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Evaluation of ADVAIR and FLOVENT Diskus in Treating COPD: Efficacy, Safety, and Key Questions

This summary outlines the efficacy and safety of ADVAIR and FLOVENT Diskus for treating Chronic Obstructive Pulmonary Disease (COPD), detailing pivotal and supportive trial outcomes. It highlights issues related to corticosteroid safety, pivotal trials, and systemic effects observed in patients. Additionally, it addresses concerns regarding efficacy endpoints and potential long-term risks, particularly regarding bone health and other systemic effects of corticosteroids. These issues will be pivotal for discussion at the upcoming PADAC meeting.

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Evaluation of ADVAIR and FLOVENT Diskus in Treating COPD: Efficacy, Safety, and Key Questions

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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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