1. 1 Statistical Issues in NDA 21239 Laura Lu, Ph.D FDA/CDER

2. 2 Outline ITT vs. Per-Protocol Analyses in Study 95-02 Definitions for A Responder in Study 95-02 –Original Definition –Window Definition Proposed by Sponsor –Window Sensitivity Analysis Subgroup Analysis in Patients with Baseline SLEDAI>2

3. 3 ITT vs. Per-Protocol Population in Study 95-02 ITT Population –Specified in the original protocol –All randomized patients Per-Protocol Population –Proposed in a later submitted statistical plan (most patients had finished study) –Excluded drop-outs within the first 60 days

4. 4 ITT Analysis Preserves randomization---the base for valid statistical inference. In general, avoids over estimation of treatment effect.

5. 5 Sponsor’s Argument for Per- Protocol Analysis Treatment needs at least 60 days to take into effect

6. 6 Patient Disposition in Patients Excluded from ITT Population

7. 7 Validity of Per-Protocol Analysis? Excluding early dropouts in the per- protocol analysis may bias conclusion--there are treatment related dropouts.

8. 8 Original Definition for A Responder in Study 95-02 Improvement or stabilization in SLAM, SLEDAI, KFSS, Patient VAS (post-baseline weighted average of each score no worsening than the baseline score) No clinical deterioration

9. 9 Result for Responder Rate (ITT)

10. 10 Later Proposed Window for Responder Definition Compared with baseline, post- baseline weighted average for –SLAM no worse than 1 –SLEDAI no worse than 0.5 –KFSS no worse than 0.5 –Patient VAS no worse than 10 No clinical deterioration

11. 11 Window Definition by Percent of Change from Baseline For example, a -5% window definition for a responder is 1) weighted average for each of SLAM, SLEDAI, KFSS and Patient VAS no worse than 5% from baseline 2) no clinical deterioration

12. 12

13. 13 Sensitivity of Responder Rate to Window Definition The numerical trend of responder rates in treatment groups is sensitive to whether worsening is allowed in the responder definition.

14. 14 Subgroup Analysis in Patients with Baseline SLEDAI>2 Study 94-01: Hypothesis Generating Study 95-02: Specified in Protocol Amendment

15. 15 Results in Study 94-01 Responder Rate

16. 16 Results in Study 94-01 (cont.) Percent Change from Baseline in Prednisone Dose in Baseline SLEDAI>2 Group

17. 17 Results in Study 95-02 Responder Rate (original definition, ITT population)

18. 18 Results in Baseline SLEDAI>2 Group In Study 94-01, the results of primary endpoints were not consistent in baseline SLEDAI>2 group. –Numerical advantage in responder rate –no advantage in mean percent change in prednisone dose

19. 19 Results in Baseline SLEDAI>2 Group In Study 95-02, DHEA showed numerical advantage over placebo in responder rate in patients with baseline SLEDAI>2. Statistical significance was not demonstrated by ITT analysis with original definition (p=0.17). A small p-value (0.005) was found by per-protocol analysis with a window definition.

20. 20 Question Are additional studies needed for the baseline SLEDAI>2 group to support an efficacy claim?

21. 21

22. 22

23. 23