A case study design of adaptive dose selection in a combined Phase II/III clinical trial. Junliang Chen, Ph.D November 18, 2016

Transcription

1 A case study design of adaptive dose selection in a combined Phase II/III clinical trial Junliang Chen, Ph.D November 18,

2 Outlines: Background Study design Statistical considerations Operational considerations 2

3 Background (I): Product: Intravenous Immune Globulin (IVIG) Disease: Post-polio syndrome (PPS) Original study plan proposed at pre-ind meeting: A single phase III study A single active arm vs placebo with monthly infusion A 6-month study duration 3

4 Background (II): Feedback from Pre-IND meeting: Experience with IGIV in PPS NOT sufficient to initiate a phase III trial at this time Consider a dosing ranging study to establish the appropriate/optimal dose with both lower and higher dose in a phase II study Study duration extended to a year Response/choice: Separate phase II study followed by a phase III study? A seamless phase II/III study with dose selection at the interim? 4

5 Study Design (I): Phase II/III Multi-national, Multi-center Randomized, placebo-controlled IVIG Higher Dose, IVIG Lower Dose, and Placebo Stratified by the main part of the body affected: upper or lower extremities Double-blind, Parallel-group Superiority study to show the benefit of IVIG over Placebo 5

6 Study Design (II): Adaptive dose selection Stage 1: dose ranging IVIG higher dose every 4 weeks IVIG lower dose every 4 weeks Placebo Stage 2: efficacy confirmation Selected dose of IVIG from Stage 1 every 4 weeks Placebo 6

7 Study Design (III): Phase II Phase III STAGE 1: Two Active Treatments vs Placebo STAGE 2: One Active Treatment vs Placebo IVIG High Dose Selected IVIG Dose IVIG Low Dose Placebo Placebo Unblinded Interim Analysis by Independent DMC: Dose selection based on pre-defined criteria Efficacy confirmation/ Overall Safety Figure 1: Study Schema 7

8 Study Design (IV): Study Schema: Treatment Period Screening Period IVIG Every 4-weeks infusions Placebo Every 4-weeks infusions Follow-up Period SV (W-4) EV/IV1 (W0) Randomization Primary Efficacy Endpoint (Baseline) Primary Efficacy Endpoint (W12, W24, W36) EoT Primary efficacy Endpoint (W52) (W64) Final Visit (W76) 8

9 Statistical Considerations (I): Dose selection at the end of Stage 1: Safety is not a concern Efficacy criteria: Dose selection rule based on the conditional power on the primary efficacy endpoint from interim analysis at Stage 1 If conditional power in IVIG High Dose is at least 10% relatively higher than that in IVIG Low Dose, choose IVIG High Dose to move forward at Stage 2 Otherwise, choose IVIG Low Dose to move forward to Stage 2 9

10 Statistical Considerations (II): Efficacy analysis of primary efficacy endpoint: Both Stage 1 and Stage 2 efficacy data are used Control the type-i error at 0.05 P-values are calculated separately for Stage 1 and Stage 2 Overall adjusted p-value by Posch & Bauer (2005) Many sensitivity analyses Similar analysis for secondary/exploratory efficacy analysis Posch M, et al. Testing and estimation in flexible group sequential designs with adaptive treatment selection. Statistics in Medicine 2005; 24:

11 Operational Considerations (I): Independent Data Monitor Committee (idmc) An idmc is established: to review the critical safety issue (if arise) to review interim analysis data to choose an active dose for Stage 2 (Phase III) portion of the study idmc is not involved in day-to-day study operations idmc voting members include: A neurologist A pharmacologist A biostatistician 11

12 Operational Considerations (II): Timing of interim data cut at the Stage 1 After 80% of subjects (instead of 100%) in Stage 1 are randomized and completed the one-year treatment phase of the study Includes any subject who has the primary efficacy measurements at the 6-month visit or afterwards at the time of data cut 12

13 Operational Considerations (III): For over-running scenario: the over-running subjects will be included in the final analysis for Stage 1 and Stage 2 will enroll the number of subjects as planned. If over-running subjects exceed 10% of the planned sample size for Stage 1, the study enrollment may be paused until the decision of the final dose selection for Stage 2 by DMC 13

14 Operational Considerations (IV) For under-running scenario: the enrollment for Stage 1 will be stopped and the remaining subjects not randomized in the Stage 1 will be reallocated to Stage 2 and included in the final analysis for Stage 2. 14

15 Operational Considerations (V): Once idmc decides the dose for Stage II, the transition is through the IRT system Transition will have no direct impact on the site activities Sites and Sponsor/CRO study team will not be notified whether higher dose or lower dose is chosen for Stage II - This is why it is called seamless 15

16 A case study design of adaptive dose selection in a combined Phase II/III clinical trial Junliang Chen, Ph.D November 18,