Following the August Public Health Emergency (PHE) declaration and an Emergency Use Authorization (EUA) declaration for vaccines, HHS has now issued a section 564 EUA declaration for monkeypox/orthopoxvirus testing products. Concurrently, FDA issued new guidance for monkeypox tests, new EUA templates and the first EUA for a monkeypox test. Per the guidance, developers have 30 days to alert the agency if they intend to offer a monkeypox test.
Quick background: Monkeypox PHE and EUA declarations
- HHS declared the monkeypox outbreak a Public Health Emergency (PHE) on August 4. 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 4th.
- Critically, the public health emergency declaration on August 4, 2022 did not yet permit the FDA to issue Emergency Use Authorizations (EUAs). Opening the EUA pathway for monkeypox products would require a separate determination and declaration that “circumstances exist justifying the authorization of emergency use” of medical products. A national Public Health Emergency (PHE) is formally declared under Section 319 of the Public Health Services Act, or PHS Act, while FDA’s authority to issue Emergency Use Authorizations (EUAs) comes from Section 564 of the Food, Drug and Cosmetic (FD&C) Act. [ Read AgencyIQ’s analysis of the differences between these two laws here.]
- On August 10, HHS issued an EUA declaration (under section 564) for monkeypox vaccines. Per the declaration, HHS determined that “circumstances exist justifying the authorization of emergency use of vaccines pursuant to section 564 of the FD&C Act,” effectively opening the EUA pathway for monkeypox vaccine products (and only vaccine products – not therapeutics or diagnostics). Concurrently, the agency issued an EUA to expand use of the JYNNEOS vaccine.
- Now, HHS has issued an EUA declaration for monkeypox tests. This announcement gives FDA the authority to leverage the EUA pathway for monkeypox tests. Notably, it comes two weeks after Toby Lowe, Associate Director for Regulatory Programs at CDRH’s Office of In Vitro Diagnostics (OHT7) indicated that that office was open to receiving and reviewing pre-EUAs for these products – so the announcement of the EUA declaration was generally expected.
- Testing for monkeypox is 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 four commercial lab networks (i.e., non-LRN labs) as well. According to the EUA declaration announcement, over 80,000 tests can be run in the U.S. per week.
- In addition, laboratory developed tests (LDTs) for monkeypox; As AgencyIQ has previously discussed, CDRH Diagnostics Office (OHT7) leadership has recommended that interested developers could begin developing a monkeypox test as a laboratory developed test (LDT) before there was another pathway (besides pre-market notification) available. At least one major developer took the agency up on that, as Quest Diagnostics ran an LDT while working to validate the CDC assay.
- The EUA declaration announcement also came with the first EUA – for the aforementioned Quest Diagnostics product, the Quest Diagnostics Monkeypox Virus Qualitative Real-Time PCR. Per the announcement, “Quest Diagnostics submitted data demonstrating that its test for distribution to other laboratories met the standards for issuance of an EUA.”
FDA has now issued a monkeypox test guidance, EUA templates and the inaugural EUA.
- Accompanying the EUA declaration, FDA issued new “immediately in effect” guidance, the “Policy for Monkeypox Tests to Address the Public Health Emergency.” Similar to the way that the agency has issued policies during the Covid-19 emergency, this direct-to-final guidance skipped the draft guidance phase and is applicable immediately. The agency also issued two voluntary EUA templates, the now-familiar downloadable documents that have been a cornerstone of the Covid-19 response. Similar to the Covid-19 test templates, the two monkeypox test EUA templates (a full and summary EUA template for molecular diagnostic tests) are automatic Word downloads on the Monkeypox EUA home page that developers can fill out as an EUA request. The summary template includes recommendations for testing on the product’s analytical and clinical validity. The full template “is a voluntary comprehensive template that provides additional details, including study design considerations and fill-in-the-blank responsive text.”
- The templates serve two purposes: First, they guide developers through the submission compilation process and help them organize their information, providing clarity on what exactly the agency needs to see. Second, the template system allows for streamlined reviews from agency staff. Notably, developers may use alternative approaches, but “should consider seeking FDA’s feedback or recommendations to help them through the EUA process.”
- First up: Review prioritization for monkeypox EUA requests. Unlike the initial approach for Covid-19 tests in early 2020, the FDA does not appear to be accepting all-comers off the bat for monkeypox diagnostics. According to the guidance, the agency will “prioritize review” for monkeypox tests in the following technology areas: “high-throughput diagnostic tests, tests with home specimen collection, or rapid diagnostic tests.” Notably, the agency defines “rapid tests” as molecular or antigen diagnostics that can be used at the point of care (POC) and deliver results within 30 minutes. Further, the agency will prioritize EUA requests from “experienced developers with high manufacturing capacity that inform FDA within 30 days after publication of the notice of availability of this guidance in the Federal Register of their intent to submit an EUA request.” In this case, an “experienced developer” is a firm already holding an EUA or a formal marketing application or “similar experience” (potentially, but not explicitly, including CE marks or other non-U.S. regulatory authorizations) and with which the agency “does not have current compliance concerns.” While the FDA does note that it may adjust these priorities as needed – including the timeline and technology types – for now, this is the type of test (and developer) for which the agency will be reviewing EUA requests.
- In effect, those who want an EUA authorization have 30 days to let the FDA know. Eligible firms that meet the “experienced developer” criterion who are thinking of submitting an EUA for one of the listed technology types (i.e., rapid tests, high throughput, home collection) would need to send an email stating their intent to submit an EUA within 30 days. That email, titled “Intent to Submit EUA Request,” should include information about the test technology, manufacturing capacity, throughput, expected timeline through the submission of an EUA request, and “any available validation data.” Upon receipt of that email, “FDA’s goal will be to respond promptly by return email on a rolling basis,” and will also let the developer know at that time if their product meets the priorities.
- For those not seeking an EUA authorization, expect enforcement discretion for certain LDTs. As the guidance explains, the FDA will “not intend to object” to high-complexity clinical laboratories (i.e., those certified for high-complexity testing by CMS under the Clinical Laboratory Improvement Amendments (CLIA)) continuing to offer certain monkeypox tests that are not EUA authorized or 510(k) cleared. However, the FDA has some criteria for this enforcement discretion – these tests must be molecular PCR products that use lesion swabs as a sampling method and must be appropriately validated. Notably, any other technology types, home specimen collection methods, at-home tests, or tests using specimen types other than lesion swabs would not fall under this enforcement discretion.
- The return of the notification pathway – with another 30-day window. For LDTs that meet the criteria above, laboratory developers have five days (either from offering the test or, for tests already offered, five business days from the date of the guidance) to notify the FDA that they are offering such a test. This notification, provided by email, would need to include information about the test’s validation as well as information about the laboratory (see pages 11-12 of the guidance), including its CLIA ID number, test methodology and estimated initial capacity per week. As for the EUA pathway, the agency will accept such notifications for 30 days (“we intend to accept notifications for 30 days after publication of the notice of availability of this guidance in the Federal Register”).
- Operationally, this means that any tests currently offered as LDTs have five days post-guidance to submit such a notification, while other laboratories must submit a notification within five days of starting to offer their product – but only for the next 30 days after the guidance is formally published. As the guidance explains, “To address the immediate capacity needs, FDA does not intend to object to the development and offering of additional diagnostic tests, as described in this section, for a period long enough to address availability and accessibility concerns, which FDA believes should be addressed by laboratories that notify FDA within 30 days given current signals.”
- Modifying cleared/authorized tests. Under the new guidance, the FDA will continue to allow certain entities to make certain changes to an EUA authorized or 510(k) cleared (i.e., the CDC assay) monkeypox test, within limits. For commercial developers seeking to modify their own EUA authorized tests, the FDA has outlined a policy similar to the one in place for Covid-19 diagnostics under the November 2021 Covid testing guidance. A manufacturer can thus update its own test, and launch the updates, without the FDA authorizing the change so long as the modification does not impact the test’s indication or the analyte specific reagents. However, the firm would need to submit validation data that supports the modification to the FDA in either “a supplemental EUA request or a new premarket submission” although, as noted, they could launch the modification before the request is cleared or authorized. For now, it’s not clear if such a “new premarket submission” could include a new EUA after the initial 30 day call for EUA request notifications. Theoretically, if a sponsor wanted to update their test to modify its use (e.g., add an at-home collection/POC designation to their product), this would need to be a separate EUA request, and could be something the FDA would likely work on with developers who already hold an EUA.
- Similarly, high-complexity CLIA labs could make the same kinds of modifications to a cleared/authorized test, actions that would technically make the product into an LDT. Per the guidance, the limitations here are the same (i.e., FDA “does not intend to object” to changes made by the high-complexity laboratory to an authorized or cleared test if the modification does not change the indication for use as authorized by the FDA or the analyte specific reagents), except that the clinical laboratory would only need to submit validation data, not an EUA supplement or new submission, to the FDA. However, these laboratories are “encouraged” to work with the original developer “so that validation data supporting the modifications can be submitted by the original developer to FDA” – and therefore potentially be used by just that specific laboratory or laboratory system.
- For tests that have been modified but not yet authorized/cleared in that form, the developer and/or laboratory would need to be clear in offering the test that it has not been reviewed by the FDA.
- A quick note on serology tests: The guidance includes a section stating that the agency does not believe that serology tests can be used to diagnose monkeypox or to assess immunity. “Therefore, it is important that results from monkeypox serology tests be used for appropriate purposes and the result be properly communicated,” says the agency. For now, the FDA states that it will allow (“does not intend to object to”) the use of serology tests for monkeypox only within the context of high-complexity CLIA labs that are “part of an entity that conducts research on diseases and is integrated into the direct medical care of the patient (often referred to as academic medical center laboratories).” Further, the lab would need to provide notification to the FDA and include specific clarifying information about the appropriate use of the technology in test reports. Going forward, the agency urges laboratories to share any lessons learned (including validation data) on serology tests with the FDA, and if there is demonstrated clinical utility in the future the agency “may decide” to review EUA requests for these technologies.
- A quick timeline: Both diagnostics firms that are thinking about an EUA submission and clinical laboratory (systems) considering a notification as an LDT have 30 days from the guidance document’s formal publication in the Federal Register (which hasn’t happened yet) to email the agency of this intent.
- At a high level, this policy reflects lessons learned from the Covid-19 pandemic. As AgencyIQ has previously discussed, the early 2020 all-comers approach in the FDA’s Covid-19 testing policy has caused longer-term concerns from the agency, including a high volume of tests available on the market. Notably, in May 2021 CDRH put out a review of the South Korean regulatory response to Covid-19, which included several components that are reflected in the U.S. EUA policy for both monkeypox and Covid-19, including a net lower number of submissions actually accepted and reviewed by the agency. For Covid-19, OHT7 has accomplished this through its priority system, in which it “declines” to review EUA submissions for certain technology types. However, the monkeypox guidance goes even a step further, putting a time limit on the EUA submissions window and only accepting EUA requests from “experienced developers” – both hallmarks of the South Korean response that were called out in the May 2021 CDRH review.
- The intention of the policy appears to be to receive fewer EUA requests overall, but that those EUA requests are of a higher quality. This could be a benefit for the already capacity stretched OHT7. Further, the continued flexibility, albeit in a limited capacity, for clinical laboratories to develop and operate LDTs (or modify existing tests) could help address issues with limited access to monkeypox testing, while still ensuring a certain level of quality for these products.
- While the guidance was “issued on the web on September 7, 2022,” the 30 day deadlines are tied to the “publication of the notice of availability… in the Federal Register,” which has yet to be issued as of publication. However, developers and laboratories will still face a quick turnaround time for any notifications they may seek to make. Further, the agency indicates throughout the guidance that it could open up additional rounds of EUA request windows – or extend the first one – as needed or appropriate.
- As previously noted, OHT7 has faced significant capacity challenges during the years of the Covid-19 pandemic, and OHT7 leadership has confirmed that a monkeypox team has been assigned within that office. However, the longer-term implications of diverting staff from regular work to monkeypox work on other IVD developers remains to be seen (e.g., continued longer review times, delayed responses, continued issues with the Q-sub process), which could vary depending on the trajectory of the monkeypox emergency.
- What does this mean for the EUA declaration for Covid-19 tests? That’s not yet clear. The FDA can, and in fact currently does, have multiple EUA declarations in place at the same time. However, what the EUA declaration for monkeypox means for the potential termination of an EUA declaration for Covid-19 tests is remains to be seen.