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FDA Draft Guidances Detail Plans for Enforcement Discretion During Public Health Emergencies

NEW YORK – In the wake of its May 6 final rule on laboratory-developed tests, the US Food and Drug Administration also released a pair of draft guidances detailing how it plans to regulate these tests during public health emergencies.

The draft guidances, issued at the beginning of May, outline how the FDA will enforce oversight of LDTs deemed necessary for response to health emergencies, both in cases where it has activated Emergency Use Authorization (EUA) authority and in cases where it has not.

While notable as guides to how the FDA may handle LDTs in future health emergencies, the drafts have received relatively little attention. They are open for public comment through July 5, but to date each has received a total of two comments, one each from private individuals and one each from genetics firm Invitae, which is being acquired by Laboratory Corporation of America. Other organizations including the Association of Public Health Laboratories (APHL) have said they plan to provide comment before the deadline.

The draft guidance, covering regulation of tests in situations where the FDA has decided to issue EUAs, suggests that the agency could adopt a more flexible approach than it did in the early days of the COVID-19 pandemic, when its refusal to allow use of LDTs that had not received EUA prevented labs from quickly deploying tests for detecting SARS-CoV-2.

Following the country's struggles to ramp up testing quickly enough to help contain the virus, a number of parties blamed the FDA's policies for the slow response and suggested that in future pandemics the agency should allow tests to go to market before they have received EUA.

In its recent draft guidance, the FDA indicated openness to this idea, noting that in future emergencies, it may choose "not to object to the limited offering of certain unapproved tests for the diagnosis of a specific disease or other condition under certain circumstances, such as to help quickly increase test availability."

The agency said that in choosing whether or not to allow the offering of unapproved tests, it would consider factors including the need to speed availability of these tests; the risks of the tests; the availability of FDA-approved or -authorized alternatives; and the ability to mitigate the risk of false test results.

It also said it would consider the experience and expertise of manufacturers looking to offer unapproved tests, taking into account factors including whether they have previously received EUA for a test, whether or not they are the subject of FDA compliance concerns, and whether or not they are participating in government evaluation programs such as the Independent Test Assessment Program developed by the National Institutes of Health's RADx program during the COVID-19 pandemic.

While the FDA has, with its recent final rule, tightened its authority over LDTs, the draft guidance represents a potential loosening of its stance on such tests compared to the initial days of the COVID-19 pandemic when labs were not permitted to bring them to market without EUA. Jonathan Genzen, chief medical officer and medical director of automation at ARUP Laboratories, maintained that the agency's legal authority to bar LDTs without EUA was uncertain. However, in practice, few clinical labs challenged it on this point and no lab offered COVID-19 testing without EUA on a broad scale until the FDA changed its policy at the end of February 2020 to allow for such testing.

Genzen said he believes the FDA issued the draft guidance in part to address criticisms that its final rule on LDTs could hamstring labs in the event of future pandemics. He noted that while the document indicates the agency may "intend to have some degree of flexibility in enforcement as the need arises," it provides little in the way of specifics.

In its comment, Invitae highlighted the agency's plans to consider lab experience and specifically whether a lab has previously received EUA for a test. The company said that "limiting consideration to FDA experience is unnecessarily narrow" and asked that experience taking tests through the New York State Department of Health's Clinical Laboratory Evaluation Program (CLEP) also be considered "suitable evidence" of a lab's competence. Under the May 6 final rule, tests approved by CLEP are exempt from FDA premarket review.

Invitae also raised questions regarding the draft guidance's standards for test validation, which call for validation with 30 positive and 30 negative clinical samples. The company asked for "additional guidance on how the positive or negative status of the samples is expected to be established" as well as flexibility around the number of samples needed given that samples may be difficult to acquire.

The second draft guidance concerns FDA policy in situations where the agency has not activated EUA authority but in which testing may nonetheless be needed to respond to a health emergency.

According to the agency, in certain "emergent situation[s]," it may, in consultation with the US Centers for Disease Control and Prevention (CDC), decide to suspend certain enforcement policies with regard to tests needed for an "immediate response."

While the draft guidance covering situations in which the FDA has implemented EUA authority arguably represents an improvement in lab flexibility compared to the status quo at the outset of the COVID-19 pandemic, the second draft guidance reflects the tighter regulation that labs and LDTs face following the May 6 final rule. Prior to the rule, labs could deploy LDTs without taking them through the FDA provided EUA authority was not in effect. Now they will only be able to do so when they meet the requirements for enforcement suspension spelled out in the document.

"This has the potential to significantly impact how fast clinical laboratories can respond to a future pandemic and could greatly limit their ability to respond, at least until an [EUA] is declared," said Nathan Ledeboer, medical director of clinical microbiology and molecular diagnostics at the Medical College of Wisconsin.

Linoj Samuel, divisional head for clinical microbiology at Henry Ford Health and chair of the American Society for Microbiology's clinical and public health microbiology committee, said that he hopes for more clarity of how the FDA will define such emergencies, including, for instance, when regional or local outbreaks might trigger suspension of enforcement policies.

"It's a considerable investment of time and resources to stand up an LDT," he said. "What happens if we stand up an LDT, and the FDA and CDC decide, well, this isn't an emergent situation. That is where we really need clarity and guidance, and we hope that will be forthcoming from FDA over time."

The draft guidance indicates that the agency plans in such situations to rely heavily on government and public health laboratories as opposed to commercial labs and academic medical centers. To offer "immediate response" testing, a lab must be a US government laboratory, a state or local public health laboratory, or a lab operating under a "formal or informal" agreement with the US government.

The exemption also applies to tests "designed, manufactured, and distributed" by the CDC for use in CLIA labs operating "within CDC, within CDC's Laboratory Response Network, or under an agreement with CDC."

The decision to make tests developed by the CDC eligible for exemption from enforcement policies comes in the wake of the CDC's failed effort to develop a molecular test for COVID-19 in the early days of the pandemic. An audit of the CDC effort released last year by the US Department of Health and Human Services (HHS) Office of Inspector General (OIG) found that the agency lab responsible for developing the test had limited experience in test development as well as limited resources and lacked formal policies and procedures for such a process.

Genzen questioned the decision to rely so heavily on government and public health labs, observing that during the COVID-19 pandemic, these labs were quickly overwhelmed by the demand for testing and that commercial and medical center labs were essential to testing on the necessary scale.

Samuel similarly suggested that the reliance on government and public health labs "means that we may not have learned the lessons of the COVID-19 pandemic."

Genzen added that the draft guidance was not clear on what exactly might constitute a "formal or informal" agreement with the government.

"That really is kind of a vague term," he said. "Is an email from the contact you work with at the CDC sufficient? Is it something that would require some type of written contract. That definitely needs clarification."

It its public comment, Invitae also criticized this element of the guidance, calling it "unnecessarily limiting."

The guidance is also vague on what might constitute an "emergent situation." For instance, one area of concern among some in the lab industry is how under the May 6 final rule laboratories will quickly develop and offer tests for new drugs of abuse. In theory, outbreaks of new drugs could meet the definition of "serious or life-threatening diseases or conditions caused by [chemical, biological, radiological, or nuclear] agents" that, according to the guidance, could trigger test enforcement discretion.

Genzen said that "on paper" the guidance could address such a situation, though he added that he is skeptical it will actually be used this way. The FDA "has never been proactive in innovation" around drugs of abuse testing, he said. The agency declined a request for comment.

Genzen said the FDA's policy on Predetermined Change Control Plans (PCCPs) is a likelier route for dealing with issues like emerging drugs of abuse. A PCCP is documentation submitted as part of a device's larger regulatory package that details future changes or updates a manufacturer may want to make to the device as well as how those changes will be implemented and validated. If approved, the PCCP allows the manufacturer to make those changes without having to take the device back through premarket review.

Peter Kyriacopoulos, chief policy officer at APHL, said that the organization plans to ask the FDA for clarification as to how drugs of abuse testing might be addressed by the guidance. He said that APHL will also seek clarification as to whether newborn screening and the addition of tests to newborn screening panels meets the definition of an emergent public health situation that could be subject to enforcement discretion.

Kyriacopoulos said APHL sees the release of the two guidance documents as just the start of a much longer process.

"We expect there will be many more than just these two guidance documents, and we are poised to respond not just to the development of these documents, but we're also going to be putting together some comments and requests for clarification beyond these guidance documents," he said.