When is it appropriate to combine phases Vlad Dragalin Statistical Research and Applications Global Biostatistics & Programming EMEA-EFPIA Workshop on Adaptive Designs in London, December 14 , 2007 Confirmatory Clinical Trials
Critical Path Initiative Calls for “New tools to get fundamentally better answers about how the safety and � effectiveness of new products can be demonstrated, in faster time frames, � with more certainty , � and at lower costs ” � Seamless Phase II/III designs offer great potential for achieving these objectives 2 V. Dragalin | EMEA-EFPIA Workshop on Adaptive Designs | Dec 14, 2007 | London
PhRMA WGAD White Paper 3 V. Dragalin | EMEA-EFPIA Workshop on Adaptive Designs | Dec 14, 2007 | London
Seamless Designs: Definition Seamless design A clinical trial design that combines into a single trial � objectives which are traditionally addressed in separate trials ( operationally seamless) Adaptive Seamless design A seamless trial in which the final analysis will use � data from patients enrolled before and after the adaptation ( inferentially seamless) 4 V. Dragalin | EMEA-EFPIA Workshop on Adaptive Designs | Dec 14, 2007 | London
Faster: Operationally Seamless Traditional Phase II + Phase III trials A B B Data Planning Analysis Phase III C Placebo Placebo Phase II End of Phase III Development Timeline Operationally Seamless Phase II/III trials Confirmatory Analysis A B B C Placebo Placebo Phase II End of Phase III 5 V. Dragalin | EMEA-EFPIA Workshop on Adaptive Designs | Dec 14, 2007 | London
At lower costs: Inferentially Seamless Operationally Seamless Phase II/III trials Confirmatory Analysis A B B C Placebo Placebo Phase II End of Phase III Development Timeline Inferentially Seamless Phase II/III trials Confirmatory Analysis A B B C Placebo Placebo Phase II End of Phase III 6 V. Dragalin | EMEA-EFPIA Workshop on Adaptive Designs | Dec 14, 2007 | London
At lower costs: Inferentially Seamless Combining data from the ‘learning’ stage with data from � the confirmation stage adds efficiency in using patient data � draws stronger conclusions with the same number of exposed � patients reduces development time � 2 nd Stage data and the relevant groups from 1 st Stage � data should be combined in a way that Guarantees the Type I error rate for the comparison with � control Produces efficient unbiased estimates and confidence intervals � with correct coverage probability 7 V. Dragalin | EMEA-EFPIA Workshop on Adaptive Designs | Dec 14, 2007 | London
Better: Adaptive Seamless Adaptive Seamless Phase II/III trials Dropped for toxicity A B C D Dropped for E futility Placebo IA IA IA IA Development Timeline 8 V. Dragalin | EMEA-EFPIA Workshop on Adaptive Designs | Dec 14, 2007 | London
Better: Adaptive Seamless More doses than in traditional Phase II can be used � Phase II part uses target population � Treatment selection may be based on a short-term � endpoint X, while confirmation stage uses a long-term (clinical) endpoint Y Complex relationship between X and Y may improve � decision making Include direct effects of treatment on Y not mediated through X � And effects of patient covariates on both Y and X � Adaptive model-based designs in Stage I may improve � selection of the target dose for Stage II 9 V. Dragalin | EMEA-EFPIA Workshop on Adaptive Designs | Dec 14, 2007 | London
More Certainty: Adaptive Dose Ranging 2 4 6 8 2 4 6 8 2 4 6 8 9 doses 9 doses 9 doses 9 doses 9 doses 9 doses 9 doses ANOVA Dopt GADA MCPMod MTT BMA LOCFIT 30 Adaptive dose- ranging 20 methods lead to: 10 • gains in power 0 7 doses 7 doses 7 doses 7 doses 7 doses 7 doses 7 doses to detect DR ANOVA Dopt GADA MCPMod MTT BMA LOCFIT • precision to 30 % Trials select target 20 dose, and 10 • to estimate DR 0 5 doses 5 doses 5 doses 5 doses 5 doses 5 doses 5 doses ANOVA Dopt GADA MCPMod MTT BMA LOCFIT 30 PhRMA ADRS WG 20 White Paper 10 JBS 2007, v 17(6) 0 2 4 6 8 2 4 6 8 2 4 6 8 2 4 6 8 Dose selected 10 V. Dragalin | EMEA-EFPIA Workshop on Adaptive Designs | Dec 14, 2007 | London
Adaptive Seamless Designs Primary objective – combine “dose selection” and “confirmation” into one trial Although dose is most common Phase IIb objective, � other choices could be made, e.g. population After dose selection, the only change is to new � enrollments (patients are generally not re-randomized) Patients on terminated treatment groups could be � followed All data from the chosen group and comparator is used � in the final analysis. Appropriate statistical methods must be used 11 V. Dragalin | EMEA-EFPIA Workshop on Adaptive Designs | Dec 14, 2007 | London
Potential Benefits More efficacy/dose information prior to triggering Phase III � by response-adaptive treatment allocation, dropping treatment � arms Reduced development timelines and cost � by cutting out the ‘white space’ between Ph II and Ph III, using the � same operational infrastructure More safety information on longer term patient exposure � by allowing for longer follow-up on patients enrolled in the 1 st Stage � Higher chance of patients within the trial to be treated with � efficacious and safe doses by making timely use of available information in the interest of � patient benefit 12 V. Dragalin | EMEA-EFPIA Workshop on Adaptive Designs | Dec 14, 2007 | London
New Challenges Drug supply and drug packaging could be more � challenging Need the final formulation available at the start of the � seamless trial Challenges regarding data review at the end of � ‘learning’ stage Decision process may require additional expertise � and/or perspective not usually represented on DMCs Sponsor involvement in decision making � Information inferable from the selection decision may � impact the operational bias 13 V. Dragalin | EMEA-EFPIA Workshop on Adaptive Designs | Dec 14, 2007 | London
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