Subpart A Subcommittee (SAS)

Subpart A Subcommittee(SAS) Elizabeth Bankert and Daniel Nelson Co-Chairs Presentation to the Secretary’s Advisory Committee on Human Research Protections (SACHRP) July 16, 2008

Outline of Today’s Presentation Subcommittee charge and membership Recommendations for consideration today Informed Consent Waiver of written documentation Institutional Responsibilities Institutional Official Outreach and Duties Tribal Approval of Research Next Steps

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

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

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  Myron Genel, Patty Marshall, Neil Powe, James Powell, Samuel Tilden With input from ex officio reps of Common Rule agencies Subcommittee MembershipPastand Present *co-chairs

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 Supplemented by Working Group calls and e-mails

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

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

Finalized Recommendations 5th SACHRP letter to Secretary Leavitt accepted Recommendations approved 2005-2006 Continuing Review Expedited Review  Federal Register notice on 10/26/07 6th SACHRP letter to Secretary Leavitt accepted 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 in preparation

Subpart A Subcommittee (SAS) Report and Recommendations to SACHRP 45 CFR 46.117(c) Waiving Documentation of Informed Consent Working Group on Informed Consent

What is the issue? What are we trying to fix? Obtaining documented informed consentof research subjects prior to their participation is regarded as a cornerstone for the ethical conduct of research, and a fundamental protection for participants’ rights. HHS regulations outline general requirements for documenting informed consent at 45 CFR 46.117.

What is the issue? What are we trying to fix? It is recognized that there is valuable research that would be difficult, or impossible, to conduct if documentationof informed consent were required for every scenario. Accordingly, the regulations allow an IRB to waive the requirement for obtaining a signed consent form under certain circumstances, as described in 45 CFR 46.117(c).

What is the issue? What are we trying to fix? • In practice, IRBs may inappropriately utilize the waiver provision for the following reasons: • Uncertainty in applying criteria (i.e., whether or not to grant the waiver). • Inconsistency in reviewing the research, including consideration of the waiver of documentation of informed consent, owing to variability across IRBs (and institutions). This is especially evident when the waiver provisions are applied in research conducted at multiple sites. • This uncertainty and variability may lead to underutilization of the waiver, when it may be warranted. Conversely, lack of understanding on how/when to apply may lead to inappropriate application of the waiver, under some circumstances.

Other Provisions Under 45 CFR 46.117 46.117(a) describes required signatures and requirement of providing a copy to subject 46.117(b) refers to options of (1) reading the consent form to the subject and (2) the use of a short form. These items are not being presented for comment today.

What do the HHS regulations at 45 CFR 46.117(c) say? (c) An IRB may waive the requirement for the investigator to obtain a signed consent form for some or all subjects if it finds either: (1) That the only record linking the subject and the research would be the consent document and the principal risk would be potential harm resulting from a breach of confidentiality. Each subject will be asked whether the subject wants documentation linking the subject with the research, and the subject's wishes will govern; or (2) That the research presents no more than minimal risk of harm to subjects and involves no procedures for which written consent is normally required outside of the research context. In cases in which the documentation requirement is waived, the IRB may require the investigator to provide subjects with a written statement regarding the research.

Is there any guidance on interpretation of the provisions of 45 CFR 46.117(c) from OHRP? OHRP website FAQ #31 : When may the requirement for documentation of informed consent or parental permission be waived or altered? Answer: When an Institutional Review Board (IRB) has not waived the requirement for seeking prospective informed consent of the subjects or the parental permission of children who are subjects, under the HHS regulations at 45CFR46.117(c), it may waive the requirement for the investigator to obtain a signed consent form for some or all subjects if it finds either:

OHRP website FAQ #31 (cont) That the only record linking the subject and the research would be the consent document and the principal risk would be potential harm resulting from a breach of confidentiality. Each subject will be asked whether the subject wants documentation linking the subject with the research and the subject’s wishes will govern; Or….

OHRP website FAQ #31 (cont) That the research presents no more than minimal risk of harm to subjects and involves no procedures for which written consent is normally required outside of the research context (e.g., drawing a blood sample, or asking shoppers in a mall about the ambient lighting or temperature).

OHRP website FAQ #31 (cont) Some subjects might refuse a copy of the consent form once signed out of concern that their possession of the form could compromise their privacy. This is fully consistent with the idea behind one of the bases for a waiver of the requirements for documentation of informed consent that harm would result to the subject if his/her identity were compromised by the documentation itself. The investigator may document that the subject refused a copy of the informed consent document and still include the subject in the study. In cases in which the documentation requirement is waived, the IRB may require the investigator to provide subjects or the parents of children who are subjects with a written statement regarding the research.

Additional Guidance • OHRP e-mails to queries on this topic: • Please note that when the IRB waives the • documentation requirements of 45 CFR 46.117, the IRB must still approve a consent procedure (or parental permission procedure) that includes all of the basic elements of informed consent under HHS regulations at 45 CFR46.116(a) and when appropriate, the elements under 45 CFR 46.116(b), UNLESS the IRB has approved a consent procedure which does not include or which alters some of these elements.

Waiver of Documentation of Informed ConsentRecommendations for Guidance and Clarification • OHRP should provide guidance on the interpretation and application of 46.117(c), using examples as appropriate, with particular emphasis on social or behavioral research • OHRP guidance should include an explanation of the documentation in 46.117(c)(1) and clarify that this provision is not limited to minimal risk research. • OHRP should clarify that the final sentence in 46.117, regarding the provision of a written statement to subjects, applies to both (c)(1) and (c)(2). • OHRP should clarify that, when the IRB requires a written statement as described under 46.117(c), the statement does not need to include the elements of consent required under 46.116. OHRP should also clarify that a waiver of consent under 46.116(d) is not required, unless some elements of consent are not presented either orally or in writing.

Waiver of Documentation of Informed ConsentRecommendation 1 • OHRP should provide guidance on the interpretation and application of 46.117(c), using examples as appropriate, with particular emphasis on social or behavioral research. Additional resources should be provided to OHRP to educate IRBs on these provisions.

Waiver of Documentation of Informed ConsentRecommendation 2 • With regard to 46.117(c)(1), OHRP guidance should clarify • that there would be no links between the subject and the research (e.g., investigator notes) other than the consent form itself. • that this provision is notlimited to minimal risk research, and is appropriate for those studies that involve greater than minimal risk (e.g., some studies of domestic violence, illegal behavior). • what the word “documentation” used in this section means

Reminder of Regulatory Language 45CFR46117 (c) An IRB may waive the requirement for the investigator to obtain a signed consent form for some or all subjects if it finds either: (1) That the only record linking the subject and the research would be the consent document… (2) That the research presents no more than minimal risk of harm to subjects… In cases in which the documentation requirement is waived, the IRB may require the investigator to provide subjects with a written statement regarding the research.

Waiver of Documentation of Informed ConsentRecommendation 3 • OHRP should clarify that the final sentence in 46.117, regarding the provision of a written statement to subjects, applies to both (c)(1) and (c)(2).

Waiver of Documentation of Informed ConsentRecommendation 4 • OHRP should clarify that, when the IRB requires a written statement as described under 46.117(c), the statement does not need to include the elements of consent required under 46.116 as long as the elements are addressed orally. • This guidance should include examples of situations where the IRB may choose to require a written statement. • OHRP should also clarify that, if some of the elements of consent are not presented either orally or in writing, the criteria for waiving consent under 46.116(c)or(d) must be met.

Waiver of Documentation of Informed Consent Recommendation 5 OHRP should explore options for modifying or accommodating the requirement under 45 CFR 46.117(c)(1) that each subject ‘will’ be asked whether they want documentation linking them to the research, including the possibility of a Secretarial waiver of this requirement.

Subpart A Subcommittee (SAS) Report and Recommendations to SACHRP Institutional Officials Working Group on Institutional Responsibilities

Institutional Responsibilities • Assurances • Engagement in Research • Institutional Official (IO) Responsibilities • Multi-site studies

What is the issue? What are we trying to fix? • Institutional Officials play a key role in human research protections • Institutional Culture • Resources • Commitments • Policies • Enforcement (and reinforcement) • Nevertheless, there is variable understanding with respect to the nature, extent and specificity of IO responsibilities  variable oversight and effectiveness of HRPPs • SAS recommendations are intended to enhance the understanding and fulfillment of expectations for organizations, institutional officials and the research community in general.

Institutional OfficialsRecommendation 1 • Given the key role in human research protections played by Institutional Officials (IOs), OHRP should continue and strengthen its efforts to reach this group through training, outreach, and guidance. HHS should provide additional resources to OHRP to achieve this goal. Among other approaches, this includes outreach through professional organizations more likely to encompass IOs who may not participate in “IRB-related” venues, conferences and organizations (e.g., NCURA, COGR, AAU, AAMC, COSSA, et al).

Institutional OfficialsRecommendation 2 • OHRP should develop standard nomenclature and definitions for terms that are currently used, such as • “Organization” • “Institution” • “Organizational Official” • “Institutional Official” • “Signatory Official” • “Head Official”

Institutional OfficialsRecommendation 3 • OHRP should continue to define the IO as the individual who is legally authorized to act for the institution and, on behalf of the institution, obligates the institution to the Terms of the Assurance. This individual should have the authority and responsibility to provide adequate resources to maintain an effective Human Research Protection Program (HRPP). It is recognized that, within some organizational structures, these responsibilities may reasonably be executed by someone other than the chief executive officer, president or counterpart, in order to ensure an active, knowledgeable role for the IO in the HRPP.

Institutional OfficialsRecommendation 4 • OHRP should develop expanded guidance on the expectations and responsibilities of IOs, including their ethical and regulatory obligations, and highlighting issues of both authority and autonomy. The guidance should recognize that some operational functions may be appropriately delegated by the IO; to the extent that selected obligations should not be delegated, these should be identified. This guidance might take the form of a simple bulleted list (draft example provided).

Institutional OfficialsRecommendation 5 • OHRP should provide periodic (e.g., annual) reminders to IOs that reinforce their central role and responsibilities in human research protections, including the guidance recommended above. These reminders might be accomplished easily using e-mail contacts on file with OHRP through the Assurance process.

Recommendations in Other Areas

Proposed Recommendation for Modification of the Common Rule • The following recommendation was presented to SACHRP at the March 2008 meeting, at the request of Dr. Francine Romero, former SACHRP member. It was referred to the Subpart A Subcommittee for further consideration. • There is concern that Tribal governments are not aware of the fact that any research done within a Tribal jurisdiction is subject to Tribal authority. Some larger tribes have implemented research codes; however, most smaller tribes have not. SACHRP should consider a recommendation that the following language be added to the Common Rule at 46.109: • “(f) For human subject research to be conducted within the jurisdiction(s) of federally recognized American Indian or Alaska native (AIAN) Tribal government(s), the IRB shall require documentation of explicit Tribal approval for the research. This approval shall come from the Tribal Council or other agency of Tribal government to whom such authority has been delegated by the Council.”

SAS Discussion • Subcommittee members endorsed this recommendation in principle and supported the underlying aims. However, there were concerns that modifying the Common Rule was neither the most efficacious, expeditious nor appropriate vehicle to accomplish those aims. After substantive discussion, the Subcommittee proposed a revised recommendation, as follows:

Recommendation Regarding Research Involving American Indian or Alaska Native Populations • SACHRP recommends that HHS promote the development of guidance and grants policy, in consultation with OHRP, other staff- and operating-divisions, and other appropriate Departments and Agencies, that address research involving American Indian or Alaska Native (AIAN) populations.

Recommendation Regarding Research Involving American Indian or Alaska Native Populations(continued) • This guidance might address general issues that would be of interest and value to any investigators considering research with these populations. Specific issues to be addressed shall include the requirement for Tribal approval for research that is to be conducted within the jurisdiction(s) of federally-recognized AIAN Tribal government(s). Such approval shall come from the Tribal Council or other agency of Tribal government to whom such authority has been delegated by the Council. The requirement for Tribal approval shall be reinforced through educational outreach, and through the terms and conditions of HHS grants supporting such research, as a matter of grants policy.

Diversity in Clinical Trials The Subcommittee continued discussion on this topic, in follow-up to the panel presentation to SACHRP in 2007. The Subcommittee agreed to prepare preliminary recommendations in this area for SACHRP to consider. This work is in progress.

What Next? Selected Topics for Consideration • In 2007 SAS formed Working Groups in the following areas… • Exemptions • Informed Consent • Institutional Responsibilities

Informed Consent • Waiver of consent • Documentation of consent • Waiver of documentation • Delinking 46.116 and 46.117 • Use of the Short Form • Use of addenda • Readability • Overly lengthy/complex consent documents • AAMC initiative to simplify and shorten consent documents • AHRQ toolkit • Liability and consent • Testing for comprehension? • What do subjects want? • Consent in international settings • Coordination with SIIIDR

Institutional Responsibilities • Assurances • Engagement in Research • Institutional Official (IO) Responsibilities • Multi-site studies

Assurances • Identifying legal components • Who is covered (who is an agent)? • FWA filing requirements • Reading/understanding the Terms of Assurance • Authorized signatures • Easier to use but more room for confusion • e.g., IRBs cited without their knowledge • Communications with institutions • Institutional models are growing and evolving • Often no longer single chair as point of contact

Assurances • Modifying the FWA for single study or limited relationships • Many don’t know this is required • Those that do know, find problematic • Frequent tinkering with high-level documents • Potentially 100s of IRBs listed for collaborative institutions • Updating rosters with OHRP • How often? When? Maybe not at all? • Use of external agreements • IRB Authorization Agreement (IAA) • Individual Investigator Agreement (IIA) • Do OHRP templates cover enough? • MOU between collaborating institutions  points to consider • Impact of privacy rights? Data sharing? Reporting obligations? • Why are institutions “unchecking the box?” • Is this healthy for the research enterprise?

Engagement in Research • Revised OHRP guidance • Must determine if something is human subjects research (HSR) first before determining engagement • Tendency to reverse this order • What happens when Principal Investigator (PI) leaves one institution and joins another in the middle of a study? How can duplicate, repetitive, and “too late” processes be avoided? What if the PI is at the data analysis stage? • Variable understanding by funding agencies and within agencies • Applies to many policies and interpretations • Requirements for additional assurances by common rule agencies catch some institutions off guard

Engagement in Research • Are there exceptions to direct awardees being considered engaged? • If not, what circumstances? • Obligations of subcontractors • What mechanisms should be used in large collaborative projects (e.g., center grants) to allocate/define duties? • Performing a commercial service vs. engaged in research? • Institutions outside the research sites administer study intervention or draw bloods, etc. • Discordance between OHRP and FDA interpretation of engagement when subject enrolled in drug study (at one site) is hospitalized at a second site and receives study drug? • Use of an institution’s facilities vs employees/agents conducting research. • Confusion with OHRP’s guidance on research using coded specimens or information • Are institutions engaged when employees or agents receive/use coded private information or specimens?

Institutional Official (IO) Responsibilities • Resources and support are needed for all components of the human resource protection program (HRPP) • Walking the fine line  Support without interference in IRB decisions • Periodic reminders from OHRP directed to IOs? • Reinforce importance of role • OHRP initiatives to reach IOs are very useful and should be endorsed so they continue • Venues to reach IOs? • Conflict of Interest (COI) • Policies and mechanisms required for investigators, IRBs, and the Institution • Data security and its implications for confidentiality • Attention to IRB “mission creep” • Clarify true responsibilities of IRB and limit “dumping” • Identifying, recruiting, rewarding, recognizing IRB member service • Conversely, avoid disincentives • Checklist of IO responsibilities

Multi-site Research • Models of IRB review  2006 conference report • How to remove barriers to cooperative review? • Liability concerns • How to allocate responsibilities? • Local accountability • VA points to consider

Subpart A Subcommittee (SAS)