Cadth 2015 e4 mcelwee cadth 041415 fnl

Newell McElwee, PharmD, MSPH

Merck Research Labs

Center for Outcomes and Real World Evidence

14 April 2015

Adaptive Design in MerckOncology Studies

Adaptive designs are not new …

• Thompson WR. Biometrika 1944; 25: 285-294

• Ellenberg SS. Statis Med 2012; 31:2798-2804

• Adaptive design methodology in RCTs evolved starting in the 1950’s … but adoption was slow until the 1990’s when the FDA created an adaptive trial pathway for devices. (Ellenberg)

Extra-Corporeal Membrane Oxygenation (ECMO)

Acknowledgements

Many people within Merck have contributed to the planning, design, and execution of the adaptive trials used in our pembrolizumab program. These include:

• Keaven Anderson, Ph.D. (Biostatistics)• Cong Chen, Ph.D. (Biostatistics)• Christine Gause, Ph.D. (Biostatistics)• Eric Rubin, M.D. (Clinical Research)

Outline

• Types of designs– Dose-finding– Single-arm response rate studies– Comparative studies– Bayesian study design

• Driving theme: Biomarker-selected patient populations

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Dose-Finding Designs

• Modified TPI (toxicity profile interval) designs– Very specific Bayesian design– Dose escalation and de-escalation are table-driven

• No need for computer interaction like CRM designs

– Preferred of traditional 3+3 designs• Start similarly• Allow confirmation of dose with further

adaptation beyond 6 patients• Simple execution

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Single-arm Response Rate Studies

• Very high response rates allow possible early access for patients– Single arm studies where no effective therapy exists– Biomarker-selected population

• Evaluate in both biomarker-positive and biomarker-negative patients

• Designs allow evaluation of effectiveness in biomarker-positive and all-comer populations

• Early interim analysis to discontinue biomarker-negative patients if no responses

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Comparative Studies

• Dual primary endpoints:– Overall survival (OS)– Progression-free survival

• Multiple populations evaluated (depending on study)– Overall– Biomarker positive– Biomarker strong-positive

• Possible early adaptation– Discontinue biomarker negative– Interim filing for PFS– Early stop for both PFS and OS (e.g., Keynote-006)

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Bayesian Adaptive Studies

• I-SPY 2 (ispy2.org)– “..an innovative public-private collaboration that

combines Personalized Medicine & Novel Trial Design to develop new cancer treatments much faster and for much less cost.”

• Neoadjuvant phase 2 breast cancer study– Accelerated development– Adaptive biomarker and drug selection to generate

high probability of success in Phase 3

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