What are adaptive clinical trials? (November 16, 2022 via “MRC Biostatistics Unit, University of Cambridge”): 2-min video.

• Summary: Adaptive designs can make clinical trials more flexible by using interim data collected during the trial to modify the trial’s course; this is done in accordance with pre-specified rules. Trials with an adaptive design can be more efficient, informative, and ethical than trials with a “fixed” design in that they may make better use of resources such as time and money and may, at times, require fewer participants.

Pallmann P, et al. Adaptive designs in clinical trials: why use them, and how to run and report them. BMC Med. 2018 Feb 28;16(1):29. (15-page paper)

• Summary: This paper encourages the wider use of adaptive designs with pre-planned opportunities to make design changes in clinical trials. It begins by explaining the rationale behind adaptive designs, clarifies ambiguous terminology, and summarizes the pros and cons of this approach.

Evaluating the Results of Platform Clinical Trials: A Guide for Clinicians (October 10, 2023 via “JAMA Network”): 26-minute interview.

• Summary: Platform trials allow for the simultaneous comparison of multiple interventions against a single control group that serves as a common control (based on a prespecified interim analysis plan). The platform trial design enables the introduction of new interventions after the trial is initiated, allowing researchers to evaluate multiple interventions in an ongoing manner. This is done using a single overarching protocol called a “master” (or core) protocol. In this interview, Drs. Jay Park and Edward Mills join JAMA Statistical Editor Dr. Roger Lewis to discuss this type of trial. * Note: To connect the concepts in this module, it may be helpful to know that while not all platform trials are adaptive by default, many platform trials use adaptive designs to manage their complexity and achieve their goals.

Park JJH, et al. Systematic review of basket trials, umbrella trials, and platform trials: a landscape analysis of master protocols. Trials. 2019 Sep 18;20(1):572. (10-page paper)

• Summary: A “master protocol” refers to a single overarching design developed to evaluate multiple hypotheses, and the general goals are improving efficiency and establishing uniformity through standardization of procedures in the development and evaluation of different interventions. Master protocols are often classified into “basket trials”, “umbrella trials”, and “platform trials.” Basket trials focus on testing a single intervention (e.g., treatment) across multiple outcomes (e.g., diseases/disease subtypes), umbrella trials evaluate multiple treatments within a single disease, and platform trials provide an ongoing framework to test multiple treatments (in the context of a single disease) and adaptively add or drop arms over time. * Note: While platform trials are almost always adaptive due to their structure, basket and umbrella trials are not inherently adaptive. However, they frequently integrate adaptive features to enhance their efficiency and flexibility.

Lauffenburger JC, et al. Designing and conducting adaptive trials to evaluate interventions in health services and implementation research: practical considerations. BMJ Med. 2022;1(1):e000158 (9-page paper)

• Summary: Adaptive trials incorporate changes as a trial proceeds, such as modifying allocation probabilities or eliminating intervention arms that are likely to be ineffective. It is argued that leveraging adaptive trials for health services and implementation research may present opportunities to improve rigor and conduct of pragmatic trials, and more rapidly facilitate delivery of optimal healthcare.

Woodcock J, LaVange LM. Master Protocols to Study Multiple Therapies, Multiple Diseases, or Both. N Engl J Med. 2017 Jul 6;377(1):62-70. (9-page paper)

• Summary: Master protocols are defined as one overarching protocol designed to answer multiple research questions. Included under this broad definition are 3 distinct entities: umbrella, basket, and platform trials, which constitute a collection of trials or sub-studies that share key design features/operational aspects. This has the goal of achieving better coordination than what is often observed in individual trials that are designed and conducted independently.