1. Flexible designs for pivotal clinical trials Vlad Dragalin, RSU-SDS-BDS-GSK FDA/Industry Workshop Session: Flexible Designs – Are We Ready Yet? Washington, D.C., September 14-16, 2005

2. 2 2 Declaimer The views expressed in this presentation are not necessarily those of PhRMA The views expressed in this presentation are not necessarily those of GlaxoSmithKline The views expressed in this presentation are not necessarily my

3. 3 3 Acknowledgment Judith Quinlan for inviting me to work on this trial GSK Clinical Team for compound SBx for giving me the opportunity to design this trial Compound SBx

4. 4 4 Outline Overview of adaptive designs GSK experience Details of Design Points to Consider

5. 5 5 What are Adaptive Designs? Adaptive Design uses accumulating data to decide on how to modify aspects of the study without undermining the validity and integrity of the trial PROTOCOL AMENDMENTS

6. 6 6 General Structure of Adaptive Designs An adaptive design requires the trial to be conducted in several stages with access to the accumulated data An adaptive design may have one or more rules: Allocation Rule: how subjects will be allocated to available arms Sampling Rule: how many subjects will be sampled at the next stage Stopping Rule: when to stop the trial (for efficacy, for harm, for futility) Decision Rule: the final decision and interim decisions pertaining to design change not covered by the previous three rules At any stage, the data may be analyzed and subsequent stages redesigned taking into account all available data

7. 7 7 Adaptive Design Process Data

8. 8 8 GSK Experience PoC Study in Neuropathic Pain: Three-stage adaptive design: p-values combination test Allocation Rule: drop the loser Stopping Rule for efficacy/futility Sampling Rule: timing of the 2 nd /3 rd stage depends on data

9. 9 9 Background Compound SBx lead indication in Psychiatry (anxiety & depression) secondary indications in Neuropathic pain, RLS & FMS Objectives : To establish superiority of SBx dose(s) versus placebo Confirm efficacy (and durability of response) 8 week treatment, but expect treatment effect at 2 weeks correlation between early and late treatment effects Establish safety profile Establish dose-response Strategic Aim: pivotal quality to potentially support registration

10. 10 Study Designs Last thing we want is to get to the end only to discover no doses are effective OR we missed obtaining a significant result because our original assumptions were too optimistic Standard Dose Ranging Design known entity, but lacks flexibility Adaptive Design Potential savings in terms of both resource and time if there are clear signs that SBx does not work Allows for addition of more patients to a promising dose Protects against underestimate of variance Potential to get to decision quicker, e.g. 5 - 9 months Full data package on doses of interest Statistical validity maintained

11. 11 Team Concerns Regulatory acceptance as a pivotal quality study statistical rigor is maintained Thought EU feedback may delay study start up concerns proving unfounded: design accepted by EMEA CPMP after one F2F meeting Patients may be enrolled before you can adapt the study performed simulations use electronic data capture GSK inexperience (e.g. protocol development, electronic data capture) may delay study start Unequal information on all doses

12. 12 Details of the Design Primary Endpoint: Primary Goal: Target Difference: STDeviation: Type I error: Power: Traditional Dsgn: Adaptive Dsgn: Efficacy Bndry: Futility Bndry: Inflation Factor: PI-NRS change from Baseline at 8 th W of treatment Comparison of three SBx doses (LD, MD, HD) with Plb 1.3 units 2.1 units = 0.05 (adjustment for multiplicity = 0.05/3 = 0.017) 90% 4 parallel groups - 72 patients/per arm (total 288) 3 stage inverse-normal combination test OBrien-Fleming type nominal levels: (0.0006, 0.014, 0.0235) nominal levels: (0.5, 0.5) 1.025 - maximum 75 patients/arm

13. 13 1234115678910Month Enrollment Period 1st Stage Data Plb MD LD HD 3rd IA2nd IA1st IA Randomization CRO 0 8w 2w 1st Stage Decisions: Stop arm for futility 49.5% Stop arm for efficacy 2.9% Stop the study for futility Stop arm(s) for safety Determine Randomization Determine timing of 2nd IA (based on 80% Cond. Power) Timing by 80% CP GSKSteeringCommitteeGSKSteeringCommittee

14. 14 1234115678910Month Enrollment Period 1st Stage Data Plb MD HD 3rd IA2nd IA1st IA Randomization CRO 0 8w 2w 2nd Stage 2nd Stage Data GSK Steering Committee Decisions: Stop arm for futility 13.1% Stop arm for efficacy 47.6% Stop the study for futility Stop arm(s) for safety Determine Randomization Determine timing of 3rd IA (based on 80% Cond. Power)

15. 15 1234115678910Month Enrollment Period 1st Stage Data Plb MD 3rd IA2nd IA1st IA Randomization CRO 0 8w 2w 3rd Stage 2nd Stage Data GSK Steering Committee 3rd Stage Data Final Analysis Overall p-value Estimate of TRT eff. Confidence Interval

16. 16 Interim Analyses: Data For each arm at each stage

17. 17 Interim Analyses: Test Null Hypothesis: Estimate of mean 8 th W endpoint: Standardized Test Statistics: Reduced Variance:

18. 18 Multiplicity Adjustment Due to interim analyses OBrien-Fleming stopping for superiority nominal levels: (0.0006, 0.014, 0.0235) Stopping for futility nominal levels: (0.5, 0.5) Due to multiple comparisons Holm procedure at each stage Due to adaptive design Inverse normal p-value combination rule

19. 19 Design Properties Parallel 4 arm Dsgn: 72 per arm

20. 20 Points to Consider Logistics issues pertaining to traditional group- sequential designs also pertain to adaptive designs Establish an IDMC (charter, contracts) for pivotal trials Have adaptation performed by an independent third party with no conflict of interest issues During interim adaptation, unblind only data that are necessary to be unblinded Patient recruitment is not interrupted

21. 21 Points to Consider Adaptation entails careful planning at the protocol design stage Every detail of the statistical design and analysis that can be fixed in advance is described in the study protocol: number of interim analyses information rates stopping guidelines tests Depending on the information rates, the interim analysis is scheduled. The time of the IA is unknown to the investigators. On IA a snapshot of the DB is made (soft close). All available data are used for IA.