1. Statistical Considerations on NDA 21-200 Sonia Castillo, Ph.D. Division of Biometrics 2 June 26, 2000

2. 2 Outline uBackground uEfficacy Analyses by Gender uAbdominal Pain as an Efficacy Endpoint uLaxative Use uPooling of Studies uSummary

3. 3 Background on Clinical Studies

4. 4 uStudy 351 was completed and analyzed first uProtocol specified efficacy results were not significant uDefinition of a responder was modified uPost-hoc analysis of data gave significant results uLed to protocol amendments for studies 301 and 307 uThere are two studies in which the analysis presented is prospective and one in which it is post-hoc

5. 5 Amendments to Protocols uOriginal protocol for all three studies uSubject Global Assessment of abdominal discomfort/pain was the primary efficacy variable uEnrollment of 591 intent-to-treat patients

6. 6 Subject Global Assessment of Abdominal Discomfort/Pain Patients placed a vertical mark on the line in response to the following question: "How much of a problem was your abdominal discomfort/pain over the last week?” discomfort/pain over the last week?”

7. 7 Definition of Responder for SGA of Abdominal Discomfort/Pain uA responder was a patient who had a  20 mm and  40% reduction in the mean VAS at study endpoint (the last 4 weeks on treatment) compared to the baseline value

8. 8 Amendments to Protocols uAn amendment was submitted prior to start of all studies uSubject Global Assessment of relief was added as a second primary efficacy variable uEnrollment of 693 intent-to-treat patients

9. 9 Subject Global Assessment of Relief Patients responded on a weekly basis to the following question: "Please consider how you felt this past week in regard to your IBS, in particular your overall well-being, and symptoms of abdominal discomfort, pain and altered bowel habit. Compared to the way you usually felt before entering the study, how would you rate your relief of symptoms during the past week?" Completely relievedConsiderably relieved Somewhat relievedUnchanged Worse

10. 10 Definition of Responder for SGA of Relief uA responder was a patient who had Complete or considerable relief at least 50% of the time at study endpoint (the last 4 weeks on treatment) uDefinition of responder took into account the following uNumber of days with laxative use during treatment period is  5 and no laxative use during the last 28 days of treatment uDuration of exposure to study medication is  28 days uAt least one post-baseline SGA of relief

11. 11 Amendments to Protocols uAfter post-hoc analysis of study 351, another amendment was submitted before breaking the blind in studies 301 and 307 uDefinition of responder for SGA of relief was modified: Complete or considerable relief at least 50% of the time at study endpoint OR Complete or considerable or somewhat relief 100% of the time at study endpoint uSGA of relief became the only primary efficacy variable uSGA of abdominal discomfort/pain was changed from a primary to a secondary efficacy variable

12. 12 Subject Global Assessment of Relief

13. 13 Subject Global Assessment of Abdominal Discomfort/Pain

14. 14 Subject Global Assessment of Relief by Gender

15. 15 Gender Conclusions uEfficacy results are mixed in female patients uEfficacy is not demonstrated in male patient uThe lack of efficacy in male patients may be due to the small sample size uThe results for female and male patients may indicate a difference in the pathophysiology of C-IBS between genders

16. 16 Importance of Abdominal Pain in Evaluating Efficacy uChanging SGA of abdominal discomfort/pain from a primary to a secondary efficacy variable is of clinical concern uPain is an important clinical component of IBS uTreatment difference for SGA of abdominal discomfort/pain was not significant in any of the 3 studies

17. 17 Not Accounting for All Laxative Use Affects the Efficacy Assessment uLaxative and bulking agent use affects bowel habit and abdominal discomfort uLaxative and bulking agent use need to be accounted for in the definition of a responder for all analyses of SGA of relief and SGA of abdominal discomfort/pain uData on the amount of bulking agent taken was not collected

18. 18 Reasons Why Pooling is not Appropriate to Demonstrate Efficacy uPooled analysis not pre-specified in the protocol uDesign of study 307 is different from the other studies uDifferent endpoint interpretations uStudy 307 tests a fixed dose group and a titration regimen group uStudies 301 and 351 test two fixed dose groups u4-12 mg titration group is not the same as 12 mg group uUp-titration was based on original definition of responder

19. 19 Reasons Why Pooling is not Appropriate to Demonstrate Efficacy (cont.) uPooling the 3 studies into one large study is inadequate uGives a larger study population and a smaller p-value uEach study is adequately sized to show efficacy individually Intent-to-treat sample size at study end was larger than planned: 27% larger in study 301 (881 vs 693) 20% larger in study 307 (835 vs 693) uWe are left with one study and no replication of results

20. 20 Reasons Why Pooling is not Appropriate to Demonstrate Efficacy (cont.) uPooling 1 negative study with 2 positive studies is problematic uAnalysis is data driven and biased  uninterpretable p-value uNegative results of study 307 appear “acceptable” in the light of a positive overview

21. 21 Summary uEfficacy was demonstrated in female patients in study 301 and supported in a post-hoc analysis of study 351 but not replicated in study 307 uEfficacy was not demonstrated for either dose in study 307. Why? uEfficacy has not been adequately assessed in male patients uThe effect of treatment on abdominal pain has not been adequately assessed and demonstrated uThe effect of laxative and bulking agent use remains to be determined uPooled study results are not appropriate to demonstrate efficacy