# Presentation: 331448

## Research with Vulnerable Populations

- Marisue Cody, PhD, RN
- IRB Chair Training
- Washington DC, April 9, 2004

## Objectives

- Criteria for permissible research
- Levels of risk justified
- Capacity assessment
- Surrogate decision-making and consent

## Subject vulnerability

- “when some or all of the subjects are likely to be vulnerable to coercion or undue influence,...additional safeguards must be included in the study to protect the rights and welfare of these subjects.”

- 45 CFR 46.111(b)

## Diminished autonomy

- Mental capacity—ability to understand and process information
- Voluntariness—freedom from the control or influence of others

## Examples of vulnerable subjects

- Children, prisoners, pregnant women
- Handicapped, or mentally disabled persons, or economically or educationally disadvantaged persons
- Students, employees, members of the armed forces
- Patients with incurable diseases, persons in nursing homes, patients in emergency situations

## What are they vulnerable to?

- Physical control
- Coercion
- Undue influence
- Manipulation

**Notes:**
Physical control—lack of voluntariness
Coercion—credible threat of harm or force to control another person
Undue influence—misuse of a position of confidence or power to lead a person to make a decision he would not have otherwise made
Manipulation—deliberate management of conditions or information to lead another to a decision he would not have otherwise made

## Impaired decision-making capacity

- VHA Handbook 1200.5
- Appendix D

## If subjects with psychiatric disorders, dementia, and other mental impairments were excluded from studies, persons with these conditions would be deprived of the improved health care research can produce.

- Dresser R. Mentally disabled research subjects: The enduring policy issues. *JAMA 1996; 276: 67-72.*

**Notes:**
Thus, the ethical challenge is to devise policies that permit promising research to continue, while protecting the rights and welfare of persons participating in such studies.
This is particularly true in the VA, which is the largest provider of mental health services in the country AND has an aging population more likely to be affected by AD.

## When can research be done?

- They comprise the only appropriate study population
- The research question focuses on an issue unique to subjects in this population

**Notes:**
1200.5 Appendix D 6c(1)
Only incompetent persons or persons with impaired decision making capacity are suitable as research subjects. Competent persons are not suitable for the proposed research. The investigator must demonstrate to the IRB that there is a compelling reason to include incompetent individuals or persons with impaired decision-making capacity as subjects. Incompetent persons or persons with impaired decision-making capacity must not be subjects in research simply because they are readily available.

## Degree of risk

- Minimal risk
- “Minor over minimal”
- Acceptable risk-knowledge ratio
- “Maximal potential risk”

**Notes:**
1200.5 Appendix D 6c(2)
The proposed research entails no significant risks, tangible or intangible, or if the research presents some probability of harm, there must be at least a greater probability of direct benefit to the participant. Incompetent people or persons with impaired decision-making capacity are not to be subjects of research that imposes a risk of injury, unless that research is intended to benefit that subject and the probability of benefit is greater than the probability of harm.

## Acceptable risk?

- Initial trials of a new drug for AD:
-  63% stops the progress of the disease
- ~50% it even produces some restoration of cognitive capacity
- 20% -- no effect.
- 15% serious and, in two cases, a fatal reaction.
- Is this level of risk acceptable?

- Post SG, Full-spectrum proxy consent for research participation when persons with Alzheimer Disease lose decisional capacities: Research ethics and common good. *Alzheimer Disease and Associated Disorders 2003; 17: S3-S11.*

**Notes:**
Initial trials of a new drug for AD have shown that it stops the progress of the disease in 63% of subjects. In about half of the participants, it even produces some restoration of cognitive capacity. In 20% it has no effect other than the moderate discomfort associated with administration. In yet another 15% it produces a serious and, in two cases, a fatal reaction. You are about to take part in a large trial and find yourself deluged with caretakers who want to enroll their family members.

Would you view this level of risk to the subject as ethically acceptable?
How would you characterize the degree of risk?
If the potential benefits of the new drug were not yet well described, would it be difficult to characterize the study as potentially therapeutic?
Would you allow family caregivers to consent on behalf of their AD-affected family member on the basis that this study might be helpful to others in the future?
What, if any, difference would it make if the subject, while still competent, agreed to participate in “any study that might help people?”

## Limiting risks

- Inclusion/exclusion criteria
- “Aggressive monitoring”
- Routine and constant
- Respect for subjects’ physical resistance or other expressed dissent
- When to halt.....

**Notes:**
There is really little practical advice about aggressive monitoring for substantial or prolonged pain, discomfort, or distress. The hardest is deciding when to halt. In some cases, backing off and allowing time to elapse before seeking cooperation may be appropriate. However, persuasive efforts may not. In our protocols with patients with schizophrenia we spell out “cooperation” and train staff on approaches to patients, when to stop being persuasive, often put a limit on number of times to approach the patient (twice is usually enough).
Becomes more difficult in studying AD patients with agitation. Our nice procedures regarding assent/dissent may be more problematic and a different level of interpretation may be needed to sort out is this agitation from the underlying disease and not affected by the research environment or is this dissent.

## Capacity to consent

- Presumed competent to consent unless there is evidence of serious mental disability
- Provide a plan for determining the incapacity

## Competence vs. capacity

- “Competence” -- legal and moral status of individuals that entitles them to make their own decisions
- “Capacity” – cognitive, affective, and volitional abilities that underlie competence

**Notes:**
The authority to deem an adult to be incompetent is vested in the judicial system, and rulings of incompetence are generally made in relation to a specific functional task (eg, write a will, manage ones own finances, make medical decisions). The evidence upon which judicial determination of competence relies includes a formal assessment of decision-making abilities by medical professionals with appropriate expertise.
In the medical setting, practical constraints frequently preclude judicial review. Judgments are made based on clinical assessment of decision-making capacity. However, this is not a dichotomous state. The is a spectrum depending on the task an individual is called to perform.

## Formal procedures for capacity assessment

- Goes against the presumption of assumed competence in adults
- Reserve for populations with high probability of decisional-impairment
- Who decides?
- Structured questionnaire
- Clinical care model: leave the decision to a disinterested 3rd party

## Surrogate consent

- When prospective patient is incompetent or has impaired decision-making capacity
- Practitioner, in consultation with the chief of service, or COS, after an appropriate medical exam
- Consultation with psychiatrist or licensed psychologist if based on a diagnosis of mental illness
- Consent disclosures to the surrogate
- Explanation to subject

**Notes:**
VHA handbook 1200.5 section 11a(3)(a-d):
Such consent may be requested and accepted only when the prospective research participant is incompetent or has an impaired decision-making capacity, as determined and documented in the person’s medical record in a signed and dated progress note. The determination must be made in accordance with the following requirements in subparagraphs a-d, or as established by a legal determination.
The practitioner, in consultation with the chief of service, or COS, may determine after appropriate medical evaluatin that the prospective research subject lacks decision-making capacity and is unlikely to regain it within a reasonable period of time.
 Consultation with a psychiatrist or licensed psychologist must be obtained when the determination that the prospective research subject lacks decision-making capacity is based on a diagnosis of mental illness.
 Disclosures required by this Handbook to be made to the subject by the investigator must be made to the subject’s surrogate.
 If feasible, the practitioner must explain the proposed research to the prospective research subject even when the surrogate gives consent. Under no circumstances may a subject be forced or coerced to participate in a research study.

## Legally authorized representative

- Court appointed guardian, only with the court’s consent
- Health care agent appointed in a durable power of attorney
- Next of kin (1200.5 pg. 20): Spouse, Adult child, Parent, Adult sibling, Grandparent, or Adult grandchild (depending on state law)

**Notes:**
1200.5 Appendix D 6c(3) 
Procedures have been devised to ensure that participant’s representatives are well informed regarding their roles and obligations to protect incompetent subjects or persons with impaired decision making capacity. Health care agents (appointed under Durable Power of Attorney for Health Care) and next-of-kin, or guardians, must be given descriptions of both proposed research studies and the obligations of the person’s representatives. 

## What to tell representative...

- Description of the proposed research and the risks and benefits of participation
- Their obligation as the patient’s representative, i.e., try to determine what the patient would do if competent or, what they think is the subjects’ best interests

**Notes:**
They must be told that their obligation is to try to determine what the subject would do if competent, or if the subject’s wishes cannot be determined, what they think is in the incompetent person’s best interest.

## Where do we go from here?