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Fair Subject Selection
David Wendler
Department of Bioethics
NIH Clinical Center
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Disclaimer
The opinions expressed are my own.They do not reflect any position or policyof the National Institutes of Health, Public
Health Service, or Department of Healthand Human Services.
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Three Aspects of Subject Selection
1.Selection: determining which groups ofindividuals are eligible
2.Recruitment: actively approachingindividuals in the eligible groups
3.Retention: retaining eligible subjects
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Goals
Selection, Recruitment, and Retention should:
1. Distribute burdens and benefits fairly
2. Ensure social value of research
3. Enhance scientific validity
4. Minimize risks to subjects
5. Maximize benefits to subjects6. Protect the vulnerable
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Potential Conflicts
In some cases, these different goals mayconflict.
For instance, minimizing risks to subjectsmay decrease the social value of the
research.
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Tradeoffs
In cases of conflict, investigators, ethicsreview committees, and sponsors must
balance the competing goals.
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Subject Selection
Subject selection involves determiningwhich subjects may enroll in the research.
Subject selection is determined by thestudys inclusion/exclusion criteria.
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Research as a Benefit
Exclusion without a good reason may beunfair or discriminatory.
People are clamoring for access to clinicaltrials...demanding they, and others like
them, are owed such as a matter ofjustice. (Levine, 1994)
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Fairness
To ensure fairness, begin by assumingeveryone is eligible.
Exclude individuals from this pool onlywith good reason.
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Priority of Science
The scientific goals of the study should bethe primary consideration in determiningwho can enroll.
This involves ensuring the value of the
study and enhancing its validity.
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Ensuring Value
Exclude individuals not suitable foranswering the scientific question.
For instance, individuals with conditionsthat make it impossible to assess the drugbeing tested (e.g. brain tumors).
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Enhancing Validity
Also exclude individuals who cannotsatisfy the protocol requirements.
For instance, subjects who cannot (or donot) make the required clinic visits.
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Minimize Physical Risks
To minimize risks, exclude individuals whowould face significantly higher risks.
Individuals with poor kidney functionmight be excluded from a phase II studyof a drug with renal clearance.
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Maximize Benefits
Select subjects who are more likely tobenefit from participation.
A study of a new anti-HIV drug mightfocus on individuals with low CD4 counts.
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Protecting the Vulnerable
There is an order of preference inselecting subjects, for instance, adultsbefore children. (Belmont Report)
Exclude vulnerable subjects unless theirparticipation is needed for scientific
reasons. (CIOMS
)
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Vulnerable Subjects
In general, vulnerable subjects are thosewho are significantly less able to protecttheir own interests.
In the context of clinical research,
vulnerable subjects typically are those notable to give voluntary informed consent.
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Address Vulnerability First
In some cases, it is possible to addressindividuals vulnerability withoutexcluding them.
Individuals who do not understandEnglish are vulnerable (in the US), but
this vulnerability can be addressed bytranslators and translated documents.
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Subjects Who Cant Consent
Exclude individuals unable to consent,unless there is a compelling reason to
enroll them.
Scientific necessity is the most obvious
reason to enroll those who cannotconsent.
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Lower Risks?
Should individuals who cannot consent beenrolled when they face significantly lowerrisks than individuals who can consent?
For example: a phase I study that can be
conducted with relatively low risks inchildren or high risks in adults.
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The Prospect of Benefit
Should subjects who cannot consent beexcluded from trials that offer potentialclinical benefit?
Should an individual unable to consent beenrolled in a phase II study of a new
chemotherapy, if the study could equallywell be completed with individuals whocan consent?
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The Justification?
In some cases, enrollment may be inriskier subjects (e.g. individuals withpoor kidney function) best interests.
Thus, a general exclusion of these
subjects cannot be justified on thegrounds that it protects them.
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Research vs. Clinical Care
It is important to distinguish research fromclinical care.
Excluding riskier subjects minimizes theaggregate risks of research.
Applies to moral (cant consent) as well asphysical risks (renal clearance example)?
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Additional Safeguards
Informed consent is a primary researchsafeguard.
Hence, when enrollment of subjectsunable to consent is justified, the study
should include additional safeguards toprotect them.
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Sufficient Evidence
Adults no longer able to consent should beenrolled only with sufficient evidence thatit is consistent with their preferences and
interests.
What about adults who were nevercompetent?
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Surrogates
Subjects unable to consent should beenrolled only with the permission of anappropriate surrogate.
Are health care surrogates sufficient forresearch purposes (evidence that those
close to us are bad predictors of ourpreferences)?
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Subject Recruitment
Subject recruitment involves activeattempts to enroll specific individuals or
groups within the pool of eligible subjects.
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Finding the Right Community
In many cases, the choice of communitiesfrom which to recruit is determined by
institution location.
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Selecting a Community
In other cases, investigators have a choiceof possible communities.
In these cases, the principles of subjectselection apply in deciding which
community to select.
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Goals of Selection and Recruitment
1. Distribute burdens and benefits fairly2. Ensure social value
3. Enhance scientific validity
4. Minimize harm
5. Maximize benefit
6. Protect the vulnerable
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Declaration of Helsinki -2008
Medical research involving adisadvantaged or vulnerable populationor community is only justified if the
research is responsive to the healthneeds and priorities of this population orcommunity and if there is a reasonable
likelihood that this population orcommunity stands to benefit from theresults of the research.
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Social Value/Community Benefit
To what extent must communities benefitfrom research involvement?
To what extent must the communitybenefit specifically from the research
results?
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Community vs. Individual Benefit
Should the requirement of benefit be
added to the conditions on selection ofindividual (vulnerable) subjects?
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The Need to Recruit
According to a 2007 survey by CenterWatch, over 70% of clinical trials aredelayed due to difficulty enrolling a
sufficient number of subjects.
To be ethical, clinical trials needs to recruit
a sufficient number of subjects to obtainvalid data.
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The Ethics of Recruitment
This provides an ethical reason to recruitand retain subjects.
Yet, recruiting and retaining researchsubjects raises important ethical issues.
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Recruitment
Targeted recruitment
Inviting referrals from colleagues/clinicians
Advertising
Inviting ones own patients
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Recruitment for good reasons
Do not focus recruitment on individualswho are (or appear to be?) vulnerable
Ensure subjects are recruited for reasonsof science, not compromised position.
(Belmont Report)
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Incentives to Enroll Subjects
Investigators are under considerablepressure to recruit subjects, sometimesreceiving financial incentives. (US Inspector General2000)
Physicians receive payments for referringtheir patients to trials.
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Concerns about Incentives
Do incentives to refer patients pose aconflict of interest?
To what extent might use of incentivesencourage investigators to enrollriskier/inappropriate subjects?
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Advertising
What effect does advertising have onrecruitment?
Does advertising affect consent?
May benefits be advertised?
Must risks be advertised?
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IRBs and AdvertisingThe IRB should review the methods and
material that investigators propose to useto recruit subjects.
Ads should not claim that investigationalinterventions are safe or effective.
IRB should evaluate the relative size oftype used and other visual effects.
www.fda.gov/oc/ohrt/irbs/toc4.html#recruiting
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Ads in Real Life: Bar Coaster
Research Subjects Wanted
Earn $50-$1295
Call555-555-5555
Daves Research Institute
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Proposed T.V. Ad Thumping music; Tie-dye colors on screen.
Attention alcohol Usersyou are a candidatefor a new research study being done at DavesInstitute.
We are enrolling men and women, 18-40, tostudy the effects of alcohol on the brain.
This study pays up to 3500 dollars and includesroom and board. Call today.
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Effect of Ads
Do advertisements affect which groupsenroll?
Does advertising affect understanding?
Does it affect motivations (does itmatter?)
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Payment
What role should payment play inrecruiting research subjects?
Is it acceptable to advertise payment?
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Concerns
Some argue that payment may coerceindividuals.
Others worry that payment may representan undue inducement.
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The Real World
Data suggest that many problemsrecruiting subjects trace to mundane,practical concerns: awareness of studies,
transportation, parking, child care.
Clinical trials should take these concernsinto account.
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Retaining Subjects
To collect valid data, recruited subjectsneed to be retained.
Future research is needed on ways toretain subjects and encourage them tocontinue to participate withoutundermining their right to withdraw.