1. 27 June 2000Victor F. C. Raczkowski, M.D.1 Benefit-Risk Reevaluation of Marketed Drugs Victor F. C. Raczkowski, M.D., M.S. Gastrointestinal Drugs Advisory Committee 27 June 2000

2. Victor F. C. Raczkowski, M.D.2 FDA Presentations: Themes Benefit-Risk Evaluation of Lotronex –Potential Benefits of Lotronex –Potential Risks of Lotronex –Benefit-Risk Balance for Lotronex Risk-Management Options Assessing the Impact of Risk-Management Interventions

3. 27 June 2000Victor F. C. Raczkowski, M.D.3 FDA Presentations Introduction and Benefit-Risk Reevaluation of Marketed Drugs –V Raczkowski, MD, MSc Lotronex and Serious Adverse Events of the GI Tract –H Gallo-Torres, MD, PhD

4. 27 June 2000Victor F. C. Raczkowski, M.D.4 FDA Presentations Risk-Management Options –V Raczkowski, MD, MSc Medication Guides –N Ostrove, PhD

5. 27 June 2000Victor F. C. Raczkowski, M.D.5 FDA Presentations Risk-Intervention Studies –E Rodriguez, MD, MPH Summary of Issues –V Raczkowski, MD, MSc

6. 27 June 2000Victor F. C. Raczkowski, M.D.6 Benefits of Lotronex Lotronex is indicated for the treatment of irritable bowel syndrome (IBS) in women whose predominant bowel symptom is diarrhea The safety and effectiveness of Lotronex in men have not been established.

7. 27 June 2000Victor F. C. Raczkowski, M.D.7 Benefits of Lotronex: Issues Limit administration of Lotronex to target population Limit administration of Lotronex to responders

8. 27 June 2000Victor F. C. Raczkowski, M.D.8 Benefits of Lotronex: Issues If a drug is not effective in a population taking a drug, those patients experience risk without benefit If a drug is not effective in an individual taking a drug (i.e., the patient is a non- responder), that patient experiences risk without benefit

9. 27 June 2000Victor F. C. Raczkowski, M.D.9 Limit Lotronex Administration to Target Population

10. 27 June 2000Victor F. C. Raczkowski, M.D.10 What is the Target Population? Target population for Lotronex is women with diarrhea-predominant IBS Not indicated for women with other subtypes of IBS Example: Subgroup analyses suggest Lotronex may not be effective in women with IBS who have alternating diarrhea and constipation

11. 27 June 2000Victor F. C. Raczkowski, M.D.11 Need for Legitimate Diagnosis of Irritable Bowel Syndrome Lotronex should be used only in women with a genuine diagnosis of diarrhea- predominant irritable bowel syndrome –Not a casual diagnosis of IBS –Not a misdiagnosis of IBS Identify specific criteria or tests needed for selection of women who might benefit from use?

12. 27 June 2000Victor F. C. Raczkowski, M.D.12 Other Populations Not indicated for men: Data suggest Lotronex is not effective in men even at dosages eight times that used in women Not indicated for pediatric use: Lack of data

13. 27 June 2000Victor F. C. Raczkowski, M.D.13 Limit Administration of Lotronex to Responders

14. 27 June 2000Victor F. C. Raczkowski, M.D.14 Lotronex Responders: The Issue 40% of women with diarrhea-predominant IBS did not improve 40-50% improved spontaneously or due to other factors (e.g., placebo effect) Only in 10-20% improvement attributable to Lotronex

15. 27 June 2000Victor F. C. Raczkowski, M.D.15 Study 3001: Diarrhea-Predominant Subgroup: Monthly Relief of IBS Pain/Discomfort: LOCF

16. 27 June 2000Victor F. C. Raczkowski, M.D.16 Study 3002: Diarrhea-Predominant Subgroup: Monthly Relief of IBS Pain/Discomfort: LOCF

17. 27 June 2000Victor F. C. Raczkowski, M.D.17 Responders: Conclusions Of women with diarrhea-predominant IBS who take Lotronex and improve, 68-80% improve spontaneously or due to other factors not attributable to Lotronex Many may continue to take Lotronex because of false belief that improvement is due to drug

18. 27 June 2000Victor F. C. Raczkowski, M.D.18 Responders: Conclusions These patients are exposed, possibly chronically, to risk without benefit Terminate treatment in patients who fail to respond to Lotronex? Identify specific conditions that should be met before drug is used on a long-term basis (e.g., identify responders)?

19. 27 June 2000Victor F. C. Raczkowski, M.D.19 Benefit: Overall Conclusions Lotronex is a palliative (not curative) treatment for IBS Lotronex has not been shown to prevent progression of IBS symptoms Proportion of women who have benefit attributable to Lotronex is modest

20. 27 June 2000Victor F. C. Raczkowski, M.D.20 Benefit: Overall Conclusions Administration of Lotronex only to target population would help optimize benefit-risk ratio Administration of Lotronex only to true responders would help optimize benefit-risk ratio