Adaptive trials are adaptive by design, and they require a wholesale change in the way drug development has traditionally been carried out.¹ The entire development of a therapeutic candidate, not just the next trial phase, needs to be mapped out in advance. More, and earlier, operational planning is a prerequisite to conducting adaptive trials, which may require a major culture shift at some companies.
Just as the technology enabling the adaptive trials themselves has come of age, so too will organizations need to move beyond traditional tools and approaches for the operational planning, forecasting, and budgeting of adaptive trials. The planning spreadsheet, a tool commonly used to estimate budget needs for clinical trials, does not provide the flexibility or granularity to quickly and accurately model and compare the many potential scenarios for an adaptive study. New, more sophisticated approaches are needed.Fundamentals
The rationale for conducting adaptive trials is that they can increase the probability of treatment success, identify ineffective drugs sooner, and require fewer patients, or fewer patients at less informative doses—all without compromising the trials' validity and integrity. They utilize learn-and-confirm concepts, whereby results get substantiated in an ongoing manner rather than waiting for a phase to complete. Examples of adaptations that might be made midstudy are changes in eligibility criteria, sample size, randomization, treatment regimens, and even the primary endpoint.²
Adaptive trials require the use of prospective statistical simulation to optimize the trial design, and the criteria for making adaptations (modifications) during the study must be defined prior to the study start.
A separate independent body, with expertise in statistics, also needs to be assembled to prepare data, conduct interim analyses of unblinded data, and prepare briefing documents for discussion with the DMC. The current randomization algorithm "in play" must be known only to unblinded personnel, and any sponsor involvement on the DMC requires careful consideration due to the increased potential for bias.
Adaptive trials will often be more expensive than similarly sized conventional studies, but the long-term savings over the course of a development program can be substantial. Savings can come from avoidance of future studies that are no longer necessary, reduced lag time between phases, and the need for fewer subjects. Ultimately, an adaptive trial may result in a product getting registered sooner.
Importantly, an adaptive clinical trial is not always necessary, and may not be viable. In some cases, enough is known about the patient population and the investigational drug to make an adaptive design unnecessary. In others, outcomes that can trigger an adaptive response won't be observable early enough in treatment in order to "adapt."3