The Latest on Diagnostics and Omicron

Test and diagnostic developers need to include omicron-specific information in their EUA requests, according to FDA diagnostic leadership, even if the request was submitted before the omicron wave in the U.S. During a town-hall style call with industry, they also provided recommendations on updates to standing EUAs – but limited information on the upcoming transition.

Both FDA and the diagnostic and testing industry had to pivot quickly to address the omicron variant.

• According to the Centers for Disease Control and Prevention (CDC) Director Rochelle Walensky at a February 9^th briefing, the omicron variant is still a significant cause for concern in the U.S., although trends show that the current wave may be receding. Walensky cited new data from the CDC that showed a 44% decrease in the weekly case rate over the previous week, as well as a decrease of 25% in 7-day hospital admissions. However, daily deaths remain high at 2,400, “an increase of about 3 percent over the prior week,” said Walensky.
• What does this mean for diagnostic developers? The FDA still wants to see omicron-specific data in Emergency Use Authorization (EUA) requests, according to Tim Stenzel, the Director of CDRH’s Office of In Vitro Diagnostics and Radiological Health (OHT7). During a town hall-style call with industry, Stenzel and Deputy Directors Toby Lowe and Kris Roth provided recommendations on how to consider test submissions and oversight during the omicron wave. Regulators highlighted the need for omicron-specific data in EUA requests given the agency’s ongoing concerns about the potential for decreased test sensitivity in omicron identification. Notably, this varies from the agency’s approach to the delta variant. “We are not asking for any delta specific data… [but] we are asking for omicron data,” Stenzel explained.
• While developers can use an authorized sequencing test, any well-validated method should do. To ensure that samples being used to validate a test are the omicron variant, developers will need to perform sequencing. As Stenzel clarified today, the agency will want to see sequence data for the entire validation set that is included in the application, not just from a subset of samples. While the FDA has authorized some sequencing products, regulators today reiterated that the agency has some flexibility to accept well-validated sequencing methods as well.
• For developers who had already submitted an EUA request before omicron became the predominant strain in the U.S., “there are two pathways that could be utilized here,” said Stenzel. Firstly, developers could add in new data to their applications from more recent studies, as “that is good evidence for what the performance will be.” However, if the application is already in-house and the data are within the limits laid out in the templates, the FDA may employ some flexibility to add the omicron sequencing in as a condition of authorization. “If the data looks good, the sequence confirmation can await a post-market commitment,” said Stenzel. In general, for applications that have already been submitted but have been awaiting review and authorization during the omicron wave, “a minimum of 10 samples that represent omicron” should be submitted to the agency, according to Stenzel.
• For serology tests, the agency is not specifically looking for omicron-specific antibodies. Rather, as with the other test types, regulators just want to ensure that the performance levels will not fall below the thresholds for authorization within the templates – or drop by more than 5% compared to the product’s performance at the time it was authorized.
• With omicron cases again declining, developers are once again asking about enrichment. Before the delta and omicron waves wave hit the U.S., FDA and the diagnostics industry were grappling with how to ensure appropriate validation of tests if test developers struggled to prospectively enroll enough positive patients into studies. However, ballooning case rates associated with the ascendency of the delta and omicron variants made moot any plans for study enrichment to address the paucity of fresh samples. Though these contingency plans have been tabled since the summer of 2021, industry members circled back to understand the agency’s current thinking at the February 9^th town hall.
• For now, OHT7’s recommendations from 2021 seem to stand. As AgencyIQ discussed at the time, OHT7 did provide a significant amount of information on the processes and protocols by which a sponsor could consider enrichment before the delta variant hit the U.S. Previously, the FDA had signaled that a developer should first try to enroll sufficient patients prospectively, and then turn to the agency if unable to garner a sufficient population through prospective enrollment methods. Stenzel reminded developers today that sponsors considering an enrichment approach should reach out to the agency via a pre-EUA so that the agency can “review the enrichment protocol so any bias is avoided.” Though omicron case rates are currently high, numbers are falling rapidly, and as Stenzel acknowledged, “I understand it does introduce… challenges.”

Other policy updates and reminders: When to submit an amendment and the nuances of the November 2021 policy changes.

• During the town hall call, developers also raised a series of questions related to more nuanced policies, including stability testing and when precisely to submit an amendment.
• What does “high throughput” mean for serology tests? The same as it does for molecular diagnostics. In the November 2021 update to the FDA’s Covid-19 testing guidance, the agency provided a firm number for what it considers to be a “high throughput” molecular test – one of the priority criteria that will contribute to whether the submission gets reviewed – after months of declining to do so. In footnote 7 on page 8 of the guidance, the agency states that it would “generally consider tests that support two 384 well thermocycler runs per 8 hours in combination with an automated extraction and liquid handling platform as ‘high throughput,’” an example specifically related to molecular diagnostics. However, Toby Lowe, associate director of the Office of In Vitro Diagnostics, clarified today that the example was intended to apply more broadly. “We didn’t include a firm definition, we included an example,” she acknowledged. The intent, she said, was that the example “would be applicable throughout.”
• An EUA application does not necessarily need real-time stability data, but it needs some stability data. As Stenzel clarified today, EUA requests do need to have stability data included, and accelerated studies can support a 6-month expiration date. If real time stability studies are available to support a longer shelf life (for example, if the test has been launched outside the U.S.) then the agency will consider those data, but they are not required. Stenzel urged sponsors to consider accelerated studies and include the protocol for a real-time stability study rather than waiting on real-time stability data or leaving the section incomplete, as the agency would be “unlikely to review” an incomplete submission.
• When to submit a change to the agency: it’s a fine line. During the February 9^th town hall, several stakeholders had specific and nuanced questions about whether a specific change to an EUA authorized test or process would require a submission to the agency. One example: if a reporting laboratory wanted to use different language than included in the test’s EUA nomenclature (e.g., “detected” rather than “positive”). In that circumstance, Stenzel urged the developer to send the question in by email. Conversely, another developer questioned whether changing the software threshold for a control would require a reanalysis of clinical data or additional clinical testing. In that circumstance, Stenzel urged a pre-EUA be submitted that referenced the current EUA, explaining that “I think we’d want to understand the motivation for that and any impact on the assay.”

What’s next? The timing of a transition is still up in the air.

• Overall, the questions raise a key point: With the pandemic in its third calendar year, the EUA policies have needed to become more complex and nuanced than ever before, as the EUA authority has been wielded in unprecedented ways by the FDA, and within OHT7 in particular. The EUA pathway was not designed to usher hundreds of individual products onto the market for an extended time.Hence, the agency has had to figure out on the fly how EUA policies can accommodate changing needs and technologies.
• Developers are anxiously awaiting news on the transition timing. In December 2021, the FDA issued two transition-related guidance documents that outline a preliminary plan for moving away from emergency-time authorities and into regular regulatory compliance. The first relates to products currently marketed under enforcement discretion, which are tied to HHS’ formal Public Health Emergency (PHE) declaration. The second, and likely more relevant to diagnostic developers, relates to the EUA authority, which is tied to the withdrawal of the EUA declaration –notably a separate authority from the PHE itself.
• Lowe provided limited insight on the call. “We can’t anticipate when the public health emergency will end. We had mentioned previously… both that we don’t know when the public health emergency will end and that we are working on a transition plan.” Notably, the transition plans were issued as draft guidance documents and are open for public comment.
• However, there are some factors to consider. As AgencyIQ previously noted, the EUA transition guidance document indicates that the agency will have time to review and consider public comment on the draft guidance before the policy will be needed (i.e., before the EUA declaration will be withdrawn). The opportunity for public comment indicates that FDA’s may not have an imminent plan for withdrawal. Second, Lowe today reminded developers that all EUAs are in effect until withdrawn, and referred developers back to the still-standing EUAs for products related to Zika and Ebola, noting that the EUA declaration has never been formally withdrawn for those emergencies.
• However, the experience with Zika and Ebola products is likely not going to be informative in the long run. As noted above, the Covid-19 pandemic resulted in an unprecedented use of the EUA authority at FDA. For example, while the Zika virus EUA declaration was issued in 2016 and has yet to be withdrawn, there are only 16 EUAs for molecular assays intended to detect Zika. By contrast, there are currently 269 EUAs listed for Covid-19 molecular diagnostics. Further, the EUAs for Zika products have all been issued to established entities such as the CDC and established diagnostic firms, while many Covid-19 EUAs have gone to entirely new market entrants. In general, it’s unlikely that the FDA will let the EUA declaration for Covid-19 products remain on the books for several years after the immediate threat is over, as evidenced by the issuance of the transition guidance documents.
• A wait-and-see approach. The FDA’s recommendations about when to prioritize submitting a formal market access application have changed as the Covid-19 pandemic has changed. For example, before the delta and omicron variants hit, CDRH leadership was urging developers to submit their market access applications early, in order to avoid a flood of submissions once the declaration was withdrawn. However, the recent surges again meant that the EUA system was prioritized, in order to respond to the changing needs of the pandemic. While CDC’s data demonstrates that the current ,case surge is resolving, it’s not clear when – or if – another variant will hit, or what the U.S. federal response will be in that situation. With the pandemic still representing a dynamic public health situation, the PHE is unlikely to be allowed to expire soon, since many additional policies are tied to that authority. As for the EUA declaration, the FDA does have some flexibility over that decision, but given the significant ongoing capacity challenges at CDRH it’s likely that they will prioritize a lengthier transition to avoid overburdening staff.

To contact the author of this item, please email Laura DiAngelo.
To contact the editor of this item, please email Kari Oakes.

Key Documents and Dates  

• Virtual Town Hall Series – Coronavirus (COVID-19) Test Development and Validation
• FAQs on Testing for SARS-CoV-2
• FDA In Vitro Diagnostics EUAs homepage
• AgencyIQ Analysis: Diagnostics Update: Omicron, policy updates and questions about the transition guidance documents