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Statistical Analyses of Efficacy in Studies IT-R-005 and IT-R-006 Shiowjen Lee, Ph.D. Mathematical Statistician Division

Statistical Analyses of Efficacy in Studies IT-R-005 and IT-R-006 Shiowjen Lee, Ph.D. Mathematical Statistician Division of Biostatistics OBE, CBER, FDA October 9 2009. Presentation of Efficacy Findings in Pivotal Studies. Overall co-primary efficacy of azfibrocel-T vs. vehicle

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Statistical Analyses of Efficacy in Studies IT-R-005 and IT-R-006 Shiowjen Lee, Ph.D. Mathematical Statistician Division

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  1. Statistical Analyses of Efficacy in Studies IT-R-005 and IT-R-006 Shiowjen Lee, Ph.D. Mathematical Statistician Division of Biostatistics OBE, CBER, FDA October 9 2009

  2. Presentation of Efficacy Findings in Pivotal Studies • Overall co-primary efficacy of azfibrocel-Tvs. vehicle • Secondary endpoints • Issues and findings • Success rate in Evaluator Wrinkle Severity Assessment • Subgroup results • Summary

  3. Overall Co-Primary Efficacy ofAzfibrocel-T vs. Vehicle

  4. Co-Primary Efficacy Endpointsin Pivotal Studies • Percent of patients who had at least 2-point improvement in Evaluator Wrinkle Severity Assessment from baseline to Month 6 • Percent of patients who had at least 2-point improvement in Subject Wrinkle Assessment from baseline to Month 6

  5. Treatment Success at Month 6 (Primary ITT Analysis)

  6. Observed Treatment Effect • Study IT-R-005: • Evaluator Wrinkle Severity Assess.: 26% • Subject Wrinkle Assess.: 27% • Study IT-R-006: • Evaluator Wrinkle Severity Assess.: 12% • Subject Wrinkle Assess.: 27%

  7. Overall Co-Primary Efficacy Generally robust • Conclusions based on Modified Intent-To-Treat (MITT) and Efficacy Evaluable (EE) analyses in agreement • Conclusions based on different statistical methods for analyses in agreement • Repeated measure • Time to event (sustained success) up to 6-month

  8. Overall Co-Primary Efficacy (cont.) • Missing data handling in ITT analyses • Missing data rate ranged 9% - 20% • Worst case – efficacy trend consistent though not statistically significant

  9. Secondary Endpoints

  10. Pre-Specified Secondary Endpointsin Pivotal Studies • Subject Wrinkle Assess. at Visit 3, 4, and 5 • Evaluator Wrinkle Severity Assess. at Visit 3, 4, and 5 • Subject Improvement Assess. at Month 6 (based on photos) • Evaluator Improvement Assess. at Month 6 (based on photos)

  11. For possible labeling claim, SAP tested following secondary endpoints in hierarchical order: • Subject Improvement Assess. at Month 6 (based on photos) • Evaluator Improvement Assess. at Month 6 (based on photos) • Time-to-sustained success on Subject Wrinkle Assess. • Time-to-sustained success on Evaluator Wrinkle Severity Assess.

  12. Result Summary of Secondary Endpoints • IT is statistically superior to vehicle at Month 6 in • Subject Improvement Assess. (photos) • Evaluator Improvement Assess. (photos) • Time-to-sustained success on Subject Wrinkle Assess. and Evaluator Wrinkle Severity Assess. • Analyses support outcomes of the co-primary endpoints • Subject Wrinkle Assess. and Evaluator Wrinkle Severity Assess. at Visit 3, 4 and 5 were not in SAP for labeling claim

  13. Issues and Findings

  14. Issues • Success rates in Evaluator Wrinkle Severity Assess. are small for IT group at sites 6100, 6300 and 6600 (i.e., 5%, 5% and 10%) • Account for 55% of enrollment in IT-R-006 • Efficacy in subgroups of • Non-white • Male • Elders (age >= 65)

  15. Evaluator Wrinkle Severity Assess. Across Site • Factors of age, baseline wrinkle severity, missing data rate, and injection volume cannot explain the low success rates in Evaluator Assessment at sites 6100, 6300 and 6600

  16. Evaluator Wrinkle Severity Assess.Across Site(Cont.) • Impact of the 3 sites

  17. Subgroup Results (co-primary) • Efficacy in subgroups of female (90%) and white subjects (92%) each is similar to the overall ITT result • Consistent efficacy trend of IT numerically better than vehicle for: • Male group (about 9.7%) • Baseline total wrinkle length • Baseline Evaluator Wrinkle Severity Assess. • Baseline Subject Wrinkle Assess.

  18. Subgroup Results by Age

  19. Subgroup Results by Age (cont.)

  20. Summary

  21. Summary of Statistical Analyses • IT is statistically superior to vehicle regarding success rates in Evaluator Wrinkle Severity Assess. and Subject Wrinkle Assess. for each study • Results of secondary endpoints support the outcomes of co-primary endpoints • Evidence of IT efficacy for male and non-white subjects is limited • Observed numerically reverse trend in different endpoints for the two trials in elders (aged >=65) • Efficacy of IT beyond 6-month has not been established

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