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

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

Motivation 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 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 3 | 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 4 | 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 5 | 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 6 | 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 7 | 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 8 | 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 9 | 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 10 | 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 11 | Seamless Case Study / KOL Series | June 12, 2009

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

Phase II/III adaptive design : Study 2 Independent Dose Selection STAGE 1 (phase IIb) STAGE 2 (phase III) High Dose Selected Dose Low Dose Placebo Selected Dose Active control Active control Screening Dose Ranging 24 weeks Interim Analysis Efficacy and Safety 52 weeks Final Analysis Ongoing treatment 13 | 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) 14 | 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 15 | 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 16 | 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 17 | 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 18 | 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) 19 | 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 20 | 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” 21 | 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 22 | 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 23 | 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 24 | 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 25 | Seamless Case Study / KOL Series | June 12, 2009