1 / 39

FLOVENT ® DISKUS ® NDA 20-833, S004 GlaxoSmithKline

FLOVENT ® DISKUS ® NDA 20-833, S004 GlaxoSmithKline. Pulmonary-Allergy Drugs Advisory Committee January 17, 2002 Charles E. Lee, M.D. Medical Reviewer Division of Pulmonary and Allergy Drug Products CDER/FDA. Proposed Indication.

istas
Download Presentation

FLOVENT ® DISKUS ® NDA 20-833, S004 GlaxoSmithKline

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript


  1. FLOVENT® DISKUS®NDA 20-833, S004GlaxoSmithKline Pulmonary-Allergy Drugs Advisory Committee January 17, 2002 Charles E. Lee, M.D. Medical Reviewer Division of Pulmonary and Allergy Drug Products CDER/FDA

  2. Proposed Indication “FLOVENT DISKUS is indicated for the long-term, twice-daily maintenance treatment of COPD (including emphysema and chronic bronchitis).”

  3. Proposed Dose “The starting dosage for adults is 1 inhalation (250 mcg) twice daily. For patients who do not respond adequately to the starting dose, increasing the dose to 500 mcg twice daily may provide additional control.”

  4. Introduction • Efficacy • Pivotal studies • Safety • Pivotal studies • Supportive studies

  5. Overview • Efficacy • Small changes in primary and secondary efficacy endpoints • Majority of patients had reversibility with bronchodilator • Safety concerns • Respiratory infections • Systemic effects • Adrenal • Bone

  6. Questions for Consideration • Efficacy • Clinical interpretation of the primary efficacy endpoint results • Higher percentage of reversibility in COPD population than generally found • All patients had chronic bronchitis, could have self-reported emphysema • Safety • Adequacy of long-term safety database • Risk versus benefit

  7. Pivotal Studies

  8. Efficacy Assessment • Primary efficacy variable • Pre-dose FEV1 • Secondary efficacy variables • CBSQ, BDI/TDI • PEFR, albuterol use • COPD exacerbations • Patient Reported Outcomes • CRDQ

  9. Safety Assessment • AEs, SAEs, Withdrawals • Vital signs, physical examination, oropharyngeal exam • ECG • Hematology and chemistry studies • Serum cortisol (FLTA3025) • Cosyntropin stimulation (SFCA3006, SFCA3007)

  10. DemographicsPivotal Studies

  11. Demographics FLTA3025 SFCA3006 SFCA3007 Gender, %M 69 66 63 Mean age, yr 64 63 64 Race, %C 94 94 93 Race, %B 4 5 4 Race, %O 1 2 3 ICS use, % 31 25 25 Current smokers, % 45 48 47

  12. ReversibilityPercent of Population Reversible % FLTA3025 59 SFCA3006 54 SFCA3007 55 Reversible: Increase in FEV1 12% and 0.2 L

  13. Mean Response to Bronchodilator % Change in FEV1 Reversible Non Overall Reversible % % % FLTA3025 32 9 23 SFCA3006 30 9 20 SFCA3007 30 9 20 Reversible: Increase in FEV1 12% and 0.2 L

  14. EfficacyPivotal Studies

  15. Mean Change From Baseline in Pre-dose FEV1, LitersDifference from Placebo *p <0.05

  16. Secondary Endpoints and Patient Reported Outcomes • Small differences from placebo group • CBSQ • BDI/TDI • COPD Exacerbations • AM PEFR • Albuterol use • CRDQ

  17. COPD Exacerbations% of Patients with 1 Exacerbation

  18. Daily Albuterol UseMean Change From Baseline Difference from Placebo Baseline: 4.5 to 5.7 puffs/day

  19. CRDQChange from Baseline in Overall Score Difference from Placebo MCIC = 10.0 Baseline: 83.6 to 88.8

  20. Subgroup AnalysisNon-reversible Group Non-reversible: Increase in FEV1 <12% or <0.2 L

  21. Subgroup Analysis, Non-reversible Group Mean Change From Baseline in Pre-dose FEV1 Difference from Placebo

  22. Efficacy, Pivotal Studies • Primary efficacy endpoint • Statistically significant and replicated for FP 500 • Not replicated for FP 250 • Smaller effect in the non-reversible group • Secondary endpoints and patient reported outcomes • Small differences from the placebo group

  23. Safety Pivotal Studies

  24. Notable AEs, Pivotal Studies

  25. Notable AEs, Pivotal Studies

  26. Adrenal Effects • Serum cortisol • FLTA3025 • Cosyntropin stimulation testing • SFCA3006, SFCA3007

  27. FLTA3025: Serum Cortisol Percent Difference from Placebo

  28. Cosyntropin Stimulation Testing • SFCA3006, SFCA3007 • No evidence of adrenal insufficiency • Insensitive test for less than complete adrenal insufficiency

  29. Safety Other Studies

  30. FLTA1003 • Phase 1 PK and PD study • Single center, open label, randomized, single dose, 4-way crossover design • 1000 mcg of FP administered with Diskus • Washout of 5 days between periods

  31. FLTA1003Mean 24 Hour Urinary Cortisol Excretion

  32. FLIT78 • Multicenter, double blind, randomized, placebo controlled, parallel group study • Flovent MDI, 500 mcg BID for 3 years • COPD • “ISOLDE” • Burge PS, et. al. BMJ 2000;320:1297-1303

  33. Notable AEs, FLIT78

  34. Notable AEs, FLIT78

  35. FLIT98 • Multicenter, randomized, double blind, placebo controlled, parallel group study • 1000 mcg BID of FP MDI for 4 weeks • Patients with acute COPD exacerbation • N = 249 (126 FP, 123 pbo) • One FP-treated patient had SAE for decreased cortisol

  36. Bone Mineral Density • 2-year studies • FLTA3001 • FLTA3017 • Asthma patients • Ages 18-50 years • Females were premenopausal • Study population at lower risk for osteoporosis than the population proposed in this NDA

  37. Bone Mineral Density • FLTA3001 • FP MDI 88 mcg BID, 440 mcg BID • N = 160 • Small decrease at lumbar spine for FP 440 mcg, but increase for FP 88 mcg and placebo • No changes for proximal femur or total body • FLTA3017 • FP Rotadisk 500 mcg BID • N = 64 • Decrease at femoral neck • No changes for lumbar spine or total body

  38. Conclusions • Primary efficacy endpoint • Replication for FP 500 only, not for FP 250 • Small differences from placebo from secondary endpoints • Majority of patients were reversible • Safety concerns • Respiratory infections • Adrenal effects • Bone density • Risk versus benefit

More Related