THE ETHICS OF PLACEBOCONTROLLED RANDOMIZED CLINICAL TRIALS

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THE ETHICS OF PLACEBO-CONTROLLED RANDOMIZED
CLINICAL TRIALS
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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

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REGULATORY PROFESSIONAL GUIDANCE
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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

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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.

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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

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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

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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

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THE MORAL BASIS FOR THE USE OF PLACEBO CONTROLS
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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

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SUBJECT WELFARE MORAL LIMITS ON THE USE OF
PLACEBO CONTROLS
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PRINCIPLE OF BENEFICENCE

• WE OUGHT TO PROTECT AND PROMOTE THE WEFARE OF
  INDIVIDUAL SUBJECTS

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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

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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

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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

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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

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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

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CIRCUMSTANCES IN WHICH PLACEBO CONTROLS MAY BE
MORALLY PERMISSIBLE
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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

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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

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PROBLEMS WITH THE PLACEBO EFFECT ARGUMENT

• RANDOMIZED CLINICAL TRIALS CONTROL FOR THE
  PLACEBO EFFECT -- ALL GROUPS RECEIVE THE BENEFITS
  OF THE PLACEBO EFFECT
• IT MISSES THE CRUCIAL ISSUE OF WHETHER PLACEBO
  SUBJECTS ARE SIGNIFICANTLY DISADVANTAGED COMPARED
  TO PATIENTS RECEIVING KNOWN EFFECTIVE TREATMENT

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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

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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