THE ETHICS OF PLACEBO-CONTROLLED RANDOMIZED CLINICAL TRIALS

1. THE ETHICS OF PLACEBO-CONTROLLED RANDOMIZED CLINICAL TRIALS

3. 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

4. REGULATORY & PROFESSIONAL GUIDANCE

5. 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”

6. 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.”

7. 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

8. 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”

9. 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

10. THE MORAL BASIS FOR THE USE OF PLACEBO CONTROLS

11. 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

13. 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

14. SUBJECT WELFARE & MORAL LIMITS ON THE USE OF PLACEBO CONTROLS

15. PRINCIPLE OF BENEFICENCE • WE OUGHT TO PROTECT AND PROMOTE THE WEFARE OF INDIVIDUAL SUBJECTS

16. 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

18. 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

19. 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

20. 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

21. 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

22. 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

23. CIRCUMSTANCES IN WHICH PLACEBO CONTROLS MAY BE MORALLY PERMISSIBLE

24. 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

25. 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

26. 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

27. 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

28. 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