FDA’s newly proposed accelerated PMA program may have a long name, but the agency hopes it will significantly shorten the time to market for a select set of devices that target unmet needs for the most serious conditions.

The “Expedited Access Premarket Approval Application for Unmet Medical Needs for Life Threatening or Irreversibly Debilitating Diseases or Conditions,” or EAP, was introduced today in a draft guidance, after CDRH signaled plans for the program earlier this year. (See Also see "CDRH Focusing On New PMA Pathway, Clinical Trials Program In 2014/2015 Priorities" - Medtech Insight, 5 February, 2014..)

To make the EAP process work, FDA plans to bring the full range of its existing regulatory toolbox into action. In particular, the program combines early and outsized interaction between reviewers and manufacturers with the promise of lightened premarket requirements for selected products – if the potential payoff to patients is large enough and postmarket controls are sufficient.

CDRH estimates that, at least in the early stages, on average, about six devices a year may qualify for the program, and the center believes it has the resources available to handle that volume.

EAP is for companies that “have really thought through what it may take to evaluate the safety and effectiveness of their device” – CDRH Director Jeff Shuren.

The new development pathway, which will not be available until guidance is finalized, would be targeted to companies developing a device that is intended to “treat or diagnose a life-threatening or irreversibly debilitating disease or condition” and meet an unmet need in doing so.

It is intended for devices that have yet to reach the pivotal study phase and may be somewhat far from it. But CDRH Director Jeffrey Shuren explains that a crucial criterion for participating is that a manufacturer of a qualifying device is well prepared enough to put together a detailed draft “data development plan.” The required plan should map out expected nonclinical and clinical data collection needs, and provide a rationale, if appropriate, for collecting some portion of that data during a postmarket rather than premarket period.

EAP is for companies that “have really thought through what it may take to evaluate the safety and effectiveness of their device,” Shuren said in an interview. The program is “for people who are prepared and have done their homework,” he said.

Innovation Pathway And Beyond

EAP builds directly on CDRH’s several-year-old Innovation Pathway pilot program, which stresses intensive collaboration between companies and reviewers, starting well before pivotal trials are designed, to map out an efficient development plan with the goal of streamlining the route to PMA review and approval. In 2012, the device center selected four early stage end-stage renal disease devices for the Innovation Pathway program, and each of them remain on that pathway. (See Also see "CDRH Launches ‘Innovation Pathway 2.0’ With End-Stage Renal Devices" - Medtech Insight, 16 April, 2012..)

While none of the four renal-disease devices involved in the Innovation Pathway have reached the point where FDA can measure the specific impact of the program on time to market, officials believe they have had enough positive experience with the program to roll out the program to a broader array of devices in the form of EAP.

An important motivation of Innovation Pathway, and now EAP, is to correct the course of the long-standing priority PMA review program (previously called the expedited review program) which awarded priority review to devices targeting unmet needs for serious diseases, but did not involve extra engagement prior to PMA submission.

“Priority review really has not been a success,” Shuren acknowledged. “It tends to take more time to review those technologies because they are new.”

EAP Criteria

The device is intended to treat or diagnose a life-threatening or irreversibly debilitating disease or condition
The device fits into one of these four categories of addressing an unmet need:

It is deemed a “breakthrough” technology that provides a clinically meaningful advantage over existing technology
No approved alternative treatment or means of diagnosis exists
It “offers significant, clinically meaningful advantages over existing approved alternatives”
The availability of the device is in “the best interest of patients”

The sponsor submits an acceptable draft data development plan

To actually have an impact on time to market, reviewers and sponsors need to come together “at the point when we are figuring out how to assess the technology, when it is still under development and we are figuring out a regulatory pathway to market,” the center director explained. EAP also references some components of the FDA’s “breakthrough” pathway for investigation drugs, which was established in 2012. (See Also see "Planned PMA Pathway Modeled On Existing Accelerated Programs" - Medtech Insight, 7 February, 2014..)

In particular, under EAP, reviewers will aim to engage in interactive review with selected companies very early in the process to help finalize the data development plan. The process will also involve more involvement by CDRH leadership than is typical and, when appropriate, a cross-disciplinary case manager will be assigned to coordinate development of a data plan. Finally, once a selected product has finally reached the PMA submission stage, it will automatically be granted priority review, according to the draft guidance.

Are FDA Postmarket Controls Up To The Job?

Paired with the early interaction is the program’s emphasis on finding creative ways, within FDA’s current authority, to reduce the burden of data that needs to be collected before a device can be approved, and shift more of the data burden to after the product is on the market.

CDRH often emphasizes the central importance of post-market data collection to device oversight and development. In parallel to the EAP draft guidance, FDA also issued a distinct draft guidance today outlining FDA’s current standards for allowing data to be collecting postmarket rather than premarket for any device, regardless of whether it would qualify for an expedited development program.

But the EAP draft guidance suggests an interest in pushing the envelope even further when the potential payoff to patients is high – though, the agency stresses that the underlying PMA approval standard of a “reasonable assurance of safety and effectiveness” will remain in force.

For instance, the draft guidance discusses the prospect of a “two-phase study” to support approval for a device, where the total necessary clinical requirements for approval are determined in advance of a pivotal trial, but only a portion of the data would need to be collected in the pre-market phase – enough to establish, for instance, a “predictive probability of success.” The additional data, necessary to clinically confirm the result, would be completed in the post-market phase, the guideline explains.

The draft also emphasizes the welcome use of surrogate endpoints (e.g., biomarkers) as a tool for pre-market approval, that can then be followed up on with more direct clinical endpoint linked to the condition in the post-market phase.

A central concept of what FDA says it will be focused on when working with EAP manufacturers on what data needs to be collected in the premarket versus the postmarket is “acceptable uncertainty”. Essentially, the agency is willing to accept more uncertainty in the pre-market phase, the higher the “probable benefit” is of patients having access to the device sooner and the better the post-market controls that have been identified.

The draft guidance also makes clear, though, that FDA will be fully exercising its authorities to enforce that manufacturers approved under the EAP program actually follow through with post-market studies and other conditions of approval. It details various FDA enforcement mechanisms including its authority to withdraw a PMA, for instance, if post-approval data questions the safety or effectiveness of a device or if the sponsor fails to complete a post-approval requirement within an established timeframe.

FDA also references in the draft guidance its continuing work to develop an enhanced national medical device postmarket surveillance system as an effort that will better allow it to shift data burden to the postmarket stage.

But Josh Rising, director of The Pew Charitable Trusts’ Medical Device Initiative, says his group and other patient safety advocates will be closely scrutinizing whether FDA’s evolving postmarket system will in fact be sufficient to support a move to less pre-market data collection for devices addressing unmet needs.

“I think definitely we have been seeing a lot of increased focused on the postmarket surveillance area” Rising said in an interview. But, he said, “We need to see even more of that in order for a program like this to work.”

Leap Ahead With EAP? FDA Proposes New Expedited PMA Pathway

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