THE ETHICS OF PLACEBO-CONTROLLED RANDOMIZED

CLINICAL TRIALS

OUTLINE OF ANALYSIS

REGULATORY & PROFESSIONAL GUIDANCE

THE MORAL BASIS FOR THE USE OF PLACEBO CONTROLS

THE WELFARE OF INDIVIDUAL SUBJECTS & THE MORAL LIMITS OF PLACEBO CONTROLS

CIRCUMSTANCES IN WHICH PLACEBO CONTROLS MAY BE MORALLY JUSTIFIED

REGULATORY & PROFESSIONAL GUIDANCE

FEDERAL REGULATIONS

“RISKS TO SUBJECTS ARE MINIMIZED …BY USING PROCEDURES…CONSISTENT WITH

SOUND RESEARCH DESIGN & WHICH DO NOT UNNECESSARILY EXPOSE SUBJECTS TO RISK”

“RISKS TO SUBJECTS ARE REASONABLE IN RELATION TO ANTICIPATED BENEFITS, IF ANY, TO SUBJECTS, AND THE IMPORTANCE OF THE

KNOWLEDGE THAT MAY REASONABLY BE EXPECTED”

DECLARATION OF HELSINKI(2000)

“THE BENEFITS, RISK, BURDENS AND EFFECTIVENESS OF A NEW METHOD SHOULD

BE TESTED AGAINST THOSE OF THE BEST CURRENT PROPHYLACTIC, DIAGNOSTIC AND

THERAPEUTIC METHODS. THIS DOES NOT EXCLUDE THE USE OF PLACEBO, OR NO

TREATMENT, IN STUDIES WHERE NO PROVEN PROPHYLACTIC, DIAGNOSTIC OR THERAPEUTIC METHOD EXISTS.”

CLARIFICATION OF HELSINKION PLACEBO CONTROLS

“IN GENERAL THIS METHODOLOGY SHOULD ONLY BE USED IN THE ABSENCE OF EXISTING PROVEN THERAPY”

EXCEPTIONS:

--“COMPELLING METHODOLOGICAL REASONS”

FOR ITS USE

--INVESTIGATION OF A MINOR CONDITION

& NO RISK OF SERIOUS OR IRREVERSIBLE HARM

TO SUBJECTS

TRI-COUNCIL POLICY STATEMENT (CANADA)

• “THE USE OF PLACEBO CONTROLS IN CLINICAL TRIALS IS GENERALLY UNACCEPTABLE WHEN STANDARD

THERAPIES OR INTERVENTIONS ARE AVAILABLE FOR A

PARTICULAR POPULATION”

CIOMS GUIDELINES ON PLACEBO CONTROLS

• NO EFFECTIVE TREATMENT EXISTS

• USE OF PLACEBO CONTROL ENTAILS MINOR RISKS TO SUBJECTS

• ACTIVE CONTROL WOULD NOT YIELD RELIABLE RESULTS

THE MORAL BASIS FOR THE USE OF PLACEBO CONTROLS

STUDY DESIGN & THE GENERAL WELFARE

• PROMOTION OF THE GENERAL WELFARE OF SOCIETY REQUIRES MINIMZATION OF HARMS

AND MAXIMIZATION OF BENEFITS

• OPTIMAL STUDY DESIGN BOTH MINIMIZES RISK TO SUBJECTS & MAXIMIZES THE PRODUCTION

OF USEFUL INFORMATION

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FACTORS FAVORING THE USE OF PLACEBO CONTROLS

IF ONLY ACTIVE CONTROL IS USED & NEW & CONTROL DRUG PERFORM SIMILARLY,

THEN THE STUDY ITSELF CANNOT DETERMINE WHETHER THEY ARE

EQUALLY EFFECTIVE OR INEFFECTIVE

A PLACEBO CONTROL PERMITS TRIALS WITH RELATIVELY SMALL NUMBERS OF

SUBJECTS, THEREBY REDUCING OVERALL RISK EXPOSURE

SUBJECT WELFARE & MORAL LIMITS ON THE USE OF PLACEBO CONTROLS

PRINCIPLE OF BENEFICENCE

WE OUGHT TO PROTECT AND PROMOTE THE WEFARE OF INDIVIDUAL SUBJECTS

ALTERNATIVE CRITERIA FOR ACCEPTABLE IMPACT ON SUJBECT

WELFARE

WHATEVER SUBJECTS KNOWINGLY & VOLUNTARILY ACCEPT

NO COMPROMISE IN THE WELFARE OF PLACEBO SUBJECTS

NO INCREASED RISK OF SERIOUS, IRREVERSIBLE HARM OR MORTALITY FOR PLACEBO SUBJECTS

RISK-BENEFIT RATIO OF RECEIVING PLACEBO NOT SIGNIFICANTLY LESS FAVORABLE THAN FOR ACTIVE

TREATMENT

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THE CONSENT JUSTIFICATION

IN PRINCIPLE, “VOLENTI NON FIT INJURIA”

GIVEN THE VAGARIES OF INFORMED CONSENT, IT CANNOT BE USED TO

JUSTIFY A SIGNIFICANT INCREMENT OF RISK TO THE WELFARE OF PLACEBO

SUBJECTS

NO COMPROMISE CRITERION

IT IS CONSIDERED ACCEPTABLE TO EXPOSE SUBJECTS TO A LIMITED

INCREMENT OF RISK IN NON-THERAPEUTIC STUDIES

BY PARITY OF REASONING, IT SHOULD BE PERMISSIBLE TO EXPOSE SUBJECTS

TO A LIMITED INCREMENT OF RISK IN PLACEBO-CONTROLLED THERAPEUTIC

STUDIES

THE MORBIDITY/MORTALITY CRITERION

EVEN IN THE ABSENCE OF SERIOUS, IRREVERSIBLE MORBIDITY OR MORTALITY,

PLACEBO SUBJECTS MAY UNDERGO INTOLERABLE SUFFERING

PERMITTING SUBJECTS TO UNDERGO INTOLERABLE SUFFERING IS INCONSISTENT

WITH THE DUTY TO PROTECT THEIR WELFARE

NO SIGNIFICANT COMPROMISE CRITERION

CONSENT NOT REQUIRED TO BEAR EXCESSIVE ETHICAL WEIGHT

RECOGNITION THAT SUBJECTS MAY BE ASKED TO BEAR SOME INCREMENT OF RISK FOR

SCIENCE

AVOIDS PERMITTING INTOLERABLE SUFFERING OF PLACEBO SUBJECTS

SUBJECT WELFARE & PERMISSIBLE RANDOMIZATION

• FOR ANY GROUP ASSIGNMENT, IT MUST NOT BE KNOWN THAT THE

RISK-BENEFIT RATIO IS SIGNIFICANTLY LESS FAVORABLE THAN ANY

ALTERNATIVE TREATMENT

CIRCUMSTANCES IN WHICH PLACEBO CONTROLS MAY BE

MORALLY PERMISSIBLE

SITUATIONS IN WHICH PLACEBO CONTROLS ARE UNCONTROVERSIAL

NO EFFECTIVE TREATMENT EXISTS FOR THE POPULATION BEING STUDIED

EFFECTIVE TREATMENT INVOLVES SIDE EFFECTS FOR MOST PATIENTS THAT ARE HIGHLY UNACCEPTABLE

NEW TREATMENT & PLACEBO CONTROL ARE ADDED ON TO STANDARD TREATMENT FOR ALL SUBJECTS

STUDY INVOLVES A MINOR AILMENT

SITUATION IN WHICH PLACEBO CONTROLS ARE CONTROVERSIAL

KNOWN EFFECTIVE THERAPY WILL BE WITHHELD

SIDE EFFECTS ARE NOT INTOLERABLE FOR MOST SUBJECTS

THE DISEASE HAS SERIOUS CONSEQUENCES FOR PERSONAL

HEALTH

PROBLEMS WITH THE PLACEBO EFFECT ARGUMENT

o RANDOMIZED CLINICAL TRIALS CONTROL FOR THE PLACEBO EFFECT -- ALL GROUPS RECEIVE THE BENEFITS OF

THE PLACEBO EFFECT

o IT MISSES THE CRUCIAL ISSUE OF WHETHER PLACEBO SUBJECTS ARE

SIGNIFICANTLY DISADVANTAGED COMPARED TO PATIENTS RECEIVING

KNOWN EFFECTIVE TREATMENT

PLACEBO CONTROLS WHEN EFFECTIVE THERAPY EXISTS

PLACING PLACEBO SUBJECTS AT SIGNIFICANT DISADVANTAGE MAY BE AVOIDED THROUGH

STUDY DESIGN FEATURES THAT MINIMIZE RISK

THESE FEATURES INCLUDE: SELECTING SUBJECTS WITH LESS SERIOUS DISEASE,

LIMITING DURATION OF PLACEBO EXPOSURE, PERMITTING CONCOMITANT & RESCUE

TREATMENTS, IMPLEMENTING RIGOROUS SUBJECT MONITORING, EMPLOYING STRINGENT WITHDRAWAL CRITERIA

SUMMARY POINTS

US REGULATIONS SILENT, INTERNATIONAL CODES UNFAVORABLY DISPOSED TO PLACEBO CONTROLS

PLACEBO CONTROLS OFTEN REFLECT SOUND STUDY DESIGN THAT MAXIMIZES THE GENERAL WELFARE

ASSIGNMENT TO PLACEBO MUST NOT SIGNIFICANTLY COMPROMISE THE WELFARE OF SUBJECTS

STUDY FEATURES CAN OFTEN BE DESIGNED TO AVOID SIGNIFICANT DISADVANTAGE TO PLACEBO SUBJECTS

EVEN WHEN EFFECTIVE THERAPY EXISTS