NDA 22 062 or Bec ODAC Clinical Review
NDA 22, 062 or. Bec ODAC Clinical Review Nancy S. Scher, M. D. Biostatistical Review Shan Sun-Mitchell, Ph. D. May 9, 2007
FDA Review Team for or. Bec NDA • Project Management Frank Cross, M. A. , MT (ASCP) • Medical Review – Nancy Scher, M. D. , Medical Officer – Ann Farrell, M. D. Acting Deputy Director • Statistical Review – Shan Sun-Mitchell, Ph. D, Reviewer – Rajeshwari Sridhara, Ph. D. , Acting Deputy Director • CMC Review – Jila Boal, Ph. D. , Reviewer – Ravi Harapanhalli, Ph. D. , Branch Chief • Pharmacology/Toxicology Review – Peyton Myers, Ph. D. , Reviewer – S. Leigh Verbois, Ph. D. Acting Team Leader • Clinical Pharmacology Review – Sophia Abraham, Ph. D. Reviewer – Brian Booth, Ph. D. 2 Deputy Director
Outline • Indication • Overview of Randomized Clinical Trials – Trial ENT 00 -02 (phase 3) – Trial 875 (phase 2) • • • Comparison of Trials Post-hoc Efficacy Endpoints Issues with Pooling Efficacy Data Statistical Analysis Safety Conclusions 3
Proposed Indication For the treatment of graft vs. host disease (GVHD) involving the gastrointestinal tract in conjunction with an induction course of highdose prednisone or prednisolone 4
ENT 00 -02 Study Design and Endpoints • Multi-center, phase 3, randomized, double-blind, placebo-controlled; completed 2005 • Primary Efficacy – Time to treatment failure through day 50 • Secondary Efficacy – Cumulative proportion failed by day 10, 30, 50, 60, 80 – Change in functional status (10, 30, 50, 60, 80) • Safety Endpoints: Mortality day 200 post-transplant; Hypothalamic-Pituitary-Adrenal (HPA) axis function; adverse events 5
ENT 00 -02 Study Populations • • Balanced for baseline demographics Heterogeneous diagnoses Half (47%) of subjects from single center Imbalance for non-myeloblative conditioning regimen – BDP = 42% (26/62) – Placebo = 22% (15/67) 6
Clinical Trial 875 • Single site, phase 2, randomized, double-blind, placebo-controlled; stratified by oral caloric intake • Completed 1996 • Primary endpoint: Oral intake >= 70% of estimated caloric requirement by study day 30 • Balanced for baseline demographics (race not specified) • Heterogeneous diagnoses but generally balanced as to disease and transplant characteristics 7
Comparison of Clinical Trials for Efficacy (1) ENT 00 -02 Design Multi-center, double blind, placebo-controlled Phase 3 Patient GI GVHD grade 2 Population/# N=129 Dates 2001 -2005 875 Single center, double-blind, placebo-controlled Phase 2 Allograft Source PBSC: 20% PBSC: 90% GI GVHD N=60 1994 -1996 8
Comparison of Clinical Trials for Efficacy (2) ENT 00 -02 Yes: 32% Non. Myeloablative Conditioning Randomization • Center Stratification • Allograft source Factors (2 HLA sib or not) • Topical steroids or not 875 No • Oral caloric intake < 40% or > 40% estimated caloric requirement 9
Comparison of Clinical Trials for Efficacy (3) ENT 00 -02 Study drug BDP 1 mg IR + regimen 1 mg EC QID or placebo X 50 days Prednisone 1 mg/kg/d x 10 regimen days, taper to. 0625 mg/kg/d by day 17 875 BDP 1 mg IRC + 1 mg ECC QID or placebo X 30 days 1 mg/kg/d x 10 days, taper to. 125 mg/kg/d by day 17 IR=Immediate-release tablet; EC=Enteric-coated tablet IRC=Immediate-release capsule; ECC=Enteric-coated capsule 10
Comparison of Clinical Trials for Efficacy (4) ENT 00 -02 Primary Endpoint Planned total Follow-up Duration 875 Time to treatment Ability to take > failure by study 70% caloric day 50 requirement by study day 30 80 days (and 200 40 days post-transplant for survival) 11
Post-hoc Efficacy Endpoints • Endpoints were not pre-specified and data collection was conducted post-hoc – Survival one year post randomization – Overall survival post randomization 12
Issues with Pooling Efficacy Data ENT 00 -02 and 875 • Treatment durations differ: 50 vs. 30 days • Advances in transplant procedures and supportive care occurred during decade separating trials • Differences in enrolled populations • Non-myeloblative patients in later trial • ENT 00 -02 failed primary endpoint • 875 met caloric primary endpoint • Post-hoc endpoints defined for both trials 13
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