Subpart A Subcommittee (SAS)

1. Subpart A Subcommittee(SAS) Elizabeth Bankert and Daniel Nelson Co-Chairs Presentation to the Secretary’s Advisory Committee on Human Research Protections (SACHRP) March 3, 2009

2. Outline of Today’s Presentation Subcommittee charge and membership Recommendations for consideration today Institutional Responsibilities  assurances Work in progress on Informed Consent Questions relating to informed consent for tissue repositories Next Steps

3. Charge to the Subcommittee Review and assess All provisions of Subpart A of 45 CFR 46 Relevant OHRP guidance documents Based on this review and assessment Develop recommendations for consideration by SACHRP in three categories: Interpretation of specific Subpart A provisions Development of new or modification of existing OHRP guidance Possible revisions to Subpart A Based on memo to Subcommittee from E. Prentice, Chair of SACHRP, 1/14/05 and subsequent discussion by SACHRP

4. Charge to the Subcommittee Goals Enhance protection of human subjects Reduce regulatory burdens that do not contribute to the protection of human subjects Promote scientifically and ethically valid research Based on memo to Subcommittee from E. Prentice, Chair of SACHRP, 1/14/05 and subsequent discussion by SACHRP

5. Elizabeth Bankert,* Dartmouth College Ricky Bluthenthal, RAND Corporation Gary Chadwick, University of Rochester Bruce Gordon, University of Nebraska Medical Center Felix Gyi, Chesapeake Research Review, Inc Isaac Hopkins, Community Research Advocate (UMDNJ) † Nancy Jones, Wake Forest University  NIH Moira Keane, University of Minnesota Susan Kornetsky, Children’s Hospital Boston Gigi McMillan, We Can Pediatric Brain Tumor Network Daniel Nelson,* University of North Carolina at Chapel Hill Ernest Prentice, University of Nebraska Medical Center Thomas Puglisi, PriceWaterhouse Coopers  VA Lorna Rhodes, University of Washington Ada Sue Selwitz, University of Kentucky David Strauss, New York State Psychiatric Institute SACHRP Members  Barbara Bierer, Myron Genel, Lisa Leiden, Patty Marshall, Suzanne Pattee With input from ex officio reps of Common Rule agencies Subcommittee MembershipPastand Present *co-chairs

6. Subcommittee Meetings January 18, 2005 via teleconference February 14, 2005 in Alexandria, VA May 20, 2005 via teleconference July 20-21, 2005 in Alexandria, VA October 4, 2005 via teleconference January 9, 2006 via teleconference January 30-31, 2006 in Rockville, MD May 11-12, 2006 in Gaithersburg, MD September 11, 2006 via teleconference October 4, 2006 via teleconference February 15-16, 2007 in Arlington, VA (with retreat) March 9, 2007 via teleconference May 31-June 1, 2007 in Arlington, VA July 16, 2007 via teleconference August 16-17, 2007 in Arlington, VA October 3, 2007 via teleconference February 21, 2008 in Rockville, MD May 15-16, 2008 in Rockville, MD September 22-23, 2008 in Rockville, MD January 26-27, 2009 in Rockville, MD Supplemented by Working Group calls and e-mails

7. Secretarial Letters Incorporating SAS Recommendations 5th SACHRP letter to Secretary Leavitt  acknowledged Recommendations approved 2005-2006 Continuing Review Expedited Review  Federal Register notice on 10/26/07 6th SACHRP letter to Secretary Leavitt  acknowledged Recommendations approved March 2007 Required Training  Federal Register notice on 07/01/08 IRB Members, IRB Staff, Institutional Officials, Investigators 7th SACHRP letter to Secretary Leavitt  submitted Recommendations approved March & July 2007 Waiver of Informed Consent Minimal Risk  Analytical framework and examples 8th SACHRP letter to Secretary Leavitt  acknowledged Recommendations approved Oct 2007, March & July 2008 Exemptions Alternative models of IRB review IRB membership rosters Waiver of documentation of informed consent Institutional Officials American Indians and Alaska Natives (Letter also addressed disaster research, and systems-level commentary)

8. Subpart A Subcommittee (SAS) Report and Recommendations to SACHRP Assurances and Related Documentation, with Particular Reference to Cooperative Review Arrangements Working Group on Institutional Responsibilities

9. Institutional Responsibilities • Assurances • Engagement in Research • Institutional Officials • Multi-site studies

10. What do the regulations say regarding assurances and designation of IRBS? • (a) Each institution engaged in research which is covered by this policy and which is conducted or supported by a federal department or agency shall provide written assurance satisfactory to the department or agency head that it will comply with the requirements set forth in this policy. • (b) Departments and agencies will conduct or support research covered by this policy only if the institution has an assurance approved as provided in this section, and only if the institution has certified to the department or agency head that the research has been reviewed and approved by an IRB provided for in the assurance, and will be subject to continuing review by the IRB. Assurances applicable to federally supported or conducted research shall at a minimum include: 45 CFR 46.103

11. What do the regulations say regarding assurances and designation of IRBS? Assurances… shall at a minimum include: • (1) A statement of principles governing the institution in the discharge of its responsibilities for protecting the rights and welfare of human subjects… • (2) Designation of one or more IRBs established in accordance with the requirements of this policy, and for which provisions are made for meeting space and sufficient staff to support the IRB's review and recordkeeping duties. • (3) A list of IRB members identified by name; earned degrees; representative capacity; indications of experience such as board certifications, licenses, etc., sufficient to describe each member's chief anticipated contributions... • (4) Written procedures which the IRB will follow (i) for conducting its initial and continuing review of research and for reporting its findings and actions… • (5) Written procedures for ensuring prompt reporting to the IRB, appropriate institutional officials, and the department or agency head of (i) any unanticipated problems involving risks to subjects or others or any serious or continuing noncompliance… 45 CFR 46.103

12. What do the regulations say regarding assurances and designation of IRBS? Assurances… shall at a minimum include: • (1) A statement of principles governing the institution in the discharge of its responsibilities for protecting the rights and welfare of human subjects… • (2) Designation of one or more IRBs established in accordance with the requirements of this policy, and for which provisions are made for meeting space and sufficient staff to support the IRB's review and recordkeeping duties. • (3) A list of IRB members identified by name; earned degrees; representative capacity; indications of experience such as board certifications, licenses, etc., sufficient to describe each member's chief anticipated contributions... • (4) Written procedures which the IRB will follow (i) for conducting its initial and continuing review of research and for reporting its findings and actions… • (5) Written procedures for ensuring prompt reporting to the IRB, appropriate institutional officials, and the department or agency head of (i) any unanticipated problems involving risks to subjects or others or any serious or continuing noncompliance… Not in FWA? 45 CFR 46.103

13. What is the issue? What are we trying to fix? • The research environment has evolved considerably since the regulations were promulgated. As with other parts of the Common Rule, the assurance requirements do not always “fit” with today’s environment. • Presumed a single-site model • Presumed a one-to-one relationship between the institution filing assurance and “their local IRB(s)” • Did not fully anticipate today’s multi-center collaborations • Works against effective and efficient implementation of alternative models of IRB review, which SACHRP and others are attempting to encourage • Cooperative review arrangements, consortia, central IRBs

14. What is the issue? What are we trying to fix? • Practical ramifications • Awkward incorporation of details that may undergo frequent modification (IRBs) within a “high-level” document that should not (FWA) • Many institutions not aware that modification of FWA is required for single project or limited relationships • Those that do find problematic • Collaborative institutions may have 100s of IRBs listed • Modern electronic environment  both blessing and curse! • Easy to file FWAs and cite IRBs (that may not have agreed) • Once added, IRBs are slow to be removed • Unfiltered notification of all IRBs listed without context or relevance •  OHRP is already aware and will address (SAS mtg, Sept 2008) • Source of regulatory burden for institutions, IRBs and OHRP, for questionable gain

15. Rationale for Proposed Change • There are many other regulatory requirements that institutions and IRBs are empowered/entrusted to implement appropriately, without federal-level review • Informed consent • Criteria for approval • Exemptions • Most of the Common Rule and Subparts… • Some “assurance requirements,” despite their identical regulatory basis, are already handled outside the actual assurance document • List(s) of members [46.103(b)(3)] • Written procedures for initial and continuing review [46.103(b)(4)] • Written procedures for reporting problems [46.103(b)(5)] • IRB registration process has largely been separated from the assurance process, as part of the conversion to FederalWide Assurances • Proposed change would effectively complete that transition

16. Recommendations • The Federalwide Assurance should be modified to remove the current requirement to designate specific IRBs (within the assurance document itself), replacing this with a commitment by the institution to rely only on registered IRBs, in satisfaction of the requirement to designate IRBs under 45 CFR 46.103. • If the regulations as currently written do not allow this modification, OHRP in conjunction with other Common Rule departments and agencies should issue a Notice of Proposed Rulemaking to amend section __.103 of the Common Rule by eliminating the requirement for institutions to designate individual IRBs under their assurances of compliance.

17. IRB Authorization Agreements • Used to document cooperative review arrangements, whereby one institution agrees to rely on the IRB of another institution • Not all institutions have (or need) their own IRB • Reduces duplication of effort in collaborative research scenarios • Key step to facilitating use of alternative models of IRB review • OHRP provides sample IAA template via website • Many institutions find helpful but rather “bare bones” • OHRP makes it clear that institutions are free to develop their own agreements • Considerable time, effort and resources are devoted to drafting expanded agreements

18. Current OHRP Sample

19. Recommendations • OHRP should continue to provide sample IRB Authorization Agreements for institutions to use in documenting cooperative review arrangements. This template should be expanded to include additional “points to consider” that collaborating institutions may wish to address, depending on the circumstances, such as: • Notification of IRB decisions • Responsibility for investigating incidents of noncompliance or unanticipated problems • Responsibility for external reporting obligations (e.g., to OHRP, FDA, funding agencies) • Liability issues • Data sharing issues, including impact of HIPAA • Required education and training • Review and management of Conflicts of Interest • Implications of optional selections in the FWA, extending (or not) federal regulations to research regardless of funding • By the relying institution:  Supervision of employees, ensuring compliance, accepting decisions of IRB • Other?

20. Subpart A Subcommittee (SAS) Report and Recommendations to SACHRP Update: Work in Progress on Informed Consent Working Group on Informed Consent

21. Statement of the Problem • While the basic and additional elements of consent have remained unchanged in the human subject protection regulations, the level of detail provided in consent forms has skyrocketed in the past few years.

22. It’s not just the form… • To improve the quality of consent, the document and the process must be addressed • Document • Can the Consent Form be “repackaged? • Process • Develop tools to: • orient the potential subject to research elements prior to the consent process • ascertain comprehension after process but prior to enrollment • determine if subject remains aware of key elements of research throughout the research project • evaluate the quality of the subject’s study experience and inform the subject of follow-up issues during an exit interview • Increase investigator education related to the consent process

23. Progress • Representative from AAMC attended the subcommittee meeting in January to discuss the status of AAMC IC project • Conference calls have been held with representatives from Glaxo Smith Kline to discuss status of their health literacy project • Demo of on-line informed consent commercial project presented at Dartmouth • SAS Informed Consent Working Group has divided further into the “forms group” and the “process group” • Each is working on items developed in the SAS meeting held in January 2009

24. Consent Document • Are there ways to make the form more meaningful ? • Desired Outcomes • Meet regulatory requirements • Contribute to better comprehension • Move away from perception it is a document designed to protect the PI and institution, rather than assist the subject in decision making • Recognize that the form is a tool to be used during the process and to document that part of that process occurred

25. Consent Document • Consider use of executive summaries or information sheets • Pull most relevant information that may pertain to decision making and provide that in addition to consent document • Consider alternate formats • Use of other technology (videos, CDs, web-based information to include regulatory elements so that the actual form that is signed is shorter) • Consider expanded use of short form (not just for language or illiterate populations)

26. Consent Document • OHRP has agreed to review an example of “repackaged” consent document(s) and determine if revamped format meets regulatory requirements • This is viewed as critical step in demonstrating acceptability to research community • FDA review is also critical

27. Consent Process • Pre-consent education • Improvement of the consent process • Determination of comprehension prior to enrollment • Ongoing determination of comprehension • Exit interview

28. Subpart A Subcommittee (SAS) Report and Recommendations to SACHRP Questions Relating to Informed Consent in the Setting of Tissue Repositories

29. Informed Consent and Tissue Repositories • Institutions, investigators and IRBs are struggling with scenarios that involve tissue banks, DNA repositories, storage of biospecimens for future unspecified use, and related issues • These scenarios are only becoming more commonplace, and more complex • Multiple reports over recent years • …but no universal or widely-accepted practices have emerged • SACHRP panel on July 15, 2008 • Research community would benefit from federal-level guidance and clarification

30. Proposal for Discussion • OHRP should provide guidance that addresses several “Frequently Asked Questions” that relate to informed consent in the setting of tissue repositories or biobanks. The following are sample scenarios to be addressed.

31. Sample FAQ • A tissue biopsy was obtained for clinical diagnostic purposes, which have now been satisfied. The hospital pathology department is willing to provide a portion of the remaining biopsy specimen to an investigator, who will perform research assays with no clinical relevance. • If the specimen is de-identified (per HIPAA) before being given to the investigator, is this considered to be human subjects research under the purview of the IRB? • If the specimen is identifiable to the researcher, is this considered to be human subjects research under the purview of the IRB? • Is consent of the patient from whom the biopsy was taken (or waiver of consent) required under either (a) or (b)?

32. Sample FAQ • Blood samples were obtained for research purposes, with informed consent of the subjects, and the original study has been completed. The original investigator wants to provide a portion of the remaining samples to another investigator, who will perform research unrelated to the original study. • If the samples are de-identified (per HIPAA) before being given to the secondary user, is this considered to be human subjects research under the purview of the IRB? • If the samples are de-identified (per HIPAA) before being given to the secondary user, but the original investigator will be collaborating as a co-investigator on the subsequent project and holds the linkage code, is this considered to be human subjects research under the purview of the IRB? • If the sample is identifiable to the secondary user, is this considered to be human subjects research under the purview of the IRB? • If the original consent was silent on the question of subsequent uses, is additional informed consent (or IRB waiver of consent) required before the sample can be used for other purposes? • If the original consent stated that “…your sample will only be used for research on diabetes,” but the secondary user is interested in studying mental illness, can the samples still be used if provided in de-identified fashion?

33. Sample FAQ • Patients undergoing surgery for colon cancer agree to donate any excess tissue (i.e., beyond that needed for clinical purposes) to a tissue bank. The creation of the bank is reviewed and approved by the IRB. The consent form makes it clear that the specimens and associated clinical data will be used for research, but does not specify or limit that use. • If the bank employs an “honest broker” mechanism, so that specimens and any associated data are de-identified (per HIPAA) before being given to researchers, is this subsequent use considered to be human subjects research under the purview of the IRB? • If specimens are provided to the researchers with clinical information that contains identifiers, do those researchers need separate IRB approval? • Is additional consent from the patient-subject (or IRB waiver of consent) required for any future uses of the banked specimens, under (a) or (b)? • If the consent form was silent on genetic testing for research purposes, is that allowable? • In this example, does the lack of specificity (for future unspecified use) satisfy requirements of the HIPAA Privacy Rule?  OCR

34. Sample FAQ • An academic medical center has established a centralized tissue bank, to make specimens available to a wide variety of researchers. • Can excess clinical specimens be placed in the bank, if there was no research consent obtained from the patients? • Can excess research specimens be transferred to the bank, after their original purpose has been served?

35. Sample FAQ • Many hospitals have a sentence on the standard admission form to the effect that “This is a teaching and research institution, and any specimens remaining after your care is complete may be used for teaching or research purposes.” • Is this sufficient to allow specimens to be used for research purposes, without any additional consent? • Is this sufficient to allow specimens to be placed into a tissue bank, if it strips them of identifiers before releasing them to researchers? • Is waiver of consent required from the IRB?

36. Sample FAQ • An investigator is performing research assays that scan for thousands of genetic fragments. Along with the research data of interest, it is possible that s/he may uncover information that has some clinical relevance for an individual subject. • What should an IRB consider if it is possible that an “incidental finding” may occur during the course of a research study? • How much information should be included in the consent form for a study like this, if the chances of “incidental findings” are realistically quite low?

37. Informed Consent and Tissue Banking • Next steps  Questions for discussion • Are there additional scenarios that should be addressed? • Who should draft answers to the FAQs? • OHRP, SACHRP, SAS… • What format should this much-needed guidance take?

38. Follow up to SAS and SACHRP Deliberations on Diversity in Clinical Trials Federal Register /Vol. 74, No. 8 /Tuesday, January 13, 2009 Notices 1695 • DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA–2009–N–0674] Participation of Certain Population Subsets in Clinical Drug Trials • Request for Comment • AGENCY: Food and Drug Administration,HHS • ACTION: Notice; request for comments Please consider submitting comments  http://www.fda.gov/OHRMS/DOCKETS/98fr/E9-450.pdf

39. Stay tuned... there is always more to come from SAS!