CDRH Unveils New PMA Guidance Documents

Tuesday, April 29, 2014

Last week FDA issued draft guidance with the hefty but descriptive title “Expedited Access for Premarket Approval Medical Devices Intended for Unmet Medical Need for Life Threatening or Irreversibly Debilitating Diseases or Conditions.”  This guidance introduces yet another term into the FDA lexicon: the “Expedited Access PMA” or “EAP.”  

As the title of the guidance implies this new program is intended to provide earlier access to high-risk devices in patients with serious conditions with unmet medical needs.  EAP is perhaps just a bit Zen, described not as a new pathway but a new process, a so-called collaborative approach between FDA and sponsors to facilitate product development under the agency’s existing regulatory authorities. Goals of this initiative are to reduce both review and product development time.  

Features of the EAP include an all hands on deck approach with early involvement of office and center management (an idea borrowed from the CDER breakthrough therapies initiative), use of case managers to ensure smooth inter-disciplinary work (also borrowed from CDER), and the application of both priority review and interactive review.

The program is voluntary and an interested sponsor must initiate the process by a request for designation as an EAP Device. The guidance provides four suggested categories warranting this assignment: 

  1. The device represents a breakthrough technology that provides a clinically meaningful advantage over existing technology
  2. No approved alternative treatment or means of diagnosis exists
  3. The device offers significant, clinically meaningful advantages over existing approved alternatives
  4. The availability of the device is in the best interest of patients

These are provided with considerable detail and specific examples. 

The price of admission to the program is the requirement that with the request for designation,  the sponsor provide a draft Data Development Plan describing the clinical and nonclinical data that would be collected premarket and post-market. FDA must accept the EAP designation and the Data Development Plan in order for the process to be a go.  

An extremely important feature of this new program appears to be an initiative to utilize post-market regulatory tools to shorten the road to market.  The guidance notes “As part of the EAP program, FDA intends to impose post-market requirements, including requiring post-approval studies as a condition for approval for devices.”   The guidance also candidly indicates FDA is emboldened to rely on post-market data by its “current authority to mandate completion of post-approval studies and to withdraw PMA approval for marketed devices for which FDA later determines that there is a lack of a showing of reasonable assurance that the device is safe or effective…”  

FDA offers one final bonus.  “On a case-by-case basis, FDA may, at its discretion, allow a sponsor to provide less manufacturing information in their PMA application …when the sponsor had a good track record for quality systems and there are not new, unique manufacturing issues…”  In cases where the sponsor has a good QSR track record, FDA may even waive the requirement for a premarket QSR inspection.

While the EAP program is all about process and ensuring that premarket review is predictable, efficient, and transparent, at the heart of this initiative is a new take on how FDA might choose to meet its statutory standard of ensuring new medical devices show reasonable assurance of safety and effectiveness. As the guidance notes “there is never 100% certainty when determining reasonable assurance of safety and effectiveness of a device. However, the degree of certainty of the benefits and risks of a device is a factor we consider when making benefit-risk determinations.” FDA notes that in cases of unmet medical need, it may “accept less certainty regarding the risk-benefit profile of these devices at the time of premarket approval, and approve an EAP Device, as long as the data still support a reasonable assurance of safety and effectiveness.”  It elaborates by explaining “FDA intends to approve an EAP Device if the uncertainty is sufficiently balanced by other factors, including the probable benefits of the device, the probable benefits of earlier patient access to the device, and post-market controls…”  

The EAP program is hence more than just a cosmetic change in the administrative niceties of the FDA art of premarket review. It is an attempt to ground risk benefit decision making in the context of the medical issue at hand. It addresses the reality that some patients without good choices may be willing to accept uncertainty and heightened risk in order to expand their menu of management options.  

In a well timed parallel initiative, FDA issued the EAP guidance in tandem with new draft guidance on post-market data collection, a document aimed generically at trying to share FDA’s insights on how it works to achieve the right balance between its pre-market versus post-market regulatory work. Although in the news release heralding these documents, this draft on balancing got second billing, it actually has a broader range of uses (potentially many if not every PMA) and hence may have a greater impact on the device regulatory program than the EAP.

The objective of the document is described up-front.  It “clarifies the Food and Drug Administration’s current policy on balancing premarket and post-market data collection during FDA review of premarket approval (PMA) applications.”  More specifically it provides insight into how FDA determines the mix of premarket versus post-market requirements in meeting its statutory standard of reasonable assurance of safety and effectiveness.

As background the document notes that at the time of device approval, certain safety and effectiveness may not be fully resolved.  Reasons for this dilemma include significant obstacles such as time and cost to address rare adverse events or long-term safety issues.  They also include the fact that controlled clinical studies in support of a PMA may not fully represent real-world use of a new device,   

The draft then proceeds to remind the reader of the law, Section 513(a)(3)(C), which  clearly creates an obligation for FDA to consider whether the extent of data required for approval of an application  can be reduced through reliance on post-market controls.  The term post-market control is used here in its most catholic sense to include all of its many forms: compliance with the Quality System regulations, post-market surveillance, the Medical Device Reporting requirements and, of course, post approval studies. 

The language used to describe the crux of the FDA review dilemma is here captured in the same words used to describe the EAP: “there is never 100% certainty when determining reasonable assurance of safety and effectiveness of a device. However, the degree of certainty of the benefits and risks of a device is a factor we consider when making benefit-risk determinations.”   

However, while for the EAP, FDA describes the use of other factors to balance uncertainty, in this document FDA makes a distinction between uncertainty regarding certain benefits or risks of the device in the context of less uncertainty about the overall benefit-risk profile at the time of premarket approval. It is here that FDA seems to target use of post-market controls to iron out the wrinkles in an application.   Seven specific examples are given that the agency views as candidates for devices in which tradeoffs between post-market and premarket studies might be successful:

  1. Devices utilizing mature technology which has been well characterized
  2. Devices with known risks and identified mitigations to confirm the adequacy of mitigation
  3. Devices with limited knowledge of adverse events in order to modify warnings, contraindications, and/or precautions in labeling
  4. Devices  intended for use with broader populations than those studied in order to reduce uncertainty about long-term performance in these expanded populations
  5. Devices requiring long-term  studies to  address long-term performance
  6. Devices with expected but unknown occurrence of rare adverse events
  7. Devices approved using bench data to confirm clinical performance

FDA provides some detail and specific examples for these including some for IVDs. There is a bit of haziness here; one example described use of common targets to approve a test and then post-market evaluation to obtain information on rare targets. But it appears these rare targets would be masked while being studied; a move that makes this more like an IUO and less like a diagnostic approved with a nod to post-market studies.  This should probably be clarified.

The document concludes with a clear menu of potential responses to unexpected surprises in post-market findings. These include submission of a PMA supplement, safety communications, having a panel meeting, or if necessary taking administrative and enforcement actions.  Again, as in the EAP guidance, FDA appears more confident in use of post-market controls because of increased capacity to enforce these.

CDRH has the sharply edged charge of both protecting public health (keeping bad products off the market) and promoting public health (getting good ones into the market quickly). To the extent good products are delayed from entering the medical market there is an opportunity cost of lost public health benefit.  FDA review staff and their families and friends are, like their stakeholders, not immune from flagging health or disease.

The thoughtful minds at CDRH have been spinning and have provided the world with more than a small bit of food for thought.


Tags: CDRH, CoDx, PMA

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