ADVAIR and FLOVENT DISKUS Supplements for the COPD

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

OVERVIEW • Efficacy Summary • Safety Summary – Corticosteroid-related Issues • Pivotal Trials • Supportive Trials • Non-Application Data (with caveats) • Wrap-up • Discussion Points for PADAC 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 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 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 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 otherwise reported in these s. NDAs for this population • Supportive trials, FLTA 3001, FLTA 3017 – Different population: • Younger (18 - 50 yrs) • Pre-menopausal • Asthmatics (mild/moderate) – BMD in LS (FLTA 3001) – BMD proximal femur (FLTA 3017) 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 premenopausal 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 Pulmonary and Allergy Drugs Advisory Committee Thursday, 17 January 2002

ICS Systemic Effects: HPA Axis • FLTA 3025: Serum Cortisol AUC 12 + PK (4 wks) – FP 250 g BID: 10% vs. placebo – FP 500 g BID: 21% vs. placebo • SFCA 3006, 3007: ACTH stimulation testing in a subset • ISOLDE (FLTA 78): 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) • FLTA 1003 (PK/PD study): Urinary Cortisol – Single dose, crossover, normals – FP 1000 g single dose: 35% - 59% vs. pre-dose 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 Pulmonary and Allergy Drugs Advisory Committee Thursday, 17 January 2002

Conclusions • 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? 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 twicedaily 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 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? Pulmonary and Allergy Drugs Advisory Committee Thursday, 17 January 2002

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