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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
0
0.5
1
1.5
2
2.5
3
3.5
Pharma NIH Devices 75% 16% 9%
