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NDA 22,062 orBec ODAC

NDA 22,062 orBec ODAC . Clinical Review - Nancy S. Scher, M.D. Biostatistical Review - Shan Sun-Mitchell, Ph.D. May 9, 2007. Project Management Frank Cross, M.A., MT (ASCP) Medical Review Nancy Scher, M.D., Medical Officer Ann Farrell, M.D. Acting Deputy Director

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NDA 22,062 orBec ODAC

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  1. NDA 22,062 orBecODAC Clinical Review - Nancy S. Scher, M.D. Biostatistical Review - Shan Sun-Mitchell, Ph.D. May 9, 2007

  2. 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. Deputy Director FDA Review Team for orBec NDA

  3. 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

  4. Proposed Indication For the treatment of graft vs. host disease (GVHD) involving the gastrointestinal tract in conjunction with an induction course of high-dose prednisone or prednisolone

  5. 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

  6. ENT 00-02Study 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)

  7. 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

  8. Comparison of Clinical Trials for Efficacy (1)

  9. Comparison of Clinical Trials for Efficacy (2)

  10. Comparison of Clinical Trials for Efficacy (3) IR=Immediate-release tablet; EC=Enteric-coated tablet IRC=Immediate-release capsule; ECC=Enteric-coated capsule

  11. Comparison of Clinical Trials for Efficacy (4)

  12. 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

  13. 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

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