When used properly, adaptive designs can reduce resource requirements and/or increase the chance of study success, the agency notes in its new draft guidance.
Vicki Anastasi, VP and Global Head of Medical Device and Diagnostics Research at Icon, told Outsourcing-Pharma.com that the draft is “encouraging” as adaptive designs are under-utilized in the device space when compared to the pharma trials space. She noted the examples of ending a trial due to early signs of efficacy and/or due to futility as two ways to increase a trial’s efficiency and ensure it remains ethically viable.
There’s “nothing surprising” in the draft document, she added, noting that Icon is “pleased to see that it’s very encouraging to industry and in asking industry to consider [adaptive trials] and come to FDA with these types of ideas… As a CRO who’s been working with adaptive trials and device manufacturers for some time, this is a welcome guidance.”
Specifics of Draft
In addition to offering three examples of times when the FDA accepted different adaptive designs, the agency also lays out when adaptations are most useful, and various adaptations using unblinded data, including:
- Group Sequential Designs
- Sample Size Adaptation
- Bayesian Sample Size Adaptation
- Group Sequential Designs with Sample Size Reassessment
- Dropping a Treatment Arm
- Changing the Randomization Ratio
- Changing the Hypothesis (Claim)
- Adaptive Enrichment
“While most of the adaptations described in this guidance are more useful and appropriate for pivotal studies, adaptive designs can apply to some late feasibility studies,” the agency says. “For example, an adaptive feasibility study could increase the statistical rigor and lead to a more accurate estimate of device performance and hence enhance decision-making and the likelihood of later success at the pivotal stage.”
However, the agency warns of the “real danger” that an unplanned modification to the study may weaken a study’s scientific validity “and therefore may not be approved or endorsed by FDA. Sponsors should anticipate and plan for modifications based on a variety of possible scenarios that could occur during the course of the trial.”
But as Anastasi mentioned, from an ethical standpoint, adaptive designs also offer ways to optimize the treatment of subjects enrolled in the study and safeguard their welfare from ineffective or unsafe treatments at the earliest possible stage.
And the FDA points to two underlying principles necessary for the design of all clinical studies and of adaptive ones in particular: control of the chance of erroneous positive and/or negative conclusions, and minimization of operational bias.
The agency concludes: “Procedures to assure the proper conduct of adaptively designed studies must be put into place so the study will provide valid scientific evidence that can be relied upon by FDA to assess the benefits and risks of the investigational medical device. Sponsors are strongly encouraged to discuss the planning of adaptive clinical study designs with the appropriate FDA review division in advance.”