NDA 22,062 orBec
ODAC
Clinical Review -
Nancy S. Scher, M.D.
Biostatistical Review -
Shan Sun-Mitchell, Ph.D.
May 9, 2007
FDA Review Team for orBec NDA
• Project Management • CMC Review
Frank Cross, M.A., MT (ASCP) – Jila Boal, Ph.D.,
Reviewer
• Medical Review – Ravi Harapanhalli, Ph.D.,
– Nancy Scher, M.D., Branch Chief
Medical Officer
– Ann Farrell, M.D. • Pharmacology/Toxicology
Acting Deputy Director Review
– Peyton Myers, Ph.D.,
• Statistical Review Reviewer
– Shan Sun-Mitchell, Ph.D, – S. Leigh Verbois, Ph.D.
Reviewer Acting Team Leader
– Rajeshwari Sridhara, Ph.D.,
Acting Deputy Director • Clinical Pharmacology Review
– Sophia Abraham, Ph.D.
Reviewer
– Brian Booth, Ph.D.
Deputy Director 2
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 high-
dose 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 00-02 875
Design Multi-center, Single center,
double blind, double-blind,
placebo-controlled placebo-controlled
Phase 3 Phase 2
Patient GI GVHD grade 2 GI GVHD
Population/# N=129 N=60
Dates 2001-2005 1994-1996
Allograft PBSC: 90% PBSC: 20%
Source 8
Comparison of Clinical Trials
for Efficacy (2)
ENT 00-02 875
Non- Yes: 32% No
Myeloablative
Conditioning
Randomization • Center • Oral caloric
Stratification • Allograft source intake 40% estimated
• Topical steroids caloric
or not requirement
9
Comparison of Clinical Trials
for Efficacy (3)
ENT 00-02 875
Study drug BDP 1 mg IR + BDP 1 mg IRC +
regimen 1 mg EC QID or 1 mg ECC QID or
placebo placebo
X 50 days X 30 days
Prednisone 1mg/kg/d x 10 1 mg/kg/d x 10
regimen days, taper to .0625 days, taper to .125
mg/kg/d by day 17 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 00-02 875
Primary Time to treatment Ability to take >
Endpoint failure by study 70% caloric
day 50 requirement by
study day 30
Planned total 80 days (and 200 40 days
Follow-up post-transplant for
Duration 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