Here’s a quick tutorial on the “emergency use authorization” (EUA) process at FDA, for folks following the coronavirus. This explains in a little more detail the information that Dr. Gottlieb posted in a Twitter thread earlier today.
The emergency use authorization process dates to the early years after the September 11 attacks and the subsequent anthrax attacks. Congress added it to FDA’s statute through the Project Bioshield Act of 2004, and the legislature has since tweaked it a few times. The provision in question is section 564 of the FDCA, and it appears at 21 U.S.C. § 360bbb-3 (here). The agency has also issued guidance describing how it interprets and implements the provision (for instance, here), and it has used the provision several times, so there are some helpful precedents to review.
Start from the premise that most medical products (drugs, biologics, and devices) require premarket review of one sort or another, before they can be shipped in interstate commerce. Drugs are the subject of new drug applications, biologics are the subject of biologics license applications, and devices are … complicated. Some require premarket approval, some go through premarket clearance, and there’s a third option relevant here, called a “de novo request.” In vitro diagnostics intended for diagnosis of a disease are considered medical devices. Per FDA regulation (here), this includes the reagents (medical devices!), the instruments (medical devices!), and the system itself (medical device!). Like any other medical device, an in vitro diagnostic might come to market through premarket approval, clearance, or the de novo pathway.
The essence of section 564 is simple. During certain types of emergencies, FDA can authorize the introduction into commerce of a medical product — for example, a vaccine, an antiviral drug, or a diagnostic kit — that would otherwise require some sort of premarket permission process.
There are three steps to the process. In the case of 2019-nCoV, they were as follows: (1) the Secretary of HHS declared a public health emergency; (2) HHS issued a declaration saying that it’s prepared to issue emergency use authorizations; and (3) on a product-by-product basis, FDA issues those authorizations. [Some other declarations would satisfy step 1, but the “public health emergency” declaration is the one relevant for the novel coronavirus.]
First, the Secretary of HHS declares that “there is a public health emergency” or a “significant potential for a public health emergency” that relates to a biological agent (or a disease attributable to one) that affects, or has a significant potential to affect, national security or the health and security of U.S. citizens living abroad. (Other things, such as chemical agents, can cause public health emergencies, but this one is a biological agent.) Section 319 of the Public Health Service Act (here) governs HHS declarations of public health emergencies. Secretary Azar issued this declaration on January 31, 2020 (here).
Second, invoking section 564 of the FDCA, HHS determines that “circumstances exist justifying” emergency use authorizations. Secretary Azar issued this on February 4, 2020 (here).
Third, on a product by product basis, in response to requests submitted by the entities that have developed the medical products in question, FDA issues letters of “authorization” that permit shipment in interstate commerce. So far, FDA has issued one EUA: to the CDC, for its Real-Time Reverse Transcriptase (RT)-PCR Diagnostic Panel (here). This diagnostic is intended for detection of nucleic acid from the 2019-nCoV in upper and lower respiratory specimens collected from individuals who meet CDC criteria for 2019-nCoV testing.
Who Seeks an EUA? And What Do They Submit?
Any entity that wants to ship the unapproved product in interstate commerce for use will have to secure emergency use authorization. This could include companies, but it could also be another part of the government — another agency within HHS, for instance, or the Department of Defense. For 2019-nCoV, so far, only the CDC has sought one.
Section 564 of the FDCA lays out the criteria for emergency use authorization of a medical product. Among other things, FDA must conclude that it is “reasonable to believe” that (1) the product “may be effective” in diagnosing, treating, or preventing the disease or condition in question, and (2) the known and potential benefits of the product, when used for this purpose, outweigh its known and potential risks, taking into account the threat posed by the agent in question. FDA guidance explains that “may be effective” is a lower level of evidence than the effectiveness standard that applies to product approval. It also explains that the decision is ultimately guided by a risk-benefit analysis based on the totality of scientific evidence available. FDA’s guidance also describes exactly what the agency would like to see in submissions (here, at pages 11-16).
How This Plays Out Over Time
Typically FDA will end up issuing more than one EUA for a particular public health emergency. There were two for MERs, for instance, and there are more than a dozen for Zika. FDA’s website lists the current EUAs (here) as well as terminated EUAs (here). And eventually, of course, one hopes that a product will complete the ordinary premarket process and secure ordinary permission to market.
It may be helpful to see the sequence of events for Ebola diagnostic tests, by way of example:
- On September 22, 2006, the Secretary of Homeland Security determined that the Ebola virus presented a material threat against the U.S. population sufficient to affect national security.
- On the basis of this, on August 4, 2014, the Secretary of Health and Human Services declared that circumstances existed to justify emergency use authorization (under section 564) of in vitro diagnostic agents for detection of Ebola virus. This was published in the Federal Register (here).
- But this just gave FDA permission to issue letters of authorization for individual in vitro diagnostic products.
- On August 5, 2014, at the request of the Department of Defense, FDA issued a letter authorizing emergency use of DoD’s Ebola Zaire (Target 1) Real-Time PCR Assay for detection of Ebola Zaire virus. It also published a notice in the Federal Register (here).
- Ultimately, FDA issued EUAs for ten diagnostics, the latest on November 9, 2018, which it then amended in April 2019. (See here.)
- And in October 2019, the first in vitro diagnostic for Ebola made it through FDA’s ordinary premarket review process (here). The manufacturer, OraSure Technologies, used the agency’s De Novo pathway for its “OraQuick Ebola Rapid Antigent Test.” The details of this pathway aren’t important here, but it is an alternative to premarket approval for new medical devices that aren’t high risk devices.
What About Labs that Develop and Use Their Own Tests?
Here comes the wrinkle.
Sometimes laboratories develop, manufacture, and use their own tests. They don’t ship them out; instead, people send specimens to them. There is a decades-old kerfuffle about FDA’s authority to regulate these “laboratory-developed tests” (LDTs), which is beyond my remit here.
The bottom line: FDA says it can regulate laboratory-developed tests (as medical devices). Historically, the agency has been hands-off, but the agency says it has simply been exercising enforcement discretion. The agency is also in the process of rethinking its approach to these tests, and there is a broader stakeholder discussion of the right overall regulatory approach here. And of course others disagree that FDA has authority here.
The wrinkle is this: FDA says that once an HHS EUA Declaration is in place, laboratories should not use their own LDTs to diagnose the disease in question until they go through the EUA process. (See here, about one third of the way down the page.) Dr. Gottlieb explained on his Twitter thread this morning: false negatives are a serious concern in public health emergencies. We need to know that test results in rapidly evolving situations are accurate, because the results inform a host of analyses and decisions, made public health authorities and others. He then offers some high level thoughts on how FDA could move forward under this framework, with help from the CDC, so that laboratories around the country can offer testing.
Update added 6 March:
On February 29, the agency published a policy document (here) in which it stated that certain laboratories could use their laboratory-developed tests while waiting for FDA to process their emergency use authorization requests.
- The policy applies to laboratories certified to perform high-complexity testing under the Clinical Laboratory Improvement Amendments (CLIA) that (a) comply with CLIA requirements, (b) have developed and are using their own validated diagnostic test, and (c) are pursuing an EUA.
- The agency describes the minimum testing it recommends labs perform to ensure these tests are both analytically and clinically valid, and it asks that labs (1) notify the agency when their tests have been validated, and (2) submit an EUA request within 15 business days thereafter.
- The key passage appears at the top of page 3: “For a reasonable period of time after validation and while they are preparing their EUA requests, FDA does not intend to object to the use of these tests for specimen testing, as described below.”
- During this period, FDA recommends that the lab state — when it reports results — that the test has been validated but that FDA review of the validation is still pending. In addition, it recommends that the lab get confirmation of the first five positive and first five negative specimens using a test that does have EUA authorization (presumably by sending the specimens to another laboratory). In other words, the first five positive and first five negative results should be double-checked.