1. Determining capacity and protecting subjects who have lost capacity Jason Karlawish, MD University of Pennsylvania

2. The problem Proxy decision whether to enroll their relative who lived in a nursing home in research that presented no direct benefit. –60% of the proxies who declined to allow their relative to participate in the study reported an important reason was their reluctance to decide for the patient. Warren. NEJM. 1986.

3. The problem Proxy decision whether to enroll their relative who lived in a nursing home in research that presented no direct benefit. –One-third (17/55) enrolled their relative even though they thought their relative would not want to enroll. Warren. NEJM. 1986.

4. Issues to discuss How do we know someone cannot provide informed consent? Do people agree with proxy consent? Who, ethically, should be the proxy? How should the proxy make the decision?

5. Core concepts The decision making abilities: choice, understanding, appreciation, reasoningThe decision making abilities: choice, understanding, appreciation, reasoning Capacity and competencyCapacity and competency –Capacity is the continuum of decision making abilities –“Being competent” or “having adequate capacity” is a judgment of a person’s decision making abilities Assessments of capacity are used to make judgments of competencyAssessments of capacity are used to make judgments of competency

6. Comparison of AD patient and caregiver performance on ability to express a choice AD patients (N = 59)*Caregivers (N = 60) Ability to Express a Choice 1.9+0.32.0+0.0 255 (93%)60 (100%) 13 (5%)0 (0%) 01 (3%)0 (0%) Very mild 31% (N =18) * Very mild 31% (N =18) Mild 32% (N =19) Mild 32% (N =19) Moderate 37% (N =22) Moderate 37% (N =22)

7. Comparison of AD patient and caregiver performance on ability to reason AD patients (N = 59)*Caregivers (N = 60) Ability to Reason5.9+1.87.7+0.6 7-827 (46%)55 (92%) 5-622 (37%)5 (8%) 0-310 (17%)0 (0%) Very mild 31% (N =18) * Very mild 31% (N =18) Mild 32% (N =19) Mild 32% (N =19) Moderate 37% (N =22) Moderate 37% (N =22)

8. Comparison of AD patient and caregiver performance on ability to understand AD patients (N = 59)*Caregivers (N = 60) Ability to Understand 17.3+6.625.4+1.1 25-269 (15%)51 (85%) 23-246 (10%)7 (12%) 21-2210 (17%)2 (3%) 13-2021 (35%)0 (0%) 0-1213 (22%)0 (0%) Very mild 31% (N =18) * Very mild 31% (N =18) Mild 32% (N =19) Mild 32% (N =19) Moderate 37% (N =22) Moderate 37% (N =22)

9. Comparison of AD patient and caregiver performance on ability to appreciate AD patients (N = 59)*Caregivers (N = 60) Ability to Appreciate 3.4+2.05.6+0.8 5-617 (29%)54 (90%) 3-421 (36%)5 (8%) 1-215 (25%)1 (2%) 06 (10%)0 (0%) Very mild 31% (N =18) * Very mild 31% (N =18) Mild 32% (N =19) Mild 32% (N =19) Moderate 37% (N =22) Moderate 37% (N =22)

10. Summary points Have some reasonable way to assess decision making ability –a quiz, a questionnaire –especially the ability to understand “Can you tell me in your own words, what are the [factual element under assessment] of this study?” –select key facts you think a person needs to understand –the rigor and detail of this assessment should be proportionate to the risks of the research

11. Issues to discuss How do we know someone cannot provide informed consent? Do people agree with proxy consent? Who, ethically, should be the proxy? How should the proxy make the decision?

12. Preferences for proxy decisionmaking Survey of 226 persons with a family history of Alzheimers disease –the vast majority willing to execute a RAD, but when offered the opportunity to execute one few did (~10%) Interviews with 538 older adults about their preferences for research advance planning –all but 20 (4%) willing to have a proxy National population weighted survey of 1,515 older adults found general support for proxy consent for research that involves persons with AD. Wendler et al. Am J Psych. 2002. Karlawish et al. Am J Psych. 2008. Kim et al. Neurology. 2009.

13. Issues to discuss How do we know someone cannot provide informed consent? Do people agree with proxy consent? Who, ethically, should be the proxy? How should the proxy make the decision?

14. Who should be the proxy – people who share the risks and benefits “What do you see as the study’s benefits for you?” Having a husband that won’t get any worse, that’s a benefit to me because right now, I don’t know what my future is, you know, if he gets any worse. Anything that I feel could help him, I’m willing to do [A453, ll. 537-40]. The better condition of my wife is a benefit to me. That’s all. The improvement in any way that we would have – it would affect our entire lives [A531, ll. 767-8]. What do you see as the study’s risks to you? The study’s risks to me are that it might exacerbate my mother’s stress levels and make it more difficult for me and my Dad to maintain her care [C137, ll. 550-51]. Karlawish et al. Neurology. 2001.

15. Issues to discuss How should the proxy make the decision?

16. LP Willingness to Participate Advance Consent ProxyNo ProxyTotal No LeewayLeeway No115 (21.4%) 145 (27.0%) 19 (3.5%) 279 (51.9%) Yes27 (5.0%) 230 (42.7%) 2 (0.4%) 259 (48.1%) Total142 (26.4%) 375 (69.7%) 21 (3.9%) 538 (100%) Karlawish et al. Am J Psych. 2009

17. How would study partner make decision for patient if patient could not choose? n (%) Choose what patient, if competent, would decide 14 (24%) Choose what will maximize patient’s well-being. 35 (59%) Other10 (17%) Can’t answer1 (0%) Total60 Karlawish et al. Am J Psych. 2008.

18. Summary points Designating a proxy (study partner) is potentially useful within a protocol where loss of capacity is anticipated

19. Summary points As the risks and hassles of the research increase or the subject population becomes more vulnerable (not able to provide informed consent) the proxy/study partner needs to be someone who fulfills roles you specify in the protocol –decisionmaker for the patient, assists with activities of daily living, reports on disease progression and response to therapies –is available during the study Document that the proxy knows they are a proxy –watch the law -- “family” hierarchy rules

20. Summary points A requirement for a substituted judgment should focus on not simply the “yes” or “no” choice for enrollment, but the factors that subjects say should guide decisionmaking –risk, trust (in science, in person), benefit

21. Contact Information Jason Karlawish, MD University of Pennsylvania 3615 Chestnut Street Philadelphia, PA 19104 Jason.karlawish@uphs.upenn.edu

22. References Review of capacity assessment Appelbaum P. Assessment of patients’ competence to consent to treatment. N Engl J Med. 357(18); 2007:1834. Review of assent/dissent and suggested steps to operationalize it Black B.S. et al. Seeking assent and respecting dissent in dementia research. Am J Geriatric Psych. 18;2010:77-85.

23. Why do people enroll? You just get involved in something and you go for it. You don’t separate one thing from the other in minute detail and say well I like this but I don’t like that, or this is an invasion of privacy but this isn’t. We don’t care. What we’re just looking for is the answer to our prayers, that’s all [C064, lines 741-748]. Karlawish et al. Neurology. 2001.

24. Why do people enroll? Essentially, I'm going in based on if [principal investigator] is in it, and the clinic is in it, and other people at the university and other patients at the university are in it, then it looks like a pretty good bet [A883, lines 655-57]. Karlawish et al. Neurology. 2001.