research involving cognitively impaired persons chin jing jih adjunct assoicate professor, nus...
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Research involving cognitively impaired persons
Chin Jing JihAdjunct Assoicate Professor, NUS Centre for Biomedical Ethics
Programme Director, NHG Research Quality AssuranceDeputy Co-Chair, NHG Research Ethics Committee
Outline
• Definition of cognitive impairment
• Recruitment into clinical research – guidelines with respect to justifications, methodology, subject selection, limiting risks
• Challenges with consent process
“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 or emotional functions to the extent that capacity
for rational judgement and reasoning is significantly diminished.
Others:
• persons under the influence of or dependant on drugs or alcohol
• those suffering from degenerative diseases affecting the brain,
• terminally ill patients
• persons with severely disabling physical handicaps
may also be compromised in their ability to make decisions in their best interests.
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
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
Decision making capacity
Persons with a medical condition that can potentially affect cognition
≠ cognitive impairment
≠decisonal impairment
≠legal incompetence
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
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
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
• “… 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)
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.
Anatomy of informed decision-making
disclosure of (material) information[ by researcher ]
capacity
comprehension
voluntarism
Consent = authorisation [by subject]
adequate information
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
Belmont ReportIncreased 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
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.
Conditions for waiver of consent for subject who is unconscious or incapable of rational judgement
Medicines (Clinical Trial) Regulations ss 11(3)
(a) PI and a doctor who is not otherwise participating in the clinical trial certify in writing that:
(i) That person is unconscious or incapable of exercising rational judgement: and
(ii) It is not likely that that person will regain consciousness and be capable of exercising rational judgement within the window period
(b) Consent thereto has been obtained from(i) The person’s spouse, parent, guardian and any other
person having charge of him
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 any other 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 will directly benefit that person
• NHG-DSRB-C16 lists an additional condition:
the trial cannot be practicably carried out in subjects who can give their own consent
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.
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.
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.
Subject selection and limiting risks (NHG-DSRB-C16)
• Appropriate psychological or medical screening
criteria to prevent or reduce adverse reactions to
the therapeutic and research procedures.
• IRB might require other health care providers
involved in the care of these patients to be
consulted to ensure that the research will not be
detrimental to ongoing therapeutic regimens.
CONSENT ISSUES IN 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.
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 legally acceptable representative provided that the following conditions are fulfilled:
a. The objectives of the trial cannot be met by means of a trial in subjects who can give informed consent personally
b. The foreseeable risks to the subjects are low
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 of such subjects, and the written approval covers this aspect
f. PI has made provisions in the study so that the subjects are closely monitored and are withdrawn if they appear to be unduly distressed.
2-components model of risk assessment limits on kind of
research proxy can accept on behalf of decisionally impaired subject
Karlawish JHT (N Engl J Med 2003;348:1389-1392)
Two components of research:
1. Interventions risks and potential benefits for subjects
permissible if benefit > risk
2. Interventions risks but NO potential benefits for the subjects permissible if justified by minimal risks + importance of knowledge anticipated
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
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
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
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
Important to remember:
• As a general principle, incapable persons
should not be involved in research that can be
conducted with capable subjects.
• Inclusion of cognitively impaired persons may
be permitted if such a research provided
access to an important benefit, particularly
one that is not otherwise available outside of
the research setting.
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
DISCUSSION