On January 31, 2020, the Secretary of Health and Human Services (HHS) declared a national emergency to combat the COVID-19 pandemic caused by the novel coronavirus SARS-CoV-2. As a result, the FDA is authorized to grant Emergency Use Authorizations (EUAs) for any medical countermeasure (MCM) that facilitates the diagnosis, prevention, or treatment of SARS-CoV-2. This blog post will help you to understand EUAs and determine whether your product may qualify, based on the 2017 FDA guidance titled Emergency Use Authorization of Medical Products and Related Authorities: Guidance for Industry and Other Stakeholder (Office of Counterterrorism and Emerging Threats).

What are EUAs, and why are they needed?

Prior to 2004, the only authorizations that allowed off-label use of MCMs or use of unapproved MCMs during an emergency were Investigational New Drug (IND) protocols or Investigational Device Exemptions (IDEs). For instance, an IND was used to provide methadone treatment to over 80,000 narcotic addicts in 1971. Similar mechanisms were used to provide pyridostigmine bromide and botulinum toxin to troops during the Gulf War in 1990 and 1991. However, INDs and IDEs are limited by their investigational nature and can be administratively burdensome, requiring Institutional Review Board (IRB) approval and oversight as well as informed consent.

Following the events of September 11, 2001, and the anthrax attacks that followed shortly thereafter, the Department of HHS realized the need for a provision that allowed for the rapid, large-scale use of unlicensed MCMs in a national emergency. It also realized that administrative requirements for investigational protocols, such as IRB approval and informed consent, might hinder the ability of health authorities to respond to an emergency. To address these issues, the EUA provision was incorporated into Section 564 of the Federal Food, Drug, and Cosmetic Act (FD&C) as part of the Project BioShield Act of 2004. It was amended by the Pandemic and All-Hazards Preparedness Reauthorization Act (PAHPRA) of 2013.

Simply put, an EUA enables the expedited authorization and use of an unapproved product or the off-label use of an already approved product in a declared emergency involving a chemical, biological, radiological, or nuclear (CBRN) agent. These MCMs can include drugs, biological products, and devices that have the potential “to diagnose, treat, or prevent serious or life-threatening diseases or conditions caused by a CBRN agent when there are no adequate, approved, and available alternatives.”

What is the process for issuing an EUA?

Issuing an EUA involves six steps:

1. Determination of a domestic, military, or public health emergency
2. Declaration of an emergency
3. Potential pre-EUA activities
4. Submission of an EUA request and review by the FDA
5. Issuance of the EUA or denial of the request
6. Termination of the EUA

First, the Department of Homeland Security, the Department of Defense, or the Department of HHS must determine the existence of a domestic, military, or public health emergency attributable to a CBRN agent. Second, the HHS Secretary must declare an emergency, which justifies the authorization (Section 564(b)(1)); this is referred to as an EUA declaration. A Sponsor can then engage in pre-EUA activities with the FDA and submit an EUA request, which the FDA will review. The FDA may then issue an EUA for unapproved products or the off-label use of approved products, provided statutory criteria are met. Finally, the end of the emergency will terminate the EUA—once the declaration expires, so does the authorization (typically in one year).

What are the criteria for EUA issuance?

A product may be granted an EUA if the following criteria are met:

1. Evidence of a serious or life-threatening condition: The CBRN agent must be capable of causing a serious or life-threatening disease or condition.
2. Evidence of effectiveness: There must be a reasonable belief, after consideration of all available scientific evidence, that the product will be effective for its intended use. The product can be used to diagnose, treat, mitigate, or prevent conditions caused by (a) the CBRN agent or (b) another FDA-licensed product (including those authorized under Section 564), used to diagnose, treat, or prevent a disease or condition caused by the CBRN agent.The guidance states that MCM products that may be considered for an EUA are those that “may be effective” to prevent, diagnose, or treat serious or life-threatening diseases caused by the CBRN agent. The phrase “may be effective” allows for a lower level of evidence than the efficacy standards typically required for FDA approvals.
3. Satisfactory risk-benefit analysis (evidence of safety): The FDA will weigh the known and potential benefits of the product against its known and potential risks. The Agency will consider all available scientific evidence to make a risk-benefit determination, considering the threat level posed by the CBRN agent.
4. Lack of alternatives: There is no adequate, approved, and available alternative to the product.

How can pre-EUA activities allow early input from the Agency?

The FDA strongly recommends early engagement between a Sponsor and the Agency about any potential EUA products, particularly those at an advanced stage of development. According to the FDA, these discussions and data submissions “facilitate more complete EUA requests and enhance FDA’s ability to review and ultimately grant the EUA.” These communications may occur prior to the submission of a formal EUA request (“pre-EUA”) or even before the HHS Secretary issues an EUA declaration. Generally, the FDA recommends that data submissions for pre-EUA activities follow recommendations for submitting pre-IND, IND, and device pre-submissions.

What is needed for a formal EUA request?

The FDA recommends that Sponsors include a well-organized summary of as much of the following as possible when applying for an EUA:

1. A description of the product and intended use
2. A description of the product’s FDA approval status
3. Efficacy and safety information, including data from any clinical studies and nonclinical in vivo and in vitro data: The threat posed and the nature of the product determine how comprehensive the evidence for EUA issuance needs to be. However, the requirements are typically less stringent than those for product approvals. The FDA considers a number of factors, including whether the product has already been approved for another indication and, if unapproved, its stage of development.
4. An analysis of the risks and benefits, including any measures taken to mitigate risk or optimize benefit, any contraindications, and any gaps in data
5. Information on the chemistry, manufacturing, and controls of your product: The request must demonstrate final product availability and the manufacturing sites’ surge capabilities. Notably, certain current Good Manufacturing Practice requirements may be waived for EUAs to accommodate emergency response needs.
6. Information on any available and approved alternatives to your product
7. A fact sheet providing information on dosing, contraindications, warnings, and adverse events for distribution to health care workers and authorized dispensers of your product

Formal EUA requests are typically submitted only after the HHS Secretary issues an EUA declaration. However, EUAs may also be granted prior to an emergency to enable Federal and local governments to plan for product use. In those cases, the HHS Secretary must formally determine that a significant potential for emergency or a material threat occur.

What timelines should you expect for the review process?

In a critical ongoing or imminent situation, the FDA aims to review EUAs within hours or days. For instance, the FDA issued EUAs for COVID-19 diagnostic tests to Roche, Thermo Fisher Scientific, and Abbott Laboratories within 24 hours of their request submissions.

However, the timeline for FDA action on an EUA request depends on several considerations, such as the regulatory history and profile of the product, the level of pre-EUA communication with the FDA, and the seriousness of the emergency.

The FDA has also established priorities for its review of EUA requests:

• The circumstances of the emergency
• The public health need and urgency of treatment
• The amount of safety and efficacy evidence
• The risks and benefits of the product
• The availability of the product (manufacturing capabilities and stockpiles)
• The availability of alternative MCMs

It is important to realize that an EUA does not signify FDA approval, licensure, or clearance and is not an accepted endpoint for product development. In general, an EUA will remain in effect only for the duration of the EUA declaration under which it was issued. Sponsors should continue to develop their product, working towards FDA approval after the termination of the emergency. In fact, the FDA encourages Sponsors to design and conduct appropriately controlled clinical trials during the emergency response.

Premier Consulting is actively supporting clients as they navigate the EUA process with the FDA. Sponsors who are developing MCMs for the diagnosis, prevention, or treatment of COVID-19 can reach out to Premier Consulting’s team for support with their EUA request here.

---