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 9-10, 2010

2. Outline of Today’s Presentation Subcommittee charge and membership Topics for consideration at this meeting Continuing Review  revisited Interpretation of “investigator” Informed consent and biospecimens Future of SAS Informed consent  Form & Process Institutional Responsibilities  assurances Other?

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, 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 June 8 & 30, 2009 via teleconference July 8, 2009 via teleconference Sept 1 & 30, 2009 via teleconference Oct 21, 2009 via teleconference Feb 24 & 26, 2010 via teleconference Supplemented by Working Group calls and e-mails

7. Dept of Education

8. There is general consensus that the Common Rule is not “broken”… so…What is the problem?What are we trying to fix?

9. Investigators Subjects IRBs Regulations that leave too much to the imagination Overly restrictive interpretations

10. Secretarial Letters Incorporating SAS Recommendations 5th SACHRP letter to Secretary Leavitt  3/14/07 Recommendations approved 2005-2006 Continuing Review  Federal Register notice on 11/06/09 Expedited Review  Federal Register notice on 10/26/07 6th SACHRP letter to Secretary Leavitt  6/15/07 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  1/31/08 Recommendations approved March & July 2007 Waiver of Informed Consent Minimal Risk  Analytical framework and examples 8th SACHRP letter to Secretary Leavitt  9/18/08 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)

11. Subpart A Subcommittee (SAS) Report and Recommendations to SACHRP Continuing Review RevisitedOHRP Draft Guidance to Address SACHRP Recommendations

12. PLEASE NOTE:The following slides are drawn from presentations in 2005-2006, when SACHRP first considered and approved recommendations on continuing review, and are included here for background and context

13. Historical Context • The requirement for continuing review is a legacy of the USPHS Study of Untreated Syphilis. • Continuing review of research was intended to prevent continuing research activities in the face of unacceptable harm, futility or scientific/ethical obsolescence. • The Belmont Report does not mention continuing review as an application of its ethical principles.

14. Working Assumptions • Continuing review plays a central, often undervalued role in the IRB process • Practices that do not demonstrably enhance the safe and ethical conduct of research diminish overall human subject protections  resource allocation

15. The Primary Regulatory Citation • Only one section addresses the continuing review process with any detail and says, in its entirety: • “An IRB shall conduct continuing review of research covered by this policy at intervals appropriate to the degree of risk, but not less than once per year, and shall have authority to observe or have a third party observe the consent process and the research.” 45 CFR 46.109(e) and 21 CFR 56.109(f)

16. Preamble to HHS Regulations “The precise procedure adopted by the IRB for continuing review without unnecessarily hindering research should be left to the discretion of the IRB.” Federal Register, vol 46 no.16, January 26, 1981

17. Preamble to HHS Regulations(next sentence) “Reporting requirements may vary from a simple annual notification, in the case of research involving little or no risk, to more frequent reporting… where the risks are greater. […for…] large clinical trials, the IRB may require a special mechanism to carry out regular data and safety monitoring functions.” Federal Register, vol 46 no.16, January 26, 1981

18. Current Guidance on Continuing Review • “Several scenarios for determining the date of continuing review apply for protocols reviewed by the IRB at a convened meeting. To determine the date by which continuing review must occur, focus on the date of the convened meeting at which IRB approval occurs.” OHRP Guidance on Continuing Review, updated Jan 15, 2007

19. Current Guidance on Continuing Review • Ignores the process employed by most IRBs to complete review and ensure that all modifications required to approve research are implemented before communicating “approval” • Allowing IRBs to set the date to the day when the research receives its final approval is a more appropriate approach and prevents both premature research activities and artificially shortened approval periods • SAS believes that that such a policy is fully supported by the regulations, conforms to the original intent stated in the 1981 preamble, and is consistent with the regulatory authority given to the IRB to extend to the Chair or experienced reviewers the full approval powers of the assembled board – i.e., the expedited review process

20. Does HHS guidance regarding setting the date of continuing review need to be changed?RECOMMENDATIONS OHRP should revise guidance to reflect that the final IRB approval of a study […and not the date of the preceding convened meeting…] “sets the clock” for continuing review. Postscript  This recommendation was approved by SACHRP and submitted via Secretarial letter on March 14, 2007

21. Calculation of Approval Period Currently Differs According to Type of Review Expedited Review Conditions Met & Study Approved Subsequent approval periods will depend on dates of actual re-approval Initial Review 5/1/2010 6/4/2010 6/4/2011 x/x/2012 Convened Meeting Review Conditions Met & Study Approved Subsequent approval periods will depend on dates of subsequent convened meetings, but tend to be progressively shorter Initial Review 5/1/2010 6/4/2010 5/1/2011   x/x/2012

22. Continuing Review Revisited • SAS acknowledges the efforts of OHRP to address these issues in “Draft Guidance on IRB Continuing Review of Research” (October 29, 2009)  Federal Register, November 6, 2009 • There are, however, concerns that the proposed guidance on determining effective dates for approval and continuing review is unnecessarily complicated and will merely “trade one problem for another” • SAS respectfully suggests that this problematic issue be revisited

23. Subpart A Subcommittee (SAS) Report and Recommendations to SACHRP Questions Relating to Informed Consent and Research Use of Biospecimens

24. Human Specimens Have Become Essential to Biomedical Research • Much biomedical research relies on use of human specimens • Tissues removed at surgery • Blood, pleural effusions, urine, CSF, other fluids • Many sources of specimens for research use (public, private and commercial)  some collected initially for clinical use, others collected specifically for research • RAND study (Eiseman, 2000) estimated >307 million specimens stored in U.S. with >20 million collected each year Slide content courtesy of Lynn Dressler, UNC

25. Stored Tissue Samples in the U.S. Slide based on Eiseman, RAND, 2000

26. Stored Tissue Samples in the U.S. Slide based on Eisman, RAND, 2000

27. Informed Consent and Biospecimens • 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, more complex, and more problematic • Multiple reports over recent years • Few universal or widely-accepted practices • Much inconsistency in what “must” or should be done • SACHRP panel on July 15, 2008 • Research community would benefit from federal-level guidance and clarification

28. Process for Development of Guidance • Preliminary concept and sample scenarios presented to SACHRP in March 2009 • Extensive review, feedback and discussion by SAS members, ad hoc consultants, ex officios and OHRP staff • Teleconferences on June 8, June 30, July 8, Sept 1, Sept 30, Oct 21, 2009; Feb 24 and 26, 2010 • First installments presented to SACHRP on July 22 and Oct 27, 2009 • Remainder (?) at this meeting

29. Process for Development of Guidance (continued) • Ultimate goal is for OHRP to issue guidance for IRBs, investigators, institutions, sponsors • Some scenarios overlap with HIPAA, FDA, others • Final guidance may not take the format of FAQs  focus on concepts and conclusions • Working Assumptions • This is not an IRB meeting • The goal is to provide a framework for IRBs (and others listed above) to make decisions when they deal with specific research projects in the future • SAS, SACHRP and/or OHRP should not attempt to pre-emptively make those decisions in advance, in the context of generic FAQs with minimal details

30. Definitions for Relevant Terms and Concepts

31. When is research with specimens not Human Subjects Research? OHRP does not consider research involving only coded private information or specimens to involve human subjects if the following conditions are both met: (1) the private information or specimens were not collected specifically for the currently proposed research projectthrough an interaction or intervention with living individuals; and (2) the investigator(s) cannot readily ascertain the identity of the individual(s) to whom the coded private information or specimens pertain because, for example, there are agreements, IRB-approved policies and procedures, or legal requirements in place that prohibit the release of the key to the code to the investigators under any circumstances until the individuals are deceased. OHRP: Guidance on Research Involving Coded Private Information or Biological Specimens, issued August 10, 2004; updated October16, 2008

32. “Coded” Defined CODED means that: (1) Identifying information (such as name or social security number) that would enable the investigator to readily ascertain the identity of the individual to whom the private information or specimens pertain has been replaced with a number, letter, symbol, or combination thereof (i.e., the code); and (2) a key to decipher the code exists, enabling linkage of the identifying information to the private information or specimens. OHRP: Guidance on Research Involving Coded Private Information or Biological Specimens, issued August 10, 2004; updated October16, 2008

33. How should “Investigator” be defined? BACKGROUND: This is a critical point for the purposes of determining whether a proposed activity is human subjects research, and therefore subject to IRB review, because… “OHRP does not consider research involving only coded private information or specimens to involve human subjects as defined under 45 CFR 46.102(f) if […] the investigator(s) cannot readily ascertain the identity of the individual(s) to whom the coded private information or specimens pertain because… OHRP: Guidance on Research Involving Coded Private Information or Biological Specimens, issued August 10, 2004; updated October16, 2008

34. How should “Investigator” be defined? BACKGROUND: Current OHRP guidance defines "investigator" as “…anyone involved in conducting the research. OHRP does not consider the act of solely providing coded private information or specimens (for example, by a tissue repository) to constitute involvement in the conduct of the research. Note that if the individuals who provide coded information or specimens collaborate on other activities related to the conduct of this research with the investigators who receive such information or specimens, then OHRP would consider such additional activities to constitute involvement in the conduct of the research. Examples of such additional activities include, but are not limited to: (1) the study, interpretation, or analysis of the data resulting from the coded information or specimens; and (2) authorship of presentations or manuscripts related to the research.” OHRP: Guidance on Research Involving Coded Private Information or Biological Specimens, issued August 10, 2004; updated October16, 2008

35. How should “Investigator” be defined? • PROBLEMS WITH CURRENT INTERPRETATION • There are many circumstances where a secondary use of coded information or specimens would not constitute human subjects research, were it not for the peripheral involvement of the individual who gathered the original data or specimens. This involvement may be such that the secondary users, and sometimes even the original collector, are unable to ascertain the identity of subjects. Examples: • Original collector involved as a coauthor on resulting manuscripts or listed on grants, in recognition of his/her work in obtaining the data or specimens, but with an agreement that prevents release of the coding key to secondary users • Original collector joins with others to form a centralized repository, with no continued personal access to identifiers • Professor provides a coded dataset for their graduate student to use in secondary analyses, with no intention or reason to share identifiers

36. How should “Investigator” be defined? • PROBLEMS WITH CURRENT INTERPRETATION • Under these circumstances, current OHRP guidance defines the original collector as an “investigator” in the secondary use, even though their role may still effectively be limited to “solely providing” coded information or specimens. • This interpretation is overly restrictive, poorly understood, and therefore variably applied by IRBs and investigators. • The 2004 guidance by OHRP has provided a valuable mechanism for investigators and IRBs to focus on activities where risk to subjects is a legitimate concern, but this particular element works counter to that goal, and does not contribute meaningfully to human subject protections.

37. Original Collector = Now an Investigator?? Original Collector Coded Data or Specimens Secondary User = Investigator Secondary User = Investigator Not Human Subjects Research Human Subjects Research?? Coded Data or Specimens

38. Original Recommendation on the Definition of “Investigator” • OHRP should revise its interpretation of who is considered an “investigator” in secondary use of coded information or specimens to exclude those individuals who are providing such information or specimens, even if they are involved in analysis of aggregate data or publication of results, provided the secondary users are unable to readily ascertain the identity of subjects. • Mechanisms to support this interpretation could include (a) the presence of an agreement that prohibits release of the key from the original provider to secondary users; or (b) the existence of a repository or banking system that prohibits the secondary users from access to identifiers. • The intent is to support a conclusion that secondary uses under such circumstances do not constitute research involving human subjects (as defined under 45 CFR 46.102(f)) and therefore do not require IRB review and approval, in keeping with OHRP’s “Guidance on Research Involving Coded Private Information or Biological Specimens.”

39. The words “without identifiers” should be added, even though this is included [in] what “coded” means. SAS  revised, but redundant It should be clear whether the same mechanisms would apply within the same institution as well as between institutions. SAS  revised It should be clear that the secondary user is using the data for a different purpose than the original purpose. SAS  already addressed within existing guidance; this definitional change is not intended to stand alone It should be clear that the role of the secondary user does not require an ability to identify data, either by the original collector or by the secondary user. SAS  revised SACHRP Comments and Questions from October 27, 2009

40. It should be clear when and whether IRB review is required. SAS  already addressed within existing guidance; this definitional change is not intended to stand alone There should be precision about what constitutes an “agreement.” SAS  already addressed within existing guidance; this definitional change is not intended to stand alone It should be clear that the published material cannot be decoded by the original investigator. (“Trust isn’t enough.”) A variety of mechanisms can be used to achieve this end, including recoding or the use of an “honest broker.” SAS  it is not entirely clear what is meant by “published material” or if this is relevant to the intent? SACHRP Comments and Questions from October 27, 2009

41. Revised Recommendation on the Definition of “Investigator” • OHRP should revise its interpretation of who is considered an “investigator” in secondary use of coded information or specimens. In circumstances where neither party will have a need to decode or re-identify data, the original collectors who are providing such information or specimens without identifiers should not be considered to be “investigators” in the secondary use, even if they are involved in analysis of aggregate data or publication of results, provided the secondary users are unable to readily ascertain the identity of subjects.

42. Revised Recommendation on the Definition of “Investigator” (continued) • Mechanisms to support this interpretation could include (a) the presence of an agreement that prohibits release of the key from the original provider to secondary users; or (b) the existence of a repository or banking system that prohibits the secondary users from access to identifiers. These same interpretations and mechanisms should be applied whether the original provider and secondary user(s) are within the same institution or at different institutions. • The intent is to support a conclusion that secondary uses under such circumstances do not constitute research involving human subjects (as defined under 45 CFR 46.102(f)) and therefore do not require IRB review and approval, in keeping with OHRP’s “Guidance on Research Involving Coded Private Information or Biological Specimens.”

43. “Honest Broker” Defined HONEST BROKER means: A neutral intermediary (person or system) between the individual whose tissue and data are being studied, and the researcher. The honest broker collects and collates pertinent information regarding the tissue source, replaces identifiers with a code, and releases only coded information to the researcher

44. “Limited Data Set” Defined As defined by HIPAA… • Limited data sets are data sets stripped of certain direct identifiers that are specified in the Privacy Rule. They are not de-identified information under the Privacy Rule. • A limited data set is protected health information that excludes the following direct identifiers of the individual or of relatives, employers, or household members of the individual: (1) names; (2) postal address information, other than town or city, State, and zip code; (3) telephone numbers; (4) fax numbers; (5) e-mail addresses; (6) social security numbers; (7) medical record numbers; (8) health plan beneficiary numbers; (9) account numbers; (10) certificate/license plate numbers; (11) vehicle identifiers and serial numbers; (12) device identifiers and serial numbers; (13) web URLs; (14) Internet Protocol (IP) address numbers; (15) biometric identifiers, including fingerprints and voiceprints; and (16) full-face photographic images and any comparable images.

45. “Limited Data Set” Defined(continued) • Importantly, unlike de-identified data, protected health information in limited data sets may include the following: • City, state and zipcodes; all elements of dates (such as admission and discharge dates); and unique codes or identifiers not listed as direct identifiers. • Recognizing that institutions, IRBs and investigators are frequently faced with applying both the Common Rule and the HIPAA Privacy Rule, OHRP does not consider a Limited Data Set (as defined under HIPAA) to constitute individually identifiable information under 45 CFR 46.102(f)(2). •  THIS INTERPRETATION WAS CONFIRMED AT SACHRP MEETING OCTOBER 27, 2009

46. Unresolved Terminology NEEDED: A word/phrase to describe the circumstance where the proposed secondary use is supported by (or not prohibited by) the original terms of consent “… is consistent with…” may imply that secondary use must be explicitly stated? “… is not inconsistent with…” double-negative may imply that any use is OK? “… is compatible with…” current suggestion, pending further discussion?

47. Points to Consider in Determining “Compatibility” The determination of whether a proposed secondary research use is compatible with the original consent is subjective and will be context-specific based on a range of considerations.  Questions to consider include: • Does the consent form prohibit or preclude the new research activity? • What is the nature of the proposed secondary research? • Could it reasonably be understood to fall within the type of disease or research that was described to the research subject at the time of consent? Or is the focus on a completely different disease or type of research? • Does the new research use impose new or significantly greater risks that are not described in the initial consent form? • Are there known concerns of the study population(s) about the proposed new use?

48. FAQs and ResponsesNote that FAQs #1-10 were previously approved, with numbering preserved

49. FAQ # 1Approved by SACHRP July 22, 2009 Tissue biopsies were obtained for clinical diagnostic purposes, which have now been satisfied. The hospital pathology department is willing to provide a portion of the remaining biopsy specimens to an investigator who will perform research assays. In order to allow matching with relevant clinical information, the specimens will be provided with identifiers such that the investigator can readily ascertain the identity of subjects. Is consent of the patient from whom the biopsy was taken (or waiver of consent) required for the secondary research use?

50. Response # 1Approved by SACHRP July 22, 2009 Yes. Under this scenario, informed consent of the subjects should either be obtained or waived under 45 CFR 46.116(d) because the samples are identifiable to the recipient investigator.