Diagnostic Update: Pre-sub acceptance, predicting the transition timeline and a new MOU on lab capacity

By LAURA DIANGELO, MPH | Jun. 01, 2022

Leadership from CDRH’s Office of In Vitro Diagnostics (OHT7, previously known as OIR) provided a regular bi-weekly update to diagnostic and test developers on next steps for Covid-19 product development, including multiplex antigen tests and their thoughts on a transition timeline.

Up first: The transition away from emergency authorities.

  • Industry has been speculating as to when the emergency authorities could come to an end. The EUA pathway for Covid-19 diagnostic and test products remains open, but both industry and regulators have been assessing the way that the pathway would eventually close. During the call with industry, OHT7 Director Tim Stenzel noted that “we are trying to get back to normal, but I don’t know when and if any changes will occur.”
  • Process-wise, what would the closing of the EUA pathway look like? The EUA pathway is legally opened by a declaration from the HHS Secretary that circumstances exist justifying its use, as outlined in section 564 of FD&C. As AgencyIQ has previously explained, this is separate from the declaration of a public health emergency (PHE, section 319 of the Public Health Services (PHS) Act) – and, unlike the PHE declaration, the EUA declaration does not need to be renewed; rather, it is in effect until it’s formally withdrawn by HHS. So long as the relevant EUA declaration is in place, FDA is authorized to issue EUAs.
  • In late 2021, FDA issued draft guidance for diagnostic/test developers that outlined their anticipated process for closing the EUA pathway and transitioning to conventional authorities. At a high level, the FDA stated that it would announce the withdrawal of the EUA declaration (notably, there are four such declarations for Covid-19, including the one for diagnostic products that was issued in February 2020) 180 days in advance. That announcement would trigger a three-phase process for manufacturers with EUAs to either come into regulatory compliance and submit (and have the FDA accept) a formal marketing application, or withdraw the product and make a plan for their stock of product already out in the field. Members of industry have raised some questions about the plan as outlined in the draft document.
  • The canary in the coalmine for a coming transition trigger is likely the issuance of the final guidance. HHS has broad authority over when and how to issue and withdraw EUA declarations. However, FDA leadership has previously indicated that their goal is to have a final transition guidance in place before the EUA declaration withdrawal is announced. This step in the process has yet to be completed. However, once that guidance is issued the administrative barriers to withdrawing the EUA declaration would be lower.
  • The testing capacity in the U.S. is a key consideration. Part of the criteria for opening/keeping open the EUA pathway is ensuring access to products that would be limited or nonexistent without EUA-authorized technologies. Currently, there is “huge manufacturing capacity, and we have an overabundance of home tests in the U.S. today, [but] I can’t predict what it will be tomorrow,” said Stenzel today. However, the demand for test products has come in waves, as different variants of the virus (with different levels of infectiousness) predominate. If HHS and FDA are of the opinion that the U.S. population will continue to be able to access tests at a level that meets anticipated demand if the declaration were withdrawn, that would factor heavily into the decision. For now, Stenzel declined to give a firm answer, noting that “I can’t predict when the need for these tests will go away,” but further citing the high numbers of authorized, available products, high manufacturing capacity and the current public health need.
  • As a reminder, the agency is currently only accepting and reviewing certain EUAs. While the EUA pathway remains open, OHT7 spent the latter half of 2021 narrowing the scope of the types of products they’ll accept to review for authorization – “declining” to review those that do not fit within their priorities. Notably, one criterion is high manufacturing volume, meaning that the agency has been purposefully prioritizing tests that can fill substantial need with limited numbers of total authorizations.
  • However, OHT7 is reviewing all pre-subs for Covid, including those with questions about transitioning certain products. This specifically includes 510(k) pre-subs for lab-based molecular diagnostics that would leverage the BioFire Respiratory Panel as a predicate, as well as those pre-subs for products for which there is no predicate of record. Notably, OHT7 Microbiology Division Deputy Director Kris Roth today urged the submission of a pre-sub for a molecular diagnostic that would be CLIA-waived, rather than high-complexity laboratory based. He also pointed developers to previously cleared CLIA-waived multiplex products, which could provide some insight into what the agency needs to support a CLIA-waived classification.
  • A small note on monkeypox. With the detection of a small number of monkeypox cases in U.S., Stenzel took a minute on the town hall call to update industry on the agency’s current thinking. Currently, there is no Section 564 declaration on tests for monkeypox – meaning that the EUA pathway is not open for any of these products — and it does not seem to be under serious consideration. As Stenzel noted, the CDC does have a “perfectly functional” 510(k) cleared orthopoxvirus test, which has already been deployed in about 67 laboratory response network (LRN) laboratories (public health and Defense Department laboratories in a network of over 100 labs). Monkeypox is one of the orthopoxviruses which can be identified, though not differentiated, by that test, and positive samples are then sent to CDC for further analysis. For right now, “for the volumes that we’re seeing right now for monkeypox,” the CDC test kit and the LRN capacity are more than meeting demand, said Stenzel. All this means that there is likely no need for an EUA declaration.

A new multi-party MOU for clinical lab surge capacity

  • In May, CDC published a Memorandum of Understanding (MOU) on surge capacity for clinical labs in times of a public health emergency. The MOU is signed by a bevy of organizations, including regulatory and governmental bodies (CDC, FDA, the Council of State and Territorial Epidemiologists), diagnostic industry groups (AdvaMed and ACLA), and laboratory oversight and accreditation entities (the College of American Pathologists, the Association for Molecular Pathology, the Association of Public Health Laboratories).
  • The MOU lays out a strategy to build diagnostic testing surge capacity in the U.S. Throughout the Covid-19 pandemic, clinical laboratory systems that run lab-based tests have faced a significant capacity crunch. This included challenges with staffing, accessing necessary supplies, navigating changing technology and federal requirements, and scaling up to respond to high workloads. Under the MOU, CDC will lead work with the other parties listed to build “external laboratory surge testing capacity for PHEs and emerging public health threats.” In effect, parties to the MOU will be tasked with devising a strategy to protect against these kinds of staff, capacity and supply crunches, as well as preventing information silos, in future emergencies.
  • What does this mean for the FDA? FDA’s role under the MOU is to “provide expertise” on diagnostics and the EUA pathway and “clinical and technical diagnostics expertise” about implementing new products during emergencies. As Stenzel clarified for industry today, however, “this does not change, in any way, the EUA statute.” In effect, FDA will maintain its authority over authorizing tests and diagnostics – including in times of emergency – while the partnership under the MOU will focus on expanding capacity in the field.

Finally: Pre-subs for Non-Covid tests and continuing questions about multiplex products

  • As AgencyIQ noted on May 31, OHT7 is now accepting pre-subs for non-Covid work. During the past few years, pre-submissions for non-Covid-related diagnostic and test products have had a difficult trajectory. While OHT7 declined to accept most non-Covid pre-subs in the early days of the pandemic, it began phasing in pre-sub acceptance for certain technologies throughout 2021 with a plan to resume business as usual in mid-2022. According to a May 31 announcement, that time is now: As of June 1, OHT7 will now be accepting all pre-subs for IVDs.
  • Stenzel: Do expect delays on pre-subs for non-Covid work. With OHT7 getting “back to normal in the sense that we’re not reviewing… all types of applications, including Q-subs”, industry will still likely see some differences compared to pre-pandemic timelines. For non-Covid pre-subs, Stenzel outlined his expectation that once a reviewer is assigned for a pre-sub, they will give the sponsor a sense of timeline within “a matter of days or a week or two.” Notably, the new iteration of the medical device user fee program (MDUFA V) is the first with dedicated performance goals for pre-submissions.
  • For Covid tests, questions on non-lab multiplex tests continue to dominate the town hall. While the FDA has authorized laboratory-based and point of care (POC) tests that can identify, and differentiate between, Covid-19 and other common respiratory viruses such as influenza A and B and RSV, at-home tests including over-the-counter (OTC) options are yet to be authorized. Challenges in developing these types of products remain significant. For example, with influenza B accounting for less than 1% of influenza cases in the U.S., developers have been having significant issues accessing enough samples to validate their product.
  • While Stenzel has previously indicated his office’s openness to receiving data from non-U.S. countries to shore up numbers, he added some additional considerations today. Specifically, it is important that “before you take an at-home test to another country, that you run that plan by the FDA in a pre-EUA just make sure the setting, the languages, are covered.” English- and Spanish-speaking countries may be most appropriate for OUS data, as at-home users’ ability to follow instructions as written is a key component of performance for these products. In addition, alternatives to fresh samples are an issue for antigen tests. As Stenzel acknowledged, “banked samples for home use is going to be a challenge… no matter what.” The agency has seen issues with the freeze/thaw cycle for banked dry swabs, and there are “significant issues with transport media” in antigen tests for swabs frozen with viral transport media. For now, the agency continues to urge developers considering a study to support such a product to submit a pre-EUA outlining their research plan for feedback.

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