# Presentation: 170047

## 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**
**	****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**

## 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

## Proposed Indication

- 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

## ENT 00-02 Study Design and Endpoints

- 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

## ENT 00-02Study Populations 

- 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)

## 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

## Comparison of Clinical Trials for Efficacy (1)

- Comparison of Clinical Trials for Efficacy (1)

|  | ENT 00-02 | 875 |
| --- | --- | --- |
| Design | Multi-center, double blind, placebo-controlled
Phase 3 | Single center, double-blind, placebo-controlled Phase 2 |
| Patient Population/# | GI GVHD grade 2
N=129 | GI GVHD
N=60 |
| Dates  | 2001-2005 | 1994-1996 |
| Allograft Source | PBSC: 90% | PBSC: 20%
 |

## Comparison of Clinical Trials for Efficacy (2)

- Comparison of Clinical Trials for Efficacy (2)

|  | ENT 00-02 | 875 |
| --- | --- | --- |
| Non-
Myeloablative
Conditioning | Yes: 32% | No |
| Randomization
Stratification Factors |  Center
 Allograft source  (2HLA sib or not)
 Topical steroids or not |  Oral caloric intake < 40% or > 40% estimated caloric requirement |

## Comparison of Clinical Trials for Efficacy (3)

- Comparison of Clinical Trials for Efficacy (3)

|  | ENT 00-02 | 875 |
| --- | --- | --- |
| Study drug regimen | BDP 1 mg IR + 
1 mg EC QID  or placebo
X 50 days | BDP 1 mg IRC + 
1 mg ECC QID  or placebo
X 30 days |
| Prednisone regimen | 1mg/kg/d x 10 days, taper to .0625 mg/kg/d by day 17 | 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*

## Comparison of Clinical Trials for Efficacy (4)

- Comparison of Clinical Trials for Efficacy (4)

|  | ENT 00-02 | 875 |
| --- | --- | --- |
| Primary Endpoint | Time to treatment failure by study day 50 | Ability to take > 70% caloric requirement by study day 30 |
| Planned total Follow-up
Duration | 80 days (and 200 post-transplant for survival) | 40 days |

## 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

## Issues with Pooling Efficacy Data ENT 00-02 and 875

- 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