Recruitment of Healthy Recruitment of Healthy Volunteers: Volunteers:

Research Ethics under Research Ethics under PressurePressure

INSIGHT Toronto October 24 INSIGHT Toronto October 24 20062006

  Michael Goodyear

Department of Medicine, Queen Elizabeth II Health Sciences Centre, Dalhousie University, Halifax NS

Learning ObjectivesLearning Objectives

• I: A Culture of SafetyI: A Culture of Safety

• II: What Motivates Volunteers?II: What Motivates Volunteers?

• III: Why Volunteers are VulnerableIII: Why Volunteers are Vulnerable

• IV: Role of Financial IncentivesIV: Role of Financial Incentives

• V: Adverse Risk-Benefit RatioV: Adverse Risk-Benefit Ratio

• VI: Defining the Ethical ProblemVI: Defining the Ethical Problem

SummarySummary

Part IPart I

A Culture of SafetyA Culture of Safety

A Healthy Volunteer

Died

Ellen RocheEllen Roche

“What's the worst that can happen to me? …I die, and it's for the babies.“New York Times, 28 Nov 1999

Jesse Jesse GelsingerGelsinger

TGN1412TGN1412

Hell of human guinea pigsHow the drug trial horror unfoldedBy MICHAEL SEAMARK, Daily Mail 17th March 2006

We saw human guinea pigs explodeVictims tearing at shirtsBy NICK PARKER, EMMA MORTON and JACQUI THORNTON 16th March 2006

Ryan, Gangrene

Khan, EyewitnessPlacebo

Elephant Man and Girlfriend

Oedema

A Culture of A Culture of SafetySafety

“The demand for human subjects is at an all time high, and the competition for human subjects for research participation is equally great. Investigators must take care to not respond to this competitive environment … The temptation to entice subjects with a large amount of money is a natural reaction to such conditions; however, the protection of human subjects must come first”Tishler CL, Bartholomae S: The recruitment of normal healthy volunteers: A review of the literature on the use of financial incentivesJ Clin Pharmacol 2002; 42: 365-375

Part IIPart II

What Motivates What Motivates Volunteers?Volunteers?

What Motivates What Motivates Volunteers?Volunteers?

• AltruismAltruism– DiseaseDisease– SocietySociety

• CuriosityCuriosity

• Medical Care (where not available)Medical Care (where not available)

• MoneyMoney

• Other incentivesOther incentives

Walter Reed Experimenting on

Yellow FeverCuba, 1898

$100 in Gold

Additional $100 in Case of Death

Research related injuryInformed Consent re

risk

Allied Research International is always recruiting for normal healthy study Allied Research International is always recruiting for normal healthy study participants for our phase I and bioequivalence studies. We conduct our participants for our phase I and bioequivalence studies. We conduct our studies in a cheerful, safe, and respectful environment. Our meals are second studies in a cheerful, safe, and respectful environment. Our meals are second to none and to none and …now with 100% more …now with 100% more pool tablespool tables!!

$950

Part IIIPart III

Why Volunteers are Why Volunteers are VulnerableVulnerable

Why Volunteers are Why Volunteers are VulnerableVulnerable

• Economically DisadvantagedEconomically Disadvantaged

• High Incidence of PsychopathologyHigh Incidence of Psychopathology– Up to 50%Up to 50%

Part IVPart IV

Role of Financial Role of Financial IncentivesIncentives

Role of Financial Role of Financial IncentivesIncentives

Difficult to assessDifficult to assess– Subjective and RelationalSubjective and Relational

– Degree of riskDegree of risk– Risk taking behaviourRisk taking behaviour– Personal valuesPersonal values– Amount of moneyAmount of money

Role of Financial Role of Financial IncentivesIncentives

• Incentives compromise autonomyIncentives compromise autonomy

• Unpaid volunteers believe there Unpaid volunteers believe there should not be paymentsshould not be payments

• Voluntariness becomes occupationVoluntariness becomes occupation

• Repeat or professional volunteersRepeat or professional volunteers

• Problems of Justice, GeneralisabilityProblems of Justice, Generalisability

Part VPart V

Adverse Risk-Benefit RatioAdverse Risk-Benefit Ratio

Adverse Risk-Adverse Risk-Benefit RatioBenefit Ratio

• Essentially no benefitEssentially no benefit

• (Social obligation)(Social obligation)

Part VIPart VI

Defining the Ethical Defining the Ethical ProblemProblem

Defining the Ethical Defining the Ethical ProblemProblem

DisadvantagedDisadvantaged

PopulationsPopulations

Require Require

Special Special

ProtectionProtectionBelmont

CFR

FDA, OHRP

Healthy Research Healthy Research VolunteersVolunteers

OHRP – IRB GuidebookOHRP – IRB Guidebook

Chapter VI: Special Classes of Subjects:Chapter VI: Special Classes of Subjects:– ““Volunteers for whom Volunteers for whom no therapeutic benefitno therapeutic benefit

can result from participation in research should, can result from participation in research should, therefore, be exposed to therefore, be exposed to risks that are risks that are minimizedminimized to the greatest extent possible.” to the greatest extent possible.”

– “…“…IRBs must ensure that any IRBs must ensure that any monetary monetary paymentspayments to subjects are to subjects are not not so great as to so great as to constitute an constitute an undue inducementundue inducement. …. …Payments should be commensurate with time, Payments should be commensurate with time, discomfort, and risk involved.”discomfort, and risk involved.”

VulnerableVulnerable PopulationsPopulations

21 CFR 56.111 (b)21 CFR 56.111 (b)

Criteria for IRB Approval of Research:Criteria for IRB Approval of Research:

“ “When some or all of the subjects, such as children, When some or all of the subjects, such as children, prisoners, pregnant women, handicapped, or mentally prisoners, pregnant women, handicapped, or mentally disabled persons, or disabled persons, or economically or educationally economically or educationally disadvantageddisadvantaged persons, are likely to be persons, are likely to be vulnerable vulnerable to coercion or undue influenceto coercion or undue influence additional additional safeguardssafeguards have been included in the study to have been included in the study to protect the rights and welfare of these subjects."protect the rights and welfare of these subjects."

Defining the Ethical Defining the Ethical ProblemProblem

Risk/Benefit

Vulnerability

SummarySummary

Summary I/IISummary I/II

• Volunteers are HarmedVolunteers are Harmed

• Are largely Motivated by Financial Are largely Motivated by Financial IncentiveIncentive

• Are Economically DisadvantagedAre Economically Disadvantaged

• Have Increased VulnerabilityHave Increased Vulnerability

• Have Compromised VoluntarinessHave Compromised Voluntariness

• Have Adverse Risk-benefit Have Adverse Risk-benefit Considerations Considerations

Summary II/IISummary II/II

Experimentation with Normal Experimentation with Normal Healthy Volunteers Requires Healthy Volunteers Requires

AA

High Degree of Review and High Degree of Review and OversightOversight

AcknowledgementsAcknowledgements

Dr Janice Parente, Ethica Clinical Research