NDA 21-240 Study MP-US-M01. Division of Oncology Drug Products 2 Federal Food, Drug, and Cosmetic Act of 1962 Substantial Evidence = Adequate and well-controlled

NDA 21-240

Study MP-US-M01

Division of Oncology Division of Oncology Drug ProductsDrug Products

22

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


33

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)


44

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


55

Hypothetical Situation - Low Prior Probability of Therapeutic

Advance

90% Power18 Tria ls D em onstrate the E ffect

10% E ffective20 True Positive T ria ls

5% False Positive R ate9 Tria ls False Positive

90% Ineffective180 True N egative T ria ls

200 Tria ls


66

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)


77

FDA Guidance for IndustryProviding 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


88

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


99

What Makes a Single Study Persuasive?

• Results should reflect a clear hypothesis documented in the protocol

• Statistically persuasive

NDA 21-240Study MP-US-M01


1111

Review

• Randomized, Controlled Multicenter Trial, BUT it is a Single Trial

• ITT Analysis of the Primary Endpoint was not Statistically Significant


1212

• 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


1313

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?


1414

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?


1515

Questions

• In view of the efficacy results, is the safety profile of the histamine/IL-2 combination acceptable?


1616

Documents

NDA 21-240 Study MP-US-M01. Division of Oncology Drug Products 2 Federal Food, Drug, and Cosmetic Act of 1962 Substantial Evidence = Adequate and well-controlled