The design was meant to optimize clinical trials by using an interim look to determine whether a study was promising, and thereby to channel more resources towards it to ensure a good drug did not fail due to the trial being underpowered. This simple adaptation has had significant effect on the way strategically enhanced clinical trial design is now understood in the industry.
"Start with modest expectations and expand only if interim results are promising." -- Cyrus Mehta
Like most adaptive designs, the Promising Zone Design uses prospectively planned interim looks to improve strategic and tactical decision-making midway through a clinical trial. A trial can still stop for futility or stop for efficacy, but there are two further options. A trial can either run to completion using the initial planned sample size, or if a trial’s results are ‘promising’ but a larger sample size is deemed necessary to power a trial, then a bigger sample size can then be utilized through a re-estimation.
Since their introduction, Promising Zone Designs have been approved in approximately 30 clinical trials ranging from oncology to diabetes and cardiovascular. The design has been combined with numerous other designs including enrichment and group sequential. Indeed, the trial has even generated a variety of related designs like ‘Adaptive Switch’ which begins as a GSD trial for non-inferiority, but given promising interim results switches to a superiority trial. The Promising Zone thereby creates more opportunities for flexible adaptations, that can respond to a number of possibilities that occur during the trial.
"Historically, biotechnology companies haven't fully appreciated the link between trial design and the ability to secure external financing. Yet, adaptive trial designs - which often reduce the risk, time and cost associated with clinical development - can make the math more attractive for investors." [Nitin Patel, Beyond Borders, p. 20].
A further benefit to a Promising Zone Design has been its use in financing modern clinical trials. Given that at an interim look, there are four possible assessments of a product or asset’s performance, many investors have tied expected returns to such performance. Thus during the VALOR Trial, investors were attracted to a Phase III trial in an area that had historically been associated with financial risk by increasing an investor’s return from 3.6% to 6.75% should a study fall in the promising zone during the interim look.
Such practices have come to be known as Stage-Gated Funding, where investors receive more information at an interim look about the quality of a risk, enabling trial sponsors to use interim looks to raise funds.
This month’s Keeping the Promise Anniversary Celebrations will reflect on the past achievements of this design, while also engaging ideas about how this design will continue to transform the industry in years to come. We invite you to celebrate along by clicking on the below:
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.