1. Subcommittee on the Inclusion of Individuals with Impaired Decision-making in Research Overview of SIIIDR Activities and Working Draft of Recommendation VIII: Approval Criteria Presented to SACHRP October 28, 2008 David H. Strauss, M.D. SIIIDR Co-chair

2. Context A history of research in which captive, incompetent and otherwise “vulnerable” populations were exploited in the name of science drove the development of the current system of research oversight. Yet, efforts to develop specific federal regulations for research with individuals unable to provide consent were not successful. Today, there are no federal regulations and no regulatory guidance which specifically address or properly guide the conduct of research with adults who are unable to provide informed consent. We are now confronting genuine gaps in regulatory coverage where pressing research questions for the most vulnerable subjects are at stake. What are the consequences of this void?

3. 1978 National Commission: research involving those institutionalized as mentally infirm 1998 NBAC: Research involving persons with mental disorders that may affect decisionmaking capacity 1999 NYS Advisory Workgroup on Human Subject Research: Recommendations on the oversight of human subject research involving the protected classes 1999 NIH Office of Extramural Research: Research involving individuals with questionable capacity to consent 2001 HHS working group on the NBAC report: Analysis and proposed actions regarding the NBAC report 2002 NHRPAC: Report from NHRPC on informed consent and the decisionally impaired 2007-8 SACHRP: in progress

4. Key Policy Questions (redux) Should persons who cannot provide voluntary consent participate in research? What standards and procedures should be used to assess prospective research participants’ capacity..? If individuals lack capacity…should others be legally authorized to consent to research on their behalf? What criteria should legally authorized representatives use to make decisions…? Should limits be placed on the degree of permissible risk? What special safeguards are needed to protect [their] rights and welfare? NYS Advisory Workgroup on Human Subject Research (1999)

5. From the SACHRP Charter The committee shall advise, consult with, and make recommendations on matters pertaining to…protections for human subjects in research…with special emphasis on special populations, such as…the decisionally impaired.

6. From SIIIDR’s Charge The Subcommittee will develop recommendations for consideration by SACHRP about whether guidance and/or additional regulations are needed for research involving individuals with impaired decision-making capacity.

7. Paul Appelbaum, Jeffrey Botkin*, Anne Donahue, Laurie Flynn, David Forster*, Lisa Leiden*, John Luce, John Oldham, Gustavo Roman, David Strauss* SIIIDR Membership Edgar Kenton, Laura Roberts, Samuel Tilden

8. Special thanks to our ex-officio members

9. SIIIDR meetings since the July ’08 SACHRP 90-Minute Teleconferences July 25 September 5 September 19 October 3 October 17 2-day Onsite Meeting, Rockville, MD August 6 and 7th

10. Regulatory Context §46.111 Approval (a)(2) Risks to subjects are reasonable in relation to anticipated benefits, if any, to subjects, and the importance of the knowledge that may reasonably be expected to result.” (b) When…subjects are likely to be vulnerable to coercion or undue influence, such as children, prisoners, pregnant women, mentally disabled persons, or economically or educationally disadvantaged persons, additional safeguards have been included… (a)(3) Subject selection is equitable…be particularly cognizant of special problems…(with) vulnerable populations.

11. Regulatory Context (Cont’d) §46.107 Membership : If an IRB regularly reviews research that involves …mentally disabled persons...consideration shall be given to the inclusion of one or more individuals who are knowledgeable about…and experienced in working with these subjects.

12. Regulatory “Context” Cont’d §46.116 “Information… shall be in language understandable to the subject…”

13. LAR and the Regulatory “Dead End” The federal regulations require the subject’s “legally effective informed consent” They also allow consent by a “legally authorized representative (LAR)” to the “procedures used in the research.” But, the federal regulations do not define LAR. This is left to the applicable local (State) law. The States, with rare exceptions, have not defined LAR for research, and some do not define it at all.

15. Balancing Acts Temper idealism with pragmatism (or vice versa) Weigh the merits of conventional vs. novel approaches Protect without diminishing autonomous decision-making Provide necessary protections without creating barriers to important areas of scientific inquiry Guide IRB review without being overly proscriptive Incorporate ethical, clinical, and empirical understanding while recognizing the limits of IRB expertise and capacity

16. Decisional Impairment Situational vs. disorder-related impairment (e.g. emergency room, “institutions,” vs. stroke) Global vs. specific impairment (e.g. sedative overdose vs. paranoid psychosis) Static vs. progressive vs. episodic vs. time limited impairment (e.g. severe mental retardation vs. Alzheimer’s disease vs. manic depressive disorder vs. TBI) Acute vs. persistent impairment (e.g. stress, or hypoxia secondary to asthma or acute pain vs. mental retardation or autism) Universal (e.g. therapeutic misconception, inadequate disclosure)

17. From SIIIDR’s Recommendation I “Consent capacity” (following the working document developed by NIH) denotes the specific abilities necessary for a prospective research participant to understand and use information relevant to consent.

18. Ability to consent? UnableAble

19. Consent capacity occurs along a continuum UnableAble Increasing Ability Unable to ConsentAble to Consent Impairments or limitations in ability

20. Consent Capacity is Task Specific Able to appoint a proxy decision-maker Able to consent to lower complexity, lower risk, high benefit research (with enhancement) Decreasing Complexity Decreasing Risk Increasing Personal Benefit Characteristics of Consent Decision Unable to consent to higher risk/lower personal benefit research

21. Approval criteria and what is a “reasonable”risk- benefit relationship when consent is provided by an LAR How do we define (and how do IRBs, Investigators Identify) the populations requiring additional protection? How do we decide who may provide consent for those who are unable to consent for themselves? Framework for SIIIDR activities

22. Population: Recommendations I, II, III LAR: Recommendations IV, VII, IX Recommendations V, VI Approval: Recommendation VIII

23. Clarifying current definition of LAR A federal definition of LAR in the absence of applicable law Promoting model state legislation Framework for SIIIDR activities Subject Selection IRB Membership Reasonable risk Defining the role of the LAR Optimizing the involvement of the subject in decision-making Extent of prior specification of wishes by the subject Relationship of LAR to subject Definition of consent capacity The nature of impairment in consent capacity Safeguards related to the identification of individuals with impaired consent capacity

24. RecommendationDescription/PurposeTypeCommentsStatus IDefines the term “consent capacity” and recommends its use GuidanceApproved by SACHRP IIDescribes the nature of impaired “consent capacity” as it pertains to research participation GuidanceApproved by SACHRP IIIDescribes safeguards related to the identification of individuals with impaired consent capacity GuidanceApproved by SACHRP IVClarifies the meaning and interpretation of LAR within Subpart A GuidanceAdditional safeguards will be provided by interim guidance on approval criteria described in recommendation VIII For preliminary presentation at the July 2008 SACHRP meeting VDefines the roles and responsibilities of the surrogate decision- maker/LAR GuidanceOutlined; for review at August SIIIDR meeting VIDefines the involvement of subjects in choice of surrogate, in consent, and in assent GuidanceServes to promote the autonomous involvement subjects with impaired capacity in research decision-making processes to the extent possible and consistent with their abilities and desires As above VIIDefines who may provide consent (the LAR) in the absence of “applicable law” Component of a new regulatory subpart to 45CFR46 Describes a hierarchy to guide institutions and IRBs on who may consent on behalf of a subject who lacks consent capacity. Will be linked to rules related to approval criteria described in recommendation VIII For preliminary presentation to SACHRP July, 2008 VIIIApproval CriteriaInterim Guidance/ a component of new regulatory subpart (?) This will serve as interim guidance (“additional safeguards”) related to review and approval of research under subpart A. It will be also be considered as a component of a new regulatory subpart Outlined, in progress. Concept for presentation at SACHRP, July 2008; For further development at August SIIIDR meeting IXRecommendation to HHSModel Legislation/Regul ation This proposal will develop and encourage the promotion of model state legislation/regulation Outlined

25. Recommendation VIII Part One: IRB Review Procedures IRB Membership and Reviewer Qualifications Subject Selection: the Decision to Include Subjects Who Lack Consent Capacity Part Two:Guidance on Risk-Benefit Analysis

26. Risks to subjects are reasonable in relation to anticipated benefits, if any, to subjects, and the importance of the knowledge that may reasonably be expected to result What is reasonable?

27. From the Belmont Report: Persons with diminished autonomy are entitled to protection. Some persons are in need of extensive protection, even to the point of excluding them from activities which may harm them; other persons require little protection beyond making sure they undertake activities freely and with awareness of possible adverse consequence.

28. Defining an approach Research risk, benefit, susceptibility to risk, and concept capacity each occur along a spectrum. A categorical approach to protection is would not be optimal. The introduction of categorical distinctions--which remain poorly defined, poorly understood and inconsistently applied—are less intuitive and may not enhance IRB review. Instead, protections can be tailored to the nature and proportional to the extent of impairment, the magnitude of the experimental risk, and a meaningful assessment of benefit. Absolute thresholds and second tier reviews may create insurmountable hurdles rather than genuine protections.

29. How do we define benefit? No prospect of direct benefitProspect of direct benefit Benefit

30. How do we define risk of harm? MinimalGreater than Minimal Minor Increment Increasing Risk

31. Fundamental Protections IRB review and informed consent represent two fundamental protections. The protections provided by consent do not relieve the IRB of its obligation to determine what is approvable, what is “reasonable.” Yet, these are not wholly independent considerations

32. What is reasonable? What is reasonable will depend on the subject’s susceptibility to risk and the subject’s ability to protect himself through the process of initial and ongoing consent. We also need to ask, are all LAR’s the same?

33. What is “reasonable” Protections afforded by IRB review should address the extent to which the subject is able to protect his or her own interests through the process of consent. Consent provided by an LAR will only, and to a varying degree approximate consent by the subject and may not provide equivalent protections. What is “reasonable” should reflect the degree of subject impairment and the non-equivalence of consent by the LAR

34. How much protection in IRB review? Paternalism/protectionism Autonomy Subject alone determines what is reasonable IRB alone determines what is reasonable With diminishing subject autonomy, an IRB may choose to “delegate” less of the risk-benefit consideration to the subject—effectively shifting the risk-benefit threshold.

35. Approvability as per subpart A Increasing Benefit Decreasing Risk Decreasing need for external protections Increasing Approvability No impairment Lacking consent capacity 2 different LARs