SPRING 2020, THE EVIDENCE FORUM, WHITE PAPER
|Kusuma Mallikaarjun, PhD
Strategic Clinical Regulatory Consulting
Evidera, a PPD business
Brief Overview of EUA Regulatory Path
The Emergency Use Authorization (EUA) is a statutory authority which allows the US Food and Drug Administration (FDA) to help strengthen the nation’s public health protections against chemical, biologic, radiological, or nuclear (CBRN) threats by facilitating the availability and use of medical countermeasures (MCMs – i.e., drugs, biologics, vaccines, diagnostic tests, etc.) during public health emergencies.1 The EUA allows for the unapproved use (i.e., off label use) of an approved medical product (drug, biologic, vaccine, or device) or the use of an investigational/unapproved product in order to diagnose, treat, or prevent serious or life-threatening diseases or conditions caused by CBRN threat agents when there are no adequate, approved, and available alternatives.
The EUA for a medical product is issued by the Commissioner of the FDA, following the declaration by the Secretary of Health and Human Services (HHS) of an emergency or threat justifying the issuance of such an EUA. The process requires a Pre-EUA Consult Meeting (following the submission of an adequate meeting package), followed by the submission of a formal EUA Request to the FDA. The recommended content of the Pre-EUA Consult Meeting package and the EUA Request are defined in the FDA’s Guidance for Industry and Other Stakeholders: Emergency Use Authorization of Medical Products and Related Authorities.2 The FDA processes Pre-EUA Consults and EUAs in as expedited a manner as feasible, with EUA applications being prioritized based on a multitude of factors, such as:
- Seriousness of the public health emergency
- Urgency of the need for medical countermeasure interventions
- Plausible mechanism of action of the product
- Extent of proof of activity/safety
- Stage of development
However, there are no mandated timelines in place for this process. A successful Pre-EUA Consult will have the potential to lead to the issuance of an EUA within hours to days, once the formal EUA Request is submitted.
The decision to approve/issue the requested EUA for a medical product will depend on multiple factors, including answers to key questions such as:
- Do the data show that the product “may be effective” in achieving the intended use to diagnose, treat, or prevent the serious or life-threatening disease or condition?
- Do the known and potential benefits of the product outweigh the known and potential risks, looking at the totality of the scientific evidence? Such evidence may include (but is not limited to): results of domestic and foreign clinical trials, in vivo efficacy data from animal models, and in vitro data.
- Would other regulatory paths, such as developing a clinical study protocol under an existing Investigational New Drug or Device Exemption (IND/IDE) or granting access to the investigational product under an Expanded Access IND/IDE authority, be more appropriate?
The FDA can impose conditions and requirements for authorized EUAs pertaining to sourcing of the product, fact sheets for healthcare workers and patients, adverse event monitoring/reporting, etc.
Authorized EUAs generally remain in effect from the date of the authorization to the date the emergency declaration by the HHS Secretary is lifted. The state of the declared emergency can periodically be reviewed by the FDA, who can revise or revoke an EUA based on such review.
Status of EUAs for the COVID-19 Pandemic
The Secretary of HHS declared a public health emergency for the COVID-19 pandemic on February 4, 2020, effectively authorizing the FDA to issue EUAs for unapproved devices, drugs, and biologics, or for unapproved uses of otherwise approved products, that may be effective medical countermeasures to combat the COVID-19 pandemic. Subsequently, the FDA has issued a large number of device EUAs, with the first one being issued on the same day as the declaration of the public health emergency by HHS. Device EUA statistics as released by the FDA on May 1, 2020, are as follows:
- 54 device EUAs issued to test kit manufacturers and laboratories
- 23 device EUAs issued for high complexity, molecular-based laboratory developed tests (LDTs)
- 9 device EUAs issued for personal protective equipment (PPE)
- 12 Device EUAs issued for ventilators, re-processing/sterilization units for PPEs and other miscellaneous devices to be used in the COVID-19 pandemic
- 380+ test developers who have interacted with the FDA stated that they will be submitting EUA requests for tests that detect the virus
- 235+ laboratories have notified the FDA that they have begun testing under the policies set forth in the Policy Guidance for Diagnostic Tests for Coronavirus Disease-2019 during the Public Health Emergency3
The FDA has issued two drug EUAs to date. The first EUA covered hydroxychloroquine phosphate and chloroquine sulfate, both of which are to be supplied from the Strategic National Stockpile (SNS) for distribution and use for certain hospitalized patients with COVID-19. These drugs will be distributed from the SNS to states for doctors to prescribe to adolescent and adult patients hospitalized with COVID-19, as appropriate, when a clinical trial is not available or feasible. The second EUA was issued on May 1, 2020, for Gilead’s investigational, antiviral drug remdesivir, to be used for the treatment of suspected or laboratory-confirmed COVID-19 in adults and children hospitalized with severe disease. Under this EUA, remdesivir is to be distributed in the US and administered intravenously by healthcare providers, as appropriate. Severe disease is defined as patients with low blood oxygen levels or needing oxygen therapy or more intensive breathing support such as a mechanical ventilator. This EUA has been issued based on the data released by the National Institute of Allergy and Infectious Diseases (NIAID) on April 29, 2020, from NIAID’s Adaptive COVID-19 Treatment Trial (ACTT), which is described as:
- A randomized, controlled trial evaluating remdesivir compared with placebo in 1063 patients
- Involving 68 sites (47 in the US and 21 in countries within Europe and Asia)
- Including patients with advanced COVID-19 who exhibited evidence of lung involvement, such as:
- Rattling sounds when breathing with a need for supplemental oxygen, or
- Abnormal chest X-rays, or
- Illness requiring mechanical ventilation.
The NIAID press release stated that the patients who received remdesivir had a 31% faster time to recovery than those who received placebo (p<0.001). Specifically, the median time to recovery was 11 days for patients treated with remdesivir compared with 15 days for those who received placebo. Results also suggested a survival benefit, with a mortality rate of 8.0% for the group receiving remdesivir versus 11.6% for the placebo group (p=0.059). It is important to note that no EUAs have been issued to-date by the FDA for biologics or vaccines. This does not imply that no such requests are being submitted or are under review.
Recommended Regulatory Strategy
Many pharmaceutical companies are examining whether they have assets that could be of use to combat COVID-19, and if so, what are the next steps in moving forward with EUA designation. The key elements companies should consider for potential COVID-19 programs include:
- Evaluate your approved and/or investigational assets which may be useful for the treatment of COVID-19 for EUA path feasibility
- Engage with the FDA via the Pre-EUA Consult or Pre-IND Meeting mechanism as soon as possible, depending on the outcome of EUA feasibility assessment
- Engage relevant external consultant experts to assist with the EUA and/or the IND path for your COVID-19 program
- Submit either an EUA Request or an IND in an expedited manner to the FDA
The issuance of an EUA serves to aid the public with immediate and urgent drugs and devices to combat health emergencies. Therefore, the process to apply for this designation should be undertaken swiftly to ensure relevance to the immediate need. Seeking guidance from experts who understand the intricacies of the process and can provide counsel on the best path forward can save a great deal of time in preparing the submission. EUAs for approved products can be issued within days if the need is great, especially since product information is already available in existing approvals or submissions. It is important to note that products receiving EUA designation do not automatically receive permanent approval for the emergency use, and normal approval processes must be continued for long-term use once the EUA has expired. However, products seeking approval through normal channels can offer hope to many people during a crisis, and exploring the issuance of an EUA is something to consider and act upon expeditiously to include your product in the list of those making a difference in fighting COVID-19.
- US Food and Drug Administration. Emergency Use Authorization. Available at: https://www.fda.gov/emergency-preparedness-and-response/mcm-legal-regulatory-and-policy-framework/emergency-use-authorization. Accessed April 25, 2020.
- US Food and Drug Administration. Guidance for Industry and Other Stakeholders: Emergency Use Authorization of Medical Products and Related Authorities. 2017. Available at: https://www.fda.gov/media/97321/download. Accessed April 26, 2020.
- US Food and Drug Administration. Policy for Diagnostic Test for Coronavirus Disease-2019 during the Public Health Emergency. March 2020. Available at: https://www.fda. gov/regulatory-information/search-fda-guidance-documents/policy-diagnostic-tests-coronavirus-disease-2019-during-public-health-emergency. Accessed April 26, 2020.