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Statistical Summary

Study Summary

BLA 125197.0 is an original submission on Provenge (Sipuleucel-T, APC8015) for the treatment of men with asymptomatic metastatic androgen independent prostate cancer. Data from two randomized, double blind, placebo-controlled studies were submitted as the main efficacy evidence under this BLA to support the licensing application.

Both studies failed to meet their primary endpoints. However, In Study D9901 with 127 patients, the median overall survival in subjects treated with APC8015 was 25.9 months, compared to 21.4 months among placebo subjects. The difference between the two arms in overall survival reached statistical significance (p = 0.01) by the log rank test. Study D9902A, an identically designed study with 98 patients, only showed a trend toward improvement in overall survival. It should be noted that overall survival as an endpoint was not defined in both study protocols and the primary statistical analysis for comparing the two arms in overall survival was not pre-specified. Although none of the pre-specified endpoints reached statistical significance when comparing the two arms in both trials, all comparisons showed a trend in favor of APC8015 arm.

Conclusions

· Based on the results of the statistical analyses of the efficacy data presented by the sponsor and the results of analysis performed by this reviewer, it appears that the two studies provide some evidence in support of using Provenge for the treatment of men with asymptomatic metastatic androgen independent prostate cancer.

· However, the key efficacy evidence (difference between the two arms in overall survival) is based on post-hoc analyses. Although it is impossible to precisely estimate the false positive rate due to the nature of the analyses, it is certain that the level of falsely claiming effectiveness for this product is substantially higher than the one in a conventional setting.

· It may be important to weigh the following points while considering the unfavorable strength of statistical evidence: 1) showing statistically significant difference in overall survival in Study 9901 and showing a trend toward improvement in overall survival in the second study; 2) showing a trend in favor of APC8015 arm in all comparisons for other important endpoints; 3) the safety profile of the product; 4) other existing effective treatments for the targeting patient population.