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OVERVIEW

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. OVERVIEW. Efficacy Summary Safety Summary Corticosteroid-related Issues Pivotal Trials

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OVERVIEW

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  1. ADVAIR and FLOVENT DISKUSSupplements for the COPD indication:SUMMARY and QUESTIONS Mary Purucker, MD, PhDMedical Team LeaderDivision of Pulmonary and Allergy Drug ProductsCDER, USFDA

  2. OVERVIEW • Efficacy Summary • Safety Summary • Corticosteroid-related Issues • Pivotal Trials • Supportive Trials • Non-Application Data (with caveats) • Wrap-up • Discussion Points for PADAC

  3. 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 FEV1) • 250/50 g BID • “Effect size” 0.164 L • 500/50 g BID • “Effect size” 0.160 L

  4. 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

  5. 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

  6. 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)

  7. 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

  8. ICS Systemic Effects: HPA Axis • FLTA3025: Serum Cortisol AUC12 + 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. 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

  10. 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?

  11. 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 FEV1 • Clinical relevance with regard to meaningful benefit to the patients? • Adequately supported by secondary endpoints? • Not just spirometry • COPD exacerbation • HRQL

  12. 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?

  13. Acknowledgements • 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

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