1. Pulmonary-Allergy Drugs Advisory Committee May 1, 2007 FDA Presentation Advair Diskus 500/50 Carol Bosken, MD, ScM, MPH Medical Officer Division of Pulmonary and Allergy Products Feng Zhou, MS Statistical Reviewer Division of Biometrics II Carol Bosken, MD, ScM, MPH Medical Officer Division of Pulmonary and Allergy Products Feng Zhou, MS Statistical Reviewer Division of Biometrics II

2. Pulmonary-Allergy Drugs Advisory Committee May 1, 2007 OutlineOutline History of development program –Dr. Carol Bosken Introduction to Efficacy results –Dr. Carol Bosken Efficacy results –Ms. Feng Zhou Safety results and summary –Dr. Carol Bosken History of development program –Dr. Carol Bosken Introduction to Efficacy results –Dr. Carol Bosken Efficacy results –Ms. Feng Zhou Safety results and summary –Dr. Carol Bosken

3. Pulmonary-Allergy Drugs Advisory Committee May 1, 2007 OutlineOutline History of development program Dr. Carol Bosken Introduction to efficacy results –Dr. Carol Bosken Efficacy results –Ms. Feng Zhou Safety results and summary –Dr. Carol Bosken History of development program Dr. Carol Bosken Introduction to efficacy results –Dr. Carol Bosken Efficacy results –Ms. Feng Zhou Safety results and summary –Dr. Carol Bosken

4. Pulmonary-Allergy Drugs Advisory Committee May 1, 2007 Original Approval of Advair Diskus for COPD Advair Diskus 250/50 was approved for the maintenance treatment of airflow obstruction in patients with COPD associated with chronic bronchitis in November 2003 Original development program designed to demonstrate contribution of each component of Advair (Fluticasone propionate [FP] and salmeterol [SAL]) to the efficacy of Advair in improving lung function Advair Diskus 250/50 was approved for the maintenance treatment of airflow obstruction in patients with COPD associated with chronic bronchitis in November 2003 Original development program designed to demonstrate contribution of each component of Advair (Fluticasone propionate [FP] and salmeterol [SAL]) to the efficacy of Advair in improving lung function

5. Pulmonary-Allergy Drugs Advisory Committee May 1, 2007 Original Approval of Advair Diskus for COPD Advair was superior to each of the relevant individual components for pre and post-dose FEV 1 endpoints but the improvement with the 500/50 mcg dose was not superior to the improvement seen with Advair 250/50 No additional benefit with other efficacy measures such as patient-reported outcomes, and exacerbation rates for either dose Patients enrolled in the study must have had a history of chronic bronchitis by the standard clinical definition Advair was superior to each of the relevant individual components for pre and post-dose FEV 1 endpoints but the improvement with the 500/50 mcg dose was not superior to the improvement seen with Advair 250/50 No additional benefit with other efficacy measures such as patient-reported outcomes, and exacerbation rates for either dose Patients enrolled in the study must have had a history of chronic bronchitis by the standard clinical definition

6. Pulmonary-Allergy Drugs Advisory Committee May 1, 2007 Original Approval of Advair Diskus for COPD The approval is limited –250/50 mcg BID only –Recommended only for patient with COPD associated with chronic bronchitis Phase IV commitment –1-year study to assess the effects of Advair 250/50 mcg BID on the incidence of COPD exacerbations –2-year study to assess the effects of Advair 250/50 mcg BID on bone mineral density The approval is limited –250/50 mcg BID only –Recommended only for patient with COPD associated with chronic bronchitis Phase IV commitment –1-year study to assess the effects of Advair 250/50 mcg BID on the incidence of COPD exacerbations –2-year study to assess the effects of Advair 250/50 mcg BID on bone mineral density

7. Pulmonary-Allergy Drugs Advisory Committee May 1, 2007 Protocol Design (Study SCO30003) –3-year treatment period –Efficacy outcome –Primary – all-cause mortality –Key secondary outcomes  COPD-related mortality  Long term oxygen therapy –Other endpoints  Moderate and severe COPD exacerbations  Patient reported outcome measures  Pulmonary function (FEV1) –3-year treatment period –Efficacy outcome –Primary – all-cause mortality –Key secondary outcomes  COPD-related mortality  Long term oxygen therapy –Other endpoints  Moderate and severe COPD exacerbations  Patient reported outcome measures  Pulmonary function (FEV1)

8. Pulmonary-Allergy Drugs Advisory Committee May 1, 2007 Protocol Design (Study SCO30003) –Treatments –Advair (SFC) 500/50 mcg BID –Fluticasone propionate (FP) 500 mcg BID –Salmeterol (SAL) 50 mcg BID –Sample size – 3800 to give an 80% power to detect a 5.0% difference between Advair and placebo –Treatments –Advair (SFC) 500/50 mcg BID –Fluticasone propionate (FP) 500 mcg BID –Salmeterol (SAL) 50 mcg BID –Sample size – 3800 to give an 80% power to detect a 5.0% difference between Advair and placebo

9. Pulmonary-Allergy Drugs Advisory Committee May 1, 2007 Agency Review (Study SCO30003) Agency Review (Study SCO30003) With mortality as the primary efficacy outcome, one study could be sufficient IF –The results are statistically robust –Safety findings do not alter the risk/benefit unfavorably International enrollment acceptable BUT –trends in the US population would have to support efficacy No objection to one dose of Advair With mortality as the primary efficacy outcome, one study could be sufficient IF –The results are statistically robust –Safety findings do not alter the risk/benefit unfavorably International enrollment acceptable BUT –trends in the US population would have to support efficacy No objection to one dose of Advair

10. Pulmonary-Allergy Drugs Advisory Committee May 1, 2007 Trial Conduct (Study SCO30003) Amendments –Moderate and severe COPD exacerbations were made the key secondary efficacy outcome –Increase in sample size to 6040 Pre-NDA discussions with Agency –Two studies would be required to support the decrease in exacerbations claim. Amendments –Moderate and severe COPD exacerbations were made the key secondary efficacy outcome –Increase in sample size to 6040 Pre-NDA discussions with Agency –Two studies would be required to support the decrease in exacerbations claim.

11. Pulmonary-Allergy Drugs Advisory Committee May 1, 2007 NDA Submission Proposed Indications –Increase survival –Decrease exacerbation rate –Decrease airflow obstruction Population –All patients with COPD Dose –500/50 mcg BID Proposed Indications –Increase survival –Decrease exacerbation rate –Decrease airflow obstruction Population –All patients with COPD Dose –500/50 mcg BID

12. Pulmonary-Allergy Drugs Advisory Committee May 1, 2007 NDA Submission –SCO30003 (Study 03)) –3 years – Mortality and exacerbation rate –SFCB3024 (Study 24) –1 yr study conducted entirely outside of the US –Lung function and exacerbation rate –No prior consultation with the Agency –SFCA3006 –Submitted with original application COPD indication –6 months –Used to support the treatment of airflow obstruction indication only –SCO30003 (Study 03)) –3 years – Mortality and exacerbation rate –SFCB3024 (Study 24) –1 yr study conducted entirely outside of the US –Lung function and exacerbation rate –No prior consultation with the Agency –SFCA3006 –Submitted with original application COPD indication –6 months –Used to support the treatment of airflow obstruction indication only

13. Pulmonary-Allergy Drugs Advisory Committee May 1, 2007 Saint George’s Respiratory Questionnaire Total ScoreSALFPSFC Study SCO30003 N Difference from placebo 980 1005 -2.0 1002 -3.1 Study SFCB3024 N Difference from placebo 321 340 -0.6 320 -2.0

14. Pulmonary-Allergy Drugs Advisory Committee May 1, 2007 OutlineOutline History of development programHistory of development program –Dr. Carol Bosken Introduction to efficacy results Introduction to efficacy results Dr. Carol Bosken Dr. Carol Bosken Efficacy resultsEfficacy results –Ms. Feng Zhou Safety results and summary – Dr. Carol Bosken History of development programHistory of development program –Dr. Carol Bosken Introduction to efficacy results Introduction to efficacy results Dr. Carol Bosken Dr. Carol Bosken Efficacy resultsEfficacy results –Ms. Feng Zhou Safety results and summary – Dr. Carol Bosken

15. Pulmonary-Allergy Drugs Advisory Committee May 1, 2007 Introduction to Efficacy Results Patient populations Efficacy endpoints Patient populations Efficacy endpoints

16. Pulmonary-Allergy Drugs Advisory Committee May 1, 2007 PopulationsPopulations Characteristic SCO30003 N=6112 SFCB3024 N=1465 History of cough and sputum production ---+ History of previous exacerbation ---1 mod/severe in 12 months prior to enrollment FEV 1, % predicted Inclusion criteria Baseline pre-BD FEV 1 < 60 40 25-70 45

17. Pulmonary-Allergy Drugs Advisory Committee May 1, 2007 Regional Variation in Demographic Variables (Study SCO30003) RegionN (%) Age ( > 65 years) Sex (M) BMI (<18 kg/m 2 ) FEV 1 % predicted (mean) USA1388 (23%)56%60%4%39 Asia758 (12%)66%90%18%36 E Europe1154 (19%)45%84%3%42 W Europe1908 (31%)56%78%3%43 Other904 (15%)60%72%6%39

18. Pulmonary-Allergy Drugs Advisory Committee May 1, 2007 Regional Variation in Medical Practice (Study SCO30003) ICS taken by 64% of W Europeans in contrast to 45 to 49% of the other populations Oxygen saturation obtained in 90% of US patients in contrast to 48% of E European patients and 55 to 73% of the other populations ICS taken by 64% of W Europeans in contrast to 45 to 49% of the other populations Oxygen saturation obtained in 90% of US patients in contrast to 48% of E European patients and 55 to 73% of the other populations

19. Pulmonary-Allergy Drugs Advisory Committee May 1, 2007 Introduction to Efficacy Results Patient populationsPatient populations Efficacy endpoints Patient populationsPatient populations Efficacy endpoints

20. Pulmonary-Allergy Drugs Advisory Committee May 1, 2007 Survival Endpoint (Study SCO30003) An unequivocal endpoint with essentially complete follow-up Cause of death –Prospectively defined –Adjudicated by the CEC Analysis –All cause mortality –On treatment mortality –COPD-related mortality An unequivocal endpoint with essentially complete follow-up Cause of death –Prospectively defined –Adjudicated by the CEC Analysis –All cause mortality –On treatment mortality –COPD-related mortality

21. Pulmonary-Allergy Drugs Advisory Committee May 1, 2007 Exacerbation Endpoint (Study SCO30003) A COPD exacerbation was defined as moderate if treated with systemic corticosteroids and/or antibiotics and severe if hospitalization was required –No required symptoms –No time limits on duration of exacerbation or requirement for a specified period of time between exacerbations –No limit on number of exacerbations A COPD exacerbation was defined as moderate if treated with systemic corticosteroids and/or antibiotics and severe if hospitalization was required –No required symptoms –No time limits on duration of exacerbation or requirement for a specified period of time between exacerbations –No limit on number of exacerbations

22. Pulmonary-Allergy Drugs Advisory Committee May 1, 2007 Exacerbation Endpoint (Study SCO30003) Exacerbation Endpoint (Study SCO30003) Duration highly variable –Median 12 days –Range 1 to 747 days –12% greater than 30 days –Multiple short treatment courses within a single Moderate/severe COPD exacerbation Would not count as an exacerbation, no matter how severe, if not treated (i.e. end of life decision, patient did not get to hospital) Antibiotic and corticosteroid-treated exacerbations not identical Duration highly variable –Median 12 days –Range 1 to 747 days –12% greater than 30 days –Multiple short treatment courses within a single Moderate/severe COPD exacerbation Would not count as an exacerbation, no matter how severe, if not treated (i.e. end of life decision, patient did not get to hospital) Antibiotic and corticosteroid-treated exacerbations not identical

23. Pulmonary-Allergy Drugs Advisory Committee May 1, 2007 Exacerbation Endpoint (Study SFCB3024) Exacerbation definition with –Guidelines for symptoms –Must have 7 days between exacerbations –Treat the exacerbation for 10 days Exacerbation definition with –Guidelines for symptoms –Must have 7 days between exacerbations –Treat the exacerbation for 10 days *****