highlights from exl pharma's multiple comparisons in clinical trials
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ExL Pharma’s Multiple Comparisons in Clinical Trials HighlightsJanuary 25-27, 2010Rockville, MD
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Subgroup analyses in Pharmaceutical Development- Must we always adjust
for multiplicity?
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What Does the FDA Say About Subgroup Analyses?•Not Much!•The need for conducting subgroups
analyses is acknowledged •No methodological guidance is provided•Subgroup analyses are lumped together
with other multiplicity issues
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FDA Position on Subgroup Analyses
• Subgroups of interest must be pre-specified in the protocol• Inferences about subgroups following the ITT analysis is
subject to multiplicity Type I error adjustment• Generally, subgroup analyses are exploratory only
▫ Hypotheses generation▫ Identify heterogeneity w.r.t baseline, demographic, geographic
variables• Generally, NDA approval requires significance of the
primary endpoint in ITT• Significance in pre-specified subgroup is not sufficient
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Fundamental Question:
Do the problems associated with subgroup analyses raise multiplicity
issues?
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MultiplicityMultiplicity issue arises when a single inference is based on
multiple repeated testing▫ Interim analyses (multiple looks)▫ Multiple comparisons (e.g. multiple doses of a drug)▫ Multiple endpoints
Error to be controlled = Family-wise Error Rate
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Multiple Comparisons Paradigm
Regulatory claim:Drug is efficacious Patient population A
Stat Decision Rule:Drug is efficacious if
Sig. on V1, OR Sig. on V2, ORSig. on V3, etc.
Testing
V1 Sig?
V2 Sig?
V3 Sig?
Yes
Yes
Yes
EFFICACIOUS
Control “family-wise” Error Rate
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Subgroup AnalysisExample:
• Placebo-controlled global trial of a new ACE inhibitor
• Sponsor is interested in investigating the drug’s efficacy in African patients
• Randomization stratified by country• Primary efficacy variable – DiPB• Target population – Patients with moderate
hypertension
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Analysis Strategy
•Test for efficacy in the ITT•Proceed to test in the subgroup of
African Patients
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Possible Outcomes
P 0.05P > 0.05
P 0.05P > 0.05P 0.05P > 0.05
Test in SubgroupTest in Subgroup
Test in ITT
A B C D
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Inferences
P 0.05P > 0.05
P 0.05P > 0.05P 0.05P > 0.05
Test in SubgroupTest in Subgroup
Test in ITT
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Treatment Selection in Multi-Armed Trials Using Confirmatory Adaptive Designs
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The term adaptive
• Adaptive randomization
• Adaptive test selection
• Adaptive dose selection
• Bayesian adaptive designs
• Confirmatory adaptive designs
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Multi-armed designs• Consider many-to-one comparisons, e.g., G treatment
arms and one control, normal case.
• In an interim stage a treatment arm is selected based on data observed so far.
• Not only selection procedures, but also other adaptive strategies (e.g., sample size reassessment) can be performed.
• Application, e.g., within an “Adaptive seamless designs” using the combination testing principle, but investigation of more than one dose in phase III is also encouraged.
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Standard2 phases
AdaptiveSeamlessDesign
Plan & DesignPhase III
Dose Selection
Learning
A
B
C
DControl
Confirming
Learning, Selecting and Confirming
Plan & DesignPhase IIb
Plan & DesignPhase IIb and III
Adaptive seamless designs
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A
B
C
DControl
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ExampleComparison of three test procedures
•Inverse normal Dunnett
•Pure conditional Dunnett
•Separate stage conditional Dunnett
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Comparison of the three procedures
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Design: two-stage, = 0.025 one-sided, u1 = , u2 = 1.96 linear dose-reponse relationship with drift
120 i.e., ,20;20 220
13
12
11
10 Nnnnnnn S
140 i.e., ,20;20 2220
13
12
11
10 21
Nnnnnnnn SS
- always select the two best:
- select all:
160 i.e., ,20;20 23
22
21
20
13
12
11
10 Nnnnnnnnn
- always select the best:
Consider three selection procedures:
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The comparison shows that • the conditional second-stage Dunnett test performs
best
• it is identical with the conventional Dunnett test if no adaptations were performed
• becomes complicated if, e.g., ▫ allocation is not constant
▫ variance is unknown
• the inverse normal technique is not optimum but enables early stopping and more general adaptations
• is straightforward if, e.g., ▫ allocation is not constant
▫ variance is unknown
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Still have any questions? For additional information on ExL Pharma’s Multiple Comparisons in
Clinical Trials Conferences, please visit www.exlpharma.com