Placebo: Why and why not?

1. Placebo: Why and why not? Group Four Mariam Ahmed, Irine Jepchirchir, Dylan Galos, Lucie Turcotte, Chris Campbell, Junghi Kim, and Brett Peterson

2. Placebo • An inactive agent, used in the study control arm, to maintain blinding in a clinical trial • Controls for changes in the course of disease and for suggestion (“placebo effect”) • Can be used as a single agent or as an “add-on” to optimal medical management to facilitate blinding

3. Consider Placebo If: • Limited knowledge of long-term or short-term effects of available therapy • Significant toxicity associated with available or standard therapy • Limited availability of current therapy in certain settings • External data is not clear and considering an active control trial

4. Ellenberg and Temple. Ann Intern Med; 133;464-470.

5. Therapeutic advances Ellenberg, S.S., & Temple, R. Ann Intern Med, 2000; 133;464-470

6. Ethical Considerations • Seriousness of illness • Does withholding treatment increase risk of significant morbidity or decrease survival? • Allergic rhinitis vs. cancer • Informed consent • Does the patient understand the possibility of not receiving active therapy? • If alternative therapies are available, is the patient aware of them and consequences of delaying treatment?

7. Declaration of Helsinki • Article II.3 of the declaration of Helsinki: “in any medical study, every patient—including those of a control group, if any—should be assured of the best proven diagnostic and therapeutic methods”

8. Active Control Trials • Comparing a standard therapy to a test therapy • In order to establish treatment efficacy, one must: • Prove superiority of test over standard, OR • Show equivalence or non-inferiority to known effective therapy • Require information external to the trial • Past placebo-controlled studies proving superiority of standard over placebo Temple and Ellenberg. Ann Int Med 2000.

9. Consider Active Control If: • Assay sensitivity can be assumed • Doing a later phase trial where superiority over standard therapy (relative effectiveness) is question of interest • Placebo is not ethically acceptable

10. Example Ann Intern Med. 2000;133:455-463.

11. Conclusions • Certain situations absolutely preclude use of placebo when effective therapy is available • Less clarity for non-life threatening conditions • Considerations must be given to: • Limitations to existing effective therapy • Importance of blinding • Potential use of optimal medical management • Ability to successfully carry out active control trial • Ultimately trial designers decide