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Current Topics in Clinical Research

Clinical Device Group Inc

Evaluations for Medical Devices

Biomedical Focus 01—Minneapolis, MN

prEN/ISO 14155 Parts 1-2Declaration of HelsinkiHIPAA Privacy Rules

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prEN/ISO DIS 14155-Part 1

Clinical Investigation of Medical Devices for Human Subjects—

General Requirements

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US Delegation

Co-chairsKimber Richter, FDANancy J Stark, CDG Inc

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Administrative

Merged with ISO 14155Expanded for more depth and

breadthHarmonized with ICH-GCPsSplit into Part 1—General

Information andPart 2—Investigational PlansNow ISO 14155: Parts 1 & 2

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Part 1: General Requirements

Scope New definitions

Adverse eventAdverse device effectSerious adverse eventSerious adverse device effect

Justification for clinical study-literature review (Annex A)

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Current Declarations of Helsinki and Lisbon must be followedHelsinki—Clinical ResearchLisbon—Patient RightsBoth published by World Medical

Association

Investigators must allow auditing

Part 1: General Requirements

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Informed Consent

Process comply with Helsinkiavoid coercion or undue influencenot waive subject’s rightsnon-technical languageample time for considerationdated signature of subject or guardianprovisions for emergency circumstances

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Informed ConsentContent

description/purpose of researchforseeable riskspotential benefitsaltenative therapiesconfidentialitycompensationquestions and/or terminationnew findings

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Informed Consent

Informed consent statementparticipation is voluntaryno penalty for refusalmay discontinue at any timeconsequences of withdrawelacknowledgment of information provided

May be separate document

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Documentation

Investigator’s Brochure Clinical investigation plan (protocol) Curriculum vitae—signed EC opinion Correspondence Agreement Case report forms Adverse event reports Names/addresses of monitors Final report

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Responsibilities

Sponsor—unchangedMonitor—unchangedClinical Investigator—unchanged

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Annexes

Literature reviewInformation for ethics committeesFinal reports

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Literature Review

Methodologyestablish a plan for identification, selection,

collation and review of studies/datadefine objectives of the reviewestablish selection criteria for articlesassess articles per selection criteria

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Literature Review

Evaluation of Literaturejustify exclusion of any documentsreview remaining documentsidentify any data gapsdated signature of authors

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Information for ECs Justification Health status of subjects Risks and mitigations Supervision Consent procedure and forms Confidentiality protections Consent process and documents Concurrent treatment of subjects Insurance Protocol Investigator’s Brochure “Progress in final report” All SAEs and adverse device effects

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Final Report

Title page Summary Table of contents Introduction Materials &

methodsDevice descriptionProtocol summary

Results

Discussion & conclusions

Abbreviations & definitions

Ethics statement Investigators &

administrative structure

Signatures

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prEN/ISO DIS Part 2

Clinical Investigation of Medical Devices for Human Subjects—

Clinical Investigation Plans

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Part 2-CIPs(Clinical Investigation Plans)

New definitionsPrimary end pointSecondary endpointFollow-up periodPoint of enrollmentRecruitmentClinical investigatorPrincipal clinical investigatorCoordinating clinical investigatorClinical investigation center

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Part 2-CIPs

Monitoring arrangementsData and quality managementLiterature reviewPreclinical testingObjectives, design, statisticsEarly terminationPublication policyCase report forms

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Annex Case report forms

ID of study ID of subjectSerial or lot number of deviceSubject selection/diagnosisSubject compliancePrevious medication or treatmentBaselineConcomitant illness, medication, treatmentProceduresFindingsFollow-upAdverse events and effectsSignatures

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US Problems & Issues

No clear statement of purpose or underlying principles—just a checklist

Insufficient harmonization with ICH-GCPs

Unclear definitions

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US Problems & Issues

Declaration of HelsinkiFDA guidance “Acceptance of Foreign

Data” March 2001.Device studies must conform to

Declaration of Helsinki of 1983Drug studies must conform to Declaration

of Helsinki of 1989

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Voting & Timeline

Voting on ISO/DIS (initial draft) is in November 2001FDA’s vote will be “no”US vote will be “yes” with condition of

immediate revision

Voting of FDIS (final draft) in 2002

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Declaration of Helsinki

World Medical Association

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Revised October 2000

Continuous review1996 version not appropriate for

developing countriesChanging research environment:

genetics, data privacy.Harmonize with other CIOMS, ICH,

other guidelines.

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Structure of 2000 Text

32 Articles9 Introduction 18 Basic Principles for Medical

Research5 Additional Principles for Medical

Research combined with Medical Care

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Article 1-Scope

Medical research involving human subjects includes research on identifiable human material or identifiable data.

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Article 9-Legal Standing

1996: …the standards…are only a guide; physicians are not relieved from criminal, civil & ethical responsibilities under the laws of their own countries.

2000: …No national, ethical, legal or regulatory requirement should be allowed to reduce or eliminate any of the protections for human subjects set forth in this Declaration.

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Article 13-ECs

Ethics committees:Have right to monitor ongoing trialsMust be given reports on SAEs.Must review information on funding,

sponsors, institutional affiliations, other potential conflicts of interest and incentives for subjects.

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Article 16-Availability

The design of all studies should be publicly available.

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Article 17-Cease Investigation

Physicians should cease any investigation…if there is conclusive proof of positive and beneficial results.

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Article 19-Benefit to Populations

Medical research is only justified if there is a reasonable likelihood that the populations in which the research is carried out stand to benefit from the results of the research.

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Article 22-Information to Subject

Each potential subject must be…informed of the…

sources of funding,

conflicts of interest,

institutional affiliations…

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Article 24 & 25-Legally Incompetent

Now includes:Physically or mentally incapableLegally incompetent minor

Should not be included unless research necessary to promote health of population, cannot be performed on others

Subject to give assent if possible

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Article 26-Lack of Consent

If no consent, proxy, or advanced consent: Physical/mental condition must be necessary

to research Protocol to explain reasons for inclusion Protocol to be approved by IEC Protocol to state consent to remain in study be

obtained asap from subject or legal representative.

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Article 27-Publications

Negative and positive results should be published.

Sources of funding, institutional affiliations, conflicts of interest specified.

Research not in accordance with Helsinki should not be accepted for publication.

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Article 29-Placebo

…new method…should be tested against…best proven prophylactic, diagnostic, and therapeutic methods…does not exclude use of placebo, or no treatment, in studies where no proven prophylactic, diagnostic or therapeutic method exists.

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Article 30-Ongoing Treatment

At conclusion of the study, every patient entered into the study should be assured of access to the best proven prophylactic, diagnostic and therapeutic methods identified by the study.

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US Problems & Issues

Declaration of HelsinkiFDA guidance “Acceptance of Foreign

Data” March 2001.Device studies must conform to

Declaration of Helsinki of 1983Drug studies must conform to Declaration

of Helsinki of 1989

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HIPAA Privacy Rules

Health Information Portability and Accountability Act

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HIPAA

45 CFR Part 164—Security & PrivacyEffective April 14, 2001Providers, insurers, information

clearinghouses

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Enforcement

Enforced by DHHS Office of Civil Rights

Civil and criminal penaltiesDoes not apply to sponsors

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Three Important Features

Investigator access to medical records

De-identified medical information Patient access to case report forms

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Access to Medical Records

Protocol design processEstimates of enrollment capabilitiesSubject recruitment

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IRB Waiver

Work is preparatory to researchMedical records will not be removed

from premisesAccess to medical records is

necessary

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Requirements for Waiver

Minimal risk to patients Privacy not adversely affected Research cannot be done without waiver Research cannot be done without access Privacy risks reasonable in relation to benefits Adequate plan to protect identifiers Adequate plan to destroy identifiers asap Written assurances that information will not be

used or disclosed for other purposes

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Additions to Informed Consent

Description of historical medical records needed for study

Statement of when authorization expires Statement that treatment, payment,

insurance, etc. not conditioned on signing Description of information that will not be

disclosed. When/if crfs will be available to subject.

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Other Areas Affected

Estimating subject availabilityCase report formsLeftover tissue samplesAccess to tissue banksPatient registriesConsentsDeceased persons

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De-identified Information

Names Zip codes Months/days Phone & fax #’s Email addresses SS numbers Medical record

numbers

Health plan numbers

Account numbers Vehicle numbers Device serial

numbers Web addresses Full face photos

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EU Data Privacy Directive

EU Directive 95/46/ECPrivacy rules make US compatible

with EU

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Unchanged

Adverse event reportingDevice trackingProduct recallsRepairsReplacementsPost-marketing surveillance

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Uncertain Future

Health-care industry opposedImplementation delayed once alreadyThompson says “may need to

review”April 2001: Bush Whitehouse

announces it will not ask for changes to regulations.

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Other US Happenings

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DHHS Offices proposed NOHRO—National Office of Human

Research Oversight OHRP—Office for Human Research

Protections (Greg Koski) National Human Research Protection

Advisory Committee Office of Research Integrity NBAC—National Bioethics Advisory

Commission OIG—Office of Inspector General

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NIH Offices

OER—Office of Extramural Research

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New FDA Offices

OHRT—Office for Human Research Trials (David LePay)

Human Subject Protection and Good Clinical Practice steering committee (David LePay)

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Private/Other

SUEE—Simplicity, Uniformity, Efficacy, Effectiveness

proposed AHRP—Association for Human Research Protection: will act as a private accrediting group to accreditate clinical research systems at investigative sites

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The Human Research Pie

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0.5

1

1.5

2

2.5

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3.5

Pharma NIH Devices 75% 16% 9%

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More Information

www.clinicaldevice.com

OrNjstark@clinicaldevice.com