When to make decisions? Strategic planning of interim looks.
Recently we discussed examining clinical development through a Bayesian lens, in honor of Cytel co-founder Nitin Patel and CSO Yannis Jemiai’s chapter on the subject appearing in the Award-winning Bayesian Designs in Pharmaceutical Research . This of course raises a related question, namely, can some of the tactical elements also be used within a trial rather than across a program or portfolio? How do we best build in decision rules that can facilitate strategic decision-making during an interim look or even at the foundations of trial design?
Within a clinical trial, the closest approximation to a Go/No-Go decision occurs during an interim look. These pre-planned adaptations enable trial sponsors to decide whether to continue a trial or stop for futility, whether to increase sample size, drop arms, or generally position a continuing trial for improved probability of success. Whenever a strategic decision has to be made, they must occur during such an interim look, and many trial sponsors are now trying to align these interim looks with the strategic insights they might yield.
Certain elements of strategic trial design are already familiar to many: we know, for example, that investors are more likely to fund a trial after an interim look shows more promising results. Such evidence helps trial sponsors both manage resources (say to stop early), but also to attract venture capital for their new medicines. We also know that when population sizes must be contained, a sample size re-estimation design will often help ensure the optimal allocation of patients to trials.
Yet, even these intuitive methods scratch the surface of what is required for strategic trial design. For example, most sponsors who plan to use interim looks to unveil a therapy’s promise to potential investors will schedule an interim look after 50% of enrollment. While everyone agrees that this is just an industry norm, and that oftentimes a look at 60% or 75% enrollment might offer superior results, a sponsor does not always have the ability to consider a range of possibilities for such analysis.
A number of Cytel statisticians now approach trial design with the view that it is vital to begin by mapping and exploring the entire design space of a clinical trial. Sometimes this means running millions of simulations, and creating a heat map of all potential designs. One of our consultants recently mapped the potential costs and benefits of interim looks from 10% enrollment to 90% enrollment, for a client who could then zero in on the perfect time to view evidence.
Another benefit to charting the entire space of all possible trial designs is to position a sponsor to achieve objectives in the least complex possible manner. For example, we know that sample size re-estimations will help sponsors to manage their sample sizes; but what if a Group Sequential Design offered a chance for early stopping that could spare sponsors even more resources. By charting the entire design space upfront, and then exploring several designs in detail, a sponsor might be able to have conversations earlier about which strategic tradeoffs to prioritize.
The critical factor, though, of what we previously called the ‘Bayesian lens’ in strategic decision-making, is treating the assimilation of new knowledge as an update about a belief regarding the probability of success of a clinical trial. What might a sponsor learn at an interim look that would affect how it could fund a trial, allocate resources or stop early? A look scheduled too early would yield fewer results, and a look which comes too late might not enable a sponsor to make use of the new learning. Therefore, it becomes more imperative to begin with a discussion of the decisions that will need to be made during the interim look, and use this to guide when sufficient evidence will likely have been generated for improved decision-making.
To learn more about broadening the trial design space, click here:
About the Author of Blog:
Dr. Esha Senchaudhuri is a research and communications specialist, committed to helping scholars and scientists translate their research findings to public and private sector executives. At Cytel Esha leads content strategy and content production across the company's five business units. She received a doctorate from the London School of Economics in philosophy, and is a former early-career policy fellow of the American Academy of Arts and Sciences. She has taught medical ethics at the Harvard School of Public Health (TH Chan School), and sits on the Steering Committee of the Society for Women in Philosophy's Eastern Division, which is responsible for awarding the Distinguished Woman in Philosophy Award.