Section 564 of the Federal Food, Drug, and Cosmetics Act: Emergency Use Authorization

March 30, 2020

American hospitals, pharmacies, and other healthcare facilities are facing critical shortages brought on by the SARS-CoV-2 pandemic. Although manufacturers and distributors indicate that the supply chain is strong, disruptions have caused drug, device, and equipment shortages. One mechanism designed to alleviate shortages during times of emergency is Emergency Use Authorization (EUA) under Section 564 of the Federal Food, Drug, and Cosmetic Act (FDCA), as amended or added by the Pandemic and All-Hazards Preparedness Reauthorization Act of 2013 (PAHPRA). EUAs permit the Commissioner of the U.S. Food and Drug Administration (FDA) to authorize the emergency use of unapproved medical products or the unapproved use of an approved medical product. The Commissioner is afforded broad discretion after the Secretary of Health and Human Services has declared an emergency or threat justifying authorization of emergency use.¹

Criteria for Issuing an Emergency Use Authorization

FDA may issue an EUA after concluding that four statutory criteria² are met:

1. The agent referred to in the declaration can cause serious or life-threatening disease or condition.

   Among other agencies and organizations, the CDC has stated that the SARS-CoV-2 pandemic poses “a serious public health risk.” It is well-documented by the World Health Organization that this disease is life-threatening and highly infectious.

2. Evidence of effectiveness based on the totality of scientific evidence available.

   Typically, a medical product, also known as a “medical countermeasure,” must demonstrate “effectiveness” under FDA standards for approval. However, EUAs offer the lower “may be effective” standard. FDA assesses potential effectiveness on a case-by-case basis, relying on the totality of scientific evidence available, to determine if the product may be effective for its specified use. Scientific evidence may include domestic and foreign clinical trials, in vivo efficacy data from animal models, and in vitro data.

3. The known potential benefits outweigh the known potential risks.

   FDA weighs the known benefits and known risks associated with the product being considered. Furthermore, FDA takes into account the material threat posed by chemical, biological, radioactive, or nuclear (“CBRN”) agent identified in the emergency declaration.

4. There is no adequate, approved, and available alternative.

   Among other reasons, an alternative may be considered unavailable if there are insufficient supplies of the approved alternative to fully meet the emergent need or if the agent is or may become resistant to approved and available alternative products. 

Requesting an Emergency Use Authorization

FDA explains that prior to applying for an EUA, there are “pre-EUA activities and submissions.” First, the Agency encourages manufacturers to contact the appropriate FDA Center before submitting a formal request for an EUA. In doing so, FDA and the industry can more quickly navigate a potential emergency that unexpectedly transitions to a response effort. These discussions allow FDA to guide potential EUA applicants through the process. Although a pre-EUA activity is completely separate from an investigational new drug application or device pre-submission, FDA recommends that data submitted by applicants follow the same guidelines.

FDA recommends that a request for an EUA include “a well-organized summary of the available scientific evidence regarding the product’s safety and effectiveness, risks (including an adverse event profile) and benefits, and any available, approved alternatives to the product.” Useful information includes a description of the product and its intended use, the product’s current FDA approval status, the unmet need the product would fulfill, and safety and efficacy data including the threat posed by the CBRN agent. Furthermore, manufacturers are encouraged to describe their surge capabilities, the quantity of the product currently on hand, and the state of their manufacturing facilities (e.g. whether the facilities are cGMP certified).

While FDA looks at the totality of all the circumstances for an EUA, two areas are particularly emphasized by the Agency:

1. Safety information

   FDA considers a number of factors when analyzing safety information. Understanding that data may be limited and time may be critical, FDA “interpret[s] safety information in light of the seriousness of the clinical condition, alternative diagnostics, prophylaxis, or alternative therapies (if any), and the specific circumstances of the emergency or threat of emergency.”

   For unapproved uses of approved products, FDA first determines how similar the two indications are with respect to dose, duration, route of administration, mechanism of action, and patient population. If the two are similar, FDA encourages the manufacturer to reference the approved application. If the two are different, FDA encourages the manufacturer, to the extent possible, to provide in vitro studies, animal toxicology studies, and human clinical data. For unapproved products, FDA acknowledges that available data will differ widely. The Agency encourages manufacturers to provide preclinical data along with human safety information from clinical trials or individual patient experiences, as well as any other available information.

2. Effectiveness information

   FDA acknowledges that many times, manufacturers do not have comprehensive effectiveness data for EUA candidate products. The Agency instead looks at all available data as well as the circumstances of the CBRN emergency and makes a case-by-case determination. Manufacturers are encouraged to submit information about the product’s mechanism of action, preclinical testing data, animal studies, and human studies. For drug products, in vitro evidence regarding toxicity as well as pharmacokinetic, pharmacodynamics, and immunogenicity data is also highly relevant.

Limitations on Liability

Section 564 of the FDCA does not confer explicit liability protection for manufacturers involved in EUAs. However, the Public Readiness and Emergency Preparedness Act (“PREP Act”) was enacted in 2005 and serves to limit tort liability for EUA medical products (see more here). More specifically, the PREP Act authorizes the HHS Secretary to issue a declaration (called a PREP Act declaration) that provides immunity (except for willful misconduct) for claims related to administration or use of countermeasures against CBRN agents to entities and individuals involved in the development, manufacture, testing, distribution, administration, and use of such countermeasures. Plaintiffs are not left entirely without recourse—those who sustain serious injury or death as a direct result of the administration or use of a Covered Countermeasure may be eligible for benefits under the Countermeasures Injury Compensation Program (CICP).

Conclusion

Manufacturers seeking an Emergency Use Authorization are encouraged to reach out directly to FDA as early as possible. Manufacturers are also encouraged to collect as much data as possible to FDA to expedite their ability to obtain an EUA. To date, FDA has granted several EUAs to manufacturers to produce diagnostic testing kits. Additionally, the Agency has issued a letter to manufacturers seeking EUAs for ventilators, anesthesia gas machines modified for use as ventilators, and positive pressure breathing devices modified for use as ventilators, ventilator tubing connectors, and ventilator accessories. The Agency has issued letters to manufacturers seeking EUAs for NIOSH-approved disposable respirators as well as non-NIOSH-approved disposable respirators. We anticipate that FDA will issue further EUAs in the coming weeks and months as the COVID-19 pandemic worsens.

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