The CIOMS view on use of placebo in clinical trials

1. The CIOMS view on use of placebo in clinical trials Professor Juhana E. Idänpään-Heikkilä, MD, PhD Secretary-General Council for International Organizations of Medical Sciences (CIOMS) c/o WHO, Geneva, Switzerland www.cioms.ch

2. What guidance is included in theCIOMS 2002 International Ethical Guidelines for Biomedical Research Involving Human Subjects ?

3. What isCIOMS? • International, non-governmental, non-profit-making organization • Established 1949 by WHO and UNESCO • A forumto consider and prepare advice on: 1. contentious issues in health and research ethics (for WHO, UNESCO and others) and 2. safe use of medicinal products Members: Over 70international/national biomedical science organizations/bodies

4. Purpose of CIOMS 2002 guidelines Indicate/advise how fundamentalethical principles can be applied effectively inmedical research worldwide in different: • cultures, religions, traditions; • socioeconomic circumstances; • national legal and administrative contexts; • and situations indeveloping countries • implementation in practice of the Declaration of Helsinki

5. Revision process • First draft prepared by a consultant in 1998 • Steering Committee in May 1999 • International Consultation in March 2000, report published in November 2000 • Drafting Group meeting in January 2001 • Draft on CIOMS website July-October 2001 • Comments from over 70 organizations/persons • Electronic editorial group in October 2001 • CIOMS Conference in February 2002 • CIOMS Executive Committee endorsed Aug.2002 • Final version on website Sept. 2002 , publication out in mid-October 2002

6. General guidance for clinical research GL. 1: Ethical justification and scientific validity of biomedical research involving human beings (Pacebo controlled study no exception) • GL. 11: Choice of control in clinical trials ( Placebo as comparator/control )

7. GL. 1: Ethical justification and scientific validity of biomedical research involving human subjects • Justification: The prospect is to discover new ways of • benefiting people’s health • Ethical justification: -Respect and protect and be fair to participating subjects -Conform to scientific principles as invalid research is unethical and exposes to risks without possible benefit -Design scientifically sound, competent investigator/staff -Protocol submitted for review / clearance / approval to scientific and ethical review committees (Items to be included in the protocol, see Appendix 1)

8. GL. 3: Ethical review of externally sponsored research • Definition: what is “externally sponsored research” • Ethical and scientific review • Committees in both country of sponsor and host 1.Committee of sponsoring country: are scientific methods sound, suitable to the aims of research, are products safe, justification for not conducting study in sponsoring country 2.Committee of host country: Responsiveness to health needs and priorities of country, understanding of customs and traditions, means of obtaining informed consent, competence of research team

9. GL. 4: Individual informed consentGL. 5: Obtaining informed consent:: prior information GL. 6:Obtaining informed consent:. Obligations of sponsor and investigator GL. 4: Adequate understanding of information (language and comprehension), choose freely to participate, documentation of consent GL. 5: For controlled trials, an explanation of features of research design (e.g. randomization, double-blinding), subjects not told of the assigned treatment until study completed GL. 6: Ensure adequacy of informed consent, answer questions, time to consider, renewal of consent

10. WMA Declaration of Helsinki Para. 29: “The benefits, risks, burdens and effectiveness of a new method should be tested against those of the best current ……. methods.” “This does not exclude the use of placebo, or no treatment, in studies where no proven …. method exists.”

11. CIOMS Guidelines versus Declaration of Helsinki CIOMS Guidelines depart in Guideline 11 from the terminology of the Declaration of Helsinki: • Declaration of Helsinki paragraph 29: “The best current…therapeutic methods” • CIOMS GL. 11:“Established effective intervention”

12. CIOMS note on GL. 11 “Best current intervention” (as the term is understood in CIOMS Guidelines): Is the term most commonly used to describe the active comparator that is ethically preferred in controlled clinical trials. For many indications, however, there is more than one established “current” intervention and expert clinicians do not agree on which is superior. In other circumstances in which there are several established “current” interventions, some expert clinicians recognize one as superior to the rest; some commonly prescribe another because the superior intervention may be locally unavailable, for example, or prohibitively expensive or unsuited to the capability of particular patients to adhere to a complex and rigorous regimen.

13. CIOMS note on GL. 11 “Established effective intervention”is used in the CIOMS GLs with the following meaning: The term (used in Guideline 11) refers to all such interventions, including the best and the various alternatives to the best. In some cases an ethical review committee may determine that it is ethically acceptable to use an established effective intervention as a comparator, even in cases where such an intervention is not considered the best current intervention. Can placebo be established effective intervention? Yes ?

14. GL. 11 Choice of control in clinical trials (placebo?) • As a general rule control group should receive an established effective intervention BUT • in some circumstances placebo or ”no treatment” may be used: -when there is no established effective intervention; -when withholding effective intervention would expose to, at most, temporary discomfort or delay in relief of symptoms; -when use of an established effective treatment as comparator would not yield scientifically reliable results and placebo would not add any risk of serious or irreversible harm

15. ARGUMENTS PRO PLACEBO • Placebo use O.K. in mild conditions (baldness, smoking cessation, overweight, headache, allergic reactions, mild elevation of cholesterol/blood pressure, etc.) • Active comparator unreliable because -no proven efficacy or scientific proof -treatment response in condition may vary or spontaneous improvement high -treatment response is modest (almost same as placebo) -study yields no reliable scientific result and thus is unethical

16. ARGUMENTS AGAINST PLACEBO USE • Comparison with existing therapy is the point, not comparison with placebo ! (but may be a regulatory requirement !: USFDA/CPMP) • Unavailability of estbalished effective intervention cannot justify a placebo study in resource-poor country if same study considered unethical in industrialized countries • Placebo use may be harmful -symptoms continue -disease may worsen, result in irreversible change -death (?)

17. Comparison of two active therapies can be unethical ! STUDY A: New therapy: expected response rate 60% Existing therapy: response rate 60% Some 300 plus 300 patients are needed to prove equivalence STUDY B: New therapy: expected response rate 60% Placebo response rate 30% Only 50 plus 50 patients needed to prove equivalence IS STUDY A UNETHICAL ? (Modified from Emanuel EJ and Miller FG: NEJM 2001;345:915-919 )

18. WHEN IS PLACEBO AS A COMPARATOR ETHICAL ? • Reason to use a placebo is scientifically sound and • Ethically acceptable as a comparator if: -no proven intervention exists -mild condition, and surveillance in place -use causes no increased harm -duration of placebo use is minimised -escape/reserve treatment available -valid informed consent obtained from volunteers -ethical review committee agrees

19. CIOMS Council for International Organizations of Medical Sciences (CIOMS) c / o WHO CH-1211 Geneva 27, Switzerland phone: +41-22-791 3406 fax: +41-22-791 3111 www.cioms.ch