# Presentation: 278318

## Research Involving Persons at Risk for Impaired Decisionmaking

**Donald L. Rosenstein, M.D.****National Institutes of Health**

**Notes:**

So my first formidable task is to convince you that research ethics is relevant to the many different things you all do professionally...and I’d like to start by suggesting that whether you like it or not and regardless of how much attention to pay to it, you are rapidly becoming a part of the CRE....so, this is what I plan to do in the next 45 minutes...first, describe what I mean by the CRE and why you ought to care about it, then talk about what the most important ethical issues related to CR are and how we might think about them; and then finish up with some recommendations about what you might do when you go back to your various activities if I’ve been at al successful in convincing you that this topic is important and relevant to you.  So what do I mean by the CRE?

## Overview

**Dimensional issues and categorical decisions**
**A recent case: the ARDS Network Trial**
**An IRB approach to protocols involving subjects at risk for impaired decisionmaking capacity (DMC) **
**Informed consent monitoring and Independent capacity assessment (ICA)**
**Advance directives for research**

## Competing or Integrated Agendas?

**Research differs fundamentally from medical care **
**in its purpose, methods, and justification of risks**

## Spectrum of Clinical Research

**Healthy Control**
**“****Non-therapeutic” study**
**Payment**

**Severely Ill Patient**
**Clinical trial**
**No payment**

## The Acute Respiratory Distress Syndrome Network Trial

**Multi-center (10 university centers), randomized trial of mechanical ventilation in patients with acute lung injury and ARDS**

**NEJM 2000; 342:1301-8**

## NHLBI ARDS Network

**Cleveland Clinic Foundation**
**Denver Health Medical Center**
**Duke University**
**Johns Hopkins University**
**UCSF**
**University of Colorado**
**University of Maryland**

**University of Utah**
**University of Pennsylvania**
**University of Washington**
**Vanderbilt University**
**Massachusetts General Hospital**
**University of Michigan**
**Jefferson University**

## The Acute Respiratory Distress Syndrome Network Trial

**Multi-center (10 university centers), randomized trial of mechanical ventilation in patients with acute lung injury and ARDS**
**Comparison of lower tidal volumes with “traditional” tidal volumes **

**NEJM 2000; 342:1301-8**

## The Acute Respiratory Distress Syndrome Network Trial

**Multi-center (10 university centers), randomized trial of mechanical ventilation in patients with acute lung injury and ARDS**
**Comparison of lower tidal volumes with “traditional” tidal volumes **
**Eligibility : intubated and mechanically ventilated**
**Manuscript stated “informed consent was obtained from the patients or surrogates at all but one hospital where this requirement was waived.”**

**NEJM 2000; 342:1301-8**

**Notes:**
How should ic be obtained? What are requirements for waiving ic

## The Acute Respiratory Distress Syndrome Network Trial

**Multicenter (10 university centers), randomized trial of mechanical ventilation in patients with acute lung injury and ARDS**
**Comparison of lower tidal volumes with “traditional” (higher) tidal volumes **
**Eligibility : intubated and mechanically ventilated**
**Death was primary outcome measure**

**NEJM 2000; 342:1301-8**

## The Acute Respiratory Distress Syndrome Network Trial

**Multicenter (10 university centers), randomized trial of mechanical ventilation in patients with acute lung injury and ARDS**
**Comparison of lower tidal volumes with “traditional” (higher) tidal volumes **
**Eligibility : intubated and mechanically ventilated**
**Death was primary outcome measure**
**Lower mortality observed in lower tidal volume group**

**NEJM 2000; 342:1301-8**

## Department of Health and Human Services (HHS)

**HHS**** **
**Office of the Secretary **

**NIH**

**OHRP **

**IRP      ERP**

**(OPRR)**

## OHRP Findings and Concerns

**Failure of IRB Review process**
**Waiver of consent**
**Inadequate informed consent documents**
**Failure to obtain “legally effective informed consent of the subject or the subject’s legally authorized representative”**
**Inconsistencies with regard to state law allowing surrogate permission**

## OHRP Findings and Concerns

- “ OHRP is concerned that (a) both the subjects, because of their impaired mental state, and the subjects’ family members, because of the psychological stress of having a critically ill family member being treated in an intensive care unit, appear likely to have been vulnerable to coercion or undue influence; and (b) the IRB failed to insure that there were additional safeguards included in the study to protect the rights and welfare of these vulnerable subjects.”
**	****	****	****OHRP Determination letter, 2/7/02**

## 45 CFR 46.111 Criteria for IRB Approval of Research

**(b) When some or all of the subjects are likely to be ****vulnerable to coercion or undue influence****, such as children, prisoners, pregnant women, ****mentally disabled persons****, or economically or educationally disadvantaged persons, ****additional safeguards**** have been included in the study to protect the rights and welfare of these subjects.**

**Notes:**
Efforts on various fronts
NBAC
MD draft legislation
NY
NIH
Canada

## Central Questions

**1.****	****Who is vulnerable because of a ****	****mental disability?**
**2.****	****What are the appropriate additional**
** ****	**** ****safeguards for vulnerable subjects****?**
**3.****	****How can these ****safeguards**** be ****	****optimally implemented ?**

**Notes:**
Complicated issue and the central questions remain unanswered
	only those unable to give IC
	those at risk, defined how?  Fxal assessment secondary to condition or as a consequence of specific study.  I want to be clear about one point here.  Just as I think it is a mistake to define the scope too broadly (as NBAC has done) to include anyone with a mental disorder, I also see a danger in defining scope too narrowly, and thereby not implementing additional protections for subjects who are vulnerable due to the nature of the study they are consenting to enroll  in.  Not all challenge studies are conducted in subjects who can be considered vulnerable.  Here is linkage between IRB and CCEC.
	here the obvious tension is between protection and excessive 		regulations
Look at what goes well not just disasters
1.  local IRB is optimum locus of review and protections 
2.  imp for IRBs to review protocols in context of program so as to assure fully informed and engaged subjects and to minimize the TM
3. Propose a mechanism for implementation
4. Importance of training of Pis
Bottom line:  we ought to protect vulnerable individuals from being exploited for the benefit of research and society

## Defining the Scope of Impaired Decisionmaking Capacity

**Imprecise language**
**competency, capacity, and consent**
**cognitive impairment does not necessarily mean decisional incapacity**
**mental disability, psychiatric illness/disorder,      and vulnerability**
**“****capacity to give informed consent for **_**this**_** study”**

**Notes:**
DIFFERENCES BETWEEN cognitive impairment and incapacity
Mental retardation
dementia
delirium
schizophrenia

## Research With Impaired or Potentially Impaired Subjects

**Medication trial for Alzheimer’s Disease**
**ECT trial for delusional depression**
**Placebo-controlled study in acute mania**
**MRS study of a delirium model**
**Establishing cell lines for genetics studies of mental retardation**
**Tryptophan depletion in autism (adults)**
**Medication-free studies of schizophrenia**

## The Most Contentious Case

**Research**
** ****with subjects who  **
**can not provide informed consent**** **
**that offers     **
**no prospect of direct medical benefit**** **
**and involves                                     **
**more than minimal risk**

**	**

**Notes:**
For example, protocol yesterday...as you might expect, reasonable people can disagree...and we find ourselves in what is quickly becoming known as a Florida situation...I take you now to a scene in at a Tallahasee car mechanic...

## The Nuremberg Code

**The voluntary consent of the human subject is absolutely essential.**
**	****	****	****	****	****	****	****1946**

## Central Tension

**	****The need for improved diagnosis and treatment through research. **
**	****	****	****versus **
**	****The danger of exploiting vulnerable individuals.**

##      unethical

**problematic**

******     ****unethical**

## Questions for the IRB 

**Can the scientific question be answered with capacitated subjects?**
**What are the relevant risks and benefits?**

**Notes:**
Nature of impairment...that is will the whole sample be impaired or just some individuals?

## risks

**risks**

**benefits**

**Institutional Review Board**

**minimal risk**
**minor increment over ****	****minimal risk (children)**
**greater than minimal risk**

**direct benefit to the subject **
**benefit to society**
**(indirect benefits to subject)**

## Questions for the IRB 

**Can the scientific question be answered with capacitated subjects?**
**What are the relevant risks and benefits?**
**What is the nature of the anticipated decisionmaking impairment?**

**Notes:**
Nature of impairment...that is will the whole sample be impaired or just some individuals?

## Factors Influencing Decisionmaking Capacity

**Memory, attention, concentration**
**Conceptual organization**
**Psychosis and hallucinations**
**“****Executive” function**

**Risk assessment**
**Mood **
**Intuition**
**Insight**
**Behavior**
**Duty and altruism**
**“****Relatedness” **

**Notes:**
Nature of impairment...that is will the whole sample be impaired or just some individuals?

## Will Subjects Be Able to Provide Informed Consent?

**Subjects ****who are currently ****unable to provide informed consent**
**Subjects ****who will become ****unable to provide informed consent**
**Subjects ****who are at increased risk ****of becoming unable to provide informed consent **

**Notes:**
Advanced dementia, retardation
Early dementia
Schizophrenia, bipolar d/o, post-operative delirium, medication-induced NP changes
Emergency research, ind subject

## Questions for the IRB 

**Can the scientific question be answered with capacitated subjects?**
**What are the relevant risks and benefits?**
**What is the nature of the anticipated decisionmaking impairment?**
**Are adequate safeguards in place?**

**Notes:**
Nature of impairment...that is will the whole sample be impaired or just some individuals?

## Additional Protections

**Clinical monitoring of ongoing research**
**Data and safety monitoring boards **
**Ethics consultation**

## Additional Protections

**Clinical monitoring of ongoing research**
**Data and safety monitoring boards **
**Ethics consultation**
**Informed consent monitoring**
**Independent capacity assessment**

## Consent Monitoring and Independent Capacity Assessment

**Disclosure and voluntary participation**

**Mastery of specific study**

**Basic understanding of clinical research**

## Decisionmaking Capacity

**Unable to make decisions**

**Fully capacitated**

**Able to assign a substitute decisionmaker**

**Appreciates the differences between clinical care and clinical research**

**Able to make medical decisions**

## National Bioethics Advisory Commission (NBAC) Report

**“****Research Involving Subjects at Risk for **
**Impaired Decisionmaking Capacity” 1998**

## National Bioethics Advisory Commission (NBAC) Report

**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****...”**

**“****Research Involving Subjects at Risk for **
**Impaired Decisionmaking Capacity” 1998**

## Triggers for Capacity Assessment

**Concern about a class of prospective subjects**
**Protocol designed to enroll “at-risk” subjects**
**Protocol that may precipitate loss of decisional capacity**

## Triggers for Capacity Assessment

**Concern about a class of prospective subjects**
**Protocol designed to enroll “at-risk” subjects**
**Protocol that may precipitate loss of decisional capacity**
**Concern about an individual**
**Prior to or at the time of enrollment**
**During study participation**

## Assessment of Decisionmaking Capacity (DMC)

**Presumption of capacity/competence**
**Medical aspects of assessment of DMC**
**Dehydration, medication toxicity, sickness, delirium, psychosis, severe depression, grief, mania**

## Capacity to Give Informed Consent for Research

**	****Does this individual have a medical, neurological or psychiatric disorder that compromises his or her capacity to understand, appreciate and reason with respect to the details of a given study?**
**Clinical judgment**
**	****Can this person give informed consent and should they be enrolled into the study?****	**
**Ethical judgment**

## Assessment of Decisionmaking Capacity (DMC)

**Presumption of capacity/competence**
**Medical aspects of assessment of DMC**
**Dehydration, medication toxicity, sickness, delirium, psychosis, severe depression, grief, mania**
**Who does this?**
**How is it done?**

## MacArthur Competence Assessment Tool (MacCAT-CR)

**	****purpose of study; what tests and procedures**
**	****major risks, discomforts and possible benefits **
**APPRECIATION**
**	****is the main purpose to benefit you?**
**	****differences between this study and regular care**
**REASONING**
**	****if you decline, what will you do instead?**
**	****whose decision, can you stop participating?**
**CHOICE**

**MacArthur Competence Assessment Tool (MacCAT-CR)**

**Notes:**
Global Impression
	Capable of giving informed consent
	Incapable of giving informed consent
	Doubtful of capacity to give informed consent

## Assessment of Decisionmaking Capacity

**Business   as usual**

**NBAC: mandated, formal ICA**

**Clinical judgment of investigator**

**McCAT-CR for each protocol**

**NIMH IRP CORE**

**Independent,     semi-structured interview based on McCAT-CR**

## Additional Protections

**Clinical monitoring of ongoing research**
**Data and safety monitoring boards **
**Ethics consultation**
**Informed consent monitoring**
**Independent capacity assessment**
**Advance directives and legally authorized representatives (e.g., guardianship, DPA)**

## NIH Advance Directive for Health Care and Medical Research Participation

**Durable Power of Attorney**
**Advance Directive for Health Care**
**Advance Directive for Research Participation**

## NIH Advance Directive for Health Care and Medical Research Participation

- If I lose the ability to make my own decisions,               I do _not_ want to participate in any medical research.
- If I lose...I am willing to participate in medical  research that might help me.
- If...won’t help me but might help others as long as it involves no more than minimal risk of harm to me.
- If...that won’t help me but might help others even if it involves greater than minimal risk of harm to me.

## Summary and Recommendations

**Is it necessary to enroll vulnerable subjects?**
**Decisional capacity with respect to providing informed consent for a specific study**
**Subject vulnerability, research risks and benefits:**
**Determined by local IRB**
**Defined by study population and specific protocol rather than by diagnosis alone**

## Summary and Recommendations (Cont.)

**Investigators should describe in detail: **
**methods of assessing decisional capacity**
**procedures for informed consent or proxy consent**
**provision of adequate safeguards**
**IRBs should promote increased use of: **
**independent capacity assessment **
**consent monitors**
**legally authorized representatives**
**research advance directives**
**IRB discretion regarding intermediate risk **