On June 18, 2020, PRIM&R hosted a webinar, Complexity in Clinical Trial Design: A Primer on Adaptive and Platform Trials. During this webinar, Luke Gelinas, PhD, MA, and Marianne Kearney Chase defined key terms, explored ethical and regulatory challenges, and provided strategies and examples to bridge the gap between IRBs and researchers in understanding adaptive trial designs. Following the webinar, Luke and Marianne reflected on the session and attendee feedback, and we’re pleased to share their reflections with the readers of Ampersand.

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The need for accelerated drug development is increasingly recognized. This has been thrown into sharp relief by the COVID-19 pandemic which has mobilized the clinical trial community and spurred quicker timelines for vaccine and novel therapeutic development. Even before COVID, however, sponsors and investigators, with the endorsement of regulators, had begun to leverage a number of complex trial designs with the potential to increase efficiency and speed therapeutic advances.

Two Types of Complex Design

Platform trials are designed to test multiple investigational products in the context of a single disease, in a perpetual manner, with investigational products allowed to enter and leave the platform on the basis of a decision algorithm. This type of design promotes efficiency by creating one optimized trial infrastructure.  Platform trials are operationalized by developing a Master Protocol which provides the framework for numerous investigational products to be tested in a defined patient population.

Adaptive studies adapt or change mid-stream in ways that are responsive to incoming data. Whereas traditional randomized controlled trials employ a mostly linear structure (design → conduct → analyze data), adaptive trials, by contrast, use a feedback loop to incorporate adjustments to study design based on data analysis at planned interim breaks. Examples of adaptive elements include increasing or decreasing the sample size to ensure an optimal number of enrolled participants in light of incoming data about the effects of an investigational therapy or changing the randomization scheme to favor the better-performing arm as the study unfolds.

Adaptive and platform studies differ (a study can be adaptive while testing a single therapy) but are highly complementary. Incorporating adaptive elements into platform trials enables optimized assessment of multiple therapies and quicker decisions about which products are promising and merit further evaluation and which do not.

Challenges

Some of the challenges with these studies may arise simply from their complexity, which often demands longer and more intensive reviews by IRBs. Other challenges may be more explicitly ethical or practical—requiring mindful decisions by IRBs and investigators.

For platform studies, one key challenge is ensuring clinical equipoise.  Participants who consent to participate in a platform trial will be assigned to one of the investigational therapies being tested, so investigators must ensure that there is good scientific rationale and genuine uncertainty in the medical community as to which therapy might provide some benefit.  This can be achieved by having scientific experts review data and provide recommendations about which therapy should be added to the trial.  Another challenge for platform trials is creating a master protocol that strikes the right balance—creating a strong framework for the trial, but also allowing enough flexibility to accommodate different therapies to be tested.

For adaptive studies, IRBs should consider whether, and how, the planned changes should be disclosed to participants in consent materials. Specifically, IRBs will need to decide whether disclosing the general plan to change a trial feature (such as dosage) suffices, or rather whether to disclose the specific changes, once implemented (e.g., that the dosage has been changed from x to y).  

A second issue concerns whether the IRB should review the specific details of changes over the course of the study (e.g., a dose escalation to 20mg) or rather whether approving a set of decision-procedures at initial review suffices (e.g., a plan to escalate dose to x under such-and-such conditions after review by a safety committee). In the latter case, care should be taken by the IRB to ensure that decision rules are clearly specified and that the role of interim review committees are clearly delineated.

Conclusion

The effort to find better and more effective therapies for a wide variety of diseases in a more cost-effective manner is one that is endorsed by patients, regulators, the medical community, and drug developers. Complex clinical trial designs hold much promise in helping to achieve these objectives, thus both ethical and practical challenges need to be well understood by all parties involved in this endeavor.

PRIM&R thanks Luke Gelinas and Marianne Kearney Chase for sharing their expertise. The recording of this webinar (and recordings of all past PRIM&R webinars) is available for purchase. If you would like to purchase the webinar for group viewing, please download the order form (PDF) and send it to registration@primr.org.

Luke Gelinas, PhD, MA, is a chairperson at Advarra IRB, where he provides analysis and guidance on complex ethical issues arising in the course of clinical research study design and human participant protection. He holds a PhD in Philosophy with a concentration in Ethics from the University of Toronto and an MA in Religion, summa cum laude, from Yale Divinity School.

From 2015-2018, Dr. Gelinas was senior researcher at Petrie-Flom Center for Health Law Policy, Biotechnology, and Bioethics at Harvard Law School. There he led collaborative and multi-stakeholder projects addressing foundational and practical issues in research ethics, including projects on the ethical issues implicated in the use of social media for research recruitment, clinical trial priority-setting, and the ethical and regulatory parameters of paying research participants.

Between 2012-2015, Dr. Gelinas completed a Postdoctoral Fellowship in the Department of Bioethics at the Clinical Center, National Institutes of Health, as well as subsequent training in clinical ethics consultation at Alden March Bioethics Institute.

Dr. Gelinas’ written work has appeared in leading medical and bioethics journals, including New England Journal of Medicine, Hastings Center Report, and Journal of Medical Ethics. He frequently lectures and consults on various issues in research ethics and human participant protection.

Marianne Kearney Chase is currently the director of research operations for the Neurological Clinical Research Institute (NCRI) and Healey Center for ALS at MGH. The Healey Center is designing a Platform Trial for ALS, with the goal of launching the trial in Q42019. The NCRI is the Clinical Coordinating Center for the National Institute of Neurological Diseases and Stroke (NINDS) Network for Excellence in Neuroscience Clinical Trials (NeuroNEXT); the Clinical and Data Coordinating Center for the Northeast Amyotrophic Lateral Sclerosis (NEALS) Network and the Parkinson’s Study Group (PSG) Network. Marianne has over 25 years’ experience in both investigator-initiated NIH / foundation funded and industry sponsored research including Pre-Clinical Study Design, Clinical Study Coordination, Clinical Site Management, Protocol Development, Regulatory Compliance and Project Management. In addition, she serves as an adjunct faculty member for the NINDS funded Clinical Trials Methodology Course and has developed and presented courses on various topics including; Good Clinical Practices, Good Source Documentation and Data Management Practices, Adverse Event Reporting, Standard Operating Procedures (SOPs) and Overall Management of Multi-Center Clinical Trials.