenomena) so that the true occurrence rate is notobscured. One way to do this is with a standard adverse reaction/events dictionary.

12.2.3 ANALYSIS OF ADVERSE EVENTS

The basic display of adverse event rates described in section 12.2.2 (and located insection 14.3.1) of the report, should be used to compare rates in treatment andcontrol groups. For this analysis it may be helpful to combine the event severitycategories and the causality categories, leading to a simpler side-by-side com-parison of treatment groups. In addition, although this is usually best done in anintegrated analysis of safety, if study size and design permit, it may be useful toexamine the more common adverse events that seem to be drug related for rela-tionship to dosage and to mg/kg or mg/m2 dose, to dose regimen, to duration oftreatment, to total dose, to demographic characteristics such as age, sex, race, toother baseline features such as renal status, to efficacy outcomes, and to drug con-centration. It may also be useful to examine time of onset and duration of adverseevents. A variety of additional analyses may be suggested by the study results or bythe pharmacology of the test drug/investigational product.

It is not intended that every adverse event be subjected to rigorous statistical eval-uation. It may be apparent from initial display and inspection of the data that asignificant relation to demographic or other baseline features is not present. If the

Adverse Events: Number Observed and Rate, with Patient Identifications

Treatment Group X N=50

Mild Moderate Severe Total Total

Related* NR* Related NR Related NR Related NR R+NR

Body System AEvent 1 6 (12%) 2 (4%) 3 (6%) 1 (2%) 3 (6%) 1 (2%) 12 (24%) 4 (8%)

N11** N21 N31 N41 N51 N61N12 N22 N32 N52N13 N33 N53N14N15N16

Event 2

**NR = not related; related could be expanded, e.g. as definite, probable, possible**Patient identification number

uate the data in these tables, it is important to identify each patient having eachadverse event. An example of such a tabular presentation is shown below.

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studies are small and if the number of events is relatively small, it may be sufficientto limit analyses to a comparison of treatment and control.

Under certain circumstances, life table or similar analyses may be more informativethan reporting of crude adverse event rates. When treatments are cyclical, e.g.cancer chemotherapy, it may also be helpful to analyse results separately for eachcycle.

12.2.4 LISTING OF ADVERSE EVENTS BY PATIENT

All adverse events for each patient, including the same event on several occasionsshould be listed in appendix 16.2.7, giving both preferred term and the originalterm used by the investigator. The listing should be by investigator and by treat-ment group and should include:

– Patient identifier

– Age, race, sex, weight (height, if relevant)

– Location of CRFs, if provided

– The adverse event (preferred term, reported term)

– Duration of the adverse event

– Severity (e.g. mild, moderate, severe)

– Seriousness (serious/non-serious)

– Action taken (none, dose reduced, treatment stopped, specific treatment insti-tuted etc.)

– Outcome (e.g. CIOMS format)

– Causality assessment (e.g. related/not related). How this was determined shouldbe described in the table or elsewhere

– Date of onset or date of clinic visit at which the event was discovered

– Timing of onset of the adverse event in relation to last dose of test drug/inves-tigational product (when applicable)

– Study treatment at time of event or most recent study treatment taken

– Test drug/investigational product dose in absolute amount, mg/kg or mg/m2 attime of event

– Drug concentration (if known)

– Duration of test drug/investigational product treatment

– Concomitant treatment during study.

Any abbreviations and codes should be clearly explained at the beginning of thelisting or, preferably, on each page.

12.3 Deaths, Other Serious Adverse Events, and Other SignificantAdverse Events

Deaths, other serious adverse events, and other significant adverse events deservespecial attention.

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12.3.1 LISTING OF DEATHS, OTHER SERIOUS ADVERSE EVENTS AND OTHER SIGNIFICANT

ADVERSE EVENTS

Listings, containing the same information as called for in section 12.2.4 above,should be provided for the following events.

12.3.1.1 Deaths

All deaths during the study, including the post treatment follow-up period, anddeaths that resulted from a process that began during the study, should be listedby patient in section 14.3.2.

12.3.1.2 Other Serious Adverse Events

All serious adverse events (other than death but including the serious adverseevents temporally associated with or preceding the deaths) should be listed in sec-tion 14.3.2. The listing should include laboratory abnormalities, abnormal vitalsigns and abnormal physical observations that were considered serious adverseevents.

12.3.1.3 Other Significant Adverse Events

Marked haematological and other laboratory abnormalities (other than thosemeeting the definition of serious) and any events that led to an intervention,including withdrawal of test drug/investigational product treatment, dose reduc-tion, or significant additional concomitant therapy, other than those reported asserious adverse events, should be listed in section 14.3.2.

12.3.2 NARRATIVES OF DEATHS, OTHER SERIOUS ADVERSE EVENTS AND CERTAIN OTHERSIGNIFICANT ADVERSE EVENTS

There should be brief narratives describing each death, each other serious adverseevent, and those of the other significant adverse events that are judged to be ofspecial interest because of clinical importance. These narratives can be placedeither in the text of the report or in section 14.3.3, depending on their number.Events that were clearly unrelated to the test drug/investigational product may beomitted or described very briefly. In general, the narrative should describe the fol-lowing:

the nature and intensity of event, the clinical course leading up to event, withan indication of timing relevant to test drug/investigational product adminis-tration; relevant laboratory measurements, whether the drug was stopped, andwhen; countermeasures; post mortem findings; investigator’s opinion oncausality, and sponsor’s opinion on causality, if appropriate.

In addition, the following information should be included:

– Patient identifier

– Age and sex of patient; general clinical condition of patient, if appropriate

– Disease being treated (if the same for all patients this is not required) with dura-tion (of current episode) of illness

– Relevant concomitant/previous illnesses with details of occurrence/duration

– Relevant concomitant/previous medication with details of dosage

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– Test drug/investigational product administered, drug dose, if this varied amongpatients, and length of time administered.

12.3.3 ANALYSIS AND DISCUSSION OF DEATHS, OTHER SERIOUS ADVERSE EVENTS ANDOTHER SIGNIFICANT ADVERSE EVENTS

The significance of the deaths, other serious adverse events and other significantadverse events leading to withdrawal, dose reduction or institution of concomitanttherapy should be assessed with respect to the safety of the test drug/investiga-tional product. Particular attention should be paid to whether any of these eventsmay represent a previously unsuspected important adverse effect of the test drug/investigational product. For serious adverse events that appear of particular impor-tance, it may be useful to use life table or similar analyses to show their relationto time on test drug/investigational product and to assess their risk over time.

12.4 Clinical Laboratory Evaluation

12.4.1 LISTING OF INDIVIDUAL LABORATORY MEASUREMENTS BY PATIENT (16.2.8) ANDEACH ABNORMAL LABORATORY VALUE (14.3.4)

When required by regulatory authorities, the results of all safety-related laboratorytests should be available in tabular listings, using a display similar to the following,where each row represents a patient visit at which a laboratory study was done, withpatients grouped by investigator (if more than one) and treatment group, andcolumns include critical demographic data, drug dose data, and the results of thelaboratory tests. As not all tests can be displayed in a single table, they should begrouped logically (haematological tests, liver chemistries, electrolytes, urinalysisetc.). Abnormal values should be identified, e.g. by underlining, bracketing etc.These listings should be submitted as part of the registration/marketing applica-tion, when this is required, or may be available on request.

List of Laboratory Measurements

Laboratory TestsPatient Time Age Sex Race Weight Dose

SGOT SGPT AP..........X

# 1 T0 70 M W 70 kg 400 mg V1* V5 V9T1 V2 V6 V10T2 V3 V7 V11T3 V4 V8 V12

# 2 T10 65 F B 59 kg 300 mg V13 V16 V19T21 V14 V17 V20T32 V15 V18 V21

* Vn = value of a particular test

For all regulatory authorities, there should be a by-patient listing of all abnormallaboratory values in section 14.3.4, using the format described above. For labora-tory abnormalities of special interest (abnormal laboratory values of potential clin-ical importance), it may also be useful to provide additional data, such as normal

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values before and after the abnormal value, and values of related laboratory tests.In some cases, it may be desirable to exclude certain abnormal values from furtheranalysis. For example, single, non-replicated, small abnormalities of some tests (e.g.uric acid or electrolytes) or occasional low values of some tests (e.g. transaminase,alkaline phosphatase, BUN etc.) can probably be defined as clinically insignificantand excluded. Any such decisions should be clearly explained, however, and thecomplete list of values provided (or available to authorities on request) shouldidentify every abnormal value.

12.4.2 EVALUATION OF EACH LABORATORY PARAMETER

The necessary evaluation of laboratory values must in part be determined by theresults seen, but, in general, the following analyses should be provided. For eachanalysis, comparison of the treatment and control groups should be carried out, asappropriate, and as compatible with study size. In addition, normal laboratoryranges should be given for each analysis.

12.4.2.1 Laboratory Values Over Time

For each parameter at each time over the course of the study (e.g. at each visit)the following should be described: the group mean or median values, the range ofvalues, and the number of patients with abnormal values, or with abnormal valuesthat are of a certain size (e.g. twice the upper limit of normal, 5 times the upperlimit; choices should be explained). Graphs may be used.

12.4.2.2 Individual Patient Changes

An analysis of individual patient changes by treatment group should be given. Avariety of approaches may be used, including:

III. “Shift tables” – These tables show the number of patients who are low, normal,or high at baseline and then at selected time intervals.

III. Tables showing the number or fraction of patients who had a change in para-meter of a predetermined size at selected time intervals. For example, for BUN,it might be decided that a change of more than 10 mg/dL BUN should benoted. For this parameter, the number of patients having a change less thanthis or greater than this would be shown for one or more visits, usuallygrouping patients separately depending on baseline BUN (normal or elevated).The possible advantage of this display, compared to the usual shift table, isthat changes of a certain size are noted, even if the final value is notabnormal.

III. A graph comparing the initial value and the on-treatment values of a labora-tory measurement for each patient by locating the point defined by the initialvalue on the abscissa and a subsequent value on the ordinate. If no changesoccur, the point representing each patient will be located on the 45° line. Ageneral shift to higher values will show a clustering of points above the 45°line. As this display usually shows only a single time point for a single treat-ment, interpretation requires a time series of these plots for treatment andcontrol groups. Alternatively the display could show baseline and most extreme

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on-treatment value. These displays identify outliers readily (it is useful toinclude patient identifiers for the outliers).

12.4.2.3 Individual Clinically Significant Abnormalities

Clinically significant changes (defined by the applicant) should be discussed. A nar-rative of each patient whose laboratory abnormality was considered a seriousadverse event and, in certain cases, considered an other significant adverse event,should be provided under sections 12.3.2 or 14.3.3. When toxicity grading scalesare used (e.g. WHO, NCI), changes graded as severe should be discussed regardlessof seriousness. An analysis of the clinically significant changes, together with arecapitulation of discontinuations due to laboratory measurements, should be pro-vided for each parameter. The significance of the changes and likely relation to thetreatment should be assessed, e.g. by analysis of such features as relationship todose, relationship to drug concentration, disappearance on continued therapy, posi-tive dechallenge, positive rechallenge, and the nature of concomitant therapy.

12.5 Vital Signs, Physical Findings and Other Observations Related to Safety

Vital signs, other physical findings, and other observations related to safety shouldbe analysed and presented in a way similar to laboratory variables. If there is evi-dence of a drug effect, any dose-response or drug concentration-response relation-ship or relationship to patient variables (e.g. disease, demographics, concomitanttherapy) should be identified and the clinical relevance of the observationdescribed. Particular attention should be given to changes not evaluated as efficacyvariables and to those considered to be adverse events.

12.6 Safety ConclusionsThe overall safety evaluation of the test drug(s)/investigational product(s) shouldbe reviewed, with particular attention to events resulting in changes of dose orneed for concomitant medication, serious adverse events, events resulting in with-drawal, and deaths. Any patients or patient groups at increased risk should be iden-tified and particular attention paid to potentially vulnerable patients who may bepresent in small numbers, e.g. children, pregnant women, frail elderly, people withmarked abnormalities of drug metabolism or excretion etc. The implication of thesafety evaluation for the possible uses of the drug should be described.

13. DISCUSSION AND OVERALL CONCLUSIONSThe efficacy and safety results of the study and the relationship of risks and benefitshould be briefly summarized and discussed, referring to the tables, figures, andsections above as needed. The presentation should not simply repeat the descrip-tion of results nor introduce new results.

The discussion and conclusions should clearly identify any new or unexpected find-ings, comment on their significance and discuss any potential problems such asinconsistencies between related measures. The clinical relevance and importance ofthe results should also be discussed in the light of other existing data. Any specific

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benefits or special precautions required for individual subjects or at-risk groups and any implications for the conduct of future studies should be identified.Alternatively, such discussions may be reserved for summaries of safety and efficacyreferring to the entire dossier (integrated summaries).

14. TABLES, FIGURES AND GRAPHS REFERRED TO BUT NOTINCLUDED IN THE TEXT

Figures should be used to visually summarize the important results, or to clarifyresults that are not easily understood from tables.

Important demographic, efficacy and safety data should be presented in summaryfigures or tables in the text of the report. However, if these become obtrusivebecause of size or number they should be presented here, cross-referenced to thetext, along with supportive, or additional, figures, tables or listings.

The following information may be presented in this section of the core clinical studyreport:

14.1 Demographic DataSummary figures and tables

14.2 Efficacy DataSummary figures and tables

14.3 Safety DataSummary figures and tables

14.3.1 DISPLAYS OF ADVERSE EVENTS

14.3.2 LISTINGS OF DEATHS, OTHER SERIOUS AND SIGNIFICANT ADVERSE EVENTS

14.3.3 NARRATIVES OF DEATHS, OTHER SERIOUS AND CERTAIN OTHER SIGNIFICANTADVERSE EVENTS

14.3.4 ABNORMAL LABORATORY VALUE LISTING (EACH PATIENT)

15. REFERENCE LISTA list of articles from the literature pertinent to the evaluation of the study shouldbe provided. Copies of important publications should be attached in an appendix(16.1.11 and 16.1.12). References should be given in accordance with the inter-nationally accepted standards of the 1979 Vancouver Declaration on “UniformRequirements for Manuscripts Submitted to Biomedical Journals” or the system usedin “Chemical Abstracts”.

16. APPENDICESThis section should be prefaced by a full list of all appendices available for thestudy report. Where permitted by the regulatory authority, some of the followingappendices need not be submitted with the report but need to be provided only onrequest.

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The applicant should therefore clearly indicate those appendices that are submittedwith the report.

N.B. In order to have appendices available on request, they should be finalized bythe time of filing of the submission.

16.1 Study Information16.1.1 Protocol and protocol amendments16.1.2 Sample case report form (unique pages only) 16.1.3 List of IECs or IRBs (plus the name of the committee Chair if required by

the regulatory authority) – Representative written information for patientand sample consent forms

16.1.4 List and description of investigators and other important participants inthe study, including brief (1 page) CVs or equivalent summaries of trainingand experience relevant to the performance of the clinical study

16.1.5 Signatures of principal or coordinating investigator(s) or sponsor’s respon-sible medical officer, depending on the regulatory authority’s requirement

16.1.6 Listing of patients receiving test drug(s)/investigational product(s) fromspecific batches, where more than one batch was used

16.1.7 Randomization scheme and codes (patient identification and treatmentassigned)

16.1.8 Audit certificates (if available) (see Annex IVa and IVb of the guideline) 16.1.9 Documentation of statistical methods16.1.10 Documentation of inter-laboratory standardization methods and quality

assurance procedures if used16.1.11 Publications based on the study 16.1.12 Important publications referenced in the report

16.2 Patient Data Listings16.2.1 Discontinued patients16.2.2 Protocol deviations16.2.3 Patients excluded from the efficacy analysis16.2.4 Demographic data16.2.5 Compliance and/or drug concentration data (if available) 16.2.6 Individual efficacy response data 16.2.7 Adverse event listings (each patient) 16.2.8 Listing of individual laboratory measurements by patient, when required by

regulatory authorities

16.3 Case Report Forms16.3.1 CRFs for deaths, other serious adverse events and withdrawals for AE16.3.2 Other CRFs submitted

16.4 Individual Patient Data Listings (US Archival Listings)

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Name of Sponsor/Company: Individual Study Table (For National AuthorityReferring to Part Use only)of the Dossier

Name of Finished Product:Volume:

Name of Active Ingredient:Page:

Title of Study:

Investigators:

Study centre(s):

Publication (reference):

Studied period (years): Phase of development:(date of first enrolment)(date of last completed)

Objectives:

Methodology:

Number of patients (planned and analysed):

Diagnosis and main criteria for inclusion:

Test product, dose and mode of administration, batch number:

Duration of treatment:

Reference therapy, dose and mode of administration, batch number:

Annex ISYNOPSIS

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Name of Sponsor/Company: Individual Study Table (For National AuthorityReferring to Part Use only)of the Dossier

Name of Finished Product:Volume:

Name of Active Ingredient:Page:

Criteria for evaluation:Efficacy:

Safety:

Statistical methods:

SUMMARY – CONCLUSIONS

EFFICACY RESULTS:

SAFETY RESULTS:

CONCLUSION:

Date of the report:

Annex I – continued

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PRINCIPAL OR COORDINATINGINVESTIGATOR(S) SIGNATURE(S)or Sponsor’s Responsible Medical Officer

_______________

STUDY TITLE:

STUDY AUTHOR(S):

I have read this report and confirm that to the best of my knowledge it accuratelydescribes the conduct and results of the study

INVESTIGATOR: ..............................................

OR SPONSOR’S RESPONSIBLEMEDICAL OFFICER

AFFILIATION: ..............................................

DATE: ..............................................

Annex II

SIGNATURE(S) ...............................................

...............................................

...............................................

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Annex IIIa

STUDY DESIGN AND SCHEDULE OF ASSESSMENTS

TREATMENT PERIOD A B C

B1 B2 C1 C2Test Drug/ Test Drug/Investigational InvestigationalProduct A Product A

5 mg 10 mg 5 mg 10 mg

Run-inTest Drug/ Test Drug/Investigational InvestigationalProduct B Product B

5 mg 10 mg 5 mg 10 mg

Week –2 (–3) 0 3 6 9 12

Visit 1 2 3 4 5 6

Exercise test 24 h x1 x2 x x x x

Medical history x

Physical examination x x

ECG x x

Lab. invest. x x

Adverse events x x x x x

1 = 14-20 days after visit 12 = 1-7 days after the first exercise test

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STUDY DESIGN AND SCHEDULE OF ASSESSMENTS

Double-blindplacebo

Single-blindScreening Placebo run-in Dose 1

1 2 3 4 11R

(7d) (7d) (7d) (7d) Dose 2 10 14d

Dose 3

(7d) (7d) (7d) (7d)5 6 7 8

9

Assessment Screening Run-in Baseline Treatment Follow-up

Study Week –2 –1 0 1 2 3 4 5 6 8

Informed consent x

History x

Physical exam. x

Effectiveness

Primary variable x x x x x x x x x x

Secondary variable x x x x x x x

Safety

Adverse events x x x x x x x x x x

Lab. tests x x x x x x

Body weight x x x x

Annex IIIb

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N =

1724

PATI

ENTS

REC

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NG

DOU

BLE-

BLIN

D M

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N

N =

1361

PATI

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COM

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N =

340

REGI

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N =

281

COM

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N=

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ITH

DRAW

N

N =

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PLET

EDST

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N=

WIT

HDR

AWN

N =

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N=

WIT

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Anne

x IV

a

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Annex IVb

N = 2670PATIENTS SCREENED

N = 1732PATIENTS RANDOMIZED

N = 1724PATIENTS RECEIVING

DOUBLE-BLINDMEDICATION

N =REGIMEN B

N = Completed

N =Withdrawn

N =REGIMEN A

N =REGIMEN C

N = 938Screening FailuresReasons:___________ (300)___________ (271)___________

N = 8DID NOT RECEIVEANY MEDICATION

Reasons:_________ (2)_________ (4)_________ (2)

ADVERSE EVENT (20)UNSAT. RESPONSE (32)etc. ......etc. ......

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Annex VSTUDY #

(Data Set Identification)

Listing of Patients who Discontinued Therapy

Centre:

Last Concomitant Reason forTreatment Patient # Sex Age Visit Duration Dose Medication Discontin.

Test Drug/ Adverse investigational reaction*product

•••Therapy failure


Active Control/ Comparator


Placebo

*The specific reaction leading to discontinuation

(Repeat for other centres)

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Annex VISTUDY #


Listing of Patients and Observations Excluded from Efficacy Analysis

Centre:

Treatment Patient # Sex Age Observation Excluded Reason(s)

Test Drug/Investigational Product


Active Drug/Comparator


Placebo

(Repeat for other centres)

Reference Tables

Summary:

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Annex VIISTUDY #


Number of Patients Excluded from Efficacy Analysis

Test Drug/Investigational Product N =

Week

Reason 1 2 4 8

Total

Similar tables should be prepared for the other treatment groups.

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Annex VIII

GUIDANCE FOR SECTION 11.4.2 – STATISTICAL/ANALYTICAL ISSUESAND APPENDIX 16.1.9

A. Statistical ConsiderationsDetails of the statistical analysis performed on each primary efficacy variable shouldbe presented in an appendix. Details reported should include at least the followinginformation:

a) The statistical model underlying the analysis. This should be presented pre-cisely and completely, using references if necessary.

b) A statement of the clinical claim tested in precise statistical terms, e.g., interms of null and alternative hypotheses.

c) The statistical methods applied to estimate effects, construct confidence inter-vals etc. Literature references should be included where appropriate.

d) The assumptions underlying the statistical methods. It should be shown,insofar as statistically reasonable, that the data satisfy crucial assumptions,especially when necessary to confirm the validity of an inference. When exten-sive statistical analyses have been performed by the applicant, it is essentialto consider the extent to which the analyses were planned prior to the avail-ability of data and, if they were not, how bias was avoided in choosing the par-ticular analysis used as a basis for conclusions. This is particularly importantin the case of any subgroup analyses, because if such analyses are not pre-planned they will ordinarily not provide an adequate basis for definitive con-clusions.

(i) In the event data transformation was performed, a rationale for thechoice of data transformation along with interpretation of the estimatesof treatment effects based on transformed data should be provided.

(ii) A discussion of the appropriateness of the choice of statistical proce-dure and the validity of statistical conclusions will guide the regulatoryauthority’s statistical reviewer in determining whether reanalysis of datais needed.

e) The test statistic, the sampling distribution of the test statistic under the nullhypothesis, the value of the test statistic, significance level (i.e. p-value), andintermediate summary data, in a format that enables the regulatory authority’sstatistical reviewer to verify the results of the analysis quickly and easily. Thep-values should be designated as one- or two-tailed. The rationale for using aone-tailed test should be provided.

For example, the documentation of a two-sample t-test should consist of thevalue of the t-statistic, the associated degrees of freedom, the p-value, the twosample sizes, mean and variance for each of the samples, and the pooled esti-mate of variance. The documentation of multi-centre studies analysed byanalysis of variance techniques should include, at a minimum, an analysis of

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variance table with terms for centres, treatments, their interaction, error, andtotal. For cross-over designs, the documentation should include informationregarding sequences, patients within sequences, baselines at the start of eachperiod, washouts and length of washouts, dropouts during each period, treat-ments, periods, treatment by period interaction, error, and total. For eachsource of variation, aside from the total, the table should contain the degreesof freedom, the sum of squares, the mean square, the appropriate F-test, thep-value, and the expected mean square.

Intermediate summary data should display the demographic data and responsedata, averaged or otherwise summarized, for each centre-by-treatment combi-nation (or other design characteristic such as sequence) at each observationtime.

B. Format and Specifications for Submission of Data Requested byRegulatory Authority’s Statistical Reviewers

In the report of each controlled clinical study, there should be data listings (tabu-lations) of patient data utilized by the sponsor for statistical analyses and tablessupporting conclusions and major findings. These data listings are necessary for theregulatory authority’s statistical review, and the sponsor may be asked to supplythese patient data listings in a computer-readable form.

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ICH Guidelines • Guideline for Good Clinical Practice (E6) • 61

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FOR HUMAN USE


GUIDELINE FORGOOD CLINICAL PRACTICE


on 1 May 1996by the ICH Steering Committee


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62 • ICH Guidelines • Guideline for Good Clinical Practice (E6)

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GUIDELINE FOR GOOD CLINICAL PRACTICE

ICH Harmonised Tripartite GuidelineHaving reached Step 4 of the ICH Process at the ICH Steering Committee meeting on 1 May 1996,

this guideline is recommended for adoption to the three regulatory parties to ICH

TABLE OF CONTENTS

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 651. Glossary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 652. The Principles of ICH GCP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 733. Institutional Review Board/Independent Ethics Committee

(IRB/IEC) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 743.1 Responsibilities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 743.2 Composition, Functions and Operations . . . . . . . . . . . . . . . . . . . . . . . . . . . 753.3 Procedures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 753.4 Records . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76

4. Investigator . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 764.1 Investigator’s Qualifications and Agreements . . . . . . . . . . . . . . . . . . . . . 764.2 Adequate Resources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 774.3 Medical Care of Trial Subjects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 774.4 Communication with IRB/IEC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 784.5 Compliance with Protocol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 784.6 Investigational Product(s) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 784.7 Randomization Procedures and Unblinding . . . . . . . . . . . . . . . . . . . . . . . . 794.8 Informed Consent of Trial Subjects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 794.9 Records and Reports . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 834.10 Progress Reports . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 844.11 Safety Reporting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 844.12 Premature Termination or Suspension of a Trial . . . . . . . . . . . . . . . . . . . 844.13 Final Report(s) by Investigator . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85

5. Sponsor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 855.1 Quality Assurance and Quality Control . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 855.2 Contract Research Organization (CRO) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 855.3 Medical Expertise . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 855.4 Trial Design . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 865.5 Trial Management, Data Handling, and Record Keeping . . . . . . . . . . 865.6 Investigator Selection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 875.7 Allocation of Responsibilities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88

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5.8 Compensation to Subjects and Investigators . . . . . . . . . . . . . . . . . . . . . . 885.9 Financing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 885.10 Notification/Submission to Regulatory Authority(ies) . . . . . . . . . . . . 885.11 Confirmation of Review by IRB/IEC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 885.12 Information on Investigational Product(s) . . . . . . . . . . . . . . . . . . . . . . . . 895.13 Manufacturing, Packaging, Labelling, and Coding Investigational

Product(s) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 895.14 Supplying and Handling Investigational Product(s) . . . . . . . . . . . . . . 905.15 Record Access . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 915.16 Safety Information . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 915.17 Adverse Drug Reaction Reporting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 915.18 Monitoring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91

5.18.1 Purpose . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 915.18.2 Selection and Qualifications of Monitors . . . . . . . . . . . . . . . . 915.18.3 Extent and Nature of Monitoring . . . . . . . . . . . . . . . . . . . . . . . . 925.18.4 Monitor’s Responsibilities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 925.18.5 Monitoring Procedures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 945.18.6 Monitoring Report . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94

5.19 Audit . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 945.19.1 Purpose . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 945.19.2 Selection and Qualification of Auditors . . . . . . . . . . . . . . . . . 945.19.3 Auditing Procedures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95

5.20 Non-compliance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 955.21 Premature Termination of a Trial . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 955.22 Clinical Trial/Study Reports . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 965.23 Multicentre Trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96

6. Clinical Trial Protocol and Protocol Amendment(s) . . . . . . . . . . . . . . . . . . . 966.1 General Information . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 966.2 Background Information . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 976.3 Trial Objectives and Purpose . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 976.4 Trial Design . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 976.5 Selection and Withdrawal of Subjects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 986.6 Treatment of Subjects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 986.7 Assessment of Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 986.8 Assessment of Safety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 986.9 Statistics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99 6.10 Direct Access to Source Data/Documents . . . . . . . . . . . . . . . . . . . . . . . . . . 996.11 Quality Control and Quality Assurance Procedures . . . . . . . . . . . . . . . . 996.12 Ethics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 996.13 Data Handling and Record Keeping . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 996.14 Financing and Insurance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 996.15 Publication Policy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 996.16 Supplements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99

7. Investigator’s Brochure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1007.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1007.2 General Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101

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7.2.1 Title Page . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1017.2.2 Confidentiality Statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101

7.3 Contents of the Investigator’s Brochure . . . . . . . . . . . . . . . . . . . . . . . . . . . 1017.3.1 Table of Contents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1017.3.2 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1017.3.3 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1017.3.4 Physical, Chemical, and Pharmaceutical Properties and

Formulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1017.3.5 Non-clinical Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1027.3.6 Effects in Humans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1037.3.7 Summary of Data and Guidance for the Investigator . . . 104

7.4 Appendix 1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1057.5 Appendix 2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105

8. Essential Documents for the Conduct of a Clinical Trial . . . . . . . . . . . . . . 1078.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1078.2 Before the Clinical Phase of the Trial Commences . . . . . . . . . . . . . . . . 1088.3 During the Clinical Conduct of the Trial . . . . . . . . . . . . . . . . . . . . . . . . . . . 1128.4 After Completion or Termination of the Trial . . . . . . . . . . . . . . . . . . . . . . 117

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GUIDELINE FOR GOOD CLINICAL PRACTICE

INTRODUCTION

Good Clinical Practice (GCP) is an international ethical and scientific quality stan-dard for designing, conducting, recording and reporting trials that involve the par-ticipation of human subjects. Compliance with this standard provides public assur-ance that the rights, safety and well-being of trial subjects are protected, consis-tent with the principles that have their origin in the Declaration of Helsinki, andthat the clinical trial data are credible.

The objective of this ICH GCP Guideline is to provide a unified standard for theEuropean Union (EU), Japan and the United States to facilitate the mutual accep-tance of clinical data by the regulatory authorities in these jurisdictions.

The guideline was developed with consideration of the current good clinical prac-tices of the European Union, Japan, and the United States, as well as those ofAustralia, Canada, the Nordic countries and the World Health Organization (WHO).

This guideline should be followed when generating clinical trial data that areintended to be submitted to regulatory authorities.

The principles established in this guideline may also be applied to other clinicalinvestigations that may have an impact on the safety and well-being of human sub-jects.

1. GLOSSARY1.1 Adverse Drug Reaction (ADR)In the pre-approval clinical experience with a new medicinal product or its newusages, particularly as the therapeutic dose(s) may not be established: all noxiousand unintended responses to a medicinal product related to any dose should be con-sidered adverse drug reactions. The phrase responses to a medicinal product meansthat a causal relationship between a medicinal product and an adverse event is atleast a reasonable possibility, i.e. the relationship cannot be ruled out.

Regarding marketed medicinal products: a response to a drug which is noxious andunintended and which occurs at doses normally used in man for prophylaxis, diag-nosis, or therapy of diseases or for modification of physiological function (see theICH Guideline for Clinical Safety Data Management: Definitions and Standards forExpedited Reporting).

1.2 Adverse Event (AE)Any untoward medical occurrence in a patient or clinical investigation subjectadministered a pharmaceutical product and which does not necessarily have acausal relationship with this treatment. An adverse event (AE) can therefore be anyunfavourable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of a medicinal (investiga-tional) product, whether or not related to the medicinal (investigational) product(see the ICH Guideline for Clinical Safety Data Management: Definitions andStandards for Expedited Reporting).

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1.3 Amendment (to the protocol)See Protocol Amendment.

1.4 Applicable Regulatory Requirement(s)Any law(s) and regulation(s) addressing the conduct of clinical trials of investiga-tional products.

1.5 Approval (in relation to Institutional Review Boards)The affirmative decision of the IRB that the clinical trial has been reviewed and maybe conducted at the institution site within the constraints set forth by the IRB, the institution, Good Clinical Practice (GCP), and the applicable regulatory require-ments.

1.6 AuditA systematic and independent examination of trial related activities and documentsto determine whether the evaluated trial related activities were conducted, and thedata were recorded, analysed and accurately reported according to the protocol,sponsor’s standard operating procedures (SOPs), Good Clinical Practice (GCP), andthe applicable regulatory requirement(s).

1.7 Audit CertificateA declaration of confirmation by the auditor that an audit has taken place.

1.8 Audit ReportA written evaluation by the sponsor’s auditor of the results of the audit.

1.9 Audit TrailDocumentation that allows reconstruction of the course of events.

1.10 Blinding/MaskingA procedure in which one or more parties to the trial are kept unaware of the treat-ment assignment(s). Single-blinding usually refers to the subject(s) being unaware,and double-blinding usually refers to the subject(s), investigator(s), monitor, and,in some cases, data analyst(s) being unaware of the treatment assignment(s).

1.11 Case Report Form (CRF)A printed, optical, or electronic document designed to record all of the protocolrequired information to be reported to the sponsor on each trial subject.

1.12 Clinical Trial/StudyAny investigation in human subjects intended to discover or verify the clinical,pharmacological and/or other pharmacodynamic effects of an investigationalproduct(s), and/or to identify any adverse reactions to an investigationalproduct(s), and/or to study absorption, distribution, metabolism, and excretion ofan investigational product(s) with the object of ascertaining its safety and/or effi-cacy. The terms clinical trial and clinical study are synonymous.

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1.13 Clinical Trial/Study ReportA written description of a trial/study of any therapeutic, prophylactic, or diagnosticagent conducted in human subjects, in which the clinical and statistical descrip-tion, presentations, and analyses are fully integrated into a single report (see theICH Guideline for Structure and Content of Clinical Study Reports).

1.14 Comparator (Product)An investigational or marketed product (i.e. active control), or placebo, used as areference in a clinical trial.

1.15 Compliance (in relation to trials)Adherence to all the trial-related requirements, Good Clinical Practice (GCP)requirements, and the applicable regulatory requirements.

1.16 ConfidentialityPrevention of disclosure, to other than authorized individuals, of a sponsor’s pro-prietary information or of a subject’s identity.

1.17 ContractA written, dated, and signed agreement between two or more involved parties thatsets out any arrangements on delegation and distribution of tasks and obligationsand, if appropriate, on financial matters. The protocol may serve as the basis of acontract.

1.18 Coordinating CommitteeA committee that a sponsor may organise to coordinate the conduct of a multi-centre trial.

1.19 Coordinating InvestigatorAn investigator assigned the responsibility for the coordination of investigators atdifferent centres participating in a multicentre trial.

1.20 Contract Research Organization (CRO)A person or an organization (commercial, academic, or other) contracted by thesponsor to perform one or more of a sponsor’s trial-related duties and functions.

1.21 Direct AccessPermission to examine, analyse, verify, and reproduce any records and reports thatare important to evaluation of a clinical trial. Any party (e.g. domestic and foreignregulatory authorities, sponsor’s monitors and auditors) with direct access shouldtake all reasonable precautions within the constraints of the applicable regulatoryrequirement(s) to maintain the confidentiality of subjects’ identities and sponsor’sproprietary information.

1.22 DocumentationAll records, in any form (including, but not limited to, written, electronic, mag-netic, and optical records, and scans, x-rays, and electrocardiograms) that describe

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or record the methods, conduct, and/or results of a trial, the factors affecting atrial, and the actions taken.

1.23 Essential DocumentsDocuments which individually and collectively permit evaluation of the conduct ofa study and the quality of the data produced (see 8. Essential Documents for theConduct of a Clinical Trial).

1.24 Good Clinical Practice (GCP)A standard for the design, conduct, performance, monitoring, auditing, recording,analyses, and reporting of clinical trials that provides assurance that the data andreported results are credible and accurate, and that the rights, integrity, and con-fidentiality of trial subjects are protected.

1.25 Independent Data-Monitoring Committee (IDMC) (Data and Safety Monitoring Board, Monitoring Committee, Data MonitoringCommittee)

An independent data-monitoring committee that may be established by the sponsorto assess at intervals the progress of a clinical trial, the safety data, and the critical efficacy endpoints, and to recommend to the sponsor whether to continue,modify, or stop a trial.

1.26 Impartial WitnessA person, who is independent of the trial, who cannot be unfairly influenced bypeople involved with the trial, who attends the informed consent process if thesubject or the subject’s legally acceptable representative cannot read, and whoreads the informed consent form and any other written information supplied to thesubject.

1.27 Independent Ethics Committee (IEC)An independent body (a review board or a committee, institutional, regional,national, or supranational), constituted of medical professionals and non-medicalmembers, whose responsibility it is to ensure the protection of the rights, safetyand well-being of human subjects involved in a trial and to provide public assur-ance of that protection, by, among other things, reviewing and approving/pro-viding favourable opinion on, the trial protocol, the suitability of the investi-gator(s), facilities, and the methods and material to be used in obtaining anddocumenting informed consent of the trial subjects.

The legal status, composition, function, operations and regulatory requirementspertaining to Independent Ethics Committees may differ among countries, butshould allow the Independent Ethics Committee to act in agreement with GCP asdescribed in this guideline.

1.28 Informed ConsentA process by which a subject voluntarily confirms his or her willingness to partici-pate in a particular trial, after having been informed of all aspects of the trial that

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are relevant to the subject’s decision to participate. Informed consent is docu-mented by means of a written, signed and dated informed consent form.

1.29 InspectionThe act by a regulatory authority(ies) of conducting an official review of documents,facilities, records, and any other resources that are deemed by the authority(ies) tobe related to the clinical trial and that may be located at the site of the trial, atthe sponsor’s and/or contract research organization’s (CRO’s) facilities, or at otherestablishments deemed appropriate by the regulatory authority(ies).

1.30 Institution (medical) Any public or private entity or agency or medical or dental facility where clinicaltrials are conducted.

1.31 Institutional Review Board (IRB)An independent body constituted of medical, scientific, and non-scientific mem-bers, whose responsibility is to ensure the protection of the rights, safety and well-being of human subjects involved in a trial by, among other things, reviewing,approving, and providing continuing review of trial protocol and amendments andof the methods and material to be used in obtaining and documenting informedconsent of the trial subjects.

1.32 Interim Clinical Trial/Study ReportA report of intermediate results and their evaluation based on analyses performedduring the course of a trial.

1.33 Investigational ProductA pharmaceutical form of an active ingredient or placebo being tested or used as areference in a clinical trial, including a product with a marketing authorizationwhen used or assembled (formulated or packaged) in a way different from theapproved form, or when used for an unapproved indication, or when used to gainfurther information about an approved use.

1.34 InvestigatorA person responsible for the conduct of the clinical trial at a trial site. If a trial isconducted by a team of individuals at a trial site, the investigator is the respon-sible leader of the team and may be called the principal investigator. See also Sub-Investigator.

1.35 Investigator / InstitutionAn expression meaning “the investigator and/or institution, where required by theapplicable regulatory requirements”.

1.36 Investigator’s BrochureA compilation of the clinical and nonclinical data on the investigational product(s)which is relevant to the study of the investigational product(s) in human subjects(see 7. Investigator’s Brochure).

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1.37 Legally Acceptable RepresentativeAn individual or juridical or other body authorized under applicable law to consent,on behalf of a prospective subject, to the subject’s participation in the clinical trial.

1.38 MonitoringThe act of overseeing the progress of a clinical trial, and of ensuring that it is con-ducted, recorded, and reported in accordance with the protocol, Standard OperatingProcedures (SOPs), Good Clinical Practice (GCP), and the applicable regulatory re-quirement(s).

1.39 Monitoring ReportA written report from the monitor to the sponsor after each site visit and/or othertrial-related communication according to the sponsor’s SOPs.

1.40 Multicentre TrialA clinical trial conducted according to a single protocol but at more than one site,and therefore, carried out by more than one investigator.

1.41 Non-clinical StudyBiomedical studies not performed on human subjects.

1.42 Opinion (in relation to Independent Ethics Committee)The judgement and/or the advice provided by an Independent Ethics Committee(IEC).

1.43 Original Medical RecordSee Source Documents.

1.44 ProtocolA document that describes the objective(s), design, methodology, statistical con-siderations, and organization of a trial. The protocol usually also gives the back-ground and rationale for the trial, but these could be provided in other protocolreferenced documents. Throughout the ICH GCP Guideline the term protocol refersto protocol and protocol amendments.

1.45 Protocol AmendmentA written description of a change(s) to or formal clarification of a protocol.

1.46 Quality Assurance (QA)All those planned and systematic actions that are established to ensure that thetrial is performed and the data are generated, documented (recorded), and reportedin compliance with Good Clinical Practice (GCP) and the applicable regulatoryrequirement(s).

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1.47 Quality Control (QC)The operational techniques and activities undertaken within the quality assurancesystem to verify that the requirements for quality of the trial-related activities havebeen fulfilled.

1.48 RandomizationThe process of assigning trial subjects to treatment or control groups using an ele-ment of chance to determine the assignments in order to reduce bias.

1.49 Regulatory Authorities Bodies having the power to regulate. In the ICH GCP guideline the expressionRegulatory Authorities includes the authorities that review submitted clinical dataand those that conduct inspections (see 1.29). These bodies are sometimes referredto as competent authorities.

1.50 Serious Adverse Event (SAE) or Serious Adverse Drug Reaction(Serious ADR)

Any untoward medical occurrence that at any dose:– results in death,– is life-threatening,– requires inpatient hospitalization or prolongation of existing hospitalization,– results in persistent or significant disability/incapacity,

or– is a congenital anomaly/birth defect (see the ICH Guideline for Clinical Safety Data Management: Definitions andStandards for Expedited Reporting).

1.51 Source DataAll information in original records and certified copies of original records of clinicalfindings, observations, or other activities in a clinical trial necessary for the recon-struction and evaluation of the trial. Source data are contained in source documents(original records or certified copies).

1.52 Source DocumentsOriginal documents, data, and records (e.g. hospital records, clinical and officecharts, laboratory notes, memoranda, subjects’ diaries or evaluation checklists,pharmacy dispensing records, recorded data from automated instruments, copies ortranscriptions certified after verification as being accurate copies, microfiches, pho-tographic negatives, microfilm or magnetic media, x-rays, subject files, and recordskept at the pharmacy, at the laboratories and at medico-technical departmentsinvolved in the clinical trial).

1.53 SponsorAn individual, company, institution, or organization which takes responsibility forthe initiation, management, and/or financing of a clinical trial.

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1.54 Sponsor-InvestigatorAn individual who both initiates and conducts, alone or with others, a clinical trial,and under whose immediate direction the investigational product is administeredto, dispensed to, or used by a subject. The term does not include any person otherthan an individual (e.g. it does not include a corporation or an agency). The obli-gations of a sponsor-investigator include both those of a sponsor and those of aninvestigator.

1.55 Standard Operating Procedures (SOPs)Detailed, written instructions to achieve uniformity of the performance of a specificfunction.

1.56 SubinvestigatorAny individual member of the clinical trial team designated and supervised by theinvestigator at a trial site to perform critical trial-related procedures and/or to makeimportant trial-related decisions (e.g. associates, residents, research fellows). Seealso Investigator.

1.57 Subject/Trial SubjectAn individual who participates in a clinical trial, either as a recipient of the inves-tigational product(s) or as a control.

1.58 Subject Identification CodeA unique identifier assigned by the investigator to each trial subject to protect thesubject’s identity and used in lieu of the subject’s name when the investigatorreports adverse events and/or other trial related data.

1.59 Trial SiteThe location(s) where trial-related activities are actually conducted.

1.60 Unexpected Adverse Drug ReactionAn adverse reaction, the nature or severity of which is not consistent with theapplicable product information (e.g. Investigator’s Brochure for an unapprovedinvestigational product or package insert/summary of product characteristics for anapproved product) (see the ICH Guideline for Clinical Safety Data Management:Definitions and Standards for Expedited Reporting).

1.61 Vulnerable SubjectsIndividuals whose willingness to volunteer in a clinical trial may be unduly influ-enced by the expectation, whether justified or not, of benefits associated with par-ticipation, or of a retaliatory response from senior members of a hierarchy in caseof refusal to participate. Examples are members of a group with a hierarchical struc-ture, such as medical, pharmacy, dental, and nursing students, subordinate hospitaland laboratory personnel, employees of the pharmaceutical industry, members of

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the armed forces, and persons kept in detention. Other vulnerable subjects includepatients with incurable diseases, persons in nursing homes, unemployed or impov-erished persons, patients in emergency situations, ethnic minority groups, homelesspersons, nomads, refugees, minors, and those incapable of giving consent.

1.62 Well-being (of the trial subjects)The physical and mental integrity of the subjects participating in a clinical trial.

2. THE PRINCIPLES OF ICH GCP2.1 Clinical trials should be conducted in accordance with the ethical principles

that have their origin in the Declaration of Helsinki, and that are consistentwith GCP and the applicable regulatory requirement(s).

2.2 Before a trial is initiated, foreseeable risks and inconveniences should beweighed against the anticipated benefit for the individual trial subject andsociety. A trial should be initiated and continued only if the anticipatedbenefits justify the risks.

2.3 The rights, safety, and well-being of the trial subjects are the most impor-tant considerations and should prevail over interests of science and society.

2.4 The available non-clinical and clinical information on an investigationalproduct should be adequate to support the proposed clinical trial.

2.5 Clinical trials should be scientifically sound, and described in a clear,detailed protocol.

2.6 A trial should be conducted in compliance with the protocol that hasreceived prior institutional review board (IRB)/independent ethics com-mittee (IEC) approval/favourable opinion.

2.7 The medical care given to, and medical decisions made on behalf of, sub-jects should always be the responsibility of a qualified physician or, whenappropriate, of a qualified dentist.

2.8 Each individual involved in conducting a trial should be qualified by educa-tion, training, and experience to perform his or her respective task(s).

2.9 Freely given informed consent should be obtained from every subject priorto clinical trial participation.

2.10 All clinical trial information should be recorded, handled, and stored in away that allows its accurate reporting, interpretation and verification.

2.11 The confidentiality of records that could identify subjects should be pro-tected, respecting the privacy and confidentiality rules in accordance withthe applicable regulatory requirement(s).

2.12 Investigational products should be manufactured, handled, and stored inaccordance with applicable good manufacturing practice (GMP). They shouldbe used in accordance with the approved protocol.

2.13 Systems with procedures that assure the quality of every aspect of the trialshould be implemented.

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3. INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE (IRB/IEC)

3.1 Responsibilities3.1.1 An IRB/IEC should safeguard the rights, safety, and well-being of all trial

subjects. Special attention should be paid to trials that may include vul-nerable subjects.

3.1.2 The IRB/IEC should obtain the following documents:

trial protocol(s)/amendment(s), written informed consent form(s) andconsent form updates that the investigator proposes for use in the trial,subject recruitment procedures (e.g. advertisements), written informationto be provided to subjects, Investigator’s Brochure (IB), available safetyinformation, information about payments and compensation available tosubjects, the investigator’s current curriculum vitae and/or other docu-mentation evidencing qualifications, and any other documents that theIRB/IEC may need to fulfil its responsibilities.

The IRB/IEC should review a proposed clinical trial within a reasonabletime and document its views in writing, clearly identifying the trial, thedocuments reviewed and the dates for the following: – approval/favourable opinion;– modifications required prior to its approval/favourable opinion;– disapproval/negative opinion; and– termination/suspension of any prior approval/favourable opinion.

3.1.3 The IRB/IEC should consider the qualifications of the investigator for theproposed trial, as documented by a current curriculum vitae and/or by anyother relevant documentation the IRB/IEC requests.

3.1.4 The IRB/IEC should conduct continuing review of each ongoing trial atintervals appropriate to the degree of risk to human subjects, but at leastonce per year.

3.1.5 The IRB/IEC may request more information than is outlined in paragraph4.8.10 be given to subjects when, in the judgement of the IRB/IEC, theadditional information would add meaningfully to the protection of therights, safety and/or well-being of the subjects.

3.1.6 When a non-therapeutic trial is to be carried out with the consent of the subject’s legally acceptable representative (see 4.8.12, 4.8.14), theIRB/IEC should determine that the proposed protocol and/or other docu-ment(s) adequately addresses relevant ethical concerns and meets applic-able regulatory requirements for such trials.

3.1.7 Where the protocol indicates that prior consent of the trial subject or thesubject’s legally acceptable representative is not possible (see 4.8.15), theIRB/IEC should determine that the proposed protocol and/or other docu-ment(s) adequately addresses relevant ethical concerns and meets applic-able regulatory requirements for such trials (i.e. in emergency situations).

3.1.8 The IRB/IEC should review both the amount and method of payment tosubjects to assure that neither presents problems of coercion or undue

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influence on the trial subjects. Payments to a subject should be proratedand not wholly contingent on completion of the trial by the subject.

3.1.9 The IRB/IEC should ensure that information regarding payment to sub-jects, including the methods, amounts, and schedule of payment to trialsubjects, is set forth in the written informed consent form and any otherwritten information to be provided to subjects. The way payment will beprorated should be specified.

3.2 Composition, Functions and Operations3.2.1 The IRB/IEC should consist of a reasonable number of members, who col-

lectively have the qualifications and experience to review and evaluate thescience, medical aspects, and ethics of the proposed trial. It is recom-mended that the IRB/IEC should include:

(a) At least five members.

(b) At least one member whose primary area of interest is in a non-scientific area.

(c) At least one member who is independent of the institution/trial site.

Only those IRB/IEC members who are independent of the investigator andthe sponsor of the trial should vote/provide opinion on a trial-relatedmatter.

A list of IRB/IEC members and their qualifications should be maintained.

3.2.2 The IRB/IEC should perform its functions according to written operatingprocedures, should maintain written records of its activities and minutesof its meetings, and should comply with GCP and with the applicable regu-latory requirement(s).

3.2.3 An IRB/IEC should make its decisions at announced meetings at which atleast a quorum, as stipulated in its written operating procedures, is pre-sent.

3.2.4 Only members who participate in the IRB/IEC review and discussion shouldvote/provide their opinion and/or advise.

3.2.5 The investigator may provide information on any aspect of the trial, butshould not participate in the deliberations of the IRB/IEC or in the vote/opinion of the IRB/IEC.

3.2.6 An IRB/IEC may invite non-members with expertise in special areas forassistance.

3.3 ProceduresThe IRB/IEC should establish, document in writing, and follow its procedures, whichshould include:

3.3.1 Determining its composition (names and qualifications of the members)and the authority under which it is established.

3.3.2 Scheduling, notifying its members of, and conducting its meetings.

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3.3.3 Conducting initial and continuing review of trials.

3.3.4 Determining the frequency of continuing review, as appropriate.

3.3.5 Providing, according to the applicable regulatory requirements, expeditedreview and approval/favourable opinion of minor change(s) in ongoingtrials that have the approval/favourable opinion of the IRB/IEC.

3.3.6 Specifying that no subject should be admitted to a trial before the IRB/IECissues its written approval/favourable opinion of the trial.

3.3.7 Specifying that no deviations from, or changes of, the protocol should beinitiated without prior written IRB/IEC approval/favourable opinion of anappropriate amendment, except when necessary to eliminate immediatehazards to the subjects or when the change(s) involves only logistical oradministrative aspects of the trial (e.g. change of monitor(s), telephonenumber(s)) (see 4.5.2).

3.3.8 Specifying that the investigator should promptly report to the IRB/IEC:

(a) Deviations from, or changes of, the protocol to eliminate immediatehazards to the trial subjects (see 3.3.7, 4.5.2, 4.5.4).

(b) Changes increasing the risk to subjects and/or affecting significantlythe conduct of the trial (see 4.10.2).

(c) All adverse drug reactions (ADRs) that are both serious and unex-pected.

(d) New information that may affect adversely the safety of the subjectsor the conduct of the trial.

3.3.9 Ensuring that the IRB/IEC promptly notify in writing the investigator/institution concerning:

(a) Its trial-related decisions/opinions.

(b) The reasons for its decisions/opinions.

(c) Procedures for appeal of its decisions/opinions.

3.4 RecordsThe IRB/IEC should retain all relevant records (e.g., written procedures, member-ship lists, lists of occupations/affiliations of members, submitted documents, min-utes of meetings, and correspondence) for a period of at least 3 years after com-pletion of the trial and make them available upon request from the regulatoryauthority(ies).

The IRB/IEC may be asked by investigators, sponsors or regulatory authorities toprovide its written procedures and membership lists.

4. INVESTIGATOR 4.1 Investigator’s Qualifications and Agreements4.1.1 The investigator(s) should be qualified by education, training, and experi-

ence to assume responsibility for the proper conduct of the trial, shouldmeet all the qualifications specified by the applicable regulatory require-ment(s), and should provide evidence of such qualifications through up-

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to-date curriculum vitae and/or other relevant documentation requestedby the sponsor, the IRB/IEC, and/or the regulatory authority(ies).

4.1.2 The investigator should be thoroughly familiar with the appropriate use ofthe investigational product(s), as described in the protocol, in the currentInvestigator’s Brochure, in the product information and in other informa-tion sources provided by the sponsor.

4.1.3 The investigator should be aware of, and should comply with, GCP and theapplicable regulatory requirements.

4.1.4 The investigator/institution should permit monitoring and auditing by thesponsor, and inspection by the appropriate regulatory authority(ies).

4.1.5 The investigator should maintain a list of appropriately qualified personsto whom the investigator has delegated significant trial-related duties.

4.2 Adequate Resources4.2.1 The investigator should be able to demonstrate (e.g. based on retrospec-

tive data) a potential for recruiting the required number of suitable sub-jects within the agreed recruitment period.

4.2.2 The investigator should have sufficient time to properly conduct and com-plete the trial within the agreed trial period.

4.2.3 The investigator should have available an adequate number of qualifiedstaff and adequate facilities for the foreseen duration of the trial to con-duct the trial properly and safely.

4.2.4 The investigator should ensure that all persons assisting with the trial areadequately informed about the protocol, the investigational product(s),and their trial-related duties and functions.

4.3 Medical Care of Trial Subjects4.3.1 A qualified physician (or dentist, when appropriate), who is an investi-

gator or a sub-investigator for the trial, should be responsible for all trial-related medical (or dental) decisions.

4.3.2 During and following a subject’s participation in a trial, the investigator/institution should ensure that adequate medical care is provided to a subject for any adverse events, including clinically significant laboratoryvalues, related to the trial. The investigator/institution should inform asubject when medical care is needed for intercurrent illness(es) of whichthe investigator becomes aware.

4.3.3 It is recommended that the investigator inform the subject’s primaryphysician about the subject’s participation in the trial if the subject has aprimary physician and if the subject agrees to the primary physician beinginformed.

4.3.4 Although a subject is not obliged to give his/her reason(s) for withdrawingprematurely from a trial, the investigator should make a reasonable effortto ascertain the reason(s), while fully respecting the subject’s rights.

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4.4 Communication with IRB/IEC4.4.1 Before initiating a trial, the investigator/institution should have written

and dated approval/favourable opinion from the IRB/IEC for the trialprotocol, written informed consent form, consent form updates, subjectrecruitment procedures (e.g. advertisements), and any other written infor-mation to be provided to subjects.

4.4.2 As part of the investigator’s/institution’s written application to theIRB/IEC, the investigator/institution should provide the IRB/IEC with acurrent copy of the Investigator’s Brochure. If the Investigator’s Brochureis updated during the trial, the investigator/institution should supply acopy of the updated Investigator’s Brochure to the IRB/IEC.

4.4.3 During the trial the investigator/institution should provide to the IRB/IECall documents subject to review.

4.5 Compliance with Protocol4.5.1 The investigator/institution should conduct the trial in compliance with

the protocol agreed to by the sponsor and, if required, by the regulatoryauthority(ies) and which was given approval/favourable opinion by theIRB/IEC. The investigator/institution and the sponsor should sign the pro-tocol, or an alternative contract, to confirm agreement.

4.5.2 The investigator should not implement any deviation from, or changes ofthe protocol without agreement by the sponsor and prior review and doc-umented approval/favourable opinion from the IRB/IEC of an amendment,except where necessary to eliminate an immediate hazard(s) to trial subjects, or when the change(s) involves only logistical or administra-tive aspects of the trial (e.g. change in monitor(s), change of telephonenumber(s)).

4.5.3 The investigator, or person designated by the investigator, should docu-ment and explain any deviation from the approved protocol.

4.5.4 The investigator may implement a deviation from, or a change of, the pro-tocol to eliminate an immediate hazard(s) to trial subjects without priorIRB/IEC approval/favourable opinion. As soon as possible, the imple-mented deviation or change, the reasons for it, and, if appropriate, theproposed protocol amendment(s) should be submitted:

(a) to the IRB/IEC for review and approval/favourable opinion,

(b) to the sponsor for agreement and, if required,

(c) to the regulatory authority(ies).

4.6 Investigational Product(s)4.6.1 Responsibility for investigational product(s) accountability at the trial

site(s) rests with the investigator/institution.

4.6.2 Where allowed/required, the investigator/institution may/should assignsome or all of the investigator’s/institution’s duties for investigationalproduct(s) accountability at the trial site(s) to an appropriate pharmacist

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or another appropriate individual who is under the supervision of theinvestigator/institution.

4.6.3 The investigator/institution and/or a pharmacist or other appropriate indi-vidual, who is designated by the investigator/institution, should maintainrecords of the product’s delivery to the trial site, the inventory at the site,the use by each subject, and the return to the sponsor or alternative dis-position of unused product(s). These records should include dates, quanti-ties, batch/serial numbers, expiration dates (if applicable), and the uniquecode numbers assigned to the investigational product(s) and trial subjects.Investigators should maintain records that document adequately that thesubjects were provided the doses specified by the protocol and reconcileall investigational product(s) received from the sponsor.

4.6.4 The investigational product(s) should be stored as specified by the sponsor(see 5.13.2 and 5.14.3) and in accordance with applicable regulatoryrequirement(s).

4.6.5 The investigator should ensure that the investigational product(s) are usedonly in accordance with the approved protocol.

4.6.6 The investigator, or a person designated by the investigator/institution,should explain the correct use of the investigational product(s) to eachsubject and should check, at intervals appropriate for the trial, that eachsubject is following the instructions properly.

4.7 Randomization Procedures and UnblindingThe investigator should follow the trial’s randomisation procedures, if any, andshould ensure that the code is broken only in accordance with the protocol. If the trial is blinded, the investigator should promptly document and explain to thesponsor any premature unblinding (e.g. accidental unblinding, unblinding due to aserious adverse event) of the investigational product(s).

4.8 Informed Consent of Trial Subjects4.8.1 In obtaining and documenting informed consent, the investigator should

comply with the applicable regulatory requirement(s), and should adhereto GCP and to the ethical principles that have their origin in theDeclaration of Helsinki. Prior to the beginning of the trial, the investigatorshould have the IRB/IEC’s written approval/favourable opinion of thewritten informed consent form and any other written information to beprovided to subjects.

4.8.2 The written informed consent form and any other written information tobe provided to subjects should be revised whenever important newinforma-tion becomes available that may be relevant to the subject’s con-sent. Any revised written informed consent form, and written informationshould receive the IRB/IEC’s approval/favourable opinion in advance ofuse. The subject or the subject’s legally acceptable representative shouldbe informed in a timely manner if new information becomes available that

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may be relevant to the subject’s willingness to continue participation inthe trial. The communication of this information should be documented.

4.8.3 Neither the investigator, nor the trial staff, should coerce or unduly influ-ence a subject to participate or to continue to participate in a trial.

4.8.4 None of the oral and written information concerning the trial, includingthe written informed consent form, should contain any language thatcauses the subject or the subject’s legally acceptable representative towaive or to appear to waive any legal rights, or that releases or appearsto release the investigator, the institution, the sponsor, or their agentsfrom liability for negligence.

4.8.5 The investigator, or a person designated by the investigator, should fullyinform the subject or, if the subject is unable to provide informed consent,the subject’s legally acceptable representative, of all pertinent aspects ofthe trial including the written information and the approval/ favourableopinion by the IRB/IEC.

4.8.6 The language used in the oral and written information about the trial,including the written informed consent form, should be as non-technicalas practical and should be understandable to the subject or the subject’slegally acceptable representative and the impartial witness, where applic-able.

4.8.7 Before informed consent may be obtained, the investigator, or a persondesignated by the investigator, should provide the subject or the subject’slegally acceptable representative ample time and opportunity to inquireabout details of the trial and to decide whether or not to participate in thetrial. All questions about the trial should be answered to the satisfactionof the subject or the subject’s legally acceptable representative.

4.8.8 Prior to a subject’s participation in the trial, the written informed consentform should be signed and personally dated by the subject or by the sub-ject’s legally acceptable representative, and by the person who conductedthe informed consent discussion.

4.8.9 If a subject is unable to read or if a legally acceptable representative isunable to read, an impartial witness should be present during the entireinformed consent discussion. After the written informed consent form and any other written information to be provided to subjects, is read andexplained to the subject or the subject’s legally acceptable representative,and after the subject or the subject’s legally acceptable representative hasorally consented to the subject’s participation in the trial and, if capableof doing so, has signed and personally dated the informed consent form,the witness should sign and personally date the consent form. By signingthe consent form, the witness attests that the information in the consentform and any other written information was accurately explained to, andapparently understood by, the subject or the subject’s legally acceptablerepresentative, and that informed consent was freely given by the subjector the subject’s legally acceptable representative.

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4.8.10 Both the informed consent discussion and the written informed consentform and any other written information to be provided to subjects shouldinclude explanations of the following:

(a) That the trial involves research.

(b) The purpose of the trial.

(c) The trial treatment(s) and the probability for random assignment toeach treatment.

(d) The trial procedures to be followed, including all invasive procedures.

(e) The subject’s responsibilities.

(f) Those aspects of the trial that are experimental.

(g) The reasonably foreseeable risks or inconveniences to the subject and,when applicable, to an embryo, fetus, or nursing infant.

(h) The reasonably expected benefits. When there is no intended clinicalbenefit to the subject, the subject should be made aware of this.

(i) The alternative procedure(s) or course(s) of treatment that may beavailable to the subject, and their important potential benefits andrisks.

(j) The compensation and/or treatment available to the subject in theevent of trial-related injury.

(k) The anticipated prorated payment, if any, to the subject for partici-pating in the trial.

(l) The anticipated expenses, if any, to the subject for participating inthe trial.

(m) That the subject’s participation in the trial is voluntary and that thesubject may refuse to participate or withdraw from the trial, at anytime, without penalty or loss of benefits to which the subject isotherwise entitled.

(n) That the monitor(s), the auditor(s), the IRB/IEC, and the regulatoryauthority(ies) will be granted direct access to the subject’s originalmedical records for verification of clinical trial procedures and/ordata, without violating the confidentiality of the subject, to theextent permitted by the applicable laws and regulations and that, bysigning a written informed consent form, the subject or the subject’slegally acceptable representative is authorising such access.

(o) That records identifying the subject will be kept confidential and, tothe extent permitted by the applicable laws and/or regulations, willnot be made publicly available. If the results of the trial are pub-lished, the subject’s identity will remain confidential.

(p) That the subject or the subject’s legally acceptable representative willbe informed in a timely manner if information becomes available thatmay be relevant to the subject’s willingness to continue participationin the trial.

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(q) The person(s) to contact for further information regarding the trialand the rights of trial subjects, and whom to contact in the event oftrial-related injury.

(r) The foreseeable circumstances and/or reasons under which the sub-ject’s participation in the trial may be terminated.

(s) The expected duration of the subject’s participation in the trial.

(t) The approximate number of subjects involved in the trial.

4.8.11 Prior to participation in the trial, the subject or the subject’s legallyacceptable representative should receive a copy of the signed and datedwritten informed consent form and any other written information providedto the subjects. During a subject’s participation in the trial, the subject orthe subject’s legally acceptable representative should receive a copy of thesigned and dated consent form updates and a copy of any amendments tothe written information provided to subjects.

4.8.12 When a clinical trial (therapeutic or non-therapeutic) includes subjectswho can only be enrolled in the trial with the consent of the subject’slegally acceptable representative (e.g., minors, or patients with severedementia), the subject should be informed about the trial to the extentcompatible with the subject’s understanding and, if capable, the subjectshould sign and personally date the written informed consent.

4.8.13 Except as described in 4.8.14, a non-therapeutic trial (i.e. a trial in whichthere is no anticipated direct clinical benefit to the subject), should beconducted in subjects who personally give consent and who sign and datethe written informed consent form.

4.8.14 Non-therapeutic trials may be conducted in subjects with consent of alegally acceptable representative provided the following conditions arefulfilled:

(a) The objectives of the trial can not be met by means of a trial in sub-jects who can give informed consent personally.

(b) The foreseeable risks to the subjects are low.

(c) The negative impact on the subject’s well-being is minimised and low.

(d) The trial is not prohibited by law.

(e) The approval/favourable opinion of the IRB/IEC is expressly sought onthe inclusion of such subjects, and the written approval/ favourableopinion covers this aspect.

Such trials, unless an exception is justified, should be conducted inpatients having a disease or condition for which the investigationalproduct is intended. Subjects in these trials should be particularly closelymonitored and should be withdrawn if they appear to be unduly distressed.

4.8.15 In emergency situations, when prior consent of the subject is not possible,the consent of the subject’s legally acceptable representative, if present,should be requested. When prior consent of the subject is not possible, and

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the subject’s legally acceptable representative is not available, enrolmentof the subject should require measures described in the protocol and/orelsewhere, with documented approval/favourable opinion by the IRB/IEC,to protect the rights, safety and well-being of the subject and to ensurecompliance with applicable regulatory requirements. The subject or thesubject’s legally acceptable representative should be informed about thetrial as soon as possible and consent to continue and other consent asappropriate (see 4.8.10) should be requested.

4.9 Records and Reports4.9.1 The investigator should ensure the accuracy, completeness, legibility, and

timeliness of the data reported to the sponsor in the CRFs and in allrequired reports.

4.9.2 Data reported on the CRF, that are derived from source documents, shouldbe consistent with the source documents or the discrepancies should beexplained.

4.9.3 Any change or correction to a CRF should be dated, initialed, and explained(if necessary) and should not obscure the original entry (i.e. an audit trailshould be maintained); this applies to both written and electronic changesor corrections (see 5.18.4 (n)). Sponsors should provide guidance to inves-tigators and/or the investigators’ designated representatives on makingsuch corrections. Sponsors should have written procedures to assure thatchanges or corrections in CRFs made by sponsor’s designated representa-tives are documented, are necessary, and are endorsed by the investigator.The investigator should retain records of the changes and corrections.

4.9.4 The investigator/institution should maintain the trial documents as speci-fied in Essential Documents for the Conduct of a Clinical Trial (see 8.) andas required by the applicable regulatory requirement(s). The investi-gator/institution should take measures to prevent accidental or prematuredestruction of these documents.

4.9.5 Essential documents should be retained until at least 2 years after the lastapproval of a marketing application in an ICH region and until there areno pending or contemplated marketing applications in an ICH region or atleast 2 years have elapsed since the formal discontinuation of clinicaldevelopment of the investigational product. These documents should beretained for a longer period however if required by the applicable regula-tory requirements or by an agreement with the sponsor. It is the responsi-bility of the sponsor to inform the investigator/institution as to whenthese documents no longer need to be retained (see 5.5.12).

4.9.6 The financial aspects of the trial should be documented in an agreementbetween the sponsor and the investigator/institution.

4.9.7 Upon request of the monitor, auditor, IRB/IEC, or regulatory authority, theinvestigator/institution should make available for direct access allrequested trial-related records.

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4.10 Progress Reports4.10.1 The investigator should submit written summaries of the trial status to the

IRB/IEC annually, or more frequently, if requested by the IRB/IEC.

4.10.2 The investigator should promptly provide written reports to the sponsor,the IRB/IEC (see 3.3.8) and, where applicable, the institution on anychanges significantly affecting the conduct of the trial, and/or increasingthe risk to subjects.

4.11 Safety Reporting4.11.1 All serious adverse events (SAEs) should be reported immediately to the

sponsor except for those SAEs that the protocol or other document (e.g.Investigator’s Brochure) identifies as not needing immediate reporting.The immediate reports should be followed promptly by detailed, writtenreports. The immediate and follow-up reports should identify subjects byunique code numbers assigned to the trial subjects rather than by the sub-jects’ names, personal identification numbers, and/or addresses. The inves-tigator should also comply with the applicable regulatory requirement(s)related to the reporting of unexpected serious adverse drug reactions tothe regulatory authority(ies) and the IRB/IEC.

4.11.2 Adverse events and/or laboratory abnormalities identified in the protocolas critical to safety evaluations should be reported to the sponsoraccording to the reporting requirements and within the time periods specified by the sponsor in the protocol.

4.11.3 For reported deaths, the investigator should supply the sponsor and theIRB/IEC with any additional requested information (e.g. autopsy reportsand terminal medical reports).

4.12 Premature Termination or Suspension of a TrialIf the trial is prematurely terminated or suspended for any reason, the investi-gator/institution should promptly inform the trial subjects, should assure appro-priate therapy and follow-up for the subjects, and, where required by the applicableregulatory requirement(s), should inform the regulatory authority(ies). In addition:

4.12.1 If the investigator terminates or suspends a trial without prior agreementof the sponsor, the investigator should inform the institution where applic-able, and the investigator/institution should promptly inform the sponsorand the IRB/IEC, and should provide the sponsor and the IRB/IEC adetailed written explanation of the termination or suspension.

4.12.2 If the sponsor terminates or suspends a trial (see 5.21), the investigatorshould promptly inform the institution where applicable and the investi-gator/institution should promptly inform the IRB/IEC and provide theIRB/IEC a detailed written explanation of the termination or suspension.

4.12.3 If the IRB/IEC terminates or suspends its approval/favourable opinion ofa trial (see 3.1.2 and 3.3.9), the investigator should inform the institution

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where applicable and the investigator/institution should promptly notifythe sponsor and provide the sponsor with a detailed written explanationof the termination or suspension.

4.13 Final Report(s) by InvestigatorUpon completion of the trial, the investigator, where applicable, should inform theinstitution; the investigator/institution should provide the IRB/IEC with a summaryof the trial’s outcome, and the regulatory authority(ies) with any reports required.

5. SPONSOR5.1 Quality Assurance and Quality Control5.1.1 The sponsor is responsible for implementing and maintaining quality

assurance and quality control systems with written SOPs to ensure that trials are conducted and data are generated, documented (recorded), andreported in compliance with the protocol, GCP, and the applicable regu-latory requirement(s).

5.1.2 The sponsor is responsible for securing agreement from all involved partiesto ensure direct access (see 1.21) to all trial related sites, source data/documents, and reports for the purpose of monitoring and auditing by thesponsor, and inspection by domestic and foreign regulatory authorities.

5.1.3 Quality control should be applied to each stage of data handling to ensurethat all data are reliable and have been processed correctly.

5.1.4 Agreements, made by the sponsor with the investigator/institution andany other parties involved with the clinical trial, should be in writing, aspart of the protocol or in a separate agreement.

5.2 Contract Research Organization (CRO)5.2.1 A sponsor may transfer any or all of the sponsor’s trial-related duties and

functions to a CRO, but the ultimate responsibility for the quality andintegrity of the trial data always resides with the sponsor. The CRO shouldimplement quality assurance and quality control.

5.2.2 Any trial-related duty and function that is transferred to and assumed bya CRO should be specified in writing.

5.2.3 Any trial-related duties and functions not specifically transferred to andassumed by a CRO are retained by the sponsor.

5.2.4 All references to a sponsor in this guideline also apply to a CRO to theextent that a CRO has assumed the trial related duties and functions of asponsor.

5.3 Medical ExpertiseThe sponsor should designate appropriately qualified medical personnel who will bereadily available to advise on trial related medical questions or problems. If neces-sary, outside consultant(s) may be appointed for this purpose.

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5.4 Trial Design5.4.1 The sponsor should utilize qualified individuals (e.g. biostatisticians, clini-

cal pharmacologists, and physicians) as appropriate, throughout all stagesof the trial process, from designing the protocol and CRFs and planning theanalyses to analysing and preparing interim and final clinical trial reports.

5.4.2 For further guidance: Clinical Trial Protocol and Protocol Amendment(s)(see 6.), the ICH Guideline for Structure and Content of Clinical StudyReports, and other appropriate ICH guidance on trial design, protocol andconduct.

5.5 Trial Management, Data Handling, and Record Keeping5.5.1 The sponsor should utilise appropriately qualified individuals to supervise

the overall conduct of the trial, to handle the data, to verify the data, toconduct the statistical analyses, and to prepare the trial reports.

5.5.2 The sponsor may consider establishing an independent data-monitoringcommittee (IDMC) to assess the progress of a clinical trial, including thesafety data and the critical efficacy endpoints at intervals, and to recom-mend to the sponsor whether to continue, modify, or stop a trial. The IDMCshould have written operating procedures and maintain written records ofall its meetings.

5.5.3 When using electronic trial data handling and/or remote electronic trialdata systems, the sponsor should:

(a) Ensure and document that the electronic data processing system(s)conforms to the sponsor’s established requirements for completeness,accuracy, reliability, and consistent intended performance (i.e. vali-dation).

(b) Maintains SOPs for using these systems.

(c) Ensure that the systems are designed to permit data changes in sucha way that the data changes are documented and that there is nodeletion of entered data (i.e. maintain an audit trail, data trail, edittrail).

(d) Maintain a security system that prevents unauthorized access to thedata.

(e) Maintain a list of the individuals who are authorized to make datachanges (see 4.1.5 and 4.9.3).

(f) Maintain adequate backup of the data.

(g) Safeguard the blinding, if any (e.g. maintain the blinding during dataentry and processing).

5.5.4 If data are transformed during processing, it should always be possible tocompare the original data and observations with the processed data.

5.5.5 The sponsor should use an unambiguous subject identification code (see1.58) that allows identification of all the data reported for each subject.

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5.5.6 The sponsor, or other owners of the data, should retain all of the sponsor-specific essential documents pertaining to the trial (see 8. EssentialDocuments for the Conduct of a Clinical Trial).

5.5.7 The sponsor should retain all sponsor-specific essential documents in con-formance with the applicable regulatory requirement(s) of the country(ies)where the product is approved, and/or where the sponsor intends to applyfor approval(s).

5.5.8 If the sponsor discontinues the clinical development of an investigationalproduct (i.e. for any or all indications, routes of administration, or dosageforms), the sponsor should maintain all sponsor-specific essential docu-ments for at least 2 years after formal discontinuation or in conformancewith the applicable regulatory requirement(s).

5.5.9 If the sponsor discontinues the clinical development of an investigationalproduct, the sponsor should notify all the trial investigators/institutionsand all the regulatory authorities.

5.5.10 Any transfer of ownership of the data should be reported to the appro-priate authority(ies), as required by the applicable regulatory require-ment(s).

5.5.11 The sponsor specific essential documents should be retained until at least2 years after the last approval of a marketing application in an ICH regionand until there are no pending or contemplated marketing applications inan ICH region or at least 2 years have elapsed since the formal discontin-uation of clinical development of the investigational product. These docu-ments should be retained for a longer period however if required by theapplicable regulatory requirement(s) or if needed by the sponsor.

5.5.12 The sponsor should inform the investigator(s)/institution(s) in writing ofthe need for record retention and should notify the investigator(s)/insti-tution(s) in writing when the trial related records are no longer needed.

5.6 Investigator Selection5.6.1 The sponsor is responsible for selecting the investigator(s)/institution(s).

Each investigator should be qualified by training and experience andshould have adequate resources (see 4.1, 4.2) to properly conduct the trialfor which the investigator is selected. If organization of a coordinatingcommittee and/or selection of coordinating investigator(s) are to beutilised in multicentre trials, their organisation and/or selection are thesponsor’s responsibility.

5.6.2 Before entering an agreement with an investigator/institution to conducta trial, the sponsor should provide the investigator(s)/institution(s) withthe protocol and an up-to-date Investigator’s Brochure, and should providesufficient time for the investigator/institution to review the protocol andthe information provided.

5.6.3 The sponsor should obtain the investigator’s/institution’s agreement:

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(a) to conduct the trial in compliance with GCP, with the applicable regu-latory requirement(s) (see 4.1.3), and with the protocol agreed to bythe sponsor and given approval/favourable opinion by the IRB/IEC(see 4.5.1);

(b) to comply with procedures for data recording/reporting;

(c) to permit monitoring, auditing and inspection (see 4.1.4); and

(d) to retain the trial related essential documents until the sponsorinforms the investigator/institution these documents are no longerneeded (see 4.9.4 and 5.5.12).

The sponsor and the investigator/institution should sign the protocol, oran alternative document, to confirm this agreement.

5.7 Allocation of ResponsibilitiesPrior to initiating a trial, the sponsor should define, establish, and allocate all trial-related duties and functions.

5.8 Compensation to Subjects and Investigators5.8.1 If required by the applicable regulatory requirement(s), the sponsor should

provide insurance or should indemnify (legal and financial coverage) theinvestigator/the institution against claims arising from the trial, exceptfor claims that arise from malpractice and/or negligence.

5.8.2 The sponsor’s policies and procedures should address the costs of treat-ment of trial subjects in the event of trial-related injuries in accordancewith the applicable regulatory requirement(s).

5.8.3 When trial subjects receive compensation, the method and manner of com-pensation should comply with applicable regulatory requirement(s).

5.9 FinancingThe financial aspects of the trial should be documented in an agreement betweenthe sponsor and the investigator/institution.

5.10 Notification/Submission to Regulatory Authority(ies)Before initiating the clinical trial(s), the sponsor (or the sponsor and the investi-gator, if required by the applicable regulatory requirement(s)) should submit anyrequired application(s) to the appropriate authority(ies) for review, acceptance,and/or permission (as required by the applicable regulatory requirement(s)) tobegin the trial(s). Any notification/submission should be dated and contain suffi-cient information to identify the protocol.

5.11 Confirmation of Review by IRB/IEC5.11.1 The sponsor should obtain from the investigator/institution:

(a) The name and address of the investigator’s/institution’s IRB/IEC.

(b) A statement obtained from the IRB/IEC that it is organized and oper-ates according to GCP and the applicable laws and regulations.

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(c) Documented IRB/IEC approval/favourable opinion and, if requestedby the sponsor, a current copy of protocol, written informed consentform(s) and any other written information to be provided to subjects,subject recruiting procedures, and documents related to payments andcompensation available to the subjects, and any other documents thatthe IRB/IEC may have requested.

5.11.2 If the IRB/IEC conditions its approval/favourable opinion upon change(s)in any aspect of the trial, such as modification(s) of the protocol, writteninformed consent form and any other written information to be providedto subjects, and/or other procedures, the sponsor should obtain from theinvestigator/institution a copy of the modification(s) made and the dateapproval/favourable opinion was given by the IRB/IEC.

5.11.3 The sponsor should obtain from the investigator/institution documenta-tion and dates of any IRB/IEC reapprovals/re-evaluations with favourableopinion, and of any withdrawals or suspensions of approval/favourableopinion.

5.12 Information on Investigational Product(s)5.12.1 When planning trials, the sponsor should ensure that sufficient safety and

efficacy data from non-clinical studies and/or clinical trials are availableto support human exposure by the route, at the dosages, for the duration,and in the trial population to be studied.

5.12.2 The sponsor should update the Investigator’s Brochure as significant newinformation becomes available (see 7. Investigator’s Brochure).

5.13 Manufacturing, Packaging, Labelling, and Coding InvestigationalProduct(s)

5.13.1 The sponsor should ensure that the investigational product(s) (includingactive comparator(s) and placebo, if applicable) is characterized as appro-priate to the stage of development of the product(s), is manufactured inaccordance with any applicable GMP, and is coded and labelled in a mannerthat protects the blinding, if applicable. In addition, the labelling shouldcomply with applicable regulatory requirement(s).

5.13.2 The sponsor should determine, for the investigational product(s), accept-able storage temperatures, storage conditions (e.g. protection from light),storage times, reconstitution fluids and procedures, and devices forproduct infusion, if any. The sponsor should inform all involved parties(e.g. monitors, investigators, pharmacists, storage managers) of thesedeterminations.

5.13.3 The investigational product(s) should be packaged to prevent contamina-tion and unacceptable deterioration during transport and storage.

5.13.4 In blinded trials, the coding system for the investigational product(s)should include a mechanism that permits rapid identification of the

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product(s) in case of a medical emergency, but does not permit unde-tectable breaks of the blinding.

5.13.5 If significant formulation changes are made in the investigational or com-parator product(s) during the course of clinical development, the results ofany additional studies of the formulated product(s) (e.g. stability, disso-lution rate, bioavailability) needed to assess whether these changes wouldsignificantly alter the pharmacokinetic profile of the product should beavailable prior to the use of the new formulation in clinical trials.

5.14 Supplying and Handling Investigational Product(s)5.14.1 The sponsor is responsible for supplying the investigator(s)/institution(s)

with the investigational product(s).

5.14.2 The sponsor should not supply an investigator/institution with the inves-tigational product(s) until the sponsor obtains all required documenta-tion (e.g. approval/favourable opinion from IRB/IEC and regulatoryauthority(ies)).

5.14.3 The sponsor should ensure that written procedures include instructionsthat the investigator/institution should follow for the handling andstorage of investigational product(s) for the trial and documentationthereof. The procedures should address adequate and safe receipt, han-dling, storage, dispensing, retrieval of unused product from subjects, andreturn of unused investigational product(s) to the sponsor (or alternativedisposition if authorised by the sponsor and in compliance with theapplicable regulatory requirement(s)).

5.14.4 The sponsor should:

(a) Ensure timely delivery of investigational product(s) to the investi-gator(s).

(b) Maintain records that document shipment, receipt, disposition, re-turn, and destruction of the investigational product(s) (see 8. Essen-tial Documents for the Conduct of a Clinical Trial).

(c) Maintain a system for retrieving investigational products and docu-menting this retrieval (e.g. for deficient product recall, reclaim aftertrial completion, expired product reclaim).

(d) Maintain a system for the disposition of unused investigationalproduct(s) and for the documentation of this disposition.

5.14.5 The sponsor should:

(a) Take steps to ensure that the investigational product(s) are stableover the period of use.

(b) Maintain sufficient quantities of the investigational product(s) usedin the trials to reconfirm specifications, should this become neces-sary, and maintain records of batch sample analyses and characteris-tics. To the extent stability permits, samples should be retained eitheruntil the analyses of the trial data are complete or as required by the

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applicable regulatory requirement(s), whichever represents the longerretention period.

5.15 Record Access5.15.1 The sponsor should ensure that it is specified in the protocol or other

written agreement that the investigator(s)/institution(s) provide directaccess to source data/documents for trial-related monitoring, audits,IRB/IEC review, and regulatory inspection.

5.15.2 The sponsor should verify that each subject has consented, in writing, todirect access to his/her original medical records for trial-related moni-toring, audit, IRB/IEC review, and regulatory inspection.

5.16 Safety Information5.16.1 The sponsor is responsible for the ongoing safety evaluation of the inves-

tigational product(s).

5.16.2 The sponsor should promptly notify all concerned investigator(s)/institu-tion(s) and the regulatory authority(ies) of findings that could affectadversely the safety of subjects, impact the conduct of the trial, or alterthe IRB/IEC’s approval/favourable opinion to continue the trial.

5.17 Adverse Drug Reaction Reporting5.17.1 The sponsor should expedite the reporting to all concerned investi-

gator(s)/institutions(s), to the IRB(s)/IEC(s), where required, and to theregulatory authority(ies) of all adverse drug reactions (ADRs) that are bothserious and unexpected.

5.17.2 Such expedited reports should comply with the applicable regulatoryrequirement(s) and with the ICH Guideline for Clinical Safety DataManagement: Definitions and Standards for Expedited Reporting.

5.17.3 The sponsor should submit to the regulatory authority(ies) all safetyupdates and periodic reports, as required by applicable regulatory require-ment(s).

5.18 Monitoring5.18.1 Purpose

The purposes of trial monitoring are to verify that:

(a) The rights and well-being of human subjects are protected.

(b) The reported trial data are accurate, complete, and verifiable fromsource documents.

(c) The conduct of the trial is in compliance with the currently approvedprotocol/amendment(s), with GCP, and with the applicable regulatoryrequirement(s).

5.18.2 Selection and Qualifications of Monitors

(a) Monitors should be appointed by the sponsor.

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(b) Monitors should be appropriately trained, and should have the scien-tific and/or clinical knowledge needed to monitor the trial adequately.A monitor’s qualifications should be documented.

(c) Monitors should be thoroughly familiar with the investigationalproduct(s), the protocol, written informed consent form and any otherwritten information to be provided to subjects, the sponsor’s SOPs,GCP, and the applicable regulatory requirement(s).

5.18.3 Extent and Nature of Monitoring

The sponsor should ensure that the trials are adequately monitored. Thesponsor should determine the appropriate extent and nature of moni-toring. The determination of the extent and nature of monitoring shouldbe based on considerations such as the objective, purpose, design, com-plexity, blinding, size, and endpoints of the trial. In general there is a needfor on-site monitoring, before, during, and after the trial; however inexceptional circumstances the sponsor may determine that central moni-toring in conjunction with procedures such as investigators’ training andmeetings, and extensive written guidance can assure appropriate conductof the trial in accordance with GCP. Statistically controlled sampling maybe an acceptable method for selecting the data to be verified.

5.18.4 Monitor’s Responsibilities

The monitor(s) in accordance with the sponsor’s requirements shouldensure that the trial is conducted and documented properly by carrying outthe following activities when relevant and necessary to the trial and thetrial site:

(a) Acting as the main line of communication between the sponsor andthe investigator.

(b) Verifying that the investigator has adequate qualifications andresources (see 4.1, 4.2, 5.6) and remain adequate throughout the trialperiod, that facilities, including laboratories, equipment, and staff,are adequate to safely and properly conduct the trial and remain ade-quate throughout the trial period.

(c) Verifying, for the investigational product(s):

ii(i) That storage times and conditions are acceptable, and that sup-plies are sufficient throughout the trial.

i(ii) That the investigational product(s) are supplied only to subjectswho are eligible to receive it and at the protocol specifieddose(s).

(iii) That subjects are provided with necessary instruction on prop-erly using, handling, storing, and returning the investigationalproduct(s).

(iv) That the receipt, use, and return of the investigationalproduct(s) at the trial sites are controlled and documented ade-quately.

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(v) That the disposition of unused investigational product(s) at thetrial sites complies with applicable regulatory requirement(s)and is in accordance with the sponsor.

(d) Verifying that the investigator follows the approved protocol and allapproved amendment(s), if any.

(e) Verifying that written informed consent was obtained before eachsubject’s participation in the trial.

(f) Ensuring that the investigator receives the current Investigator’sBrochure, all documents, and all trial supplies needed to conduct thetrial properly and to comply with the applicable regulatory require-ment(s).

(g) Ensuring that the investigator and the investigator’s trial staff areadequately informed about the trial.

(h) Verifying that the investigator and the investigator’s trial staff areperforming the specified trial functions, in accordance with the pro-tocol and any other written agreement between the sponsor and theinvestigator/institution, and have not delegated these functions tounauthorised individuals.

(i) Verifying that the investigator is enroling only eligible subjects.

(j) Reporting the subject recruitment rate.

(k) Verifying that source documents and other trial records are accurate,complete, kept up-to-date and maintained.

(l) Verifying that the investigator provides all the required reports, noti-fications, applications, and submissions, and that these documentsare accurate, complete, timely, legible, dated, and identify the trial.

(m) Checking the accuracy and completeness of the CRF entries, sourcedocuments and other trial-related records against each other. Themonitor specifically should verify that:

ii(i) The data required by the protocol are reported accurately on theCRFs and are consistent with the source documents.

i(ii) Any dose and/or therapy modifications are well documented foreach of the trial subjects.

(iii) Adverse events, concomitant medications and intercurrent ill-nesses are reported in accordance with the protocol on theCRFs.

(iv) Visits that the subjects fail to make, tests that are not con-ducted, and examinations that are not performed are clearlyreported as such on the CRFs.

i(v) All withdrawals and dropouts of enrolled subjects from the trialare reported and explained on the CRFs.

(n) Informing the investigator of any CRF entry error, omission, or illegi-bility. The monitor should ensure that appropriate corrections, addi-

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tions, or deletions are made, dated, explained (if necessary), and ini-tialled by the investigator or by a member of the investigator’s trialstaff who is authorized to initial CRF changes for the investigator. Thisauthorization should be documented.

(o) Determining whether all adverse events (AEs) are appropriatelyreported within the time periods required by GCP, the protocol, theIRB/IEC, the sponsor, and the applicable regulatory requirement(s).

(p) Determining whether the investigator is maintaining the essentialdocuments (see 8. Essential Documents for the Conduct of a ClinicalTrial).

(q) Communicating deviations from the protocol, SOPs, GCP, and theapplicable regulatory requirements to the investigator and takingappropriate action designed to prevent recurrence of the detecteddeviations.

5.18.5 Monitoring Procedures

The monitor(s) should follow the sponsor’s established written SOPs aswell as those procedures that are specified by the sponsor for monitoringa specific trial.

5.18.6 Monitoring Report

(a) The monitor should submit a written report to the sponsor after eachtrial-site visit or trial-related communication.

(b) Reports should include the date, site, name of the monitor, and nameof the investigator or other individual(s) contacted.

(c) Reports should include a summary of what the monitor reviewed andthe monitor’s statements concerning the significant findings/facts,deviations and deficiencies, conclusions, actions taken or to be takenand/or actions recommended to secure compliance.

(d) The review and follow-up of the monitoring report with the sponsorshould be documented by the sponsor’s designated representative.

5.19 AuditIf or when sponsors perform audits, as part of implementing quality assurance, theyshould consider:

5.19.1 Purpose

The purpose of a sponsor’s audit, which is independent of and separatefrom routine monitoring or quality control functions, should be to evaluatetrial conduct and compliance with the protocol, SOPs, GCP, and the applic-able regulatory requirements.

5.19.2 Selection and Qualification of Auditors

(a) The sponsor should appoint individuals, who are independent of theclinical trials/systems, to conduct audits.

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(b) The sponsor should ensure that the auditors are qualified by trainingand experience to conduct audits properly. An auditor’s qualificationsshould be documented.

5.19.3 Auditing Procedures

(a) The sponsor should ensure that the auditing of clinical trials/systemsis conducted in accordance with the sponsor’s written procedures onwhat to audit, how to audit, the frequency of audits, and the form andcontent of audit reports.

(b) The sponsor’s audit plan and procedures for a trial audit should beguided by the importance of the trial to submissions to regulatoryauthorities, the number of subjects in the trial, the type and com-plexity of the trial, the level of risks to the trial subjects, and anyidentified problem(s).

(c) The observations and findings of the auditor(s) should be docu-mented.

(d) To preserve the independence and value of the audit function, theregulatory authority(ies) should not routinely request the audit re-ports. Regulatory authority(ies) may seek access to an audit report on a case by case basis when evidence of serious GCP non-complianceexists, or in the course of legal proceedings.

(e) When required by applicable law or regulation, the sponsor shouldprovide an audit certificate.

5.20 Non-compliance5.20.1 Non-compliance with the protocol, SOPs, GCP, and/or applicable regulatory

requirement(s) by an investigator/institution, or by member(s) of thesponsor’s staff should lead to prompt action by the sponsor to secure com-pliance.

5.20.2 If the monitoring and/or auditing identifies serious and/or persistent non-compliance on the part of an investigator/institution, the sponsor shouldterminate the investigator’s/institution’s participation in the trial. Whenan investigator’s/institution’s participation is terminated because of non-compliance, the sponsor should notify promptly the regulatory au-thority(ies).

5.21 Premature Termination or Suspension of a TrialIf a trial is prematurely terminated or suspended, the sponsor should promptlyinform the investigators/institutions, and the regulatory authority(ies) of the ter-mination or suspension and the reason(s) for the termination or suspension. TheIRB/IEC should also be informed promptly and provided the reason(s) for the ter-mination or suspension by the sponsor or by the investigator/institution, as speci-fied by the applicable regulatory requirement(s).

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5.22 Clinical Trial/Study ReportsWhether the trial is completed or prematurely terminated, the sponsor shouldensure that the clinical trial reports are prepared and provided to the regulatoryagency(ies) as required by the applicable regulatory requirement(s). The sponsorshould also ensure that the clinical trial reports in marketing applications meet thestandards of the ICH Guideline for Structure and Content of Clinical Study Reports.(NOTE: The ICH Guideline for Structure and Content of Clinical Study Reports speci-fies that abbreviated study reports may be acceptable in certain cases.)

5.23 Multicentre TrialsFor multicentre trials, the sponsor should ensure that:

5.23.1 All investigators conduct the trial in strict compliance with the protocolagreed to by the sponsor and, if required, by the regulatory authority(ies),and given approval/favourable opinion by the IRB/IEC.

5.23.2 The CRFs are designed to capture the required data at all multicentre trialsites. For those investigators who are collecting additional data, supple-mental CRFs should also be provided that are designed to capture the addi-tional data.

5.23.3 The responsibilities of coordinating investigator(s) and the other partici-pating investigators are documented prior to the start of the trial.

5.23.4 All investigators are given instructions on following the protocol, on com-plying with a uniform set of standards for the assessment of clinical andlaboratory findings, and on completing the CRFs.

5.23.5 Communication between investigators is facilitated.

6. CLINICAL TRIAL PROTOCOL AND PROTOCOL AMENDMENT(S)The contents of a trial protocol should generally include the following topics.However, site specific information may be provided on separate protocol page(s),or addressed in a separate agreement, and some of the information listed below maybe contained in other protocol referenced documents, such as an Investigator’sBrochure.

6.1 General Information6.1.1 Protocol title, protocol identifying number, and date. Any amendment(s)

should also bear the amendment number(s) and date(s).

6.1.2 Name and address of the sponsor and monitor (if other than the sponsor).

6.1.3 Name and title of the person(s) authorized to sign the protocol and theprotocol amendment(s) for the sponsor.

6.1.4 Name, title, address, and telephone number(s) of the sponsor’s medicalexpert (or dentist when appropriate) for the trial.

6.1.5 Name and title of the investigator(s) who is (are) responsible for con-ducting the trial, and the address and telephone number(s) of the trialsite(s).

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6.1.6 Name, title, address, and telephone number(s) of the qualified physician(or dentist, if applicable), who is responsible for all trial-site related med-ical (or dental) decisions (if other than investigator).

6.1.7 Name(s) and address(es) of the clinical laboratory(ies) and other medicaland/or technical department(s) and/or institutions involved in the trial.

6.2 Background Information6.2.1 Name and description of the investigational product(s).

6.2.2 A summary of findings from non-clinical studies that potentially haveclinical significance and from clinical trials that are relevant to the trial.

6.2.3 Summary of the known and potential risks and benefits, if any, to humansubjects.

6.2.4 Description of and justification for the route of administration, dosage,dosage regimen, and treatment period(s).

6.2.5 A statement that the trial will be conducted in compliance with the pro-tocol, GCP and the applicable regulatory requirement(s).

6.2.6 Description of the population to be studied.

6.2.7 References to literature and data that are relevant to the trial, and thatprovide background for the trial.

6.3 Trial Objectives and PurposeA detailed description of the objectives and the purpose of the trial.

6.4 Trial DesignThe scientific integrity of the trial and the credibility of the data from the trialdepend substantially on the trial design. A description of the trial design, shouldinclude:

6.4.1 A specific statement of the primary endpoints and the secondary end-points, if any, to be measured during the trial.

6.4.2 A description of the type/design of trial to be conducted (e.g. double-blind, placebo-controlled, parallel design) and a schematic diagram of trialdesign, procedures and stages.

6.4.3 A description of the measures taken to minimise/avoid bias, including:

(a) Randomization.

(b) Blinding.

6.4.4 A description of the trial treatment(s) and the dosage and dosage regimenof the investigational product(s). Also include a description of the dosageform, packaging, and labelling of the investigational product(s).

6.4.5 The expected duration of subject participation, and a description of thesequence and duration of all trial periods, including follow-up, if any.

6.4.6 A description of the “stopping rules” or “discontinuation criteria” for indi-vidual subjects, parts of trial and entire trial.

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6.4.7 Accountability procedures for the investigational product(s), including theplacebo(s) and comparator(s), if any.

6.4.8 Maintenance of trial treatment randomization codes and procedures forbreaking codes.

6.4.9 The identification of any data to be recorded directly on the CRFs (i.e. noprior written or electronic record of data), and to be considered to besource data.

6.5 Selection and Withdrawal of Subjects6.5.1 Subject inclusion criteria.

6.5.2 Subject exclusion criteria.

6.5.3 Subject withdrawal criteria (i.e. terminating investigational product treat-ment/trial treatment) and procedures specifying:

(a) When and how to withdraw subjects from the trial/ investigationalproduct treatment.

(b) The type and timing of the data to be collected for withdrawn sub-jects.

(c) Whether and how subjects are to be replaced.

(d) The follow-up for subjects withdrawn from investigational producttreatment/trial treatment.

6.6 Treatment of Subjects6.6.1 The treatment(s) to be administered, including the name(s) of all the

product(s), the dose(s), the dosing schedule(s), the route/mode(s) ofadministration, and the treatment period(s), including the follow-upperiod(s) for subjects for each investigational product treatment/trialtreatment group/arm of the trial.

6.6.2 Medication(s)/treatment(s) permitted (including rescue medication) andnot permitted before and/or during the trial.

6.6.3 Procedures for monitoring subject compliance.

6.7 Assessment of Efficacy6.7.1 Specification of the efficacy parameters.

6.7.2 Methods and timing for assessing, recording, and analysing of efficacyparameters.

6.8 Assessment of Safety6.8.1 Specification of safety parameters.

6.8.2 The methods and timing for assessing, recording, and analysing safetyparameters.

6.8.3 Procedures for eliciting reports of and for recording and reporting adverseevent and intercurrent illnesses.

6.8.4 The type and duration of the follow-up of subjects after adverse events.

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6.9 Statistics6.9.1 A description of the statistical methods to be employed, including timing

of any planned interim analysis(ses).

6.9.2 The number of subjects planned to be enrolled. In multicentre trials, thenumbers of enrolled subjects projected for each trial site should be speci-fied. Reason for choice of sample size, including reflections on (or calcu-lations of) the power of the trial and clinical justification.

6.9.3 The level of significance to be used.

6.9.4 Criteria for the termination of the trial.

6.9.5 Procedure for accounting for missing, unused, and spurious data.

6.9.6 Procedures for reporting any deviation(s) from the original statistical plan(any deviation(s) from the original statistical plan should be described andjustified in protocol and/or in the final report, as appropriate).

6.9.7 The selection of subjects to be included in the analyses (e.g. all ran-domised subjects, all dosed subjects, all eligible subjects, evaluable sub-jects).

6.10 Direct Access to Source Data/DocumentsThe sponsor should ensure that it is specified in the protocol or other written agree-ment that the investigator(s)/institution(s) will permit trial-related monitoring,audits, IRB/IEC review, and regulatory inspection(s), providing direct access tosource data/documents.

6.11 Quality Control and Quality Assurance

6.12 EthicsDescription of ethical considerations relating to the trial.

6.13 Data Handling and Record Keeping

6.14 Financing and InsuranceFinancing and insurance if not addressed in a separate agreement.

6.15 Publication PolicyPublication policy, if not addressed in a separate agreement.

6.16 Supplements(NOTE: Since the protocol and the clinical trial/study report are closely related, fur-ther relevant information can be found in the ICH Guideline for Structure andContent of Clinical Study Reports.)

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7. INVESTIGATOR’S BROCHURE7.1 IntroductionThe Investigator’s Brochure (IB) is a compilation of the clinical and non-clinicaldata on the investigational product(s) that are relevant to the study of theproduct(s) in human subjects. Its purpose is to provide the investigators and othersinvolved in the trial with the information to facilitate their understanding of therationale for, and their compliance with, many key features of the protocol, such asthe dose, dose frequency/interval, methods of administration: and safety moni-toring procedures. The IB also provides insight to support the clinical managementof the study subjects during the course of the clinical trial. The information shouldbe presented in a concise, simple, objective, balanced, and non-promotional formthat enables a clinician, or potential investigator, to understand it and makehis/her own unbiased risk-benefit assessment of the appropriateness of the pro-posed trial. For this reason, a medically qualified person should generally partici-pate in the editing of an IB, but the contents of the IB should be approved by thedisciplines that generated the described data.

This guideline delineates the minimum information that should be included in anIB and provides suggestions for its layout. It is expected that the type and extentof information available will vary with the stage of development of the investiga-tional product. If the investigational product is marketed and its pharmacology iswidely understood by medical practitioners, an extensive IB may not be necessary.Where permitted by regulatory authorities, a basic product information brochure,package leaflet, or labelling may be an appropriate alternative, provided that itincludes current, comprehensive, and detailed information on all aspects of theinvestigational product that might be of importance to the investigator. If a mar-keted product is being studied for a new use (i.e. a new indication), an IB specificto that new use should be prepared. The IB should be reviewed at least annuallyand revised as necessary in compliance with a sponsor’s written procedures. Morefrequent revision may be appropriate depending on the stage of development andthe generation of relevant new information. However, in accordance with GoodClinical Practice, relevant new information may be so important that it should becommunicated to the investigators, and possibly to the Institutional Review Boards(IRBs)/Independent Ethics Committees (IECs) and/or regulatory authorities beforeit is included in a revised IB.

Generally, the sponsor is responsible for ensuring that an up-to-date IB is madeavailable to the investigator(s) and the investigators are responsible for providingthe up-to-date IB to the responsible IRBs/IECs. In the case of an investigator spon-sored trial, the sponsor-investigator should determine whether a brochure is avail-able from the commercial manufacturer. If the investigational product is providedby the sponsor-investigator, then he or she should provide the necessary informa-tion to the trial personnel. In cases where preparation of a formal IB is impractical,the sponsor-investigator should provide, as a substitute, an expanded backgroundinformation section in the trial protocol that contains the minimum current infor-mation described in this guideline.

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7.2 General ConsiderationsThe IB should include:

7.2.1 Title Page

This should provide the sponsor’s name, the identity of each investiga-tional product (i.e. research number, chemical or approved generic name,and trade name(s) where legally permissible and desired by the sponsor),and the release date. It is also suggested that an edition number, and areference to the number and date of the edition it supersedes, be provided.An example is given in Appendix 1.

7.2.2 Confidentiality Statement

The sponsor may wish to include a statement instructing the investi-gator/recipients to treat the IB as a confidential document for the soleinformation and use of the investigator’s team and the IRB/IEC.

7.3 Contents of the Investigator’s BrochureThe IB should contain the following sections, each with literature references whereappropriate:

7.3.1 Table of Contents

An example of the Table of Contents is given in Appendix 2

7.3.2 Summary

A brief summary (preferably not exceeding two pages) should be given,highlighting the significant physical, chemical, pharmaceutical, pharma-cological, toxicological, pharmacokinetic, metabolic, and clinical informa-tion available that is relevant to the stage of clinical development of theinvestigational product.

7.3.3 Introduction

A brief introductory statement should be provided that contains the chem-ical name (and generic and trade name(s) when approved) of the investi-gational product(s), all active ingredients, the investigational product(s)pharmacological class and its expected position within this class (e.g.advantages), the rationale for performing research with the investigationalproduct(s), and the anticipated prophylactic, therapeutic, or diagnosticindication(s). Finally, the introductory statement should provide the gen-eral approach to be followed in evaluating the investigational product.

7.3.4 Physical, Chemical, and Pharmaceutical Properties and Formulation

A description should be provided of the investigational product sub-stance(s) (including the chemical and/or structural formula(e)), and abrief summary should be given of the relevant physical, chemical, andpharmaceutical properties.

To permit appropriate safety measures to be taken in the course of thetrial, a description of the formulation(s) to be used, including excipients,should be provided and justified if clinically relevant. Instructions for thestorage and handling of the dosage form(s) should also be given.

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Any structural similarities to other known compounds should be men-tioned.

7.3.5 Non-clinical Studies

Introduction

The results of all relevant non-clinical pharmacology, toxicology, pharma-cokinetic, and investigational product metabolism studies should be pro-vided in summary form. This summary should address the methodologyused, the results, and a discussion of the relevance of the findings to theinvestigated therapeutic and the possible unfavourable and unintendedeffects in humans.

The information provided may include the following, as appropriate, ifknown/available:• Species tested• Number and sex of animals in each group• Unit dose (e.g., milligram/kilogram (mg/kg))• Dose interval• Route of administration• Duration of dosing• Information on systemic distribution• Duration of post-exposure follow-up• Results, including the following aspects:

– Nature and frequency of pharmacological or toxic effects– Severity or intensity of pharmacological or toxic effects– Time to onset of effects– Reversibility of effects– Duration of effects– Dose response

Tabular format/listings should be used whenever possible to enhance theclarity of the presentation.

The following sections should discuss the most important findings from thestudies, including the dose response of observed effects, the relevance tohumans, and any aspects to be studied in humans. If applicable, the effec-tive and non-toxic dose findings in the same animal species should becompared (i.e. the therapeutic index should be discussed). The relevanceof this information to the proposed human dosing should be addressed.Whenever possible, comparisons should be made in terms of blood/tissuelevels rather than on a mg/kg basis.

(a) Non-clinical Pharmacology

A summary of the pharmacological aspects of the investigationalproduct and, where appropriate, its significant metabolites studied in animals, should be included. Such a summary should incorporatestudies that assess potential therapeutic activity (e.g. efficacymodels, receptor binding, and specificity) as well as those that assess

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safety (e.g. special studies to assess pharmacological actions otherthan the intended therapeutic effect(s)).

(b) Pharmacokinetics and Product Metabolism in Animals

A summary of the pharmacokinetics and biological transformation anddisposition of the investigational product in all species studied shouldbe given. The discussion of the findings should address the absorp-tion and the local and systemic bioavailability of the investigationalproduct and its metabolites, and their relationship to the pharmaco-logical and toxicological findings in animal species.

(c) Toxicology

A summary of the toxicological effects found in relevant studies con-ducted in different animal species should be described under the fol-lowing headings where appropriate: – Single dose– Repeated dose– Carcinogenicity– Special studies (e.g. irritancy and sensitisation) – Reproductive toxicity– Genotoxicity (mutagenicity)

7.3.6 Effects in Humans

Introduction

A thorough discussion of the known effects of the investigationalproduct(s) in humans should be provided, including information on phar-macokinetics, metabolism, pharmacodynamics, dose response, safety, effi-cacy, and other pharmacological activities. Where possible, a summary ofeach completed clinical trial should be provided. Information should alsobe provided regarding results of any use of the investigational product(s)other than from in clinical trials, such as from experience during mar-keting.

(a) Pharmacokinetics and Product Metabolism in Humans

– A summary of information on the pharmacokinetics of the investi-gational product(s) should be presented, including the following, ifavailable:

– Pharmacokinetics (including metabolism, as appropriate, andabsorption, plasma protein binding, distribution, and elimination).

– Bioavailability of the investigational product (absolute, where pos-sible, and/or relative) using a reference dosage form.

– Population subgroups (e.g. gender, age, and impaired organ func-tion).

– Interactions (e.g. product-product interactions and effects offood).

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– Other pharmacokinetic data (e.g. results of population studies per-formed within clinical trial(s).

(b) Safety and Efficacy

A summary of information should be provided about the investiga-tional product’s/products’ (including metabolites, where appropriate)safety, pharmacodynamics, efficacy, and dose response that wereobtained from preceding trials in humans (healthy volunteers and/orpatients). The implications of this information should be discussed. Incases where a number of clinical trials have been completed, the useof summaries of safety and efficacy across multiple trials by indica-tions in subgroups may provide a clear presentation of the data.Tabular summaries of adverse drug reactions for all the clinical trials(including those for all the studied indications) would be useful.Important differences in adverse drug reaction patterns/incidencesacross indications or subgroups should be discussed.

The IB should provide a description of the possible risks and adversedrug reactions to be anticipated on the basis of prior experiences withthe product under investigation and with related products. A descrip-tion should also be provided of the precautions or special monitoringto be done as part of the investigational use of the product(s).

(c) Marketing Experience

The IB should identify countries where the investigational product hasbeen marketed or approved. Any significant information arising fromthe marketed use should be summarized (e.g. formulations, dosages,routes of administration, and adverse product reactions). The IBshould also identify all the countries where the investigationalproduct did not receive approval/registration for marketing or waswithdrawn from marketing/registration.

7.3.7 Summary of Data and Guidance for the Investigator

This section should provide an overall discussion of the non-clinical andclinical data, and should summarize the information from various sourceson different aspects of the investigational product(s), wherever possible.In this way, the investigator can be provided with the most informativeinterpretation of the available data and with an assessment of the impli-cations of the information for future clinical trials.

Where appropriate, the published reports on related products should bediscussed. This could help the investigator to anticipate adverse drug reac-tions or other problems in clinical trials.

The overall aim of this section is to provide the investigator with a clear under-standing of the possible risks and adverse reactions, and of the specific tests,observations, and precautions that may be needed for a clinical trial. Thisunderstanding should be based on the available physical, chemical, pharma-ceutical, pharmacological, toxicological, and clinical information on the in-

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vestigational product(s). Guidance should also be provided to the clinicalinvestigator on the recognition and treatment of possible overdose and adversedrug reactions that is based on previous human experience and on the phar-macology of the investigational product.

7.4 Appendix 1

TITLE PAGE (Example)

SPONSOR’S NAME

Product:Research Number:Name(s): Chemical, Generic (if approved)

Trade Name(s) (if legally permissible and desired by the sponsor)

INVESTIGATOR’S BROCHURE

Edition Number:

Release Date:

Replaces Previous Edition Number:

Date:

7.5 Appendix 2

TABLE OF CONTENTS OF INVESTIGATOR’S BROCHURE (Example)

– Confidentiality Statement (optional) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00– Signature Page (optional) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 001. Table of Contents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 002. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 003. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 004. Physical, Chemical, and Pharmaceutical Properties and Formulation . . . . 005. Non-clinical Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 005.1 Non-clinical Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 005.2 Pharmacokinetics and Product Metabolism in Animals . . . . . . . . . . . . . . . . . . . 005.3 Toxicology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 006. Effects in Humans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 006.1 Pharmacokinetics and Product Metabolism in Humans . . . . . . . . . . . . . . . . . . . 00

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6.2 Safety and Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 006.3 Marketing Experience . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 007. Summary of Data and Guidance for the Investigator . . . . . . . . . . . . . . . . . . . . . 00

NB: References on 1. Publications2. Reports

These references should be found at the end of each chapterAppendices (if any)

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8.ES

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8.2

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8.2.

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ial-

rela

ted

inju

ry w

ill b

e av

aila

ble

8.2.

6Si

gned

Agr

eem

ent

betw

een

Invo

lved

Par

ties

,To

doc

umen

t ag

reem

ents

XX

e.g.

:–

inve

stig

ator

/ins

titu

tion

and

spo

nsor

XX

–in

vest

igat

or/i

nsti

tuti

on a

nd C

ROX

X–

spon

sor

and

CRO

X(w

here

re

quire

d)–

inve

stig

ator

/ins

titu

tion

and

aut

hori

ty(i

es)

X(w

here

req

uire

d)X

8.2.

7Da

ted,

Doc

umen

ted

Appr

oval

/Fav

oura

ble

To d

ocum

ent

that

the

tria

l has

bee

n su

bjec

t to

X

XOp

inio

n of

Ins

titu

tion

al R

evie

w B

oard

(IR

B)/

IRB/

IEC

revi

ew a

nd g

iven

app

rova

l/fa

vour

able

In

depe

nden

t Et

hics

Com

mit

tee

(IEC

) of

the

op

inio

n. T

o id

enti

fy t

he v

ersi

on n

umbe

r an

d fo

llow

ing:

date

of

the

docu

men

t(s)

–pr

otoc

ol a

nd a

ny a

men

dmen

ts–

CRF

(if

appl

icab

le)

–in

form

ed c

onse

nt f

orm

(s)

–an

y ot

her

wri

tten

inf

orm

atio

n to

be

prov

ided

to

the

sub

ject

(s)

–ad

vert

isem

ent

for

subj

ect

recr

uitm

ent

(if

used

)–

subj

ect

com

pens

atio

n (i

f an

y)–

any

othe

r do

cum

ents

giv

en a

ppro

val/

fa

vour

able

opi

nion

3020-TDR-WkBk-m13.XP4 8/26/02 16:39 Page 109


WOR

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K FO

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VEST

IGAT

ORS

• SE

CTIO

N 1

8.2.

8In

stit

utio

nal

Revi

ew B

oard

/Ind

epen

dent

To

doc

umen

t th

at t

he I

RB/I

EC i

s co

nsti

tute

d X

XEt

hics

Com

mit

tee

Com

posi

tion

in a

gree

men

t w

ith

GCP

(whe

re

requ

ired)

8.2.

9Re

gula

tory

Aut

hori

ty(i

es)

To d

ocum

ent

appr

opria

te a

utho

riza

tion

/X

XAu

thor

izat

ion/

Appr

oval

/Not

ific

atio

nap

prov

al/n

otif

icat

ion

by t

he r

egul

ator

y (w

here

(w

here

of

Pro

toco

lau

thor

ity(

ies)

has

bee

n ob

tain

ed p

rior

to

requ

ired)

requ

ired)

(whe

re r

equi

red)

init

iati

on o

f th

e tr

ial i

n co

mpl

ianc

e w

ith

the

appl

icab

le r

egul

ator

y re

quire

men

t(s)

8.2.

10Cu

rric

ulum

Vit

ae a

nd/o

r Ot

her

Rele

vant

To

doc

umen

t qu

alif

icat

ions

and

elig

ibili

ty t

o X

XDo

cum

ents

evi

denc

ing

Qual

ific

atio

ns o

f co

nduc

t tr

ial a

nd/o

r pr

ovid

e m

edic

al

Inve

stig

ator

(s)

and

Sub-

Inve

stig

ator

(s)

supe

rvis

ion

of s

ubje

cts

8.2.

11N

orm

al V

alue

(s)/

rang

e(s)

for

Med

ical

/ To

doc

umen

t no

rmal

val

ues

and/

or r

ange

s of

X

XLa

bora

tory

/Tec

hnic

al P

roce

dure

(s)

and/

or

the

test

sTe

st(s

) in

clud

ed i

n th

e Pr

otoc

ol

8.2.

12M

edic

al/L

abor

ator

y/Te

chni

cal

Proc

edur

es/

To d

ocum

ent

com

pete

nce

of f

acili

ty t

o pe

rfor

m

XX

Test

sre

quire

d te

st(s

), a

nd s

uppo

rt r

elia

bilit

y of

(w

here

–

cert

ific

atio

n or

resu

lts

requ

ired)

–ac

cred

itat

ion

or–

esta

blis

hed

qual

ity

cont

rol a

nd/o

r ex

tern

al

qual

ity

asse

ssm

ent

or–

othe

r va

lidat

ion

(whe

re r

equi

red)

Titl

e of

Doc

umen

tPu

rpos

eLo

cate

d in

File

s of

Inve

stig

ator

/Sp

onso

rIn

stit

utio

n

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WOR

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VEST

IGAT

ORS

• SE

CTIO

N 1

8.2.

13Sa

mpl

e of

Lab

el(s

) at

tach

ed t

o in

vest

i-To

doc

umen

t co

mpl

ianc

e w

ith

appl

icab

le

Xga

tion

al p

rodu

ct c

onta

iner

(s)

labe

lling

reg

ulat

ions

and

app

ropr

iate

ness

of

inst

ruct

ions

pro

vide

d to

the

sub

ject

s

8.2.

14In

stru

ctio

ns f

or H

andl

ing

of I

nves

tiga

tion

al

To d

ocum

ent

inst

ruct

ions

nee

ded

to e

nsur

e X

XPr

oduc

t(s)

and

Tri

al-R

elat

ed M

ater

ials

prop

er s

tora

ge,

pack

agin

g, d

ispe

nsin

g an

d (i

f no

t in

clud

ed i

n Pr

otoc

ol o

r In

vest

igat

or’s

disp

osit

ion

of i

nves

tiga

tion

al p

rodu

cts

and

Broc

hure

)tr

ial-

rela

ted

mat

eria

ls

8.2.

15Sh

ippi

ng R

ecor

ds f

or I

nves

tiga

tion

al

To d

ocum

ent

ship

men

t da

tes,

bat

ch n

umbe

rs

XX

Prod

uct(

s) a

nd T

rial

-Rel

ated

Mat

eria

lsan

d m

etho

d of

shi

pmen

t of

inv

esti

gati

onal

pr

oduc

t(s)

and

tria

l-re

late

d m

ater

ials

. Al

low

s tr

acki

ng o

f pr

oduc

t ba

tch,

rev

iew

of

ship

ping

co

ndit

ions

, an

d ac

coun

tabi

lity

8.2.

16Ce

rtif

icat

e(s)

of

Anal

ysis

of

Inve

stig

atio

nal

To d

ocum

ent

iden

tity

, pu

rity

, an

d st

reng

th o

f X

Prod

uct(

s) S

hipp

edin

vest

igat

iona

l pro

duct

(s)

to b

e us

ed i

n th

e tr

ial

8.2.

17De

codi

ng P

roce

dure

s fo

r Bl

inde

d Tr

ials

To d

ocum

ent

how,

in

case

of

an e

mer

genc

y,

XX

iden

tity

of

blin

ded

inve

stig

atio

nal p

rodu

ct c

an

(thi

rd

be r

evea

led

wit

hout

bre

akin

g th

e bl

ind

for

the

part

y if

rem

aini

ng s

ubje

cts’

trea

tmen

tap

plic

able

)

8.2.

18M

aste

r Ra

ndom

izat

ion

List

To d

ocum

ent

met

hod

for

rand

omiz

atio

n of

tria

l X

popu

lati

on(t

hird

pa

rty

ifap

plic

able

)

8.2.

19Pr

e-Tr

ial

Mon

itor

ing

Repo

rtTo

doc

umen

t th

at t

he s

ite

is s

uita

ble

for

the

Xtr

ial (

may

be

com

bine

d w

ith

8.2.

20)

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WOR

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IGAT

ORS

• SE

CTIO

N 1

8.2.

20Tr

ial

Init

iati

on M

onit

orin

g Re

port

To d

ocum

ent

that

tria

l pro

cedu

res

wer

e re

view

ed

XX

wit

h th

e in

vest

igat

or a

nd t

he i

nves

tiga

tor’s

tr

ial s

taff

(m

ay b

e co

mbi

ned

wit

h 8.

2.19

)

8.3

Duri

ng t

he C

linic

al C

ondu

ct o

f th

e Tr

ial

In a

ddit

ion

to h

avin

g on

file

the

abo

ve d

ocum

ents

, th

e fo

llow

ing

shou

ld b

e ad

ded

to t

he f

iles

duri

ng t

he t

rial

as e

vide

nce

that

all

new

re

leva

nt i

nfor

mat

ion

is d

ocum

ente

d as

it

beco

mes

ava

ilabl

e

Titl

e of

Doc

umen

tPu

rpos

eLo

cate

d in

File

s of

Inve

stig

ator

/Sp

onso

rIn

stit

utio

n

8.3.

1In

vest

igat

or’s

Bro

chur

e U

pdat

esTo

doc

umen

t th

at i

nves

tiga

tor

is i

nfor

med

in

XX

a ti

mel

y m

anne

r of

rel

evan

t in

form

atio

n as

it

beco

mes

ava

ilabl

e

8.3.

2An

y Re

visi

on t

o:To

doc

umen

t re

visi

ons

of t

hese

tria

l rel

ated

X

X–

prot

ocol

/am

endm

ent(

s) a

nd C

RFdo

cum

ents

tha

t ta

ke e

ffec

t du

ring

tria

l–

info

rmed

con

sent

for

m–

any

othe

r w

ritt

en i

nfor

mat

ion

prov

ided

to

subj

ects

–ad

vert

isem

ent

for

subj

ect

recr

uitm

ent

(if

used

)

Titl

e of

Doc

umen

tPu

rpos

eLo

cate

d in

File

s of

Inve

stig

ator

/Sp

onso

rIn

stit

utio

n

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WOR

KBOO

K FO

R IN

VEST

IGAT

ORS

• SE

CTIO

N 1

8.3.

3Da

ted,

Doc

umen

ted

Appr

oval

/Fav

oura

ble

To d

ocum

ent

that

the

am

endm

ent(

s) a

nd/o

r X

XOp

inio

n of

Ins

titu

tion

al R

evie

w B

oard

(IR

B)/

revi

sion

(s)

have

bee

n su

bjec

t to

IRB

/IEC

In

depe

nden

t Et

hics

Com

mit

tee

(IEC

) of

the

re

view

and

wer

e gi

ven

appr

oval

/fav

oura

ble

follo

win

g:op

inio

n. T

o id

enti

fy t

he v

ersi

on n

umbe

r an

d –

prot

ocol

am

endm

ent(

s)da

te o

f th

e do

cum

ent(

s)–

revi

sion

(s)

of:

–in

form

ed c

onse

nt f

orm

–an

y ot

her

wri

tten

inf

orm

atio

n to

be

prov

ided

to

the

subj

ect

–ad

vert

isem

ent

for

subj

ect

recr

uitm

ent

(if

used

) –

any

othe

r do

cum

ents

giv

en a

ppro

val/

favo

urab

le o

pini

on–

cont

inui

ng r

evie

w o

f tr

ial (

whe

re r

equi

red)

8.3.

4Re

gula

tory

Aut

hori

ty(i

es)

Auth

oriz

atio

ns/

To d

ocum

ent

com

plia

nce

wit

h ap

plic

able

X

XAp

prov

als/

Not

ific

atio

ns w

here

req

uire

d fo

r:re

gula

tory

req

uire

men

ts(w

here

–

prot

ocol

am

endm

ent(

s) a

nd o

ther

doc

umen

tsre

quire

d)

8.3.

5Cu

rric

ulum

Vit

ae f

or N

ew I

nves

tiga

tor(

s)

(see

8.2

.10)

XX

and/

or S

ub-I

nves

tiga

tor(

s)

8.3.

6U

pdat

es t

o N

orm

al V

alue

(s)/

Rang

e(s)

for

To

doc

umen

t no

rmal

val

ues

and

rang

es t

hat

are

XX

Med

ical

/ La

bora

tory

/ Te

chni

cal

Proc

edur

e(s)

/re

vise

d du

ring

the

tria

l (se

e 8.

2.11

)te

st(s

) in

clud

ed i

n th

e Pr

otoc

ol

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WOR

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R IN

VEST

IGAT

ORS

• SE

CTIO

N 1

8.3.

7U

pdat

es o

f M

edic

al/L

abor

ator

y/Te

chni

cal

To d

ocum

ent

that

tes

ts r

emai

n ad

equa

te

XX

Proc

edur

es/T

ests

thro

ugho

ut t

he t

rial p

erio

d (s

ee 8

.2.1

2)(w

here

–

cert

ific

atio

n or

requ

ired)

–ac

cred

itat

ion

or–

esta

blis

hed

qual

ity

cont

rol a

nd/o

r ex

tern

al

qual

ity

asse

ssm

ent

or–

othe

r va

lidat

ion

(whe

re r

equi

red)

8.3.

8Do

cum

enta

tion

of

Inve

stig

atio

nal

Prod

uct(

s)

(see

8.2

.15)

XX

and

Tria

l-Re

late

d M

ater

ials

Shi

pmen

t

8.3.

9Ce

rtif

icat

e(s)

of

Anal

ysis

for

New

Bat

ches

(s

ee 8

.2.1

6)X

of I

nves

tiga

tion

al P

rodu

cts

8.3.

10M

onit

orin

g Vi

sit

Repo

rts

To d

ocum

ent

site

vis

its

by,

and

find

ings

of,

X

the

mon

itor

8.3.

11Re

leva

nt C

omm

unic

atio

ns o

ther

tha

n To

doc

umen

t an

y ag

reem

ents

or

sign

ific

ant

XX

Site

Vis

its

disc

ussi

ons

rega

rdin

g tr

ial a

dmin

istr

atio

n,

–le

tter

spr

otoc

ol v

iola

tion

s, t

rial c

ondu

ct,

adve

rse

–m

eeti

ng n

otes

even

t (A

E) r

epor

ting

–no

tes

of t

elep

hone

cal

ls

8.3.

12Si

gned

Inf

orm

ed C

onse

nt F

orm

sTo

doc

umen

t th

at c

onse

nt i

s ob

tain

ed i

n X

acco

rdan

ce w

ith

GCP

and

prot

ocol

and

dat

ed

prio

r to

par

tici

pati

on o

f ea

ch s

ubje

ct i

n tr

ial.

Also

to

docu

men

t di

rect

acc

ess

perm

issi

on

(see

8.2

.3)

Titl

e of

Doc

umen

tPu

rpos

eLo

cate

d in

File

s of

Inve

stig

ator

/Sp

onso

rIn

stit

utio

n

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WOR

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R IN

VEST

IGAT

ORS

• SE

CTIO

N 1

8.3.

13So

urce

Doc

umen

tsTo

doc

umen

t th

e ex

iste

nce

of t

he s

ubje

ct a

nd

Xsu

bsta

ntia

te i

nteg

rity

of

tria

l dat

a co

llect

ed.

To

incl

ude

orig

inal

doc

umen

ts r

elat

ed t

o th

e tr

ial,

to m

edic

al t

reat

men

t, a

nd h

isto

ry o

f su

bjec

t

8.3.

14Si

gned

, da

ted

and

Com

plet

edTo

doc

umen

t th

at t

he i

nves

tiga

tor

or a

utho

rize

d X

XCa

se R

epor

t Fo

rms

(CRF

)m

embe

r of

the

inv

esti

gato

r’s s

taff

con

firm

s th

e (c

opy)

(orig

inal

)ob

serv

atio

ns r

ecor

ded

8.3.

15Do

cum

enta

tion

of

CRF

Corr

ecti

ons

To d

ocum

ent

all c

hang

es/a

ddit

ions

or

corr

ec-

XX

tion

s m

ade

to C

RF a

fter

ini

tial

dat

a w

ere

reco

rded

(cop

y)(o

rigin

al)

8.3.

16N

otif

icat

ion

by O

rigi

nati

ng I

nves

tiga

tor

to

Noti

ficat

ion

by o

rigin

atin

g in

vest

igat

or t

o X

XSp

onso

r of

Ser

ious

Adv

erse

Eve

nts

and

spon

sor

of s

erio

us a

dver

se e

vent

s an

d re

late

d Re

late

d Re

port

sre

port

s in

acc

orda

nce

wit

h 4.

11

8.3.

17N

otif

icat

ion

by S

pons

or a

nd/o

r In

vest

igat

or,

Noti

ficat

ion

by s

pons

or a

nd/o

r in

vest

igat

or,

Xw

here

app

licab

le,

to R

egul

ator

y Au

thor

ity(

ies)

w

here

app

licab

le,

to r

egul

ator

y au

thor

itie

s an

d (w

here

an

d IR

B(s)

/IEC

(s)

of U

nexp

ecte

d Se

riou

s IR

B(s)

/IEC

(s)

of u

nexp

ecte

d se

rious

adv

erse

re

quire

d)Ad

vers

e Dr

ug R

eact

ions

and

of

Othe

r Sa

fety

dr

ug r

eact

ions

in

acco

rdan

ce w

ith

5.17

and

In

form

atio

n4.

11.1

and

of

othe

r sa

fety

inf

orm

atio

n in

ac

cord

ance

wit

h 5.

16.2

and

4.1

1.2

8.3.

18N

otif

icat

ion

by S

pons

or t

o In

vest

igat

ors

of

Noti

ficat

ion

by s

pons

or t

o in

vest

igat

ors

of

XX

Safe

ty I

nfor

mat

ion

safe

ty i

nfor

mat

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8.3.

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8.4

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8.4.

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ICH Guidelines • Statistical Principles for Clinical trials (E9) • 119

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FOR HUMAN USE


STATISTICAL PRINCIPLES FORCLINICAL TRIALS


on 5 February 1998by the ICH Steering Committee


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120 • ICH Guidelines • Statistical Principles for Clinical trials (E9)

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STATISTICAL PRINCIPLES FOR CLINICAL TRIALS


ICH Steering Committee meeting on 5 February 1998, this guideline is recommended for adoption


TABLE OF CONTENTS

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1221.1 Background and Purpose . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1221.2 Scope and Direction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123

2. Considerations for Overall Clinical Development . . . . . . . . . . . . . . . . . . . . . . 1242.1 Trial Context . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124

2.1.1 Development Plan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1242.1.2 Confirmatory Trial . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1252.1.3 Exploratory Trial . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125

2.2 Scope of Trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1262.2.1 Population . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1262.2.2 Primary and Secondary Variables . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1262.2.3 Composite Variables . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1272.2.4 Global Assessment Variables . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1282.2.5 Multiple Primary Variables . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1282.2.6 Surrogate Variables . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1292.2.7 Categorized Variables . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129

2.3 Design Techniques to Avoid Bias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1302.3.1 Blinding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1302.3.2 Randomization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131

3. Trial Design Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1333.1 Design Configuration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133

3.1.1 Parallel Group Design . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1333.1.2 Cross-over Design . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1333.1.3 Factorial Designs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 134

3.2 Multicentre Trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1353.3 Type of Comparison . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137

3.3.1 Trials to Show Superiority . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1373.3.2 Trials to Show Equivalence or Non-inferiority . . . . . . . . . . . . . . 1373.3.3 Trials to Show Dose-response Relationship . . . . . . . . . . . . . . . . . 139

3.4 Group Sequential Designs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1393.5 Sample Size . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1403.6 Data Capture and Processing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141

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4. Trial Conduct Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1424.1 Trial Monitoring and Interim Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1424.2 Changes in Inclusion and Exclusion Criteria . . . . . . . . . . . . . . . . . . . . . . . . 1424.3 Accrual Rates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1434.4 Sample Size Adjustment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1434.5 Interim Analysis and Early Stopping . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1434.6 Role of Independent Data Monitoring Committee (IDMC) . . . . . . . . . 145

5. Data Analysis Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1455.1 Prespecification of the Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1455.2 Analysis Sets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146

5.2.1 Full Analysis Set . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1465.2.2 Per Protocol Set . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1485.2.3 Roles of the Different Analysis Sets . . . . . . . . . . . . . . . . . . . . . . . . 148

5.3 Missing Values and Outliers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1495.4 Data Transformation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1505.5 Estimation, Confidence Intervals and Hypothesis Testing . . . . . . . . . . 1505.6 Adjustment of Significance and Confidence Levels . . . . . . . . . . . . . . . . . 1515.7 Subgroups, Interactions and Covariates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1515.8 Integrity of Data and Computer Software Validity . . . . . . . . . . . . . . . . . . 152

6. Evaluation of Safety and Tolerability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1526.1 Scope of Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1526.2 Choice of Variables and Data Collection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1536.3 Set of Subjects to be Evaluated and Presentation of Data . . . . . . . . . 1536.4 Statistical Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1546.5 Integrated Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155

7. Reporting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1557.1 Evaluation and Reporting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1557.2 Summarizing the Clinical Database . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157

7.2.1 Efficacy Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1577.2.2 Safety Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158

Glossary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159

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STATISTICAL PRINCIPLES FOR CLINICAL TRIALS

1. INTRODUCTION1.1 Background and PurposeThe efficacy and safety of medicinal products should be demonstrated by clinicaltrials which follow the guidance in ‘Good Clinical Practice: Consolidated Guideline’(ICH E6) adopted by the ICH, 1 May 1996. The role of statistics in clinical trialdesign and analysis is acknowledged as essential in that ICH guideline. The proli-feration of statistical research in the area of clinical trials coupled with the criticalrole of clinical research in the drug approval process and health care in generalnecessitate a succinct document on statistical issues related to clinical trials. Thisguidance is written primarily to attempt to harmonize the principles of statisticalmethodology applied to clinical trials for marketing applications submitted inEurope, Japan and the United States.

As a starting point, this guideline utilized the CPMP (Committee for ProprietaryMedicinal Products) Note for Guidance entitled ‘Biostatistical Methodology inClinical Trials in Applications for Marketing Authorizations for Medicinal Products’(December, 1994). It was also influenced by ‘Guidelines on the Statistical Analysisof Clinical Studies’ (March, 1992) from the Japanese Ministry of Health and Welfareand the U.S. Food and Drug Administration document entitled ‘Guideline for theFormat and Content of the Clinical and Statistical Sections of a New DrugApplication’ (July, 1988). Some topics related to statistical principles and method-ology are also embedded within other ICH guidelines, particularly those listedbelow. The specific guidance that contains related text will be identified in varioussections of this document.

E1A: The Extent of Population Exposure to Assess Clinical Safety

E2A: Clinical Safety Data Management: Definitions and Standards for ExpeditedReporting

E2B: Clinical Safety Data Management: Data Elements for Transmission ofIndividual Case Safety Reports

E2C: Clinical Safety Data Management: Periodic Safety Update Reports forMarketed Drugs

E3: Structure and Content of Clinical Study Reports

E4: Dose-Response Information to Support Drug Registration

E5: Ethnic Factors in the Acceptability of Foreign Clinical Data

E6: Good Clinical Practice: Consolidated Guideline

E7: Studies in Support of Special Populations: Geriatrics

E8: General Considerations for Clinical Trials

E10: Choice of Control Group in Clinical Trials

M1: Standardization of Medical Terminology for Regulatory Purposes

M3: Non-Clinical Safety Studies for the Conduct of Human Clinical Trials forPharmaceuticals.

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This guidance is intended to give direction to sponsors in the design, conduct,analysis, and evaluation of clinical trials of an investigational product in the con-text of its overall clinical development. The document will also assist scientificexperts charged with preparing application summaries or assessing evidence of effi-cacy and safety, principally from clinical trials in later phases of development.

1.2 Scope and DirectionThe focus of this guidance is on statistical principles. It does not address the useof specific statistical procedures or methods. Specific procedural steps to ensurethat principles are implemented properly are the responsibility of the sponsor.Integration of data across clinical trials is discussed, but is not a primary focus ofthis guidance. Selected principles and procedures related to data management orclinical trial monitoring activities are covered in other ICH guidelines and are notaddressed here.

This guidance should be of interest to individuals from a broad range of scientificdisciplines. However, it is assumed that the actual responsibility for all statisticalwork associated with clinical trials will lie with an appropriately qualified and expe-rienced statistician, as indicated in ICH E6. The role and responsibility of the trialstatistician (see Glossary), in collaboration with other clinical trial professionals, isto ensure that statistical principles are applied appropriately in clinical trials sup-porting drug development. Thus, the trial statistician should have a combination ofeducation/training and experience sufficient to implement the principles articu-lated in this guidance.

For each clinical trial contributing to a marketing application, all important detailsof its design and conduct and the principal features of its proposed statisticalanalysis should be clearly specified in a protocol written before the trial begins. Theextent to which the procedures in the protocol are followed and the primary analysisis planned a priori will contribute to the degree of confidence in the final resultsand conclusions of the trial. The protocol and subsequent amendments should beapproved by the responsible personnel, including the trial statistician. The trial sta-tistician should ensure that the protocol and any amendments cover all relevant sta-tistical issues clearly and accurately, using technical terminology as appropriate.

The principles outlined in this guidance are primarily relevant to clinical trials con-ducted in the later phases of development, many of which are confirmatory trials ofefficacy. In addition to efficacy, confirmatory trials may have as their primary vari-able a safety variable (e.g. an adverse event, a clinical laboratory variable or anelectrocardiographic measure), a pharmacodynamic or a pharmacokinetic variable(as in a confirmatory bioequivalence trial). Furthermore, some confirmatory findingsmay be derived from data integrated across trials, and selected principles in thisguidance are applicable in this situation. Finally, although the early phases of drugdevelopment consist mainly of clinical trials that are exploratory in nature, statis-tical principles are also relevant to these clinical trials. Hence, the substance of thisdocument should be applied as far as possible to all phases of clinical development.

Many of the principles delineated in this guidance deal with minimizing bias (seeGlossary) and maximizing precision. As used in this guidance, the term ‘bias’

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describes the systematic tendency of any factors associated with the design,conduct, analysis and interpretation of the results of clinical trials to make theestimate of a treatment effect (see Glossary) deviate from its true value. It is im-portant to identify potential sources of bias as completely as possible so thatattempts to limit such bias may be made. The presence of bias may seriously com-promise the ability to draw valid conclusions from clinical trials.

Some sources of bias arise from the design of the trial, for example an assignmentof treatments such that subjects at lower risk are systematically assigned to onetreatment. Other sources of bias arise during the conduct and analysis of a clinicaltrial. For example, protocol violations and exclusion of subjects from analysis basedupon knowledge of subject outcomes are possible sources of bias that may affectthe accurate assessment of the treatment effect. Because bias can occur in subtleor unknown ways and its effect is not measurable directly, it is important to eval-uate the robustness of the results and primary conclusions of the trial. Robustnessis a concept that refers to the sensitivity of the overall conclusions to variouslimitations of the data, assumptions, and analytic approaches to data analysis.Robustness implies that the treatment effect and primary conclusions of the trialare not substantially affected when analyses are carried out based on alternativeassumptions or analytic approaches. The interpretation of statistical measures ofuncertainty of the treatment effect and treatment comparisons should involve con-sideration of the potential contribution of bias to the p-value, confidence interval,or inference.

Because the predominant approaches to the design and analysis of clinical trialshave been based on frequentist statistical methods, the guidance largely refers tothe use of frequentist methods (see Glossary) when discussing hypothesis testingand/or confidence intervals. This should not be taken to imply that otherapproaches are not appropriate: the use of Bayesian (see Glossary) and otherapproaches may be considered when the reasons for their use are clear and whenthe resulting conclusions are sufficiently robust.

2. CONSIDERATIONS FOR OVERALL CLINICAL DEVELOPMENT2.1 Trial Context2.1.1 DEVELOPMENT PLAN

The broad aim of the process of clinical development of a new drug is to find outwhether there is a dose range and schedule at which the drug can be shown to besimultaneously safe and effective, to the extent that the risk-benefit relationshipis acceptable. The particular subjects who may benefit from the drug, and the spe-cific indications for its use, also need to be defined.

Satisfying these broad aims usually requires an ordered programme of clinical trials,each with its own specific objectives (see ICH E8). This should be specified in aclinical plan, or a series of plans, with appropriate decision points and flexibility to allow modification as knowledge accumulates. A marketing application shouldclearly describe the main content of such plans, and the contribution made by eachtrial. Interpretation and assessment of the evidence from the total programme of

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trials involves synthesis of the evidence from the individual trials (see Section 7.2).This is facilitated by ensuring that common standards are adopted for a number offeatures of the trials such as dictionaries of medical terms, definition and timing ofthe main measurements, handling of protocol deviations and so on. A statisticalsummary, overview or meta-analysis (see Glossary) may be informative when medi-cal questions are addressed in more than one trial. Where possible this should beenvisaged in the plan so that the relevant trials are clearly identified and anynecessary common features of their designs are specified in advance. Other majorstatistical issues (if any) that are expected to affect a number of trials in a com-mon plan should be addressed in that plan.

2.1.2 CONFIRMATORY TRIAL

A confirmatory trial is an adequately controlled trial in which the hypotheses arestated in advance and evaluated. As a rule, confirmatory trials are necessary to pro-vide firm evidence of efficacy or safety. In such trials the key hypothesis of interestfollows directly from the trial’s primary objective, is always pre-defined, and is thehypothesis that is subsequently tested when the trial is complete. In a confirma-tory trial it is equally important to estimate with due precision the size of theeffects attributable to the treatment of interest and to relate these effects to theirclinical significance.

Confirmatory trials are intended to provide firm evidence in support of claims andhence adherence to protocols and standard operating procedures is particularlyimportant; unavoidable changes should be explained and documented, and theireffect examined. A justification of the design of each such trial, and of other impor-tant statistical aspects such as the principal features of the planned analysis,should be set out in the protocol. Each trial should address only a limited numberof questions.

Firm evidence in support of claims requires that the results of the confirmatorytrials demonstrate that the investigational product under test has clinical benefits.The confirmatory trials should therefore be sufficient to answer each key clinicalquestion relevant to the efficacy or safety claim clearly and definitively. In addi-tion, it is important that the basis for generalization (see Glossary) to the intendedpatient population is understood and explained; this may also influence the numberand type (e.g. specialist or general practitioner) of centres and/or trials needed. Theresults of the confirmatory trial(s) should be robust. In some circumstances theweight of evidence from a single confirmatory trial may be sufficient.

2.1.3 EXPLORATORY TRIAL

The rationale and design of confirmatory trials nearly always rests on earlier clin-ical work carried out in a series of exploratory studies. Like all clinical trials, theseexploratory studies should have clear and precise objectives. However, in contrastto confirmatory trials, their objectives may not always lead to simple tests of pre-defined hypotheses. In addition, exploratory trials may sometimes require a moreflexible approach to design so that changes can be made in response to accumu-lating results. Their analysis may entail data exploration; tests of hypothesis maybe carried out, but the choice of hypothesis may be data dependent. Such trials

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cannot be the basis of the formal proof of efficacy, although they may contributeto the total body of relevant evidence.

Any individual trial may have both confirmatory and exploratory aspects. Forexample, in most confirmatory trials the data are also subjected to exploratoryanalyses which serve as a basis for explaining or supporting their findings and forsuggesting further hypotheses for later research. The protocol should make a cleardistinction between the aspects of a trial which will be used for confirmatory proofand the aspects which will provide data for exploratory analysis.

2.2 Scope of Trials2.2.1 POPULATION

In the earlier phases of drug development the choice of subjects for a clinical trialmay be heavily influenced by the wish to maximize the chance of observing specificclinical effects of interest, and hence they may come from a very narrow subgroupof the total patient population for which the drug may eventually be indicated.However by the time the confirmatory trials are undertaken, the subjects in thetrials should more closely mirror the target population. Hence, in these trials it isgenerally helpful to relax the inclusion and exclusion criteria as much as possiblewithin the target population, while maintaining sufficient homogeneity to permitprecise estimation of treatment effects. No individual clinical trial can be expectedto be totally representative of future users, because of the possible influences ofgeographical location, the time when it is conducted, the medical practices of theparticular investigator(s) and clinics, and so on. However the influence of such fac-tors should be reduced wherever possible, and subsequently discussed during theinterpretation of the trial results.

2.2.2 PRIMARY AND SECONDARY VARIABLES

The primary variable (‘target’ variable, primary endpoint) should be the variablecapable of providing the most clinically relevant and convincing evidence directlyrelated to the primary objective of the trial. There should generally be only one pri-mary variable. This will usually be an efficacy variable, because the primary objec-tive of most confirmatory trials is to provide strong scientific evidence regardingefficacy. Safety/tolerability may sometimes be the primary variable, and will alwaysbe an important consideration. Measurements relating to quality of life and healtheconomics are further potential primary variables. The selection of the primary vari-able should reflect the accepted norms and standards in the relevant field ofresearch. The use of a reliable and validated variable with which experience hasbeen gained either in earlier studies or in published literature is recommended.There should be sufficient evidence that the primary variable can provide a validand reliable measure of some clinically relevant and important treatment benefit inthe patient population described by the inclusion and exclusion criteria. The pri-mary variable should generally be the one used when estimating the sample size(see Section 3.5).

In many cases, the approach to assessing subject outcome may not be straightfor-ward and should be carefully defined. For example, it is inadequate to specify mor-

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tality as a primary variable without further clarification; mortality may be assessedby comparing proportions alive at fixed points in time, or by comparing overall dis-tributions of survival times over a specified interval. Another common example is arecurring event; the measure of treatment effect may again be a simple dichoto-mous variable (any occurrence during a specified interval), time to first occurrence,rate of occurrence (events per time units of observation), etc. The assessment offunctional status over time in studying treatment for chronic disease presents otherchallenges in selection of the primary variable. There are many possible approaches,such as comparisons of the assessments done at the beginning and end of theinterval of observation, comparisons of slopes calculated from all assessmentsthroughout the interval, comparisons of the proportions of subjects exceeding ordeclining beyond a specified threshold, or comparisons based on methods forrepeated measures data. To avoid multiplicity concerns arising from post hoc defi-nitions, it is critical to specify in the protocol the precise definition of the primaryvariable as it will be used in the statistical analysis. In addition, the clinical rele-vance of the specific primary variable selected and the validity of the associatedmeasurement procedures will generally need to be addressed and justified in theprotocol.

The primary variable should be specified in the protocol, along with the rationalefor its selection. Redefinition of the primary variable after unblinding will almostalways be unacceptable, since the biases this introduces are difficult to assess.When the clinical effect defined by the primary objective is to be measured in morethan one way, the protocol should identify one of the measurements as the primaryvariable on the basis of clinical relevance, importance, objectivity, and/or other rel-evant characteristics, whenever such selection is feasible.

Secondary variables are either supportive measurements related to the primaryobjective or measurements of effects related to the secondary objectives. Their pre-definition in the protocol is also important, as well as an explanation of theirrelative importance and roles in interpretation of trial results. The number ofsecondary variables should be limited and should be related to the limited numberof questions to be answered in the trial.

2.2.3 COMPOSITE VARIABLES

If a single primary variable cannot be selected from multiple measurements associ-ated with the primary objective, another useful strategy is to integrate or combinethe multiple measurements into a single or ‘composite’ variable, using a pre-definedalgorithm. Indeed, the primary variable sometimes arises as a combination of mul-tiple clinical measurements (e.g. the rating scales used in arthritis, psychiatric dis-orders and elsewhere). This approach addresses the multiplicity problem withoutrequiring adjustment to the type I error. The method of combining the multiplemeasurements should be specified in the protocol, and an interpretation of theresulting scale should be provided in terms of the size of a clinically relevant ben-efit. When a composite variable is used as a primary variable, the components ofthis variable may sometimes be analysed separately, where clinically meaningful andvalidated. When a rating scale is used as a primary variable, it is especially impor-tant to address such factors as content validity (see Glossary), inter- and intra-rater

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reliability (see Glossary) and responsiveness for detecting changes in the severityof disease.

2.2.4 GLOBAL ASSESSMENT VARIABLES

In some cases, ‘global assessment’ variables (see Glossary) are developed to mea-sure the overall safety, overall efficacy, and/or overall usefulness of a treatment.This type of variable integrates objective variables and the investigator’s overallimpression about the state or change in the state of the subject, and is usually ascale of ordered categorical ratings. Global assessments of overall efficacy are wellestablished in some therapeutic areas, such as neurology and psychiatry.

Global assessment variables generally have a subjective component. When a globalassessment variable is used as a primary or secondary variable, fuller details of thescale should be included in the protocol with respect to:

1) the relevance of the scale to the primary objective of the trial;

2) the basis for the validity and reliability of the scale;

3) how to utilize the data collected on an individual subject to assign him/her toa unique category of the scale;

4) how to assign subjects with missing data to a unique category of the scale, orotherwise evaluate them.

If objective variables are considered by the investigator when making a globalassessment, then those objective variables should be considered as additional pri-mary, or at least important secondary, variables.

Global assessment of usefulness integrates components of both benefit and risk andreflects the decision making process of the treating physician, who must weighbenefit and risk in making product use decisions. A problem with global usefulnessvariables is that their use could in some cases lead to the result of two productsbeing declared equivalent despite having very different profiles of beneficial andadverse effects. For example, judging the global usefulness of a treatment as equi-valent or superior to an alternative may mask the fact that it has little or no effi-cacy but fewer adverse effects. Therefore it is not advisable to use a global useful-ness variable as a primary variable. If global usefulness is specified as primary, it isimportant to consider specific efficacy and safety outcomes separately as additionalprimary variables.

2.2.5 MULTIPLE PRIMARY VARIABLES

It may sometimes be desirable to use more than one primary variable, each of which(or a subset of which) could be sufficient to cover the range of effects of the ther-apies. The planned manner of interpretation of this type of evidence should be care-fully spelled out. It should be clear whether an impact on any of the variables, someminimum number of them, or all of them, would be considered necessary to achievethe trial objectives. The primary hypothesis or hypotheses and parameters ofinterest (e.g. mean, percentage, distribution) should be clearly stated with respectto the primary variables identified, and the approach to statistical inferencedescribed. The effect on the type I error should be explained because of the poten-tial for multiplicity problems (see Section 5.6); the method of controlling type I

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error should be given in the protocol. The extent of intercorrelation among the pro-posed primary variables may be considered in evaluating the impact on type I error.If the purpose of the trial is to demonstrate effects on all of the designated primaryvariables, then there is no need for adjustment of the type I error, but the impacton type II error and sample size should be carefully considered.

2.2.6 SURROGATE VARIABLES

When direct assessment of the clinical benefit to the subject through observingactual clinical efficacy is not practical, indirect criteria (surrogate variables – seeGlossary) may be considered. Commonly accepted surrogate variables are used in anumber of indications where they are believed to be reliable predictors of clinicalbenefit. There are two principal concerns with the introduction of any proposed sur-rogate variable. First, it may not be a true predictor of the clinical outcome ofinterest. For example it may measure treatment activity associated with one spe-cific pharmacological mechanism, but may not provide full information on the rangeof actions and ultimate effects of the treatment, whether positive or negative.There have been many instances where treatments showing a highly positive effecton a proposed surrogate have ultimately been shown to be detrimental to the sub-jects‘ clinical outcome; conversely, there are cases of treatments conferring clinicalbenefit without measurable impact on proposed surrogates. Secondly, proposed sur-rogate variables may not yield a quantitative measure of clinical benefit that canbe weighed directly against adverse effects. Statistical criteria for validating surro-gate variables have been proposed but the experience with their use is relativelylimited. In practice, the strength of the evidence for surrogacy depends upon (i) thebiological plausibility of the relationship, (ii) the demonstration in epidemiologicalstudies of the prognostic value of the surrogate for the clinical outcome and(iii) evidence from clinical trials that treatment effects on the surrogate correspondto effects on the clinical outcome. Relationships between clinical and surrogatevariables for one product do not necessarily apply to a product with a differentmode of action for treating the same disease.

2.2.7 CATEGORIZED VARIABLES

Dichotomization or other categorization of continuous or ordinal variables maysometimes be desirable. Criteria of ‘success’ and ‘response’ are common examples ofdichotomies which require precise specification in terms of, for example, a minimumpercentage improvement (relative to baseline) in a continuous variable, or a rankingcategorized as at or above some threshold level (e.g. ‘good’) on an ordinal ratingscale. The reduction of diastolic blood pressure below 90 mmHg is a commondichotomization. Categorizations are most useful when they have clear clinical rel-evance. The criteria for categorization should be pre-defined and specified in theprotocol, as knowledge of trial results could easily bias the choice of such criteria.Because categorization normally implies a loss of information, a consequence willbe a loss of power in the analysis; this should be accounted for in the sample sizecalculation.

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2.3 Design Techniques to Avoid BiasThe most important design techniques for avoiding bias in clinical trials areblinding and randomization, and these should be normal features of most controlledclinical trials intended to be included in a marketing application. Most such trialsfollow a double-blind approach in which treatments are pre-packed in accordancewith a suitable randomization schedule, and supplied to the trial centre(s) labelledonly with the subject number and the treatment period so that no one involved inthe conduct of the trial is aware of the specific treatment allocated to any partic-ular subject, not even as a code letter. This approach will be assumed in Section2.3.1 and most of Section 2.3.2, exceptions being considered at the end.

Bias can also be reduced at the design stage by specifying procedures in the pro-tocol aimed at minimising any anticipated irregularities in trial conduct that mightimpair a satisfactory analysis, including various types of protocol violations, with-drawals and missing values. The protocol should consider ways both to reduce thefrequency of such problems, and also to handle the problems that do occur in theanalysis of data.

2.3.1 BLINDING

Blinding or masking is intended to limit the occurrence of conscious and uncon-scious bias in the conduct and interpretation of a clinical trial arising from theinfluence which the knowledge of treatment may have on the recruitment and allo-cation of subjects, their subsequent care, the attitudes of subjects to the treat-ments, the assessment of end-points, the handling of withdrawals, the exclusion ofdata from analysis, and so on. The essential aim is to prevent identification of thetreatments until all such opportunities for bias have passed.

A double-blind trial is one in which neither the subject nor any of the investigatoror sponsor staff who are involved in the treatment or clinical evaluation of the sub-jects are aware of the treatment received. This includes anyone determining subjecteligibility, evaluating endpoints, or assessing compliance with the protocol. Thislevel of blinding is maintained throughout the conduct of the trial, and only whenthe data are cleaned to an acceptable level of quality will appropriate personnel beunblinded. If any of the sponsor staff who are not involved in the treatment or clin-ical evaluation of the subjects are required to be unblinded to the treatment code(e.g. bioanalytical scientists, auditors, those involved in serious adverse eventreporting), the sponsor should have adequate standard operating procedures toguard against inappropriate dissemination of treatment codes. In a single-blindtrial the investigator and/or his staff are aware of the treatment but the subject isnot, or vice versa. In an open-label trial the identity of treatment is known to all.The double-blind trial is the optimal approach. This requires that the treatments tobe applied during the trial cannot be distinguished (appearance, taste, etc.) eitherbefore or during administration, and that the blind is maintained appropriatelyduring the whole trial.

Difficulties in achieving the double-blind ideal can arise: the treatments may be ofa completely different nature, for example, surgery and drug therapy; two drugs mayhave different formulations and, although they could be made indistinguishable by

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the use of capsules, changing the formulation might also change the pharmacoki-netic and/or pharmacodynamic properties and hence require that bioequivalence ofthe formulations be established; the daily pattern of administration of two treat-ments may differ. One way of achieving double-blind conditions under these cir-cumstances is to use a ‘double-dummy’ (see Glossary) technique. This technique maysometimes force an administration scheme that is sufficiently unusual to influenceadversely the motivation and compliance of the subjects. Ethical difficulties mayalso interfere with its use when, for example, it entails dummy operative procedures.Nevertheless, extensive efforts should be made to overcome these difficulties.

The double-blind nature of some clinical trials may be partially compromised byapparent treatment induced effects. In such cases, blinding may be improved byblinding investigators and relevant sponsor staff to certain test results (e.g.selected clinical laboratory measures). Similar approaches (see below) to mini-mizing bias in open-label trials should be considered in trials where unique or spe-cific treatment effects may lead to unblinding individual patients.

If a double-blind trial is not feasible, then the single-blind option should be con-sidered. In some cases only an open-label trial is practically or ethically possible.Single-blind and open-label trials provide additional flexibility, but it is particularlyimportant that the investigator’s knowledge of the next treatment should not influ-ence the decision to enter the subject; this decision should precede knowledge ofthe randomized treatment. For these trials, consideration should be given to the useof a centralized randomization method, such as telephone randomization, to admin-ister the assignment of randomized treatment. In addition, clinical assessmentsshould be made by medical staff who are not involved in treating the subjects andwho remain blind to treatment. In single-blind or open-label trials every effortshould be made to minimize the various known sources of bias and primary vari-ables should be as objective as possible. The reasons for the degree of blindingadopted should be explained in the protocol, together with steps taken to minimizebias by other means. For example, the sponsor should have adequate standard oper-ating procedures to ensure that access to the treatment code is appropriatelyrestricted during the process of cleaning the database prior to its release foranalysis.

Breaking the blind (for a single subject) should be considered only when knowledgeof the treatment assignment is deemed essential by the subject’s physician for thesubject’s care. Any intentional or unintentional breaking of the blind should bereported and explained at the end of the trial, irrespective of the reason for itsoccurrence. The procedure and timing for revealing the treatment assignmentsshould be documented.

In this document, the blind review (see Glossary) of data refers to the checking ofdata during the period of time between trial completion (the last observation onthe last subject) and the breaking of the blind.

2.3.2 RANDOMIZATION

Randomization introduces a deliberate element of chance into the assignment oftreatments to subjects in a clinical trial. During subsequent analysis of the trial

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data, it provides a sound statistical basis for the quantitative evaluation of the evi-dence relating to treatment effects. It also tends to produce treatment groups inwhich the distributions of prognostic factors, known and unknown, are similar. Incombination with blinding, randomization helps to avoid possible bias in the selec-tion and allocation of subjects arising from the predictability of treatment assign-ments.

The randomization schedule of a clinical trial documents the random allocation oftreatments to subjects. In the simplest situation it is a sequential list of treatments(or treatment sequences in a cross-over trial) or corresponding codes by subjectnumber. The logistics of some trials, such as those with a screening phase, maymake matters more complicated, but the unique pre-planned assignment of treat-ment, or treatment sequence, to subject should be clear. Different trial designs willrequire different procedures for generating randomization schedules. The random-ization schedule should be reproducible (if the need arises).

Although unrestricted randomization is an acceptable approach, some advantagescan generally be gained by randomising subjects in blocks. This helps to increasethe comparability of the treatment groups, particularly when subject characteristicsmay change over time, as a result, for example, of changes in recruitment policy. Italso provides a better guarantee that the treatment groups will be of nearly equalsize. In cross-over trials it provides the means of obtaining balanced designs withtheir greater efficiency and easier interpretation. Care should be taken to chooseblock lengths that are sufficiently short to limit possible imbalance, but that arelong enough to avoid predictability towards the end of the sequence in a block.Investigators and other relevant staff should generally be blind to the block length;the use of two or more block lengths, randomly selected for each block, can achievethe same purpose. (Theoretically, in a double-blind trial predictability does notmatter, but the pharmacological effects of drugs may provide the opportunity forintelligent guesswork.)

In multicentre trials (see Glossary) the randomization procedures should be orga-nized centrally. It is advisable to have a separate random scheme for each centre,i.e. to stratify by centre or to allocate several whole blocks to each centre. Moregenerally, stratification by important prognostic factors measured at baseline (e.g.severity of disease, age, sex, etc.) may sometimes be valuable in order to promotebalanced allocation within strata; this has greater potential benefit in small trials.The use of more than two or three stratification factors is rarely necessary, is lesssuccessful at achieving balance and is logistically troublesome. The use of adynamic allocation procedure (see below) may help to achieve balance across anumber of stratification factors simultaneously provided the rest of the trial proce-dures can be adjusted to accommodate an approach of this type. Factors on whichrandomization has been stratified should be accounted for later in the analysis.

The next subject to be randomized into a trial should always receive the treatmentcorresponding to the next free number in the appropriate randomization schedule(in the respective stratum, if randomization is stratified). The appropriate numberand associated treatment for the next subject should only be allocated when entryof that subject to the randomized part of the trial has been confirmed. Details of

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the randomization that facilitate predictability (e.g. block length) should not becontained in the trial protocol. The randomization schedule itself should be filedsecurely by the sponsor or an independent party in a manner that ensures thatblindness is properly maintained throughout the trial. Access to the randomizationschedule during the trial should take into account the possibility that, in an emer-gency, the blind may have to be broken for any subject. The procedure to be fol-lowed, the necessary documentation, and the subsequent treatment and assessmentof the subject should all be described in the protocol.

Dynamic allocation is an alternative procedure in which the allocation of treatmentto a subject is influenced by the current balance of allocated treatments and, in astratified trial, by the stratum to which the subject belongs and the balance withinthat stratum. Deterministic dynamic allocation procedures should be avoided andan appropriate element of randomization should be incorporated for each treatmentallocation. Every effort should be made to retain the double-blind status of thetrial. For example, knowledge of the treatment code may be restricted to a centraltrial office from where the dynamic allocation is controlled, generally through tele-phone contact. This in turn permits additional checks of eligibility criteria andestablishes entry into the trial, features that can be valuable in certain types ofmulticentre trial. The usual system of pre-packing and labelling drug supplies fordouble-blind trials can then be followed, but the order of their use is no longersequential. It is desirable to use appropriate computer algorithms to keep personnelat the central trial office blind to the treatment code. The complexity of the logis-tics and potential impact on the analysis should be carefully evaluated when con-sidering dynamic allocation.

3. TRIAL DESIGN CONSIDERATIONS3.1 Design Configuration3.1.1 PARALLEL GROUP DESIGN

The most common clinical trial design for confirmatory trials is the parallel groupdesign in which subjects are randomized to one of two or more arms, each armbeing allocated a different treatment. These treatments will include the investiga-tional product at one or more doses, and one or more control treatments, such asplacebo and/or an active comparator. The assumptions underlying this design areless complex than for most other designs. However, as with other designs, there maybe additional features of the trial that complicate the analysis and interpretation(e.g. covariates, repeated measurements over time, interactions between designfactors, protocol violations, dropouts (see Glossary) and withdrawals).

3.1.2 CROSS-OVER DESIGN

In the cross-over design, each subject is randomized to a sequence of two or moretreatments, and hence acts as his own control for treatment comparisons. Thissimple manoeuvre is attractive primarily because it reduces the number of subjectsand usually the number of assessments needed to achieve a specific power, some-times to a marked extent. In the simplest 2×2 cross-over design each subjectreceives each of two treatments in randomized order in two successive treatment

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periods, often separated by a washout period. The most common extension of thisentails comparing n(>2) treatments in n periods, each subject receiving all n treat-ments. Numerous variations exist, such as designs in which each subject receives a subset of n(>2) treatments, or ones in which treatments are repeated within asubject.

Cross-over designs have a number of problems that can invalidate their results. Thechief difficulty concerns carry-over, that is, the residual influence of treatments insubsequent treatment periods. In an additive model the effect of unequal carry-overwill be to bias direct treatment comparisons. In the 2×2 design the carry-over ef-fect cannot be statistically distinguished from the interaction between treatmentand period and the test for either of these effects lacks power because the corre-sponding contrast is ‘between subject’. This problem is less acute in higher orderdesigns, but cannot be entirely dismissed.

When the cross-over design is used it is therefore important to avoid carry-over.This is best done by selective and careful use of the design on the basis of ade-quate knowledge of both the disease area and the new medication. The diseaseunder study should be chronic and stable. The relevant effects of the medicationshould develop fully within the treatment period. The washout periods should besufficiently long for complete reversibility of drug effect. The fact that these con-ditions are likely to be met should be established in advance of the trial by meansof prior information and data.

There are additional problems that need careful attention in cross-over trials. Themost notable of these are the complications of analysis and interpretation arisingfrom the loss of subjects. Also, the potential for carry-over leads to difficulties inassigning adverse events which occur in later treatment periods to the appropriatetreatment. These, and other issues, are described in ICH E4. The cross-over designshould generally be restricted to situations where losses of subjects from the trialare expected to be small.

A common, and generally satisfactory, use of the 2×2 cross-over design is todemonstrate the bioequivalence of two formulations of the same medication. In thisparticular application in healthy volunteers, carry-over effects on the relevant phar-macokinetic variable are most unlikely to occur if the wash-out time between thetwo periods is sufficiently long. However it is still important to check this assump-tion during analysis on the basis of the data obtained, for example by demon-strating that no drug is detectable at the start of each period.

3.1.3 FACTORIAL DESIGNS

In a factorial design two or more treatments are evaluated simultaneously throughthe use of varying combinations of the treatments. The simplest example is the 2×2factorial design in which subjects are randomly allocated to one of the four pos-sible combinations of two treatments, A and B say. These are: A alone; B alone;both A and B; neither A nor B. In many cases this design is used for the specificpurpose of examining the interaction of A and B. The statistical test of interactionmay lack power to detect an interaction if the sample size was calculated based onthe test for main effects. This consideration is important when this design is used

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for examining the joint effects of A and B, in particular, if the treatments are likelyto be used together.

Another important use of the factorial design is to establish the dose-responsecharacteristics of the simultaneous use of treatments C and D, especially when theefficacy of each monotherapy has been established at some dose in prior trials. Anumber, m, of doses of C is selected, usually including a zero dose (placebo), anda similar number, n, of doses of D. The full design then consists of m×n treatmentgroups, each receiving a different combination of doses of C and D. The resultingestimate of the response surface may then be used to help to identify an appro-priate combination of doses of C and D for clinical use (see ICH E4).

In some cases, the 2×2 design may be used to make efficient use of clinical trialsubjects by evaluating the efficacy of the two treatments with the same number ofsubjects as would be required to evaluate the efficacy of either one alone. Thisstrategy has proved to be particularly valuable for very large mortality trials. Theefficiency and validity of this approach depends upon the absence of interactionbetween treatments A and B so that the effects of A and B on the primary efficacyvariables follow an additive model, and hence the effect of A is virtually identicalwhether or not it is additional to the effect of B. As for the cross-over trial, evi-dence that this condition is likely to be met should be established in advance ofthe trial by means of prior information and data.

3.2 Multicentre Trials Multicentre trials are carried out for two main reasons. Firstly, a multicentre trial isan accepted way of evaluating a new medication more efficiently; under some cir-cumstances, it may present the only practical means of accruing sufficient subjectsto satisfy the trial objective within a reasonable time-frame. Multicentre trials ofthis nature may, in principle, be carried out at any stage of clinical development.They may have several centres with a large number of subjects per centre or, in thecase of a rare disease, they may have a large number of centres with very few sub-jects per centre.

Secondly, a trial may be designed as a multicentre (and multi-investigator) trial pri-marily to provide a better basis for the subsequent generalization of its findings.This arises from the possibility of recruiting the subjects from a wider populationand of administering the medication in a broader range of clinical settings, thuspresenting an experimental situation that is more typical of future use. In this casethe involvement of a number of investigators also gives the potential for a widerrange of clinical judgement concerning the value of the medication. Such a trialwould be a confirmatory trial in the later phases of drug development and would belikely to involve a large number of investigators and centres. It might sometimesbe conducted in a number of different countries in order to facilitate generaliz-ability (see Glossary) even further.

If a multicentre trial is to be meaningfully interpreted and extrapolated, then themanner in which the protocol is implemented should be clear and similar at all cen-tres. Furthermore the usual sample size and power calculations depend upon theassumption that the differences between the compared treatments in the centres

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are unbiased estimates of the same quantity. It is important to design the commonprotocol and to conduct the trial with this background in mind. Procedures shouldbe standardized as completely as possible. Variation of evaluation criteria andschemes can be reduced by investigator meetings, by the training of personnel inadvance of the trial and by careful monitoring during the trial. Good design shouldgenerally aim to achieve the same distribution of subjects to treatments withineach centre and good management should maintain this design objective. Trialsthat avoid excessive variation in the numbers of subjects per centre and trials thatavoid a few very small centres have advantages if it is later found necessary to takeinto account the heterogeneity of the treatment effect from centre to centre,because they reduce the differences between different weighted estimates of thetreatment effect. (This point does not apply to trials in which all centres are verysmall and in which centre does not feature in the analysis.) Failure to take theseprecautions, combined with doubts about the homogeneity of the results may, insevere cases, reduce the value of a multicentre trial to such a degree that it cannotbe regarded as giving convincing evidence for the sponsor’s claims.

In the simplest multicentre trial, each investigator will be responsible for the sub-jects recruited at one hospital, so that ‘centre’ is identified uniquely by eitherinvestigator or hospital. In many trials, however, the situation is more complex. Oneinvestigator may recruit subjects from several hospitals; one investigator may rep-resent a team of clinicians (subinvestigators) who all recruit subjects from theirown clinics at one hospital or at several associated hospitals. Whenever there isroom for doubt about the definition of centre in a statistical model, the statisticalsection of the protocol (see Section 5.1) should clearly define the term (e.g. byinvestigator, location or region) in the context of the particular trial. In mostinstances centres can be satisfactorily defined through the investigators and ICH E6provides relevant guidance in this respect. In cases of doubt the aim should be todefine centres so as to achieve homogeneity in the important factors affecting themeasurements of the primary variables and the influence of the treatments. Anyrules for combining centres in the analysis should be justified and specifiedprospectively in the protocol where possible, but in any case decisions concerningthis approach should always be taken blind to treatment, for example at the timeof the blind review.

The statistical model to be adopted for the estimation and testing of treatmenteffects should be described in the protocol. The main treatment effect may beinvestigated first using a model which allows for centre differences, but does notinclude a term for treatment-by-centre interaction. If the treatment effect is homo-geneous across centres, the routine inclusion of interaction terms in the modelreduces the efficiency of the test for the main effects. In the presence of trueheterogeneity of treatment effects, the interpretation of the main treatment effectis controversial.

In some trials, for example some large mortality trials with very few subjects percentre, there may be no reason to expect the centres to have any influence on theprimary or secondary variables because they are unlikely to represent influences ofclinical importance. In other trials it may be recognized from the start that the

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limited numbers of subjects per centre will make it impracticable to include thecentre effects in the statistical model. In these cases it is not appropriate to includea term for centre in the model, and it is not necessary to stratify the randomiza-tion by centre in this situation.

If positive treatment effects are found in a trial with appreciable numbers of sub-jects per centre, there should generally be an exploration of the heterogeneity oftreatment effects across centres, as this may affect the generalizability of the con-clusions. Marked heterogeneity may be identified by graphical display of the resultsof individual centres or by analytical methods, such as a significance test of thetreatment-by-centre interaction. When using such a statistical significance test, itis important to recognize that this generally has low power in a trial designed todetect the main effect of treatment.

If heterogeneity of treatment effects is found, this should be interpreted with careand vigorous attempts should be made to find an explanation in terms of other fea-tures of trial management or subject characteristics. Such an explanation willusually suggest appropriate further analysis and interpretation. In the absence ofan explanation, heterogeneity of treatment effect as evidenced, for example, bymarked quantitative interactions (see Glossary) implies that alternative estimatesof the treatment effect may be required, giving different weights to the centres, inorder to substantiate the robustness of the estimates of treatment effect. It is evenmore important to understand the basis of any heterogeneity characterized bymarked qualitative interactions (see Glossary), and failure to find an explanationmay necessitate further clinical trials before the treatment effect can be reliablypredicted.

Up to this point the discussion of multicentre trials has been based on the use offixed effect models. Mixed models may also be used to explore the heterogeneity ofthe treatment effect. These models consider centre and treatment-by-centre effectsto be random, and are especially relevant when the number of sites is large.

3.3 Type of Comparison3.3.1 TRIALS TO SHOW SUPERIORITY

Scientifically, efficacy is most convincingly established by demonstrating superi-ority to placebo in a placebo-controlled trial, by showing superiority to an activecontrol treatment or by demonstrating a dose-response relationship. This type oftrial is referred to as a ‘superiority’ trial (see Glossary). Generally in this guidancesuperiority trials are assumed, unless it is explicitly stated otherwise.

For serious illnesses, when a therapeutic treatment which has been shown to beefficacious by superiority trial(s) exists, a placebo-controlled trial may be consid-ered unethical. In that case the scientifically sound use of an active treatment asa control should be considered. The appropriateness of placebo control vs. activecontrol should be considered on a trial by trial basis.

3.3.2 TRIALS TO SHOW EQUIVALENCE OR NON-INFERIORITY

In some cases, an investigational product is compared to a reference treatmentwithout the objective of showing superiority. This type of trial is divided into two

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major categories according to its objective; one is an ‘equivalence’ trial (seeGlossary) and the other is a ‘non-inferiority’ trial (see Glossary).

Bioequivalence trials fall into the former category. In some situations, clinicalequivalence trials are also undertaken for other regulatory reasons such as demon-strating the clinical equivalence of a generic product to the marketed product whenthe compound is not absorbed and therefore not present in the blood stream.

Many active control trials are designed to show that the efficacy of an investiga-tional product is no worse than that of the active comparator, and hence fall intothe latter category. Another possibility is a trial in which multiple doses of theinvestigational drug are compared with the recommended dose or multiple doses ofthe standard drug. The purpose of this design is simultaneously to show a dose-response relationship for the investigational product and to compare the investiga-tional product with the active control.

Active control equivalence or non-inferiority trials may also incorporate a placebo,thus pursuing multiple goals in one trial; for example, they may establish superi-ority to placebo and hence validate the trial design and simultaneously evaluate thedegree of similarity of efficacy and safety to the active comparator. There are wellknown difficulties associated with the use of the active control equivalence (ornon-inferiority) trials that do not incorporate a placebo or do not use multipledoses of the new drug. These relate to the implicit lack of any measure of internalvalidity (in contrast to superiority trials), thus making external validation neces-sary. The equivalence (or non-inferiority) trial is not conservative in nature, so thatmany flaws in the design or conduct of the trial will tend to bias the results towardsa conclusion of equivalence. For these reasons, the design features of such trialsshould receive special attention and their conduct needs special care. For example,it is especially important to minimize the incidence of violations of the entry cri-teria, non-compliance, withdrawals, losses to follow-up, missing data and otherdeviations from the protocol, and also to minimize their impact on the subsequentanalyses.

Active comparators should be chosen with care. An example of a suitable activecomparator would be a widely used therapy whose efficacy in the relevant indica-tion has been clearly established and quantified in well designed and well docu-mented superiority trial(s) and which can be reliably expected to exhibit similarefficacy in the contemplated active control trial. To this end, the new trial shouldhave the same important design features (primary variables, the dose of the activecomparator, eligibility criteria, etc.) as the previously conducted superiority trialsin which the active comparator clearly demonstrated clinically relevant efficacy, takinginto account advances in medical or statistical practice relevant to the new trial.

It is vital that the protocol of a trial designed to demonstrate equivalence or non-inferiority contain a clear statement that this is its explicit intention. An equiva-lence margin should be specified in the protocol; this margin is the largest differ-ence that can be judged as being clinically acceptable and should be smaller thandifferences observed in superiority trials of the active comparator. For the activecontrol equivalence trial, both the upper and the lower equivalence margins are

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needed, while only the lower margin is needed for the active control non-inferioritytrial. The choice of equivalence margins should be justified clinically.

Statistical analysis is generally based on the use of confidence intervals (seeSection 5.5). For equivalence trials, two-sided confidence intervals should be used.Equivalence is inferred when the entire confidence interval falls within the equiva-lence margins. Operationally, this is equivalent to the method of using two simul-taneous one-sided tests to test the (composite) null hypothesis that the treatmentdifference is outside the equivalence margins versus the (composite) alternativehypothesis that the treatment difference is within the margins. Because the twonull hypotheses are disjoint, the type I error is appropriately controlled. For non-inferiority trials a one-sided interval should be used. The confidence intervalapproach has a one-sided hypothesis test counterpart for testing the null hypoth-esis that the treatment difference (investigational product minus control) is equalto the lower equivalence margin versus the alternative that the treatment differ-ence is greater than the lower equivalence margin. The choice of type I error shouldbe a consideration separate from the use of a one-sided or two-sided procedure.Sample size calculations should be based on these methods (see Section 3.5).

Concluding equivalence or non-inferiority based on observing a non-significant testresult of the null hypothesis that there is no difference between the investigationalproduct and the active comparator is inappropriate.

There are also special issues in the choice of analysis sets. Subjects who withdrawor dropout of the treatment group or the comparator group will tend to have a lackof response, and hence the results of using the full analysis set (see Glossary) maybe biased toward demonstrating equivalence (see Section 5.2.3).

3.3.3 TRIALS TO SHOW DOSE-RESPONSE RELATIONSHIP

How response is related to the dose of a new investigational product is a questionto which answers may be obtained in all phases of development, and by a varietyof approaches (see ICH E4). Dose-response trials may serve a number of objectives,amongst which the following are of particular importance: the confirmation of effi-cacy; the investigation of the shape and location of the dose-response curve; theestimation of an appropriate starting dose; the identification of optimal strategiesfor individual dose adjustments; the determination of a maximal dose beyond whichadditional benefit would be unlikely to occur. These objectives should be addressedusing the data collected at a number of doses under investigation, including aplacebo (zero dose) wherever appropriate. For this purpose the application of pro-cedures to estimate the relationship between dose and response, including the con-struction of confidence intervals and the use of graphical methods, is as importantas the use of statistical tests. The hypothesis tests that are used may need to betailored to the natural ordering of doses or to particular questions regarding theshape of the dose-response curve (e.g. monotonicity). The details of the plannedstatistical procedures should be given in the protocol.

3.4 Group Sequential DesignsGroup sequential designs are used to facilitate the conduct of interim analysis (seeSection 4.5 and Glossary). While group sequential designs are not the only accept-

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able types of designs permitting interim analysis, they are the most commonlyapplied because it is more practicable to assess grouped subject outcomes at peri-odic intervals during the trial than on a continuous basis as data from each subjectbecome available. The statistical methods should be fully specified in advance ofthe availability of information on treatment outcomes and subject treatmentassignments (i.e. blind breaking, see Section 4.5). An Independent Data MonitoringCommittee (see Glossary) may be used to review or to conduct the interim analysisof data arising from a group sequential design (see Section 4.6). While the designhas been most widely and successfully used in large, long-term trials of mortalityor major non-fatal endpoints, its use is growing in other circumstances. In par-ticular, it is recognized that safety must be monitored in all trials and therefore the need for formal procedures to cover early stopping for safety reasons shouldalways be considered.

3.5 Sample SizeThe number of subjects in a clinical trial should always be large enough to providea reliable answer to the questions addressed. This number is usually determined bythe primary objective of the trial. If the sample size is determined on some otherbasis, then this should be made clear and justified. For example, a trial sized on thebasis of safety questions or requirements or important secondary objectives mayneed larger numbers of subjects than a trial sized on the basis of the primary effi-cacy question (see, for example, ICH E1a).

Using the usual method for determining the appropriate sample size, the followingitems should be specified: a primary variable, the test statistic, the null hypothesis,the alternative (‘working’) hypothesis at the chosen dose(s) (embodying consider-ation of the treatment difference to be detected or rejected at the dose and in thesubject population selected), the probability of erroneously rejecting the nullhypothesis (the type I error), and the probability of erroneously failing to reject thenull hypothesis (the type II error), as well as the approach to dealing with treat-ment withdrawals and protocol violations. In some instances, the event rate is ofprimary interest for evaluating power, and assumptions should be made to extrapo-late from the required number of events to the eventual sample size for the trial.

The method by which the sample size is calculated should be given in the protocol,together with the estimates of any quantities used in the calculations (such as vari-ances, mean values, response rates, event rates, difference to be detected). Thebasis of these estimates should also be given. It is important to investigate thesensitivity of the sample size estimate to a variety of deviations from these assump-tions and this may be facilitated by providing a range of sample sizes appropriatefor a reasonable range of deviations from assumptions. In confirmatory trials,assumptions should normally be based on published data or on the results of ear-lier trials. The treatment difference to be detected may be based on a judgementconcerning the minimal effect which has clinical relevance in the management ofpatients or on a judgement concerning the anticipated effect of the new treatment,where this is larger. Conventionally the probability of type I error is set at 5% orless or as dictated by any adjustments made necessary for multiplicity considera-

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tions; the precise choice may be influenced by the prior plausibility of the hypoth-esis under test and the desired impact of the results. The probability of type II erroris conventionally set at 10% to 20%; it is in the sponsor’s interest to keep thisfigure as low as feasible especially in the case of trials that are difficult or impos-sible to repeat. Alternative values to the conventional levels of type I and type IIerror may be acceptable or even preferable in some cases.

Sample size calculations should refer to the number of subjects required for theprimary analysis. If this is the ‘full analysis set’, estimates of the effect size mayneed to be reduced compared to the per protocol set (see Glossary). This is to allowfor the dilution of the treatment effect arising from the inclusion of data frompatients who have withdrawn from treatment or whose compliance is poor. Theassumptions about variability may also need to be revised.

The sample size of an equivalence trial or a non-inferiority trial (see Section 3.3.2)should normally be based on the objective of obtaining a confidence interval forthe treatment difference that shows that the treatments differ at most by a clini-cally acceptable difference. When the power of an equivalence trial is assessed at atrue difference of zero, then the sample size necessary to achieve this power isunderestimated if the true difference is not zero. When the power of a non-inferi-ority trial is assessed at a zero difference, then the sample size needed to achievethat power will be underestimated if the effect of the investigational product is lessthan that of the active control. The choice of a ‘clinically acceptable’ differenceneeds justification with respect to its meaning for future patients, and may besmaller than the ‘clinically relevant’ difference referred to above in the context ofsuperiority trials designed to establish that a difference exists.

The exact sample size in a group sequential trial cannot be fixed in advance becauseit depends upon the play of chance in combination with the chosen stopping guide-line and the true treatment difference. The design of the stopping guideline shouldtake into account the consequent distribution of the sample size, usually embodiedin the expected and maximum sample sizes.

When event rates are lower than anticipated or variability is larger than expected,methods for sample size re-estimation are available without unblinding data ormaking treatment comparisons (see Section 4.4).

3.6 Data Capture and ProcessingThe collection of data and transfer of data from the investigator to the sponsor can take place through a variety of media, including paper case record forms,remote site monitoring systems, medical computer systems and electronic transfer.Whatever data capture instrument is used, the form and content of the informationcollected should be in full accordance with the protocol and should be establishedin advance of the conduct of the clinical trial. It should focus on the data neces-sary to implement the planned analysis, including the context information (such astiming assessments relative to dosing) necessary to confirm protocol compliance oridentify important protocol deviations. ‘Missing values’ should be distinguishablefrom the ‘value zero’ or ‘characteristic absent’.

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The process of data capture through to database finalization should be carried outin accordance with GCP (see ICH E6, Section 5). Specifically, timely and reliableprocesses for recording data and rectifying errors and omissions are necessary toensure delivery of a quality database and the achievement of the trial objectivesthrough the implementation of the planned analysis.

4. TRIAL CONDUCT CONSIDERATIONS4.1 Trial Monitoring and Interim AnalysisCareful conduct of a clinical trial according to the protocol has a major impact onthe credibility of the results (see ICH E6). Careful monitoring can ensure that dif-ficulties are noticed early and their occurrence or recurrence minimized.

There are two distinct types of monitoring that generally characterize confirmatoryclinical trials sponsored by the pharmaceutical industry. One type of monitoringconcerns the oversight of the quality of the trial, while the other type involvesbreaking the blind to make treatment comparisons (i.e. interim analysis). Bothtypes of trial monitoring, in addition to entailing different staff responsibilities,involve access to different types of trial data and information, and thus differentprinciples apply for the control of potential statistical and operational bias.

For the purpose of overseeing the quality of the trial the checks involved in trialmonitoring may include whether the protocol is being followed, the acceptability ofdata being accrued, the success of planned accrual targets, the appropriateness ofthe design assumptions, success in keeping patients in the trials, etc. (see Sections4.2 to 4.4). This type of monitoring does not require access to information on com-parative treatment effects, nor unblinding of data and therefore has no impact ontype I error. The monitoring of a trial for this purpose is the responsibility of thesponsor (see ICH E6) and can be carried out by the sponsor or an independent groupselected by the sponsor. The period for this type of monitoring usually starts withthe selection of the trial sites and ends with the collection and cleaning of the lastsubject’s data.

The other type of trial monitoring (interim analysis) involves the accruing of com-parative treatment results. Interim analysis requires unblinded (i.e. key breaking)access to treatment group assignment (actual treatment assignment or identifica-tion of group assignment) and comparative treatment group summary information.This necessitates that the protocol (or appropriate amendments prior to a firstanalysis) contains statistical plans for the interim analysis to prevent certain typesof bias. This is discussed in Sections 4.5 and 4.6.

4.2 Changes in Inclusion and Exclusion CriteriaInclusion and exclusion criteria should remain constant, as specified in the pro-tocol, throughout the period of subject recruitment. Changes may occasionally beappropriate, for example, in long term trials, where growing medical knowledgeeither from outside the trial or from interim analyses may suggest a change of entrycriteria. Changes may also result from the discovery by monitoring staff that regu-lar violations of the entry criteria are occurring, or that seriously low recruitment

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rates are due to over-restrictive criteria. Changes should be made without breakingthe blind and should always be described by a protocol amendment which shouldcover any statistical consequences, such as sample size adjustments arising fromdifferent event rates, or modifications to the planned analysis, such as stratifyingthe analysis according to modified inclusion/exclusion criteria.

4.3 Accrual RatesIn trials with a long time-scale for the accrual of subjects, the rate of accrual shouldbe monitored and, if it falls appreciably below the projected level, the reasonsshould be identified and remedial actions taken in order to protect the power of thetrial and alleviate concerns about selective entry and other aspects of quality. In amulticentre trial these considerations apply to the individual centres.

4.4 Sample Size AdjustmentIn long term trials there will usually be an opportunity to check the assumptionswhich underlay the original design and sample size calculations. This may be par-ticularly important if the trial specifications have been made on preliminary and/oruncertain information. An interim check conducted on the blinded data may revealthat overall response variances, event rates or survival experience are not as antic-ipated. A revised sample size may then be calculated using suitably modifiedassumptions, and should be justified and documented in a protocol amendment andin the clinical study report. The steps taken to preserve blindness and the conse-quences, if any, for the type I error and the width of confidence intervals should beexplained. The potential need for re-estimation of the sample size should be envis-aged in the protocol whenever possible (see Section 3.5).

4.5 Interim Analysis and Early StoppingAn interim analysis is any analysis intended to compare treatment arms with respectto efficacy or safety at any time prior to formal completion of a trial. Because thenumber, methods and consequences of these comparisons affect the interpretationof the trial, all interim analyses should be carefully planned in advance anddescribed in the protocol. Special circumstances may dictate the need for an interimanalysis that was not defined at the start of a trial. In these cases, a protocolamendment describing the interim analysis should be completed prior to unblindedaccess to treatment comparison data. When an interim analysis is planned with theintention of deciding whether or not to terminate a trial, this is usually accom-plished by the use of a group sequential design which employs statistical moni-toring schemes as guidelines (see Section 3.4). The goal of such an interim analysisis to stop the trial early if the superiority of the treatment under study is clearlyestablished, if the demonstration of a relevant treatment difference has becomeunlikely or if unacceptable adverse effects are apparent. Generally, boundaries formonitoring efficacy require more evidence to terminate a trial early (i.e. they aremore conservative) than boundaries for monitoring safety. When the trial designand monitoring objective involve multiple endpoints then this aspect of multiplicitymay also need to be taken into account.

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The protocol should describe the schedule of interim analyses, or at least the con-siderations which will govern its generation, for example if flexible alpha spendingfunction approaches are to be employed; further details may be given in a protocolamendment before the time of the first interim analysis. The stopping guidelinesand their properties should be clearly described in the protocol or amendments. Thepotential effects of early stopping on the analysis of other important variablesshould also be considered. This material should be written or approved by the DataMonitoring Committee (see Section 4.6), when the trial has one. Deviations fromthe planned procedure always bear the potential of invalidating the trial results. Ifit becomes necessary to make changes to the trial, any consequent changes to thestatistical procedures should be specified in an amendment to the protocol at theearliest opportunity, especially discussing the impact on any analysis and infer-ences that such changes may cause. The procedures selected should always ensurethat the overall probability of type I error is controlled.

The execution of an interim analysis should be a completely confidential processbecause unblinded data and results are potentially involved. All staff involved inthe conduct of the trial should remain blind to the results of such analyses, becauseof the possibility that their attitudes to the trial will be modified and cause changesin the characteristics of patients to be recruited or biases in treatment comparisons.This principle may be applied to all investigator staff and to staff employed by thesponsor except for those who are directly involved in the execution of the interimanalysis. Investigators should only be informed about the decision to continue orto discontinue the trial, or to implement modifications to trial procedures.

Most clinical trials intended to support the efficacy and safety of an investigationalproduct should proceed to full completion of planned sample size accrual; trialsshould be stopped early only for ethical reasons or if the power is no longer accept-able. However, it is recognized that drug development plans involve the need forsponsor access to comparative treatment data for a variety of reasons, such as plan-ning other trials. It is also recognized that only a subset of trials will involve thestudy of serious life-threatening outcomes or mortality which may need sequentialmonitoring of accruing comparative treatment effects for ethical reasons. In eitherof these situations, plans for interim statistical analysis should be in place in theprotocol or in protocol amendments prior to the unblinded access to comparativetreatment data in order to deal with the potential statistical and operational biasthat may be introduced.

For many clinical trials of investigational products, especially those that have majorpublic health significance, the responsibility for monitoring comparisons of efficacyand/or safety outcomes should be assigned to an external independent group, oftencalled an Independent Data Monitoring Committee (IDMC), a Data and SafetyMonitoring Board or a Data Monitoring Committee whose responsibilities should beclearly described.

When a sponsor assumes the role of monitoring efficacy or safety comparisons andtherefore has access to unblinded comparative information, particular care shouldbe taken to protect the integrity of the trial and to manage and limit appropriatelythe sharing of information. The sponsor should assure and document that the

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internal monitoring committee has complied with written standard operating pro-cedures and that minutes of decision making meetings including records of interimresults are maintained.

Any interim analysis that is not planned appropriately (with or without the conse-quences of stopping the trial early) may flaw the results of a trial and possiblyweaken confidence in the conclusions drawn. Therefore, such analyses should beavoided. If unplanned interim analysis is conducted, the clinical study report shouldexplain why it was necessary, the degree to which blindness had to be broken, pro-vide an assessment of the potential magnitude of bias introduced, and the impacton the interpretation of the results.

4.6 Role of Independent Data Monitoring Committee (IDMC)(see Sections 1.25 and 5.52 of ICH E6)

An IDMC may be established by the sponsor to assess at intervals the progress of aclinical trial, safety data, and critical efficacy variables and recommend to thesponsor whether to continue, modify or terminate a trial. The IDMC should havewritten operating procedures and maintain records of all its meetings, includinginterim results; these should be available for review when the trial is complete. Theindependence of the IDMC is intended to control the sharing of important compar-ative information and to protect the integrity of the clinical trial from adverseimpact resulting from access to trial information. The IDMC is a separate entity froman Institutional Review Board (IRB) or an Independent Ethics Committee (IEC), andits composition should include clinical trial scientists knowledgeable in the appro-priate disciplines including statistics.

When there are sponsor representatives on the IDMC, their role should be clearlydefined in the operating procedures of the committee (for example, coveringwhether or not they can vote on key issues). Since these sponsor staff would haveaccess to unblinded information, the procedures should also address the control ofdissemination of interim trial results within the sponsor organization.

5. DATA ANALYSIS CONSIDERATIONS5.1 Prespecification of the Analysis When designing a clinical trial the principal features of the eventual statisticalanalysis of the data should be described in the statistical section of the protocol.This section should include all the principal features of the proposed confirmatoryanalysis of the primary variable(s) and the way in which anticipated analysis prob-lems will be handled. In case of exploratory trials this section could describe moregeneral principles and directions.

The statistical analysis plan (see Glossary) may be written as a separate documentto be completed after finalising the protocol. In this document, a more technicaland detailed elaboration of the principal features stated in the protocol may beincluded (see Section 7.1). The plan may include detailed procedures for executingthe statistical analysis of the primary and secondary variables and other data. Theplan should be reviewed and possibly updated as a result of the blind review of the

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data (see 7.1 for definition) and should be finalized before breaking the blind.Formal records should be kept of when the statistical analysis plan was finalized aswell as when the blind was subsequently broken.

If the blind review suggests changes to the principal features stated in the pro-tocol, these should be documented in a protocol amendment. Otherwise, it will suf-fice to update the statistical analysis plan with the considerations suggested fromthe blind review. Only results from analyses envisaged in the protocol (includingamendments) can be regarded as confirmatory.

In the statistical section of the clinical study report the statistical methodologyshould be clearly described including when in the clinical trial process methodologydecisions were made (see ICH E3).

5.2 Analysis SetsThe set of subjects whose data are to be included in the main analyses should bedefined in the statistical section of the protocol. In addition, documentation for allsubjects for whom trial procedures (e.g. run-in period) were initiated may be useful.The content of this subject documentation depends on detailed features of the par-ticular trial, but at least demographic and baseline data on disease status shouldbe collected whenever possible.

If all subjects randomized into a clinical trial satisfied all entry criteria, followedall trial procedures perfectly with no losses to follow-up, and provided completedata records, then the set of subjects to be included in the analysis would be self-evident. The design and conduct of a trial should aim to approach this ideal asclosely as possible, but, in practice, it is doubtful if it can ever be fully achieved.Hence, the statistical section of the protocol should address anticipated problemsprospectively in terms of how these affect the subjects and data to be analysed. Theprotocol should also specify procedures aimed at minimizing any anticipated ir-regularities in study conduct that might impair a satisfactory analysis, includingvarious types of protocol violations, withdrawals and missing values. The protocolshould consider ways both to reduce the frequency of such problems, and also tohandle the problems that do occur in the analysis of data. Possible amendments tothe way in which the analysis will deal with protocol violations should be identi-fied during the blind review. It is desirable to identify any important protocol vio-lation with respect to the time when it occurred, its cause and influence on the trialresult. The frequency and type of protocol violations, missing values, and otherproblems should be documented in the clinical study report and their potentialinfluence on the trial results should be described (see ICH E3).

Decisions concerning the analysis set should be guided by the following principles:1) to minimize bias, and 2) to avoid inflation of type I error.

5.2.1 FULL ANALYSIS SET

The intention-to-treat (see Glossary) principle implies that the primaryanalysis should include all randomized subjects. Compliance with this prin-ciple would necessitate complete follow-up of all randomized subjects forstudy outcomes. In practice this ideal may be difficult to achieve, for rea-

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sons to be described. In this document the term ‘full analysis set’ is usedto describe the analysis set which is as complete as possible and as closeas possible to the intention-to-treat ideal of including all randomized sub-jects. Preservation of the initial randomization in analysis is important inpreventing bias and in providing a secure foundation for statistical tests.In many clinical trials the use of the full analysis set provides a conserva-tive strategy. Under many circumstances it may also provide estimates oftreatment effects which are more likely to mirror those observed in subse-quent practice.

There are a limited number of circumstances that might lead to excludingrandomized subjects from the full analysis set including the failure to satisfymajor entry criteria (eligibility violations), the failure to take at least onedose of trial medication and the lack of any data post randomization. Suchexclusions should always be justified. Subjects who fail to satisfy an entrycriterion may be excluded from the analysis without the possibility ofintroducing bias only under the following circumstances:

ii(i) the entry criterion was measured prior to randomization;

i(ii) the detection of the relevant eligibility violations can be made com-pletely objectively;

(iii) all subjects receive equal scrutiny for eligibility violations; (This maybe difficult to ensure in an open-label study, or even in a double-blind study if the data are unblinded prior to this scrutiny, empha-sising the importance of the blind review.)

(iv) all detected violations of the particular entry criterion are excluded.

In some situations, it may be reasonable to eliminate from the set of allrandomized subjects any subject who took no trial medication. The inten-tion-to-treat principle would be preserved despite the exclusion of thesepatients provided, for example, that the decision of whether or not tobegin treatment could not be influenced by knowledge of the assignedtreatment. In other situations it may be necessary to eliminate from theset of all randomized subjects any subject without data post randomiza-tion. No analysis is complete unless the potential biases arising from thesespecific exclusions, or any others, are addressed.

When the full analysis set of subjects is used, violations of the protocolthat occur after randomization may have an impact on the data and con-clusions, particularly if their occurrence is related to treatment assign-ment. In most respects it is appropriate to include the data from such sub-jects in the analysis, consistent with the intention-to-treat principle.Special problems arise in connection with subjects withdrawn from treat-ment after receiving one or more doses who provide no data after thispoint, and subjects otherwise lost to follow-up, because failure to includethese subjects in the full analysis set may seriously undermine theapproach. Measurements of primary variables made at the time of the lossto follow-up of a subject for any reason, or subsequently collected in

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accordance with the intended schedule of assessments in the protocol, arevaluable in this context; subsequent collection is especially important instudies where the primary variable is mortality or serious morbidity. Theintention to collect data in this way should be described in the protocol.Imputation techniques, ranging from the carrying forward of the lastobservation to the use of complex mathematical models, may also be usedin an attempt to compensate for missing data. Other methods employed to ensure the availability of measurements of primary variables for everysubject in the full analysis set may require some assumptions about thesubjects’ outcomes or a simpler choice of outcome (e.g. success/failure).The use of any of these strategies should be described and justified in thestatistical section of the protocol and the assumptions underlying anymathematical models employed should be clearly explained. It is also impor-tant to demonstrate the robustness of the corresponding results of analysisespecially when the strategy in question could itself lead to biased esti-mates of treatment effects.

Because of the unpredictability of some problems, it may sometimes bepreferable to defer detailed consideration of the manner of dealing withirregularities until the blind review of the data at the end of the trial, and,if so, this should be stated in the protocol.

5.2.2 PER PROTOCOL SET

The ‘per protocol’ set of subjects, sometimes described as the ‘valid cases’,the ‘efficacy’ sample or the ‘evaluable subjects’ sample, defines a subset ofthe subjects in the full analysis set who are more compliant with the pro-tocol and is characterized by criteria such as the following:

ii(i) the completion of a certain pre-specified minimal exposure to thetreatment regimen;

i(ii) the availability of measurements of the primary variable(s);

(iii) the absence of any major protocol violations including the violationof entry criteria.

The precise reasons for excluding subjects from the per protocol set shouldbe fully defined and documented before breaking the blind in a mannerappropriate to the circumstances of the specific trial.

The use of the per protocol set may maximize the opportunity for a newtreatment to show additional efficacy in the analysis, and most closelyreflects the scientific model underlying the protocol. However, the corre-sponding test of the hypothesis and estimate of the treatment effect mayor may not be conservative depending on the trial; the bias, which may besevere, arises from the fact that adherence to the study protocol may berelated to treatment and outcome.

The problems that lead to the exclusion of subjects to create the per protocol set, and other protocol violations, should be fully identified andsummarized. Relevant protocol violations may include errors in treatment

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assignment, the use of excluded medication, poor compliance, loss tofollow-up and missing data. It is good practice to assess the pattern ofsuch problems among the treatment groups with respect to frequency andtime to occurrence.

5.2.3 ROLES OF THE DIFFERENT ANALYSIS SETS

In general, it is advantageous to demonstrate a lack of sensitivity of theprincipal trial results to alternative choices of the set of subjects analysed.In confirmatory trials it is usually appropriate to plan to conduct both ananalysis of the full analysis set and a per protocol analysis, so that any dif-ferences between them can be the subject of explicit discussion and inter-pretation. In some cases, it may be desirable to plan further explorationof the sensitivity of conclusions to the choice of the set of subjectsanalysed. When the full analysis set and the per protocol set lead to essen-tially the same conclusions, confidence in the trial results is increased,bearing in mind, however, that the need to exclude a substantial propor-tion of subjects from the per protocol analysis throws some doubt on theoverall validity of the trial.

The full analysis set and the per protocol set play different roles in superi-ority trials (which seek to show the investigational product to be supe-rior), and in equivalence or non-inferiority trials (which seek to show theinvestigational product to be comparable, see Section 3.3.2). In superi-ority trials the full analysis set is used in the primary analysis (apart fromexceptional circumstances) because it tends to avoid over-optimistic esti-mates of efficacy resulting from a per protocol analysis, since the non-compliers included in the full analysis set will generally diminish the esti-mated treatment effect. However, in an equivalence or non-inferiority trialuse of the full analysis set is generally not conservative and its role shouldbe considered very carefully.

5.3 Missing Values and OutliersMissing values represent a potential source of bias in a clinical trial. Hence, everyeffort should be undertaken to fulfil all the requirements of the protocol concerningthe collection and management of data. In reality, however, there will almost alwaysbe some missing data. A trial may be regarded as valid, nonetheless, provided themethods of dealing with missing values are sensible, and particularly if thosemethods are pre-defined in the protocol. Definition of methods may be refined byupdating this aspect in the statistical analysis plan during the blind review.Unfortunately, no universally applicable methods of handling missing values can berecommended. An investigation should be made concerning the sensitivity of theresults of analysis to the method of handling missing values, especially if thenumber of missing values is substantial.

A similar approach should be adopted to exploring the influence of outliers, the sta-tistical definition of which is, to some extent, arbitrary. Clear identification of aparticular value as an outlier is most convincing when justified medically as well as

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statistically, and the medical context will then often define the appropriate action.Any outlier procedure set out in the protocol or the statistical analysis plan shouldbe such as not to favour any treatment group a priori. Once again, this aspect ofthe analysis can be usefully updated during blind review. If no procedure for dealingwith outliers was foreseen in the trial protocol, one analysis with the actual valuesand at least one other analysis eliminating or reducing the outlier effect should beperformed and differences between their results discussed.

5.4 Data TransformationThe decision to transform key variables prior to analysis is best made during thedesign of the trial on the basis of similar data from earlier clinical trials.Transformations (e.g. square root, logarithm) should be specified in the protocoland a rationale provided, especially for the primary variable(s). The general princi-ples guiding the use of transformations to ensure that the assumptions underlyingthe statistical methods are met are to be found in standard texts; conventions forparticular variables have been developed in a number of specific clinical areas. Thedecision on whether and how to transform a variable should be influenced by thepreference for a scale which facilitates clinical interpretation.

Similar considerations apply to other derived variables, such as the use of changefrom baseline, percentage change from baseline, the ‘area under the curve’ ofrepeated measures, or the ratio of two different variables. Subsequent clinical inter-pretation should be carefully considered, and the derivation should be justified inthe protocol. Closely related points are made in Section 2.2.2.

5.5 Estimation, Confidence Intervals and Hypothesis TestingThe statistical section of the protocol should specify the hypotheses that are to betested and/or the treatment effects which are to be estimated in order to satisfythe primary objectives of the trial. The statistical methods to be used to accomplishthese tasks should be described for the primary (and preferably the secondary) vari-ables, and the underlying statistical model should be made clear. Estimates of treat-ment effects should be accompanied by confidence intervals, whenever possible,and the way in which these will be calculated should be identified. A descriptionshould be given of any intentions to use baseline data to improve precision or toadjust estimates for potential baseline differences, for example by means of analysisof covariance.

It is important to clarify whether one- or two-sided tests of statistical significancewill be used, and in particular to justify prospectively the use of one-sided tests. Ifhypothesis tests are not considered appropriate, then the alternative process forarriving at statistical conclusions should be given. The issue of one-sided or two-sided approaches to inference is controversial and a diversity of views can be foundin the statistical literature. The approach of setting type I errors for one-sided testsat half the conventional type I error used in two-sided tests is preferable in regu-latory settings. This promotes consistency with the two-sided confidence intervalsthat are generally appropriate for estimating the possible size of the differencebetween two treatments.

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The particular statistical model chosen should reflect the current state of medicaland statistical knowledge about the variables to be analysed as well as the statis-tical design of the trial. All effects to be fitted in the analysis (for example inanalysis of variance models) should be fully specified, and the manner, if any, inwhich this set of effects might be modified in response to preliminary results shouldbe explained. The same considerations apply to the set of covariates fitted in ananalysis of covariance. (See also Section 5.7.). In the choice of statistical methodsdue attention should be paid to the statistical distribution of both primary and sec-ondary variables. When making this choice (for example between parametric andnon-parametric methods) it is important to bear in mind the need to provide sta-tistical estimates of the size of treatment effects together with confidence inter-vals (in addition to significance tests).

The primary analysis of the primary variable should be clearly distinguished fromsupporting analyses of the primary or secondary variables. Within the statisticalsection of the protocol or the statistical analysis plan there should also be an out-line of the way in which data other than the primary and secondary variables willbe summarized and reported. This should include a reference to any approachesadopted for the purpose of achieving consistency of analysis across a range of trials,for example for safety data.

Modelling approaches that incorporate information on known pharmacological para-meters, the extent of protocol compliance for individual subjects or other biologi-cally based data may provide valuable insights into actual or potential efficacy,especially with regard to estimation of treatment effects. The assumptions under-lying such models should always be clearly identified, and the limitations of anyconclusions should be carefully described.

5.6 Adjustment of Significance and Confidence LevelsWhen multiplicity is present, the usual frequentist approach to the analysis of clin-ical trial data may necessitate an adjustment to the type I error. Multiplicity mayarise, for example, from multiple primary variables (see Section 2.2.2), multiplecomparisons of treatments, repeated evaluation over time and/or interim analyses(see Section 4.5). Methods to avoid or reduce multiplicity are sometimes preferablewhen available, such as the identification of the key primary variable (multiple vari-ables), the choice of a critical treatment contrast (multiple comparisons), the useof a summary measure such as ‘area under the curve’ (repeated measures). In con-firmatory analyses, any aspects of multiplicity which remain after steps of this kindhave been taken should be identified in the protocol; adjustment should always beconsidered and the details of any adjustment procedure or an explanation of whyadjustment is not thought to be necessary should be set out in the analysis plan.

5.7 Subgroups, Interactions and CovariatesThe primary variable(s) is often systematically related to other influences apartfrom treatment. For example, there may be relationships to covariates such as ageand sex, or there may be differences between specific subgroups of subjects suchas those treated at the different centres of a multicentre trial. In some instances

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an adjustment for the influence of covariates or for subgroup effects is an integralpart of the planned analysis and hence should be set out in the protocol. Pre-trialdeliberations should identify those covariates and factors expected to have animportant influence on the primary variable(s), and should consider how to accountfor these in the analysis in order to improve precision and to compensate for anylack of balance between treatment groups. If one or more factors are used tostratify the design, it is appropriate to account for those factors in the analysis.When the potential value of an adjustment is in doubt, it is often advisable to nom-inate the unadjusted analysis as the one for primary attention, the adjustedanalysis being supportive. Special attention should be paid to centre effects and tothe role of baseline measurements of the primary variable. It is not advisable toadjust the main analyses for covariates measured after randomization because theymay be affected by the treatments.

The treatment effect itself may also vary with subgroup or covariate – for example,the effect may decrease with age or may be larger in a particular diagnostic cate-gory of subjects. In some cases such interactions are anticipated or are of partic-ular prior interest (e.g. geriatrics), and hence a subgroup analysis, or a statisticalmodel including interactions, is part of the planned confirmatory analysis. In mostcases, however, subgroup or interaction analyses are exploratory and should beclearly identified as such; they should explore the uniformity of any treatmenteffects found overall. In general, such analyses should proceed first through theaddition of interaction terms to the statistical model in question, complemented byadditional exploratory analysis within relevant subgroups of subjects, or withinstrata defined by the covariates. When exploratory, these analyses should be inter-preted cautiously; any conclusion of treatment efficacy (or lack thereof) or safetybased solely on exploratory subgroup analyses are unlikely to be accepted.

5.8 Integrity of Data and Computer Software ValidityThe credibility of the numerical results of the analysis depends on the quality andvalidity of the methods and software (both internally and externally written) usedboth for data management (data entry, storage, verification, correction andretrieval) and also for processing the data statistically. Data management activitiesshould therefore be based on thorough and effective standard operating procedures.The computer software used for data management and statistical analysis should bereliable, and documentation of appropriate software testing procedures should beavailable.

6. EVALUATION OF SAFETY AND TOLERABILITY 6.1 Scope of EvaluationIn all clinical trials evaluation of safety and tolerability (see Glossary) constitutesan important element. In early phases this evaluation is mostly of an exploratorynature, and is only sensitive to frank expressions of toxicity, whereas in later phasesthe establishment of the safety and tolerability profile of a drug can be character-ized more fully in larger samples of subjects. Later phase controlled trials represent

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an important means of exploring in an unbiased manner any new potential adverseeffects, even if such trials generally lack power in this respect.

Certain trials may be designed with the purpose of making specific claims aboutsuperiority or equivalence with regard to safety and tolerability compared toanother drug or to another dose of the investigational drug. Such specific claimsshould be supported by relevant evidence from confirmatory trials, similar to thatnecessary for corresponding efficacy claims.

6.2 Choice of Variables and Data CollectionIn any clinical trial the methods and measurements chosen to evaluate the safetyand tolerability of a drug will depend on a number of factors, including knowledgeof the adverse effects of closely related drugs, information from non-clinical andearlier clinical trials and possible consequences of the pharmacodynamic/pharma-cokinetic properties of the particular drug, the mode of administration, the type of subjects to be studied, and the duration of the trial. Laboratory tests concern-ing clinical chemistry and haematology, vital signs, and clinical adverse events (diseases, signs and symptoms) usually form the main body of the safety andtolerability data. The occurrence of serious adverse events and treatment discon-tinuations due to adverse events are particularly important to register (see ICH E2Aand ICH E3).

Furthermore, it is recommended that a consistent methodology be used for the datacollection and evaluation throughout a clinical trial program in order to facilitatethe combining of data from different trials. The use of a common adverse event dic-tionary is particularly important. This dictionary has a structure which gives thepossibility to summarize the adverse event data on three different levels; system-organ class, preferred term or included term (see Glossary). The preferred term isthe level on which adverse events usually are summarized, and preferred termsbelonging to the same system-organ class could then be brought together in thedescriptive presentation of data (see ICH M1).

6.3 Set of Subjects to be Evaluated and Presentation of DataFor the overall safety and tolerability assessment, the set of subjects to be sum-marized is usually defined as those subjects who received at least one dose of theinvestigational drug. Safety and tolerability variables should be collected as com-prehensively as possible from these subjects, including type of adverse event,severity, onset and duration (see ICH E2B). Additional safety and tolerability eval-uations may be needed in specific subpopulations, such as females, the elderly (seeICH E7), the severely ill, or those who have a common concomitant treatment.These evaluations may need to address more specific issues (see ICH E3).

All safety and tolerability variables will need attention during evaluation, and thebroad approach should be indicated in the protocol. All adverse events should bereported, whether or not they are considered to be related to treatment. All avail-able data in the study population should be accounted for in the evaluation.Definitions of measurement units and reference ranges of laboratory variables

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should be made with care; if different units or different reference ranges appear inthe same trial (e.g. if more than one laboratory is involved), then measurementsshould be appropriately standardized to allow a unified evaluation. Use of a toxi-city grading scale should be prespecified and justified.

The incidence of a certain adverse event is usually expressed in the form of a pro-portion relating number of subjects experiencing events to number of subjects atrisk. However, it is not always self-evident how to assess incidence. For example,depending on the situation the number of exposed subjects or the extent of expo-sure (in person-years) could be considered for the denominator. Whether the pur-pose of the calculation is to estimate a risk or to make a comparison between treat-ment groups it is important that the definition is given in the protocol. This isespecially important if long-term treatment is planned and a substantial proportionof treatment withdrawals or deaths are expected. For such situations survivalanalysis methods should be considered and cumulative adverse event rates calcu-lated in order to avoid the risk of underestimation.

In situations when there is a substantial background noise of signs and symptoms(e.g. in psychiatric trials) one should consider ways of accounting for this in theestimation of risk for different adverse events. One such method is to make use ofthe ‘treatment emergent’ (see Glossary) concept in which adverse events arerecorded only if they emerge or worsen relative to pretreatment baseline.

Other methods to reduce the effect of the background noise may also be appropriatesuch as ignoring adverse events of mild severity or requiring that an event shouldhave been observed at repeated visits to qualify for inclusion in the numerator.Such methods should be explained and justified in the protocol.

6.4 Statistical EvaluationThe investigation of safety and tolerability is a multidimensional problem. Althoughsome specific adverse effects can usually be anticipated and specifically monitoredfor any drug, the range of possible adverse effects is very large, and new and unfore-seeable effects are always possible. Further, an adverse event experienced after aprotocol violation, such as use of an excluded medication, may introduce a bias.This background underlies the statistical difficulties associated with the analyticalevaluation of safety and tolerability of drugs, and means that conclusive informa-tion from confirmatory clinical trials is the exception rather than the rule.

In most trials the safety and tolerability implications are best addressed by applyingdescriptive statistical methods to the data, supplemented by calculation of confi-dence intervals wherever this aids interpretation. It is also valuable to make use ofgraphical presentations in which patterns of adverse events are displayed bothwithin treatment groups and within subjects.

The calculation of p-values is sometimes useful either as an aid to evaluating a spe-cific difference of interest, or as a ‘flagging’ device applied to a large number ofsafety and tolerability variables to highlight differences worth further attention.This is particularly useful for laboratory data, which otherwise can be difficult tosummarize appropriately. It is recommended that laboratory data be subjected toboth a quantitative analysis, e.g. evaluation of treatment means, and a qualitative

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analysis where counting of numbers above or below certain thresholds are calcu-lated.

If hypothesis tests are used, statistical adjustments for multiplicity to quantify thetype I error are appropriate, but the type II error is usually of more concern. Careshould be taken when interpreting putative statistically significant findings whenthere is no multiplicity adjustment.

In the majority of trials investigators are seeking to establish that there are no clin-ically unacceptable differences in safety and tolerability compared with either acomparator drug or a placebo. As is the case for non-inferiority or equivalence eval-uation of efficacy the use of confidence intervals is preferred to hypothesis testingin this situation. In this way, the considerable imprecision often arising from lowfrequencies of occurrence is clearly demonstrated.

6.5 Integrated SummaryThe safety and tolerability properties of a drug are commonly summarized acrosstrials continuously during an investigational product’s development and in partic-ular at the time of a marketing application. The usefulness of this summary, how-ever, is dependent on adequate and well-controlled individual trials with high dataquality.

The overall usefulness of a drug is always a question of balance between risk andbenefit and in a single trial such a perspective could also be considered, even if the assessment of risk/benefit usually is performed in the summary of the entireclinical trial program. (See Section 7.2.2)

For more details on the reporting of safety and tolerability, see Chapter 12 of ICH E3.

7. REPORTING7.1 Evaluation and ReportingAs stated in the Introduction, the structure and content of clinical study reports isthe subject of ICH E3. That ICH guidance fully covers the reporting of statisticalwork, appropriately integrated with clinical and other material. The current sectionis therefore relatively brief.

During the planning phase of a trial the principal features of the analysis shouldhave been specified in the protocol as described in Section 5. When the conduct ofthe trial is over and the data are assembled and available for preliminary inspec-tion, it is valuable to carry out the blind review of the planned analysis alsodescribed in Section 5. This pre-analysis review, blinded to treatment, should coverdecisions concerning, for example, the exclusion of subjects or data from theanalysis sets; possible transformations may also be checked, and outliers defined;important covariates identified in other recent research may be added to the model;the use of parametric or non-parametric methods may be reconsidered. Decisionsmade at this time should be described in the report, and should be distinguishedfrom those made after the statistician has had access to the treatment codes, asblind decisions will generally introduce less potential for bias. Statisticians or other

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staff involved in unblinded interim analysis should not participate in the blindreview or in making modifications to the statistical analysis plan. When the blindingis compromised by the possibility that treatment induced effects may be apparentin the data, special care will be needed for the blind review.

Many of the more detailed aspects of presentation and tabulation should be final-ized at or about the time of the blind review so that by the time of the actualanalysis full plans exist for all its aspects including subject selection, data selec-tion and modification, data summary and tabulation, estimation and hypothesistesting. Once data validation is complete, the analysis should proceed according tothe pre-defined plans; the more these plans are adhered to, the greater the credi-bility of the results. Particular attention should be paid to any differences betweenthe planned analysis and the actual analysis as described in the protocol, protocolamendments or the updated statistical analysis plan based on a blind review ofdata. A careful explanation should be provided for deviations from the plannedanalysis.All subjects who entered the trial should be accounted for in the report, whether ornot they are included in the analysis. All reasons for exclusion from analysis shouldbe documented; for any subject included in the full analysis set but not in the perprotocol set, the reasons for exclusion from the latter should also be documented.Similarly, for all subjects included in an analysis set, the measurements of all impor-tant variables should be accounted for at all relevant time-points.The effect of all losses of subjects or data, withdrawals from treatment and majorprotocol violations on the main analyses of the primary variable(s) should be con-sidered carefully. Subjects lost to follow up, withdrawn from treatment, or with asevere protocol violation should be identified, and a descriptive analysis of themprovided, including the reasons for their loss and its relationship to treatment andoutcome.Descriptive statistics form an indispensable part of reports. Suitable tables and/orgraphical presentations should illustrate clearly the important features of the pri-mary and secondary variables and of key prognostic and demographic variables. Theresults of the main analyses relating to the objectives of the trial should be the sub-ject of particularly careful descriptive presentation. When reporting the results ofsignificance tests, precise p-values (e.g. ‘p = 0.034’) should be reported rather than making exclusive reference to critical values.Although the primary goal of the analysis of a clinical trial should be to answer thequestions posed by its main objectives, new questions based on the observed datamay well emerge during the unblinded analysis. Additional and perhaps complexstatistical analysis may be the consequence. This additional work should be strictlydistinguished in the report from work which was planned in the protocol.The play of chance may lead to unforeseen imbalances between the treatmentgroups in terms of baseline measurements not pre-defined as covariates in theplanned analysis but having some prognostic importance nevertheless. This is bestdealt with by showing that an additional analysis which accounts for these imbal-ances reaches essentially the same conclusions as the planned analysis. If this isnot the case, the effect of the imbalances on the conclusions should be discussed.

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In general, sparing use should be made of unplanned analyses. Such analyses areoften carried out when it is thought that the treatment effect may vary accordingto some other factor or factors. An attempt may then be made to identify subgroupsof subjects for whom the effect is particularly beneficial. The potential dangers ofover-interpretation of unplanned subgroup analyses are well known (see alsoSection 5.7), and should be carefully avoided. Although similar problems of inter-pretation arise if a treatment appears to have no benefit, or an adverse effect, ina subgroup of subjects, such possibilities should be properly assessed and shouldtherefore be reported. Finally statistical judgement should be brought to bear on the analysis, interpreta-tion and presentation of the results of a clinical trial. To this end the trial statisti-cian should be a member of the team responsible for the clinical study report, andshould approve the clinical report.

7.2 Summarizing the Clinical DatabaseAn overall summary and synthesis of the evidence on safety and efficacy from allthe reported clinical trials is required for a marketing application (Expert report inEU, integrated summary reports in USA, Gaiyo in Japan). This may be accompanied,when appropriate, by a statistical combination of results.

Within the summary a number of areas of specific statistical interest arise:describing the demography and clinical features of the population treated duringthe course of the clinical trial programme; addressing the key questions of efficacyby considering the results of the relevant (usually controlled) trials and highlightingthe degree to which they reinforce or contradict each other; summarising the safetyinformation available from the combined database of all the trials whose resultscontribute to the marketing application and identifying potential safety issues.During the design of a clinical programme careful attention should be paid to theuniform definition and collection of measurements which will facilitate subsequentinterpretation of the series of trials, particularly if they are likely to be combinedacross trials. A common dictionary for recording the details of medication, medicalhistory and adverse events should be selected and used. A common definition ofthe primary and secondary variables is nearly always worthwhile, and essential formeta-analysis. The manner of measuring key efficacy variables, the timing of assess-ments relative to randomization/entry, the handling of protocol violators and devi-ators and perhaps the definition of prognostic factors, should all be kept compat-ible unless there are valid reasons not to do so.

Any statistical procedures used to combine data across trials should be described indetail. Attention should be paid to the possibility of bias associated with the selec-tion of trials, to the homogeneity of their results, and to the proper modelling ofthe various sources of variation. The sensitivity of conclusions to the assumptionsand selections made should be explored.

7.2.1 EFFICACY DATA

Individual clinical trials should always be large enough to satisfy their objectives.Additional valuable information may also be gained by summarising a series of clin-

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ical trials which address essentially identical key efficacy questions. The mainresults of such a set of trials should be presented in an identical form to permitcomparison, usually in tables or graphs which focus on estimates plus confidencelimits. The use of meta-analytic techniques to combine these estimates is often auseful addition, because it allows a more precise overall estimate of the size of thetreatment effects to be generated, and provides a complete and concise summaryof the results of the trials. Under exceptional circumstances a meta analyticapproach may also be the most appropriate way, or the only way, of providing suf-ficient overall evidence of efficacy via an overall hypothesis test. When used for thispurpose the meta-analysis should have its own prospectively written protocol.

7.2.2 SAFETY DATAIn summarizing safety data it is important to examine the safety database thor-oughly for any indications of potential toxicity, and to follow up any indications bylooking for an associated supportive pattern of observations. The combination ofthe safety data from all human exposure to the drug provides an important sourceof information, because its larger sample size provides the best chance of detectingthe rarer adverse events and, perhaps, of estimating their approximate incidence.However, incidence data from this database are difficult to evaluate because of thelack of a comparator group, and data from comparative trials are especially valuablein overcoming this difficulty. The results from trials which use a common com-parator (placebo or specific active comparator) should be combined and presentedseparately for each comparator providing sufficient data.

All indications of potential toxicity arising from exploration of the data should bereported. The evaluation of the reality of these potential adverse effects should takeaccount of the issue of multiplicity arising from the numerous comparisons made.The evaluation should also make appropriate use of survival analysis methods toexploit the potential relationship of the incidence of adverse events to duration ofexposure and/or follow-up. The risks associated with identified adverse effectsshould be appropriately quantified to allow a proper assessment of the risk/benefitrelationship.

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GLOSSARY

Bayesian ApproachesApproaches to data analysis that provide a posterior probability distribution forsome parameter (e.g. treatment effect), derived from the observed data and a priorprobability distribution for the parameter. The posterior distribution is then used asthe basis for statistical inference.

Bias (Statistical & Operational)The systematic tendency of any factors associated with the design, conduct,analysis and evaluation of the results of a clinical trial to make the estimate of atreatment effect deviate from its true value. Bias introduced through deviations inconduct is referred to as ‘operational’ bias. The other sources of bias listed aboveare referred to as ‘statistical’.

Blind ReviewThe checking and assessment of data during the period of time between trial com-pletion (the last observation on the last subject) and the breaking of the blind, forthe purpose of finalizing the planned analysis.

Content ValidityThe extent to which a variable (e.g. a rating scale) measures what it is supposed tomeasure.

Double-DummyA technique for retaining the blind when administering supplies in a clinical trial,when the two treatments cannot be made identical. Supplies are prepared forTreatment A (active and indistinguishable placebo) and for Treatment B (active andindistinguishable placebo). Subjects then take two sets of treatment; either A(active) and B (placebo), or A (placebo) and B (active).

DropoutA subject in a clinical trial who for any reason fails to continue in the trial untilthe last visit required of him/her by the study protocol.

Equivalence TrialA trial with the primary objective of showing that the response to two or moretreatments differs by an amount which is clinically unimportant. This is usuallydemonstrated by showing that the true treatment difference is likely to lie betweena lower and an upper equivalence margin of clinically acceptable differences.

Frequentist MethodsStatistical methods, such as significance tests and confidence intervals, which canbe interpreted in terms of the frequency of certain outcomes occurring in hypo-thetical repeated realizations of the same experimental situation.

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Full Analysis SetThe set of subjects that is as close as possible to the ideal implied by the inten-tion-to-treat principle. It is derived from the set of all randomized subjects by min-imal and justified elimination of subjects.

Generalizability, GeneralizationThe extent to which the findings of a clinical trial can be reliably extrapolated fromthe subjects who participated in the trial to a broader patient population and abroader range of clinical settings.

Global Assessment VariableA single variable, usually a scale of ordered categorical ratings, which integratesobjective variables and the investigator’s overall impression about the state orchange in state of a subject.

Independent Data Monitoring Committee (IDMC) (Data and Safety MonitoringBoard, Monitoring Committee, Data Monitoring Committee)An independent data-monitoring committee that may be established by the sponsorto assess at intervals the progress of a clinical trial, the safety data, and the criti-cal efficacy endpoints, and to recommend to the sponsor whether to continue,modify, or stop a trial.

Intention-To-Treat PrincipleThe principle that asserts that the effect of a treatment policy can be best assessedby evaluating on the basis of the intention to treat a subject (i.e. the planned treat-ment regimen) rather than the actual treatment given. It has the consequence thatsubjects allocated to a treatment group should be followed up, assessed andanalysed as members of that group irrespective of their compliance to the plannedcourse of treatment.

Interaction (Qualitative & Quantitative)The situation in which a treatment contrast (e.g. difference between investigationalproduct and control) is dependent on another factor (e.g. centre). A quantitativeinteraction refers to the case where the magnitude of the contrast differs at the dif-ferent levels of the factor, whereas for a qualitative interaction the direction of thecontrast differs for at least one level of the factor.

Inter-Rater ReliabilityThe property of yielding equivalent results when used by different raters on dif-ferent occasions.

Intra-Rater ReliabilityThe property of yielding equivalent results when used by the same rater on differentoccasions.

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Interim AnalysisAny analysis intended to compare treatment arms with respect to efficacy or safetyat any time prior to the formal completion of a trial.

Meta-AnalysisThe formal evaluation of the quantitative evidence from two or more trials bearingon the same question. This most commonly involves the statistical combination ofsummary statistics from the various trials, but the term is sometimes also used torefer to the combination of the raw data.

Multicentre TrialA clinical trial conducted according to a single protocol but at more than one site,and therefore, carried out by more than one investigator.

Non-Inferiority TrialA trial with the primary objective of showing that the response to the investiga-tional product is not clinically inferior to a comparative agent (active or placebocontrol).

Preferred and Included TermsIn a hierarchical medical dictionary, for example MedDRA, the included term is thelowest level of dictionary term to which the investigator description is coded. Thepreferred term is the level of grouping of included terms typically used in reportingfrequency of occurrence. For example, the investigator text “Pain in the left arm”might be coded to the included term “Joint pain”, which is reported at the preferredterm level as “Arthralgia”.

Per Protocol Set (Valid Cases, Efficacy Sample, Evaluable Subjects Sample)The set of data generated by the subset of subjects who complied with the protocolsufficiently to ensure that these data would be likely to exhibit the effects of treat-ment, according to the underlying scientific model. Compliance covers such consid-erations as exposure to treatment, availability of measurements and absence ofmajor protocol violations.

Safety & TolerabilityThe safety of a medical product concerns the medical risk to the subject, usuallyassessed in a clinical trial by laboratory tests (including clinical chemistry andhaematology), vital signs, clinical adverse events (diseases, signs and symptoms),and other special safety tests (e.g. ECGs, ophthalmology). The tolerability of themedical product represents the degree to which overt adverse effects can be toler-ated by the subject.

Statistical Analysis PlanA statistical analysis plan is a document that contains a more technical and detailedelaboration of the principal features of the analysis described in the protocol, and

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includes detailed procedures for executing the statistical analysis of the primary andsecondary variables and other data.

Superiority TrialA trial with the primary objective of showing that the response to the investiga-tional product is superior to a comparative agent (active or placebo control).

Surrogate VariableA variable that provides an indirect measurement of effect in situations where directmeasurement of clinical effect is not feasible or practical.

Treatment EffectAn effect attributed to a treatment in a clinical trial. In most clinical trials thetreatment effect of interest is a comparison (or contrast) of two or more treatments.

Treatment EmergentAn event that emerges during treatment having been absent pre-treatment, orworsens relative to the pre-treatment state.

Trial StatisticianA statistician who has a combination of education/training and experience suffi-cient to implement the principles in this guidance and who is responsible for thestatistical aspects of the trial.

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Declaration of Helsinki

Recommendations guiding physicians in biomedical research involving humansubjects

Adopted by the 18th World Medical Assembly, Helsinki, Finland, June 1964 andamended in Tokyo 1975, in Venice 1983, in Hong Kong 1989 and in South Africa,October 1996.

Introduction

It is the mission of the physician to safeguard the health of the people. His or herknowledge and conscience are dedicated to the fulfilment of this mission.

The Declaration of Geneva of the World Medical Association binds the physician withthe words, “The health of my patient will be my first consideration”, and theInternational Code of Medical Ethics declares that “A physician shall act only in thepatient’s interest when providing medical care which might have the effect of weak-ening the physical and mental condition of the patient”.

The purpose of biomedical research involving human subjects must be to improvediagnostic, therapeutic and prophylactic procedures and the understanding of aeti-ology and pathogenesis of disease.

In current medical practice most diagnostic, therapeutic or prophylactic proceduresinvolve hazards. This applies especially to biomedical research.

Medical progress is based on research in which ultimately must rest in part onexperimentation involving human subjects.

In the field of biomedical research a fundamental distinction must be recognizedbetween medical research in which the aim is essentially diagnostic or therapeuticfor a patient, and medical research, the essential object of which is purely scien-tific and without implying direct diagnostic or therapeutic value to the person sub-jected to the research.

Special caution must be exercized in the conduct of research, which may affect theenvironment, and the welfare of animals used for research must be respected.

Because it is essential that the results of laboratory experiments be applied tohuman beings to further scientific knowledge and to help suffering humanity, theWorld Medical Association has prepared the following recommendations as a guideto every physician in biomedical research involving human subjects. They should bekept under review in the future. It must be stressed that the standards as draftedare only a guide to physicians all over the world. Physicians are not relieved fromcriminal, civil and ethical responsibilities under the laws of their own countries.

I. Basic principles

1. Biomedical research involving human subjects must conform to generallyaccepted scientific principles and should be based on adequately performed labora-

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tory and animal experimentation and on a thorough knowledge of the scientificliterature.

2. The design and performance of each experimental procedure involving humansubjects should be clearly formulated in an experimental protocol which should betransmitted for consideration, comment and guidance to a especially appointedcommittee independent of the investigator and the sponsor provided that this inde-pendent committee is in conformity which the laws and the regulation of thecountry in which the research is performed.

3. Biomedical research involving human subjects should be conducted only byscientifically qualified persons and under the supervision of a clinically competentmedical person. The responsibility for the human subject must always rest with amedically qualified person and never rest on the subject of the research, eventhough the subject has given his or her consent.

4. Biomedical research involving human subjects cannot legitimately be carriedout unless the importance of the objective is in proportion to the inherent risk tothe subject.

5. Every biomedical research project involving human subjects should be precededby careful assessment of predictable risks in comparison with foreseeable benefitsto the subject or to others. Concern for the interests of the subject must always pre-vail over other interests of science and society.

6. The right of the research subject to safeguard his or her integrity must alwaysbe respected. Every precaution should be taken to respect the privacy of the sub-ject and to minimize the impact of the study on the subject’s physical and mentalintegrity and on the personality of the subject.

7. Physicians should abstain from engaging in research projects involving humansubjects unless they are satisfied that the hazards involved are believed to be pre-dictable. Physicians should cease any investigation if the hazards are found to out-weigh the potential benefits.

8. In publication of the results of his or her research, the physician is obliged topreserve the accuracy of the results. Reports of experimentation not in accordancewith the principles laid down in this Declaration should not be accepted for publi-cation.

9. In any research on human beings, each potential subject must be adequatelyinformed of the aims, methods, anticipated benefits and potential hazards of thestudy and the discomfort it may entail. He or she should be informed that he or sheis at liberty to abstain from participation in the study and that he or she is free towithdraw his or her consent to participation at any time. The physician should thenobtain the subject’s freely-given informed consent, preferably in writing.

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10. When obtaining informed consent for the research project the physicianshould be particularly cautious if the subject is in a dependent relationship to himor her or may consent under duress. In that case the informed consent should beobtained by a physician who is not engaged in the investigation and who is com-pletely independent of this official relationship.

11. In the case of legal incompetence, informed consent should be obtained fromthe legal guardian in accordance with national legislation. Where physical or mentalincapacity makes it impossible to obtain informed consent, or when the subject isa minor, permission from the responsible relative replaces that of the subject inaccordance with national legislation.

Whenever the minor child is in fact able to give a consent, the minor’s consent mustbe obtained in addition to the consent of the minor’s legal guardian.

12. The research protocol should always contain a statement of the ethical con-siderations involved and should indicate that the principles enunciated in the pre-sent Declaration are complied with.

II. Medical research combined with professional care (clinical research)

1. In the treatment of the sick person, the physician must be free to use a newdiagnostic and therapeutic measure, if in his or her judgement it offers hope ofsaving life, re-establishing health or alleviating suffering.

2. The potential benefits, hazards or discomfort of a new method should beweighed against the advantages of the best current diagnostic and therapeuticmethods.

3. In any medical study, every patient – including those of a control group, if any – should be assured of the best proven diagnostic and therapeutic method. Thisdoes not exclude the use of inert placebo in studies where no proven diagnostic ortherapeutic method exists.

4. The refusal of the patient to participate in a study must never interfere withthe physician-patient relationship.

5. If the physician considers it essential not to obtain informed consent, the spe-cific reasons for this proposal should be stated in the experimental protocol fortransmission to the independent committee.

6. The physician can combine medical research with professional care, the objec-tive being the acquisition of new medical knowledge, only to the extent thatmedical research is justified by its potential diagnostic or therapeutic value for thepatient.

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III. Non therapeutic biomedical research involving human subjects(non-clinical biomedical research)

1. In the purely scientific application of medical research carried out on a humanbeing, it is the duty of the physician to remain the protector of the life and healthof that person on whom biomedical research is being carried out.

2. The subjects should be volunteers – either healthy persons or patients forwhom the experimental design is not related to the patient’s illness.

3. The investigator or the investigating team should discontinue the research ifin his/her or their judgement it may, if continued, be harmful to the individual.

4. In research on man, the interests of science and society should never takeprecedence over considerations related to the well-being of the subject.

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Initiated: 1964 17.COriginal: English

WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI

Ethical Principlesfor

Medical Research Involving Human Subjects

Adopted by the 18th WMA General AssemblyHelsinki, Finland, June 1964

and amended by the29th WMA General Assembly, Tokyo, Japan, October 197535th WMA General Assembly, Venice, Italy, October 198341st WMA General Assembly, Hong Kong, September 1989

48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996and the

52nd WMA General Assembly, Edinburgh, Scotland, October 2000

A. INTRODUCTION

1. The World Medical Association has developed the Declaration of Helsinki as astatement of ethical principles to provide guidance to physicians and otherparticipants in medical research involving human subjects. Medical researchinvolving human subjects includes research on identifiable human material oridentifiable data.

2. It is the duty of the physician to promote and safeguard the health of thepeople. The physician’s knowledge and conscience are dedicated to the fulfil-ment of this duty.

3. The Declaration of Geneva of the World Medical Association binds the physi-cian with the words, “The health of my patient will be my first consideration”,and the International Code of Medical Ethics declares that, “A physician shallact only in the patient’s interest when providing medical care which mighthave the effect of weakening the physical and mental condition of thepatient”.

4. Medical progress is based on research which ultimately must rest in part onexperimentation involving human subjects.

5. In medical research on human subjects, considerations related to the well-being of the human subject should take precedence over the interests ofscience and society.

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6. The primary purpose of medical research involving human subjects is toimprove prophylactic, diagnostic and therapeutic procedures and the under-standing of the aetiology and pathogenesis of disease. Even the best provenprophylactic, diagnostic, and therapeutic methods must continuously be chal-lenged through research for their effectiveness, efficiency, accessibility andquality.

7. In current medical practice and in medical research, most prophylactic, diag-nostic and therapeutic procedures involve risks and burdens.

8. Medical research is subject to ethical standards that promote respect for allhuman beings and protect their health and rights. Some research populationsare vulnerable and need special protection. The particular needs of the eco-nomically and medically disadvantaged must be recognized. Special attentionis also required for those who cannot give or refuse consent for themselves,for those who may be subject to giving consent under duress, for those whowill not benefit personally from the research and for those for whom theresearch is combined with care.

9. Research Investigators should be aware of the ethical, legal and regulatoryrequirements for research on human subjects in their own countries as well asapplicable international requirements. No national ethical, legal or regulatoryrequirement should be allowed to reduce or eliminate any of the protectionsfor human subjects set forth in this Declaration.

B. BASIC PRINCIPLES FOR ALL MEDICAL RESEARCH

10. It is the duty of the physician in medical research to protect the life, health,privacy, and dignity of the human subject.

11. Medical research involving human subjects must conform to generallyaccepted scientific principles, be based on a thorough knowledge of thescientific literature, other relevant sources of information, and on adequatelaboratory and, where appropriate, animal experimentation.

12. Appropriate caution must be exercised in the conduct of research which mayaffect the environment, and the welfare of animals used for research must berespected.

13. The design and performance of each experimental procedure involving humansubjects should be clearly formulated in an experimental protocol. This pro-tocol should be submitted for consideration, comment, guidance, and whereappropriate, approval to a specially appointed ethical review committee,which must be independent of the investigator, the sponsor or any other kindof undue influence. This independent committee should be in conformity with

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the laws and regulations of the country in which the research experiment is performed. The committee has the right to monitor ongoing trials. Theresearcher has the obligation to provide monitoring information to the com-mittee, especially any serious adverse events. The researcher should also sub-mit to the committee, for review, information regarding funding, sponsors,institutional affiliations, other potential conflicts of interest and incentivesfor subjects.

14. The research protocol should always contain a statement of the ethical con-siderations involved and should indicate that there is compliance with theprinciples enunciated in this Declaration.

15. Medical research involving human subjects should be conducted only byscientifically qualified persons and under the supervision of a clinically com-petent medical person. The responsibility for the human subject must alwaysrest with a medically qualified person and never rest on the subject of theresearch, even though the subject has given consent.

16. Every medical research project involving human subjects should be precededby careful assessment of predictable risks and burdens in comparison withforeseeable benefits to the subject or to others. This does not preclude theparticipation of healthy volunteers in medical research. The design of allstudies should be publicly available.

17. Physicians should abstain from engaging in research projects involving humansubjects unless they are confident that the risks involved have been ade-quately assessed and can be satisfactorily managed. Physicians should ceaseany investigation if the risks are found to outweigh the potential benefits orif there is conclusive proof of positive and beneficial results.

18. Medical research involving human subjects should only be conducted if theimportance of the objective outweighs the inherent risks and burdens to thesubject. This is especially important when the human subjects are healthyvolunteers.

19. Medical research is only justified if there is a reasonable likelihood that thepopulations in which the research is carried out stand to benefit from theresults of the research.

20. The subjects must be volunteers and informed participants in the researchproject.

21. The right of research subjects to safeguard their integrity must always berespected. Every precaution should be taken to respect the privacy of thesubject, the confidentiality of the patient’s information and to minimize the impact of the study on the subject’s physical and mental integrity and onthe personality of the subject.

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22. In any research on human beings, each potential subject must be adequate-ly informed of the aims, methods, sources of funding, any possible conflictsof interest, institutional affiliations of the researcher, the anticipated bene-fits and potential risks of the study and the discomfort it may entail. The sub-ject should be informed of the right to abstain from participation in the studyor to withdraw consent to participate at any time without reprisal. Afterensuring that the subject has understood the information, the physicianshould then obtain the subject’s freely-given informed consent, preferably inwriting. If the consent cannot be obtained in writing, the non-written con-sent must be formally documented and witnessed.

23. When obtaining informed consent for the research project the physicianshould be particularly cautious if the subject is in a dependent relationshipwith the physician or may consent under duress. In that case the informedconsent should be obtained by a well-informed physician who is not engagedin the investigation and who is completely independent of this relationship.

24. For a research subject who is legally incompetent, physically or mentally in-capable of giving consent or is a legally incompetent minor, the investigatormust obtain informed consent from the legally authorized representative in accordance with applicable law. These groups should not be included inresearch unless the research is necessary to promote the health of the popu-lation represented and this research cannot instead be performed on legallycompetent persons.

25. When a subject deemed legally incompetent, such as a minor child, is able togive assent to decisions about participation in research, the investigator mustobtain that assent in addition to the consent of the legally authorized repre-sentative.

26. Research on individuals from whom it is not possible to obtain consent,including proxy or advance consent, should be done only if the physical/mental condition that prevents obtaining informed consent is a necessarycharacteristic of the research population. The specific reasons for involvingresearch subjects with a condition that renders them unable to give informedconsent should be stated in the experimental protocol for consideration andapproval of the review committee. The protocol should state that consent toremain in the research should be obtained as soon as possible from the indi-vidual or a legally authorized surrogate.

27. Both authors and publishers have ethical obligations. In publication of theresults of research, the investigators are obliged to preserve the accuracy ofthe results. Negative as well as positive results should be published or other-wise publicly available. Sources of funding, institutional affiliations and anypossible conflicts of interest should be declared in the publication. Reportsof experimentation not in accordance with the principles laid down in thisDeclaration should not be accepted for publication.

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C. ADDITIONAL PRINCIPLES FOR MEDICAL RESEARCH COMBINED WITH MEDICAL CARE

28. The physician may combine medical research with medical care, only to theextent that the research is justified by its potential prophylactic, diagnosticor therapeutic value. When medical research is combined with medical care,additional standards apply to protect the patients who are research subjects.

29. The benefits, risks, burdens and effectiveness of a new method should betested against those of the best current prophylactic, diagnostic, and thera-peutic methods. This does not exclude the use of placebo, or no treatment,in studies where no proven prophylactic, diagnostic or therapeutic methodexists.

30. At the conclusion of the study, every patient entered into the study should beassured of access to the best proven prophylactic, diagnostic and therapeuticmethods identified by the study.

31. The physician should fully inform the patient which aspects of the care arerelated to the research. The refusal of a patient to participate in a study mustnever interfere with the patient-physician relationship.

32. In the treatment of a patient, where proven prophylactic, diagnostic andtherapeutic methods do not exist or have been ineffective, the physician,with informed consent from the patient, must be free to use unproven or new prophylactic, diagnostic and therapeutic measures, if in the physician’sjudgement it offers hope of saving life, re-establishing health or alleviatingsuffering. Where possible, these measures should be made the object ofresearch, designed to evaluate their safety and efficacy. In all cases, newinformation should be recorded and, where appropriate, published. The otherrelevant guidelines of this Declaration should be followed.

7.10.2000 09h14

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TDR/PRD/ETHICS/2000.1

Operational Guidelinesfor

Ethics Committees thatReview Biomedical Research

World Health OrganizationGeneva2000

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This document is not issued to the general public, and all rights are reserved by the World Health

Organization (WHO). The document may not be reviewed, abstracted, quoted, reproduced or trans-

lated, in part or in whole, without the prior written permission of WHO. No part of this document

may be stored in a retrieval system or transmitted in any form or by any means – electronic,

mechanical or other – without the prior written permission of WHO.

The views expressed in documents by named authors are solely the responsibility of those authors.

© World Health Organization 2000

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TABLE OF CONTENTS

Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1761. Objective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1772. The Role of an EC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1773. Establishing a System of Ethical Review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1774. Constituting an EC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 178

4.1 Membership Requirements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1784.2 Terms of Appointment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1794.3 Conditions of Appointment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1794.4 Offices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1794.5 Quorum Requirements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1794.6 Independent Consultants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1804.7 Education for EC Members . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 180

5. Submitting an Application . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1805.1 Application . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1805.2 Application Requirements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1805.3 Documentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181

6. Review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1826.1 Meeting Requirements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1826.2 Elements of the Review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1826.3 Expedited Review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185

7. Decision-Making . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1858. Communicating a Decision . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1869. Follow-Up . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 186

10. Documentation and Archiving . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187Glossary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 189Supporting Documents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191Committees . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 192Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194

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176 • Operational Guidelines for Ethics Committees that Review Biomedical Research

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PREFACE

The ethical and scientific standards for carrying out biomedical research on humansubjects have been developed and established in international guidelines, includ-ing the Declaration of Helsinki, the CIOMS International Ethical Guidelines forBiomedical Research Involving Human Subjects, and the WHO and ICH Guidelinesfor Good Clinical Practice. Compliance with these guidelines helps to ensure that thedignity, rights, safety, and well-being of research participants are promoted andthat the results of the investigations are credible.

All international guidelines require the ethical and scientific review of biomedicalresearch alongside informed consent and the appropriate protection of those unableto consent as essential measures to protect the individual person and the commu-nities who participate in research. For the purposes of these Guidelines, biomedicalresearch includes research on pharmaceuticals, medical devices, medical radiationand imaging, surgical procedures, medical records, and biological samples, as wellas epidemiological, social, and psychological investigations.

These Guidelines are intended to facilitate and support ethical review in all coun-tries around the world. They are based on a close examination of the requirementsfor ethical review as established in international guidelines, as well as on an eval-uation of existing practices of ethical review in countries around the world. They donot, however, purport to replace the need for national and local guidelines for theethical review of biomedical research, nor do they intend to supersede national lawsand regulations.

The majority of biomedical research has been predominantly motivated by concernfor the benefit of already privileged communities. This is reflected by the fact thatthe WHO estimates that 90% of the resources devoted to research and developmenton medical problems are applied to diseases causing less than 10% of the presentglobal suffering. The establishment of international guidelines that assist instrengthening the capacity for the ethical review of biomedical research in all coun-tries contributes to redressing this imbalance.

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1. OBJECTIVEThe objective of these Guidelines is to contribute to the development of quality and consistency in the ethical review of biomedical research. The Guidelines areintended to complement existing laws, regulations, and practices, and to serve asa basis upon which ethics committees (ECs) can develop their own specific writtenprocedures for their functions in biomedical research. In this regard, the Guidelinesestablish an international standard for ensuring quality in ethical review. TheGuidelines should be used by national and local bodies in developing, evaluating,and progressively refining standard operating procedures for the ethical review ofbiomedical research.

2. THE ROLE OF AN ECThe purpose of an EC in reviewing biomedical research is to contribute to safe-guarding the dignity, rights, safety, and well-being of all actual or potentialresearch participants. A cardinal principle of research involving human participantsis ‘respect for the dignity of persons’. The goals of research, while important, shouldnever be permitted to override the health, well-being, and care of research partici-pants. ECs should also take into consideration the principle of justice. Justicerequires that the benefits and burdens of research be distributed fairly among allgroups and classes in society, taking into account age, gender, economic status,culture, and ethnic considerations.

ECs should provide independent, competent, and timely review of the ethics ofproposed studies. In their composition, procedures, and decision-making, ECs need to have independence from political, institutional, professional, and market influ-ences. They need similarly to demonstrate competence and efficiency in their work.

ECs are responsible for carrying out the review of proposed research before the com-mencement of the research. They also need to ensure that there is regular evalua-tion of the ethics of ongoing studies that received a positive decision.

ECs are responsible for acting in the full interest of potential research participantsand concerned communities, taking into account the interests and needs of theresearchers, and having due regard for the requirements of relevant regulatory agen-cies and applicable laws.

3. ESTABLISHING A SYSTEM OF ETHICAL REVIEWCountries, institutions, and communities should strive to develop ECs and ethicalreview systems that ensure the broadest possible coverage of protection for poten-tial research participants and contribute to the highest attainable quality in thescience and ethics of biomedical research. States should promote, as appropriate,the establishment of ECs at the national, institutional, and local levels that areindependent, multi-disciplinary, multi-sectorial, and pluralistic in nature. ECs re-quire administrative and financial support.

Procedures need to be established for relating various levels of review in order toensure consistency and facilitate cooperation. Mechanism for cooperation and com-munication need to be developed between national committees and institutional

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and local committees. These mechanisms should ensure clear and efficient commu-nication. They should also promote the development of ethical review within acountry as well as the ongoing education of members of ethics committees. In addi-tion, procedures need to be established for the review of biomedical research pro-tocols carried out at more than one site in a country or in more than one country.A network of ethical review should be established at the regional, national, andlocal levels that ensures the highest competence in biomedical review while alsoguaranteeing input from all levels of the community.

4. CONSTITUTING AN ECECs should be constituted to ensure the competent review and evaluation of allethical aspects of the research projects they receive and to ensure that their taskscan be executed free from bias and influence that could affect their independence.

ECs should be multidisciplinary and multi-sectorial in composition, including rele-vant scientific expertise, balanced age and gender distribution, and laypersonsrepresenting the interests and the concerns of the community.

ECs should be established in accordance with the applicable laws and regulations ofthe country and in accordance with the values and principles of the communitiesthey serve.

ECs should establish publicly available standard operating procedures that state the authority under which the committee is established, the functions and duties of the EC, membership requirements, the terms of appointment, the conditions ofappointment, the offices, the structure of the secretariat, internal procedures, andthe quorum requirements. ECs should act in accordance with their written operatingprocedures.

It may be helpful to summarize the activities of the EC in a regular (annual) report.

4.1 Membership RequirementsClear procedures for identifying or recruiting potential EC members should be estab-lished. A statement should be drawn up of the requirements for candidacy thatincludes an outline of the duties and responsibilities of EC members.

Membership requirements should be established that include the following:

4.1.1 the name or description of the party responsible for making appointments;

4.1.2 the procedure for selecting members, including the method for appointinga member (e.g. by consensus, by majority vote, by direct appointment);

4.1.3 conflicts of interest should be avoided when making appointments, butwhere unavoidable there should be transparency with regard to such in-terests.

A rotation system for membership should be considered that allows for continuity,the development and maintenance of expertise within the EC, and the regular inputof fresh ideas and approaches.

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4.2 Terms of AppointmentTerms of appointment should be established that include the following:

4.2.1 the duration of an appointment,

4.2.2 the policy for the renewal of an appointment,

4.2.3 the disqualification procedure,

4.2.4 the resignation procedure,

4.2.5 the replacement procedure.

4.3 Conditions of AppointmentA statement of the conditions of appointment should be drawn up that includes thefollowing:

4.3.1 a member should be willing to publicize his/her full name, profession, andaffiliation;

4.3.2 all reimbursement for work and expenses, if any, within or related to an ECshould be recorded and made available to the public upon request;

4.3.3 a member should sign a confidentiality agreement regarding meetingdeliberations, applications, information on research participants, and re-lated matters; in addition, all EC administrative staff should sign a similarconfidentiality agreement.

4.4 OfficesECs should establish clearly defined offices for the good functioning of ethicalreview. A statement is required of the officers within the EC (e.g. chairperson, sec-retary), the requirements for holding each office, the terms and conditions of eachoffice, and the duties and responsibilities of each office (e.g. agenda, minutes,notification of decisions). Clear procedures for selecting or appointing officersshould be established.

In addition to the EC officers, an EC should have adequate support staff for carryingout its responsibilities.

4.5 Quorum RequirementsECs should establish specific quorum requirements for reviewing and deciding on anapplication. These requirements should include:

4.5.1 the minimum number of members required to compose a quorum (e.g.more than half the members);

4.5.2 the professional qualifications requirements (e.g. physician, lawyer, statis-tician, paramedical, layperson) and the distribution of those requirementsover the quorum; no quorum should consist entirely of members of oneprofession or one gender; a quorum should include at least one memberwhose primary area of expertise is in a non-scientific area, and at least onemember who is independent of the institution/research site.

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4.6 Independent ConsultantsECs may call upon, or establish a standing list of, independent consultants who mayprovide special expertise to the EC on proposed research protocols. These consul-tants may be specialists in ethical or legal aspects, specific diseases or methodolo-gies, or they may be representatives of communities, patients, or special interestgroups. Terms of reference for independent consultants should be established.

4.7 Education for EC MembersEC members have a need for initial and continued education regarding the ethicsand science of biomedical research. The conditions of appointment should state theprovisions available for EC members to receive introductory training in the work ofan EC as well as ongoing opportunities for enhancing their capacity for ethicalreview. These conditions should also include the requirements or expectationsregarding the initial and continuing education of EC members. This education maybe linked to co-operative arrangements with other ECs in the area, the country, andthe region, as well as other opportunities for the initial and continued training ofEC members.

5. SUBMITTING AN APPLICATIONECs are responsible for establishing well-defined requirements for submitting anapplication for review of a biomedical research project. These requirements shouldbe readily available to prospective applicants.

5.1 ApplicationAn application for review of the ethics of proposed biomedical research should besubmitted by a qualified researcher responsible for the ethical and scientific con-duct of the research.

5.2 Application RequirementsThe requirements for the submission of a research project for ethical review shouldbe clearly described in an application procedure. These requirements should includethe following:

5.2.1 the name(s) and address(es) of the EC secretariat or member(s) to whomthe application material is to be submitted;

5.2.2 the application form(s);

5.2.3 the format for submission;

5.2.4 the documentation (see 5.3);

5.2.5 the language(s) in which (core) documents are to be submitted;

5.2.6 the number of copies to be submitted;

5.2.7 the deadlines for submission of the application in relation to review dates;

5.2.8 the means by which applications will be acknowledged, including the com-munication of the incompleteness of an application;

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5.2.9 the expected time for notification of the decision following review;

5.2.10 the time frame to be followed in cases where the EC requests supplemen-tary information or changes to documents from the applicant;

5.2.11 the fee structure, if any, for reviewing an application;

5.2.12 the application procedure for amendments to the protocol, the recruitmentmaterial, the potential research participant information, or the informedconsent form.

5.3 DocumentationAll documentation required for a thorough and complete review of the ethics of pro-posed research should be submitted by the applicant. This may include, but is notlimited to,

5.3.1 signed and dated application form;

5.3.2 the protocol of the proposed research (clearly identified and dated),together with supporting documents and annexes;

5.3.3 a summary (as far as possible in non-technical language), synopsis, or dia-grammatic representation (‘flowchart’) of the protocol;

5.3.4 a description (usually included in the protocol) of the ethical considera-tions involved in the research;

5.3.5 case report forms, diary cards, and other questionnaires intended forresearch participants;

5.3.6 when the research involves a study product (such as a pharmaceutical ordevice under investigation), an adequate summary of all safety, pharma-cological, pharmaceutical, and toxicological data available on the studyproduct, together with a summary of clinical experience with the studyproduct to date (e.g. recent investigator’s brochure, published data, a sum-mary of the product’s characteristics);

5.3.7 investigator’s(s’) curriculum vitae (updated, signed, and dated);

5.3.8 material to be used (including advertisements) for the recruitment ofpotential research participants;

5.3.9 a description of the process used to obtain and document consent;

5.3.10 written and other forms of information for potential research participants(clearly identified and dated) in the language(s) understood by the poten-tial research participants and, when required, in other languages;

5.3.11 informed consent form (clearly identified and dated) in the language(s)understood by the potential research participants and, when required, inother languages;

5.3.12 a statement describing any compensation for study participation(including expenses and access to medical care) to be given to researchparticipants;

5.3.13 a description of the arrangements for indemnity, if applicable;

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5.3.14 a description of the arrangements for insurance coverage for research par-ticipants, if applicable;

5.3.15 a statement of agreement to comply with ethical principles set out inrelevant guidelines;

5.3.16 all significant previous decisions (e.g. those leading to a negative deci-sion or modified protocol) by other ECs or regulatory authorities for theproposed study (whether in the same location or elsewhere) and an indi-cation of modification(s) to the protocol made on that account. The rea-sons for previous negative decisions should be provided.

6. REVIEWAll properly submitted applications should be reviewed in a timely fashion andaccording to an established review procedure.

6.1 Meeting RequirementsECs should meet regularly on scheduled dates that are announced in advance. Themeeting requirements should include the following:

6.1.1 meetings should be planned in accordance with the needs of the workload;

6.1.2 EC members should be given enough time in advance of the meeting toreview the relevant documents;

6.1.3 meetings should be minuted; there should be an approval procedure for theminutes;

6.1.4 the applicant, sponsor, and/or investigator may be invited to present theproposal or elaborate on specific issues;

6.1.5 independent consultants may be invited to the meeting or to providewritten comments, subject to applicable confidentiality agreements.

6.2 Elements of the ReviewThe primary task of an EC lies in the review of research proposals and their sup-porting documents, with special attention given to the informed consent process,documentation, and the suitability and feasibility of the protocol. ECs need to takeinto account prior scientific reviews, if any, and the requirements of applicable lawsand regulations. The following should be considered, as applicable:

6.2.1 Scientific Design and Conduct of the Study

6.2.1.1 the appropriateness of the study design in relation to the objec-tives of the study, the statistical methodology (including samplesize calculation), and the potential for reaching sound conclu-sions with the smallest number of research participants;

6.2.1.2 the justification of predictable risks and inconveniences weighedagainst the anticipated benefits for the research participantsand the concerned communities;

6.2.1.3 the justification for the use of control arms;

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6.2.1.4 criteria for prematurely withdrawing research participants;

6.2.1.5 criteria for suspending or terminating the research as a whole;

6.2.1.6 the adequacy of provisions made for monitoring and auditing theconduct of the research, including the constitution of a datasafety monitoring board (DSMB);

6.2.1.7 the adequacy of the site, including the supporting staff, avail-able facilities, and emergency procedures;

6.2.1.8 the manner in which the results of the research will be reportedand published;

6.2.2 Recruitment of Research Participants

6.2.2.1 the characteristics of the population from which the researchparticipants will be drawn (including gender, age, literacy, cul-ture, economic status, and ethnicity);

6.2.2.2 the means by which initial contact and recruitment is to be con-ducted;

6.2.2.3 the means by which full information is to be conveyed to poten-tial research participants or their representatives;

6.2.2.4 inclusion criteria for research participants;

6.2.2.5 exclusion criteria for research participants;

6.2.3 Care and Protection of Research Participants

6.2.3.1 the suitability of the investigator(s)’s qualifications and ex-perience for the proposed study;

6.2.3.2 any plans to withdraw or withhold standard therapies for thepurpose of the research, and the justification for such action;

6.2.3.3 the medical care to be provided to research participants duringand after the course of the research;

6.2.3.4 the adequacy of medical supervision and psycho-social supportfor the research participants;

6.2.3.5 steps to be taken if research participants voluntarily withdrawduring the course of the research;

6.2.3.6 the criteria for extended access to, the emergency use of, and/orthe compassionate use of study products;

6.2.3.7 the arrangements, if appropriate, for informing the research par-ticipant’s general practitioner (family doctor), including proce-dures for seeking the participant’s consent to do so;

6.2.3.8 a description of any plans to make the study product availableto the research participants following the research;

6.2.3.9 a description of any financial costs to research participants;

6.2.3.10 the rewards and compensations for research participants(including money, services, and/or gifts);

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6.2.3.11 the provisions for compensation/treatment in the case of theinjury/disability/death of a research participant attributable toparticipation in the research;

6.2.3.12 the insurance and indemnity arrangements;

6.2.4 Protection of Research Participant Confidentiality

6.2.4.1 a description of the persons who will have access to personaldata of the research participants, including medical records andbiological samples;

6.2.4.2 the measures taken to ensure the confidentiality and security ofpersonal information concerning research participants;

6.2.5 Informed Consent Process

6.2.5.1 a full description of the process for obtaining informed consent,including the identification of those responsible for obtainingconsent;

6.2.5.2 the adequacy, completeness, and understandability of writtenand oral information to be given to the research participants,and, when appropriate, their legally acceptable representa-tive(s);

6.2.5.3 clear justification for the intention to include in the researchindividuals who cannot consent, and a full account of thearrangements for obtaining consent or authorization for the par-ticipation of such individuals;

6.2.5.4 assurances that research participants will receive informationthat becomes available during the course of the research rele-vant to their participation (including their rights, safety, andwell-being);

6.2.5.5 the provisions made for receiving and responding to queries andcomplaints from research participants or their representativesduring the course of a research project;

6.2.6 Community Considerations

6.2.6.1 the impact and relevance of the research on the local communityand on the concerned communities from which the research par-ticipants are drawn;

6.2.6.2 the steps taken to consult with the concerned communitiesduring the course of designing the research;

6.2.6.3 the influence of the community on the consent of individuals;

6.2.6.4 proposed community consultation during the course of theresearch;

6.2.6.5 the extent to which the research contributes to capacitybuilding, such as the enhancement of local healthcare, research,and the ability to respond to public health needs;

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6.2.6.6 a description of the availability and affordability of any suc-cessful study product to the concerned communities followingthe research;

6.2.6.7 the manner in which the results of the research will be madeavailable to the research participants and the concerned com-munities.

6.3 Expedited ReviewECs should establish procedures for the expedited review of research proposals.These procedures should specify the following:

6.3.1 the nature of the applications, amendments, and other considerations thatwill be eligible for expedited review;

6.3.2 the quorum requirement(s) for expedited review;

6.3.3 the status of decisions (e.g. subject to confirmation by full EC or not).

7. DECISION-MAKINGIn making decisions on applications for the ethical review of biomedical research,an EC should take the following into consideration:

7.1 a member should withdraw from the meeting for the decision procedure con-cerning an application where there arises a conflict of interest; the conflictof interest should be indicated to the chairperson prior to the review of theapplication and recorded in the minutes;

7.2 a decision may only be taken when sufficient time has been allowed forreview and discussion of an application in the absence of non-members (e.g.the investigator, representatives of the sponsor, independent consultants)from the meeting, with the exception of EC staff;

7.3 decisions should only be made at meetings where a quorum (as stipulated inthe EC’s written operating procedures) is present;

7.4 the documents required for a full review of the application should be com-plete and the relevant elements mentioned above (see 6.2) should be con-sidered before a decision is made;

7.5 only members who participate in the review should participate in the decision;

7.6 there should be a predefined method for arriving at a decision (e.g. by con-sensus, by vote); it is recommended that decisions be arrived at throughconsensus, where possible; when a consensus appears unlikely, it is recom-mended that the EC vote;

7.7 advice that is non-binding may be appended to the decision;

7.8 in cases of conditional decisions, clear suggestions for revision and the pro-cedure for having the application re-reviewed should be specified;

7.9 a negative decision on an application should be supported by clearly statedreasons.

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8. COMMUNICATING A DECISIONA decision should be communicated in writing to the applicant according to EC pro-cedures, preferably within two weeks’ time of the meeting at which the decision wasmade. The communication of the decision should include, but is not limited to, thefollowing:

8.1 the exact title of the research proposal reviewed;

8.2 the clear identification of the protocol of the proposed research or amend-ment, date and version number (if applicable), on which the decision isbased;

8.3 the names and (where possible) specific identification numbers (versionnumbers/dates) of the documents reviewed, including the potential researchparticipant information sheet/material and informed consent form;

8.4 the name and title of the applicant;

8.5 the name of the site(s);

8.6 the date and place of the decision;

8.7 the name of the EC taking the decision;

8.8 a clear statement of the decision reached;

8.9 any advice by the EC;

8.10 in the case of a conditional decision, any requirements by the EC, includingsuggestions for revision and the procedure for having the application re-reviewed;

8.11 in the case of a positive decision, a statement of the responsibilities of theapplicant; for example, confirmation of the acceptance of any requirementsimposed by the EC; submission of progress report(s); the need to notify theEC in cases of protocol amendments (other than amendments involving onlylogistical or administrative aspects of the study); the need to notify the EC in the case of amendments to the recruitment material, the potentialresearch participant information, or the informed consent form; the need toreport serious and unexpected adverse events related to the conduct of thestudy; the need to report unforeseen circumstances, the termination of thestudy, or significant decisions by other ECs; the information the EC expectsto receive in order to perform ongoing review; the final summary or finalreport;

8.12 the schedule/plan of ongoing review by the EC;

8.13 in the case of a negative decision, clearly stated reason(s) for the negativedecision;

8.14 signature (dated) of the chairperson (or other authorized person) of the EC.

9. FOLLOW-UPECs should establish a follow-up procedure for following the progress of all studiesfor which a positive decision has been reached, from the time the decision wastaken until the termination of the research. The ongoing lines of communication

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between the EC and the applicant should be clearly specified. The follow-up proce-dure should take the following into consideration:

9.1 the quorum requirements, the review procedure, and the communication pro-cedure for follow-up reviews, which may vary from the requirements and pro-cedures for the initial decision on an application;

9.2 the follow-up review intervals should be determined by the nature and theevents of research projects, though each protocol should undergo a follow-up review at least once a year;

9.3 the following instances or events require the follow-up review of a study:

a. any protocol amendment likely to affect the rights, safety, and/or well-being of the research participants or the conduct of the study;

b. serious and unexpected adverse events related to the conduct of thestudy or study product, and the response taken by investigators, spon-sors, and regulatory agencies;

c. any event or new information that may affect the benefit/risk ratio ofthe study;

9.4 a decision of a follow-up review should be issued and communicated to theapplicant, indicating a modification, suspension, or termination of the EC’soriginal decision or confirmation that the decision is still valid;

9.5 in the case of the premature suspension/termination of a study, the appli-cant should notify the EC of the reasons for suspension/termination; a sum-mary of results obtained in a study prematurely suspended/terminated shouldbe communicated to the EC;

9.6 ECs should receive notification from the applicant at the time of the com-pletion of a study;

9.7 ECs should receive a copy of the final summary or final report of a study.

10. DOCUMENTATION AND ARCHIVINGAll documentation and communication of an EC should be dated, filed, and archivedaccording to written procedures. A statement is required defining the access andretrieval procedure (including authorized persons) for the various documents, files,and archives.

It is recommended that documents be archived for a minimum period of 3 years fol-lowing the completion of a study.

Documents that should be filed and archived include, but are not limited to,

10.1 the constitution, written standard operating procedures of the EC, and regu-lar (annual) reports;

10.2 the curriculum vitae of all EC members;

10.3 a record of all income and expenses of the EC, including allowances and re-imbursements made to the secretariat and EC members;

10.4 the published guidelines for submission established by the EC;

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10.5 the agenda of the EC meetings;

10.6 the minutes of the EC meetings;

10.7 one copy of all materials submitted by an applicant;

10.8 the correspondence by EC members with applicants or concerned partiesregarding application, decision, and follow-up;

10.9 a copy of the decision and any advice or requirements sent to an applicant;

10.10 all written documentation received during the follow-up;

10.11 the notification of the completion, premature suspension, or premature ter-mination of a study;

10.12 the final summary or final report of the study.

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GLOSSARY

The definitions provided within this glossary apply to terms as they are used inthese Guidelines. The terms may have different meanings in other contexts.

AdviceNon-binding considerations adjoined to a decision intended to provide ethical assis-tance to those involved in the research.

ApplicantA qualified researcher undertaking the scientific and ethical responsibility for aresearch project, either on his/her own behalf or on behalf of an organization/firm,seeking a decision from an ethics committee through formal application.

CommunityA community is a group of people understood as having a certain identity due tothe sharing of common interests or to a shared proximity. A community may beidentified as a group of people living in the same village, town, or country and,thus, sharing geographical proximity. A community may be otherwise identified asa group of people sharing a common set of values, a common set of interests, or acommon disease.

Conflict of interestA conflict of interest arises when a member (or members) of the EC holds interestswith respect to specific applications for review that may jeopardize his/her (their)ability to provide a free and independent evaluation of the research focused on theprotection of the research participants. Conflicts of interests may arise when an ECmember has financial, material, institutional, or social ties to the research.

DecisionThe response (either positive, conditional or negative), by an EC to an applicationfollowing the review in which the position of the EC on the ethical validity of theproposed study is stated.

InvestigatorA qualified scientist who undertakes scientific and ethical responsibility, either onhis/her own behalf or on behalf of an organization/firm, for the ethical and scien-tific integrity of a research project at a specific site or group of sites. In someinstances a coordinating or principal investigator may be appointed as the respon-sible leader of a team of subinvestigators.

ProtocolA document that provides the background, rationale, and objective(s) of a bio-medical research project and describes its design, methodology, and organization,including ethical and statistical considerations. Some of these considerations maybe provided in other documents referred to in the protocol.

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Protocol amendmentA written description of a change to, or formal clarification of, a protocol.

RequirementsIn the context of decisions, requirements are binding elements that express ethicalconsiderations whose implementation the ethics committee requires or views asobligatory in pursuing the research.

Research participantAn individual who participates in a biomedical research project, either as the directrecipient of an intervention (e.g. study product or invasive procedure), as a control,or through observation. The individual may be a healthy person who volunteers toparticipate in the research, or a person with a condition unrelated to the researchcarried out who volunteers to participate, or a person (usually a patient) whosecondition is relevant to the use of the study product or questions being investi-gated.

SponsorAn individual, company, institution, or organization that takes responsibility for theinitiation, management, and/or financing of a research project.

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SUPPORTING DOCUMENTS

Council for International Organizations of Medical Sciences (CIOMS), in collabora-tion with the World Health Organization (WHO). International Ethical Guidelines forBiomedical Research Involving Human Subjects. Geneva 1993.

Council for International Organizations of Medical Sciences (CIOMS). InternationalGuidelines for Ethical Review of Epidemiological Studies. Geneva 1991.

Council of Europe. Convention for the Protection of Human Rights and Dignity of theHuman Being with Regard to the Application of Biology and Medicine: Convention onHuman Rights and Biomedicine. European Treaty Series – No. 164. Oviedo, 4 April1997.

Department of Health, Education, and Welfare, Office of the Secretary, Protection ofHuman Subjects. Belmont Report: Ethical Principles and Guidelines for the Protectionof Human Subjects of Research. Report of the National Committee for the Protectionof Human Subjects of Biomedical and Behavioural Research. DHEW Publication No.(OS) 78-0013 and No. (OS) 78-0014. 18 April 1979.

International Conference on Harmonization of Technical Requirements for theRegistration of Pharmaceuticals for Human Use (ICH). Note for Guidance on GoodClinical Practice (CPMP/ICH/135/95) 1 May 1996.

World Health Organization (WHO). Guidelines for Good Clinical Practice (GCP) forTrials on Pharmaceutical Products. Annex 3 of The Use of Essential Drugs. SixthReport of the WHO Expert Committee. Geneva: World Health Organization, 1995: 97-137.

World Medical Association, Declaration of Helsinki: Recommendations GuidingPhysicians in Biomedical Research Involving Human Subjects. Adopted by the 18thWorld Medical Assembly, Helsinki, Finland, June 1964. Amended by the 29th WorldMedical Assembly, Tokyo, Japan, October 1975; the 35th World Medical Assembly,Venice, Italy, October 1983; the 41st World Medical Assembly, Hong Kong,September 1989; and the 48th General Assembly, Somerset West, Republic of SouthAfrica, October 1996.

World Medical Association, Declaration of Lisbon on the Rights of the Patient.Adopted by the 34th World Medical Assembly, Lisbon, Portugal, September/October1981 and amended by the 47th General Assembly, Bali, Indonesia, September 1995.

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Operational Guidelines for Ethics Committees Reviewing Biomedical Research

UNDP/World Bank/WHO

Special Programme for Research & Training

in Tropical Diseases

(TDR)

COMMITTEES

International Working PartySolomon Benatar, South AfricaChifumbe Chintu, ZambiaFrancis P. Crawley, Belgium (Chairman)Dafna Feinholz, MexicoChristine Grady, USADirceau Greco, BrazilHakima Himmich, MoroccoAndrew Kitua, TanzaniaOlga Kubar, RussiaMary Ann Lansang, PhilippinesReidar Lie, NorwayVasantha Muthuswamy, IndiaRenzong Qiu, ChinaJudit Sándor, Hungary

SecretariatJuntra Karbwang, TDR WHO (Project Coordinator)Howard Engers, TDR WHODavid Griffin, WHOTikki Pang, WHODaniel Wikler, WHOMyint Htwe, SEARO, WHOChen Ken, WPRO, WHOAbdelhay Mechbal, EMRO, WHOAntoine Kaboré, AFRO, WHOAlberto Pellegrini-Filho, AMRO, WHOMariam Maluwa, UNAIDSClaire Pattou, UNAIDSJohn Bryant, CIOMSRyuichi Ida, UNESCODelon Human, WMA

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Consultation Partners

Odette Morin Carpentier, International Federation of Pharmaceutical Manufacturers’Associations

Elaine Esber, Food and Drug Administration, USA and FDA Representative to theInternational Conference on Harmonization

Nadia Tornieporth, SmithKline Beecham Biologics

Wen Kilama, African Malaria Vaccine Testing Network

Robert Eiss, National Institutes of Health, USA

Melody H. Lin, Office for Protection from Research Risks (OPRR), USA

Dixie Snider, Centers for Disease Control and Prevention, USA

Henry Dinsdale, National Council on Ethics in Human Research, Canada

Elaine Gadd, Steering Committee on Bioethics, Council of Europe

Laurence Cordier, European Commission

Fergus Sweeney, European Medicines Evaluation Agency

Betty Dodet, Fondation Marcel Mérieux

Kries De Clerck, European Forum for Good Clinical Practice

Jean-Marc Husson, International Federation of Associations of PharmaceuticalPhysicians

Denis Lacombe, European Organization for Research & Treatment of Cancer

Frank Wells, Faculty of Pharmaceutical Medicine, UK

Frédérick Gay, Regional Malaria Control Programme in Cambodia, Laos, and Vietnam,European Commission

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BACKGROUND

The Operational Guidelines for Ethics Committees that Review Biomedical Research isthe result of a wide international consultation begun in August 1999 at A Seminaron the Ethical Review of Clinical Research in Asian & Western Pacific Countries orga-nized by TDR WHO in Chiang Mai, Thailand. The participants at the seminarexpressed a need for international guidance on the constitution and operation ofethics committees.

The first draft of these Guidelines was discussed at a workshop for members ofAfrican Ethical Review Committees organized by TDR WHO and the African MalariaVaccine Testing Network in Arusha, Tanzania, on 5 November 1999. The draft wassubsequently presented to an Interim Meeting of the Forum for Ethical ReviewCommittees in the Asian & Western Pacific Regions (FERCAP) in Bethesda, MD, USA,on 9 November 1999. It was also distributed for consultation at the Global Forumfor Bioethics in Research organized by the NIH and WHO in Bethesda on 7-10November 1999. Following these initial consultations the Guidelines were redraftedand widely distributed for comment.

Further development of these Guidelines was carried out under the auspices of aSecretariat composed of representatives from WHO, UNAIDS, CIOMS, UNESCO, andthe WMA. Responsibility for drafting these Guidelines was given to an InternationalDrafting Committee of 14 experts from various continents representing a wide rangeof disciplines in biomedical research and bioethics. The consultation process wascarried out through representatives from the African Malaria Vaccine TestingNetwork, Council of Europe, European Commission, European Medicines EvaluationAgency, National Institutes of Health (USA), Food & Drug Administration (USA),Office for Protection from Research Risks (USA), Centers for Disease Control andPrevention (USA), National Council on Ethics in Human Research (Canada), Facultyof Pharmaceutical Medicine (United Kingdom), European Organization for Research& Treatment of Cancer, International Federation of Pharmaceutical Physicians,Foundation Marcel Mérieux, International Federation of Pharmaceutical Manu-facturers’ Associations, International Conference on Harmonization, and EuropeanForum for Good Clinical Practice. In addition, the draft text was widely distributedto organizations of ethics committees in Europe and the United States as well as toexperts in the field of biomedical research ethics. On 2 January 2000 a new draftwas prepared and distributed to the members of the Drafting Working Party, theSecretariat, and the Consultation Partners as well as to other parties who had com-mented or expressed an interest.

Following on the reception of a wide range of detailed comments from around theworld, the text was then widely discussed at a Meeting on Guidelines and StandardOperating Procedures for Ethical Review Committees held in Bangkok on 10-12January 2000. Participants in this meeting were drawn from the regions of Africa,Asia, Latin America, North America, and Europe, from international organizations,(including WHO, UNAIDS, UNESCO, CIOMS, EFGCP, and IFPMA), and from universitiesand research institutions. A final deliberation took place at a Drafting Meeting held

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on 13 January 2000 in Bangkok. Following the Drafting Meeting a final set of com-ments were solicited and integrated into the final document.

The purpose of this wide consultative process was to ensure extensive input whilefostering the sharing of knowledge from developing and developed countries along-side organizations and institutions with varying degrees of experience and exper-tise. This process also help to prepare for the dissemination of the final textthrough an international process of capacity building that would strengthennational and local infrastructures for ethical review throughout the world.

The Operational Guidelines for Ethics Committees That Review Biomedical Researchare proposed by the WHO and CIOMS as a support for improving the organization,quality, and standards of ethical review around the world. These Guidelines take intoaccount current practices while suggesting guidance for a harmonized state-of-the-art approach.

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Comments and suggestions on all aspects of these guidelines are welcome for con-sideration in future revisions of this document. Please correspond with:

Dr Juntra KarbwangClinical Coordinator

Product Research and DevelopmentTDR/CDS/WHO

CH-1211 Geneva 27Switzerland

Tel. (41) 22 791 3867/8Fax (41) 22 791 4854

E-mail: [email protected]

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TDR/PRD/SOP/01.1

STANDARD OPERATING PROCEDURESFOR CLINICAL INVESTIGATORS

SOP Authors: Juntra Karbwang and Claire Pattou

Final SOP status

Revised and approved by the Product Research and Development R&D Committee

UNDP/World Bank/WHOSpecial Programme for Research andTraining in Tropical Diseases (TDR)

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TABLE OF CONTENTS

Policy/Scope/Aims/Applicable to . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 199Glossary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 200

Investigator Standard Operating Procedures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207Prior to Initiation of the Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 208During the Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213

Investigator’s file, including storage and retention . . . . . . . . . . . . . . . . . . . . . . 213Screening and recruitment of study subjects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213Obtaining informed consent from trial subjects . . . . . . . . . . . . . . . . . . . . . . . . . . 213Protocol compliance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 216Providing medical care for trial subjects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217Randomization procedures and unblinding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217Safety reporting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217Completion and validation of the case report form . . . . . . . . . . . . . . . . . . . . . . 220Source data and documents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221Product storage and accountability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223Premature termination or suspension of a trial . . . . . . . . . . . . . . . . . . . . . . . . . . 223Progress and final reports . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 224

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 224Annexes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225

198 • TDR/PRD (SOPs) and guidelines • CT 05 Investigator’s Responsibilities

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TDR/PRD (SOPs) and guidelines • CT 05 Investigator’s Responsibilities • 199

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Clinical DevelopmentStandard Operating Procedures (SOPs)

SOPs Title: Investigator’s Responsibilities

SOPs No.: CT 05

SOPs Author(s): Juntra Karbwang & Claire Pattou

SOPs Approbation: PRD R&D Committee

SOPs Status: Final Revision due date: March 2004

Status Date: 10 April 2002

Implementation Date: _____________

Document received by: _____________ _____________ _____________Date Signature

Agreement to comply with these SOPs: _____________ _____________Date Signature

Policy: All clinical studies supported by TDR will be carried out according toInternational Conference on Harmonisation (ICH)/WHO good clinical prac-tice (GCP) standards, regulatory authorities’ requirements and TDR stan-dard operating procedures (SOPs).

All TDR investigators have an obligation to follow and adhere to the estab-lished TDR clinical study SOPs.

Note: When a trial is sponsored by another agency/pharmaceutical company, theinvestigator may also be requested to follow their procedures in order tocomply with company obligations. Agreement between all parties will bediscussed before initiating the trial.

Scope: Phase I, II and III clinical trials conducted by the TDR unit on ProductResearch and Development (TDR/PRD).

Aims: To define investigators’ responsibilities and to provide instruction whenperforming clinical study(ies) supported by TDR according to GCP (ICH)standards and under applicable regulatory requirements.

Applicable to: TDR investigators and, where relevant, UNAIDS investigators.

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GLOSSARY*

Adverse drug reaction (ADR)In the pre-approval clinical experience with a new medicinal product or a product’snew usage, particularly as the therapeutic dose(s) may not be established: allnoxious and unintended responses to a medicinal product related to any doseshould be considered adverse drug reactions (the phrase ‘responses to a medicinalproduct’ means that a causal relationship between a medicinal product and anadverse event is at least a reasonable possibility, i.e. the relationship cannot beruled out).

Regarding marketed medicinal products: a response to a drug which is noxious and unintended and which occurs at doses normally used in human subjects forprophylaxis, diagnosis, or therapy of diseases or for modification of physiologicalfunction.

Adverse event (AE)Any untoward medical occurrence in a patient or clinical investigation subjectadministered a pharmaceutical product which does not necessarily have a causalrelationship with this treatment. An adverse event (AE) can therefore be anyunfavourable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of a medicinal (investiga-tion) product, whether or not related to the medicinal (investigation) product.

Applicable regulatory requirement(s)Any law(s) and regulation(s) addressing the conduct of clinical trials of investiga-tion products.

Approval (in relation to institutional review boards)The affirmative decision of the institutional review board (IRB) that the clinicaltrial has been reviewed and may be conducted at the institution site within theconstraints set forth by the IRB, the institution, good clinical practice (GCP), andthe applicable regulatory requirements.

AuditA systematic and independent examination of trial-related activities and documentsto determine whether the evaluated trial-related activities were conducted, and thedata were recorded, analysed and accurately reported, according to the protocol,sponsor’s standard operating procedures (SOPs), good clinical practice (GCP), andthe applicable regulatory requirement(s).

*Unless otherwise stated, these definitions are derived from the International Conferenceon Harmonisation of Technical Requirements for Registration of Pharmaceuticals for HumanUse. ICH Harmonised Tripartite Guidelines.

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BlindingA procedure in which one or more parties to the trial are kept unaware of the treat-ment assignment(s). Single-blinding usually refers to the subject(s) being unaware,and double-blinding usually refers to the subject(s), investigator(s), monitor, and,in some cases, data analyst(s), being unaware of the treatment assignment(s).

Case report form (CRF)A printed, optical, or electronic document designed to record all of the protocol-required information to be reported to the sponsor on each trial subject.

Clinical trial/studyAny investigation in human subjects intended to discover or verify the clinical,pharmacological and/or other pharmacodynamic effects of an investigationproduct(s), and/or to identify any adverse reactions to an investigation product(s),and/or to study the absorption, distribution, metabolism, and excretion of an inves-tigation product(s) with the object of ascertaining its safety and/or efficacy. Theterms ‘clinical trial’ and ‘clinical study’ are synonymous.

Clinical trial/study reportA written description of a trial/study of any therapeutic, prophylactic, or diagnosticagent conducted in human subjects, in which the clinical and statistical descrip-tion, presentations, and analyses are fully integrated into a single report (see ICHGuideline for structure and content of clinical study reports).

Compliance (in relation to trials)Adherence to all the trial-related requirements, GCP requirements, and the applic-able regulatory requirements.

ConfidentialityPrevention of disclosure, to unauthorized individuals, of a sponsor’s proprietaryinformation or of a subject’s identity.

ContractA written, dated, and signed agreement between two or more involved parties thatsets out any arrangements on delegation and distribution of tasks and obligationsand, if appropriate, financial matters. The protocol may serve as the basis of a con-tract.

Direct accessPermission to examine, analyse, verify, and reproduce any records and reports thatare important to evaluation of a clinical trial. Any party (e.g. domestic and foreignregulatory authorities, sponsor’s, monitors and auditors) with direct access shouldtake all reasonable precautions within the constraints of the applicable regulatoryrequirement(s) to maintain the confidentiality of subjects’ identities and thesponsor’s proprietary information.

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DocumentationAll records, in any form (including, but not limited to, written, electronic, mag-netic, and optical records; scans; X-rays; electrocardiograms) that describe or recordthe methods, conduct and/or results of a trial, the factors affecting a trial, and theactions taken.

Essential documentsDocuments which individually and collectively permit evaluation of the conduct ofa study and the quality of the data produced.

Good clinical practice (GCP)A standard for the design, conduct, performance, monitoring, auditing, recording,analyses, and reporting of clinical trials that provides assurance that the data andreported results are credible and accurate, and that the rights, integrity, and con-fidentiality of trial subjects are protected.

Impartial witnessA person, who is independent of the trial, who cannot be unfairly influenced bypeople involved in the trial, who attends the informed consent process if the sub-ject or the subject’s legally acceptable representative cannot read, and who readsthe informed consent form and any other written information supplied to the sub-ject.

Independent ethics committee (IEC)An independent body (a review board or a committee, institutional, regional,national, or supranational), constituted of medical/scientific professionals and non-medical/non-scientific members, whose responsibility is to ensure protection of therights, safety and well-being of human subjects involved in a trial and to providepublic assurance of that protection, by, among other things, reviewing andapproving/providing favourable opinion on the trial protocol, suitability of theinvestigator(s), facilities, and the methods and materials to be used in obtainingand documenting informed consent of the trial subjects.

The legal status, composition, function, operations and regulatory requirementspertaining to Independent Ethics Committee may differ among countries, butshould allow the Independent Ethics Committee to act in agreement with GCP.

Informed consentA process by which a subject voluntarily confirms his or her willingness to partici-pate in a particular trial, after having been informed of all aspects of the trial thatare relevant to the subject’s decision to participate. Informed consent is docu-mented by means of a written, signed and dated informed consent form.

InspectionThe act by a regulatory authority(ies) of conducting an official review of documents,facilities, records, and any other resources that are deemed by the authority(ies) tobe related to the clinical trial and that may be located at the site of the trial, at

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the sponsor’s and/or contract research organization’s (CRO’s) facilities, or at otherestablishments deemed appropriate by the regulatory authority(ies).

Institution (medical)Any public or private entity or agency or medical or dental facility where clinicaltrials are conducted.

Institutional review board (IRB)An independent body constituted of medical, scientific, and non-scientific mem-bers, whose responsibility is to ensure the protection of the rights, safety and well-being of human subjects involved in a trial by, among other things, reviewing,approving, and providing continuing review of the trial protocol and amendmentsand of the methods and materials to be used in obtaining and documentinginformed consent of the trial subjects.

Interim clinical trial/study reportA report of intermediate results and their evaluation based on analyses performedduring the course of a trial.

Investigation productA pharmaceutical form of an active ingredient or placebo being tested or used as areference in a clinical trial, including a product with a marketing authorizationswhen used or assembled (formulated or packaged) in a way different from theapproved form, or when used for an unapproved indication, or when used to gainfurther information about an approved use.

InvestigatorA person responsible for the conduct of a clinical trial at a trial site. If a trial isconducted by a team of individuals at a trial site, the investigator is the respon-sible leader of the team and may be called the principal investigator. See also ‘sub-investigator’.

Investigator/institutionAn expression meaning ‘the investigator and/or institution, where required by theapplicable regulatory requirements.

Investigator’s brochure (IB)A compilation of the clinical and non-clinical data on the investigation product(s)which is relevant to the study of the investigation product(s) in human subjects.

Legally acceptable representativeAn individual or juridical or other body authorized under applicable law to consent,on behalf of a prospective subject, to the subject’s participation in the clinical trial.

MonitoringThe act of overseeing the progress of a clinical trial, and of ensuring that it is con-ducted, recorded, and reported in accordance with the protocol, standard operating

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procedures (SOPs), good clinical practice (GCP), and applicable regulatory require-ment(s).

Monitoring reportA written report from the monitor to the sponsor after each site visit and/or othertrial-related communication according to the sponsor’s SOPs.

Multicentre trialA clinical trial conducted according to a single protocol but at more than one site,and therefore carried out by more than one investigator.

Open trialThe opposite of a double-blind study, in that everyone knows what medication eachpatient is receiving. This may occur in a study involving either one or more thanone treatment. (Definition from: Winslade J., Hutchinson D.R., 1992. Dictionary ofclinical research. Surrey, UK: Brookwood Medical Publications Ltd.)

Opinion (in relation to an independent ethics committee)The judgement and/or advice provided by an independent ethics committee (IEC).

ProtocolA document that describes the objective(s), design, methodology, statistical con-siderations, and organization of a trial. The protocol usually also gives the back-ground and rationale for the trial, but these could be provided in other protocol ref-erenced documents. Throughout the ICH GCP Guideline, the term ‘protocol’ refers toprotocol and protocol amendments.

Protocol amendmentA written description of a change(s) to, or formal clarification of a protocol.

Protocol deviation/violationNoncompliance with protocol requirements. This may include noncompliance withthe following protocol provisions: inclusion and exclusion criteria, randomizationprocedures, blinding procedures, informed consent procedure, assignment of subjectidentification numbers, dosing and assessment schedules, reporting and proceduresfor adverse events, concomitant medications. (Definition from the authors)

Quality assurance (QA)All those planned and systematic actions that are established to ensure that thetrial is performed and the data are generated, documented (recorded), and reportedin compliance with good clinical practice (GCP) and applicable regulatory require-ment(s).

Quality control (QC)The operational techniques and activities undertaken within the quality assurancesystem to verify that the requirements for quality of the trial-related activities havebeen fulfilled.

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RandomizationThe process of assigning trial subjects to treatment or control groups using an ele-ment of chance to determine the assignments, in order to reduce bias.

Regulatory authoritiesBodies having the power to regulate. In the ICH GCP Guideline the expression ‘regu-latory authorities’ includes the authorities that review submitted clinical data andthose that conduct inspections. These bodies are sometimes referred to as ‘compe-tent authorities’.

Serious adverse event (SAE) or serious adverse drug reaction (serious ADR)Any untoward medical occurrence that, at any dose, has one or more of the fol-lowing attributes:– Results in death.– Is life-threatening.– Requires inpatient hospitalization or prolongation of existing hospitalization.– Results in persistent or significant disability/incapacity. – Is a congenital anomaly/birth defect.– Results in an important medical event that may not be immediately life-threat-

ening or does not directly result in death or hospitalization, but which may jeop-ardize the patient or may require intervention to prevent the other outcomeslisted above.

Source dataAll information, in original records and certified copies of original records, of clini-cal findings, observations, or other activities in a clinical trial necessary for thereconstruction and evaluation of the trial. Source data are contained in sourcedocuments (original records or certified copies).

Source documentsOriginal documents, data, and records (e.g. hospital records, clinical and officecharts, laboratory notes, memoranda, subjects’ diaries or evaluation checklists,pharmacy dispensing records, recorded data from automated instruments, copies ortranscriptions certified after verification as being accurate copies, microfiches, pho-tographic negatives, microfilm or magnetic media, X-rays, subject files, and recordskept at the pharmacy, at the laboratories, and at medico-technical departmentsinvolved in the clinical trial).

SponsorAn individual, company, institution, or organization which takes responsibility forthe initiation, management, and/or financing of a clinical trial.

Standard operating procedures (SOPs)Detailed written instructions to achieve uniformity of the performance of a specificfunction.

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Study site/trial siteThe location(s) where trial-related activities are actually conducted.

Sub-investigatorAny individual member of the clinical trial team designated and supervised by theinvestigator at a trial site to perform critical trial-related procedures and/or makeimportant trial-related decisions (e.g. associates, resident physicians, research fel-lows). See also ‘investigator’.

Subject/trial subjectAn individual who participates in a clinical trial, either as a recipient of the inves-tigation product(s) or as a control.

Subject identification codeA unique identifier assigned by the investigator to each trial subject to protect thesubject’s identity and used in lieu of the subject’s name when the investigatorreports adverse events and/or other trial-related data.

Unexpected adverse drug reactionAn adverse reaction, the nature or severity of which is not consistent with theapplicable product information (e.g. investigator’s brochure for an unapprovedinvestigation product, or package insert/summary of product characteristics for anapproved product) (see the ICH Guideline for clinical safety data management: defi-nitions and standards for expedited reporting (E2A)).

Well-being (of the trial subjects)The physical and mental integrity of the subjects participating in a clinical trial.

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INVESTIGATOR STANDARD OPERATING PROCEDURES

Objectives:

• To provide the investigator with general instructions to ensure that he/sheunderstands and accepts the obligations incurred in undertaking the study.

• To ensure that the study is planned, set up, conducted, documented andreported according to the protocol, related standard operating procedures(SOPs), International Conference on Harmonisation (ICH) good clinical prac-tice (GCP), and applicable regulatory requirements.

• To ensure that the rights, safety, and welfare of study subjects are properlyprotected.

• To ensure that data are generated, collected and documented with accuracy,consistency and integrity.

• To ensure that the investigator is acquainted with the study procedures, veri-fication procedures, audits and inspection procedures.

The principal investigator is the one who will sign this document. He/she is respon-sible for sharing the information contained in this document with all of his/herteam.

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PRIOR TO INITIATION OF THE STUDY

The investigator should:

Be interested in the scientific aspects of the study and ensure that the studyis responsive to the needs of public health within the country or the popula-tion in which it will be conducted.

Ensure the confidentiality of the product, the protocol and trial procedures by giving a confidentiality agreement in writing to the Product Research andDevelopment unit at TDR (TDR/PRD) and/or the other sponsoring agencies.

Have sufficient time free from other obligations to prepare and conduct thetrial. Clinical trials are time consuming and the investigator should ensure thatsufficient time can be dedicated to the study, including time for informing andsupervising study staff.

Review the investigator’s brochure (IB) and any up to date information on the investigation product. The investigator must be familiar with the product,including preclinical toxicology, pharmacology, pharmacokinetics and up-to-dateclinical data.

Review, and discuss in detail, the ICH GCP guideline, investigators’ SOPs andprotocol with the clinical monitor. The investigator should clearly define:

• Factors that may alter the feasibility and acceptability of the trial.

• An adequate recruitment rate for the trial by providing retrospective data onnumbers of patients who would have satisfied the proposed entrance criteriaduring preceding time periods.

Ensure that the procedures stated in the study protocol are applicable inhis/her centre and fully understood. The investigator should ask the clinicalmonitor to clarify any points of possible misunderstanding.

Ensure that there are sufficient medical, paramedical and clerical staff to sup-port the study and deal with foreseeable emergencies.

• Provide a list of study personnel and functions in the study to the clinical mon-itor/product manager (see annex 2, authorized signatory form).

• Provide his/her curriculum vitae and the curricula vitae of the sub-investigatorsand the head of the laboratory

Ensure that all persons assisting with the trial are adequately informed aboutthe protocol, the investigation product(s), and their trial-related duties andfunctions.

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Ensure that the physical location and facilities are sufficient to allow the studyto be undertaken efficiently. Ensure:

• Confidentiality and safety conditions for trial subjects.

• Adequate equipment/facilities for subject follow-up, examination and care.

• Adequate facilities for product storage.

• Adequate facilities for laboratory assay. The laboratory assay should be validatedaccording to ‘good clinical practice laboratory for clinical trials’ (Annex A).

• Adequate facilities for retention of trial documents, ensuring confidentiality ofall information about trial subjects and information supplied by TDR and/or othersponsoring agencies.

Discuss the case report form (CRF), serious adverse event (SAE) reporting formand source documents in detail with the clinical monitor (see annexes 3 and 4for sample forms). Clearly define:

• Who will be responsible for CRF completion.

• Source documents/source data and access to source data.

Arrange for archiving of trial documents according to GCP and regulatoryrequirements. It is important to check the duration of retention of patient recordswith the institution’s archive. In case the institution’s archive does not ensureretention of documents for the period of time requested by TDR and/or other spon-sors, the investigator must arrange for the retention of the subjects’ source docu-ments/records for the period requested by TDR and/or other sponsors and regula-tory requirements.

Finalize the informed consent forms (see annex 5 for sample form) and associ-ated trial subject information materials (advertisements); and establish pro-cedures regarding application for local clearance (e.g. dean of the institution)and independent ethical committee (IEC)/institutional review board (IRB)approval.

• Clearly define how subjects will be approached and informed, who will informthem, and what material will be used. The informed consent form and all infor-mation (leaflet written in simple language, video) should be developed collabo-ratively with head members of the study population/community to ensure themethods are appropriate.

• In case of the need for screening tests, including biological specimen collection,before entering a trial, two types of consent form can be developed: one for bio-logical specimen collection and analysis, and one for participation in the studyafter obtaining satisfactory laboratory results and respecting inclusion criteria.

• As a rule, the advertisement must not make reference to TDR or the compound,or make any claims.

• Informed consent forms and advertisements must be submitted to TDR for reviewand must be included in documentation submitted to the IEC/IRB.

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Ensure that the local ethics committee fulfils the ICH GCP requirements:

ICH GCP composition and operations of the Independent EthicsCommittee (IEC) and Institutional Review Board (IRB)

The IEC/IRB should determine the authority under which it is established, andthe composition (names and qualifications) of its members, which should con-sist of:

• A reasonable number of members who collectively have the qualificationsand experience to review and evaluate the science, medical aspects andethics of the proposed trial.

• At least five members.

• At least one member whose primary interest is in a non-scientific area.

• At least one member who is independent of the trial site.

The IEC/IRB may invite non-members with expertise in special areas to giveassistance.

The investigator may provide information on any aspect of the trial, but maynot participate in the IEC/IRB deliberations, vote, or provide opinion.

Only members who participate in review and discussion of the protocol, andwho are independent of the investigator and the sponsor, can vote or provideopinion.

The IEC/IRB should perform initial and continual reviews of the trials accord-ing to the written operating procedures, and maintain records of activities andminutes of meetings.

The IEC/IRB should notify promptly, and in writing, all trial-related decisionsand opinions, specifying the reasons for each.

See ICH GuidelinesGuideline for GCP Part. 3.2

(See also: Operational guidelines for ethics committees that review biomedicalresearch. Geneva, World Health Organization, 2000, TDR/PRD/ETHICS/2000.1)

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Prepare the required documents to be submitted to the IEC/IRB:

Documents usually required by ethics committees

• Investigator brochure and up to date safety information.

• Trial protocol (final version and amendments).

• Consent form(s) and subject information sheets.

• Subject recruitment procedures (e.g. advertisement).

• Information on payment and compensation available to subjects.

• Current curriculum vitae for each investigator.

• Any other document requested by the IEC/IRB.

See ICH GuidelinesGuideline for GCP Part. 3.1.2

Obtain the approval document from the ethics committee, which must identifythe documents reviewed and state that the study is acceptable and can beinitiated.

Send the approval document of the ethics committee, with a list of committeemembers, to TDR/PRD as a supporting document for approval of the WHOSecretariat Committee on Research Involving Human Subjects (SCRIHS).

Prepare the application for health authority clearance in collaboration withTDR and other sponsoring agencies.

Prepare the application for product exportation/importation in collaborationwith TDR and other sponsoring agencies.

If the IEC/IRB and others approve the trial, sign the final copy of the protocoland confirm in writing that he/she has read and understood, and will adhereto, the protocol, study procedures and ICH good clinical practice, will collabo-rate with the monitor, and accords with TDR and/or other sponsoring agencieson publication policy.

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Submit requested documents to the clinical monitors, including:

• Signed agreement to comply with these SOPs (page 1; see also annex 6).

• Approved protocol, signed and dated.

• Approved informed consent form (see annex 5) and other subject information,and the advertisement (local language and English translation).

• Investigator’s and co-investigator’s curricula vitae.

• Authorized signatory form (see annex 2).

• Product exportation/importation authorization.

• Laboratory certification/list of normal laboratory ranges, dated and signed byinvestigator.

• Technical services agreement (TSA), signed and dated.

• Signed agreement that the product will not be used before the trial initiationmonitoring visit has been made and authorization obtained from the TDR clinicalcoordinator (if applicable).

• Signed FDA 1572 form (if applicable, e.g. study under investigation new drug[IND]) (see annex 8).

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DURING THE STUDY

The trial can be initiated (begin screening and/or enrolling trial subjects) only afterthe clinical monitor has satisfactorily conducted a trial initiation monitoring visitand the TDR clinical coordinator has given written authorization.

Investigator’s file, including storage and retentionOn initiation of the study, the investigator must prepare a file containing docu-ments related to the trial (see investigator’s file form, annex 1). During the study,the investigator is responsible for updating the file and regularly adding trial-related documents.

The investigator should keep the file in a locked cabinet, in a secure area acces-sible only to the investigator and authorized study staff. The investigator file andassociated source documents should be retained for the time agreed with TDRand/or other sponsors. Patient identification codes should be kept for at least 15 years after completion of the trial. Written approval from all sponsors mustbe obtained prior to destroying records.

Screening and recruitment of study subjects It is important that the investigator resolves all questions from his/her staff con-cerning the interpretation of inclusion/exclusion criteria.

The investigator should be able to dedicate time to the recruitment of suitable trialsubjects – the consultation time for recruitment of each subject is likely to belonger than the time required for normal consultation.

The investigator must ensure the unbiased selection of an adequate number of suit-able study subjects as defined by the protocol.

The investigator must allow study subjects who meet the inclusion criteria theopportunity to decide for themselves whether or not to be entered into the study.

The investigator must document the identification of subjects who enter trialscreening by completing a subject screening/enrolment log (see annexes 9 and 10).

Obtaining informed consent from trial subjects The concept of obtaining informed consent is considered to be the heart of GCP.Informed consent is the process by which a study subject voluntarily confirmshis/her willingness to participate in the trial. Only study subjects who have fullyunderstood all aspects of their participation in the trial can make proper judge-ments and give their consent to participate in the trial.

Information on disease prevention and transmission must be provided to the studysubjects for the whole of the trial period.

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Before any subject enters a trial, and before any study-related procedures begin,written informed consent must be obtained from the subject and/or his/her legallyacceptable representative. In the case of a screening test that requires the collec-tion of biological specimens prior to entering a trial, two types of consent form canbe obtained; one for biological specimen collection and analysis, and the other forparticipation in the study having obtained satisfactory laboratory results respectingthe inclusion criteria. Study subjects found ineligible at screening (for medical rea-sons) should receive, if appropriate, supportive counselling, any necessary availabletreatment, and referral for continued counselling.

The investigator can delegate the consent process to an appropriately qualifiedperson; however, the investigator should see the subject afterwards to ensure thatthe consent has been properly obtained. Verbal and written information given tothe trial subject should be in simple terms and in his/her first language. Medicalterms should be avoided.

The investigator/designated person should perform informed consent proceduresfully with each subject during recruitment:

• The informed consent form (see annex 5 for a sample form) should be personallydated and signed by the trial subject and/or his/her legally acceptable repre-sentative as well as the investigator/designated person responsible for theinformed consent procedures.

• If the study subject and/or legally acceptable representative is (are) unable to read, an impartial witness for the investigator should be present during theentire informed consent discussion. After oral approval by the study subject and/or legally acceptable representative, the witness must sign and personally datethe informed consent form and attest that the information was accuratelyexplained and apparently understood, and that informed consent was given freelyby the subject and/or legally acceptable representative. The subject and/orlegally acceptable representative should personally sign and date the form ifcapable of doing so.

• The study subject and/or legally acceptable representative should be given acopy of the signed and dated informed consent form and any other written infor-mation.

• The original signed and dated informed consent form should be kept in theinvestigator’s file (see annex 1) with the study subject’s data.

Trial subjects and/or their legally acceptable representatives should be keptinformed throughout the trial of any new findings or information about thetested product which might be of consequence to their participation in the trial.They should receive updates of the signed and dated consent form as well ascopies of any amendments to the written information. Updates of the originalsigned and dated consent form should be kept in the investigator’s file.

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INFORMED CONSENT PROCEDURES

• Give information regarding the trial to the subject/patient, making surehe/she understands that the study involves research.

• Give the purpose of the study, trial treatment and the probability for randomassignment to each treatment.

• Explain in simple language the procedures to be followed, including invasiveprocedures.

• Explain the responsibilities of the subject/patient.• List the expected risks or inconvenience to the subject/patient.• List the expected benefits, making it clear if there is no intended clinical

benefit to the subject.• List the alternative treatment that may be available to the subject.• List the treatment available in the event of study-related injury.• Discuss the anticipated prorated payment, if any, to the subject for partici-

pating in the trial.• Discuss the anticipated expenses, if any, to the subject for participating in

the trial.• Let the patient know that the trial is voluntary and that he/she may refuse

to participate or can withdraw from the trial at any time, without penalty orloss of benefits to which he/she is otherwise entitled.

• Let the subject/patient know that the monitor, the auditor, the IEC/IRB andthe regulatory authority will be granted direct access to his/her originalmedical records for verification of clinical trial procedures and/or data,without violating the confidentiality of the subject, to the extent permittedby the applicable laws and regulations, and that, by signing a writteninformed consent form, the subject or the subject’s legally acceptable repre-sentative is authorizing such access.

• Assure the subject/patient that records identifying him/her will be kept con-fidential and, to the extent permitted by the applicable laws and/or regula-tions, will not be made publicly available; and that, if the results of the trialare published, the subject’s identity will remain confidential.

• Assure that the subject or the subject’s legally acceptable representative willbe informed in a timely manner if information becomes available that maybe relevant to the subject’s willingness to continue participation in the trial.

• Provide the name(s) of the person(s) to contact for further informationregarding the trial and the rights of trial subjects, and in the event of trial-related injury.

• Explain to the subject/patient the foreseeable circumstances and/or reasonsunder which his/her participation in the trial may be terminated.

• Provide the expected duration of the subject’s participation in the trial.• Provide the approximate number of study subjects involved in the trial.

See ICH GuidelinesGuideline for GCP Part. 4.8.10

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Protocol complianceOnce the study has started, the investigator must adhere to the protocol and ensurethat it is strictly followed. Deviations to protocol procedure(s) should not be madewithout the agreement of TDR and/or other sponsoring agencies, except whennecessary to avoid immediate danger to a trial subject. Whenever the investigatorfeels that changes are required, these can be suggested to, and discussed with, theclinical monitor/clinical coordinator. If changes are agreed by the product manager,clinical coordinator and sponsor, then the change(s) can be made in the form of aprotocol amendment, signed by the investigator and sponsor, and appended to theoriginal protocol.

The amendment should be described in an appropriate format, as follows:

PROTOCOL AMENDMENT FORMAT

• Protocol number and date.

• Protocol title.

• Date of approval of the amendment.

• Protocol amendment number.

• Text to be amended, with reference to the page, paragraph and line of theprotocol.

• New text of the amendment.

• Signatures of the investigator, product manager and/or sponsor.

Amendments that are likely to affect the safety of a subject/patient or the conductof a trial must be submitted in writing to the ethics committee. The changes cannotbe implemented until the IEC/IRB has approved the amendment to the protocol.However, implementation of the change(s) may take place prior to IEC/IRB approvalto avoid immediate danger(s) to a subject/patient. In this situation, the investi-gator must immediately notify the ethics committee of the reasons for the changesand submit the proposed protocol amendment(s) to TDR and/or other sponsors foragreement and to the IEC/IRB for approval. A copy of the IEC/IRB approval shouldbe kept on the investigator’s file and a further copy given to TDR and/or othersponsors.

In the case of minor modifications that do not have impact on the safety or burdenrequested of the subject/patient for participation in the trial, or that only impacton administrative activities, the modification might be considered a simple notifi-cation, which does not require formal approval.

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Providing medical care for trial subjectsA qualified physician, who is an investigator or sub-investigator, must be respon-sible for all trial-related medical decisions:

• The investigator should ensure that adequate medical care is provided to the trialsubject for any adverse events, including clinically significant laboratory abnor-malities related to the trial.

• The investigator should inform the subject’s primary physician about his/her par-ticipation in the trial if the subject has a primary physician and agrees thathe/she be informed.

The investigator should make a reasonable effort to ascertain the reason(s) forwithdrawing prematurely from the trial, while fully respecting the subject’s rights.


Randomization procedures and unblinding The investigator must follow the randomization procedures, if any. In the case of a randomized, controlled, double-blinded trial, the code is usually prepared in theform of numbered envelopes, each containing the identification of the corre-sponding treatment in order to enable the investigator to open the code whenneeded, without identifying other patients’ treatment (follow SOP CT 06: BreakingCode).

• Ensure that the code is broken only in accordance with the protocol and mainlyfor medical reason(s).

• Premature unblinding must be reported immediately to the clinical monitor andshould be documented in the investigator’s file. The reason for prematureunblinding of the investigation product should be given, e.g. due to a seriousadverse event.

• At the end of the trial, the investigator must return all the unbroken codes tothe clinical monitor to prove that the study was blinded throughout.

Safety reportingTrial subjects should be instructed to report any adverse event (AE) that they expe-rience to the investigator. Investigators should assess AEs at each visit. The AE is considered to be serious when it is fatal, life threatening, causes permanentdisability, causes or prolongs hospitalization, or causes congenital anomaly (seeglossary).

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Terms for causality assessment(Note: these categories and definitions are recommended by TDR; they may be modi-fied according to the aims of the study and the nature of the trial product.)

Not related

The experience is clearly related to other factors such as the patient’s clinicalstate, therapeutic intervention or concomitant therapy.

Unlikely

The experience was most probably produced by other factors such as thepatient’s clinical state, therapeutic intervention or concomitant therapy, anddoes not follow a known response pattern to the trial product.

Possible

The experience:

• follows a reasonable temporal sequence from the time of product adminis-tration; and/or

• follows a known response pattern to the trial product; but

• could have been produced by other factors such as the patient’s clinicalstate, therapeutic intervention or concomitant therapy.

Probable

The experience:


• follows a known response pattern to the trial product; and

• could not have been produced by other factors such as the patient’s clinicalstate, therapeutic intervention or concomitant therapy.

Most probable

The experience:


• follows a known response pattern to the trial product; and

• could not have been produced by other factors such as the patient’s clinicalstate, therapeutic intervention or concomitant therapy; and

• either occurs immediately following trial product administration, or improveson stopping the product, or there is positive reaction at the application site.

Insufficient data to assess

There is not enough clinical and/or laboratory information to suggest the rela-tionship between the experience and the trial product.

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Follow up of adverse eventThe investigator must ensure the safety of the trial subject. When a trial subjectexperiences adverse event(s) (AEs), the following action should be taken:

• The occurrence of the AE(s) must be monitored carefully.

• The investigator must provide the best possible care available and follow up thetrial subject’s adverse event until its complete disappearance. An adverse eventthat is likely to be related to the product and that persists at the end of the trial,or any serious adverse event (SAE) occurring after termination of the trial andlikely to be related to the product, should be followed up by the investigatoruntil its complete disappearance.

• A thorough investigation must be conducted to determine causality.

• The adverse event must be recorded in detail during the course of the trial, irre-spective of the possible causal relationship with the investigation product.

Adverse event reporting procedureAll adverse events occurring during the trial should be accurately reported in theappropriate annex of the case report form.

REPORTING OF SERIOUS ADVERSE EVENTS

The investigator should report all serious adverse events (SAEs) immediately(within 24h) to the TDR clinical monitor, the TDR clinical coordinator and/orthe TDR product manager, and, when appropriate, the other sponsors, even ifthe adverse event is considered not to be related to the investigation product.

The investigator should also comply with the applicable regulatory require-ment(s) related to the reporting of unexpected serious adverse drug reactionsto the regulatory authority(ies) and the IEC/IRB.

The anonymity of the subjects shall be respected when forwarding all infor-mation.


• Notification should be made by faxing the alert form for SAE (specific form forthe trial, see annex 3) and/or by telephone communication.

• The investigator should send promptly, within five working days, the seriousadverse event report form (see annex 4), by fax or express mail, to the TDR clini-cal monitor, the TDR clinical coordinator and/or the TDR product manager, and,when appropriate, to the other sponsors.

• Any relevant information concerning the SAE that becomes available after theSAE report form has been sent (outcome, precise description of medical history,results of the investigation, copy of hospitalization report, etc.) should be for-warded as soon as possible to the TDR clinical monitor, the TDR clinical co-ordinator and/or the TDR product manager, and when appropriate, to the other

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sponsors. For reports of deaths, the investigator should provide TDR and/or othersponsors/IEC/IRB with any additional requested information, e.g. autopsy re-ports and terminal medical reports.

Completion and validation of the case report form

The investigator must ensure the accuracy, legibility and completeness of data entryin the case report forms (CRFs) and in all other required report forms/logs. All CRFsand other required forms will be validated by the TDR clinical monitor during moni-toring visits.

Completion

Only authorized study staff (names shown in the authorized signatory form, seeannex 2) are allowed to enter data into the CRF and other required report forms.

Ballpoint pen must be used.

Capital letters must be used for all entries in the CRF.

All items must be completed by entering a number or text in the space provided.

When a subject is recruited to the trial, the initial and allocated numbers areentered in the CRF against the subject’s name on the subject identification codelist. The subject’s name should never be entered in the CRF to protect confiden-tiality.

As far as possible, the results of assessment should first be entered into the sub-ject file and then transcribed into the CRF. This will allow data to be verified duringthe process of source data verification.

The CRF should be completed during subject participation in the trial.

Data reported on the CRFs that are derived from source documents should be con-sistent with the source documents or the discrepancies should be explained.

Case report form corrections

Only authorized study staff can make corrections.

Do not allow the clinical monitor/sponsor to make corrections in the CRF.

Corrections should not obscure the original entry:

• Do not erase.

• Do not overwrite.

• Never use correcting fluid.

To make a correction:

• Cross out the wrong entry with a single line.

• Write the correct entry alongside, above or under the wrong entry.

• Date the correction.

• Initial the correction.

• Explain the correction (if necessary).

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Source data and documentsICH international guidelines for good clinical practice, and other applicable regula-tory guidelines pertaining to clinical trials, require direct access to source data anddocuments for trial related monitoring, audits, IEC/IRB review, and regulatoryinspection.

Source documents are all original documents, or certified copies containing datarelated to clinical trial activities (source data), necessary for ‘reconstruction andevaluation’ of the trial.

Source documents (non-exhaustive list)Informed consent form.

Subject medical file: • Medical and medication history.• Outpatient or inpatient chart. • Serious adverse event form.• Instrument printouts.• Traces and laboratory results.• Subjects’ visit dates.

Subject identification list.

Clinical and office charts.

Product dispensing records, accountability.

Laboratory notes.

Trial agenda.

Memoranda.

Example:PAZPAT jk

29/03/02

Sex 1Male: 1 Female: 2 2 jk

29/03/99

Date of vaccination 2/10/952/10/01 jk

Site of injection: Left RightMissing data M.D. jk

29/03/02

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Source dataThe subject source documents should contain at least the following original data:

• Subject identification: last name, first name, date of birth, sex, and identifica-tion number in the trial.

• Protocol identification number/study reference.

• Name of product on test.

• Date of first screening and/or enrolment in the trial.

• Dates of product administration and dosage.

• Dates of assessment visits and name of individual responsible for making theassessment.

• Serious adverse event(s) and related medication.

• Dates of laboratory sample collection.

NoteBefore initiating the trial, the source document and source data will be clearlydefined with the TDR clinical monitor. If no source documents exist at the centre,one should be created.

• If the subject data are directly entered into the provided CRF, then the CRFbecomes a source document. If this is the case, it should be stated clearly in theprotocol in order to avoid problems with verification of source data that mayarise during audits by TDR quality assurance personnel or inspections by regula-tory authorities.

• Where a subject’s diary exists (when subjects are asked to report eventual adverseevent(s), medical consultation and/or medication taken during the trial), thediary must be validated by the investigator and kept in the subject’s file.

In order to comply with GCP:The investigator must guarantee that the monitor(s), the auditors and the regula-tory authority(ies) will have direct access to source data and documents for verifi-cation of trial procedures and/or trial data.

The investigator must pledge that the study subject will be informed both orally andin writing – in the consent form – that the monitor(s), auditors(s), IEC/IRB, andregulatory authority(ies) will be granted direct access to his/her original medicalrecords, without violating confidentiality, for the verification of clinical trial proce-dures and/or data. By signing the informed consent form, the trial subject or legallyacceptable representative is authorizing access to his/her medical records.

The investigator is required to retain the patient identification list for a minimumof 15 years after completion or suspension of the trial (or for a longer period ifrequired by local regulations). The investigator is required to retain all patient filesand source documents for the maximum period of time permitted by the hospital,institution, or private practice, but for not less than 10 years, in order to meetinternational registration requirements (or for longer periods if required by local

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regulation). The investigator should keep documents in a safe place and take mea-sures to prevent accidental or premature destruction of source documents.

The investigator should inform TDR and the sponsor of any change of place ofarchiving. TDR and/or the sponsor will inform the investigator(s) when thedocuments no longer need to be retained.

Product storage and accountabilityThe investigator may assign an appropriate person (pharmacist/nurse) to beresponsible for investigation product storage and accountability at the trial site.The investigator should ensure that the investigation product is properly received,stored and handled.

The investigator/designated person must:

• Store the product in the condition that has been specified in writing by TDRand/or other sponsors and in accordance with the protocol and applicable regu-latory requirement(s).

• Ensure that the storage temperature is maintained as specified in the protocol.There should be a daily temperature log.

• Maintain records of the product’s delivery, inventory and return.

• Maintain up to date accountability on the trial ‘product accountability log’.

• Ensure that the product is used only in accordance with the approved protocol.

• Document the use of the product by each subject, and if appropriate, check atregular intervals that each subject is following the instructions properly (com-pliance).

• Return any unused product to TDR and/or other sponsors at the end of the trial.

Premature termination or suspension of a trial In the case of premature termination/suspension of the trial for any reason, theinvestigator should inform:

• The regulatory authority(ies), if applicable.

• The trial subject, assuring him/her of appropriate treatment and follow-up.

If the investigator terminates or suspends a trial without prior agreement of thesponsor, then the institution should:

• Promptly inform and provide the sponsor and the IEC/IRB with a detailed writtenexplanation of the termination or suspension.

If the sponsor terminates/suspends a trial, then the institution should:

• Promptly inform and provide the IEC/IRB with a detailed written explanation ofthe termination or suspension.

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If the IEC/IRB terminates or suspends its approval of a trial, then the institutionshould:

• Promptly notify and provide the sponsor with a detailed written explanation ofthe termination or suspension.


Progress and final reports

The investigator should submit written summaries of the trial status to the IEC/IRBannually, or more frequently if requested by the IEC/IRB.

The investigator should provide written reports promptly to the clinical monitor/sponsor and the IEC/IRB about any changes, which significantly affect the conductof the trial and/or increase the risk to the subjects.

The investigator should provide the IEC/IRB, regulatory authority(ies), TDR and/orother sponsors with a summary outcome and any reports required at the end of the trial.

References

The clinical study site team: roles and responsibilities. The Barnette InternationalSelf-Instructional Study-Site Curriculum, Barnett-Parexel, Philadelphia, USA, 1993.

Winslade J., Hutchinson D.R. Dictionary of clinical research. Surrey, UK: BrookwoodMedical Publications Ltd. 1992.

ICH guideline for good clinical practice, recommended for adoption at Step 4 of theICH Process on 1 May 1996 by the ICH Steering Committee.

Operational guidelines for ethics committees that review biomedical research, Geneva,World Health Organization, 2000, TDR/PRD/ETHICS/2000.1

A practical guide to FDA GCP for investigators. Neher and Hutchinson, eds. Brook-wood Medical Publications Ltd, Surrey, UK, 1993.

The trial investigator’s GCP handbook: a practical guide to ICH requirements.Hutchinson, ed. Brookwood Medical Publications Ltd. Surrey, UK, 1997.

WHO guidelines for good clinical practice (GCP) for trials on pharmaceutical products.World Health Organization, Geneva, 1995 (WHO Technical Report Series, No. 850:97-137).

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Annexes– Annex 1: Investigator’s file form . . . . . . . . . . . . . . . . . . . . . . . . . . 226

– Annex 2: Authorized signatory form . . . . . . . . . . . . . . . . . . . . . . . . 233

– Annex 3: Serious adverse event alert form . . . . . . . . . . . . . . . . . . . . 236

– Annex 4: Serious adverse event report form . . . . . . . . . . . . . . . . . . . 237

– Annex 5: Example of an informed consent form . . . . . . . . . . . . . . . . . 240

– Annex 6: Agreement between WHO/TDR and the investigator . . . . . . . . 243

– Annex 7: Not relevant

– Annex 8: Form FDA 1572 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 244

– Annex 9: Identification of screened and enrolled participants . . . . . . . . 246

– Annex 10: Identification of enrolled participants . . . . . . . . . . . . . . . . 249

– Annex A: Good clinical practice laboratory for clinical trials1 . . . . . . . . 252

1 Annex A is a separate TDR annex. Annexes 1-10 form part of a global set of TDR annexeson standard operating procedures.

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Annex 1

INVESTIGATOR’S FILE FORMPROTOCOL TITLE:

Study ID No.Sponsor:Clinical monitor:

Tel: Fax: Email:

Investigation product:Principal investigator:

Tel: Fax: Email:Study site:

INVESTIGATOR’S and MONITOR’S SIGNATURETo be signed during the closeout visit.

I hereby confirm that I have checked the content of the investigator’s file against the infor-mation contained in this form and that the file is complete.

Monitor’s signature: _______________________________ name: ___________________

I hereby agree that the content of the investigator’s file matches the information given on thisform and I agree to retain the documents for the required period of time.

Investigator’s signature: ____________________________ name: ___________________

INVESTIGATOR’S FILE LOCATION1. Administrative and regulatory documents:

2. Correspondence and monitoring:

3. Trial documents:

a) General file:

b) Data reporting:

c) Products:

d) Samples:

e) Trial material/equipment:

f) Study Subjects data and documents

YES NO NA*

– Is/Are the trial documents storage room(s) adequate? ■■ ■■ ■■

– Is there a possibility of “locking” the storage place(s)? ■■ ■■ ■■

– Does/Do the storage place(s) have limited access? ■■ ■■ ■■

*NA: Not applicable

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INVESTIGATOR’S FILE On File

The investigator’s file should be checked and updated for the whole duration of the trial YES NO NA*

1. ADMINISTRATIVE AND REGULATORY DOCUMENTS

• Composition of IEC/IRB who gave final approval ■■ ■■ ■■

• Local regulatory requirements ■■ ■■ ■■

• IEC/IRB and other authorities’ written approval for all documents (protocol, informed consent and any other ■■ ■■ ■■written information including advertisement for study subjects recruitment)

• IEC/IRB and other authorities’ written approval for protocol amendments ■■ ■■ ■■

• Correspondence with IEC/IRB and other authorities ■■ ■■ ■■

– Protocol submission ■■ ■■ ■■

– Amendment submission (if any) ■■ ■■ ■■

– Protocol modification notification (if any) ■■ ■■ ■■

– Interim report/written summaries of the trial ■■ ■■ ■■

– Documentation of serious adverse events reporting ■■ ■■ ■■

to the IEC/IRB/authorities

– Termination of the study ■■ ■■ ■■

• Product importation authorization ■■ ■■ ■■

• Correspondence about product importation ■■ ■■ ■■

• For studies under IND, copy of the completed and signed form FDA 1572 ■■ ■■ ■■

• Investigator and sub-investigators curriculum vitae (CV) ■■ ■■ ■■

• Copy of the up to date authorized signatory form (ASF) ■■ ■■ ■■

• Investigator agreement (TSA contract) signed and dated by both parties ■■ ■■ ■■

– Payment receipt ■■ ■■ ■■

• Signed confidential agreement ■■ ■■ ■■

• Signed agreement that products will not be used before the clinical trial initiation monitoring visit and approval from the TDR clinical coordinator

■■ ■■ ■■

• Copy of the insurance certificate/other insurance documents ■■ ■■ ■■

• ICH GCP Guideline ■■ ■■ ■■

• TDR/PRD investigator’s SOPs ■■ ■■ ■■

• Other administrative and regulatory trial documents ■■ ■■ ■■

If yes, please specify _______

Annex 1 – continued

*NA: Not applicable

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2. CORRESPONDENCE AND MONITORING

• Correspondence with TDR and/or other sponsoring agencies ■■ ■■ ■■

• Notes of meetings with TDR and/or other sponsoring agencies ■■ ■■ ■■

• Copy of the summary list of site visits ■■ ■■ ■■

• Trial initiation monitoring report ■■ ■■ ■■

• Notification by the investigator to TDR and/or other sponsors of serious adverse events and related reports ■■ ■■ ■■

• Documentation of serious adverse event reporting by TDR and/or other sponsors to other investigators ■■ ■■ ■■

• Correspondence about important requests ■■ ■■ ■■

• Investigator interim report/summaries of the trial for TDR and/or other sponsors ■■ ■■ ■■

3. TRIAL DOCUMENTS

a) General documents

• Copy of the investigator’s brochure (version no. ) ■■ ■■ ■■

• Copy of the approved protocol, signed and dated by all investigator(s) and sponsoring agencies (version no. ) ■■ ■■ ■■

• Copy of the approved protocol amendment(s), signed and dated by all investigator(s) and sponsoring agencies

(version no. ) ■■ ■■ ■■

• One blank copy of the approved informed consent (IC) andany other written information including all translations and the advertisement for study subject recruitment ■■ ■■ ■■

• One blank copy of the approved revision of the informed consent (IC) and any other written information amendmentsincluding all translations and the advertisement for study subject recruitment ■■ ■■ ■■

• Informed consent procedure ■■ ■■ ■■

b) Data reporting

• One blank copy of the CRF (version no. ) ■■ ■■ ■■

• One blank copy of the SAE Forms (version no. ) ■■ ■■ ■■

• One blank copy of the source document (version no. ) ■■ ■■ ■■

• Case report form completion procedure ■■ ■■ ■■

• Adverse event reporting procedure ■■ ■■ ■■


*NA: Not applicable

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c) Products

• Product certificate/batch release ■■ ■■ ■■

• Certificate of extension of the batch expiry date ■■ ■■ ■■

• Product acknowledgement of receipts (copy) ■■ ■■ ■■

• Return of unused product form(s) (copy) ■■ ■■ ■■

• Product destruction certificate if destroyed on site, and TDR authorization ■■ ■■ ■■

• Product management procedures (administration, storage, ) ■■ ■■ ■■

• Complete product accountability log (copy) ■■ ■■ ■■

• Complete product management log (copy) ■■ ■■ ■■

• Randomization list, envelopes and acknowledgement of receipts ■■ ■■ ■■

• Randomization list, envelopes and retrieval certificate ■■ ■■ ■■

• Copy of the temperature recording log if appropriate (especially for vaccines) ■■ ■■ ■■

• Other products related trial documents ■■ ■■ ■■


d) Samples

• Laboratory certification/normal ranges ■■ ■■ ■■

• Reactive acknowledgement of receipt ■■ ■■ ■■

• Specimen management procedures (collection, storage, results) ■■ ■■ ■■

• Temperature recording log if appropriate (e.g. deep freeze sample) ■■ ■■ ■■

• Shipment note (if appropriate) ■■ ■■ ■■

• Record of retained laboratory specimens (if any) To document location and identification of retained specimens if assays need to be repeated

■■ ■■ ■■

• Other laboratory specimen products-related trial documents ■■ ■■ ■■



*NA: Not applicable

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e) Trial material and equipment

• Acknowledgement of receipt ■■ ■■ ■■

Specifymaterial/equipment: ■■ ■■ ■■

■■ ■■ ■■

■■ ■■ ■■

• Return of trial material/equipment certificate (copy) ■■ ■■ ■■

Specifymaterial/equipment: ■■ ■■ ■■

■■ ■■ ■■

■■ ■■ ■■

f) Study subjects’ data and documents

• Signed and dated informed consent forms (for all subjects) ■■ ■■ ■■

• Identification of screened and enrolled participants log ■■ ■■ ■■

• Identification of enrolled participants log ■■ ■■ ■■

• All case report forms (with copy of the CRF for terminated subjects) ■■ ■■ ■■

• Copy of the subject assignment list ■■ ■■ ■■

• Copy of the laboratory sample log ■■ ■■ ■■

• Copy of all serious adverse event forms ■■ ■■ ■■

• Documentation of CRF corrections ■■ ■■ ■■

• Copy of the completed CRFs retrieval certificate ■■ ■■ ■■

• All study subjects’ source documents, including laboratory results ■■ ■■ ■■

COMMENTS AND ACTIONS:

*NA: Not applicable

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• Composition of the Institutional Review Board/Independent Ethics Committee ■■ ■■ ■■

• Local regulatory requirements ■■ ■■ ■■

• Form FDA 1572 For US studies (under IND) completed, signed and dated by all principal investigators who are to participate (can be sent before or after local IEC/IRB approval but a minimum of 45 days before product delivery date)

■■ ■■ ■■

• Investigator and sub-investigators curriculum vitae (CV) ■■ ■■ ■■

• Signed investigator SOP ■■ ■■ ■■

• Informed consent and any other written information including all translations and advertisement for study subject recruitment

■■ ■■ ■■

• Laboratory certification and accreditation ■■ ■■ ■■

• Laboratory technical procedure and normal ranges ■■ ■■ ■■

Other documents

Please specify:

• ■■ ■■ ■■

• ■■ ■■ ■■

• ■■ ■■ ■■

• ■■ ■■ ■■


DOCUMENTS TO BE OBTAINED DURING THE PRE-TRIAL MONITORING VISIT

(or on agreed date ___________ (dd/mm/yy) if not obtained during the pre-trialmonitoring visit)

*NA: Not applicable

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These documents should be submitted to TDR before initiation of the trial. A copy of the approval should be given as soon as possible in order to finalize/print all trial documents and prepare product packaging.

YES NO NA*

• Technical services agreement, signed and dated ■■ ■■ ■■

• Signed approved protocol (can be collected during the initiation visit) ■■ ■■ ■■

• Composition of IEC/IRB who gave approval ■■ ■■ ■■

• IEC/IRB and other authorities' written approval for all documents (protocol, informed consent and any other written information including advertisement for study subject recruitment) ■■ ■■ ■■

• Product importation authorization ■■ ■■ ■■

• Signed agreement that products will not be used before the written approval by the TDR Clinical Coordinator ■■ ■■ ■■

• Authorized signatory form (ASF) (can be collected during the initiation visit) ■■ ■■ ■■

Other documents

Please specify:

• ■■ ■■ ■■

• ■■ ■■ ■■

• ■■ ■■ ■■

• ■■ ■■ ■■


Follow up actions Person(s) responsible

DOCUMENTS TO BE OBTAINED DURING THE PRE-TRIAL MONITORING VISIT

(or on agreed date ___________ (dd/mm/yy) if not obtained during the pre-trialmonitoring visit)

*NA: Not applicable

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Annex 3

Date of report (dd-mm-yy): _________________

Source – Investigator/reporter name: _________________/Signature____________________

Address: ___________________________________________________________________

Tel. no.: _______________ Fax no.: ____________ Email: _________________

Subject identification (initials of last name, first name): __________

Age (in years): _____ Date of birth, if known (dd-mm-yy): _________________

Sex: ______________

Race (white; black; oriental; other): ____________________

Hospital number (if applicable/available): _______________

Protocol title: _________________________________________________________

Protocol no.: _______________

Centre: _____________________________________________________________________

Subject number: ______________

Relevant medical history; including laboratory, X-ray or ECG data.

SERIOUS ADVERSE EVENT ALERT FORM

General information

Adverse event

Concomitant medication

Subject history

Description of event: ___________________________________________________

Onset date (dd-mm-yy): ________________

Outcome(s): __________________________________________________________

Relationship to test product by the investigator / reporting physician: __________________

Treatment required: ____________________________________________________

Name of medication: ___________________________________________________

Date started (dd-mm-yy): ________________________

Date discontinued (dd-mm-yy): ___________________

Dose: ____________________________

Reason for use: ____________________

Route of administration: _____________

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Annex 4

SERIOUS ADVERSE EVENT REPORT FORMPROTOCOL TITLE: Protocol ID no: Centre:

Trial informationSubject’s Investigation product: Report typestudy no. 1=Initial

2=Follow-up

Adverse event information

Expedited report criteria(Tick all appropriate to event)

Suspected trial product information16. Suspected product: 17. Daily dose at onset 18. Route of

of event administration

19. Indication for use:

20.Therapy dates (from/to, dd/mm/yy)

21. Therapy duration until onset (hh/dd/mm)

22. Did the event abate after stopping product? 1 = No 2 = Yes 3 = NA*

Concomitant drug(s)23. Relevant concomitant drugs and dates of administration 1 = No 2 = YesIf yes, then list the name(s) and details

Dose Unit

Drug name

Route Schedule

1. Patientinitials

2. Date of birth(dd/mm/yy)

3. Age(year)

4. Sex

1 = female2 = male

5. Height(cm)

6. Weight(kg)

7. Eventonset

(dd/mm/yy)

8. Adverse event in MEDICAL TERMS:

9.Patient diedDate:_______

(dd/mm/yy)

10.Life-threatening

11.Prolongedhospitalization

12.Significant disability

13.Congenital anomaly

14.OtherSAE

15. Description:

Datestarted

(dd/mm/yy)

Datediscontinued(dd/mm/yy)

Continue1 = No2 = Yes

Reasonfor use

*NA: Not applicable

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Serious Adverse Event Protocol Centre:Report Form ID no:

Other relevant history, laboratory findings and action taken24. Other relevant history:

25. Relevant test/laboratory findingsLaboratory test Unit Date Value Comments on laboratory

(dd/mm/yy) finding

26. Action taken by investigator:

__0 = none __5 = Concomitant drug discontinued__1 = Trial dosage change __6 = New drug therapy added__3 = Trial drug discontinued __7 = Prolonged hospitalization__4 = Non-drug therapy

27. Outcome:

1 = Completely recovered on (dd/mm/yy) __________________________2 = Recovered with sequel 5 = Condition deteriorated3 = Condition improving 6 = Death, autopsy done (attach summary)4 = Condition still unchanged 7 = Death, autopsy not done

28. Causality assessment by investigator (is there any relationship with test product?):

0 = Not related 3 = Probable1 = Unlikely 4 = Most probable2 = Possible 5 = Insufficient data to assess

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Serious Adverse Event Protocol Centre:Report Form ID no:

Information source

29. Name, address, telephone and email address of the investigator

Name: ______________________________ Profession (speciality) ____________________

Address: ____________________________________________________________________

____________________________________________________________________________

___________________________________________________________________________

Tel: ________________________ Email: ______________________________

Signature of investigator reporting event ______________________________

Reporting date (dd/mm/yy) ___________________

Sponsor information

30. Name and address of reporting sponsor/manufacturer:

Name:Address:

____________________________________________________________________________

____________________________________________________________________________

____________________________________________________________________________

31. Date received by sponsor (dd/mm/yy) 32. Date of this report (dd/mm/yy)

Signature___________________________ _____________________________________

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Annex 5

EXAMPLE OF AN INFORMED CONSENT FORMThe doctor has confirmed that you have the skin disease called salak. As you prob-ably know, this disease is very common in this area, and is transmitted by the biteof a sandfly. If not treated, your sores will probably increase in size and cause a lot of discomfort to you, but after some time they may heal by themselves, pro-ducing deep scars. Unfortunately, the medicines available for treatment are not verygood – several injections are required, and you may experience vomiting and painat the site of injection.

The Centre for Research and Training in Skin Diseases and Leprosy is looking forbetter drugs that can be given by mouth, and a cream that can be applied to thesores. From the experience we have had with the treatment of other skin diseasesusing a medicine called fluconazole and a cream that contains a drug called keto-conazole, we believe that this may also be a good treatment for salak.

The Centre is now inviting (recruiting) around 200 patients with salak to partici-pate in a study to see whether this new treatment can be used to cure salak. If youagree to participate in the study, we will provide you with all the explanation youneed, and you will receive special medical attention from the Centre.

In order to see if this medication really is good for salak, we need to compare theresults of treatment with results from another group of patients who will receivesome pills and a cream which look similar but have no effect on the sores. The doc-tors will examine each patient several times during the course of treatment. Neitherthe doctors nor the patients will know which medication and cream was given.

The treatment will be provided to you at no cost. It will consist of taking one pilla day and applying the cream twice a day. Depending on the type of disease youhave, the treatment may last for a period of 6 or 12 weeks. You will have to comeback here 3, 6 and 12 weeks after starting treatment to collect the medication, seethe doctor, and have some laboratory tests done. Each time, the laboratory techni-cian will prepare a slide from a scraping of your sores.

The Centre will compensate you if you have to leave your work to come here, andwill pay for transportation between your home and the centre. We are going to paycareful attention in case the medication has any undesired effect on you, and ablood examination will be performed when you finish the treatment after 6 weeks,or after 6 and 12 weeks if you have to be treated for 12 weeks.

Only patients in good health will be invited to participate, and an initial blood testwill be carried out to check your condition of health. The total amount of blood col-lected for examination each time will not be more than a regular syringe (10ml)full. You should know that this new treatment may produce, in more sensitivepatients, some vomiting and skin rash. If you feel any discomfort, please come tothe Centre at any time. The doctor will decide if you can continue the medicationor should withdraw from the trial for safety reasons and be treated with an alter-native drug. The Centre will be responsible for any additional treatment you mayneed as a consequence of this disease or the new treatment.

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You are not obliged to enter into this study, and in this case the standard injectablemedication will be offered to you, consisting of ……. injections of glucantime. Onthe other hand, if you agree to participate, we would very much like you to followall the medical instructions, but you should know that you can leave the study at any time without any prejudice of health care in the future for you and yourfamily.

All the information collected from you during the trial will be kept confidential. Ifthe results of the trial are published, your identity will remain confidential.

This study has been approved by the Ministry of Health and Tehran University, whichgave the approval on …….

If you have any further questions, you can contact a member of staff at the clinic of Dr …………..… Address …………………………….…... Phone number……..…….

If any relevant information which could modify your participation in the trial shouldbecome available during the course of treatment, you will be informed by the physi-cian.

In case of any urgency regarding the treatment, you can contact Dr …......... at any time through his/her private telephone number……….………............ homeaddress:………….…

CONSENT FORM

I have read the information in this form, or it has been read to me. I have had theopportunity to ask questions about it and any questions that I have asked havebeen answered to my satisfaction. I know that I can refuse to participate in thestudy without penalty or loss of benefit to which I would have been otherwise enti-tled, or that if I agree to participate, I can drop out at any time without losing anybenefits or services to which I or my family are entitled.

I freely agree to participate in the study. After signing below, I will receive a copyof this consent form.

By signing this form I agree that the data collected about me will be accessible tothe sponsor’s representatives (monitors/auditors/..), the ethics committee and theregulatory authorities.

PRINT NAME OF PARTICIPANT DATE AND SIGNATURE

______________________________ ____/____/_____(dd/mm/yy)

Subject inclusion no. ____________ ________________________

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PRINT NAME OF THE WITNESS DATE AND SIGNATURE

_____________________________ ____/____/_____ (dd/mm/yy)

__________________________

PRINT NAME OF THE WITNESS DATE AND SIGNATURE

_____________________________ ____/____/_____ (dd/mm/yy)

__________________________


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Annex 6

AGREEMENT BETWEEN WHO/TDR AND THE INVESTIGATOR ON THECONDUCT OF THE WHO/TDR PROTOCOL

The investigator hereby confirms that he/she has read and understood the trial pro-tocol, any amendments to the trial protocol, as well as the appendices to the trial protocol, and that these documents contain all details necessary to perform the trial.Unclear passages were clarified in a discussion between TDR and the investigator.

The investigator undertakes to delegate the whole study (or parts thereof) only toqualified personnel, to inform them about the study and their duties, and to super-vise the correct conduct of the study. The persons involved in the conduct of thestudy are named in the “authorized signatory form”.

The investigator agrees that WHO/TDR and health authority representatives shouldhave free access to all documents of the study participant, if they so wish, to ascer-tain that the study is conducted in accordance with the protocol. Thus the existenceof the study participant and his/her informed consent should be proved. The spon-sors declare that neither WHO/TDR representatives nor personnel of the healthauthorities will handle data, which may identify the study participant outside theinvestigation site.

The investigator agrees to the protocol, amendments to the protocol, and appen-dices I-X in all details and will perform the study in accordance with these docu-ments, with the Declaration of Helsinki, the ICH Guidelines on Good Clinical Practice(CPMP/ICH/135/95, Topic E6), and local regulations.

The investigator will treat the conduct and the results of this study as confidential. Thefilled out case report forms and all other study materials remain the property of TDR.Publications will be made in mutual agreement between the investigator and TDR.

Information related to the investigation should only be transferred to third personsafter written consent from WHO/TDR has been obtained. This does not apply if theinformation transfer is mandatory (e.g. information of patients, submission to eth-ical committees).

Despite the above, it is the general policy of WHO/TDR to encourage publication ofresults from clinical investigations. The manuscript should be based on the final reportof the study. According to good scientific practice, no interim data should be pub-lished. Prior to publication the manuscript should be sent to TDR for review and com-ment; TDR should comment within four weeks after submission of the manuscript.

Investigator’s name and signature date (dd/mm/yy)

________________________________________________ ____/____/____

WHO/TDR representative’s name and signature: date (dd/mm/yy)

________________________________________________ ____/____/____

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Annex 8

DEPARTMENT OF HEALTH AND HUMAN SERVICESPUBLIC HEALTH SERVICE

FOOD AND DRUG ADMINISTRATIONSTATEMENT OF INVESTIGATOR

(TITLE 21, CODE OF FEDERAL REGULATIONS (CFR) Part 312)(See instructions on reverse side.)

1. Name and address of investigator

2. Education, training, and experience that qualifies the investigator as an expert in the clin-ical investigation of the drug for the use under investigation. One of the following isattached:

■■ Curriculum vitae ■■ Other statement of qualifications

3. Name and address of any medical school, hospital, or other research facility where the clinical investigation(s) will be conducted.

4. Name and address of any clinical laboratory facilities to be used in the study.

5. Name and address of the institutional review board (irb) that is responsible for review andapproval of the study(ies).

6. Names of the subinvestigators (e.g., research fellows, residents, associates) who will beassisting the investigator in the conduct of the investigation(s).

7. Name and code number, if any, of the protocol(s) in the ind for the study(ies) to be con-ducted by the investigator.

Form Approved: OMB No 0910-0014Expiration Date: September 30, 2002See OMB Statement on Reverse.

NOTE: No investigator may participate in an investigation until he/she provides the sponsor-with a completed, signed Statement ofInvestigator. Form FDA 1572 (21 CFR 312.53 (c)

Form FDA 1572 (10/99) Previous edition is obsolete Page 1 of 2

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8. Attach the following clinical protocol information.For phase 1 investigations, a general outline of the planned investigation including the estimated dura-tion of the study and the maximum number of subjects that will be involved.For phase 2 or 3 investigations, an outline of the study protocol including an approximation of thenumber of subjects to be treated with the drug and the number to be employed as controls, if any; theclinical uses to be investigated; characteristics of subjects by age, sex, and condition; the kind of clin-ical observations and laboratory tests to be conducted; the estimated duration of the study; and copiesor a description of case report forms to be used.

9. Commitments:I agree to conduct the study(ies) in accordance with the relevant, current protocol(s) and will onlymake changes in a protocol after notifying the sponsor, except when necessary to protect the safety,rights, or welfare of subjects.I agree to personally conduct or supervise the described investigation(s).I agree to inform any patients, or any persons used as controls, that the drugs are being used for inves-tigational purposes and i will ensure that the requirements relating to obtaining informed consent in21 CFR part 50 and institutional review board (IRB) review and approval in 21 CFR part 56 are met.I agree to report to the sponsor adverse experiences that occur in the course of the investigation(s)in accordance with 21 CFR 312.64.I have read and understand the information in the investigator’s brochure, including the potential risksand side effects of the drug.I agree to ensure that all associates, colleagues, and employees assisting in the conduct of thestudy(ies) are informed about their obligations in meeting the above commitments.I agree to maintain adequate and accurate records in accordance with 21 CFR 312.62 and to make thoserecords available for inspection in accordance with 21 CFR 312.68.

I will ensure that an irb that complies with the requirements of 21 CFR part 56 will be responsible forthe initial and continuing review and approval of the clinical investigation. i also agree to promptlyreport to the irb all changes in the research activity and all unanticipated problems involving risks tohuman subjects or others. Additionally, i will not make any changes in the research without irbapproval, except where necessary to eliminate apparent immediate hazards to human subjects.I agree to comply with all other requirements regarding the obligations of clinical investigators and allother pertinent requirements in 21 CFR part 312.

INSTRUCTIONS FOR COMPLETING FORM FDA 1572 STATEMENT OF INVESTIGATOR:1. Complete all sections. Attach a separate page if additional space is needed.2. Attach a curriculum vitae or other statement of qualifications as described in section 2.3. Attach protocol outline as described in section 8.4. Sign and date below.5. FORWARD THE COMPLETED FORM AND ATTACHMENTS TO THE SPONSOR. The sponsor willincorporate this information along with other technical data into an investigational newdrug application (IND).

10.SIGNATURE OF INVESTIGATOR 11. Date

WARNING: a willfully false statement is a criminal offense. U.S.C. title 18, sec. 1001.)

Public reporting burden for this collection of information is estimated to average 100 hoursper response, including the time for reviewing instructions, searching existing data sources,gathering and maintaining the data needed, and completing reviewing the collection ofinformation. Send comments regarding this burden estimate or any other aspect of this col-lection of information, including suggestions for reducing this burden to:Food and Drug Administration Food and Drug Administration “An agency may not conduct or sponsor, and CBER (HFM-99) CDER (HFD-94) a person is not required to respond to, a1401 Rockville Pike 5516 Nicholson Lane collection of information unless it displaysRockville, MD 20852-1448 Kensington, MD 20859 a currently valid OMB control number.”

Form FDA 1572 (10/99) Previous edition is obsolete Page 2 of 2

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Annex A

GCP LABORATORY FOR CLINICAL TRIALS

IntroductionIn an attempt to ensure that the data generated by clinical laboratories for TDRsponsored studies comply with GCP and other regulatory requirements, and thatanalytical tests, reporting, interpretation and verification are accurate, a set of criteria have been defined that should be applied when considering a laboratory’sparticipation in a study.

ScopeAll hospital/clinical laboratories which are to provide support for TDR clinical trials.

The term ‘clinical laboratory’ refers to laboratories performing in the following spe-cialities and related areas:

– clinical chemistry– haematology– histopathology– immunology (serology)– microbiology– pharmacokinetics.

Clinical laboratory standards

Personnel and organization

The work is to be undertaken by experienced laboratory personnel who are quali-fied for the task by education and training and are professionally directed by apathologist or clinical scientist.

The number of suitably trained staff should be sufficient to perform the necessarylaboratory procedures both in normal working hours and on an on-call basis, ifrequired. The tests and procedures performed by both technical and non-technicalstaff must fall within their experience and training.

Qualification and training records should exist for all personnel. Training pro-grammes should be available to ensure that a baseline standard of ability exists andthat personnel are kept up to date with new assay techniques and equipment.

Quality control/assurance

Personnel within the laboratory who implement and monitor internal and externalquality control/proficiency tests should have the authority to halt the release ofresults which do not meet the appropriate quality control standards.

All laboratories should have effective internal quality control and participate in pro-ficiency test schemes, or hold accreditation by an appropriate professional or reg-ulatory body where such a scheme is available.

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Internal quality control measures should be implemented for all assays detailed inthe clinical investigation protocol.

The laboratory should participate in at least one external quality control or profi-ciency testing scheme for all assays detailed in the clinical investigation protocol(where such schemes exist).

Laboratories should have validated and updated laboratory normal ranges or normalvalues.

Validations

The laboratories should follow the principles of good laboratory practice. All proce-dures should be designed to detect results that do not conform with the stipulatedquality specifications. Samples should be stable throughout all analytical assess-ments. Each laboratory test must be validated to establish its performance charac-teristics in terms of frequency of malfunction, sensitivity, specificity, precision andreliability. Calibration and validation of methodologies should be maintained.

Facilities/equipment/maintenance

Provision should be made to restrict access to paper, magnetic and optical storagemedia.

Controls should be in place to ensure that faults in freezers/refrigerators that housetemperature-sensitive clinical investigation samples and analytical reagents arerapidly identified and resolved.

Where a risk of contamination of TDR clinical investigation samples exists, suitablebarrier measures should be in place to reduce the possibility of contamination.

Assay equipment should be suitable for those assays defined in the clinical inves-tigation protocol.

Where methodology is specified by TDR/the sponsor, the laboratory should have sufficient capability, in terms of both personnel and facilities, for the execution ofsuch assays.

The sample processing capability of the laboratory should be sufficient to ensuretimely evaluation and reporting of results.

Apparatus should be periodically inspected, cleaned, maintained and calibrated ac-cording to the written procedures and manufacturers’ recommendations. Calibrationand maintenance of records should be routine.

Maintenance contracts should exist for all items of equipment for which user main-tenance is not possible e.g. automated analysers or robotic equipment. Mainten-ance records should be retained.

Where the study protocol requires laboratory analyses to be performed frequently for safety purposes, arrangements should be in place for back-up assay facilities inthe event of power or equipment failure.

Laboratory reagents must be appropriately labelled with expiry date, preparationdate, identity and concentration. They must be stored under the appropriate condi-tions.

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Standard operating procedures (SOPs)

The laboratory should have pre-established systematic procedures for sample col-lection, transport, preparation, identification, analysis, documentation and verifi-cation of laboratory data. There should be readily available written procedures cov-ering, as a minimum requirement, the following key aspects of operations:

– cleaning, maintenance and calibration of laboratory equipment– operation of laboratory equipment– analytical methods– data transformation techniques.

Procedures must be appropriate for their intended use, and compatible with thenature of the samples to be tested. Methods should be written, in the form of amanual or SOP, in a clear and unambiguous manner, such that an experienced ana-lyst who is unfamiliar with the method is able to use the procedure and interpretthe results. SOPs should follow a pre-established format which includes the fol-lowing:

– title– date of authorisations– references– basic principles– apparatus and reagents– procedural details– safety precautions– calculations and statistics– quality assurance.

A policy should be in place defining the procedure to be followed in the event ofabnormal results.

Sample handling/storage

Each clinical sample must be accompanied by appropriate documentation to clearlyindicate from whom the sample was taken and what analyses should be performedon it.

Each sample received by the laboratory should be coded with a unique accessionnumber that permits tracking of the sample through receipt, analysis and reporting.

Where required by the protocol, there should be sufficient refrigerators/freezers toensure the safe storage of clinical investigation samples.

Reporting of results

A mechanism must be in place to ensure that all investigation personnel areinformed promptly of the results of laboratory analyses. If a time period for thereporting of laboratory analyses is specified or implied by the study protocol, thenprocedures must be in operation to ensure compliance with these reporting require-ments.

A procedure should be in place to alert investigation staff to any revision to labo-ratory normal ranges.

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Manual or electronic checks must be in place to ensure that only technically validresults are released. All results must be checked/approved prior to release. In addi-tion, any abnormal results must be reviewed by senior laboratory personnel prior toissue.

Source documentation requirements

Raw laboratory data, analysis request forms and reports of results must be retainedin a manner consistent with the requirements of the study protocol.

Procedures should be in place to routinely back up data held in electronic form.

References

Organisation for Economic Co-operation and Development. OECD Principles of GoodLaboratory Practice. Environment Monograph, 7: 45-48, 1992.

Susan Makkink. How to select a GCP compliant central laboratory. Good ClinicalPractice Journal, 6 (1): 27-30, 1999.

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SOP title: Breaking Code

SOP No.: CT 06

SOP author(s): Juntra Karbwang & Claire Pattou

SOP approbation:

SOP status: Final Revision due date: September 2004

Status date: 10 April 2002

Implementation date: _____________

Document received by: _____________ _____________ _____________Date Signature

Policy: Medical need: Individual randomization codes must only be broken andrevealed to investigators (or others responsible for managing the sub-ject/patient) when identification of the study medication is required inorder to manage a subject/ patient, i.e. when a medical emergency orserious medical condition has arisen.

Regulatory need.

Randomization code-breaks must be fully documented.

The clinical monitor will ensure that a system is in place to facilitate out-of-hours emergency contact between investigators and the clinicalmonitor/clinical co-ordinator/product manager.

Scope: All Phase I, II and III trials which are blinded to investigators.

Individual randomization codes, where the blind is to be broken on anindividual basis due to a medical emergency/severe adverse event(SAE).

Research and Development Unit, TDR Clinical Development

Standard Operating Procedures (SOPs)

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Applicable to: The clinical monitor/clinical co-ordinator/product manager, if con-tacted regarding the breaking of individual randomization codes.

Objective: To define the circumstances under which individual patient/subjectrandomization codes may be broken in the case of a medical emergencyduring a clinical study, and how to document this event.

Conducting the code-break procedures: Explain the code-break procedure to thestaff at the study site during the study initiation visit:

• Make sure that the investigator knows that the code break will be per-formed only in the event of a medical emergency, when the physician incharge of a subject/patient feels that the patient cannot be treatedadequately unless the identity of the investigation product is known orif the information is essential for further management of the other sub-jects/patients already included or to be included.

• It should be emphasized to the investigator that he/she must makeevery effort to contact the TDR clinical monitor prior to breaking thecode. If this is not possible, and the situation is an emergency, theinvestigator may break the code and contact the TDR clinical monitor assoon as possible thereafter.

Following a request from the investigator or other physician in charge ofthe subject/patient, and when a set of individual codes is held at thesponsor’s office, the individual code for the subject/patient in questionshould be broken and the investigator/physician informed of the medica-tion.

Whoever is responsible for breaking the code will need to document thefollowing:

• Protocol number.

• Study number.

• Subject/patient number.

• Date of code break.

• Identification and signature of person breaking the code.

• Identification of person(s) requesting the code break.

• Reason(s) for breaking the code.

• Investigator’s signature.

The information should be recorded on an emergency code-break form (seeAnnex 26 for sample form) and directly on the case report form (CRF).

If the code is concealed in an envelope which is then opened, the personwho broke the code must sign and date the envelope. If opened at thestudy site, the envelope will be returned to TDR/sponsor (after collectionby the clinical monitor at the next site visit).

Provide all information regarding this event to the clinical co-ordinator/product manager.

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If the randomization code was not declared in the investigator’s initialserious adverse experience report, update the serious adverse experienceworksheet once the blind is broken for the study.

Ensure that the clinical data management personnel are informed.

Ensure that all documentation relating to the code break is included in thestudy file.

TDR/PRD

TDR – Product Research and Development Unit – Clinical Development

SOP CT 06, 10 April 2002

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EMERGENCY CODE BREAK FORM

PROTOCOL TITLE:

Study ID No: Study Site:

Subject’s Study No: ....................................................

Subject’s Initials: .......................................................

Date of randomisation break: ..............................

Name/function of the person who break the code: ........................................................

Name/function of the person requesting the code break: ...........................................

REASON FOR BREAKING THE CODE

Signature of person breaking the codeInvestigator’s signature(if not the investigator)

Date _______________________ Date ______________________

Note: if available, the opened, signed and dated code envelope must be attached to this form.

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A serious adverse event is any untoward medical occurrence that, at any dose,has one or more of the following:

• results in death: all deaths on study defined as while on protocol therapy orwithin 30 days of the last dose. Deaths occurring later need not be reportedunless they are a result of an event that started within the time frame coveredby on study definition

• is life-threatening: it is defined as an event in which the patient was at risk ofdeath at the time of the event; it does not refer to an event which hypotheti-cally might have caused death if it were more severe

• requires inpatient hospitalization or prolongation of existing hospitalization

• results in persistent or significant disability/incapacity

• is a congenital anomaly/birth defect?

• results in important medical events that may not be immediately life threateningor does not directly result in death or hospitalization but may jeopardize thepatient or may require intervention to prevent on of the other outcomes listedabove.

ICH Guideline – Clinical Safety Data Management (E2A)

Manual for Completing the SAE Reporting Form

All Reports of Serious Adverse Events (SAEs) must be expedited and sentto the Clinical Monitor or Sponsor within 24 hours of identification of

SAE occurrence

Responsibility of Investigator when SAE Occurs

• All serious adverse events (SAEs) should be reported immediately by phone, fax(using form provided, (see Annex 3, page 236). The immediate report should be promptly followed by a detailed, written report (see Annex 4, page 237). Theinvestigator should follow the AE report instructions agreed with TDR/sponsor andwithin time periods stated in the protocol. The investigator should also complywith the local regulatory requirement(s) related to the AE reporting to healthauthorities; regulatory authority and the IRB/IEC specified in the protocol.

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Procedures to Complete the SAE Form

Trial Information

Adverse Event Information

• For reported deaths, the investigator should provide TDR/sponsor/IRB/IEC withany additional requested information, e.g. autopsy reports and terminal medicalreports.

• The SAE form must be completed in English.

• It should be legible, preferably typewritten

• Use black pen, if handwritten

• Avoid abbreviations

• Avoid leaving blank fields, use “N/A” instead

• Make sure that the information provided on the SAE form is consistent with thedata recorded in the CRF and the source data.

Patient No.

• Enter the same number as on the CRF

• In the case of an SAE in an open trial: enter the patient number (entry number)

• If the SAE occurred after randomization: enter the randomization number, notthe patient number. The randomization number is important for the codebreaking.

Trial Product Name

• Enter the TDR/sponsor trial product under investigation in this trial. Not thesuspected product, placebo, or comparator administered to the patient (see fieldno. 15)

Report type

• Immediate: detailed immediate data on this SAE is reported to TDR/sponsor afterinitial report of SAE

• Follow-up: this should be additional information that pertains to a specific SAEthat has already been reported as immediate.

1. Patient initials

• Enter the initials of the patient. These initials must be the same as those onthe CRF.

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2. Date of Birth

• Enter full birth date using digits (dd-mm-yy) as on CRF

3. Age

• Enter patient’s age in years at the time of the SAE

4. Sex

• Provide correspond number in the space provided: 1 = female 2 = male

5. Height

• Enter the height of the patient in centimetres in the space provided

6. Weight

• Enter the weight of the patient at the time of onset of SAE, in kilograms

7. Event onset

• Enter the date (dd-mm-yy) when the first sign/symptom of the SAE occurred

8. Adverse events in medical terms

• Use precise medical terminology. This is important in order to allow a cor-rect coding of the term(s) when data are entered into the data base

• Enter the diagnosis whenever possible. If the diagnosis is not yet known,enter signs and symptoms that fulfil one of the SAE criteria. However, insuch cases the diagnosis should be provided on a follow-up report.

• Enter all information pertaining to aetiologies, course and treatment of SAE,which cannot be entered elsewhere on the form.

• Do not use the term ‘death’, as this is the outcome of SAE. Use the medicalterm of the AE which resulted in death.

Expedited Report Criteria

Expedited Report Criteria (item 9 to 13)

• Tick the appropriate box in front of the number

9. Death, enter the date (dd-mm-yy) the patient died

10. Life threatening

• An event in which the patient was at risk of death at the time of the event;it does not refer to an event which hypothetically might have caused deathif it were more severe

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Suspected Trial Product Information

11. Involved or prolonged inpatient hospitalization

• If the patient had to be admitted to the hospital as inpatient or hospital-ization of the patient had to be extended as a result of this AE, specify thereason for hospitalization in field no. 14 under ‘Description’. If the patientwas treated as an emergency case but not admitted as an inpatient, it is notconsidered as hospitalization. In this case, it should be considered underfield no. 8.

12. Significant disability

• If it involved permanent and/or persistent or severe disability, which dis-rupts the patient’s ability to carry out normal life functions. When an AEwhich results in ‘an irreversible structural or functional impairment’, specifydisability (e.g. deafness) under field no. 14, ‘Description’.

13. Congenital anomaly/birth defect

• Any anatomical malformation occurring in the offspring of a trial patient.

14. Other SAE

• Any other SAE which results in important medical events that may not beimmediately life-threatening or do not directly result in death or hospital-ization but may jeopardize the patient or may require intervention to pre-vent the other outcomes listed above.

15. Description of SAE

• Use this field for a description of the SAE (nature, severity, course etc.) andfor all additional associated sign/symptoms

• Enter all information pertaining to aetiologies, course, and treatment of theSAE, which cannot be entered elsewhere on the form.

16. Suspected product

• Trial treatment not known/blinded: enter ‘code not open’

• Trial treatment known: if the code has been broken or if the patientreceived an open-label treatment, enter the respective trial treatmentadministered last before the time the SAE occurred i.e. trial product, placebo,comparator.

17. Daily dose at onset of event

• For open-label treatment or if the code has been broken, enter the dailydose of the suspected trial product the patient received last before the onsetof the SAE

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• Enter the total daily dose (value, unit) the patient received, regardless ofschedule.

18. Route of administration

• Enter the route by which the trial product was administered, e.g. oral, intra-muscular, subcutaneous, etc.

19. Indication for use

• This refers to the indication(s) for which the product is being studied in thetrial or the indication for which the named patient treatment is beingadministered.

20. Therapy dates (from/to)

• Start date: enter the date (dd-mm-yy) the patient started trial treatmentwith the suspected product

• End date: enter the last date (dd-mm-yy) the patient received trial treat-ment with the suspected product

• If the drug is not withdrawn: enter ‘X’ instead of end date.

21. Therapy duration until onset

• If the SAE occurred during the treatment period of the trial, enter the timeduration between first dose administered the product and onset of SAE.Indicate the unit in hours-days-months (h/d/m)

• If the SAE occurred after the treatment period: enter ‘NA’ as the patient hasnot been under trial treatment at the onset of the event

• If the SAE occurred during the run-in period, wash-out period or post-trialfollow-up period, enter ‘NA’ as the patient has not been under trial treat-ment at the onset of the event.

22. Did the event abate after stopping product?

• Write 0 for ‘No’ if SAE did not improve after stopping the trial product

• Write 1 for ‘Yes’ if SAE improves spontaneously (i.e. without treatment) afterstopping the trial product

• If the treatment has not been withdrawn or if information is not yet avail-able, write 3 for ‘N/A’ .

23. Relevant concomitant drugs and dates of administration

• Indicate whether or not there is information on any relevant concomitantdrugs taken by the patient

• Enter only concomitant drugs which may have contributed to the occurrenceand the course of the SAE. Provide detailed information of use.

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Other relevant history, laboratory findings and action taken

24. Other relevant history

• Enter patient’s medical history and present condition which may have con-tributed to the occurrence or the course of the SAE.

25. Relevant test/laboratory findings

• Enter only those test/lab findings that would help in the diagnosis, ordescribe the SAE, e.g. increase in liver enzyme, etc.

• Enter details of laboratory tests and findings.

26. Action taken by Investigator

• Tick one or more action(s) taken regarding the SAE.

27. Outcome

• Provide numbers that correspond with the outcome. If the patient com-pletely recovered, enter the date of complete recovery in the space provided.

28. Causality assessment by Investigator

Provide causality assessment:

• Not related: The event is clearly related to other factors such as thepatient’s clinical state, therapeutic intervention or concomitant therapy.

• Unlikely: The event was most probably produced by other factors such asthe patient’s clinical state, therapeutic intervention or concomitant therapyand does not follow a known response pattern to the trial product.

• Possible: The event:

– follows a reasonable temporal sequence from the time of product admin-istration

– and/or follows a known response pattern to the trial product

– but could have been produced by other factors such as the patient’s clin-ical state, therapeutic intervention or concomitant therapy.

• Probable: The event:



– and could have been produced by other factors such as the patient’sclinical state, therapeutic intervention or concomitant therapy.

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• Most probable: The event:



– and could have been produced by other factors such as the patient’s clin-ical state, therapeutic intervention or concomitant therapy

– and either occurs immediately following trial product administration, orimproves on stopping the product or there is positive reaction at theapplication site.

• Insufficient data to assess: There is not enough clinical and/or laboratoryinformation to suggest the relationship of the event to the trial product.

Information Source

Sponsor Information

29. Name, address, telephone and e-mail address of investigator reporting theSAE

• Enter the name, address, telephone number and e-mail address (if available)of the investigator who reports the SAE to Clinical Monitor/Clinical Co-ordi-nator/Product Manager/Sponsor

• Sign and date (dd-mm-yy) of reporting.

TDR/PRD

TDR – Product Research and Development Unit – Clinical Development, June 2001

30. Name and address of reporting Sponsor/manufacturer

• Enter the name of the Clinical monitor/Product Manager/Sponsor whoreceives the SAE form from the investigator reporting the SAE.

31. Date received by sponsor

• Enter the date (dd-mm-yy) the particular SAE report is received byTDR/Sponsor

• If SAE was detected through reviewing the patient’s CRF enter the datedetection here.

32. Date of this report

• This refers to the date (dd-mm-yy) on which this SAE case is released forlocal submission to the Health Authorities. The date has to be updated foreach follow-up report.

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GCP Laboratory for Clinical Trials

IntroductionIn an attempt to ensure that the data generated by clinical laboratories for TDRsponsored studies comply with GCP and other regulatory requirements, and thatanalytical tests, reporting, interpretation and verification are accurate, a set ofcriteria have been defined that should be applied when considering a laboratory’sparticipation in a study.

ScopeAll hospital and clinical laboratories providing support for TDR clinical trials.

The term ‘clinical laboratory’ refers to laboratories performing the followingspecialities and related areas:

– clinical chemistry– haematology– histopathology– immunology (serology)– microbiology– pharmacokinetics.

Clinical laboratory standardsPersonnel and organizationThe work should be undertaken by experienced laboratory personnel who are quali-fied for the task by education and training, and who are professionally directed bya pathologist or clinical scientist.

The number of suitably trained staff should be sufficient to perform the necessarylaboratory procedures both in normal working hours and on an on-call basis, ifrequired. The tests and procedures performed by both technical and non-technicalstaff must fall within their experience and training.

Qualification and training records should exist for all personnel. Training pro-grammes should be available to ensure that a baseline standard of ability exists andthat personnel are kept up to date with new assay techniques and equipment.

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Quality control assurancePersonnel within the laboratory who implement and monitor internal and externalquality control and proficiency tests should have the authority to halt the releaseof results that do not meet the appropriate quality control standards.

All laboratories should have effective internal quality control and participate inproficiency test schemes, or hold accreditation by an appropriate professional orregulatory body where such a scheme is available.

Internal quality control measures should be implemented for all assays detailed inthe clinical investigation protocol.

The laboratory should participate in at least one external quality control or pro-ficiency testing scheme for all assays detailed in the clinical investigation protocol(where such schemes exist).

Laboratories should have validated and updated laboratory normal ranges or normalvalues.

ValidationsThe laboratories should follow the principles of good laboratory practice. All proce-dures should be designed to detect results that do not conform with the stipulatedquality specifications. Samples should be stable throughout all analytical assess-ments. Each laboratory test must be validated to establish its performance charac-teristics in terms of frequency of malfunction, sensitivity, specificity, precision andreliability. Calibration and validation of methodologies should be maintained.

Facilities/equipment/maintenanceProvision should be made to restrict access to paper, magnetic and optical storagemedia.

Controls should be in place to ensure that faults in freezers and refrigeratorshousing temperature-sensitive clinical investigation samples and analyticalreagents are rapidly identified and resolved.

Where a risk of sample contamination exists, suitable barrier measures should be inplace to reduce the possibility of contamination.

Assay equipment should be suitable for those assays defined in the clinical inves-tigation protocol.

Where methodology is specified by TDR and/or other sponsors, the laboratoryshould have sufficient capability, in terms of both personnel and facilities, for theexecution of such assays.

The sample processing capability of the laboratory should be sufficient to ensuretimely evaluation and reporting of results.

Apparatus should be periodically inspected, cleaned, maintained and calibratedaccording to the written procedures and manufacturers’ recommendations.Calibration and maintenance of records should be routine.

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Maintenance contracts should exist for all items of equipment for which usermaintenance is not possible, e.g. automated analysers or robotic equipment. Main-tenance records should be retained.

Where the study protocol requires laboratory analyses to be performed frequently forsafety purposes, arrangements should be in place for back-up assay facilities in theevent of power or equipment failure.

Laboratory reagents must be appropriately labelled with expiry date, preparationdate, identity and concentration. They must be stored under the appropriate condi-tions.

Standard operating procedures (SOPs)The laboratory should have pre-established systematic procedures for sample col-lection, transport, preparation, identification, analysis, documentation and verifi-cation of laboratory data. There should be readily available written procedures cov-ering, as a minimum requirement, the following key aspects of operations:

– cleaning, maintenance and calibration of laboratory equipment– operation of laboratory equipment– analytical methods– data transformation techniques.

Procedures must be appropriate for their intended use, and be compatible with thenature of the samples to be tested. Methods should be written, in the form of amanual or SOP, in a clear and unambiguous manner, such that an experienced ana-lyst who is unfamiliar with the method is able to use the procedure and interpretthe results. SOPs should follow a pre-established format which includes the fol-lowing:

– title– date of authorizations– references– basic principles– apparatus and reagents– procedural details– safety precautions– calculations and statistics– quality assurance.

A policy should be in place defining the procedure to be followed in the event ofabnormal results.

Sample handling/storageEach clinical sample must be accompanied by appropriate documentation to clearlyindicate from whom the sample was taken and what analyses should be performedon it.

Each sample received by the laboratory should be coded with a unique accessionnumber that permits tracking of the sample through receipt, analysis and reporting.

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Where required by the protocol, there should be sufficient refrigerators and freezersto ensure the safe storage of clinical investigation samples.

Reporting of resultsA mechanism must be in place to ensure that all investigation personnel areinformed promptly of the results of laboratory analyses. If a time period for thereporting of laboratory analyses is specified or implied by the study protocol, thenprocedures must be in operation to ensure compliance with these reporting require-ments.

A procedure should be in place to alert investigation staff to any revision to labo-ratory normal ranges.

Manual or electronic checks must be in place to ensure that only technically validresults are released. All results must be checked and approved prior to release. In addition, any abnormal results must be reviewed by senior laboratory personnelprior to issue.

Source documentation requirementsRaw laboratory data, analysis request forms and reports of results must be retainedin a manner consistent with the requirements of the study protocol.

Procedures should be in place to routinely back up data held in electronic form.

References

Organization for Economic Co-operation and Development. OECD Principles of GoodLaboratory Practice. Environment Monograph, 7: 45-48, 1992.

Susan Makkink. How to select a GCP compliant central laboratory. Good ClinicalPractice Journal, 6 (1): 27-30, 1999.

TDR/PRD

TDR – Product Research and Development Unit – Clinical Development, Jan 2001Annex A

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Mailing address:WHO/TDRAvenue Appia 201211 Geneva 27Switzerland

Street address:WHO/TDRCentre Casai51-53 Avenue Louis-Casai1216 Geneva Switzerland

Tel: (+41-22) 791-3725Fax: (+41-22) 791-4854E-mail: [email protected]: www.who.int/tdr

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