By Cynthia Nolte, Sandra White, and Vicki Anastasi
As another year draws to a close, several guidance documents released by FDA in 2014 should be on every medical device manufacturer’s radar.
In general, recent FDA guidances are more prescriptive and contain more specific recommendations and examples than those we have seen in the past. Overall, regulated industry has embraced this approach, but FDA continues to walk a fine line between ensuring patient safety and stifling innovation.
Mobile Medical Applications (Apps)
One year after its publication in late 2013, this guidance remains unclear to many manufacturers.
What FDA says: A continuum of mobile medical apps exists ranging from those that are clearly not medical devices to those that are distinctly medical devices and thus require regulation. For apps in the gray area of regulation, FDA will exercise enforcement discretion. This means that as long as no safety issues arise, it will not require pre-market submissions or compliance with FDA medical device requirements.
The Good: The guidance provides a shorter, easier path to market for low-risk apps.
The Bad: The industry is worried that the increased cost and time to market associated with FDA regulation will stifle innovation.
The Path Forward: FDA manages mobile medical apps within the existing regulatory framework and has been doing so for years. The software that conducts and analyzes CT scans is a great example. Manufacturers should make an informed decision regarding their place in the regulation continuum. For those apps that will be subject to FDA enforcement, and which represent a novel approach for which there is no predicate, the de novo classification guidance may be applicable.
Framework for Regulatory Oversight of Laboratory Developed Tests
The most sweeping changes FDA announced in 2014 were for laboratory developed tests (LDTs).
What FDA Says: FDA is ceasing enforcement discretion and establishing active oversight to ensure the validity and safety of LDTs, which have grown increasingly complex and critical to diagnosis.
The Good: For IVD developers that compete against LDTs, the playing field may soon be more level. LDTs can remain on the market during the new registration and approval processes.
The Bad: More than 11,000 laboratories currently regulated under CLIA must quickly register and list tests performed and begin reporting adverse events, which may be difficult to precisely define. That, combined with a relatively short 1 to 5-year horizon for institution of approval processes for most LDTs, as well as the new quality systems requirements, will place significant demands on industry resources.
The Path Forward: As this is a draft guidance, significant uncertainty remains and particularly so for DNA sequencing-based and rare disease LDTs. However, increased regulation of LDTs, whether through FDA or CLIA reform, is inevitable. Advance preparation is required to reduce barriers to rapid, efficient, and cost-effective LDT development and marketing.
In Vitro Companion Diagnostic Devices
The companion diagnostic devices (CDx) guidance is an example of FDA’s effort to accelerate access to treatment by improving the development process.
What FDA Says: A CDx provides information for the safe and effective use of a corresponding therapeutic. Ideally, a CDx and its corresponding therapeutic should be developed and approved or cleared contemporaneously. FDA will use a risk-based approach to determine the regulatory pathway. In general, the agency will not approve a new therapeutic or new indication if an already cleared/approved CDx does not exist.
The Good: CDx and potential regulatory pathways are now clearly defined.
The Bad: Codevelopment may require a longer upfront planning period and strain the resources of small manufacturers. Sponsors must now meet with both the drug and device divisions of FDA.
The Path Forward: The CDx developer should partner with the therapeutic manufacturer as early as possible, stay involved in decision making, and meet regularly with FDA to ensure development is on course.
De Novo Classification Process (Evaluation of Automatic Class III Designation)
510(k) clearance hinges on a device’s substantial equivalence to an existing product. Novel devices with a risk profile consistent with a Class I or II designation are classified as Class III, which requires approval via a PMA if a predicate device cannot be identified.
What FDA Says: The de novo pathway allows FDA to clear new technology devices with low or moderate risk via a 510(k)-like process, instead of a PMA.
The Good: This guidance streamlines the de novo process.
The Bad: The review timeframe is uncertain. Prior to FDA’s recent efforts to streamline the process, manufacturers waited a year or longer to complete the de novo process.
The Path Forward: Manufacturers with new technology devices should use the Pre-Submission process to determine if de novo designation is applicable.
IDEs for Early Feasibility Medical Device Clinical Studies, Including Certain First In Human Studies
Many U.S. device manufacturers conduct first in human (FIH) studies offshore because of stringent IDE requirements.
What FDA Says: This guidance was designed to introduce flexibility into the IDE process, in a manner that will not impact patient safety. Depending on risk profile FDA may be more flexible about technical aspects or gaps in the submission, provided a sponsor is clear on how it will manage the design process.
The Good: Sponsors can collect the clinical data needed to make design decisions even though the device design is not finalized.
The Bad: FDA will not compromise patient safety. Thus, a company considering a U.S. FIH study must perform a thorough analysis of the risks to health and controls introduced to mitigate these risks.
The Path Forward: Schedule early conversations with FDA to determine the applicability of U.S.-based FIH studies.
Presubmission Program and Meetings with FDA Staff
FDA has held presubmission meetings for 20 years, but this guidance formalizes the process.
What FDA says: This guidance provides specific information and illustrative examples of the meeting process, including the types of meetings, when to request a meeting, and materials to submit prior to the meeting.
The Good: Sponsors have successfully used these meetings to obtain informal scientific input from FDA before engaging in expensive animal and/or clinical testing.
The Bad: A presubmission meeting, or any other type of FDA meeting, can add three to four months to a timeline.
The Path Forward: Straightforward devices for which FDA requirements are known do not require presubmission meetings. However, novel devices without a clear regulatory path should be discussed in a Pre-Submission Meeting.
Refuse-to-Accept Policy for 510(k)s
Though the current refuse-to-accept (RTA) policy described in this guidance has been in effect for nearly two years, FDA reports that approximately 50% of 510(k) submissions are still rejected during RTA review.
What FDA Says: The RTA review is an administrative “pre-review” to ensure completeness of a 510(k) submission prior to substantive review. Within 14 calendar days of submission a document is either approved for regulatory review or it receives an RTA designation due to a missing component.
The Good: This process helps sponsors ensure their applications are complete. Also, as part of its MDUFA III performance goals, FDA pledges to review compliant submissions in 60 days. It’s a win for sponsors and FDA.
The Bad: It is no longer a viable strategy to submit while testing is in progress or to omit certain tests from a submission. Sponsors must complete all testing and supporting information and submit their 510(k) when the design validation is complete. In addition, though the RTA review is intended to be administrative, some reviewers may ask out of scope questions.
The Path Forward: Follow the checklist exactly and leave nothing open to interpretation. Use the comments section to inform FDA of the rationale for anything outside of the norm. Be prepared to make revisions and address any out of scope questions.
eCopy Program for Medical Device Submissions
The eCopy is a significant step on the road to fully electronic premarket device submissions. In fact, FDA is now running a pilot program for fully electronic 510(k) submissions.
What FDA Says: A paper submission must be accompanied by an electronic copy that is its exact duplicate—an eCopy.
The Good: Sponsors are no longer required to submit two paper copies.
The Bad: Any discrepancies between the paper submission and the eCopy will lead to rejection. Minutiae such as file naming conventions are also strictly controlled.
The Path Forward: Follow the rules. There is no other choice. Use FDA’s free eCopy validation tool before submission. Avoid the electronic 510(k) submission program until it progresses past the pilot stage.
Cynthia Nolte, Ph.D., RAC is the senior director of regulatory affairs at ICON plc.
Sandra White, M.S., RAC is the director of regulatory affairs at ICON plc.
Vicki Anastasi is the vice president and global head of medical device and diagnostics research at ICON plc.
[image courtesy of SALVATORE VUONO/FREEDIGITALPHOTOS.NET]