1. Pulmonary and Allergy Drugs Advisory Committee Thursday, 17 January 2002 ADVAIR and FLOVENT DISKUS Supplements for the COPD indication: SUMMARY and QUESTIONS Mary Purucker, MD, PhD Medical Team Leader Division of Pulmonary and Allergy Drug Products CDER, USFDA

2. Pulmonary and Allergy Drugs Advisory Committee Thursday, 17 January 2002 OVERVIEWOVERVIEW Efficacy Summary Safety Summary –Corticosteroid-related Issues Pivotal Trials Supportive Trials Non-Application Data (with caveats) Wrap-up Discussion Points for PADAC Efficacy Summary Safety Summary –Corticosteroid-related Issues Pivotal Trials Supportive Trials Non-Application Data (with caveats) Wrap-up Discussion Points for PADAC

3. Pulmonary and Allergy Drugs Advisory Committee Thursday, 17 January 2002 EFFICACY SUMMARY Flovent Diskus –250  g BID Primary endpoint not replicated –500  g BID Effect size 0.050 L, 0.113 L Advair Diskus (pre-dose FEV 1 ) –250/50  g BID “Effect size” 0.164 L –500/50  g BID “Effect size” 0.160 L Flovent Diskus –250  g BID Primary endpoint not replicated –500  g BID Effect size 0.050 L, 0.113 L Advair Diskus (pre-dose FEV 1 ) –250/50  g BID “Effect size” 0.164 L –500/50  g BID “Effect size” 0.160 L

4. Pulmonary and Allergy Drugs Advisory Committee Thursday, 17 January 2002 SAFETY ISSUES Corticosteroid moiety common to the 2 products Dose-related CS AE’s observed in pivotal trials Systemic availability and activity demonstrated –PK studies show dose-related effect on HPA-axis Potential for CS systemic effects should be assumed (on bone, eyes, connective tissue, and metabolism) Pivotal and supportive studies not designed or powered to detect a difference in many aspects of CS systemic safety Corticosteroid moiety common to the 2 products Dose-related CS AE’s observed in pivotal trials Systemic availability and activity demonstrated –PK studies show dose-related effect on HPA-axis Potential for CS systemic effects should be assumed (on bone, eyes, connective tissue, and metabolism) Pivotal and supportive studies not designed or powered to detect a difference in many aspects of CS systemic safety

5. Pulmonary and Allergy Drugs Advisory Committee Thursday, 17 January 2002 ICS and COPD: AERS Database Search by indication (COPD, emphysema, chronic bronchitis) for all ICS (including fluticasone) 206 cases accounted for 213 AE’s –All but 14 cases after 1997 –Mean age 68.8 years, 50% female Adverse Events –> 50% worsening COPD/ lack of effectiveness –cataract - 5, bone - 6, HPA-axis - 8, skin - 4, fungal infection - 8, hyperglycemia - 8 Search by indication (COPD, emphysema, chronic bronchitis) for all ICS (including fluticasone) 206 cases accounted for 213 AE’s –All but 14 cases after 1997 –Mean age 68.8 years, 50% female Adverse Events –> 50% worsening COPD/ lack of effectiveness –cataract - 5, bone - 6, HPA-axis - 8, skin - 4, fungal infection - 8, hyperglycemia - 8

6. Pulmonary and Allergy Drugs Advisory Committee Thursday, 17 January 2002 ICS Systemic Effects: Bone (1) Chronic systemic CS can lead to osteoporosis ICS are systemically available  bone effects may occur and ideally should be quantified Bone/BMD not studied in 3 pivotal trials or other- wise reported in these sNDAs for this population Supportive trials, FLTA3001, FLTA3017 –Different population: Younger (18 - 50 yrs) Pre-menopausal Asthmatics (mild/moderate) –  BMD in LS (FLTA3001) –  BMD proximal femur (FLTA3017) Chronic systemic CS can lead to osteoporosis ICS are systemically available  bone effects may occur and ideally should be quantified Bone/BMD not studied in 3 pivotal trials or other- wise reported in these sNDAs for this population Supportive trials, FLTA3001, FLTA3017 –Different population: Younger (18 - 50 yrs) Pre-menopausal Asthmatics (mild/moderate) –  BMD in LS (FLTA3001) –  BMD proximal femur (FLTA3017)

7. Pulmonary and Allergy Drugs Advisory Committee Thursday, 17 January 2002 ICS Systemic Effects: Bone (2) LHS II showed decline in BMD over 3 years: –Lumbar spine (p=0.007), N=328 –Femur (p<0.001), N=359 Asthma: –Israel, NEJM 2001; 3-yr. prospective cohort study of pre- menopausal women  dose-related  BMD at hip – Wong, Lancet 2000; cross-sectional study of young adults, mean exposure 6 yrs  cumulative dose-related decrease in BMD at hip and LS IMPORTANT CAVEATS: –Different Moiety, Formulation (TAA vs. FP) –Different Populations LHS II showed decline in BMD over 3 years: –Lumbar spine (p=0.007), N=328 –Femur (p<0.001), N=359 Asthma: –Israel, NEJM 2001; 3-yr. prospective cohort study of pre- menopausal women  dose-related  BMD at hip – Wong, Lancet 2000; cross-sectional study of young adults, mean exposure 6 yrs  cumulative dose-related decrease in BMD at hip and LS IMPORTANT CAVEATS: –Different Moiety, Formulation (TAA vs. FP) –Different Populations

8. Pulmonary and Allergy Drugs Advisory Committee Thursday, 17 January 2002 ICS Systemic Effects: HPA Axis FLTA3025: Serum Cortisol AUC 12 + PK (4 wks) –FP 250  g BID:  10% vs. placebo –FP 500  g BID:  21% vs. placebo SFCA3006, 3007: ACTH stimulation testing in a subset ISOLDE (FLTA78): AM Cortisol –FP 500  g BID X 36 months:  10-15% mean AM Cortisol for FP vs. placebo at all time-points (p<0.01) –20% FP had Cortisol “shift” from N to L (9% placebo) FLTA1003 (PK/PD study): Urinary Cortisol –Single dose, crossover, normals –FP 1000  g single dose:  35% - 59% vs. pre-dose FLTA3025: Serum Cortisol AUC 12 + PK (4 wks) –FP 250  g BID:  10% vs. placebo –FP 500  g BID:  21% vs. placebo SFCA3006, 3007: ACTH stimulation testing in a subset ISOLDE (FLTA78): AM Cortisol –FP 500  g BID X 36 months:  10-15% mean AM Cortisol for FP vs. placebo at all time-points (p<0.01) –20% FP had Cortisol “shift” from N to L (9% placebo) FLTA1003 (PK/PD study): Urinary Cortisol –Single dose, crossover, normals –FP 1000  g single dose:  35% - 59% vs. pre-dose

9. Pulmonary and Allergy Drugs Advisory Committee Thursday, 17 January 2002 ICS Systemic Effects: Ocular CAVEATS: –Epidemiologic studies not RCT –ICS in general, not FP specifically –All cataracts not just PSC Australian study (Cumming, NEJM 1997) –ICS users age 49 - 82 years –2-fold  in PSC, further  with cumulative lifetime dose Canadian study: (Garbe, NEJM 1998) –ICS-users age  70 yrs with  3 years –3-fold  in cataract extraction, dose response CAVEATS: –Epidemiologic studies not RCT –ICS in general, not FP specifically –All cataracts not just PSC Australian study (Cumming, NEJM 1997) –ICS users age 49 - 82 years –2-fold  in PSC, further  with cumulative lifetime dose Canadian study: (Garbe, NEJM 1998) –ICS-users age  70 yrs with  3 years –3-fold  in cataract extraction, dose response

10. Pulmonary and Allergy Drugs Advisory Committee Thursday, 17 January 2002 ConclusionsConclusions Efficacy has been closely studied, substantial data, open to clinical interpretation. If approval recommended, labeling issues remain but are not insurmountable Safety database for this population is limited in describing long-term risks. How to adequately label for the potential long-term effects, particularly with regard to bone? Efficacy has been closely studied, substantial data, open to clinical interpretation. If approval recommended, labeling issues remain but are not insurmountable Safety database for this population is limited in describing long-term risks. How to adequately label for the potential long-term effects, particularly with regard to bone?

11. Pulmonary and Allergy Drugs Advisory Committee Thursday, 17 January 2002 Agency Concerns for Discussion by PADAC: EFFICACY Patient population –Representative of COPD population? Reversibility –Supportive of broad indication of “…long-term twice- daily maintenance treatment of COPD (including chronic bronchitis and emphysema)”? Primary Endpoint: Change from baseline in FEV 1 –Clinical relevance with regard to meaningful benefit to the patients? –Adequately supported by secondary endpoints? Not just spirometry COPD exacerbation HRQL Patient population –Representative of COPD population? Reversibility –Supportive of broad indication of “…long-term twice- daily maintenance treatment of COPD (including chronic bronchitis and emphysema)”? Primary Endpoint: Change from baseline in FEV 1 –Clinical relevance with regard to meaningful benefit to the patients? –Adequately supported by secondary endpoints? Not just spirometry COPD exacerbation HRQL

12. Pulmonary and Allergy Drugs Advisory Committee Thursday, 17 January 2002 Agency Concerns for Discussion by PADAC: SAFETY Fluticasone is systemically available (by PK) and impact on HPA axis can be measured after single dose in normals, 4 wks in COPD –Other systemic CS effects should be assumed Are data sufficient for labeling with regard to impact on: –Bone (BMD or fractures)? –Ocular structures (PSC/cataracts, IOP)? –HPA-axis? –Connective tissue, metabolic, or other systemic events? Fluticasone is systemically available (by PK) and impact on HPA axis can be measured after single dose in normals, 4 wks in COPD –Other systemic CS effects should be assumed Are data sufficient for labeling with regard to impact on: –Bone (BMD or fractures)? –Ocular structures (PSC/cataracts, IOP)? –HPA-axis? –Connective tissue, metabolic, or other systemic events?

13. Pulmonary and Allergy Drugs Advisory Committee Thursday, 17 January 2002 AcknowledgementsAcknowledgements Don Collier Tayo Fadiran James Gebert Lydia Gilbert-McClain Ted Guo Ladan Jafari Claudia Karwoski Charles Lee Robert Meyer Sandra Suarez Kimberly Topper Joyce Weaver Don Collier Tayo Fadiran James Gebert Lydia Gilbert-McClain Ted Guo Ladan Jafari Claudia Karwoski Charles Lee Robert Meyer Sandra Suarez Kimberly Topper Joyce Weaver