1. Copyright © 2009 AAHRPP ® All rights reserved Accreditation for your Human Research Protection Program David H. Strauss, M.D. NYS Psychiatric Institute, and Department of Psychiatry, Columbia University Including Subjects with Impaired Decision-making Abilities: IRB Considerations Columbia University April 20, 2010

2. Acknowledgement/Disclosure Some of the material discussed draws upon collaborative work by members of SACHRP’s Subcommittee on the Inclusion of Individuals with Impaired Decision-making. It is not presented as a product of that subcommittee or SACHRP and I am not here in my role or as a representative of those groups.

3. Introduction o When subjects are unable to participate fully in the consent process, the protections ordinarily provided by consent are not available to them. o A consent decision made by a surrogate on behalf of an impaired subject is not always ethically equivalent to a decision made by a capable subject for himself. o Vulnerability to undue influence and susceptibility to risk for these subjects extend beyond the point of study enrollment; a great responsibility falls on the IRB to protect. o The current framework of regulations and guidance require “additional safeguards,” but provide little if any direction to IRBs.

4. IRB Responsibilities o Understanding impaired decision-making o Determining the appropriate level of review o Approving the inclusion of impaired subjects o Requiring assessment of consent capacity o Supporting autonomy/self-determination o Defining the LAR, subject advocate and their roles o Analyzing risk and benefit o Consent by surrogates on behalf of impaired subjects is not fully equivalent. o Further, the vulnerabilities and susceptibilities of these subjects extend beyond the point of study enrollment; a great responsibility falls on the IRB to protect. o The current framework of regulations and guidance require “additional safeguards,” but provide little if any direction to IRBs.

5. Consent Capacity …the specific abilities necessary for a prospective research participant to understand and use information relevant to the consent decision (and to ongoing participation?). o Impairment occurs in a wide range of conditions and disease states; o It is best understood as occurring along a continuum; o It is task-specific; o It is not a static phenomenon.

6. Dimensions of Decisional Impairment o Situational vs. disorder-related impairment o Delivery room vs. head injury o Global vs. specific impairment o Sedation (intensive care) vs. paranoid delusions o Static vs. progressive vs. episodic vs. time limited impairment o Mental retardation vs. Alzheimer’s vs. manic-depressive illness vs. traumatic brain injury o Adult onset vs. persistent and lifelong impairment o Stroke vs. mental retardation o Cognitive vs. social/interpersonal impairment o Alzheimer’s vs. autism spectrum

7. Level of Review o The process of identifying and minimizing risk requires reviewer expertise and knowledge of the context of the research. o A study may include individuals who lack consent capacity and still be eligible for expedited review. o But, the unique circumstances and susceptibilities of the proposed research participants have to figure into a determination that a study is minimal risk. o Convened review should involve at least one member or consultant knowledgeable about and experienced in working with the population.

8. Subject Selection o Remember the past o Participant availability, ease of recruitment, and study cost should never alone justify the inclusion of individuals who lack consent capacity. o Instead, consider whether the scientific questions can be answered in those who have capacity to consent. o In general, study “less burdened” groups first.

9. Subject Selection (Cont’d) Ask: Is inclusion ethically appropriate and scientifically necessary? Does the research: o seek to improve the understanding, diagnosis, prevention or treatment of the disorders or conditions that are the cause of the incapacity? o study related conditions, phenomena, or circumstances that affect the research participants? o offer unique therapeutic or other benefits to the individual participant?

10. Assessing Capacity o Local policy should require investigators to consider/attend to each subject’s consent capacity in all research. o Researchers should be appropriately qualified and trained; o Formal methods can be used to support or supplement the assessment of consent capacity. o The choice of the method must be informed by the characteristics of the population and setting. o Safeguards might be necessary at specific time points in the study or throughout the study.

11. Assessing Capacity o More intensive approaches involve burdens for participants and researchers. Use when: o impairment is more likely to be present or uncertain, o anticipated benefits are fewer, and o foreseeable risks are greater. o When changes in participants’ consent capacity are anticipated reassessment of consent capacity should be considered.

12. Enhancement/Accommodation o Consent enhancements may enable some individuals who otherwise lack consent capacity to make capable decisions. o Common-sense approaches: o involve individuals trusted by the prospective research participant during the consent process, o allow additional time for decision-making, o Approve consent materials that support rather than hinder understanding o When impairments in consent capacity may be amenable to intervention which may improve or enhance decision-making, such efforts should be undertaken.

13. Supporting Self-determination o Individuals should be informed that o their capacity has been judged to be impaired o consent for research by an LAR is being considered. o Encourage involvement o in the decision to appoint an LAR o In expressing opinions with regard to participation o Seek assent initially and repeatedly, as needed o Define what constitutes “dissent” or unwillingness to take part

14. Choice of LAR For consideration by the IRB/investigator: o The process by which LARs will be identified and selected o The ability and willingness of the LAR to fulfill the required duties o The potential for financial or other conflicts of interest o Unwanted effects of study compensation and other financial incentives

15. Not all LARs are Equal o May have little or no experience in the required role and o Will vary in degree of kinship or familiarity with prospective participants o May or may not know the subjects wishes with regard to research participation. o May be appointed in advance by individuals to consent to research on their behalf with varying authority, instructions, etc. o May themselves evidence compromised ability to make a research decision.

16. Defining a role for the LAR o Observing the assent of the research participant o Monitoring participant well-being, and o Consider when formal re-consent by LARs in a longitudinal study is a necessary safeguard. o LARs should receive information about the research participant’s status and “important new information” o Consider involving subject advocates

17. Defining a role for the LAR (cont’d) For review/consideration by the IRB: o The expectations, obligations and authority of LARs in a particular study o Methods used to assist LARs in understanding their roles. o Guidance as to the basis (or standards) upon which LAR consent decisions are to be made.

18. Risk Benefit Considerations What is “reasonable” requires a careful analysis by the IRB of several continuous variables o What is the nature and extent of risk? o Does it offer a prospect of benefit available only in the research? o How does treatment depart from standard care? o Will it yield knowledge of benefit to the group? o To what extent can consent by an LAR be considered equivalent to that of the research participants?

19. LARs and the Approval Process o An IRB may specify that only certain categories of surrogates may provide consent for certain types of research. o An IRB may require investigators and/or independent monitors to assess the ability of LARs to perform necessary duties. o An IRB may require that LARs be educated as to their roles. o An IRB may choose to limit or prohibit consent for certain categories of research by institutional authorities.

20. Flexible Threshold for Reasonable Risk Paternalism/protectionism Autonomy Subject alone determines what is reasonable Subject alone determines what is reasonable IRB 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. 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.

21. Acceptable Risk o IRBs will ordinarily establish a lower threshold for acceptable risk in studies in which consent is provided by an LAR. o Standards for upper limits of allowable risk should be developed and applied. o 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. o Research involving significant risk and little unique benefit for subjects requires special attention in review.