Adaptive Trial Design Can Save Device Makers Time and Money

FDA has made it clear that manufacturers truly can use adaptive design in medical device trials. An expert shares the benefits of adaptive design and offers advice to companies considering it.

In late July, FDA issued its final guidance on using adaptive designs for medical device trials, a followup to the agency's draft guidance on the topic in May 2015. MD+DI asked Vicki Anastasi, vice president and global head of Medical Devices & Diagnostics Research at ICON plc to discuss adaptive design in more detail. Here, she makes clear FDA's acceptance of adaptive design, how the strategy can bring multiple benefits to device makers, and how to get started.

This Q&A has been edited slightly.

MD+DI: Did anything in FDA's final guidance stand out to you as being different from the draft guidance or particularly meaningful/impactful?

Vicki Anastasi: The guidance provides the first explicit indication that the FDA is ready and equipped to handle the use of adaptive designs in medical device clinical trials. In the guidance, the FDA clearly encourages industry to understand the utility of adaptive trials in addressing the inefficiencies in current study designs, and it provides an overview of how to incorporate adaptive elements into protocols submitted to the FDA.

To the FDA, adaptive design is not a new concept; in fact, the CDRH has been evaluating adaptive designs for over ten years. Between 2007 and 2012, they received 120 submissions that included adaptive elements. The guidance makes it clear that regulators support this approach. It should lead to a rapid change in how manufacturers design studies across their portfolios.

I'd think that FDA setting out draft guidance on adaptive trial designs last year might have spurred more medical device companies to try an adaptive design. Did this happen? Have you noticed any changes in how device companies are approaching their trial designs or consideration of an adaptive trial design?

Yes, we have since received many more inquiries from device manufacturers about the utility of adaptive designs in their trials. Companies that adopted adaptive designs have found them to be beneficial.

For example, a manufacturer developing an electrostimulation device approached us to design a trial that supported registration of the device as early as possible. We suggested and designed an adaptive trial that would not only yield useful results quickly, but also protect the company against potential delays and risks. The design specified two prospectively planned interim analyses. We set thresholds for the sham control response rate and observed a treatment effect at the first and second interim analyses, respectively, that allowed the manufacturer opportunities to right-size study enrollment for optimal statistical power or to terminate the study early on efficacy or futility grounds.

At the second interim analysis, after enrolling only half of the total planned number of patients, ICON identified a response rate much lower than the prospectively planned threshold. The manufacturer deemed the device ineffective and then, with the $1.9 million of funds and five months of time that would have otherwise been spent on the ineffective device, they accelerated development of an improved treatment regime and delivery methodology that would be more efficient to prove in a future clinical study.

In another case, a company came to us after being encouraged by positive data on a disc replacement device from a non-inferiority trial. These data had spurred a desire to conduct an additional superiority trial, which would be a rare claim in that indication. However, they found that it would be cost-prohibitive to start a new superiority trial from scratch with new protocols, a new recruitment strategy, and new sites.

To reduce costs and save time, ICON supported negotiations with FDA to allow a midstream change to the non-inferiority trial that would allow the simultaneous collection of superiority data. ICON designed and executed an adaptive design to collect both non-inferiority and superiority data using a single, patient-sparing, efficient trial. This strategy ended up saving the manufacturer $5 million and accelerated their go-to-market timeline with a stronger value proposition.

What questions, if any, still remain for you after the final guidance?

We have seen many presentations and spoken to many regulators over the years, and their support of adaptive designs is clear.

The one remaining question is, how may the trials in your portfolio benefit from adaptive designs? And, how quickly will your organization or its competitors integrate adaptive across a portfolio?

From a commercial point of view, the value of adaptive design is greatest when applied at a portfolio level. This is, namely, by mitigating the risk that errant trial parameters could cause an effective device to fail or suffer delays, and by augmenting opportunities to ensure that limited resources are directed to the most productive products.

Achieving the portfolio-level benefits of adaptive design requires establishing a checkpoint early in every product's lifecycle to assess the relevancy of various adaptive designs for its clinical development programme. While not all trials are appropriate for adaptive design--for example, fast-enrolling trials that last only a few weeks would logistically preclude an interim analysis--most device trials would benefit from simulations to identify risks that may arise over the course of a trial and development of designs that optimally addresses those risks.

It is important to note that this review process does require an upfront investment of time as well as access to statisticians and other experts who are specifically knowledgeable in device-relevant adaptive trials. These preparations are important, as the strategies and operational processes used for pharmaceuticals do not necessarily translate to benefits in device development. This early investment, however, is offset by adaptations that, for example, compress study duration through combined pilot and pivotal studies, adjust the sample size to preserve statistical significance, or prevent an overpowered design from continuing to recruit unnecessary subjects.

What advice do you have for device companies considering or still uncertain about using an adaptive trial design?

No matter how big or how small a manufacturer is, adaptive designs are achievable. Adaptive designs are especially significant for smaller manufacturers because a trial's outcome can have an outsized effect on their success as a company.

In terms of concerns manufacturers should have, it's important to heed FDA's guidance and the requirements they note for conducting an adaptive trial. For example, regulators stress that manufacturers need to update their infrastructure, from their monitoring and data management systems to how they work with IRBs [Institutional Review Boards] to maintain data integrity. Clinical trial management systems need to be purpose-built to handle data more securely. They also require that if manufacturers use an adaptive design, they must use statistical software that can perform Bayesian analyses.

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