# Presentation: 707639

## Luveris®New Drug Application (21-322) 

**Kate Meaker, M.S.**
**Statistical Reviewer **
**Division of Biometrics II**

**Center for Drug Evaluation and Research**** **

## Objectives

**Present FDA analyses of  three main studies**** **
**Discuss lack of sufficient evidence of efficacy**

## Main Issue

**FDA believes that patients whose cycles were cancelled due to risk of OHSS should be classified as treatment failures.**

## Studies Reviewed

**Study 6905 – Dose-finding Phase II **
**Study 6253 – Dose-finding Phase II**** **
**Study 21008 – Phase III **

## Phase II StudiesPlanned Analysis = Trend Test

**Appropriate for dose-finding**** **
**Weights are assigned to each dose group**** **
**Typically weights reflect a linear dose response or other dose relationship**

## Phase II StudiesPlanned Analyses = Trend test

**In these Phase II protocols the weights were not pre-specified**** **
**Sponsor selected weights after unblinding data **** **
**Sponsor applied equal weight to 75 and 225 IU groups**

## Phase II StudiesPlanned Analyses = Trend test

**Selected weights:****	****placebo****	****-2****	****25 IU****	****	****0****	****75 IU****	****	****1****	****225 IU****	****1**** **

## % Success – Follicular DevelopmentStudy 6905 (Phase II)

## Study 6905 (Phase II)

**FDA analysis classified OHSS risk as treatment failure**
**Conclusion:  The evidence is insufficient to show a statistically significant difference between Luveris 75 IU and placebo (p=0.670).**

## % Success – Follicular DevelopmentStudy 6253 (Phase II)

## Study 6253 (Phase II)

**FDA analysis classified OHSS risk as treatment failure**
**Conclusion:  The evidence is insufficient to show a statistically significant difference between Luveris 75 IU and placebo (p=0.157)**

## % Success – Follicular DevelopmentStudy 21008 (Phase III)

## Study 21008 (Phase III)

**FDA analysis classified OHSS risk as treatment failure**
**Conclusion:  The evidence is insufficient to show a statistically significant difference between Luveris 75 IU and placebo (p=0.063).**

## % Success – Follicular Development Risk of OHSS = Failure

## Secondary Endpoint:Ovulation Rate

**Desired indication was ovulation induction**** **
**FDA requested sponsor use ovulation rate (determined by P****4**** level) as primary endpoint**
**Sponsor included ovulation rate as secondary endpoint**

## Secondary EndpointOvulation Rate(determined by P4 level)

## Summary of Individual Studies

**None of the placebo-controlled studies provides sufficient evidence to support the efficacy of ****Luveris 75 IU**

## Post hoc Pooled Analyses

**FDA does not typically consider unplanned pooling of studies, particularly when the individual studies do not meet statistical significance on their own.**

## Post hoc Pooled Analyses

**ICH E9: Statistical Principles for Clinical Trials****“ Only results from analyses envisaged in the protocol (including amendments) can be regarded as confirmatory.”**

## Post hoc Pooled Analyses

**If pooled analyses were to be considered, a more stringent level of statistical significance would be required than alpha = 0.05.**** **
**Need to adjust alpha for all possible ways studies could be picked to combine (multiplicity issue)**

## Post hoc Pooled Analyses

**Combine two studies which have same endpoint definition and patient population (21008 + 6253)**** **
**Combine all 3 gives largest sample size (Note: 6905 has design differences)**** **
**Neither of these combination achieves statistical significance**

## Post hoc Pooled Analyses Conclusions

**Pooled analyses were not prospectively planned**** **
**FDA would generally not consider for confirmatory evidence**** **
**Analyses of the combined studies do not show sufficient evidence of efficacy of Luveris 75 IU vs. placebo**

## Summary

**Compare Luveris 75 IU to placebo**
**FDA endpoint classifies patients whose cycles were cancelled due to risk of OHSS as treatment failures**

## Summary

**The three studies do not provide sufficient evidence to conclude the differences between Luveris 75 IU and placebo are statistically significantly. **** **
**Post hoc pooled analyses do not show Luveris 75 IU is statistically significantly different from placebo.**