Flexible designs for pivotal clinical trials

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

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. 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. Adaptive Design Process

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 2nd/3rd stage depends on data

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. 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. 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. 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 8thW of treatment Comparison of three SBx doses (LD, MD, HD) with Plb 1.3 units 2.1 units a = 0.05 (adjustment for multiplicity a = 0.05/3 = 0.017) 90% 4 parallel groups - 72 patients/per arm (total 288) 3 stage inverse-normal combination test O’Brien-Fleming type nominal levels: (0.0006, 0.014, 0.0235) nominal levels: (0.5, 0.5) 1.025 - maximum 75 patients/arm

13. CRO 1st Stage GSK Steering Committee Randomization HD • 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) MD LD Plb 8w 0 2w 1st Stage Data Timing by 80% CP 1st IA 2nd IA 3rd IA 1 2 3 4 5 6 7 8 9 10 11 Month Enrollment Period

14. CRO 2nd Stage GSK Steering Committee Randomization HD • 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) MD 2nd Stage Data Plb 8w 0 2w 1st Stage Data 1st IA 2nd IA 3rd IA 1 2 3 4 5 6 7 8 9 10 11 Month Enrollment Period

15. CRO 3rd Stage GSK Steering Committee Randomization • Final Analysis • Overall p-value • Estimate of TRT eff. • Confidence Interval MD 2nd Stage Data Plb 8w 0 2w 3rd Stage Data 1st Stage Data 1st IA 2nd IA 3rd IA 1 2 3 4 5 6 7 8 9 10 11 Month Enrollment Period

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

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

18. Multiplicity Adjustment • Due to interim analyses • O’Brien-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. Design Properties Parallel 4 arm Dsgn: 72 per arm

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. 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.