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 PROCEDURESCONSISTENT 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 HELSINKI
ON 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