Device and diagnostic companies need to recalibrate how they work with FDA during the ongoing pandemic. Joshua D. Levin, a former FDA reviewer and consultant with several SARS-CoV-2 product clients, offers up advice on key considerations for managing that relationship in these unprecedented times, particularly within the context of IVDs.
It has become common these days to hear “We live in unprecedented times.” The medical device industry and FDA have been at the forefront of working to combat the SARS-CoV-2 virus, through the development and authorization of diagnostic tests, personal protective equipment, ventilators, and more. However, the response to the virus has also changed the way that industry and FDA work with each other. While the Emergency Use Authorization (EUA) process potentially provides a way for industry to collaborate more closely with FDA, it also brings new challenges. This article is primarily focused on the in vitro diagnostics (IVD) industry, which accounts for the largest portion of the device EUA activities, but these concepts are also applicable to the medical device industry at large.
FDA has been working with EUA applications for emerging pathogenic diseases for quite some time and had developed a solid, reliable method for dealing with outbreaks. During previous emergencies, for example the 2016 Zika virus and 2014 Ebola virus outbreaks, FDA was able to seamlessly work its EUA efforts into the agency’s existing workload, and industry sponsors saw little, if any, impact to their pre-submissions, 510(k) and PMA applications. A total of 15 Zika virus assays and 10 Ebola virus assays were authorized under EUA.
In contrast, the unprecedented public health needs caused by the SARS-CoV-2 virus has led the diagnostic industry as a whole to focus a great deal of effort on the development of molecular, serology, antigen, and medical management tests for SARS-CoV-2 virus or antibodies to the virus and the symptoms associated with the COVID-19 disease. There has never been as much public and media focus on in vitro diagnostic testing than with the current pandemic. As of October 1, 2020, FDA has authorized over 200 diagnostic products related to COVID-19 under EUA. Based on information presented at weekly town halls hosted by Timothy Stenzel, MD, PhD, the FDA Office Director overseeing the regulation of IVD tests, FDA has received thousands of EUA applications and pre-EUA applications for COVID-19 diagnostics.
Under FDA’s MDUFA IV User Fee agreement with industry, FDA is required to meet certain review timelines for premarket applications, including pre-submissions, 510(k)s, de novo applications, PMAs, and PMA supplements. EUAs, however, have no such statutory review timeline requirements despite the unrelenting urgency of the pandemic’s demands. Thus, it should be expected that FDA would need to carefully balance the need to meet the public health requirements of addressing the COVID-19 pandemic with the agency’s other responsibilities and commitments.
Let us look at how this situation might be viewed, both from the sponsor (industry) side and from the FDA side, using an example scenario. This example scenario is intended to be anecdotal and is not meant to be based on any specific technology, sponsor or FDA interaction.
Sponsor ABC is a small company with a promising diagnostic technology. It pivoted at the start of the pandemic and placed a big bet on using its technology for diagnosing SARS-CoV-2 infection. The sponsor has recently submitted their EUA application and is now anxious to get feedback. The company is frustrated by the uncertainty around the EUA review timelines, which makes resource and investment planning difficult, particularly since receiving an EUA would lead to a huge increase in demand for their product. The Regulatory Affairs lead at Sponsor ABC has been listening to the weekly Town Halls where FDA has committed to providing feedback on how the EUA (or pre-EUA) review is progressing. However, Sponsor ABC’s lead FDA reviewer has not been as responsive as hoped.
Under FDA’s current policy for certain types of SARS-CoV-2 assays, Sponsor ABC may notify FDA and begin to market the product prior to receiving the EUA. However, the labeling carries with it the disclaimer that “Validation of this test has not been reviewed by FDA. Review under the EUA program is pending”, which creates a market barrier for Sponsor ABC because customers may not be willing to purchase the test until the EUA is granted. Thus, Sponsor ABC is highly dependent on timely FDA feedback.
Meanwhile at FDA, the lead reviewer for Sponsor ABC is concerned about their workload and ability to meet their review goals, and how to balance the mission of “promote and protect” the public health as instructed by FDA leadership. The lead reviewer notes that during the initial stages of the pandemic, FDA was fully in “promote the public health” mode and was rapidly turning around EUA authorizations to support COVID-19 testing. Naturally, many of these were from the large IVD manufacturers, which have the infrastructure, capability, and platforms to be able to quickly develop a SARS-CoV-2 assay, and which also have extensive experience with FDA submissions in general. Now, however, after many SARS-CoV-2 tests have been authorized, the lead reviewer has been instructed by leadership to apply a greater degree of selectivity in how they approach EUA and pre-EUA applications. The types of EUAs that should be prioritized for review has changed over time (for example CLIA-waived, point-of-care tests are prioritized over “me-too” lab-based molecular assays), influencing how the lead reviewer manages the EUAs on their plate. The lead reviewer may have 10 (or more) applications in their queue, and Sponsor ABC’s EUA may be fifth or sixth on the reviewer’s priority list. The lead reviewer may become irritated if the Regulatory Affairs lead at Sponsor ABC constantly emails them asking for updates.
The best practice for working together is to try to understand where the other party is coming from and the pressures it is under. Sponsors need to understand that FDA is overworked and is trying its best to manage all the inquiries coming its way. FDA, for its part, has committed to a weekly check-in so that sponsors can keep track of what is going on with their submission. FDA has also committed, through the weekly Town Halls, to having reviewers respond to an inquiry within 24 hours (if even to say “I received your inquiry and will get back to you shortly”). Sponsors also need to understand that in normal times, the FDA follows an unbiased process where each manufacturer, regardless of size, is provided the same level of support from the agency, including the review of applications in the order they are received. However, during a pandemic, FDA needs to prioritize their efforts to align with the overall interests of public health. And FDA needs to understand that each sponsor believes that their test is the most important advance in fighting SARS-CoV-2 to date.
Expediting the EUA Process
As with everything else in our business, it is crucial to communicate and set appropriate expectations. For sponsors, it is important to have a well-thought out and coherent plan for submission and assay validation, even for an EUA. FDA is more likely to be able to give rapid, targeted, and useful feedback if the sponsor provides a coherent validation plan. Thus, it is beneficial for both the sponsor and FDA to sufficiently plan its studies before engaging with FDA. One mechanism to support this strategy is the pre-EUA process. While not an official “pre-submission”, FDA has indicated that it has increased flexibility to provide comments and feedback during pre-EUA review, facilitating (in theory) a more rapid EUA decision once the EUA is submitted. Also, while not required, sponsors should consider employing design controls to manage the design and validation of the device. These regulations are extremely helpful from a business standpoint to ensure that the device is designed correctly, risks have been mitigated, and that the device meets user needs and the intended use.
Tips for EUA Sponsors
Naturally, not all potential sponsors are equally able to develop and validate a new assay and then manufacture a high volume of consistent, reliable product. We should recognize that designing, developing, validating and then manufacturing a new in vitro diagnostic device in a matter of weeks or months is unprecedented. Typically, new products like these take one to three years to bring to market, even for an established company. Sponsors need to be realistic about their company’s capabilities and the maturity of the technology, and to follow the FDA’s templates and guidance documents closely. Reviewing other recently published authorizations can also be helpful. Finally, if sponsors do not have sufficient internal resources or experience, they should consider reaching out to a qualified regulatory consultant to assist with reviewing or developing appropriate validation protocols, verifying that they have met the relevant regulatory requirements, and communicating with FDA as effectively and efficiently as possible.
Along with the many unprecedented challenges our society has had to deal with during this pandemic, the working relationship between sponsors and FDA, at least for IVD products targeted at SARS-CoV-2 and COVID-19, has been fundamentally changed. The agency’s work on traditional, non-SARS-CoV-2 IVD products has also been impacted by the pandemic in many ways. For example, in the past, FDA, and particularly the IVD review group, have championed the pre-submission process as a method to provide sponsors with early feedback. Currently, lack of review resources may, in some cases, delay FDA’s ability to review pre-submissions. It remains to be seen whether the relationship between FDA and industry will return to a pre-pandemic “normal” or if some of these temporary changes will remain in place.
Note: After this article was drafted, FDA provided additional guidance, stating that it is prioritizing review of EUA requests for tests where authorization would increase testing accessibility (e.g., point of care tests, home collection tests, at-home tests) or would significantly increase testing capacity (e.g., tests that reduce reliance on test supplies, high-throughput, widely distributed tests). FDA stated that it would also be declining to review EUA requests for laboratory developed tests at this time.
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