What Accounts for Placebo Group Improvements and Can They Be Reduced?

1. What Accounts for Placebo Group Improvements and Can They Be Reduced? John T. Farrar, MD, PhD Departments of Epidemiology Anesthesia (Secondary) and Neurology (Secondary) University of Pennsylvania

2. “Placebo Response” Versus Placebo Group Response • Response in a placebo treated group • Natural history of disease • Regression to the mean • Brain-body effect (placebo effect) • Response in a drug treated group • Natural history of disease • Regression to the mean • Brain-body effect (placebo effect) • Specific effect of the therapy

3. Factors That AffectIndividual Response • Natural history • Regression to the mean • Brain-body effect • This is the only truly individual characteristic “placebo” effect • Specific effect of therapy

4. Descending Pain Modulation Pathways Kandel and Schwartz, Principles of Neural Science

5. Issues in Considering Placebo Response Reduction • Physiologic placebo response • Appropriate to control • Independent from treatment response • No major overlap with treatment response • In-appropriate to control • Similar or related to treatment mechanism • Facilitates treatment response

6. Potential Reasons to Reduce Placebo Group Response Rate • Statistical – Comparison of change in group levels is harder to detect the closer the underlying group response is to 0.5 or 50% • Measurement – Ceiling affect • Reduction in size of the detectable difference between groups (more efficient)

7. Does the Placebo ResponseAffect the Success Rate of RCTs • Larger placebo response is associated with lower likelihood of a statistically positive study* • This does not prove that the higher group placebo rate causes the study failure • Also does not prove that excluding placebo responders would change the results *Katz, Finnerup, Dworkin: Neurology 2008

8. Thoughts About Reducing Placebo Response Rate • Exclude placebo responders? (which type?) • Conduct longer trials – placebo response may not last as long (controversial) • Select patients with worse pain • Lower physiologic placebo response (maybe) • Larger placebo group response (probably) • (Regression to the mean?) 1.Dworkin RH, Turk DC, Peirce-Sandner S, et al. Placebo and treatment group responses in postherpetic neuralgia vs. painful diabetic peripheral neuropathy clinical trials in the REPORT database. Pain. Jul 2010;150(1):12-16.

9. Placebo Rates in Neuropathic Pain Clinical Trials • Placebo response level increased with time up to 19 weeks • Calendar time (since 1990s )– placebo rates have been flat • Placebo response by disease: • PHN average 15% • DPN average 26% *Quessy, Rowbotham: Pain 2008

10. Problems in Placebo “Responder”Exclusion • Placebo run-in responder • Does not definitively identify brain-body placebo responder or non-responder • Natural history/ Regression to the mean • If you remove those getting better will be left with only those getting worse • Those may be likely to get better again in the next period

11. Other Issues to Think About • Even if know it is placebo may respond * • Ranking of placebo – pill vs shot** • Nocebo effect of delayed treatment group • Knowing not getting the new treatment • Proof of concept studies • If can’t show an effect with unblinded administration, then unlikely to be an appreciable effect * Kaptchuk TJ, Friedlander E, Kelley JM, et al. Placebos without deception: a randomized controlled trial in irritable bowel syndrome. PLoS One. 2010;5(12):e15591. **Kaptchuk TJ, Stason WB, Davis RB, et al. Sham device v inert pill: randomised controlled trial of two placebo treatments. BMJ. Feb 18 2006;332(7538):391-397.

12. Design Considerations • Placebo run in • Has not made a difference in depression • Suppressing placebo response may be unhelpful or even counter productive* *Quessy, Rowbotham: Pain 2008

13. Osteo-Arthritis Trials • Did study to look at M-F response to Cox-2 vs Non-specific vs Placebo • Harmonized 6 OA and 5 RA studies • Analyzed to look at prediction of response in placebo and treatment

14. Data Shown – Not Yet Published • Demographics of 9 NSAID Trials • Comparison of Male and Female Response • Predictive Models

15. Neuropathic Pain Studies • Harmonized 8 studies with pain diaries • Neuropathic Pain Group • 3 Diabetic Neuropathy • 1 Post-herpetic neuralgia • 1 Mixed neuropathic pain • 3 Fibromyalgia Studies

16. Data Shown – Not Yet Published • Demographics for Neuropathic Pain • Univariate Model Neuropathic Pain • Multivariate Model Neuropathic Pain • Demographics for Fibromyalgia • Univariate Model Fibromyalgia • Multivariate Model Fibromyalgia

17. BOCF Response Rate in DPNP Studies Variation of Baseline Daily Pain Rating Zhang S, SkljarevskiV, Dworkin RH Poster @ADEPT 2011

18. Future Considerations • Look at other patient characteristics • Baseline SF-36 subscales • Depression measures • Look at other study characteristics • Number of arms • Countries included • Number of recruits per site

19. Thank you • Andrea Troxel • Kevin Haynes • Ann Tierney • FDA • ACTION