FDA is exercising significant emergency authorities during the COVID‑19 pandemic. Not all of industry is affected, but those who are manufacturing or distributing (or using) devices being used to fight the pandemic can benefit by understanding FDA’s emergency‑related policies and practices. These are evolving every day, but we have gained enough experience, and there is now enough FDA guidance, that it seemed worthwhile to try to sketch out a roadmap, even if somewhat rudimentary.
Although the EUA authority applies to drugs, devices, and biological products, our focus in this blog post is confined to devices. We will cover these topics:
- How to obtain an emergency use authorization (EUA) for devices under section 564 of the Federal Food, Drug, and Cosmetic Act (FDC Act).
- Practical information about how to import EUA devices and devices marketed under enforcement discretion.
- Postmarket compliance for EUA devices.
- PREP Act immunity for EUA devices.
FDA’S EUA AUTHORITY
Under the FDC Act, it is unlawful to introduce into interstate commerce a medical device that lacks 510(k) clearance or premarket application (PMA) approval when required. An EUA is effectively a substitute clearance or approval issued by FDA in a time of emergency pursuant to Section 564 of the FDC Act. An EUA authorizes emergency use of a device that (1) is not approved or cleared for commercial distribution or (2) is approved or cleared, but not for the emergency intended use.
FDA may only issue EUAs within the scope of an applicable HHS emergency declaration. The Secretary of HHS, Alex Azar, has issued three EUA device-related emergency declarations to date for the COVID-19 pandemic. The first two emergency declarations issued relate to in vitro diagnostic (IVD) devices (see Federal Register notice here) and personal protective respiratory devices (see Federal Register notice here). Following publication of these emergency declarations, FDA issued over fifteen EUAs for IVDs, and two EUAs for facial respirators (see list of COVID-19 EUAs here).
This week, HHS issued a third device-related emergency declaration, which is broadly applicable to “emergency use of medical devices, including alternative products used as medical devices” and has a retroactive effective date of March 24 (see Federal Register notice here). FDA has already issued one EUA for a ventilator (see EUA here) pursuant to the authority granted by this broad emergency declaration. Other EUAs seem likely to follow.
Preparation of a Request for EUA
Under Section 564 of the FDC Act, an EUA request must satisfy the following criteria:
- There is an applicable HHS declaration related to a serious or life‑threatening disease or condition;
- Based on the totality of scientific evidence, it is reasonable to believe that the device may be effective in diagnosing, preventing, or treating the disease or condition;
- The known and potential benefits of the device outweigh the known and potential risks of the device; and
- There are no adequate, approved, and available alternatives to the device.
FDA issued an EUA guidance document in 2017 expanding on FDA’s expectations for these four criteria. The guidance clarifies that the fourth criterion, regarding no available alternatives, does not mean that only one EUA can be issued for a device type or category. Rather, a device manufacturer can establish that there are no available alternatives if there are “insufficient supplies of the approved alternative to fully meet the emergency need.”
The 2017 guidance does not specify any particular format for EUAs, but for the COVID-19 pandemic, FDA has requested use of FDA-created EUA templates. FDA has posted to its website two EUA templates for IVD EUAs, one for laboratories to perform high-complexity testing under the Clinical Laboratory Amendments (CLIA) (see template here) and one for commercial test kit manufacturers (see template here). FDA has stated that templates for non-diagnostic devices can be requested via email at CDRH-NonDiagnosticEUA-Templates@fda.hhs.gov, but has not yet posted any non‑diagnostic EUA templates to its website. We are aware of one that is being used by an FDA review team but it has not been publicly released to our knowledge.
In our experience with the EUA process so far during the current emergency, the review divisions we have worked with have requested initial submission of the request as a “Pre‑EUA.” The Pre-EUA submission has the same content and data as an EUA submission, but submitting as a Pre-EUA apparently allows FDA to work interactively with the device manufacturer to gather the necessary data and information to compile a complete EUA request that is ready for approval.
FDA’s Current Policies for IVD EUAs
The COVID-19 pandemic has led to a pressing need throughout the country for appropriate screening and diagnostic tests. As a result, FDA established policies related to COVID-19 tests early in the Agency’s response to the pandemic. Perhaps because the IVD policies were created early, they have evolved over time to adapt to the test market.
On February 29, FDA issued a guidance document describing a policy that would allow laboratories certified under CLIA to perform high-complexity testing to develop, validate, and use diagnostic tests for the SARS-CoV-2 virus, prior to submission of a request for EUA. The grace period was approximately 15 business days. This policy allows laboratories to proceed to market quickly with validated laboratory-developed test while simultaneously seeking an EUA.
Under this policy, once a laboratory has a validated test, it must notify FDA via email (at CDRH-EUA-Templates@fda.hhs.gov) that it has a validated assay and will begin clinical testing. During the 15-day grace period, lab reports must include a statement that the test has been validated, but FDA’s independent review of the validation is pending. While awaiting FDA’s determination on the request for EUA, the laboratory must obtain confirmation of the first five positive and first five negative clinical specimens using an EUA-authorized assay. If FDA ultimately refuses to issue the EUA, the laboratory must terminate testing patient specimens and issue corrected test reports that indicate the prior test result may not be valid.
On March 16, FDA issued an updated version of this guidance document (Policy for Diagnostic Tests for Coronavirus Disease-2019 during the Public Health Emergency), which retained the February 29th policy regarding high-complexity laboratories without modification, and added three additional policies addressing various testing scenarios that arose as states and commercial laboratories attempted to respond to the call for additional tests.
The updated guidance included a policy that permitted state authorization of laboratory tests developed by high-complexity laboratories in lieu of an EUA. Prior to publication of this guidance, on March 12, FDA issued enforcement discretion for laboratory tests authorized by the Wadsworth Center of the New York State Department of Health. On March 13, the President issued a Memorandum on Expanding State-Approved Diagnostic Tests, which explicitly gave FDA authority to offer the same enforcement discretion policy to any other state that requests it. FDA is requesting that states choosing to exercise this option notify FDA. Additionally, FDA has asked laboratories with tests authorized by a state, rather than through the EUA process, submit a notification to FDA via email at CDRH-EUA-Templates@fda.hhs.gov.
Originally, the grace period applied to laboratory-developed tests in high-complexity CLIA certified laboratories. This updated guidance extended the policy to commercial test kit manufacturers and distributors, who now may begin distribution of a test kit prior to submission of a request for EUA for a period of 15 business days, so long as the test has been validated, the manufacturer sends an email notification to FDA, and the test report includes the disclaimer that the validation has not been reviewed by FDA. Unlike the policy for high-complexity laboratories, FDA recommends that commercial test manufacturers post to their website the instructions for use and a summary of assay performance.
The fourth policy in the March 16 updated guidance relates serology tests. Serology tests that identify antibodies (e.g., IgM, IgG) to SARS-CoV-2 from clinical specimens do not require an EUA. To qualify for this enforcement discretion policy, a test must be appropriately validated, the test manufacturer or laboratory must send a notification to FDA via email, and the test reports must have the following disclaimers:
- The test has not been reviewed by the FDA.
- Negative results do not rule out SARS-CoV-2 infection, particularly in those who have been in contact with the virus. Follow-up testing with a molecular diagnostic should be considered to rule out infection in these individuals.
- Results from antibody testing should not be used as the sole basis to diagnose or exclude SARS-CoV-2 infection or to inform infection status.
- Positive results may be due to past or present infection with non-SARS-CoV-2 coronavirus strains, such as coronavirus HKU1, NL63, OC43, or 229E.
There has been some confusion among laboratories and test kit manufacturers as to whether the policies in the March 16 guidance apply to home testing and/or home collection. FDA’s guidance states that none of the four policies applies to home testing. FDA’s Frequently Asked Questions webpage on diagnostic testing for SARS-CoV-2 clarifies that the policies also do not apply to home collection tests that are performed in a laboratory. So, all home tests or tests using home specimen collection require an EUA, and laboratories and manufacturers cannot begin distribution prior to approval.
FDA is hosting a weekly virtual town hall series to provide policy updates and answer questions regarding COVID-19 diagnostic tests. These webinars may prove to be a useful channel for policy updates on FDA review and regulation of COVID-19 IVDs in the coming weeks.
The first virtual town hall was held on March 25 (see slides here), during which Elizabeth Hillebrenner, Associate Director for Scientific and Regulatory Programs in the Office of the Center Director, and Timothy Stenzel, Director of the Office of In Vitro Diagnostics, summarized the policies in the March 16th guidance and answered questions from industry. Many questions related to CLIA requirements, which FDA stated should be directed to CMS rather than FDA. Though, FDA did clarify that the March 16th policies would not alter the relevant CLIA requirements for a test. For example, if a test is moderate or high complexity, it can only be used in a doctor’s office if the doctor has the appropriate CLIA certification.
HOW TO IMPORT EUA AND ENFORCEMENT DISCRETION DEVICES
During the past week, FDA has provided increased clarity on importing devices subject to EUAs, devices subject to enforcement discretion, and alternative products to be used as medical devices. Imports have been a source of consternation for industry as, even under the best of circumstances and with clear guidance, products do not always enter the U.S. at an efficient pace.
As background, FDA has broad authority over imports of products subject to its jurisdiction. FDA may refuse admission of a product if the product “appears from the examination of . . . [a] sample or otherwise” to violate the law. FDC Act § 801(a). This standard is flexible, and permits FDA to refuse product entry into the U.S. based on subjective criteria. Historically, this created inconsistency among different FDA Import Offices and even inconsistent approaches among reviewers within the same office.
Since mid-2016, we have seen many consistency issues addressed by the onboarding of the Automated Commercial Environment (ACE) for FDA-regulated products. As we previously blogged, ACE provides importers with a “single window” to submit information to government agencies, reducing redundant submissions to different agencies that may have jurisdiction over the products proposed for import. The ACE system relies heavily on the use of appropriate codes to identify manufacturers, products and product uses. The FDA Supplemental Guidance, last updated in April 2018, provides the appropriate codes for use with FDA-regulated products.
One of the biggest issues for importers during the COVID-19 public health emergency has been the lack of appropriate codes in the FDA Supplemental Guidance to address devices that may be subject to EUAs, those subject to enforcement discretion, or alternative products intended to be used as medical devices. Although FDA published final guidance in 2017 on Emergency Use Authorizations of Medical Products and Related Authorities making clear that products subject to EUA could be legally imported, no mechanism was provided in that guidance on how to appropriately code these imports – with the guidance merely stating that, “[t]he letter of authorization should serve as appropriate documentation or certification that the product may be legally imported or exported.” While the FDA Supplemental Guidance includes a “compassionate use/emergency use” code for medical devices, it was unclear whether importers could apply the code to commercial shipments of EUA products or whether the code applies to more discrete utilizations of a device for more traditional compassionate use purposes.
On March 24, FDA issued a statement that it had taken action to increase COVID-19 response supplies by providing instructions to the import community on importing personal protective equipment and other devices.
These instructions provide specific codes for importers to utilize when importing 3 categories of products:
- Non-FDA-regulated general purpose protective equipment – importers should utilize, if available, Harmonized Tariff Schedule codes (HTS codes) that do not flag the entry for FDA review. If an HTS code has a flag, importers should do a ‘disclaim’ for FDA;
- Products authorized under EUA – importers should use Intended Use Code 940.000: Compassionate Use/Emergency Use as well as the applicable FDA product code;
- Products regulated by FDA as a device, not authorized by an EUA, but where an enforcement discretion policy has been published in guidance – importers should use Intended Use Code 081.006: Enforcement discretion per final guidance as well as the applicable FDA product code.
While these import instructions are helpful, gaps remain. FDA has historically required importers to identify products’ intended uses at the time of import. It is unclear whether importers may use HTS codes that avoid FDA review for general purpose products that do not meet medical device requirements but are intended for use as medical devices. FDA has provided published guidance on certain face masks (and importers can now use intended use code 081.006 for these products). As of March 25, there was not guidance for other types of personal protective equipment such as surgical gowns, although we are aware that FDA has provided email guidance to members of industry stating its willingness to exercise enforcement discretion in certain circumstances.
In a March 26 email response from the newly established COVID19FDAIMPORTINQUIRIES@fda.hhs.gov, we received confirmation that there is no mechanism to import personal protective equipment for a medical use (Gloves, Gowns, Surgical Apparel, etc.,) that is not in compliance with traditional medical device requirements, even if FDA has provided email guidance that it would exercise enforcement discretion in certain circumstances. FDA confirmed that for these products, “There are no exemptions from registration, listing, and/or clearance/approval requirements at this time.”
To its credit, FDA appears to recognize many of these issues and is taking steps to partner with industry. We are aware that FDA has proactively reached out to importers to facilitate information exchanges that may help expedite U.S. entry of these much‑needed products.
To date, FDA has not issued general guidance to address postmarket compliance of EUA devices and the issue of enforcement has not arisen in any meaningful way in the current pandemic. That could change later, so it is at least worth knowing what the statute authorizes FDA to do.
Under Section 564 of the FDC Act, FDA has authority to set “conditions of authorization” for an EUA. For on any device with an EUA, the letter of authorization will set forth specific conditions of approval. This authority is somewhat different for products not previously regulated versus those already regulated but being put to a new emergency use.
For products previously unapproved under the FDC Act: An EUA may specify appropriate conditions to ensure that healthcare professionals administering the product (and patients receiving it) know that it is being used under FDA’s emergency use authority and the significant known benefits and risks and alternatives. Patients specifically may be told of an option to refuse or accept it and the consequences.
In addition to these informational requirements, FDA may set appropriate conditions for monitoring and reporting adverse events associated with the emergency use. FDA also may subject manufacturers to appropriate conditions concerning recordkeeping and reporting, as well as inspection of the records, with respect to the emergency use.
Finally, FDA has broad authority over distribution (including who may distribute and/or receive product), who may administer and to whom it may be administered, and requirements for collection and analysis of information about the safety and effectiveness of the product.
For unapproved new uses: For a manufacturer of a device subject to an EUA for a new emergency use, FDA is required to apply the informational requirements above, to the extent practical, and FDA is authorized to apply adverse event reporting and recordkeeping and reporting.
Interestingly, if an EUA requires a change in labeling, the manufacturer may choose not to comply. In this situation, FDA may not authorize a distributor or other person to obscure or alter the original labeling. FDA may authorize a distributor to add supplemental labeling not subject to the misbranding requirements (502 of the FDC Act).
All devices: FDA has broad authority to waive or limit compliance with good manufacturing practice (for devices, the Quality System Regulation), including any adulteration requirements (section 501 of the FDC Act).
Finally, FDA may establish conditions on advertisements and other promotional descriptive printed matter for the emergency use. This authority includes the right to invoke the restricted device authority over advertising in Section 502(r) of the FDC Act.
PREP ACT IMMUNITY
The Public Readiness and Emergency Preparedness Act (PREP Act) is a broad and complex public health emergency statute. Of interest here, it has a provision that authorizes the Secretary of HHS to issue a declaration (i.e., a PREP Act declaration) that triggers broad statutory immunity from liability under federal and state law. This immunity applies to claims of loss caused or resulting from administration or use of countermeasures to diseases, threats and conditions determined by the Secretary to constitute a present or credible risk of a future public health emergency. The immunity is applicable to entities and individuals involved in the development, manufacture, testing, distribution, administration, and use of such countermeasures. The exception for “willful misconduct” is exceedingly narrow.
As mentioned, the immunity from liability is triggered by a PREP Act declaration. A PREP Act declaration has been issued for COVID‑19. Although the immunity provisions in the PREP Act are too complex for this already quite long blog post, it is at least worth knowing that a device receiving EUA approval for fighting COVID‑19 also receives immunity under the PREP Act. Specifically, the statute defines a “covered countermeasure,” to include “a . . . device . . . authorized for emergency use in accordance with section 564.”