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