LuverisLuveris®®

New Drug Application (21-322New Drug Application (21-322)) LuverisLuveris®®

New Drug Application (21-322New Drug Application (21-322))

Kate Meaker, M.S.Kate Meaker, M.S.

Statistical Reviewer Statistical Reviewer Division of Biometrics IIDivision of Biometrics II

Kate Meaker, M.S.Kate Meaker, M.S.

Statistical Reviewer Statistical Reviewer Division of Biometrics IIDivision of Biometrics II

Center for Drug Evaluation and ResearchCenter for Drug Evaluation and Research

2Title of Advisory Committee Title of Advisory Committee Meeting DateMeeting Date

ObjectivesObjectives

• Present FDA analyses of three main studies

• Discuss lack of sufficient evidence of efficacy

• Present FDA analyses of three main studies

• Discuss lack of sufficient evidence of efficacy

3Title of Advisory Committee Title of Advisory Committee Meeting DateMeeting Date

Main IssueMain IssueMain IssueMain Issue

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

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

4Title of Advisory Committee Title of Advisory Committee Meeting DateMeeting Date

Studies ReviewedStudies Reviewed

• Study 6905 – Dose-finding Phase II • Study 6253 – Dose-finding Phase II

• Study 21008 – Phase III

• Study 6905 – Dose-finding Phase II • Study 6253 – Dose-finding Phase II

• Study 21008 – Phase III

5Title of Advisory Committee Title of Advisory Committee Meeting DateMeeting Date

Phase II StudiesPlanned Analysis = Trend Test

Phase II StudiesPlanned 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

• Appropriate for dose-finding

• Weights are assigned to each dose group

• Typically weights reflect a linear dose response or other dose relationship

6Title of Advisory Committee Title of Advisory Committee Meeting DateMeeting Date

Phase II StudiesPlanned Analyses = Trend test

Phase II StudiesPlanned 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

• 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

7Title of Advisory Committee Title of Advisory Committee Meeting DateMeeting Date

Phase II StudiesPlanned Analyses = Trend test

Phase II StudiesPlanned Analyses = Trend test

• Selected weights:placebo -225 IU 075 IU 1225 IU 1

• Selected weights:placebo -225 IU 075 IU 1225 IU 1

8Title of Advisory Committee Title of Advisory Committee Meeting DateMeeting Date

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

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

Luveris 6905 (ITT) 25 IU

n=9 75 IU n=11

225 IU n=9

Placebo

n=11

p-value

Sponsor Analysis

9 (100%)

8 (73%)

6 (67%)

7 (64%)

Trend test

0.774 FDA Analysis

7 (78%)

7 (64%)

6 (67%)

5 (45%)

Fisher’s Exact 0.670

9Title of Advisory Committee Title of Advisory Committee Meeting DateMeeting Date

Study 6905 (Phase II)Study 6905 (Phase II)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).

• 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).

10Title of Advisory Committee Title of Advisory Committee Meeting DateMeeting Date

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

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

Luveris 6253 (ITT) 25 IU

n=8 75 IU n=11

225 IU n=10

Placebo

n=9

p-value

Sponsor’s Analysis

2 (25%)

7 (64%)

7 (70%)

1 (11%)

Trend test

0.004 FDA Analysis

2 (25%)

5 (45%)

4 (40%)

1 (11%)

Fisher’s Exact 0.157

11Title of Advisory Committee Title of Advisory Committee Meeting DateMeeting Date

Study 6253 (Phase II)Study 6253 (Phase II)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)

• 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)

12Title of Advisory Committee Title of Advisory Committee Meeting DateMeeting Date

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

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

21008 Luveris 75

IU n=26

Placebo n=13

p-value (Fisher’s Exact)

Sponsor’s Analysis (Evaluable)

16 / 24 (67%)

2 / 10 (20%)

0.008

FDA Analysis (ITT)

10 / 26 (38%)

1 / 13 (8%)

0.063

13Title of Advisory Committee Title of Advisory Committee Meeting DateMeeting Date

Study 21008 (Phase III)Study 21008 (Phase III)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).

• 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).

14Title of Advisory Committee Title of Advisory Committee Meeting DateMeeting Date

% Success – Follicular Development% Success – Follicular Development

Risk of OHSS = FailureRisk of OHSS = Failure

% Success – Follicular Development% Success – Follicular Development

Risk of OHSS = FailureRisk of OHSS = Failure

B

B

B

Study 21008

Study 6253

Study 6905

0.1 1 10 100

Odds Ratio and 95% CI

p=0.67

p=0.16

p=0.06

75 IU vs. Placebo

Plotted on Log Scale

15Title of Advisory Committee Title of Advisory Committee Meeting DateMeeting Date

Secondary Endpoint:Secondary Endpoint:Ovulation RateOvulation Rate

Secondary Endpoint:Secondary Endpoint:Ovulation RateOvulation Rate

• Desired indication was ovulation induction

• FDA requested sponsor use ovulation rate (determined by P4 level) as primary endpoint

• Sponsor included ovulation rate as secondary endpoint

• Desired indication was ovulation induction

• FDA requested sponsor use ovulation rate (determined by P4 level) as primary endpoint

• Sponsor included ovulation rate as secondary endpoint

16Title of Advisory Committee Title of Advisory Committee Meeting DateMeeting Date

Secondary EndpointSecondary EndpointOvulation RateOvulation Rate

(determined by P(determined by P44 level) level)

Secondary EndpointSecondary EndpointOvulation RateOvulation Rate

(determined by P(determined by P44 level) level)

Study Luveris 75 IU Placebo 6905 P4 > 10.0 ng/mL

8 / 11 (73%)

8 / 11 (73%)

6253 P4 > 7.9 ng/mL

5 / 11 (45%)

1 / 9 (11%)

21008 P4 > 7.9 ng/mL

12 / 26 (46%)

2 / 13 (15%)

All NSD at alpha = 0.05

17Title of Advisory Committee Title of Advisory Committee Meeting DateMeeting Date

Summary of Individual StudiesSummary of Individual StudiesSummary of Individual StudiesSummary of Individual Studies

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

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

18Title of Advisory Committee Title of Advisory Committee Meeting DateMeeting Date

Post hoc Pooled AnalysesPost hoc Pooled AnalysesPost hoc Pooled AnalysesPost 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.

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

19Title of Advisory Committee Title of Advisory Committee Meeting DateMeeting Date

Post hoc Pooled AnalysesPost hoc Pooled AnalysesPost hoc Pooled AnalysesPost 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.”

• ICH E9: Statistical Principles for Clinical Trials

“ Only results from analyses envisaged in the protocol (including amendments) can be regarded as confirmatory.”

20Title of Advisory Committee Title of Advisory Committee Meeting DateMeeting Date

Post hoc Pooled AnalysesPost hoc Pooled AnalysesPost hoc Pooled AnalysesPost 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)

• 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)

21Title of Advisory Committee Title of Advisory Committee Meeting DateMeeting Date

Post hoc Pooled AnalysesPost hoc Pooled AnalysesPost hoc Pooled AnalysesPost 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

• 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

22Title of Advisory Committee Title of Advisory Committee Meeting DateMeeting Date

Post hoc Pooled Analyses Post hoc Pooled Analyses ConclusionsConclusions

Post hoc Pooled Analyses Post hoc Pooled Analyses ConclusionsConclusions

• 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

• 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

23Title of Advisory Committee Title of Advisory Committee Meeting DateMeeting Date

SummarySummarySummarySummary

• Compare Luveris 75 IU to placebo

• FDA endpoint classifies patients whose cycles were cancelled due to risk of OHSS as treatment failures

• Compare Luveris 75 IU to placebo

• FDA endpoint classifies patients whose cycles were cancelled due to risk of OHSS as treatment failures

24Title of Advisory Committee Title of Advisory Committee Meeting DateMeeting Date

SummarySummarySummarySummary

• 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.

• 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.