Following the HHS Secretary’s determination to open up the Emergency Use Authorization (EUA) pathway to diagnostics for the monkeypox virus, CDRH Diagnostics leadership held the first town hall on the development and regulation of these products. Going forward, these meetings will be weekly, and combined with the Covid-19 town hall on September 28.
The EUA declaration for monkeypox diagnostics was issued on September 7
- Monkeypox has become a global concern. In late July, the World Health Organization (WHO) declared monkeypox a public health emergency of international concern (see the statement from WHO Director General Tedros Adhanom Ghebreyesus here). This was followed by a U.S.-specific announcement on August 4.
- The U.S. Public Health Emergency (PHE) declaration, the authority for which is located at Section 319 of the Public Health Services (PHS) Act, was further followed by two separate EUA declarations under Section 564 of the Federal Food, Drug and Cosmetics (FD&C) Act: one on August 10th for vaccine products and another on September 7 for diagnostics.
- At that point, testing for monkeypox was already underway. There is an existing FDA cleared diagnostic for orthopoxvirus, sponsored by the Centers for Disease Control and Prevention (CDC), which can detect monkeypox, cowpox, and vaccinia viruses. That diagnostic is currently in use in the CDC and Defense Department’s Laboratory Response Network (LRN), a “national bioterrorism preparedness initiative” that qualifies certain member public health/DoD laboratories to respond to certain high-risk “agents of concern.” As concerns about monkeypox – and incidence of infections – have spread in the U.S., CDC and FDA have worked to expand access to the CDC assay, which is now in use in several commercial lab networks (i.e., non-LRN labs) as well. However, only the labs authorized by the CDC can run the CDC’s (FDA cleared) assay.
- CDRH’s Diagnostics Office took several actions on September 7. In conjunction with the declaration to legally open the EUA pathway for diagnostics, the agency took several steps to operationally open the pathway. Notably, CDRH Diagnostics Office (OHT7) leadership had already indicated that such a move was expected, telling test developers that they could send in pre-EUAs with specific questions about monkeypox test development programs. On September 7, the agency issued an immediately-in-effect guidance outlining its policies for EUA requests and review for monkeypox tests and released two templates for EUA submissions. In addition, the agency issued its first EUA for a monkeypox test to Quest Diagnostics.
The agency also scheduled its inaugural monkeypox test development and validation town hall and announced a new schedule.
- The monkeypox town halls will be weekly, from 12-1 PM (EST) on Wednesdays. This means that the next monkeypox test town hall is September 21. These types of meetings have been a CDRH hallmark of the last over two years during the Covid-19 pandemic. At the meetings, leadership from OHT7 provides policy and operational updates and test developers, while clinical laboratories and other interested entities (e.g., state public health officials, suppliers, consultants) can call in to ask specific questions or elevate operational issues in developing, designing, validating, marketing or distributing tests under the EUA process.
- What does this mean for the Covid-19 town halls? Since these calls were decreased in cadence to monthly, the next scheduled Covid-19 town hall call with OHT7 leadership is scheduled for September 28. According to Stenzel and Lowe, this will now be a combined town hall, answering questions and providing policy updates on both Covid-19 and monkeypox tests.
- This announcement comes as changes could be coming to the Covid-19 testing policy. The last update to the Covid-19 testing guidance came in November 2021. That policy introduced formal policy on EUA review prioritization and policies around modifying authorized tests. Nearly a year after that update, AgencyIQ noticed that what appears to be a revision to that immediately-in-effect guidance is currently pending regulatory review with the Office of Management and Budget’s Office of Information and Regulatory Affairs (OIRA). Practically, this would mean that CDRH has drafted a new version of that guidance, which OIRA must put eyes on before it can be published. What those changes are remain to be seen – although it could include a new prioritization policy or introducing some of the new concepts in the monkeypox guidance to the Covid-19 policies. [See AgencyIQ’s analysis of the guidance here.]
The first monkeypox virus test development town hall largely reviewed the guidance and templates
- The monkeypox guidance, webpages and what’s still to come. The new guidance was issued as an immediately-in-effect guidance (i.e., skipping the draft guidance stage), and is organizationally similar to the Covid-19 testing guidance. The guidance document includes information on the FDA’s policy to prioritize certain submissions, validation recommendations, policies specific to clinical laboratories, policies on modifying certain tests, and information about how to engage with the FDA. The agency then issued a FAQ page, again similar to the “very popular” Covid-19 policy FAQ page, according to OHT7 Associate Director for Regulatory Programs Toby Lowe, which provides information from the guidance document in Q&A format. There are two EUA templates for molecular diagnostics accompanying the guidance, including a summary template and full EUA submission template. The summary template explains “top level what we’re looking for on validation,” said OHT7 Director Tim Stenzel, while the full template is “more in line with the level of detail you may be familiar with from the Covid templates.” [See AgencyIQ’s analysis of the guidance here.]
- Quick recap: What’s OHT7’s approach for monkeypox tests for test developers? Similar to the Covid-19 testing policy, OHT7 is “prioritizing” some EUAs for review, and declining to review others. For monkeypox, there are two main criteria for EUA prioritization: the source of the request and the technology type. In order to be a priority, the request must meet both metrics. First, FDA is looking for EUA requests from “experienced developers” (i.e., those who already have FDA approved/cleared/authorized products on the market) with a high manufacturing capacity. Second, the agency will prioritize only EUA requests for specific technology types, including high-throughput molecular diagnostics, rapid tests and tests with home specimen collection. The agency includes validation recommendations – including the use of contrived samples to validate molecular tests using lesion swabs – in the guidance and in the templates.
- The “experienced developers” criterion “is a new concept that we’ve added here in this guidance,” Lowe acknowledged – although, as AgencyIQ has previously pointed out, it’s a policy idea that CDRH has floated in the past. Under this criterion for EUA prioritization, “we are asking developers to send in some information ahead of time so that we can prioritize our workload and… provide as much information as early as possible… so that you know right away whether we intend to prioritize review of your EUA,” said Lowe.
- The timeline for EUAs is also new. The guidance states that the agency will accept “notifications” from firms that they intend to/are interested in submitting an EUA within 30 days of the guidance document’s official publication. With an official Federal Register publication date of September 13, this means that the deadline for these notifications is October 13. While the agency may adjust the timeline, or open another window later, right now CDRH is only going to accept EUA submissions from entities that have notified them of their intent by this date. At a high level, it appears this policy is intended to help CDRH plan its own workflow and try to keep a manageable number of individual tests on the market.
- Rapid antigen policies are not yet fully defined – but developers can get started. While the guidance specifies that rapid diagnostic tests for monkeypox are a priority, there is not yet an EUA template for antigen tests. “We are working on a template” for antigen tests, Stenzel confirmed, but for now the agency is urging developers to contact the NIH’s Independent Test Assessment Program (ITAP) “as the method to validate and seek authorization” for antigen tests, said Stenzel.
- What’s OHT7’s approach to monkeypox laboratory developed tests (LDTs)? The agency will allow certain LDTs for monkeypox – specifically, molecular diagnostics using lesion swabs as a specimen type (i.e., the same kind of test as the CDC’s cleared assay) – in clinical laboratories certified by CMS as high-complexity under the Clinical Laboratory Improvement Amendments (CLIA). While these tests can be offered without an EUA, so long as they are of that specific technology type and are developed and performed in a single site high complexity CLIA lab, the FDA does want labs to notify them that they have completed validation of their assay within five business days of offering the test. Notably, the agency is “intending to accept notifications for 30 days” as well, but “we may adjust as needed,” according to Lowe. The guidance also lays out a policy by which high-complexity CLIA labs can modify cleared/authorized tests – within limits – and thereby technically create an LDT without needing an EUA. A laboratory system seeking to use different sample types (e.g., one stakeholder from the California State Public Health Department called in on this issue) or technology would need to contact the FDA. While the FDA does intend to maintain a list of labs that have notified the agency that they are running a validated monkeypox assay (as it does with Covid-19 products), this is not yet available.
- A key issue so far: Supplies and options for validating tests. For now, “contrived samples are acceptable if natural samples are not available” for monkeypox diagnostics, explained Lowe, but “this is only recommended for lesion swab samples for molecular tests.” Notably, this is the technology-type and specimen method of the CDC assay, so the technology with which the FDA has some established experience. While some developers questioned processes for natural samples, it seems that the agency is still working out its recommendations in this area. As a preliminary piece of advice, Lowe noted that at least 30 positive and 30 negative samples would be needed. However, as noted above, there are only two monkeypox tests with authorization from the agency: the cleared CDC test and Quest’s EUA authorized test. The CDC’s test can only be used in specific laboratories designated by that public health agency, which means that developers cannot simply access that product to use as a comparator in their program. If a developer can work with a CDC-designated lab, which may provide leftover samples and their results, that is a likely path forward – but Stenzel and Lowe urged developers to reach out proactively. For tests that do end up authorized using contrived samples, a post-market commitment to further validate the test in clinical samples is likely to apply, but the agency does not yet have guidance on the timing for those studies. Going forward, antigen tests may need clinical samples – but those issues are currently best directed to the ITAP.
Key Documents and Dates
- AgencyIQ Analysis: Monkeypox EUA declaration: New guidance, templates and the return of the notification pathway
- Webinar on the Policy for Monkeypox Tests
- Next monkeypox test town hall: September 21, 2022
- Next monkeypox/Covid-19 combined town hall: September 28, 2022