1. NIH’s Efforts to Promote the Harmonization of Clinical Research Policies Secretary’s Advisory Committee on Human Research Protections October 27, 2009

2. 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

3. 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

4. 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

5. CRpac Outreach and Engagement Formal Liaison Formal Liaison –HHS Office for Human Research Protections (OHRP) –Food and Drug Administration (FDA) Designated Agency Representative Designated Agency Representative –Secretary’s Advisory Committee on Human Research Protections –White House National Science and Technology Council, Committee on Science, Human Subjects Research Sub-Committee (HSRS) Committee Leadership Committee 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

6. CRpac Outreach and Engagement CRpac Outreach and Engagement International Organizations – –World Health Organization (WHO) – –European Commission – –Council of Europe – –Organization for Economic Cooperation and Development (OECD) Academic, Professional and Industry Associations Academic, Professional and Industry Associations – –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

7. 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

8. Harmonizing and Streamlining Adverse Event Reporting Major trans-Federal effort to enhance consistency of Federal policies and approaches Major trans-Federal effort to enhance consistency of Federal policies and approaches Federal Adverse Event Task Force (FAET) Federal Adverse Event Task Force (FAET) – –FDA – –OHRP – –CDC – –DOD – –DVA – –NIH (Chair)

9. FAET Objectives Develop best practices blueprint for reporting, analysis, and application of safety information Develop best practices blueprint for reporting, analysis, and application of safety information One AE report that PIs can send to multiple agencies – Basal Adverse Event Report (BAER) One AE report that PIs can send to multiple agencies – Basal Adverse Event Report (BAER) Optimize communication of analyzed safety information Optimize communication of analyzed safety information

10. Basal Adverse Event Report (BAER) Overview Scope –Draws upon a single baseline set of core medical information adopted by all FAET agencies to report –Encompasses all forms of clinical research Safety information to multiple agencies, IRBs, and DSMBs Safety information to multiple agencies, IRBs, and DSMBs –Unanticipated problems to OHRP –Pre and Post-market adverse events to FDA Incorporation of HHS standards for data transmission and vocabularies Incorporation of HHS standards for data transmission and vocabularies Aims –Offer utility for reporting at local and federal level –Offer standards for full spectrum of clinical research

11. 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

12. Goal of the Federal-Wide Safety Reporting Portal Development of a user- friendly, standardized electronic submission system to report an adverse event or unanticipated problem to the federal government by: Development of a user- friendly, standardized electronic submission system to report an adverse event or unanticipated problem to the federal government by: –Investigators –Sponsors –Manufacturers –Physicians –Consumers Post-market reporting Human subjects research reporting, Pre-market reporting

13. Portal Features Single site for the collection and transmission of adverse events and unanticipated problems Single site for the collection and transmission of adverse events and unanticipated problems –Encompasses pre- and post- market data Single data entry, multiple uses Single data entry, multiple uses –Relevant AE data may be submitted to multiple agencies Interactive help system for reporters Interactive help system for reporters –Decision-tree based logic (wizard) to assist reporters in identifying appropriate agencies and data sets for submission Incorporate appropriate data standards Incorporate appropriate data standards –Will utilize HL7 transmission message for routing information to Federal agencies First practical implementation of the BAER First practical implementation of the BAER –Will establish feasibility of the BAER for data collection

15. Current Status of Portal: NIH/FDA Prototype FDA and NIH established collaboration to develop an initial portal prototype to test feasibility FDA and NIH established collaboration to develop an initial portal prototype to test feasibility –1st release of the Portal in Winter 2009 FDA products in the first release will include selected reporting on animal drugs, animal foods, and human foods FDA products in the first release will include selected reporting on animal drugs, animal foods, and human foods NIH feasibility testing on data exchange using gene transfer research adverse event report (GeMCRIS) NIH feasibility testing on data exchange using gene transfer research adverse event report (GeMCRIS)

16. Next Steps for Portal Development Complete Portal system requirements and design Complete Portal system requirements and design Launch Release 1 in Winter 2009/10 Launch Release 1 in Winter 2009/10 Evaluation of criteria/performance measures Evaluation of criteria/performance measures Begin preparation for Release 2 in early summer 2010 Begin preparation for Release 2 in early summer 2010 Extend the Portal to incorporate other agencies Extend the Portal to incorporate other agencies

17. 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

18. Optimizing IRB Review: Need for National Dialogue National Conference National Conference – –November 20-21, 2006 Sponsors Sponsors – –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

19. Optimizing IRB Review: An Evolving Research Landscape IRB Models IRB Models –Facilitated review (e.g., NCI CIRB) –CTSAs –Reciprocal IRB review (e.g., MACRO) –Consortia (e.g., BRANY) –Independent (e.g., Western, Chesapeake) Institutional Challenges to Implementing Alternative IRBs 1 : Institutional Challenges to Implementing Alternative IRBs 1 : –Liability concerns –Desire for local control –Misunderstanding of federal policies 1 Academic Medicine, July 2004

20. IRB Models of Review TypeCharacteristics Typical Use Local Review  An institution ’ s IRB conducts reviews of its own research  Academic & private research institutions; government conducted research  Public or private multi-site studies where each site has own IRB (e.g. federally funded or industry studies using academic sites Delegated Review  An institution delegates review to another institution ’ s IRB or an institution or group of institutions delegate review to a independent IRB  An Institution lacks resources or expertise to conduct its own IRB review  Drug, device or biologic research conducted under IND; some non-product-oriented academic research as well Cooperative Resource Sharing  IRBs at different research sites share resource materials, SOPs, informed consent documents, etc.  Each site conducts its own review  Multi-site studies where individual IRBs may benefit from the experience & resources developed by others- may be particularly valuable for complex or hi-risk studies Consortium  A group of institutions manage, audit, & monitor clinical research, including IRB review  Consortiums may choose a central IRB or develop arrangements for reciprocal review  Institutions that share common attributes & seek to outsource IRB review & trial monitoring  Institutions that have resources, motivation, & common 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.  Facilitated review where a local IRB or its representative accepts a central IRB review, modify it or opt to conduct a full review  Multiple IRBs review a protocol concurrently or sequentially, e.g., a national and regional IRB, or domestic & international sites in a U.S.- sponsored international study  Certain studies conducted with NCI support  Studies requiring extra oversight, particularly where inclusion of certain communities or knowledge of local context is especially important  International research, e.g. National Institute of Allergy & Infectious Diseases (NIAID)/Division of Acquired Immunodeficiency Syndrome (DAIDS) studies Hybrid  Collaborating institutions design their own approach based on the study, available resources, timing considerations, their relationships, etc.  An institution may use different strategies for review, e.g. use of a central IRB that has relationships with other IRBs where an independent IRB is used for industry trials, reciprocal reviews for other studies, & facilitated local reviews in collaboration with NCI ’ s Central IRB

21. Current Efforts Points to Consider in Selecting Models of Review by Institutional Review Boards Points to Consider in Selecting Models of Review by Institutional Review Boards Under development Under development NIH Request for Information NIH Request for Information Collaboration with CTSA program Collaboration with CTSA program Assess needs & programs for planning & monitoring multisite studies Assess needs & programs for planning & monitoring multisite studies Pending Pending

22. Informed Consent Processes and expectations have become increasingly more complex Processes and expectations have become increasingly more complex –Esp. for certain areas of research (hi-tech, hi-risk) Tools and resources needed to optimize the effectiveness and value of the informed consent process Tools and resources needed to optimize the effectiveness and value of the informed consent process Pilot project developed with OHRP, FDA, NIH Pilot project developed with OHRP, FDA, NIH –Informed consent for gene transfer research –http://www4.od.nih.gov/oba/rac/ic/

23. Informed Consent Points to Consider: Points to Consider: Research Involving Individuals with Questionable Capacity to Consent Points to Consider Points to Consider on developing informed consent forms and conducting informed consent – –Alternatives to participation – –Assent – –Comprehensibility – –Privacy and Confidentially – –Conflict of Interest

24. International Issues: HHS Comments on Revisions to the Declaration of Helsinki

25. International Issues: EU Clinical Trial Directive EU CTD Implemented by Member States (MS) EU CTD Implemented by Member States (MS) May 1, 2004 May 1, 2004 Applies to interventional trials Applies to interventional trials Concern the directive missed facilitation & harmonization goals Concern the directive missed facilitation & harmonization goals NIH is documenting its experiences in partnering with EU MS on multisite clinical trials NIH is documenting its experiences in partnering with EU MS on multisite clinical trials Significant complications with indemnity, legal representative of the sponsor, single sponsor & GMP/QP, definitional problems (IMP and non-interventional) Significant complications with indemnity, legal representative of the sponsor, single sponsor & GMP/QP, definitional problems (IMP and non-interventional)

26. Privacy Issues in Research Is the HIPAA Privacy Rule adversely affecting research? Is the HIPAA Privacy Rule adversely affecting research? –Examples: Multi-site research Harmonization issues NIH Funded IOM Study: NIH Funded IOM Study: Beyond the HIPAA Privacy Rule: Enhancing Privacy, Improving Health Through Research –Addressed the need for more systematic information regarding the impact of the Rule –Calls for: Bold new approach to privacy protections in research Changes in Rule and additional guidance

27. Research Involving Specimens and Data Repositories Disharmony in regulations and policies Disharmony 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 Paper Public Responsibility in Medicine & Research White Paper – –Identified barriers and approaches for overcoming them – –CRpac supported –PRIM&R White Paper: –PRIM&R White Paper: Report of the Public Responsibility in Medicine and Research (PRIM&R) Human Tissue/Specimen Banking Working GroupPRIM&R White PaperPRIM&R White Paper

28. NIH NIH – –Developing NIH-wide guidelines on ethical issues related to the collection, storage, use and sharing of specimens and data in research HHS HHS – –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

29. 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 and areas that may benefit from additional policy guidance and/or educational materials Identified inconsistencies in regulations and policies and areas that may benefit from additional policy guidance and/or educational materials Developing educational document on key terminology Developing 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

30. Web-accessible Tools and Resources Compendium of NIH Resources on Informed Consent Compendium of NIH Resources on Informed Consent Clinical Trial Monitoring Guidelines Clinical Trial Monitoring Guidelines IRB Models Workshop & Conference Proceedings IRB Models Workshop & Conference Proceedings Bioethics Resources on the Web Bioethics Resources on the Web PRIM&R Working Group White Paper on Human Specimen/Tissue Banking PRIM&R Working Group White Paper on Human Specimen/Tissue Banking

32. NIH Clinical Research Policy Analysis and Coordination Program Office of Biotechnology Activities Office of Science Policy Office of the Director, NIH 6705 Rockledge Drive, Suite 750 Bethesda, MD 20892 301-496-9838 301-496-9839 (fax) Email: CRpac@od.nih.gov http://crpac.od.nih.gov/