NIH’s Efforts to Promote the Harmonization of

Clinical Research Policies

Secretary’s Advisory Committee on Secretary’s Advisory Committee on Human Research ProtectionsHuman Research Protections

October 27, 2009October 27, 2009

Overview of Presentation

Clinical Research Policy Analysis and Coordination (CRpac) Program – Background

Key Initiatives– Federal Adverse Event Task Force– Optimizing IRB Review– Informed Consent– International – Privacy – Specimens and Data

CRpac Program

Aims– Promote clear, effective, and coordinated

policies and regulations for the conduct and oversight of clinical research

– Maintain the integrity and enhance the effectiveness of federal and institutional systems of oversight

Methods– Conduct technical and policy analysis– Providing advice and recommendations– Build partnerships and develop new mechanisms

of interaction– Develop tools and resources

Formally established as an OD program in 2004

CRpac Priority Issues

Adverse Event Reporting Clinical Trial Issues Optimizing IRB Review Informed Consent Privacy and Confidentiality Research Using Specimens and Data Application of Human Subjects Regulations

CRpac Outreach and Engagement

Formal LiaisonFormal Liaison– HHS Office for Human Research Protections (OHRP)HHS Office for Human Research Protections (OHRP)– Food and Drug Administration (FDA)Food and Drug Administration (FDA)

Designated Agency RepresentativeDesignated Agency Representative– Secretary’s Advisory Committee on Human Research Secretary’s Advisory Committee on Human Research

ProtectionsProtections– White House National Science and Technology Council, White House National Science and Technology Council,

Committee on Science, Human Subjects Research Sub-Committee on Science, Human Subjects Research Sub-Committee (HSRS)Committee (HSRS)

Committee LeadershipCommittee Leadership– Trans NIH Bioethics Committee– Trans-HHS Taskforce on Harmonization of Ethical and Legal

Policies Related to the Use of Human Specimens and Data in Research (HELPS)

– Federal Adverse Event Task Force

CRpac Outreach and CRpac Outreach and EngagementEngagement

International Organizations– World Health Organization (WHO)– European Commission – Council of Europe– Organization for Economic Cooperation and Development (OECD)

Academic, Professional and Industry Academic, Professional and Industry AssociationsAssociations– Public Responsibility in Medicine and Research (PRIM&R)– American Society for Bioethics and the Humanities (ASPH)– Association of American Medical Colleges (AAMC)– International Society for Biological and Environmental

Repositories– Institute of Medicine Forum on Drug Discovery, Development and

Translation – FDA-Duke Clinical Trials Transformation Initiative (CTTI)– Society for Clinical Trials– American Medical Association (AMA) and World Medical

Association (WMA)– Biotechnology Industry Organization (BIO)– Pharmaceutical Research and Manufactures Association

Adverse Event Reporting Issues

Divergent federal reporting policies creates confusion, non-compliance, increased costs

Poor quality of information, no standards, incomplete reports

Deluge of AERs that cannot be interpreted in multi-site trials

Safety implications

Harmonizing and Streamlining Adverse Event Reporting

Major trans-Federal effort to enhance Major trans-Federal effort to enhance consistency of Federal policies and consistency of Federal policies and approachesapproaches

Federal Adverse Event Task Force Federal Adverse Event Task Force (FAET)(FAET)

– FDA– OHRP– CDC– DOD– DVA– NIH (Chair)

FAET ObjectivesFAET Objectives

Develop best practices blueprint for Develop best practices blueprint for reporting, analysis, and application of reporting, analysis, and application of safety informationsafety information

One AE report that PIs can send to multiple One AE report that PIs can send to multiple agencies – Basal Adverse Event Report agencies – Basal Adverse Event Report (BAER)(BAER)

Optimize communication of analyzed safety Optimize communication of analyzed safety informationinformation

Basal Adverse Event Report (BAER) Overview

Scope

– Draws upon a single baseline set of core medical Draws upon a single baseline set of core medical information adopted by all FAET agencies to information adopted by all FAET agencies to reportreport

– Encompasses all forms of clinical research Encompasses all forms of clinical research Safety information to multiple agencies, IRBs, Safety information to multiple agencies, IRBs,

and DSMBsand DSMBs– Unanticipated problems to OHRPUnanticipated problems to OHRP– Pre and Post-marketPre and Post-market adverse events to FDA adverse events to FDA

Incorporation of HHS standards for data Incorporation of HHS standards for data transmission and vocabularies transmission and vocabularies

Aims– Offer utility for reporting at local and federal level Offer utility for reporting at local and federal level

– Offer standards for full spectrum of clinical Offer standards for full spectrum of clinical researchresearch

Implementation of Harmonized Adverse Event Reporting

Harmonized AE reporting dataset across FAET members– Benefits to clinical research

community will be seen as practical implementation steps continue

Endorsed by:– Secretary’s Advisory Committee on

Human Research Protections

Goal of the Federal-Wide Goal of the Federal-Wide Safety Reporting PortalSafety Reporting Portal

Development of a user- friendly, Development of a user- friendly, standardized electronic submission standardized electronic submission system to report an adverse event or system to report an adverse event or unanticipated problem to the federal unanticipated problem to the federal government by:government by:

– InvestigatorsInvestigators– SponsorsSponsors– ManufacturersManufacturers– Physicians Physicians – ConsumersConsumers

Post-market reportingPost-market reporting

Human subjects research reporting, Human subjects research reporting, Pre-market reportingPre-market reporting

Portal FeaturesPortal Features

Single site for the collection and transmission Single site for the collection and transmission of adverse events and unanticipated problemsof adverse events and unanticipated problems– Encompasses pre- and post- market dataEncompasses pre- and post- market data

Single data entry, multiple usesSingle data entry, multiple uses– Relevant AE data may be submitted to multiple Relevant AE data may be submitted to multiple

agenciesagencies Interactive help system for reportersInteractive help system for reporters

– Decision-tree based logic (wizard) to assist reporters Decision-tree based logic (wizard) to assist reporters in identifying appropriate agencies and data sets for in identifying appropriate agencies and data sets for submissionsubmission

Incorporate appropriate data standardsIncorporate appropriate data standards– Will utilize HL7 transmission message for routing Will utilize HL7 transmission message for routing

information to Federal agenciesinformation to Federal agencies First practical implementation of the BAERFirst practical implementation of the BAER

– Will establish feasibility of the BAER for data Will establish feasibility of the BAER for data collectioncollection

Current Status of Portal:Current Status of Portal:NIH/FDA PrototypeNIH/FDA Prototype

FDA and NIH established collaboration FDA and NIH established collaboration to develop an initial portal prototype to to develop an initial portal prototype to test feasibilitytest feasibility

– 1st release of the Portal in Winter 1st release of the Portal in Winter 20092009 FDA products in the first release will FDA products in the first release will

include selected reporting on animal include selected reporting on animal drugs, animal foods, and human foodsdrugs, animal foods, and human foods

NIH feasibility testing on data exchange NIH feasibility testing on data exchange using gene transfer research adverse using gene transfer research adverse event report (GeMCRIS)event report (GeMCRIS)

Next Steps for Portal Next Steps for Portal DevelopmentDevelopment

Complete Portal system requirements Complete Portal system requirements and designand design

Launch Release 1 in Winter 2009/10Launch Release 1 in Winter 2009/10 Evaluation of criteria/performance Evaluation of criteria/performance

measuresmeasures Begin preparation for Release 2 in Begin preparation for Release 2 in

early summer 2010early summer 2010 Extend the Portal to incorporate other Extend the Portal to incorporate other

agenciesagencies

Optimizing IRB Review: Principles and Potential Models

Historically IRBs

– Conceptualized at a time when primarily large academic institutions conducted human research

– Established as a local, institutional body– Obligated to consider local context– Single-site research predominated

Evolving research landscape

– Research increasingly a collaborative enterprise Growing prominence of multi-site trials

– Central and other models of IRB review increasingly attractive

Efficiency Consistency Rigor

Optimizing IRB Review: Need for National Dialogue

National ConferenceNational Conference – November 20-21, 2006

SponsorsSponsors– NIH CRpac, OHRP, VA, DoD,

AAMC, ASCO, PRIM&R, AAU, COGR, COSSA, NACUA

Explored:Explored:– Shared responsibility between

institutions and independent review boards

– Characteristics of alternative IRBs and impact on quality of review

– Liability issues

– Economic considerations

Optimizing IRB Review: An Evolving Research Landscape

IRB Models IRB Models

– Facilitated review (e.g., NCI CIRB)Facilitated review (e.g., NCI CIRB)– CTSAs CTSAs – Reciprocal IRB review (e.g., MACRO)Reciprocal IRB review (e.g., MACRO)– Consortia (e.g., BRANY)Consortia (e.g., BRANY)– Independent (e.g., Western, Chesapeake) Independent (e.g., Western, Chesapeake)

Institutional Challenges to Implementing Institutional Challenges to Implementing Alternative IRBsAlternative IRBs11::

– Liability concernsLiability concerns– Desire for local controlDesire for local control– Misunderstanding of federal policiesMisunderstanding of federal policies

1Academic Medicine, July 2004

IRB Models of ReviewIRB Models of Review

TypeType CharacteristicsCharacteristics Typical UseTypical Use

Local Review An institution’s IRB conducts reviews of its own researchAn institution’s IRB conducts reviews of its own research

Academic & private research institutions; Academic & private research institutions; government conducted researchgovernment conducted researchPublic or private multi-site studies where each site Public or private multi-site studies where each site has own IRB (e.g. federally funded or industry studies has own IRB (e.g. federally funded or industry studies using academic sites using academic sites

Delegated Review

An institution delegates review to another institution’s IRB An institution delegates review to another institution’s IRB or an institution or group of institutions delegate review to a or an institution or group of institutions delegate review to a independent IRB independent IRB

An Institution lacks resources or expertise to conduct An Institution lacks resources or expertise to conduct its own IRB reviewits own IRB reviewDrug, device or biologic research conducted under Drug, device or biologic research conducted under IND; some non-product-oriented academic research as IND; some non-product-oriented academic research as wellwell

Cooperative Resource Sharing

IRBs at different research sites share resource materials, IRBs at different research sites share resource materials, SOPs, informed consent documents, etc.SOPs, informed consent documents, etc.

Each site conducts its own reviewEach site conducts its own review

Multi-site studies where individual IRBs may benefit Multi-site studies where individual IRBs may benefit from the experience & resources developed by others- from the experience & resources developed by others- may be particularly valuable for complex or hi-risk may be particularly valuable for complex or hi-risk studiesstudies

Consortium

A group of institutions manage, audit, & monitor clinical A group of institutions manage, audit, & monitor clinical research, including IRB review research, including IRB review Consortiums may choose a central IRB or develop Consortiums may choose a central IRB or develop arrangements for reciprocal reviewarrangements for reciprocal review

Institutions that share common attributes & seek to Institutions that share common attributes & seek to outsource IRB review & trial monitoring outsource IRB review & trial monitoring Institutions that have resources, motivation, & Institutions that have resources, motivation, & common interest to form a consortiumcommon interest to form a consortium

Joint Review Arrangements

- Central & local IRB review

- Concurrent or sequential review

Reviews are shared between two or more IRBs, e.g. Reviews are shared between two or more IRBs, e.g.

Facilitated review where a local IRB or its representative Facilitated review where a local IRB or its representative accepts a central IRB review, modify it or opt to conduct a accepts a central IRB review, modify it or opt to conduct a full review full review

Multiple IRBs review a protocol concurrently or sequentially, Multiple IRBs review a protocol concurrently or sequentially, e.g., a national and regional IRB, or domestic & international e.g., a national and regional IRB, or domestic & international sites in a U.S.-sponsored international study sites in a U.S.-sponsored international study

Certain studies conducted with NCI supportCertain studies conducted with NCI supportStudies requiring extra oversight, particularly where Studies requiring extra oversight, particularly where inclusion of certain communities or knowledge of local inclusion of certain communities or knowledge of local context is especially importantcontext is especially importantInternational research, e.g. National Institute of International research, e.g. National Institute of Allergy & Infectious Diseases (NIAID)/Division of Allergy & Infectious Diseases (NIAID)/Division of Acquired Immunodeficiency Syndrome (DAIDS) studies Acquired Immunodeficiency Syndrome (DAIDS) studies

HybridCollaborating institutions design their own approach based Collaborating institutions design their own approach based on the study, available resources, timing considerations, on the study, available resources, timing considerations, their relationships, etc.their relationships, etc.

An institution may use different strategies for review, An institution may use different strategies for review, e.g. use of a central IRB that has relationships with e.g. use of a central IRB that has relationships with other IRBs where an independent IRB is used for other IRBs where an independent IRB is used for industry trials, reciprocal reviews for other studies, & industry trials, reciprocal reviews for other studies, & facilitated local reviews in collaboration with NCI’s facilitated local reviews in collaboration with NCI’s Central IRBCentral IRB

Current Efforts

Points to Consider in Selecting Points to Consider in Selecting Models of Review by Institutional Models of Review by Institutional Review BoardsReview Boards

Under developmentUnder development

NIH Request for InformationNIH Request for Information Collaboration with CTSA programCollaboration with CTSA program Assess needs & programs for planning & Assess needs & programs for planning &

monitoring multisite studiesmonitoring multisite studies PendingPending

Informed ConsentInformed Consent

Processes and Processes and expectations have become expectations have become increasingly more complexincreasingly more complex– Esp. for certain areas of

research (hi-tech, hi-risk)

Tools and resources Tools and resources needed to optimize the needed to optimize the effectiveness and value of effectiveness and value of the informed consent the informed consent processprocess

Pilot project developed Pilot project developed with OHRP, FDA, NIHwith OHRP, FDA, NIH– Informed consent for gene

transfer research– http://www4.od.nih.gov/oba/rac/ic/

Informed Consent

Points to Consider:Points to Consider: Research Involving Individuals with Questionable Capacity to Consent

Points to ConsiderPoints to Consider on developing informed consent forms and conducting informed consent

– Alternatives to participation – Assent – Comprehensibility – Privacy and Confidentially – Conflict of Interest

International Issues:International Issues:HHS Comments on Revisions to the HHS Comments on Revisions to the

Declaration of HelsinkiDeclaration of Helsinki

International Issues: EU Clinical Trial Directive

EU CTD Implemented by Member States (MS) EU CTD Implemented by Member States (MS) May 1, 2004May 1, 2004 Applies to interventional trialsApplies to interventional trials Concern the directive missed facilitation & Concern the directive missed facilitation &

harmonization goalsharmonization goals NIH is documenting its experiences in partnering NIH is documenting its experiences in partnering

with EU MS on multisite clinical trialswith EU MS on multisite clinical trials Significant complications with indemnity, legal Significant complications with indemnity, legal

representative of the sponsor, single sponsor & representative of the sponsor, single sponsor & GMP/QP, definitional problems (IMP and non-GMP/QP, definitional problems (IMP and non-interventional)interventional)

Privacy Issues in Research

Is the HIPAA Privacy Rule adversely Is the HIPAA Privacy Rule adversely affecting research?affecting research?– Examples:Examples:

Multi-site researchMulti-site research Harmonization issuesHarmonization issues

NIH Funded IOM Study:NIH Funded IOM Study: Beyond the HIPAA Privacy Rule: Enhancing Beyond the HIPAA Privacy Rule: Enhancing Privacy, Improving Health Through ResearchPrivacy, Improving Health Through Research– Addressed the need for more systematic information Addressed the need for more systematic information

regarding the impact of the Ruleregarding the impact of the Rule– Calls for:Calls for:

Bold new approach to privacy protections in researchBold new approach to privacy protections in research Changes in Rule and additional guidanceChanges in Rule and additional guidance

Research Involving Specimens and Data Repositories

Disharmony in regulations and policiesDisharmony in regulations and policies– Creates barriers to biobanking and sharing data

Guidance needed to clarify complex issues Guidance needed to clarify complex issues – e.g., ownership, intellectual property, return of research

results

Public Responsibility in Medicine & Research White Public Responsibility in Medicine & Research White Paper Paper – Identified barriers and approaches for overcoming them– CRpac supported– PRIM&R White PaperPRIM&R White Paper:: Report of the Public Responsibility in

Medicine and Research (PRIM&R) Human Tissue/Specimen Banking Working Group

NIHNIH– Developing NIH-wide guidelines on ethical issues

related to the collection, storage, use and sharing of specimens and data in research

HHSHHS– Promoting harmonization of policies across HHS

federal regulatory and funding agencies– FDA Guidance on Informed Consent for In Vitro

Diagnostic Device Studies Using Leftover Human Specimens that are Not Individually Identifiable (April 25, 2006)

Research Involving Specimens and Data:

Promoting Harmonization at Several Levels

Trans-HHS HELPS* Taskforce

Goals Goals

AHRQ, ASPE, CDC, FDA, OCR, OHRP, ONC, NIH (Chair)AHRQ, ASPE, CDC, FDA, OCR, OHRP, ONC, NIH (Chair)

Identified inconsistencies in regulations and policies Identified inconsistencies in regulations and policies and areas that may benefit from additional policy and areas that may benefit from additional policy guidance and/or educational materialsguidance and/or educational materials

Developing educational document on key terminologyDeveloping educational document on key terminology

* Trans-HHS Taskforce on Harmonization of Ethical and Legal Policies Related to the Use of Human Specimens and Data in Research

Web-accessible Tools and Web-accessible Tools and ResourcesResources

Compendium of NIH Compendium of NIH Resources on Informed Resources on Informed Consent Consent

Clinical Trial Monitoring Clinical Trial Monitoring GuidelinesGuidelines

IRB Models Workshop & IRB Models Workshop & Conference Proceedings Conference Proceedings

Bioethics Resources on the Bioethics Resources on the WebWeb

PRIM&R Working Group PRIM&R Working Group White Paper on Human White Paper on Human Specimen/Tissue BankingSpecimen/Tissue Banking

NIH Clinical Research Policy Analysis and Coordination Program

Office of Biotechnology ActivitiesOffice of Science Policy

Office of the Director, NIH6705 Rockledge Drive, Suite 750

Bethesda, MD 20892301-496-9838

301-496-9839 (fax)Email: CRpac@od.nih.govhttp://crpac.od.nih.gov/