SC03 - Design and Implementation of Master Protocols for Complex Diseases: What Have We Learned?

Room: Salon A,Salon B 

As medical research continues to push into new frontiers of discovery and personalized patient care, along with new complex diseases and worldwide pandemics (COVID-19), new clinical trial designs and statistical methodologies are emerging to impact global public health. One key innovation is the master protocol, in which adaptive "platform" trial designs can evaluate multiple therapies simultaneously under a common protocol. To better direct the discussion, we will focus on adaptive platform trials that have been designed, operationalized, and have released results for select interventions: This includes the HEALEY ALS platform trial for Amyotrophic Lateral Sclerosis, the GBM-AGILE platform trial for Glioblastoma (GBM), the ACTIV platform trials for COVID-19, and the PrecISE platform trial for severe asthma. These platform trials have all been implemented under an IND with extensive regulatory interactions. Having been deeply involved in the design, implementation, and releasing of results for select interventions from these platform trials, the instructors will focus on lessons learned in the design and implementation of master protocol trials. This includes 1) statistical properties & efficiencies of trial design; 2) master protocol structure; 3) logistical and operational challenges; 4) regulatory concerns and interactions; 5) challenges in the release of results with an ongoing (perpetual) platform trial.

Upon completion of the course, participants will have a general understanding of Bayesian adaptive platform trials in both design and practice, including regulatory and pragmatic considerations. They will gain appreciation for the purpose, flexibility, and complexity of the master protocol, and understand key aspects of design and implementation that need to be addressed to achieve a successful trial.

Master protocols

Adaptive platform trials

ALS, Glioblastoma, COVID-19, severe asthma

trial design and implementation 

Dr. Saville: (45 minutes)
• Introduce Master Protocols
• Efficiencies of Platform Trials
• ALS platform trial design

Dr. McGlothlin: (30 minutes)
• GBM-AGILE design

Dr. LaVange: (30 minutes)
• ACTIV platform trials for COVID-19
• A regulatory perspective on platform trial design

BREAK: (15 minutes)

Dr. Saville: (30 minutes)
• ALS Trial implementation from the blinded side
• Data sharing
• New interventions
• Changes in SOC and the use of non-concurrent randomized controls

Dr. McGlothlin: (30 minutes)
• GBM-AGILE implementation from the blinded side
• Response-Adaptive Randomization

Dr. LaVange: (30 minutes)
• PrecISE platform trial for severe asthma
• A regulatory perspective on platform trial implementation

Dr. Saunders: (30 minutes)
• A perspective from the unblinded statistical team implementing interim analyses
• Operations/Logistics
• Infrastructure (database, randomization system)
• Communication plan, data sharing
 

Instructors’ Background on Platform Trials:
• Dr. Saville, Dr. McGlothlin, and Dr. Saunders are statistical scientists at Berry Consultants, and have been involved in the design and implementation of several complex and innovative adaptive platform trials. All three instructors have multiple publications regarding the design and results of platform trials. In addition, Dr. Saville has published in peer-reviewed statistical journals on the design of adaptive platform trials, including statistical efficiencies and methods for the use of non-concurrent randomized controls.
• Dr. LaVange is the former Director of the Office of Biostatistics in the Center for Drug Evaluation and Research (CDER), and has been involved in the regulatory review of several master protocol trials. In her current role as Professor and Chair of the Department of Biostatistics at the University of North Carolina at Chapel Hill, she has been actively involved in the design and implementation of platform trials in COVID-19 (ACTIV trials) and severe asthma (PrecISE).

Instructors’ Teaching background
• Dr. Saville, Dr. McGlothlin, and Dr. Saunders have taught half-day and full-day short courses on Master Protocols together at ENAR 2021 and WNAR 2021.
• Dr. Saville has taught half day short courses on Master protocols at SCT 2016 and SCT 2018, as well as half-day, full-day, and multiple day course on adaptive trials at ICSA (2017), Vanderbilt University (2016), University of Western Australia (2019), and Biopharmaceutical Applied Statistics Symposium (2015).
• Dr. Saville taught both graduate and undergraduate statistical courses at Vanderbilt University from 2008-2014, including introductory statistics courses and theory of generalized linear models.
• Dr. McGlothlin co-taught a half-day short course on creating clinical trial simulators at Regulator-Industry Statistics Workshop (2016), co-taught a full-day short course on adaptive clinical trials at ASH (2018), and served as an instructor for the NINDS-supported Clinical Trials Methodology Course (2017), specifically the advanced track that focused on the design and simulation of adaptive designs.
• Dr. LaVange has decades of experience teaching graduate courses for the University of Chapel Hill, covering topics such as design and analysis of clinical trials, regulatory science, statistical consulting, and statistical leadership.

Instructors’ Short Bios:
Ben Saville, PhD, is a Director & Senior Statistical Scientist for Berry Consultants, where he specializes in the design of innovative Bayesian adaptive clinical trials. He works primarily with medical device companies, pharmaceutical companies, and academic investigators to solve challenging problems via Bayesian designs, many of which are reviewed by the U.S. Food and Drug Administration (FDA). He has designed Bayesian clinical trials in a variety of therapeutic areas, including cardiovascular diseases, rare and progressive diseases, infectious diseases, traumatic brain injury, respiratory and digestive disorders, and neurological diseases. Dr. Saville is a frequent invited speaker at statistical conferences, academic seminars, and lecture series, including short courses on Bayesian adaptive clinical trial design. He earned his Ph.D. in Biostatistics from the University of North Carolina at Chapel Hill in 2008 and was an Assistant Professor of Biostatistics at Vanderbilt University from 2008-2014. Dr. Saville has authored approximately 100 peer-reviewed publications in the statistical and medical literature, with expertise in Bayesian hierarchical models and Bayesian adaptive platform trial designs.

Anna McGlothlin, PhD is a Director and Senior Statistical Scientist for Berry Consultants where she leads statistical design and implementation teams for adaptive and Bayesian clinical trials, with specific expertise in the execution of adaptive platform trials. Dr. McGlothlin has designed dozens of clinical trials, providing statistical support that includes extensive simulations as well as consulting on interactions with regulators. Dr. McGlothlin has participated in the execution of > 25 adaptive clinical trials, focusing on interim analyses and interactions with data and safety monitoring boards. This experience includes multiple platform trials. A PhD graduate of Baylor University, Dr. McGlothlin has authored or co-authored over a dozen peer-reviewed manuscripts, including 2 first author publications in JAMA that were accompanied by author interview podcasts. She has presented adaptive design and simulation courses to academics, regulators, and industry. Prior to joining Berry Consultants, Dr. McGlothlin was a Senior Research Scientist in early phase oncology at Eli Lilly and Company.

Christina T. Saunders, PhD, is a Statistical Scientist at Berry Consultants where she specializes in the implementation of complex adaptive trials. This experience includes several large adaptive platform trials in the areas of oncology and the fast-paced COVID-19 environment. She earned her Ph.D. in Biostatistics from Vanderbilt University and her B.S. in Mathematics from Baylor University. While at Vanderbilt, Christina’s doctoral research focused on methods in mediation analysis and causal inference. She collaborated with investigators in Vanderbilt’s Center for Kidney Disease, studying the relationship between acute kidney injury and ICU outcomes, and in the Department of Thoracic Surgery, studying genetic ancestry and lung cancer in African Americans. She was a predoctoral trainee on the NIH Clinical and Translational Science Grant.

Lisa LaVange, PhD, is a professor and chair of the Department of Biostatistics. She formerly served as the director of UNC’s Collaborative Studies Coordinating Center (2006-2011; 2018-2021.)
Dr. LaVange has a broad background in the biostatistics field, including leadership roles in industry (RTI, Quintiles, Inspire Pharmaceuticals); academia (UNC/CSCC); and government (Center for Drug Evaluation and Research at the FDA). She was also the 2018 president of the American Statistical Association. At the CSCC, she was formerly PI on the NHLBI-funded HCHS/SOL and SPIROMICS studies and, more recently, contact PI for the NICHD-funded Adolescent Medicine Trials Network for HIV/AIDS Intervention (ATN). Currently, she is co-PI of the NHLBI-funded Precision Interventions for Severe and/or Exacerbation-Prone Asthma Network (PrecISE) and the NIAMS-funded Back Pain Consortium (BACPAC Research Consortium, part of the NIH Helping to End Addition Long-Term (HEAL) initiative.

Relevant selected publications:
Saville, B. R., & Berry, S. M. (2016). Efficiencies of platform clinical trials: a vision of the future. Clinical Trials, 13(3), 358-366.

Saville, B. R., Berry, D. A., Berry, N. S., Viele, K., & Berry, S. M. (2022). The Bayesian time machine: accounting for temporal drift in multi-arm platform trials. Clinical Trials, 19(5), 490-501.

Paganoni, S., Berry, J. D., Quintana, M., Macklin, E., Saville, B. R., Detry, M. A., ... & Eydinov, M. (2022). Adaptive platform trials to transform amyotrophic lateral sclerosis therapy development. Annals of neurology, 91(2), 165-175.

LaVange, L., Adam, S. J., Currier, J. S., Higgs, E. S., Reineck, L. A., Hughes, E. A., ... & ACTIV Therapeutics-Clinical Working Group. (2021). Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV): designing master protocols for evaluation of candidate COVID-19 therapeutics. Annals of Internal Medicine, 174(9), 1293-1300.

Ivanova, A., Israel, E., LaVange, L. M., Peters, M. C., Denlinger, L. C., Moore, W. C., ... & White, S. R. (2020). The precision interventions for severe and/or exacerbation-prone asthma (PrecISE) adaptive platform trial: statistical considerations. Journal of biopharmaceutical statistics, 30(6), 1026-1037.

Israel, E., Denlinger, L. C., Bacharier, L. B., LaVange, L. M., Moore, W. C., Peters, M. C., ... & Ivanova, A. (2021). PrecISE: Precision Medicine in Severe Asthma: an adaptive platform trial with biomarker ascertainment. Journal of Allergy and Clinical Immunology, 147(5), 1594-1601.

Alexander, B. M., Ba, S., Berger, M. S., Berry, D. A., Cavenee, W. K., Chang, S. M., ... & Barker, A. D. (2018). Adaptive Global Innovative Learning Environment for Glioblastoma: GBM AGILEAdaptive Global Innovative Learning Environment for GBM. Clinical Cancer Research, 24(4), 737-743.
 

Clinical Trial Design (e.g., Innovative/Complex Design, Estimands, Master Protocol)

ASA Biopharmaceutical Section Regulatory-Industry Statistics Workshop 2023