1. Food and Drug Administration Division of Pulmonary and Allergy Drug Products Pulmonary-Allergy Drugs Advisory Committee Meeting July 13, 2005 Safety of Long-acting Beta-agonist Bronchodilators Salmeterol Sally M. Seymour, M.D. Medical Officer Division of Pulmonary and Allergy Drug Products

2. Food and Drug Administration Division of Pulmonary and Allergy Drug Products July 13, 2005 PADAC Meeting 2 Salmeterol  Regulatory History  Post-marketing Studies  Serevent Nationwide Surveillance Study (SNS)  Salmeterol Multicenter Asthma Research Trial (SMART)  Post-marketing Spontaneous Reports  Product Label  Summary

3. Food and Drug Administration Division of Pulmonary and Allergy Drug Products July 13, 2005 PADAC Meeting 3 Salmeterol  Regulatory History  Post-marketing Studies  Serevent Nationwide Surveillance Study (SNS)  Salmeterol Multicenter Asthma Research Trial (SMART)  Post-marketing Spontaneous Reports  Product Label  Summary

4. Food and Drug Administration Division of Pulmonary and Allergy Drug Products July 13, 2005 PADAC Meeting 4 Regulatory History  Serevent Inhalation Aerosol  Approved February 1994 for asthma  Maintenance treatment of asthma & prevention of bronchospasm in patients with reversible obstructive airways disease  Discontinued by Sponsor as part of CFC phase out  Serevent Diskus  Approved September 1997  Advair Diskus  Fluticasone propionate & salmeterol xinafoate  Approved August 2000

5. Food and Drug Administration Division of Pulmonary and Allergy Drug Products July 13, 2005 PADAC Meeting 5 Regulatory History  Salmeterol Inhalation Aerosol NDA  Two Phase 3 twelve-week clinical trials (n=556) Improvement in FEV1 Improvement in AM PEFR Improvement in mean % days and mean % nights with no asthma symptoms Less rescue medication use  SNS results considered  Advisory committee February 1993  Approved February 1994 for asthma

6. Food and Drug Administration Division of Pulmonary and Allergy Drug Products July 13, 2005 PADAC Meeting 6 Regulatory History  Reports of life-threatening respiratory events and fatalities within first 6 months after approval  Label revised January 1995 – new WARNINGS  Serious acute respiratory events, including fatalities have been reported with salmeterol  Salmeterol not for acute symptoms  Salmeterol not a substitute for inhaled corticosteroids  Salmeterol should not be initiated in worsening or acutely deteriorating asthma  Patients should have a short acting beta agonist for acute symptoms

7. Food and Drug Administration Division of Pulmonary and Allergy Drug Products July 13, 2005 PADAC Meeting 7 Regulatory History  Physician and patient education program  Sponsor committed to safety study  Salmeterol Multicenter Asthma Research Trial (SMART)  Safety study in 30K patients with asthma  SMART initiated July 1996  Amended June 1999 to increase population from 30K to 60K

8. Food and Drug Administration Division of Pulmonary and Allergy Drug Products July 13, 2005 PADAC Meeting 8 Regulatory History  SMART  Planned Interim analysis in 2002 26K enrolled  DSMB analysis Point estimates suggested excess risk with salmeterol in total population African Americans may be at particular risk  DSMB recommendations Optimal to continue study if timely recruitment feasible If timely recruitment not feasible, terminate study and disseminate findings within 3-6 months

9. Food and Drug Administration Division of Pulmonary and Allergy Drug Products July 13, 2005 PADAC Meeting 9 Regulatory History  Sponsor terminated SMART in January 2003  Dear Healthcare Professional Letter January 2003  Label revised August 2003 based upon preliminary SMART data  Boxed Warning  Information regarding SMART in Clinical Trials Section  Full SMART data submitted August 2003  NDI search performed and adjudication pending  SMART study report submitted February 2004  Included adjudicated NDI data  Label revised September 2004

10. Food and Drug Administration Division of Pulmonary and Allergy Drug Products July 13, 2005 PADAC Meeting 10 Salmeterol  Regulatory History  Post-marketing Studies  Serevent Nationwide Surveillance Study (SNS)  Salmeterol Multicenter Asthma Research Trial (SMART)  Post-marketing Spontaneous Reports  Product Label  Summary

11. Food and Drug Administration Division of Pulmonary and Allergy Drug Products July 13, 2005 PADAC Meeting 11 Serevent Nationwide Surveillance Study (SNS)  Randomized, double-blind, active-controlled (salbutamol), parallel group, 16-week trial in UK  N=25,180 (2:1 randomization)  Salmeterol 50mcg BID vs. salbutamol 200mcg QID  Clinic visits after 4, 8, and 16 weeks  Outcome measures  Serious adverse events  Reasons for withdrawals BMJ 1993; 306:1034-7

12. Food and Drug Administration Division of Pulmonary and Allergy Drug Products July 13, 2005 PADAC Meeting 12 Serevent Nationwide Surveillance Study (SNS) - Results BMJ 1993; 306:1034-7

13. Food and Drug Administration Division of Pulmonary and Allergy Drug Products July 13, 2005 PADAC Meeting 13 Salmeterol  Regulatory History  Post-marketing Studies  Serevent Nationwide Surveillance Study (SNS)  Salmeterol Multicenter Asthma Research Trial (SMART)  Post-marketing Spontaneous Reports  Product Label  Summary

14. Food and Drug Administration Division of Pulmonary and Allergy Drug Products July 13, 2005 PADAC Meeting 14 Salmeterol Multicenter Asthma Research Trial (SMART) Protocol  Multi-center, randomized, double-blind, placebo- controlled, parallel group study  Treatment period: 28 weeks  Sample Size: 30,000 (increased to 60,000 in 1999)  Age  12 yrs  Clinical diagnosis of asthma  Currently taking asthma medications, but no LABA  Treatment groups:  Salmeterol MDI 50mcg BID  Placebo BID  One clinic visit then phone calls Q 4wks

15. Food and Drug Administration Division of Pulmonary and Allergy Drug Products July 13, 2005 PADAC Meeting 15 SMART Protocol  Primary Endpoint: Combined respiratory-related deaths and respiratory-related life-threatening experiences (intubation & mechanical ventilation)  Key Secondary Endpoints:  Asthma-related death  Asthma-related deaths and life-threatening experiences  All-cause SAEs  All-cause death

16. Food and Drug Administration Division of Pulmonary and Allergy Drug Products July 13, 2005 PADAC Meeting 16 SMART Protocol  Non-inferiority design - not designed to show a difference between salmeterol and placebo  Powered to rule out  40% increase in combined respiratory related deaths and life threatening experiences  3 times increase in asthma related deaths  Planned interim analysis after ~half of subjects enrolled  Stopping Criteria RR of 1.4 for primary endpoint, alpha =.01 RR of 3 for asthma related deaths, alpha =.01

17. Food and Drug Administration Division of Pulmonary and Allergy Drug Products July 13, 2005 PADAC Meeting 17 SMART – Interim Analysis  Interim analysis performed after 26K enrolled in 2002  DSMB reviewed data  Potential treatment group difference  African Americans may be at particular risk  DSMB recommended  Continue study if recruitment feasible  Terminate study if recruitment not feasible and disseminate findings within 3-6 months  SMART terminated January 2003

18. Food and Drug Administration Division of Pulmonary and Allergy Drug Products July 13, 2005 PADAC Meeting 18 SMART Results  Results from early termination of study  Did not meet pre-specified stopping criteria  Did not meet non-inferiority objective  Suggested a difference in some endpoints  Based upon 28 week treatment period  Inclusion of NDI search data  Life table analyses

19. Food and Drug Administration Division of Pulmonary and Allergy Drug Products July 13, 2005 PADAC Meeting 19 SMART Results - Disposition

20. Food and Drug Administration Division of Pulmonary and Allergy Drug Products July 13, 2005 PADAC Meeting 20 SMART Results - Demographics

21. Food and Drug Administration Division of Pulmonary and Allergy Drug Products July 13, 2005 PADAC Meeting 21 SMART Results – Primary EP *Intubation and mechanical ventilation

22. Food and Drug Administration Division of Pulmonary and Allergy Drug Products July 13, 2005 PADAC Meeting 22 SMART Results – Key Secondary EP

23. Food and Drug Administration Division of Pulmonary and Allergy Drug Products July 13, 2005 PADAC Meeting 23 SMART Results Inhaled Corticosteroid (ICS) Use  ICS analyses all post hoc  ICS use recorded at baseline  ICS not randomly assigned  47% total population used ICS  50% Caucasians used ICS  38% African Americans used ICS

24. Food and Drug Administration Division of Pulmonary and Allergy Drug Products July 13, 2005 PADAC Meeting 24 SMART Results - ICS Use

25. Food and Drug Administration Division of Pulmonary and Allergy Drug Products July 13, 2005 PADAC Meeting 25 SMART Results - ICS Use

26. Food and Drug Administration Division of Pulmonary and Allergy Drug Products July 13, 2005 PADAC Meeting 26 SMART - Conclusions  SMART stopped early  Interim analysis and difficulty with recruitment  Total population  RR 1.4 for primary outcome events -respiratory related deaths or life threatening experiences CI did not exclude one  RR 4.37 for asthma related deaths CI excludes one  RR 2.16 for respiratory related deaths CI excludes one

27. Food and Drug Administration Division of Pulmonary and Allergy Drug Products July 13, 2005 PADAC Meeting 27 SMART - Conclusions  Caucasian Subpopulation  No treatment group difference for primary endpoint  Numeric increase in asthma related deaths and respiratory related deaths in salmeterol group  African American Subpopulation  Numeric increase in salmeterol group for primary endpoint events  Numeric increase in salmeterol group for Asthma related deaths Respiratory related deaths Combined asthma related deaths or life threatening experiences (CI excludes 1)  No definitive conclusions regarding ICS use

28. Food and Drug Administration Division of Pulmonary and Allergy Drug Products July 13, 2005 PADAC Meeting 28 Salmeterol  Regulatory History  Post-marketing Studies  Serevent Nationwide Surveillance Study (SNS)  Salmeterol Multicenter Asthma Research Trial (SMART)  Post-marketing Spontaneous Reports  Product Label  Summary

29. Food and Drug Administration Division of Pulmonary and Allergy Drug Products July 13, 2005 PADAC Meeting 29 Post-Marketing Reports  Adverse Events Reporting System  May 1994-February 2005  Reviewed by Office of Drug Safety  201 deaths reported in US with salmeterol  91 asthma-related deaths  10 possible asthma-related deaths  Difficult to draw conclusions

30. Food and Drug Administration Division of Pulmonary and Allergy Drug Products July 13, 2005 PADAC Meeting 30 Salmeterol  Regulatory History  Post-marketing Studies  Serevent Nationwide Surveillance Study (SNS)  Salmeterol Multicenter Asthma Research Trial (SMART)  Post-marketing Spontaneous Reports  Product Label  Summary

31. Food and Drug Administration Division of Pulmonary and Allergy Drug Products July 13, 2005 PADAC Meeting 31 Current Label  Clinical Trials: SMART  Results for primary and key secondary endpoints

32. Food and Drug Administration Division of Pulmonary and Allergy Drug Products July 13, 2005 PADAC Meeting 32 Salmeterol  Regulatory History  Post-marketing Studies  Serevent Nationwide Surveillance Study (SNS)  Salmeterol Multicenter Asthma Research Trial (SMART)  Post-marketing Spontaneous Reports  Product Label  Summary

33. Food and Drug Administration Division of Pulmonary and Allergy Drug Products July 13, 2005 PADAC Meeting 33 Summary  Regulatory History  SNS  Numerical increase in respiratory/asthma deaths in salmeterol group  Fewer withdrawals due to respiratory or asthma events  SMART  Total population Increase in asthma and respiratory related deaths  African American Subpopulation Increase primary events Increase combined asthma related deaths or life threatening experiences  Not designed to assess the effects ICS use on outcomes  Product label

34. Food and Drug Administration Division of Pulmonary and Allergy Drug Products July 13, 2005 PADAC Meeting 34 Questions for Committee 1. The product labels of salmeterol containing products have been modified to include warnings related to the SMART study. a. Based on currently available information, what further actions, if any, do you recommend that the Agency take to communicate or otherwise manage the risks of severe asthma exacerbations seen in the SMART study? b. Based on the currently available information, do you agree that salmeterol should continue to be marketed in the United States?

35. Food and Drug Administration Division of Pulmonary and Allergy Drug Products July 13, 2005 PADAC Meeting 35 Questions for Committee 3. What further investigation, if any, do you recommend to be performed by GSK that can improve the understanding of the nature and magnitude of the risk of salmeterol?

36. Food and Drug Administration Division of Pulmonary and Allergy Drug Products July 13, 2005 PADAC Meeting 36 Division of Pulmonary and Allergy Drug Products Parklawn Building, Room 10B-45 5600 Fishers Lane, HFD-570 Rockville, MD 20857 Phone: 301-827-1050 Fax: 301-827-1271