Research involving cognitively impaired persons

1. Research involving cognitively impaired persons Chin Jing Jih Adjunct Assoicate Professor, NUS Centre for Biomedical Ethics Programme Director, NHG Research Quality Assurance Deputy Co-Chair, NHG Research Ethics Committee

2. Outline • Definition of cognitive impairment • Recruitment into clinical research – guidelines with respect to justifications, methodology, subject selection, limiting risks • Challenges with consent process

3. “Cognitively impaired”: definition (NHG-DSRB-C16) Having either • a psychiatric disorder (e.g. psychosis,neurosis, personality or behavior disorders) • an organic impairment (e.g. dementia) • or a development disorder (e.g. mental retardation) that affects cognitive oremotional functions to the extent that capacity for rational judgement and reasoning issignificantly diminished. Others: • persons under the influence of ordependant on drugs or alcohol • those suffering from degenerative diseases affectingthe brain, • terminally ill patients • persons with severely disabling physicalhandicaps may also be compromised in their ability to make decisions in their bestinterests.

4. Cognitive impairment :Varying degrees of cognitive impairment A continuous spectrum:very mild  mild moderate severe Different degrees of functional impairments: • Comprehension • Appreciation of significance and relevance to self • Reasoning • Expressing a choice

5. Understanding of informed consent by demented individuals • Subjects (250 demented + 165 nondemented) assessed for their understanding of elements of informed consent in a longitudinal (nontreatment) study of healthy aging and dementia • Perfromance varied with dementia severity % with scores  8/10 in: nondemented 100% very mild (CDR 0.5) dementia 100% mild dementia (CDR 1.0) 92% moderate demtia (CDR 2.0) 67% Bucles VD et al. Neurology 2003;61:1662-1666

6. Decision making capacity Persons with a medical condition that can potentially affect cognition ≠ cognitive impairment ≠ decisonal impairment ≠ legal incompetence

7. Vulnerability – susceptible to harm • “those who are relatively (or absolutely incapable of protecting their own interests.” (Levine, 1986 p.72) • Harm – social, economic, legal, psychological, and physical (Belmont Report) • extra protection  ethical principles, institutional policies, laws and regulations

8. Policies, Guidelines and Regulations • Medicines Act – Medicines (Clinical Trial Regulations) • ICH GCP and SCGCP • NHG DSRB SOP: • NHG DSRB C16: cognitively impaired persons • US OHRP Guidelines

9. Research recruiting cognitively impaired subjects permissible only if: • “…the research is necessary to promote the health of the population represented and this research cannot instead be performed on legally competent persons.” • “…the physical/mental condition that prevents obtaining informed consent is a necessary characteristic of the research population.” Declaration of Helsinki

10. “… should not approve research protocols targeting persons with mental disorders as subjects when such research can be done with other subjects.” (NBAC Report & Recommendations: Research involving persons with mental disorders that may affect decisionmaking capacity, 1998) • “…the research could not be carried out equally well with less vulnerable subjects…intended to obtain knowledge that will lead to improved diagnosis, prevention or treatment of diseases or other health problems characteristic of, or unique to, the vulnerable class – either the actual subjects or other similarly situated members of the vulnerable class” (CIOMS International Ethical Guidelines for Biomedical Research Involving Human Subjects ,2002)

11. Research involving persons with mental disorders that may affect decisionmaking capacityReport and Recommendations of the National Bioethics Advisory Commission (1998) Recommendation 8: • For research protocols that present greater than minimal risk, an IRB should require that an independent, qualified professional assess the potential subject’s capacity to consent. • An IRB should permit investigators to use less formal procedures to assess potential subjects’ capacity if there are good reasons for doing so.

12. Anatomy of informed decision-making disclosure of (material) information [ by researcher ] adequate information  capacity comprehension voluntarism Consent = authorisation [by subject]

13. Vulnerability in research subjects can be created by any factor which: • Impedes access / reception of relevant information • Impedes communication of adequate information • Impair subject’s capacity to comprehend information provided • Affects the voluntarism of research subjects

14. Belmont Report Increased scrutiny for vulnerable individuals is from the basic premises of the Belmont Report : • Respect for persons: two basic ethical convictions: • individuals should be treated as autonomous agents, • persons with diminished autonomy and thus in need or protection are entitled to such protections.”National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research • Justice: • distribution of scarce benefits fits with distribution of burden – fair sharing of burdens (risks) and benefits

15. Legally Acceptable Representative Medicines (Clinical Trial) Regulations ‘Legal representative’ = An individual or judicial or other body authorised under the law to consent on behalf of that person to his participation in the clinical trial ICH –GCP guidelines: An individual or juridical or other body authorized under applicable law to consent, on behalf of a prospective subject, to the subject's participation in the clinical trial.

16. Conditions for waiver of consent for subject who is unconscious or incapable of rational judgement Medicines (Clinical Trial) Regulations ss 11(3) • PI and a doctor who is not otherwise participating in the clinical trial certify in writing that: • That person is unconscious or incapable of exercising rational judgement: and • It is not likely that that person will regain consciousness and be capable of exercising rational judgement within the window period • Consent thereto has been obtained from (i) The person’s spouse, parent, guardian and any other person having charge of him

17. Conditions for waiver of consent for subject who is unconscious or incapable of rational judgement Medicines (Clinical Trial) Regulations ss 11(3) (b) consent has been obtained from – (i) that person’s spouse, parent, guardian (if there is no parent) or anyother person having charge of him; and (ii) if different from (i) above, that person’s legal representative; and (c) there is a reasonable prospect that participation in the clinical trial willdirectly benefit that person • NHG-DSRB-C16 lists anadditional condition: the trial cannot be practicably carried out in subjects who can give their own consent

18. Minimal Risk: • A risk is minimal where the probability and magnitude of harm or discomfort anticipated in the proposed research are not greater, in and of themselves, than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests. • For example, the risk of drawing a small amount of blood from a healthy individual for research purposes is no greater than the risk of doing so as part of routine physical examination.

19. Degree of Risk (NHG-DSRB-C16) • Research that presents more than minimal risk should involve cognitively impaired persons only when the research holds prospects of direct benefit to these individuals. • A minor increase over minimal risk may be permitted in research involving institutionalized individuals only where research is designed to evaluate an intervention of foreseeable benefit to their care. • If a research study poses more than minimal risk and no prospect of direct benefit to the individuals, the DSRB should obtain advice from experts regarding the appropriateness of the research study.

20. Selection of Subjects (NHG-DSRB-C16) • Research involving persons whose autonomy is compromised by disability or restraints on their personal freedom should bear some direct relationship to their condition or circumstances. • Persons who are institutionalized should not be chosen for studies that bear no relation to their situation just because it would be convenient for the researcher.

21. Subject selection and limiting risks (NHG-DSRB-C16) • Appropriate psychological or medical screening criteria to prevent orreduce adverse reactions to the therapeutic and research procedures. • IRB might require other health care providers involved in the careof these patients to be consulted to ensure that the research will not be detrimentalto ongoing therapeutic regimens.

22. CONSENT ISSUESIN RESEARCH INVOLVING COGNITIVELY IMPARIED PERSONS • Informed consent is required unless waived under the applicable criteria. • For research that poses no more than minimal risk, family members of cognitively impaired persons may consent to research.

23. For non therapeutic trials (i.e. a trial in which there is no anticipated direct clinical benefit to the subject): NHG-DSRB-C16 The trial may be conducted with the consent of a legallyacceptable representative provided that the following conditions are fulfilled: a. The objectives of the trial cannot be met by means of a trial in subjectswho can give informed consent personally b. The foreseeable risks to the subjects are low

24. For non therapeutic trials (i.e. a trial in which there is no anticipated direct clinical benefit to the subject): NHG-DSRB-C16 c. The negative impact on the subjects well-being is minimized and low d. The trial is not prohibited by law e. Approval is expressly sought on the inclusion ofsuch subjects, and the written approval covers this aspect f. PI has made provisions in the study so that thesubjects are closely monitored and are withdrawn if they appear to beunduly distressed.

25. 2-components model of risk assessment  limits on kind of research proxy can accept on behalf of decisionally impaired subjectKarlawish JHT (N Engl J Med 2003;348:1389-1392) Two components of research: • Interventions  risks and potential benefits for subjects  permissible if benefit > risk • Interventions  risks but NO potential benefits for the subjects  permissible if justified by minimal risks+importance of knowledge anticipated

26. Enhancing capacity during informed consent process • Elements of informed consent of a particular study • Extra exposure at initial visit • periodic review at subsequent visits • Videotapes, photographs, Power-point presentations • Breaking down information into more easily understood components • Language and manner of communication • Involvement of family member or friend • Subject education

27. Informed consent: timing (1) Depending on underlying cause, cognitive impairment may have variable courses: • Fluctuating vs stable vs progressive • Transient vs long term • Reversible vs irreversible / permanent And severity of cognitive impairment varies: • Very mild cognitive impairment • Mild cognitive impairment • Moderate cognitive impairment • Severe cognitive impairment, e.g. advanced dementia

28. Informed consent: timing (2) Informed consent – a continuous, ongoing process. Cognitive impairment – may fluctuate or worsen progressively with time. • If progression of cognitive impairment is anticipated  prospective authorisation for later stages of study • Consent process repeated at subsequent parts of research, especially when there is an amendment involving risk-benefit ratio  Decision making capacity reassessed with respect to new information or new decline in cognition

29. Role of independent monitors? • Monitor consent for research that involves greater than a minor increment over minimal risk and is not clinically equivalent; • Monitor participation for risky research

30. Important to remember: • As a general principle, incapable persons should not be involved inresearch that can be conducted with capable subjects. • Inclusion of cognitivelyimpaired persons may be permitted if such aresearch provided access to an important benefit, particularly one that is nototherwise available outside of the research setting.

31. A delicate balancing act • History of maltreatment of vulnerable persons + Potential social disadvantages and vulnerabilities  Extra protection Versus • Careful inclusion of some of these groups in research so that they can benefit from knowledge gained through each research

32. DISCUSSION