Ivana Knezevic, WHO/FCH/IVB/QSB, Jan2005 Principles for clinical evaluation of vaccines: WHO...

Ivana Knezevic, WHO/FCH/IVB/QSB, Jan2005

Principles for clinical

evaluation of vaccines: WHO

guidelines

World Health Organization - WHO

Dr Ivana KnezevicWHO, Immunization, Vaccines & Biologicals Quality Assurance and Safety of Biologicals

Ivana Knezevic, WHO/FCH/IVB/QSB, Jan 2005

Vaccine development and evaluation

Product development

Product development

LicensingLicensing

Characterization

of candidate

vaccine

Characterization

of candidate

vaccine

Preclinical/Nonclinical

testing

Preclinical/Nonclinical

testing

Clinical trials

Clinical trials

PMSPMS

Development of standards

and stand. of assays

Establishment of WHO standards

and recommendations for production and control

Monitoring performance

and development of new

standards/replacement

of existing


Production and control of vaccines

The role of NRAs at different stages of vaccine

development, production and evaluation

Research and Development of vaccines

Research and Development of vaccines

The role of the National RegulatoryAuthorities in vaccine evaluation

4 Based on National Regulation

4 Diff erent in diff erent countries4 Clinical trial approval4 Review of the manufacturer dossier

as a part of licensing procedure

4 Lot release4 Surveillance of vaccine field

performance

4 Regular inspections for GMP

The role of the National RegulatoryAuthorities in vaccine evaluation

4 Based on National Regulation

4 Diff erent in diff erent countries4 Clinical trial approval4 Review of the manufacturer dossier

as a part of licensing procedure

4 Lot release4 Surveillance of vaccine field

performance

4 Regular inspections for GMP

Clinical trials

Licensing

Postmarketing surveillance

Preclinical testing


What is the role of regulators in clinical trials?

4 DEFINITION OF VACCINE OF ASSURED QUALITY RELY ON THE STRONG NRA!

4 Regulators should play an active role from early stages of vaccine development to post-licensing by: Establishing regulation of clinical trials (CTs) at

national level Interacting with the other bodies (e.g., ethical

committee) By providing the expert advice on quality aspect of

vaccines By establishing an early dialogue with the

manufacturers since regulatory compliance is the basis for eventual approval of clinical trials

4 National regulation of CTs is essential component (e.g., written guidelines, mechanism to approve trial but also to terminate it)


Clinical Trial Approval

4 Clinical Trial Approval takes different forms such as Investigational New Drug Application (IND) in the United States and Clinical Trial Certificate (CTC) or Clinical Trial Exemption (CTX) in the United Kingdom.

4 This is in addition to ethical clearance which is required in all countries for clinical trials.


How WHO standards may help regulators to review clinical trials?

By providing:1. Measurement standards for quality control of

clinical lots http://www.who.int/biologicals/IBRP/Catalogue.htm

2. Measurement standards and standardized assays for the measurement of immune response in clinical trials

3. By providing written standards for production, control and evaluation of vaccines

4. By providing technical advice when needed by using the international expertise


WHO standards for vaccines and biologicals:

http://www.who.int/biologicals/

Recommendations, Requirements and Guidelines for production and control of vaccines: 4 1) General (e.g., GMP, quality assurance for biological products)4 2) Guidelines for DNA vaccines, synthetic peptide vaccines, etc.4 3) Requirements for a number of bacterial and viral vaccines: OPV,MMR,DTP etc.)

Global written standardsGlobal written standards Global measurement standardsGlobal measurement standards


WHO Guidelines for nonclinical and clinical evaluation of

vaccines

4 Good Laboratory Practice

4 Good Clinical Practice (under

revision)

4 Clinical Evaluation of Vaccines:

Regulatory Expectations (TRS 924)

4 Nonclinical Evaluation of Vaccines

(in press)


WHO Guidelines for Clinical Evaluation of Vaccines

4 To assist in evaluation of clinical trials as a part of the regulatory overview

4 Audience: NRAs, Vaccine Industry, but also clinical researchers and investigators

4 Reviewed by more than 100 experts and discussed at the global Consultations

4 Adopted by the Expert Committee on Biological Standardization (ECBS), 2001


Scope and contents of clinical guidelines

4Prophylactic vaccines

4Therapeutic vaccines are NOT

considered


Contents of the clinical guidelines

4 Introduction4 Regulation of vaccines4 Scope of the document

4 PART A. PRECLINICAL AND LAB EVALUATION OF VACCINES

4 PART B. CLINICAL EVALUATION OF VACCINES4 General Remarks4 Methodological considerations4 Statistical considerations4 Ethical considerations


Contents cont.

4 Phase I studies4 Phase II studies4 Phase III studies4 Bridging studies4 Post-licensure and surveillance4 Combination vaccines4 Annex 1: Glossary4 Annex 2: Summary protocol for vaccine

evaluation4 Annex 3: References


WHO GCP

4 All clinical trials should adhere to standards described in GCP

4 Definition of CT: A systematic study on pharmaceutical products in human subjects (including patients and other volunteers) in order to discover or verify the effects of and/or identify any adverse reaction to investigational products, and/or to study the absorption, distribution, metabolism and excretion of the products with the objective of ascertaining their efficacy and safety


In which circumstances clinical trials should be considered?

4 1. For novel vaccines – with no prior nonclinical and clinical experience, more extensive testing than for those licensed and used for long time

4 2. For new vaccines (e.g., new for the manufacturer, new adjuvant, new route of administration etc)

4 3. For licensed vaccines – subsequent change in production methods or scale-up following licensure will require further product characterisation. The extent of comparability testing needed depends of tha nature of the changes implemented


Characterization of vaccines

4 Key issues: characterization and standardization during vaccine development

4 Comprehensive characterization of initial batches - essential for consistency; to be completed by end of phase III

4 If protective in clinical trials, candidate vaccine MUST be made to the same specifications as successful preparation

4 Following licensing, the vaccine is a subject to batch release by NRA/NCL

4 A clear distinction between comprehensive characterization of a vaccine during the development and selected tests for the purpose of batch release


Preclinical and clinical lots4 Vaccine lots - adequately representative of

the formulation intended for the clinical investigation

4 Ideally: preclinical testing should be done on the same lots as proposed for the clinical trials (at least comparable: physico-chemical data, stability, formulation etc)

4 At minimum, lots prepared under conditions of GMP for clinical trial material; at later stage full GMP.


Design of a clinical trial

4 Epidemiology of the pathogen or disease of interest in the intended population

4 Clinical spectrum of illness, definition of high risk groups (age, gender, ethnic or population group membership, geography, social characteristics or seasonality)

4 Laboratory values in the intended population

4 Sero-prevalence studies4 Characteristics of a vaccine


Design of an efficacy study

4 Randomized double-blind controlled trial4 Double blinding- to avoid bias in the

assessment of endpoints4 Randomization – to avoid bias in assignment to

one of the study groups and permits statistically valid comparisons between arms

4 Possible approaches: prospective cohort studies and pre-exposure cohort studies in groups at risk (e.g., traveller vaccination)

4 The unit of randomisation: the individual, clusters or groups (school, geographic region)


General considerations for efficacy trials

4 Size of trial4 Choice of control

Placebo control Active control Correlates of protection

4 Duration of protection4 Safety evaluation in phase III trials

Serious adverse events


Methodological Considerations

4Study population4Outcome measurement4Case detection/ case

ascertainment/ case definition4Monitoring and reporting

adverse events


Study population

4 At least the initial phase I in healthy, immunocompetent adults at low risk

4 In phase II and III - target population 4 If a vaccine is intended for children or other

vulnerable populations, vaccine should be tested in small number of intended population before proceeding to larger number

4 Criteria for inclusion or exclusion of subjects for enrolment in the clinical trial should be established

4 Special considerations for HIV trials http://www.who.int/biologicals/Meeting-Reports/Doc/VHIV01mar13.pdf


Outcome measurement

4 The primary endpoint should be the most relevant for the disease in the target population

4 Safety – focus on adverse events and reactogenicity

4 Immunogenicity – outcome in phase I, II and III

4 Efficacy – outcome of clinical protection and/or immunological surrogate endpoints in CTs


Ethical considerations4 WHO GCP guidelines4 Ethical guidance (WHO, CIOMS, UNAIDS)4 Independent ethics committee4 Involvement of children4 Placebo4 Human challenge studies4 Prevent exposure of the individual to unreasonable risk

of illness; full benefit of scientific innovation to be provided

4 Prevent harm to the national immunization programmes

4 ! REGULATORS SHOULD BE INVOLVED IN THE ETHICAL COMMITTEE BY PROVIDING THE EXPERT ADVICE AND RAISING REGULATORY CONCERNS


Statistical Considerations

4 General principles4 Trial objectives: efficacy, safety4 Superiority trials4 Equivalence and non-inferiority trials4 Accepted difference in equivalence

and non-inferiority trials4 Sample size4 Duration of study


Bridging studies

4 Design and extent of a clinical bridging study4 When bridging studies could be required?

1. For manufacturing change – changes in the composition or in production process, site or scale after the efficacy trial or after licensing

2. For new dosing schedule – changes in the immunization schedule, dose and/or ROA

3. For new population – a concern that safety and/or efficacy profiles may differ in different population

4. For safety - specific safety concerns in the target population; power of the study sufficient to address the rates of common adverse events


Post licensure studies and surveillance

4 Safety evaluation4 Vaccine effectiveness evaluation4 Study design

Observational cohort studies Case-control studies Stepped wedge design Outbreak interventions

4 Monitoring of post marketing surveillance


Summary protocol for vaccine evaluation

4 Title and summary4 Brief description of the study site (s)4 Investigators4 Background and rationale4 Preclinical and laboratory evaluation of

vaccines4 Summary of product characteristics4 Primary and secondary objectives4 Study design4 Study population4 Methods and procedures4 Monitoring of the trial4 Timetable


Acknowledgement

4 Many thanks to the experts involved in the development of WHO guidelines for:

1) Clinical evaluation of vaccines: Regulatory Expectations

2) Nonclinical evaluation of vaccines

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