# Presentation: 784286

## Statistical Review

- Dr. Shan Sun-Mitchell

## ENT 00-02Primary endpoint: Time to treatment failure by day 50

**ENT 00-02****Primary endpoint: Time to treatment failure by day 50**

-                                                                            Placebo                       BDP_  _Patients randomized 	                        67 	                       62
- Number of treatment failures 	        30(45%) 	                    18 (29%)
- Adjusted hazard ratio (95% CI) 	0.63 (0.35, 1.13)
- Stratified log rank test 	              P = 0.1177

## Multiplicity

-  Multiple analyses on multiple pre-specified and non-specified endpoints for study ENT 00-02, study 875 and both studies combined were conducted.
- Once the study failed on the primary endpoint, any further analyses are exploratory and statistical significance cannot be determined.

##   Post-Hoc Endpoints

-   Post-Hoc Endpoints

**Survival at Day 200 Post-Transplant**
- Based on the timing of the transplant, not on randomization date or study drug administration
- Not a valid endpoint for comparison
**Survival at One Year Post-Randomization**
- Not pre-specified for either trial
- Sponsor’s p=0.04 in ENT 00-02 can not be compared with the 0.05 level
-           ---primary failed, no α left
-             ---multiple analyses on multiple endpoints
**Overall Survival Post-Randomization**
- Not pre-specified for either trial
- No planned uniform follow-up

## Problems with Post-Hoc Analyses

- Study ENT 00-02 failed to demonstrate efficacy based on the primary endpoint
- There was no uniform  follow-up for patients post study treatment and any post study treatment or other conditions that may influence survival were not captured---potential bias in the analyses.
- All subsequent analyses are considered exploratory since there is no type I error rate left for further testing. Any subsequent analyses can only inflate type I error rate. All the p-values in the subsequent analyses are not interpretable.

## Problems with Pooling / Meta Analyses

**Problems with Pooling / Meta Analyses**

## Problems with Pooling

**The two trials are not concurrent—10 years apart**
**Two  different study designs**
**Primary objective and study endpoints were different **
**The stratification factors were different**
** **
**Different study therapy and follow-up durations **
** ****Different enrolled populations**
**Follow-up on all patients for survival not planned**

## Guidelines on Meta Analyses

**ICH Guidance E9:** “*Under exceptional circumstances a meta analytic approach may also be most appropriate way, or the only way, of providing sufficient overall evidence of efficacy via an overall hypothesis test.* **When used for this purpose the meta-analysis should have its own prospectively written protocol”**

## Guidelines for Meta Analyses

**EMEA 2001 **Points to consider on applications with 1. Meta analyses; 2. One pivotal study, Section 11.1.3 Regulatory prerequisites of retrospective meta-analysis:* “prerequisites for a retrospective meta-analysis to provide sufficient evidence for a claim include:--Some studies clearly positive”... “A retrospective meta-analysis of only two studies originally intended to stand on their own is not expected to add any useful information”*

## Post-Hoc Exploratory Analyses:Overall survival post-randomization for studies 875 and ENT 00-02

**Post-Hoc Exploratory Analyses:****Overall survival post-randomization ****for studies 875 and ENT 00-02**

-                                                     **	****	****	****   ****875                                00-02                             **
**                                                   ****Placebo  BDP                Placebo    BDP                 **
**Subjects randomized                    ****29          31                     67             62**
**Survival status (dead )        ****17(59%)  10(32%)          32(48%)    27(44%)****            **
**Hazard ratio (95% CI)             ****0.47 (0.22, 1.04)             0.71(0.42, 1.20) ****              **
**Stratified logrank test*                      ****p=0.06                            p=0.20****                    **

- * p-value can not be compared to 0.05

## 	No pooling / Meta analyses can be  conducted (ICHE9 and EMEA 2001) as neither of the studies demonstrated efficacy with respect to survival

**	**No pooling / Meta analyses can be  conducted (ICHE9 and EMEA 2001) as neither of the studies demonstrated efficacy with respect to survival

## Summary

- Failed primary endpoint
- Further analyses of pre-specified /unspecified endpoints increases the false positive error rate
- Multiple analyses of multiple endpoints have been conducted
- Survival at day 200 post-transplant—not  valid efficacy endpoint
- Pooling /Meta analysis not acceptable

## Safety

- Clinically significant safety issue is HPA axis suppression
- ACTH stimulation tests done at baseline and, also day 51, if normal baseline and no treatment failure by day 50, ENT 00-02
- Abnormal HPA axis function day 51 in 86% of BDP patients vs. 58% of control group (77% vs. 57% in a second analysis)

##  Registration Study

-  Registration Study

- Failed primary efficacy endpoint
- Abnormal HPA axis function at day 51 was identified as a safety issue

## Conclusion

- Additional studies are necessary to demonstrate efficacy and safety