An updated policy from the FDA will permit states to validate and oversee the development and distribution of tests to detect COVID-19 without first receiving approval from the FDA, and manufacturers to begin using certain tests before obtaining FDA approval. The extraordinary policy reflects considerable urgency to increase testing capacity in the US in the face of a mounting crisis.
Executive IQ Brief
- How Things Work Now: In times of public health emergency, the FDA can “authorize” products intended to diagnose, treat, or prevent an emergent threat to be legally marketed without approval. Since the identification of the novel coronavirus, COVID19, there have been six diagnostics that have received such an authorization. However, testing capacity in the US remains small and below current needs.
- What’s New: The FDA issued new guidance that will allow states to oversee development and distribution of diagnostics within their own borders without needing authorization from the agency. Additionally, the FDA will allow manufacturers of diagnostics to begin distributing their test kit before they’ve submitted—or received—an authorization from the FDA.
- Impact: The actions are intended to increase testing capacity in the US by allowing states to follow a model currently being implemented by the NY State Department of Health (NYSDOH) and expanding policy previously only available to labs to traditional manufactures. However, uptake and diagnostic quality will be key to determining whether the diagnostic kits will be available and accurate.
- What’s Next: The guidance is effective immediately, superseding guidance form February 29.
KEY DATES AND DOCUMENTS
Under federal law, the FDA may allow the use of certain unapproved medical products in emergency situations.
In such scenarios, the FDA “authorizes”—rather than approves—products using Emergency Use Authorizations (EUAs), which are only permitted after HHS has both declared an emergency situation and declared that the emergency warrants the use of specific medical products. Such products may include those used to diagnose, treat or prevent serious or life-threatening disease or conditions.
EUAs are only temporary and expire after the public health emergency concludes. At such time, any products granted an EUA and not subsequently granted full FDA approval must be removed from market.
In general, the regulatory standards for a product sponsor to obtain an EUA is lower than that for a New Drug Application (NDA) or medical device clearance or approval, but developers are still required to submit certain evidence on safety and efficacy for authorization. The FDA will also generally waive certain other regulatory requirements related to quality or manufacturing.
Without an authorized EUA, the FDA may also permit distribution of products to respond (diagnose, prevent, or treat) to a declared public health emergency if the products have been declared a medical countermeasure (MCM) under the Pandemic and All-Hazards Preparedness Reauthorization Act of 2019 (PAHPRA). If the Secretary of the Department of Health and Human Services (HHS) issues a declaration that diagnostics, vaccines, or treatments for the specific threat are covered countermeasures, the FDA can utilize “enforcement discretion,” or choose not to enforce approval or authorization requirements for countermeasures.
A novel coronavirus originating in Hubei province of China has emerged as an emerging global threat to public health. The virus, known as SARS-CoV-2, leads to a disease known as Coronavirus Disease 2019, or COVID-19.
One crucial challenge in the US has been the capacity of emergency responders to test for and identify persons infected by the virus. In response, public health laboratories have recently urged the FDA to allow them to create and validate their own diagnostics to identify the virus.
This represents a shift from typical regulatory procedures, in which diagnostic products developed within a laboratory are not subject to FDA review.
Diagnostic products, including in vitro diagnostics (IVDs), have traditionally been regulated as medical devices under the Medical Device Amendments of 1976 (MDA). As devices, IVDs are typically developed by a device manufacturer and brought to the FDA for either approval or market clearance. The device is then distributed to hospitals, doctors’ offices and other facilities where the devices are used.
A subset of IVDs called laboratory developed tests (LDTs) have traditionally been excluded from regulatory oversight. LDTs are diagnostics that are developed within laboratories, intended for use in the laboratory in which they were developed, and are not commercially distributed.
Since the 1970s, the FDA has typically allowed these types of diagnostics to operate outside the scope of the agency’s purview—despite recent regulatory and legislative actions to bring LDTs into compliance with medical device regulations. Without FDA oversight, the laboratories in which LDTs are developed are primarily overseen by the Centers for Medicare and Medicaid Services (CMS), under authority from the Clinical Laboratory Improvement Amendments (CLIA) of 1988.
However, laboratory developed tests (LDTs), or diagnostics that are developed and used within a clinical laboratory, rather than manufactured for commercial use, are not required to meet medical device requirements.
The FDA’s policy of enforcement discretion (or not enforcing applicable regulations based on the need to focus on higher-risk products) typically doesn’t apply in the case of an emergent public health threat. In those cases, LDTs are regulated in much the same way as other diagnostics—requiring an EUA and validation for use. According to the agency, the increased risk associated with an emergency, and an EUA declaration from HHS, indicate that LDTs intended for use during an emergency represent a higher risk than regularly-used LDTs, and are therefore subject to FDA oversight.
The FDA has recently taken several actions to reduce regulatory burden for diagnostic developers to increasing testing capacity and ensure that the most patients possible can be screened for COVID-19.
On February 29th, the FDA issued guidance intended to encourage clinical laboratories to submit EUAs for their laboratory developed diagnostics. Under that guidance, which went into effect immediately, the FDA currently allows in-house testing to be performed in CLIA-certified laboratories before the agency grants an EUA—as long as certain criteria are met. The policy stated that the FDA will not take enforcement action against these laboratories for using IVDs not cleared through the EUA process, so long as the laboratory pursues an EUA within 15 days of first using the device. It also outlined the steps that labs should take to validate their test.
According to the most recent figures available, there were 17,480 laboratories with a CLIA compliance certificate in 2019 and 15,732 accredited laboratories. Those laboratories are the only ones permitted to conduct high-complexity testing, and therefore eligible to develop a diagnostic for an EUA under the February 29th guidance. However, they represent a significant minority of all CLIA laboratories (an additional 192,332 laboratories can only conduct waived tests, while 30,570 can only conduct waived tests and certain microscopy testing).
While the FDA stated that allowing CLIA-certified laboratories to develop EUA products will “rapidly expand testing capacity,” the pace of testing has remained slow and below the targets set by White House and HHS officials. Further, clinical laboratories are—by definition—not manufacturers, which was expected to create new difficulties in scaling up any widespread diagnostic policies. No high-complexity CLIA certified laboratories have yet had an EUA granted by the FDA.
As part of its work to increase testing capacity in the US, on March 12 the FDA announced that the agency will allow the New York State Department of Health (NYSDOH) to validate tests in the state, in lieu of requiring laboratories in New York to submit an EUA to the FDA for approval. Effectively, this means that the NYSDOH could validate its own diagnostics for use within the state. Aligning with the February 29th policy, however, the laboratories would have 15 days after implementing their diagnostic to provide validation data to the DOH. According to the FDA, the policy is needed “based on the urgent public health need for additional testing capacity.” The agency further cites the unique features in New York that could lend themselves to allowing the state to effectively implement its own testing infrastructure, namely that “the NYSDOH has a long-established framework in place for oversight of laboratory developed tests in New York State.”
On March 13, the White House issued a memo indicating that it would be willing to allow additional states to take similar actions, stating that “should additional states request flexibility to authorize laboratories within the State to develop and perform tests used to detect COVID-19, the Secretary shall take appropriate action, consistent with the law, to facilitate the request.”
On March 16, the FDA updated its February 29th guidance on diagnostic testing during the course of the public health emergency. The new guidance is immediately in effect and supersedes the original February guidance.
The new iteration of the guidance allows additional states to authorize their own testing and to develop and distribute certain tests prior to (or without) an EUA.
Under the new guidance, the FDA is expanding its policy of enforcement discretion, previously applicable only in New York, that would allow a state to authorize labs within the state to develop and perform testing for COVID-19 under its own authority. The agency states that, if a state (or territory) “takes responsibility” for diagnostic development and implementation within its borders during the public health emergency, the FDA “does not intend to object” that the test has not been submitted for, or been granted, an EUA. However, the FDA does request that the state notify the agency if it does intend to choose to validate its own tests.
Additionally, the agency is expanding the policy that allows laboratories to begin using their test while awaiting the FDA’s decision on an EUA. Under the new guidance, the FDA will allow traditional diagnostic manufacturers to begin distributing test kits for the novel coronavirus “for a reasonable period of time,” defined as 15 days, after the manufacturer completes its validation but before an EUA has been submitted. The FDA notes that, in order to utilize this option, manufacturers need to provide instructions for the use of their diagnostic online and publicly post data of its performance characteristics. The guidance notes that this transparency would be intended to “mitigate potential adverse impacts from a poorly designed test.”
The FDA further states that it does not believe that serology tests, whether developed by a manufacturer or by a lab, will need an EUA at this time. Serology tests look for antibodies in serum rather than the virus itself.
The FDA wrote that it “does not intend to object” to the development or distribution of serology tests as long as the test is validated and the agency is notified of its distribution. The policy is limited to serological tests that would not be intended to provide a sole basis to diagnose or exclude SARS-CoV-2 infection, and any definitive diagnostic that is serologically based would still need an EUA. In general, the FDA defines SARS-CoV-2 serological diagnostics as tests identifying the antibodies to the virus from clinical specimens and recommends specific validation studies for these products (i.e., cross reactivity/analytical specificity, class specificity, clinical agreement studies).
Currently, the FDA has granted six EUAs for diagnostics to test for the novel coronavirus, from LabCorps, Hologic, Thermo Fisher, Roche, NYSDOH (Wadsworth), and the Centers for Disease Control and Prevention (CDC). However, diagnostic testing capacity remains a significant issue in the US. According to POLITICO, there have been 41,552 diagnostic tests given in the US, with 4,019 confirmed cases (data updated as of 3/16 at 8:19 PM). However, both public health advocates and lawmakers have raised concerns that testing capacity remains insufficient. The Trump administration has said it plans to roll out high-volume testing to 2,000 sites across the country within the week.
The testing roll-out has faced several challenges, including issues with the CDC diagnostic kit’s manufacturing that led to a shortage of available tests, limited state public health laboratory capacity to run the tests, and concerns about a shortage of other basic supplies like cotton swabs needed for testing.
The FDA’s new guidance is intended to increase diagnostic capacity by allowing manufacturers to begin distributing tests before they are granted an EUA, and allowing entities (manufacturers and labs) developing serological tests to skip the EUA process entirely in certain circumstances.
This could raise questions as to the accuracy, quality, and safety of certain diagnostics that are rolled out without an EUA. However, with COVID-19 cases expected to rapidly increase, those concerns are likely to come second to major concerns about under-testing.
Additionally, it’s not clear if any states will have the ability to ramp up testing independently, as New York has done, before a traditional diagnostic manufacturer with an EUA is able to ramp-up manufacturing of a nationally available diagnostic.
The NYSDOH system is likely not reproducible for other states. The NYSDOH boasts research-focused complex diagnostic capabilities through the Wadsworth Center, a public health laboratory that is accredited as a third party reviewer by the FDA for medical device clearances. Wadsworth administrates the NYSDOH’s Clinical Laboratory Evaluation Program, which oversees clinical laboratory licensure standards and requirements, which are either equal to or more stringent than those under CLIA.
Although New York is in a unique position to establish state-specific laboratory and diagnostic policy and dissemination, other states are likely to face challenges in doing so.