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THE COMMITTEE ON HUMAN RESEARCH

UCSF GUIDANCE ON RESEARCH TOPICS AND ISSUES

Vulnerable Subject Populations – Those with Cognitive Impairments

• Brief Overview
• Background
• Basic Principles
• Exclusion from Study or Use of Surrogate Consent
• Decisional Capacity Assessment for Research
    • No Single Set of Standards
    • When Explicit Assessment Is Necessary
    • Who Should Assess Capacity
    • Methods of Assessment
    • Decisional Capacity Assessment Flowchart
 • Subject Safeguards
    • Primary and Added Safeguards
    • Subject's Dissent
• Documentation Requirements
    • CHR Application
    • Subject's Research File
• Additional Useful Information
    • Indications of Potentially Diminished Capacity for Consent
    • Defining "Decisional Capacity"
    • Additional Methods of Assessing Capacity
 • Useful Links and References

Brief Overview

The CHR must exercise special care when considering subjects whose ability to give free and informed consent is compromised in any way.

Some studies propose to involve subjects whose capacity to make meaningful decisions is in question because they are "cognitively impaired.“ Such subjects may include mentally disabled persons, and those with diagnosed psychoses, Alzheimer's disease, or other cognitive disorders, permanent or temporary. Since many people with these conditions retain the capacity to consent to research, not allowing them to consent for themselves when able could compromise their rights.

Federal regulations, California state code, and UC policy indicate that research studies may involve subjects who have cognitive impairments, if adequate safeguards are in place. While it is agreed that persons signing valid research consent forms for themselves must have adequate decisional capacity, the relevant regulatory documents do not say how capacity should be determined.

The following presents CHR guidance for research involving subjects with cognitive impairments. In order to have such studies approved by the CHR, investigators must submit applications which satisfy relevant regulations and provide appropriate methods of safeguarding their subjects—especially assessment of decisional capacity—as outlined below.

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Background

Relevant regulations and policies: Federal regulations (45 CFR 46.111) direct the IRB to approve a study only if it determines that informed consent will be sought from each prospective subject (unless specific exceptions are justified), and that for “subjects…vulnerable to coercion or undue influence, such as …mentally disabled persons…[the study includes] additional safeguards.”

Effective January 1, 2003, California law (Health & Safety Code §24178) allows surrogate consent for certain research subjects with cognitive impairment “if (the) person is unable to consent.” The University of California provides related UCOP Guidance on Surrogate Consent for Research.

Additional Sources: These CHR guidelines are based on several sources, including UC San Diego's Decision-Making Capacity Guidelines (the work of UCSD’s Task Force for Recommending Procedures for Determination of Decisional Capacity in Subjects Participating in Research Protocols) and the UCSF Memory and Aging Center’s "Capacity to Consent" policies (see Useful Links and References).

Applicability: The following guidance is meant to apply not only to primary conditions of cognitive impairment such as dementia or psychosis, but also to conditions in which patients might reasonably be expected to have cognitive impairments as a consequence of severe pain, anxiety, or confusion, such as cancer, trauma, or life-threatening illness. Excluded are pediatric subjects and emergency research, since there are separate guidelines for these areas (see Minors in Research and Research in Emergency Settings). These guidelines are not meant to supersede more restrictive or specific local requirements or policies.

Basic Principles

The CHR will consider the following principles in reviewing research applications:

1. Studies involving subjects with cognitive impairment can only be approved if justified and appropriate additional safeguards are in place.



2. Studies should not arbitrarily exclude cognitively impaired subjects if they might be able to give informed, voluntary consent and there is a chance they could benefit from participation.



3. Higher risk studies need a higher level of safeguards.



4. The primary additional safeguard for this vulnerable subject population is assessment of decisional capacity.



5. If adequate decisional capacity is not found upon assessment, the investigator usually needs to either exclude the prospective subject from the study or seek surrogate consent for their participation.

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Exclusion from Study or Use of Surrogate Consent

A key choice in study design is whether to (1) exclude people who cannot consent for themselves or (2) include them with surrogate consent from the subject's legally authorized representative.

Exclusion from the study: Excluding those who do not show adequate capacity to consent is the first option, since it is generally considered preferable to do studies with those who can consent for themselves if possible.

Surrogate consent: Many studies cannot be done without including subjects who are unable to consent for themselves. In some studies, there is potential direct benefit to subjects, and it might be unethical to deny this possible benefit to those with impaired decisional capacity. In other studies, even with no direct benefits for subjects, the only practical way to answer scientific questions may be to enroll subjects without the capacity to consent for themselves. In such cases, surrogate consent may be sought, but only if this is justified in the protocol and conforms to state law and UCOP guidance on surrogate consent in research (see Surrogate Consent).

Other possible options: In limited circumstances, studies may be approved for waiver of all consent (see CHR Consent Guidelines - Waiver of All Consent, including Research in Emergency Settings). In planning a study involving those who have cognitive impairments, investigators should check this information for applicability.

Decisional Capacity Assessment for Research

No Single Set of Standards

No single set of standards for defining and implementing assessment of decisional capacity has received universal acceptance by experts in the field. A number of sources propose lists of standard elements that should be considered in making this type of assessment. There are also differing opinions as to who is most appropriate to administer such assessments, what instruments should be used, and how formal the assessment procedure should be.

At minimum, the CHR application should describe who will conduct the assessment, the method by which prospective subjects’ decisional capacity will be evaluated, and the criteria for identifying incapable subjects. Less formal procedures to assess potential subjects’ capacity—including, for example, the ways professionals often make judgments about capacity in routine interactions—may be permitted if a formal assessment is not feasible or necessary.

When Explicit Assessment of Decisional Capacity Is Necessary

• Studies intended to include cognitively impaired subjects
  • More than minimal risk: If a study involves more than “minimal risk” (as defined in 45 CFR 46.102), and target subjects can reasonably be expected to have diminished decision-making capacity, the CHR will generally require assessment of decisional capacity for all prospective subjects.
  
  
  
  • No more than minimal risk: Even in research involving only minimal risk, the CHR may still require such assessment if it believes that it is appropriate to safeguard the subjects’ welfare.
• Studies not intended to include cognitively impaired subjects
  • Presumption of capacity: All persons who have reached the age of majority (in California, 18 years old) are presumed to have capacity to give informed consent to research. In the absence of any indication to the contrary, such capacity can be assumed without further evaluation or documentation.
  
  
  
  • Indications of potentially diminished capacity: On the other hand, if there are indications of potentially diminished capacity in an individual subject, assessment of decisional ability may need to be done.

  Note: Potential subjects who are found to have diminished capacity must be excluded unless the CHR has approved the use of surrogate consent from legally authorized representatives for the study in question.

Who Should Assess Capacity

In general, the consent assessor should be a researcher or consultant familiar with dementias and qualified to assess and monitor capacity and consent in such subjects on an ongoing basis. The CHR will consider the qualifications of the proposed individual(s).

Methods of Assessment

Various methods of assessment may be acceptable for differing studies. In general, a greater capacity to consent and more rigorous methods of assessing capacity are needed in studies that have higher risks for subjects. If a study anticipates using surrogate consent from legally authorized representatives, the method of assessment must be specified in the Surrogate Consent Supplement.

• UCOP Guidance: In its Guidance on Surrogate Consent for Research, the University of California Office of the President offers the following advice:
  
  

  “While there are no standardized measures for determining capacity to consent, investigators may assess subjects on their abilities to understand and to express a reasoned choice concerning the:

  • Nature of the research and the information relevant to his/her participation;
  
  
  
  • Consequences of participation for the subject’s own situation, especially concerning the subject’s health condition; and
  
  
  
  • Consequences of the alternatives to participation.
    [Applebaum, PS and T. Grisso. “MacCAT-CR: MacArthur Competence Assessment Tool for Clinical Research. Professional Resource Press, 2001]”



• Other Forms and Instruments:
  • The UCSF Memory & Aging Center’s policy and procedure on Capacity to Consent and “Capacity Assessment Record for Research Informed Consent (CAR)” (copyright Daniel Marson) are very detailed and clear.
  
  
  
  • A standardized, validated instrument that can be tailored to the specific study may be used, such as The MacArthur Competence Assessment Tool – Clinical Research (MacCAT-CR) (see reference in section directly above).
  
  
  
  • A post-consent quiz documenting the subjects’ knowledge of critical elements in the consent form may be used (see linked samples at end of UC San Diego's Decision-Making Capacity Guidelines).
  
  
  
  • Study investigators may develop alternative procedures for evaluating decision-making capacity.



• Also see Additional Methods of Assessing Capacity below.

Decisional Capacity Assessment Flowchart

For a graphical presentation of actions appropriate to studies proposing to involve those with cognitive impairments, see Decisional Capacity Assessment Flowchart (adapted from UCSD's "Decision-Making Capacity Guidelines").

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Subject Safeguards

Primary and added safeguards: As noted above, the CHR considers decisional capacity assessment the primary safeguard for prospective subjects with cognitive impairments. Depending on the protocol and the level of risk involved, the CHR may require additional safeguards, including use of an independent monitor; special informational or educational techniques; use of waiting periods to decide about participation; and/or assent in addition to surrogate permission for subjects who do not have decisional capacity to consent for themselves.

Subject’s dissent: The prospective subject's objection or resistance to participation in any way, at any time, must be taken as a refusal or withdrawal and be honored immediately. Adult subjects may refuse to enter a study and may withdraw at any time, even if a surrogate consenter or the study doctor disagrees with the decision.

Documentation Requirements

CHR Application

The protocol and consent form should present information on rationale, risk level, decisional capacity assessment procedures, etc., as discussed above. If a standardized decisional capacity instrument is to be used, a copy of the instrument tailored to the specific protocol should be included. Likewise, copies of any other instruments to be used (e.g., post-test questionnaire, form or method developed by the investigator) should be included.

Subjects’ research files

The decision-making capacity determination should be documented in each participant’s research file by saving copies of all completed instruments/forms for that individual, as well as other relevant documents used in the process (including, of course, any consent forms).

Additional Useful Information

Indications of Potentially Diminished Capacity for Consent

The following are usually considered indications of potentially diminished capacity, although many individuals with these conditions may have sufficient capacity to consent:

• a diagnosis of dementia or cognitive impairment;



• presenting for an evaluation of dementia or cognitive impairment;



• a report, in medical records or from a family member or person well acquainted with the subject, that the subject has symptoms of dementia or cognitive impairment;



• psychotic symptoms, bizarre or abnormal behavior exhibited by the individual;



• an abnormal degree of confusion, forgetfulness, or difficulties in communication that is observed in the course of interacting with the individual.

Defining "Decisional Capacity"

This term refers to a potential participant’s ability to make a meaningful decision about whether or not to participate in a study.

• "Decisional capacity" in the research context has been interpreted by the American Psychiatric Association as including the following elements
  1. Ability to understand relevant information;
  
  
  
  2. Ability to appreciate the situation and its likely consequences;
  
  
  
  3. Ability to manipulate information rationally [i.e., to reason]; and
  
  
  
  4. Ability to evidence a choice.

Other sources, e.g., UCSD's "Decision-Making Capacity Guidelines" and the UCSF Memory and Aging Center’s "Capacity to Consent" policies, offer variations of the above list.

• “Decisional Capacity” versus “Competence”: “Decisional capacity” should not be confused with the concept of “competence.” Incompetence is a legal determination made by a court of law. However, someone who was judged legally incompetent to handle their own financial affairs might still retain sufficient decision-making capacity to make a meaningful choice about taking part in a particular study. As well, a person with normal cognitive functioning (i.e., legally competent) might be put into circumstances where their decision-making capacity is temporarily impaired by severe pain or overwhelming anxiety.



• Decisional capacity is protocol-specific and situation-specific. Thus a subject may have capacity to consent to a low-risk research protocol in usual circumstances, but not have the capacity to consent to a high-risk protocol or when under duress.

Additional Methods of Assessing Capacity

Assessment standards and instruments: The potential research subject may be evaluated on the four elements or standards for decisional capacity listed above (or others if proposed and approved by the CHR). The individual’s capacity to understand all of these concepts may not be necessary in order to consent to participate in a particular research protocol—greater capacity is required for higher risk protocols. One or more of the decisional capacity assessment forms or instruments discussed above may be used

Review of consent documents with the subject: The assessor may review the CHR-approved consent form with the prospective subject in the normal manner used to obtain consent. A simplified study summary may be used as an aid to emphasize/remind subjects of major points.

Capacity assessment: The assessor can ask the prospective subject to explain the main elements of this study and indicate a decision about taking part or not. The prospective subject may use a simplified study summary to answer the questions. Based on these responses, and whether the decision to participate or not appears to be a rational choice reflecting an appreciation of the facts, the assessor can then make a final determination about capacity for consent.

Sample questions to assess consent capacity: These questions pick up at the point that consent form review has been completed. They are examples only; the CHR recognizes that clinical judgment remains the best guide for what to ask.

• Are we offering you your usual medical care, or asking you to be in a research study?



• Do you have to take part in this study, or is it OK to say “no”?



• What is the purpose of this study?



• Tell me the main things that would happen to you in this study. ? Tell me the main risks to you of being in this study.



• Will this study mainly help you or others?



• If you want to drop out of the study, when can you do this?



• Considering the risks and benefits we’ve discussed, what have you decided about taking part in this study?

Educational procedures: For subjects scoring less than perfect on the initial presentation, educational procedures may be employed to raise understanding to sufficient levels for them to make a meaningful choice about participating. Potential measures include repetitive teaching, group sessions, and audiovisual presentations.
For examples of educational procedures and quizzes, see Carpenter et al. (Arch Gen Psychiatry, 2000; 57:533-538), Dunn and Jeste (Neuropsychopharmacology, 2001; 24:595-607), Dunn et al. (Am J Psychiatry, 2001; 18: 1911-1913), Dunn et al. (Am J Geriatric Psychiatry, 2002 Mar-Apr; 10(2):207-11), Wirshing et al. (Am J Psychiatry, 1998; 155:1508-1511).

Useful Links and References

U.S. Department of Health and Human Services (DHHS), Code of Federal Regulations, Title 45 Public Welfare, DHHS, NIH, Office for Protection from Research Risks, Part 46, Protection of Human Subjects http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm, especially Section 46.111.

Food and Drug Administration (FDA), Department of Health and Human Services, Part 50 – Protection of Human Subjects (21 CFR 50). http://www.access.gpo.gov/nara/cfr/waisidx_98/21cfr50_98.html.

Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research. http://www.hhs.gov/ohrp/humansubjects/guidance/belmont.htm

UC San Diego's Decision-Making Capacity Guidelines

UCSF Memory and Aging Center's "Capacity to Consent" policies and form (not available online).