Trial Design in the Time of COVID-19: Complex and Efficient
The immense negative health, social, and economic impact of COVID-19 demands a wide array of clinical trials evaluating diverse therapies for ameliorating and preventing the disease. To date, government and industry funders have been quick to respond. In a recent webinar, US Food and Drug Administration (FDA) representative Janet Woodcock estimated that the FDA has received over 950 inquiries or proposals for COVID-19 drugs, with 72 of those currently being evaluated and over 200 in the planning stages.
While these numbers are encouraging, Woodcock expressed concern about the ability of the research community to evaluate all of them. “Although we may not run out of patients, unfortunately,” she said, “we may run out of research personnel and time availability to do that in this way of having separate development programs.” Woodcock went on to extol the virtues of “adaptive” and “platform” trials as a way of eliminating less-promising investigational treatments quickly and speeding development of COVID-19 therapies, as exemplified in the current UK-based RECOVERY trial.
Such designs have gained favor recently with regulators and sponsors but remain under-utilized. Moreover, many IRBs may be unfamiliar with reviewing them. The current circumstances give us a chance to reflect on their features and benefits, challenges for IRB review, and strategies for facilitating adoption.
What Are Adaptive Platform Studies?
Platform and adaptive trials are not the same; a study can be a platform study but not adaptive, and vice-versa. Nonetheless, platform and adaptive trial features are compatible and indeed highly complementary.
Platform studies, sometimes also referred to as “umbrella” or ”basket” designs, test multiple interventions under a single protocol, often with a shared placebo group for comparison. Unlike traditional randomized controlled trials, which require a separate infrastructure for each product tested, platform trials permit ongoing evaluation of multiple interventions under the same basic infrastructure. Because of this, platform studies promise increased scientific and operational efficiency.
As the name suggests, adaptive trials are designed to permit changes mid-study in ways that preserve scientific integrity. Traditional randomized controlled trials employ a linear structure of design → conduct → analyze data. Adaptive trials, by contrast, use planned interim breaks to adjust key study features on the basis of incoming data. Common adaptive design features include modifying the sample size to ensure a study enrolls enough participants in light of incoming data about the effects of an investigational therapy or changing the randomization scheme to favor the better-performing arm.
Combining adaptive features in a platform study provides the opportunity to pause and:
- Evaluate incoming data about the multiple different therapies being evaluated,
- Tweak study design to ensure that robust evaluation is possible, and
- Decide as quickly as possible which interventions are, and which are not, worthy of further investigation.
Moreover, once the basic platform infrastructure is established, new interventions can be added for evaluation as others are dropped. All of this is especially valuable when, as in the present circumstances, there are a large number of investigational therapies to sift through, little or no previous clinical data for how those therapies perform in COVID-19 positive populations, and time is of the essence.
Complex Trial Design and the IRB
While IRBs should acknowledge the benefits of these designs, they may also find reviewing them challenging. The following three points, by no means exhaustive, are likely to arise and warrant consideration:
- Adaptive platform protocols often include decision-rules that guide interim analyses and mid-study changes. The IRB should ensure that these rules are appropriate at time of initial review. If the IRB is comfortable with the decision-rules, this may remove the need to review and approve mid-study changes that conform with the rules.
- Similarly, adaptive studies often rely on data monitoring boards, either independent or internal to sponsors, to inform decisions about mid-study changes. The IRB should ensure that the proposed interim decision-making process is adequate at time of initial review. The IRB should also consider whether this mitigates the need for prospective approval of specific mid-study changes when those changes are consistent with the approved protocol.
- Adaptive trials generally raise questions about informed consent and whether, or when, mid-study changes should be disclosed to participants. IRBs should keep in mind that re-consent for currently enrolled participants is necessary only when there is new information that may be relevant for continued participation. In light of this, as well as the burdens of re-consent on sites and investigators, consent materials submitted at initial review should ideally outline in broad strokes the possibility of different mid-study changes. IRBs should consider whether this mitigates the need for re-consent when the changes are enacted.
Continued reflection on these and other aspects of complex trial design may help increase comfort level among IRBs, promote quality and consistent review standards, and further help increase efficiency at a time when it is sorely needed.
Looking for more information on IRB review of complex trial designs? Read our blog IRB Review of Adaptive Design Studies. Considering using an alternative trial design approach in your next study? Advarra can help.