When is it appropriate to combine phases · EMEA-EFPIA Workshop on Adaptive Designs in Confirmatory...
Transcript of When is it appropriate to combine phases · EMEA-EFPIA Workshop on Adaptive Designs in Confirmatory...
EMEA-EFPIA Workshop on Adaptive Designs in Confirmatory Clinical Trials
London, December 14 , 2007
When is it appropriate to combine phases
Vlad DragalinStatistical Research and Applications Global Biostatistics & Programming
V. Dragalin | EMEA-EFPIA Workshop on Adaptive Designs | Dec 14, 2007 | London 2
Critical Path Initiative
Calls for “New tools to get
n fundamentally better answers about how the safety and effectiveness of new products can be demonstrated,
n in faster time frames,n with more certainty, n and at lower costs”
Seamless Phase II/III designs offer great potentialfor achieving these objectives
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PhRMA WGAD White Paper
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Seamless Designs: Definition
Seamless designn A clinical trial design that combines into a single trial
objectives which are traditionally addressed in separate trials (operationally seamless)
Adaptive Seamless designn A seamless trial in which the final analysis will use
data from patients enrolled before and after the adaptation (inferentially seamless)
V. Dragalin | EMEA-EFPIA Workshop on Adaptive Designs | Dec 14, 2007 | London 5
Faster: Operationally SeamlessTraditional Phase II + Phase III trials
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B
C
Placebo
B
Placebo
Data
Analysis
Planning
Phase III
Development Timeline
Operationally Seamless Phase II/III trials
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B
C
Placebo
B
Placebo
Phase II
Phase II
End of Phase III
End of Phase III
Confirmatory Analysis
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At lower costs: Inferentially Seamless
Development Timeline
Inferentially Seamless Phase II/III trials
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B
C
Placebo
B
Placebo
Phase II End of Phase III
Confirmatory Analysis
Operationally Seamless Phase II/III trials
A
B
C
Placebo
B
Placebo
Phase II End of Phase III
Confirmatory Analysis
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At lower costs: Inferentially Seamless
n Combining data from the ‘learning’ stage with data from the confirmation stage l adds efficiency in using patient datal draws stronger conclusions with the same number of exposed
patientsl reduces development time
n 2nd Stage data and the relevant groups from 1st Stage data should be combined in a way thatl Guarantees the Type I error rate for the comparison with
controll Produces efficient unbiased estimates and confidence intervals
with correct coverage probability
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Better: Adaptive Seamless
Development Timeline
D
E
Placebo
Adaptive Seamless Phase II/III trials
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B
C
IA IA IA IA
Dropped for toxicity
Dropped for futility
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Better: Adaptive Seamless
n More doses than in traditional Phase II can be usedn Phase II part uses target population n Treatment selection may be based on a short-term
endpoint X, while confirmation stage uses a long-term (clinical) endpoint Y
n Complex relationship between X and Y may improve decision makingl Include direct effects of treatment on Y not mediated through Xl And effects of patient covariates on both Y and X
n Adaptive model-based designs in Stage I may improve selection of the target dose for Stage II
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More Certainty: Adaptive Dose Ranging
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10
20
30
2 4 6 8
ANOVA5 doses
Dopt5 doses
2 4 6 8
GADA5 doses
MCPMod5 doses
2 4 6 8
MTT5 doses
BMA5 doses
2 4 6 8
LOCFIT5 doses
ANOVA7 doses
Dopt7 doses
GADA7 doses
MCPMod7 doses
MTT7 doses
BMA7 doses
0
10
20
30
LOCFIT7 doses
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20
30
ANOVA9 doses
2 4 6 8
Dopt9 doses
GADA9 doses
2 4 6 8
MCPMod9 doses
MTT9 doses
2 4 6 8
BMA9 doses
LOCFIT9 doses
Dose selected
% T
rials
PhRMA ADRS WG
White Paper
JBS 2007, v 17(6)
Adaptive dose-ranging methods lead to:
• gains in power to detect DR
• precision to select target dose, and
• to estimate DR
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Adaptive Seamless Designs
Primary objective – combine “dose selection” and “confirmation” into one trial
n Although dose is most common Phase IIb objective, other choices could be made, e.g. population
n After dose selection, the only change is to new enrollments (patients are generally not re-randomized)
n Patients on terminated treatment groups could be followed
n All data from the chosen group and comparator is used in the final analysis. Appropriate statistical methods must be used
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Potential Benefitsn More efficacy/dose information prior to triggering Phase III
l by response-adaptive treatment allocation, dropping treatment arms
n Reduced development timelines and costl by cutting out the ‘white space’ between Ph II and Ph III, using the
same operational infrastructure
n More safety information on longer term patient exposurel by allowing for longer follow-up on patients enrolled in the 1st Stage
n Higher chance of patients within the trial to be treated with efficacious and safe dosesl by making timely use of available information in the interest of
patient benefit
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New Challenges
n Drug supply and drug packaging could be more challenging
n Need the final formulation available at the start of the seamless trial
n Challenges regarding data review at the end of ‘learning’ stage
n Decision process may require additional expertise and/or perspective not usually represented on DMCs
n Sponsor involvement in decision makingn Information inferable from the selection decision may
impact the operational bias