Diagnostics Update: First combined Covid/monkeypox town hall focuses on new guidance, expectations

Leadership from the CDRH Office of In Vitro Diagnostics (OHT7) today held their first combined call on Covid-19 and monkeypox test development and regulation, following weekly monkeypox calls and now-monthly Covid policies. At the town hall-style call, regulators discussed new changes to the Covid-19 test EUA system and how to move forward with authorized tests.

CDRH first addressed the impending monkeypox notification deadline.

• OHT7 and the town hall call system: These calls allow OHT7 leadership including office Director Tim Stenzel, Associate Director Toby Lowe and Microbiology Division Branch Chief Kris Roth to provide near-real time updates on agency policies and perspectives for tests to address ongoing public health emergencies. While the Covid-19 town halls have been a regular occurrence since early 2020, the monkeypox calls are fairly new.
• The monkeypox calls are still weekly, but the Covid-19 town hall calls have decreased in cadence. This call (9/28) was the first time that the topics overlapped.
• For monkeypox, some tight timing: Per the monkeypox testing guidance, developers have until October 13 to submit a notification of intent to submit an Emergency Use Authorization (EUA) to the FDA for a monkeypox product (i.e., one day after the last town hall that’s current only the schedule). As AgencyIQ has noted, developers are still awaiting new EUA templates, which inform how EUA submissions are formatted and what information is needed, for monkeypox products. This includes waiting for an EUA template for rapid tests. However, the October 13 deadline is just for an intent to submit an EUA, and not for an EUA itself, so there is still some time for these templates to be published. However, it’s likely that developers would want to know what kinds of validation data they’ll be expected to submit in advance of making a decision on EUA submission. In particular, the FDA wants to see certain information in these notifications (e.g., anticipated timeline for EUA submission) that could benefit from access to templates.
• A point of clarification from last week’s monkeypox call: As AgencyIQ has previously discussed, OHT7 is willing to accept validation using contrived samples for monkeypox test EUAs at this time, given still-limited access to clinical samples. At a high level, only appropriate comparator at this time is the CDC’s FDA-cleared assay, which is in use only in CDC-designated laboratories (i.e., those of the Laboratory Response Network (LRN) and five commercial labs authorized to use the assay by the CDC). At the last monkeypox town hall, Stenzel noted that the CDC was prioritizing diagnostic uses of their assay, rather than repeated testing for the purposes of validation other tests, saying that they were “trying to manage [supplies] and meet the response needs.” Today, he clarified that this is not because of a known shortage of monkeypox test kits or reagents. Instead, the CDC “has asked that their test be primarily reserved for diagnostic [purposes]… not validation” of other tests.
• If a monkeypox developer does want to use clinical samples, they will need to partner with the LRN/commercial lab authorize to use the CDC assay, in order to get leftover samples, the report and the CT levels from that laboratory. However, “we are not recommending asking those laboratories to use clinical samples that are acquired elsewhere,” cautioned Stenzel. In effect, a test developer would need to work their development program into the diagnostic use of the assay, they could not ask for additional testing to support their own program using the CDC assay.

A significant portion of the town hall call focused on clarifications to the FDA’s new Covid-19 testing policy.

• A quick recap: FDA issued a revised Covid-19 testing guidance on September 27^th, effectively narrowing access to the EUA pathway. In the first update to the immediately-in-effect Covid-19 testing guidance since November 2021, CDRH outlined a new set of “priorities” for Covid tests. As a reminder, meeting the “priority” criteria is the only way that an EUA request would be processed and reviewed by the FDA, and the agency will be “declining” to review all other EUA requests. The new priority list significantly narrows the EUA pathway, limiting both the new EUA requests and supplements that will be accepted for review by the agency. Specifically, these include EUA requests that will have “significant benefit to public health,” that “fulfill an unmet need” (e.g., address new variants), or are from or were supported by FDA’s federal partners (BARDA, NIH RADx). The only EUA supplements that the agency will be reviewing are those that meet the above priorities or fulfill a condition of authorization for an existing EUA.
• The policies are intended to limit new “me-too” tests on the market. As Stenzel explained on the call, the changes to the priority criteria intentionally narrow access to the pathway only to truly novel products or those that will fulfill an unmet need. For example, he defined “unmet need” as a product that is “valuable to the ongoing Covid emergency… and isn’t a ‘me-too’ product.” Given the existing availability of products on the market, Stenzel indicated that the agency does not see the value in having more individual offerings of the same technology types that are already available as the agency is “steering away from” multiple examples of the same technologies in the same categories.
• What would be an “unmet need”? There are some categories of testing technologies that likely still fall under this bucket. First, Stenzel confirmed that “we’re willing to accept additional breath tests,” as there is currently only one authorized breath test. Second, developers of multianalyte assays intended to be more easily accessible (i.e., non-lab, potentially home use or over-the-counter (OTC)) could make the case that they are looking to address an unmet need, especially going into the winter months. Third, Stenzel has previously specifically called at-home molecular tests for Covid-19 an “unmet need” in past town halls, and especially those that would be offered at a lower price point than the options currently on the market (notably, the FDA does not consider product pricing, but a developer could engage with the agency about distribution plans as part of a pre-submission to ask about their level of priority).
• What happens to EUA requests that are already in the queue at the FDA? That depends. For EUA requests that are already in the queue but may not meet the new priorities, the review process will be determined on a case-by-case basis. As Lowe explained, “submissions that are currently pending will remain in the queue until we respond to the developer, so we will be making our way through those to determine whether or not they will proceed towards authorization or whether… we will decline to issue. Those decisions will be made based on… a combination of the priorities and where they are in the review.” While every EUA request that is already submitted will receive a response, there is not yet a firm timeline on when such a response can be expected. “Sit tight, if you will,” said Lowe.
• Submissions that are further along have a better chance. “Something that’s not going to meet the new priorities but was, you know, a couple days away from being authorized? We’re probably going to move forward with that,” said Lowe. However, an EUA that is in the queue and does not meet the priorities that is not far along in the process (or was just recently submitted) may not be reviewed. The agency’s approach to tests in the queue is intended to “ensure that there’s not a blanket decision being made on submissions that are in the queue,” explained Lowe – they’re neither automatically declined nor automatically granted.
• What about Pre-EUAs? OHT7 will “be making our way through” the Pre-EUAs that are still pending and responding, but “that response may be that this is closed and that we’re not providing feedback at this time,” said Lowe. Going forward, the agency is still accepting Pre-EUAs for priority tests (and Pre-EUAs to ask if a specific product would be a priority) but the Pre-EUAs in the hopper are not going to automatically be converted to a pre-sub or Q-sub.
• The definition of “experienced developer” has been updated in the new priorities. Per the November 2021 version of the Covid-19 testing guidance, an “experienced developer” (i.e., one from whom the FDA would prioritize a submission) was one that had previously interacted with the FDA in an EUA or Pre-EUA submission. However, as AgencyIQ explained in our analysis of the new guidance update, that has now changed to defined experienced developer solely as one with a “successful” (i.e., authorized) EUA request or “similar experience” – which Stenzel confirmed today meant “positive decision” from the FDA (e.g., market approval, clearance or de novo request granted) under traditional market access pathways.
• The new policies also mean that developers will only be able to make limited modifications to their EUA-authorized tests. The agency will continue to accept supplements that either meet the priorities or fulfill a condition of authorization (as noted above), but smaller tweaks to existing EUAs are likely no longer possible. In these circumstances, the agency is urging developers, again, to consider a traditional market access submission.
• Antigen test developers are still awaiting a new template. As AgencyIQ has discussed, antigen test developers are still anticipating an update to the antigen testing requirements, giving ongoing concerns about performance of these products. The policy updates will reflect newly published research from an NIH-supported study from UMass, which was previously cited in an FDA safety communication (while in pre-print) offering new evidence for an updated orthogonal testing strategy that can bolster performance. Lowe today confirmed that the agency will “be updating our recommendations in the template to reflect that” research.
• However, the timing is not yet clear. Stenzel again confirmed that “we are continuing to work on that process, because we will probably reach out to all relevant EUA holders at once with one process, so we’re just refining that so it goes as smoothly as possible.”
• For now, it doesn’t seem that antigen test developers will need additional studies to align with the new policy when it comes out. The study is intended to be “broadly applicable,” said Lowe, so it should be sufficient to rely on. “At this time, the FDA’s not likely to request additional studies to support additional [serial testing] under EUA” tests, she explained.

AgencyIQ presents: The traditional market access pathways paradox.

• The intent of these policy change is to nudge developers towards the traditional market access pathways. In effect, seek to convert an EUA into a formal market access decision, either via a De Novo request or a 510(k) pre-market notification. Both the policies in the guidance and the OHT7’s statements during the town hall specifically state that this is the intent of narrowing eligibility for the EUA pathway.
• However, the way the device pathways work makes this challenging. For a new technology type (i.e., Covid-19 tests of different technology types), the first product to receive a full market access decision will need to be granted as a De Novo request, which will create a regulatory citation and special controls for the generic technology type and serve as the predicate device for the 510(k) pathway. Right now, there is only one granted De Novo (BioFire 2.1) – which means that the 510(k) pathway is only open for tests of the same technology type (high complexity laboratory molecular diagnostics) as the granted De Novo. So far, there is only one cleared 510(k), which is also for a BiuoFire product. While this means that lab-based molecular tests can move towards full market clearance, the pathway is not yet open for other types of tests (e.g., point of care molecular tests, any antigen test, any serology test), for which there are no appropriate predicates and no established special controls.
• In effect, the FDA is urging developers to use a pathway that it can’t actually open by itself. In order for developers to move to full market access for any technology type besides those that could use BioFire as a predicate, the 510(k) pathway would need to be open to them – which it currently is not. Further, if the agency hasn’t yet granted a De Novo for a specific technology type, then “we cannot yet say with certainty what will be required for a 510(k),” Lowe acknowledged, as the special controls would be established under the De Novo process. Although OHT7 does have some recommendations that can be provided to test developer that do want to move towards full market access, the agency can’t accept – or provide full guidance on what would be needed – 510(k)s until a De Novo is granted. For now, the agency is still requesting that any developer interested in full market access reach out via the Q-submission or pre-submission process to receive individualized recommendations.
• Another complication: The De Novo system itself. There can only be one De Novo granted for any particular technology type – if another De Novo is pending for the same technology when another is granted, then that submission will be converted into a 510(k). However, De Novo requests are significantly more extensive and expensive than 510(k)s, meaning that the first product seeking a De Novo will pay the hefty fee to open an easier market access pathway for its market competition’s follow-on submissions.
• While the current situation is technically unprecedented, it does highlight these interesting and unique facets of the market access pathways for devices. In particular, the onerous (and expensive) system for novel moderate-risk products, which then opens the 510(k) pathway for competitors.
• It also raises continued questions for a potential transition. Under the draft transition plan, which would be triggered by a notice that HHS intends to withdraw the EUA declaration (and thereby close the EUA pathway), firms would have a time-limited window to submit full market access submissions and stay on the market after their EUAs are revoked. Reasonably, though, in order for that plan to be practical the 510(k) pathway would need to be open for each technology type, with special controls in place that could support 510(k) submissions. While HHS has not indicated that it is actively considering a revocation of the EUA declaration, the availability of the 510(k) pathway might be a contributing factor when those decisions are discussed.

What’s next:

• The town hall schedule is set for the next few weeks. The monkeypox calls remain scheduled weekly, set to take place on October 5^th and October 12^th. It’s not yet clear if there will be another monkeypox town hall the following Wednesday – October 19^th – or if the agency will continue its scheduling of having the Covid-19 town hall call on the fourth Wednesday of the month (that would be October 26^th). As AgencyIQ has recently noted, the timing for the town halls has been a bit confusing, but it appears that the schedule is set for the next few weeks.

To contact the author of this item, please email Laura DiAngelo.
To contact the editor of this item, please email Alexander Gaffney

Key Documents and Dates

• • Diagnostics Update: New Covid testing guidance nudges developers towards traditional market access decisions
  • Virtual Town Hall Series – Test Development and Validation During Public Health Emergencies (COVID-19 and Monkeypox)