Group Sequential and Adaptive Designs Part II: Adaptive Designs May - PowerPoint PPT Presentation

Group Sequential and Adaptive Designs Part II: Adaptive Designs May 2, 2015 Cyrus Mehta, Ph.D. – Cytel Inc.

Adaptive Designs • Adaptive designs are defined as: “… changes in design or analyses guided by examination of the accumulated data at an interim point in the trial … ” -- 2010 FDA guidance • Two types: “generally well understood” and “less well understood” 2

Adaptive Designs in Confirmatory Trials • Well Understood: • Group sequential designs • Blinded sample size re-estimation • Less Well Understood: • Unblinded sample size re-estimation • Dose selection • Population enrichment • Switching endpoints 3

Opportunities for Adaptive Methods • Respond flexibly to accumulating data • Efficiently and effectively streamline drug development • Reduce costs and time to market • Increase probability of success • Combine adaptive design with adaptive financing 4

Challenges for Adaptive Methods Opportunities yes, but … Potential for operational bias: • premature unblinding of interim results • investigator behavior changes after interim • misclassification of primary outcome • open label studies especially prone to this bias Inflation of type I error rate • handled by appropriate statistical methodology Adaptations may not match pre-planned decision rules • handled by adjusting the final significance level (like GSD) 5

Case Study I: VALOR Trial for AML • Therapy for relapsed or refractory AML is generally unsatisfactory; no approved drugs; dismal prognosis • Vosaroxin and Ara-C combination evaLuating Overall survival in Relapsed/refractory AML • Phase 3, double-blind, placebo-controlled, multinational trial for first-relapsed or refractory Acute Myeloid Leukemia (AML) • Evaluate efficacy and safety of Vos+Ara-C versus Vos+Placebo 6

VALOR Phase 3 Schema After Cycle 1, all subsequent cycles at 70 mg/m2 vosaroxin on Days 1 and 4. 7

Design Objectives • Primary endpoint is overall survival • Design for 90% power at 5% (2-sided) significance level • Complete the trial in 30 months • Enroll for 24 months • Follow for 6 additional months 8

Prior Phase 2 Data • Limited information on Vosaroxin from a single phase 2 trial of 69 patients with no active comparator • Median OS for Vosaroxin estimated at 7 months from phase 2 trial • Median OS for Cytarabine estimated at 5 months from meta- analysis of prior studies and consultation with KOLs • Hazard ratio estimated to be 0.71 amidst considerable uncertainty 9

Sponsor’s Dilemma • Based on phase 2 data: • Assume 5/7 month median for Ctrl/Trtm (HR=0.71) • Require 375 events and 450 subjects @ 19/month • But phase 2 estimates are subject to uncertainty • What if 5/6.5 mth median on Ctrtl/Trtm (HR=0.77)? • HR=0.77 is still clinically meaningful • Require 616 events and 732 subjects @ 31/month • Not a feasible option for sponsor • Given these constraints, how to design this single pivotal trial? 10

Sponsor is Resource and Time Constrained Power if designed Power if designed True HR with base-case with conservative assumption (HR=0.71) assumption (HR=0.77) 0.71 91% 99% 0.74 83% 97% 0.77 71% 90% Resources Needed 450 patients@19/mth 732 patients@31/mth Risk of designing for the base case (HR=0.71) • Pilots or POC trials often demonstrate greater efficacy than larger multicenter • trials (Pereira et. al., JAMA 2012; 308(16) 1676-1684) Difficulty of designing with the conservative assumption (HR=0.77) • Unable to muster up the resources for such a large investment up-front • Rule of thumb: cost/patient is about $50-80K for an oncology trial with OS 11

A Strategy of Staged Investment • Design up-front for 90% power at HR=0.71 (requires 375 events; 450 subjects @ 19/mth) • One interim analysis after 50% information (187 events) • Stop early if overwhelming evidence of efficacy • Stop early for futility if low conditional power • Increase sample size and events if interim results are promising • Key Idea: Milestone Driven Investment Invest additional resources and re-power the study only after seeing promising interim results 12

The Promising Zone Design Partition the interim outcome into three zones based on the interim estimate of conditional power: • Unfavorable: CP < 30%; no change to design • Promising: 30% ≤ CP < 90%; increase resources • Favorable: CP > 90% ; no change to design 13

Increase Maximum Information in Promising Zone 14

Increasing events from 374 to 561 if in Promising Zone at interim 15

Conditional Power of Conventional Design (375 events) if HR = 0.77 16

Conditional Power of Adaptive Design at interim if HR = 0.77 17

Superimpose CP Curves of Conventional and Adaptive Designs 18

Include distribution of Zstat at interim analysis time point 19

Preserving the Type-1 Error 20

Operating Characteristics 21

Regulatory Interactions and Confidentiality • Design specification including simulation results and method for controlling type-1 error presented for FDA review • Actual decision rule for triggering the adaptation was included as a restricted appendix in the FDA briefing book and the DMC charter • Sponsor’s briefing book and DMC charter did not contain the restricted appendix 22

Results at Interim Analysis • The estimate of the hazard ratio is 0.7628 • The Conditional Power was 82% -- in the promising zone • Sample size and events were increased by 50% 23

Kaplan-Meier Plots at Interim 24

Interim Result Triggered Additional Investment 25

Preserving the Type I Error (CHW Adjustment) 26

VALOR Results • Primary Endpoint Overall Survival : • 7.5 months on Vos vs. 6.1 months on Placebo. • unstratified results: HR = 0.87, p=0.06 • stratified results: HR = 0.83, p=0.02 • Unfortunately, protocol pre-specified unstratified analysis as primary and stratified analysis as key secondary • Complete Response rate : 30.1% vosaroxin arm vs. 16.3% placebo arm, p<0.0001 27

Concluding Remarks • Totality of data suggest benefit of vosaroxin in relapsed/refractory AML. • Adaptive design played an important role in demonstrating drug activity. • Staged investment • Careful implementation led to − Control of Type I error − Minimized potential for operational bias • Without the sample size adaptation p-value = 0.22 • Practical questions emerge with implementation 28

Case Study II. The ADVENT Trial for the treatment of HIV induced diarrhea • Diarrhea affects 20-30% of HIV-infected individuals in post-highly active anti-retroviral therapy (HAART) era 1 • No existing therapy has been shown to be effective, safe, and well-tolerated by individuals with HIV diarrhea. 2 • Diarrhea negatively impacts quality of life 1,3 and compliance with antiretroviral medications 4,5 . • Noncompliance leads to reduced drug levels, higher viral loads, and drug resistance. 6,7 • Successful treatment of diarrhea could improve HIV treatment outcomes. 29

Crofelemer: From Plant to Molecule Crofelemer Molecule Croton lechleri Latex from Croton lechleri 30

Results of Phase II Trial (37554-210) • Previous Phase 3 HIV diarrhea study (37554-210) design – Double-blind placebo-controlled randomized trial • 1-day Baseline and 6-day inpatient stool collection period • Responders were eligible for 3-week double-blind outpatient treatment period; followed by 1-week treatment washout inpatient Outpatient Period washout Withdraw week 2 week 3 week 4 antidiarrheals 1 7 14 21 28 35 2 3 4 5 6 Percent Change in Abnormal Stool Weight (Inpatient Period) Percent Change in Abnormal Stool Frequency (Inpatient Period) Significant Baseline Diarrhea (SBD) Subset Significant Baseline Diarrhea (SBD) Subset 0 0 2 3 4 5 6 7 2 3 4 5 6 7 -10 % Change in Frequency -10 -20 -20 % Change -30 -30 -40 -40 -50 -50 -60 -60 -70 -80 -70 DAYS DAYS 500 mg T Placebo 500 mg T Placebo 500 mg B 250 mg T 250 mg T 500 mg B Analysis of patients with secretory diarrhea and urgency at Analysis of patients with secretory diarrhea and urgency at baseline showed significant effect of 250 mg and 500 mg baseline showed significant effect of 250 mg and 500 mg crofelemer tablets in percent reduction in abnormal stool weight crofelemer tablets in percent reduction in number of abnormal (p=0.014 and p=0.005 respectively); significant in 500 mg beads as stools (p=0.019 and p=0.003 respectively); significant in 500 mg well beads as well 31

Option 1: A Single 4-Arm Trial 125 mg bid 250 mg bid Randomize 500 mg bid Placebo • 80% power to detect: p 0 =35%; p 1 =35%; p 2 =35%; p 3 =55% • Perform the Bonferroni-Holm Test for the final analysis • Require 520 patients (130/arm) for 80% power with 1-sided a =0.025 32

Option 2: Separate Phase 2 and Phase 3 Trials (Operationally Seamless) • Trial 1 : make a dose selection (sponsor involvement permitted) Trial 2 : test selected dose versus placebo with 216 patients at FULL a =0.025 • • This design requires 200 + 216 = 416 patients for 80% power Advantage : Very flexible for dose selection; Disadvantage : data from Trial 1 cannot be used for final analysis of Trial 2 33