Platform Trial Designs in Drug Development Umbrella Trials and Basket Trials

Platform trials test multiple therapies in one indication, one therapy for multiple indications, or both. These novel clinical trial designs can dramatically increase the cost-effectiveness of drug development, leading to life-altering medicines for people suffering from serious illnesses, possibly at lower cost. Currently, the cost of drug development is unsustainable. Furthermore, there are particular problems in rare diseases and small biomarker defined subsets in oncology, where the required sample sizes for traditional clinical trial designs may not be feasible. The editors recruited the key innovators in this domain. The 20 articles discuss trial designs from perspectives as diverse as quantum computing, patient’s rights to information, and international health. The book begins with an overview of platform trials from multiple perspectives. It then describes impacts of platform trials on the pharmaceutical industry’s key stakeholders: patients, regulators, and payers. Next it provides advanced statistical methods that address multiple aspects of platform trials, before concluding with a pharmaceutical executive’s perspective on platform trials. Except for the statistical methods section, only a basic qualitative knowledge of clinical trials is needed to appreciate the important concepts and novel ideas presented.

Contents Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ix Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xiii List of Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .xv Part I Overview of Platform Clinical Trials . . . . . . . . . . 1 1 I-SPY2: Unlocking the Potential of the Platform Trial . . . . . . . . . . . . . .3 Laura Esserman, Nola Hylton, Smita Asare, Christina Yau, Doug Yee, Angie Demichele, Jane Perlmutter, Fraser Symmans, Laura van’t Veer, Jeff Matthews, Donald A. Berry, and Anna Barker 2 The Challenges with Multi-Arm Targeted Therapy Trials . . . . . . . . .23 Ryan J. Sullivan and Keith T. Flaherty 3 Basket Trials at the Confirmatory Stage . . . . . . . . . . . . . . . . . . . . . . . . .37 Robert A. Beckman and Cong Chen 4 Harnessing Real-World Data to Inform Platform Trial Design . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .55 Daphne Guinn, Subha Madhavan, and Robert A. Beckman 5 Impact of Platform Trials on Pharmaceutical Frameworks . . . . . . . . .73 Zoran Antonijevic, Ed Mills, Jonas Häggström, and Kristian Thorlund Part II Stakeholders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83 6 Friends of Cancer Research Perspective on Platform Trials . . . . . . . .85 Jeffrey D. Allen, Madison Wempe, Ryan Hohman, and Ellen V. Sigal 7 Regulatory and Policy Aspects of Platform Trials . . . . . . . . . . . . . . . .97 Rasika Kalamegham, Ramzi Dagher, and Peter Honig 8 Multi-Arm, Multi-Drug Trials from a Reimbursement Perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .119 Anja Schiel and Olivier Collignon 9 Highly Efficient Clinical Trials: A Resource-Saving Solution for Global Health . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .125 Edward J. Mills, Jonas Häggström, and Kristian Thorlund 10 Decision Analysis from the Perspectives of Single and Multiple Stakeholders. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141 Robert A. Beckman, Carl-Fredrik Burman, Cong Chen, Sebastian Jobjörnsson, Franz König, Nigel Stallard, and Martin Posch 11 Optimal Approach for Addressing Multiple Stakeholders’ Requirements in Drug Development . . . . . . . . . . . . . . . . . . . . . . . . . . 153 Zoran Antonijevic and Zhongshen Wang Part III StatisticalMethodology. . . . . . . . . . . . . . . . . . . . 165 12 Primary Site Independent Clinical Trials in Oncology . . . . . . . . . . . 167 Richard M. Simon 13 Platform Trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181 Ben Saville and Scott Berry 14 Efficiencies of Platform Trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197 Satrajit Roychoudhury and Ohad Amit 15 Control of Type I Error for Confirmatory Basket Trials . . . . . . . . . . 211 Cong Chen and Robert A. Beckman 16 Benefit-Risk Assessment for Platform Trials. . . . . . . . . . . . . . . . . . . . 231 Chunlei Ke and Qi Jiang 17 Effect of Randomization Schemes in Umbrella Trials When There Are Unknown Interactions between Biomarkers. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 253 Janet J. Li, Shuai Sammy Yuan, and Robert A. Beckman 18 Combinatorial and Model-Based Methods in Structuring and Optimizing Cluster Trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 265 Valerii V. Fedorov and Sergei L. Leonov Part IV Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 287 19 An Executive’s View of Value of Platform Trials . . . . . . . . . . . . . . . . 289 David Reese and Phuong Khanh Morrow Index. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .295

Zoran Antonijevic is Owner and Consultant of Z-Adaptive Design. He held executive positions in Pharmaceutical Companies and CROs and has designed more than 100 clinical trials in numerous therapeutic areas, many of which included adaptive designs. He has authored numerous papers and scientific presentations and edited Optimization of Pharmaceutical R&D Programs and Portfolios. Robert Beckman is Professor of Oncology and of Biostatistics, Bioinformatics, and Biomathematics at the Lombardi Comprehensive Cancer Center and the Innovation Center of Biomedical Informatics, Georgetown University Medical Center. He has played significant leadership roles in developing new oncology clinical research groups at four pharmaceutical companies, while co-inventing several novel clinical and statistical development strategies. His versatile publication record comprises more than 250 contributions ranging from computational chemistry to clinical oncology. The editors are past and current chairs of the Drug Information Association Adaptive Design Scientific Working Group, an international group of over 200 statisticians focused on novel clinical study designs and their role in bringing new medicines to patients.