Luveris Luveris ® ® New Drug Application (21- New Drug Application (21- 322 322 ) ) Kate Meaker, M.S. Kate Meaker, M.S. Statistical Reviewer Statistical Reviewer Division of Biometrics II Division of Biometrics II Center for Drug Evaluation and Research Center for Drug Evaluation and Research
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Luveris ® New Drug Application (21-322 ) Kate Meaker, M.S. Statistical Reviewer Division of Biometrics II Kate Meaker, M.S. Statistical Reviewer Division.
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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
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.