Competence to Consent to Research: Concepts and

Assessment

Paul S. Appelbaum, MDDollard Professor of Psychiatry, Medicine &

LawDirector, Division of Psychiatry, Law &

EthicsDepartment of Psychiatry

Columbia University

History of Concern with Research Ethics

Birth of research ethics often traced back to Nazi atrocities and the Nuremberg trials after WW II.

But even before then investigators seem to have recognized the importance of subjects’ competent consent to research.

1st known consent form: Walter Reed’s yellow fever experiments in Cuba (1898).

Example of Early Recognition of Importance of Consent to

Research

Just over 100 years ago, George Bernard Shaw was writing Pygmalion (later My Fair Lady).

Consider this dialogue that occurs just as Prof. Henry Higgins is about to begin his experiment of turning the flower-girl, Eliza Doolittle into a “lady.”

Col. Pickering: Excuse me, Higgins; but I really must interfere… If this girl is to put herself in your hands for six months for an experiment in teaching, she must understand thoroughly what she’s doing.

Prof. Higgins:How can she? She’s incapable of understanding anything. Besides, do any of us understand what we are doing? If we did, would we ever do it?

Col. Pickering:Very clever, Higgins, but not sound sense.

Prof. Higgins:No use explaining. As a military man, you ought to know that. Give her her orders: that’s what she wants.

Nature of the StudyEliza: You are to live here for the next six

months, learning how to speak beautifully, like a lady in a florist’s shop. If you’re good and do whatever you’re told, you shall sleep in a proper bedroom, and have lots to eat, and money to buy chocolates and take rides in taxis. If you’re naughty and idle, you will sleep in the back kitchen among the black beetles, and be walloped by Mrs. Pearce with a broomstick.

Risks

At the end of six months, you shall go to Buckingham Palace in a carriage, beautifully dressed. If the King finds out you’re not a lady, you will be taken by the police to the Tower of London, where your head will be cut off as a warning to other presumptuous flower girls.

Benefits

If you are not found out, you shall have a present of seven-and-sixpence to start life with as a lady in a shop.

Right to Withhold Consent

If you refuse this offer, you will be a most ungrateful and wicked girl and the angels will weep for you.

Now are you satisfied, Pickering?

Doctrine of Informed Consent Three elements:

Disclosure – Pickering’s concern Competence – Higgins’ focus and

our topic today Voluntariness – Liza’s bottom line Liza: You’re a big bully you are. I won’t

stay here if I don’t like. I won’t let nobody wallop me.

Role of Competence Requirement

Right to make decisions is key value in liberal societies

But balanced against concern that some people lack capacity to make decisions consistent with their interests

Hence, informed consent doctrine creates exception for persons lacking competence

Core Characteristics of Competence

Task specific – Can be competent for some decisions, but not others (e.g., focal delusions).

Time specific – May be competent at one point but not earlier or later.

Responsive to demand characteristics of decision – Riskier decisions may require higher level of capacity.

Criteria for Competence to Consent to Research

Evidencing a choice Understanding disclosure of

information Appreciation of the nature of the

situation and its consequences Reasoning (ability to weigh risks

and benefits)

What is Different About Competence to Consent to

Research and to Treatment?

Subjects must appreciate the differences between the two contexts.

Treatment:Primary goal is the provision of “personal care.”

Research:Primary goal is the production

of generalizable knowledge.

Research Methods that Favor Validity Over Patients’ Interests

Random assignment to treatment Placebos Double blind procedures Adherence to protocol to determine

dosages Limitations on adjunctive treatments

Subject #50Interviewer: Do you know how treatment in this study

is different from ordinary care? Did they say what your treatment would be if you weren’t in the study?

Subject: No, no.

Interviewer: They didn’t discuss what the treatment would be?

Subject: No, no, I’ll leave that up to them. I want them to give me the best treatment for what I have.

Interviewer: Do you think by being in the study this is the best treatment you could get?

[continued]

Subject #50[continued]

Subject: Okay, if they don’t, then I’ll drop out.Interviewer: Hopefully they will give you the best

treatment you can get?Subject: Right, right.Interviewer: So you are not sure they have different

groups or anything? As far as you know if they did have different groups, would the doctors decide which is the best one for you?

Subject: I would assume he would decide which one was the best one for me.

Therapeutic Misconception Study: Participants

243 participants from 44 clinical research studies at 2 academic medical centers

Age (mean) 53.1 years (range 18-32) Gender (female) 69.8% Race (white) 90.5% Education (mean) 14.2 years

Therapeutic Misconception Study: Dependent Variables

Incorrect belief that participant’s individualized needs would determine assignment to treatment conditions or lead to modification of the treatment regimen (Individualization)

Unreasonable belief about the nature or likelihood of medical benefit based on misunderstanding of research design (Benefit)

Therapeutic Misconception Study: Frequency of TM (n=243)

Individualization 31.1% (n=70)Benefit 51.1% (n=115)

Total 61.8% (n=139)

Role of Therapeutic Misconception in Impairing

Competence

Subjects who don’t appreciate the differences between research and treatment contexts can’t make meaningful decisions about participation

Therapeutic misconception is highly prevalent among potential research subjects and needs to be considered in competence evaluation

How Competent are Research Subjects with Conditions That

May Impair Capacity?

Data available on subjects with schizophrenia, depression, Alzheimer’s disease

Most studies use MacCAT-CR; many compare with normal populations

Both hypothetical and in vivo studies

Diagnosis and Competence

Performance on competence measures: normals > depression > schizophrenia > Alzheimer’s disease.

Schizophrenics vs. Normals

Pre-test MeansNormal

Schizophrenia Comparison Subjects (n=24) Group (n=24) P

Understanding (0-26) 12.9 (8.5) 20.2 (3.8) 0.001Reasoning (0-8) 3.5 (2.8) 5.5 (1.4) 0.002Appreciation (0-6) 2.3 (2.0) 4.4 (1.5) 0.0001Choice (0-2) 1.6 (0.7) 1.9 (0.3) 0.06

Carpenter, et al. Arch Gen Psychiatry 57: 533-8, 2000

Correlates of Impaired Competence

Positive and negative psychotic symptoms have weak or no correlations with performance on competence measures.

Neuropsychological variables consistently show the strongest correlations with impairment

Cognitive Impairment and Competence

Effectiveness of Remedial Interventions Puzzle of Carpenter, et al. data Many subjects with impaired capacity

respond well to additional education Special teaching techniques may be

helpful (e.g., multimedia) After intervention, many subjects able

to make decisions for themselves

Example of Effects of Additional Education

Pre Post PUnderstanding (0-26) 8.35 18.35

<0.00001Appreciation (0-6) 1.35 3.25

<0.0001

Reasoning (0-8) 2.35 3.7 <0.04

Many Patients with Psychiatric or Neurologic Disorders Are Competent to Consent to

Research

There is great heterogeneity within diagnostic categories, but many persons in every diagnostic category (fewest in AD) retain decisional competence.

Proportions of competent patients will vary depending on diagnosis, clinical state, and nature of research study.

Data from CATIE Study - 1 Kim (2003) had 3 psychiatrists

assess competence of sample of schizophrenic subjects and compared with MacCAT-CR scores

Cut-offs were established using ROC analyses.

Data from CATIE Study - 2 Of 900 subjects in preliminary analysis,

approximate % falling below cut-offs were: Understanding: 9% Appreciation: 16% Reasoning: 24%

Conclusion: vast majority of chronic schizophrenic subjects in this study are competent to consent—but not all

Approaches to Impaired Capacity

Screening increasingly prevalent in higher risk studies (e.g., placebo-controlled)

Can be done with: Clinical interview Symptom measures (e.g., MMSE, BPRS) Competence screening instruments

(e.g., MacCAT-CR)

MacCAT-CR Overview Assesses understanding,

appreciation, reasoning, and choice Series of disclosures followed by

questions and reasoning tasks Takes approximately 20-25 minutes Provides quantitative scores, but

not competent/incompetent decision

MacCAT-CR UnderstandingMacCAT-CR DisclosureU-1 (ii) Disclosure (Procedures of Project)—

Patients who agree to be in this study will do the following things:

- First, they will stop all medications for schizophrenia for 2 weeks; this is called the washout period- Second, after the washout period, they will receive either the new medication or the old medication for 8 weeks; this is called the treatment phase of the study- Altogether, the study lasts 10 weeks; 2-week washout and an 8-week treatment phase

MacCAT-CR UnderstandingMacCAT-CR Questions “Do you have any questions about what I

just said?” “Can you tell me your understanding of

what I just said?” If subject fails to mention spontaneously,

ask “How long will the research study last?” “What will happen to your medication at the beginning of the study?” “ What medication will your receive in the

study?”

Understanding - Scoring 2 Subject recalls content of item and

offers fairly clear version. 1 Subject shows some recollection of

item content, but describes in a way that renders understanding uncertain, even after efforts to clarify

0 Subject does not recall, is clearly inaccurate, or seriously distorts meaning

MacCAT-CR Appreciation A-1 – “Do you believe that you

have been asked to be in this study primarily for your personal benefit?”

Then ask: “What makes you believe that this (was/wasn’t) the reason you were asked?”

Appreciation - Scoring 2 Subject acknowledges being

recruited for reason unrelated to personal benefit

1 Subject says recruited both for and not for personal benefit; or for personal benefit with plausible reason

0 Subjects maintains being recruited only for personal benefit

MacCAT-CR - Choice “As you know, you have been

invited to participate in a research project testing a new medication for the treatment of schizophrenia. Do you think you are more likely to want to participate or not to want to participate?”

Choice - Scoring 2 Subject states a choice

1 Subject states more than one choice, seems ambivalent

0 Subject does not state a choice

MacCAT-CR Reasoning R1/R2 - “You think that you are more

likely to want (to participate/not to participate) in the study. Tell me what it is that makes that option better than the other.”

Probe to explore reasoning process.

Reasoning – Scoring(Consequential Reasoning)

2 Subject mentions at least 2 specific consequences

1 Subject mentions only 1 specific consequence

0 Subject mentions no specific consequences, even after direct probe

Use of Screening Instruments Thresholds can be set based on

data from similar populations or a priori judgments

Failure can trigger clinical evaluation and/or remediation

Retesting after remediation allows participation for those able to improve performance

Who Should Do the Screening?

NBAC (1999) suggested independent evaluation

But use of objective measures may allow clear documentation of decisions and obviate the need for outside assessor

What If Impairment is Detected?

Presence of impairment doesn’t imply subject should be excluded from study

Proper response is remediation, e.g., Repetition of disclosure Videotape/computer programs Group discussions with former subjects

Still likely that some subjects will have to be excluded, unless someone else can make decision

Use of Proxy Decision Makers Status unclear in US

Federal rules allow “legally authorized representative”

But case law suggests usual proxies in treatment settings (e.g., family members, guardians) may not be authorized to consent to research

However, without proxy consent, some disorders will never be understood (e.g., AD)

NBAC Recommendations for Use of Proxies

NBAC suggested use of proxies in minimal risk research, or more than minimal risk but with some prospect of benefit (e.g., treatment trials)

But this would disallow proxies in studies seeking understanding of pathophysiology (e.g., PET studies, indwelling catheters)

Reasonable Approach to Proxies

Permit persons authorized to consent for medical treatment to consent to research, so long as some prospect of benefit or risk represents no more than minor increment over minimal.

A New Kind of Proxy: The Subject Advocate - 1

Persons with mental illness often experience fluctuations in mental state

Though competent at the time of enrollment, they may become incompetent and unable to make decisions about withdrawal from the study later on

A New Kind of Proxy: The Subject Advocate - 2

CATIE used a subject advocate, appointed at time of consent

Person assists with enrollment decision Remains available to become involved if

subject becomes incompetent At that point, considers whether

risk/benefit ratio has so changed that subject should be withdrawn from the study

Use of Advance Directives Again, status generally unclear in

US Not mentioned in federal rules Most statutes allowing advance

directives for treatment make no mention of research

NBAC Recommendations for Use of Advance

Directives NBAC endorsed advance directives, but

only if subject gave authorization to a class of research after risk, potential benefits, and other pertinent information explained

Unlikely that it will be possible to specify this information in advance for most subjects, hence not a practical approach

Reasonable Approach to Advance Directives

Competent subjects should be able to agree in advance to enter any IRB-approved studies on their disorders, even without prospect of personal benefit

Or they may set limits of extent of risk, or defer to proxy decision maker

Conclusions - 1 Psychiatric or neurologic illness

may lead to decisional impairment, but is neither a necessary nor sufficient condition for incompetence

Screening for incompetence is reasonable in higher risk studies with more impaired populations

Conclusions - 2 Before incapable subjects are

excluded from participation, efforts should generally be made to remediate their impairments

But not every potential subject will respond to remediation

Conclusions - 3 Use of proxy decision makers and

advance directives hold promise for allowing research to proceed on important conditions while protecting subjects’ rights