FDA Explains Alternative Means To Generate Evidence For Device Studies

By Jof Enriquez,
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Food and Drug Administration (FDA) officials wrote in a recent issue of The New England Journal of Medicine (NEJM) that flexible and alternative means to generate clinical evidence, such as existing registries and computer modeling techniques, could form the basis for approving more medical devices in the future.

Consistent with the U.S. regulatory standard to prove "reasonable assurance of safety and effectiveness" for medical products, device companies and sponsors of high-risk medical devices may provide FDA with clinical data from trials that are similar in design to a “gold standard large,” double-blind, randomized, controlled drug trial.

In a viewpoint article, Owen Faris, Ph.D., acting Clinical Trials Director, Office of Device Evaluation, Center for Devices and Radiological Health (CDRH), and Jeffrey Shuren, CDHR Director, wrote that "for many devices, however, practical limitations related to the device or disease condition require alternative approaches."

They consider it infeasible to conduct a blinded trial of an implantable device because it is impractical or unethical to implant placebo devices due to the risk of the implantation or procedure itself. Instead, alternative data sources may be tapped to determine for regulators the safety and efficacy of the device without the need for detailed clinical studies. Among several examples where alternative data could be leveraged in a clinical trial, they detailed two cases when FDA had been flexible in considering atypical means to approve medical devices.

Shuren and Faris cited FDA’s approval in 2011 of Medtronic's Revo device as the first pacemaker indicated to allow patients implanted with the device to undergo magnetic resonance imaging (MRI). Relying on a standard clinical trial to prove that the pacemaker's lead will not heat up during an MRI scan and ablate cardiac tissue would have required many thousands of trial participants. Instead, FDA based their approval on robust mathematical modeling that was validated with bench studies and studies in animals, which indicated a low-risk for lead heating under worst-case scenarios. A follow-up trial conducted by Medtronic confirmed the results.

"This approach of gathering a modest clinical data set to confirm robust bench and modeling data has been used to support a number of subsequent approvals for pacemakers and ICDs that allow MRI," they wrote in the NEJM article. "As our experience with relying on modeling as a primary data set grows, premarketing clinical studies for next-generation devices may not even be necessary."

"In the future, computer-based modeling may change the way we think about device validation in other ways, allowing for much smaller clinical trials, or may change the way we think about running trials, in that some “clinical” information may be derived from simulations," they wrote.

They mentioned that device companies are now using stochastic engineering models to simulate clinical outcomes for “virtual patients” by modeling a relationship between bench outcomes and clinical end points. This could mean virtual patients, rather than real ones, could be involved in future trials.

The Medical Device Innovation Consortium (MDIC), a public–private partnership, is now looking for ways to apply computer modeling and simulations to clinical trials, according to FDA officials. Also, MDIC last month began operationalizing the Coordinating Center for the Medical Device National Evaluation System for Health Technology (NEST), which will "improve the efficiency, timeliness, and comprehensiveness of postmarketing evidence generation."

Another example given in the article is the use of real-world evidence — specifically, registry studies — to support device approvals. FDA used data from the Transcatheter Valve Therapy (TVT) Registry to grant an expansion of an earlier approved indication to also include nontransfemoral access for the SAPIEN transcatheter heart valve (THV) from Edwards Lifesciences. As a result, many patients with an unmet clinical need benefited.

For device technologies designed to satisfy an unmet clinical need, "it may be appropriate to accept a greater degree of uncertainty in order to expedite the availability of the device for patients, relying on postmarketing data to provide greater certainty about the safety or effectiveness of a device. This is the concept behind the FDA’s Expedited Access Pathway for ‘breakthrough’ medical devices," wrote the officials.

Faris and Shuren also highlighted the potential for registries to simplify future trials.

"For example, a next-generation unapproved device that requires a clinical trial to support approval could be studied under a protocol designed to have its data requirements aligned with an existing registry that gathers high-quality outcomes data for approved devices of that type," they wrote.