Collaborative Platform Trials to Fight COVID-19: Methodological and Regulatory Considerations for a Better Societal Outcome

Abstract

For the development of coronavirus disease 2019 (COVID-19) drugs during the ongoing pandemic, speed is of essence whereas quality of evidence is of paramount importance. Although thousands of COVID-19 trials were rapidly started, many are unlikely to provide robust statistical evidence and meet regulatory standards (e.g., because of lack of randomization or insufficient power). This has led to an inefficient use of time and resources. With more coordination, the sheer number of patients in these trials might have generated convincing data for several investigational treatments. Collaborative platform trials, comparing several drugs to a shared control arm, are an attractive solution. Those trials can utilize a variety of adaptive design features in order to accelerate the finding of life-saving treatments. In this paper, we discuss several possible designs, illustrate them via simulations, and also discuss challenges, such as the heterogeneity of the target population, time-varying standard of care, and the potentially high number of false hypothesis rejections in phase II and phase III trials. We provide corresponding regulatory perspectives on approval and reimbursement, and note that the optimal design of a platform trial will differ with our societal objective and by stakeholder. Hasty approvals may delay the development of better alternatives, whereas searching relentlessly for the single most efficacious treatment may indirectly diminish the number of lives saved as time is lost. We point out the need for incentivizing developers to participate in collaborative evidence-generation initiatives when a positive return on investment is not met.

Figure 1

Probability of phase III go (P(Go)) for competing phase II strategies. [Colour figure can be viewed at wileyonlinelibrary.com]

Figure 2

Probability of phase III go (P(Go)), phase III power, and overall probability of success (POS). [Colour figure can be viewed at wileyonlinelibrary.com]

Figure 3

Distribution of mortality rates: before phase II; qualifying from phase II, succeeding in phase III. [Colour figure can be viewed at wileyonlinelibrary.com]

Figure 4

Response rates in the different arms of the platform trial when all treatments are like the standard of care. If in the control arm by chance a low response is observed, for all the experimental treatments an erroneous significant result becomes more likely. [Colour figure can be viewed at wileyonlinelibrary.com]

Figure 5

The platform trial starts as a three‐arm randomized trial including drugs D ₁, D ₂, and an active comparator C ₁. As data accrue the treatment arms D ₃ and D ₄ and another active comparator C ₂ are added. [Colour figure can be viewed at wileyonlinelibrary.com]