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Phase II/III Design: Case Study Case study: Seamless Phase II/III Design for Registration Program Jeff Maca, Ph.D. Senior Associate Director Novartis Pharmaceuticals.

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Presentation on theme: "Phase II/III Design: Case Study Case study: Seamless Phase II/III Design for Registration Program Jeff Maca, Ph.D. Senior Associate Director Novartis Pharmaceuticals."— Presentation transcript:

1 Phase II/III Design: Case Study Case study: Seamless Phase II/III Design for Registration Program Jeff Maca, Ph.D. Senior Associate Director Novartis Pharmaceuticals

2 2 | Seamless Case Study / KOL Series | June 12, 2009 Outline – Adaptive Seamless Case Study  Motivation/definitions  Adaptive seamless designs considerations  Case study example Simulation details  Conclusions

3 3 | Seamless Case Study / KOL Series | June 12, 2009 Motivation  An adaptive trial can plan at the design stage to correct for incorrect assumptions  Adaptive trials can merge what might be considered two separate trials into one trial  Improve efficiency in clinical development  Careful planning is necessity Adaptive Designs: Using accumulating data to decide on how to modify aspects of the trial design, during the conduct of the trial and without violating the integrity of the trial

4 4 | Seamless Case Study / KOL Series | June 12, 2009 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, change usually to new enrollments (patients could be re-randomized, and analyzed separately)  Patients on terminated treatment groups can be followed  All data from the chosen group and comparator is used in the final analysis. Appropriate statistical methods must be used

5 5 | Seamless Case Study / KOL Series | June 12, 2009 Adaptive Seamless designs Statistical methodology for Adaptive Seamless Designs must account for potential biases and statistical issues  Selection bias (multiplicity)  Multiple looks at the data (interim analysis)  Combination of data from independent stages Closed testing procedure (data from stages are separated) and Bonferroni type adjustment (data is pooled across stages) are two possible methods

6 6 | Seamless Case Study / KOL Series | June 12, 2009 Adaptive Seamless designs With the added flexibility of seamless designs, comes added complexity.  Careful consideration should be given to the feasibility for a seamless design for the project.  Not all projects can use seamless development  Even if two programs can use seamless development, one might be better suited than the other  Many characteristics add or subtract to the feasibility

7 7 | Seamless Case Study / KOL Series | June 12, 2009 Adaptive Seamless designs Enrollment vs. Endpoint  The length of time needed to make a decision relative to the time of enrollment must be small Otherwise enrollment must be paused  Endpoint must be well known and accepted If the goal of Phase II is to determine the endpoint for registration, seamless development would be difficult  If surrogate marker will be used for dose selection, it must be accepted, validated and well understood

8 8 | Seamless Case Study / KOL Series | June 12, 2009 Adaptive Seamless designs Clinical Development Time  There will usually be two pivotal trials for registration  Entire program must be completed in shorter timelines, not just the adaptive trial

9 9 | Seamless Case Study / KOL Series | June 12, 2009 Adaptive Seamless designs Logistical considerations  Helpful if final product is available for adaptive trial (otherwise bioequivalence study is needed)  Decision process, and personnel must be carefully planned and pre-specified

10 10 | Seamless Case Study / KOL Series | June 12, 2009 Phase II/III Adaptive Design – Case Study Case Study Introduction  Indication is a chronic disease  Adaptive seamless design (ASD) to select final dose to support registration of new formulation  Study will provide pivotal confirmation of efficacy, safety and tolerability of selected dose  Two adaptive studies are running concurrently, one in mono-therapy, one in add-on therapy

11 11 | Seamless Case Study / KOL Series | June 12, 2009 Phase II/III Adaptive Design – Case Study Case Study Introduction  Bias towards selecting the lower dose, unless Low dose would not have high likelihood of success High dose had considerably better efficacy  Selection probabilities and overall power derived via extensive simulation study  Studies are planned to have interim analysis occurring at the same time Dose selection simultaneous for both studies

12 12 | Seamless Case Study / KOL Series | June 12, 2009 High Dose Low Dose Placebo Selected Dose Active control Dose Ranging 24 weeks Screening Interim Analysis Efficacy and Safety 52 weeks STAGE 2 (phase III) STAGE 1 (phase IIb) Ongoing treatment Phase II/III adaptive design : Study 1 Final Analysis Independent Dose Selection

13 13 | Seamless Case Study / KOL Series | June 12, 2009 High Dose Low Dose Placebo Active control Selected Dose Active control Dose Ranging 24 weeks Screening Interim Analysis Efficacy and Safety 52 weeks STAGE 2 (phase III) STAGE 1 (phase IIb) Ongoing treatment Phase II/III adaptive design : Study 2 Final Analysis Independent Dose Selection

14 14 | Seamless Case Study / KOL Series | June 12, 2009 Phase II/III Adaptive Design – Case Study Studies are divided into three periods  Period 1 (Dose selection)  Intermediate period (during dose selection)  Period 2 (long term safety and efficacy)

15 15 | Seamless Case Study / KOL Series | June 12, 2009 Phase II/III Adaptive Design – Case Study Period 1  Patients randomized equally to high dose, low dose and control (s)  All patients complete 24 weeks of treatment which is the time to primary endpoint  Roughly 100 and 150 patients in the two studies will be randomized  Data from both studies will be used in selection

16 16 | Seamless Case Study / KOL Series | June 12, 2009 Phase II/III Adaptive Design – Case Study Intermediate Period  Patients randomized to non-placebo treatments will stay on treatment until dose selection is complete  Patients on placebo will be switched to active treatment (if completed 24 weeks)  Recruitment continues through this period

17 17 | Seamless Case Study / KOL Series | June 12, 2009 Phase II/III Adaptive Design – Case Study Period 2  Patients randomized to non selected dose(s) are switched to selected dose  Placebo patients are switched to active treatment  Patient randomized to selected dose or active control

18 18 | Seamless Case Study / KOL Series | June 12, 2009 Phase II/III adaptive design: Case study  Primary endpoint Continuous variable – measured after 24 weeks Dose selected on a 12 week measurement (early readout) Comparison with placebo for superiority  Secondary endpoints Comparison of safety and efficacy over 24 weeks Long term safety measured over 52 weeks

19 19 | Seamless Case Study / KOL Series | June 12, 2009 Phase II/III adaptive design: Case study Objective of interim analysis  To investigate two doses of new treatment versus placebo and active controls with respect to primary endpoint after 12 weeks of treatment (early read-out)  Independent external DMC will select dose to continue into period 2  DMC would see analysis from both studies, and make same selection of dose for both studies  Interim analyses must be timed to occur at the same time (harder to do in practice than on paper)

20 20 | Seamless Case Study / KOL Series | June 12, 2009 Phase II/III adaptive design: Simulations  Sample sizes for stage 1 and 2 based on extensive simulation work Stage 1 sample size chosen to ensure the “optimal” dose was chosen with high probability Various dose responses were investigated  Stage 2 sample size sufficient to satisfy primary and secondary objectives of the study

21 21 | Seamless Case Study / KOL Series | June 12, 2009 Phase II/III adaptive design: Simulations  Decision rule has tendency towards picking lower dose  In general, the low dose is selected unless high dose has “much” higher efficacy outcome, or low dose does not have “much” chance to succeed.  Different thresholds were investigated to make this determination of “much”

22 22 | Seamless Case Study / KOL Series | June 12, 2009 Phase II/III adaptive design: Simulations Output from simulation  Selection probabilities for each of the two treatment doses  Power conditional on the dose selected  Overall power that the selected doses would be confirmed

23 23 | Seamless Case Study / KOL Series | June 12, 2009 Phase II/III adaptive design: Simulations Statistical methodology  A multiplicity correction will be used for the final analysis to account for the two treatments Dunnett step-down methodology will be used Data not split by period with separate p-values (inverse normal/closed testing methodology), although would have similar power  Procedure will control family-wise type I error rate for the primary endpoint

24 24 | Seamless Case Study / KOL Series | June 12, 2009 Phase II/III adaptive design: Case study DMC guidelines  Numerical values given (not inferential)  Thresholds are pre-defined (results from simulations ), for implementation by DMC  Trials will not be stopped for efficacy at interim analysis  Trials currently ongoing, with dose selection analysis upcoming shortly

25 25 | Seamless Case Study / KOL Series | June 12, 2009 Conclusions  Adaptive seamless designs have an ability to improve the development process by reducing timelines for approval  Extra planning is necessary to implement an adaptive seamless design protocol  Simulations can be used to determine decision rules, and operating characteristics of such a design  This case study successfully used simulations to plan and execute two simultaneous adaptive seamless designs which incorporate dose selection


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