1. NDA 21-240 Study MP-US-M01

2. Division of Oncology Drug Products 2 Federal Food, Drug, and Cosmetic Act of 1962 Substantial Evidence = Adequate and well-controlled investigations Modernization Act 1997 –Data from one adequate and well controlled clinical investigation and confirmatory evidence can be considered substantial evidence by the Agency

3. Division of Oncology Drug Products 3 Reasons a Single Study is Generally Not Adequate Any trial may be subject to unanticipated, undetected, systematic biases that could lead to flawed conclusions Inherent variability may produce a positive trial by chance alone –1/40 studies of ineffective drugs will be positive (p=0.05)

4. Division of Oncology Drug Products 4 Causes of False-Positive Studies (Tannock, JCO Nov 2000) Chance Prognostic Factor Imbalances Multiplicity Low Prior Probability a New Treatment will be a Therapeutic Advance –1/3 “positive trials” are false positive in this hypothetical setting

5. Division of Oncology Drug Products 5 Hypothetical Situation - Low Prior Probability of Therapeutic Advance

6. Division of Oncology Drug Products 6 Role of Tamoxifen in the Treatment of Metastatic Melanoma Cocconi, et al NEJM August 1992. – Dacarbazine + Tamoxifen vs. Dacarbazine –Survival 48 weeks vs. 29 weeks, p=0.02 Subsequent Non-Confirmatory Trials –ECOG (Falkson, et al; JCO May 1998) –Intergroup (Chapman, et al; JCO 1999) –NCI Canada (Rusthoven, et al; JCO 1996) –Mayo (Creagan, et al; JCO June 1999) –U. Pittsburgh (Agarwala, et al; Cancer 1999)

7. Division of Oncology Drug Products 7 FDA Guidance for Industry Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products Reliance on a single study “whether alone or with substantiation from related trial data leaves little room for study imperfections or nonsupportive information” Limited to where confirmation would be practically or ethically impossible

8. Division of Oncology Drug Products 8 What Makes a Single Study Persuasive? Large, multicenter study Appropriate Design Flawless conduct Minimal possibility of bias due to baseline imbalances, unblinding and post-hoc changes in analysis

9. Division of Oncology Drug Products 9 What Makes a Single Study Persuasive? Results should reflect a clear hypothesis documented in the protocol Statistically persuasive

10. NDA 21-240 Study MP-US-M01

11. Division of Oncology Drug Products 11 Review Randomized, Controlled Multicenter Trial, BUT it is a Single Trial ITT Analysis of the Primary Endpoint was not Statistically Significant

12. Division of Oncology Drug Products 12 Apparent Survival Benefit in a Subset Analysis - Liver Metastases BUT there were imbalances in prognostic factors favoring the histamine/IL-2 arm AND the FDA’s adjusted analyses showed that imbalances influenced the observed treatment effect

13. Division of Oncology Drug Products 13 Questions Does the survival difference in the planned primary analysis of this single study, the ITT analysis of survival, represent substantial evidence of the efficacy of histamine dihydrochloride as an adjunctive treatment with IL-2 for patients with metastatic melanoma?

14. Division of Oncology Drug Products 14 Questions Does the survival difference observed in the subgroup of patients with liver metastases in this single study represent substantial evidence of the efficacy of histamine dihydrochloride as an adjunctive treatment with IL-2 for patients with melanoma that has metastasized to the liver?

15. Division of Oncology Drug Products 15 Questions In view of the efficacy results, is the safety profile of the histamine/IL-2 combination acceptable?

16. Division of Oncology Drug Products 16