Regulatory considerations for EUA during the COVID-19 public health emergency for medical device manufacturers

This article examines regulatory considerations for emergency use authorizations for medical device manufacturers in response to the COVID-19 pandemic. The authors summarize the four phases of issuance as:  phase 1 ‒ in vitro diagnostic products; phase 2 ‒ personal protective equipment; phase 3 ‒ ventilators and components; and phase 4 ‒ other relevant medical devices. They emphasize the EUA is subject to statutory limits tied to the end of the public health emergency and suggest manufacturers evaluate whether a candidate product is a better fit for EUA or expanded use under enforcement discretion by the FDA.
 
Introduction
The first case of 2019 novel coronavirus (2019-nCoV) infection was confirmed in the US on 20 January 2020. By 30 January,  a total of 9,976 cases had been reported in at least 21 countries.¹ As a result of confirmed cases of COVID-19, the US secretary of Health & Human Services (HHS), Alex M. Azar II, determined on 31 January  that, pursuant to section 319 of the Public Health Service (PHS) Act, there was a nationwide public health emergency.² Subsequently, on 4 February, the secretary issued a separate determination and declaration that, pursuant to his authority under section 564(b)(1)(C) of the Federal Food, Drug, and Cosmetic (FD&C) Act, the public health emergency had significant potential to affect national security or the health and security of US citizens living abroad.³
 
The latter public health emergency declaration under section 564(b) of the FD&C Act enabled the FDA to issue an emergency use authorization (EUA). The measure authorizes the emergency use of an unapproved drug, an unapproved or uncleared device, or an unlicensed biological product; or an unapproved use of an approved drug, approved or cleared device, or licensed biological product, provided that other statutory requirements are met. This article will discuss EUAs for medical devices relevant in the pandemic response.
 
General FDA guidelines for EUA were finalized in the 2017 guidance document, Emergency Use Authorization of Medical Products and Related Authorities – Guidance for Industry and Other Stakeholders.⁴ In addition, several guidance documents, FAQs, and informational articles were published by the agency to provide information to manufacturers who might wish to pursue emergency use of their products.⁵
 
EUA issuance in response to the COVID-19 pandemic
Upon the HHS declaration of public health emergency under section 564(b) of the FD&C Act, FDA may issue an EUA if the agency determines that the following criteria for such issuance under section 564(c) of the Act are met:

• SARS-CoV-2 can cause a serious or life-threatening disease or condition, including severe respiratory illness, to humans infected by this virus.
• Based on the totality of scientific evidence available to FDA, it is reasonable to believe that the chemical, biological, radiological, and nuclear (CBRN) subject may be effective in its intended purpose in response to COVID-19, and that, when used under the conditions described in the authorization, the known and potential benefits of the CBRN outweigh the known and potential risks of such products.
• There is no adequate, approved, and available alternative to the emergency use of the subject CBRN for COVID-19‒related efforts.

 
On 4 February, same day as the HHS declaration, FDA issued its first EUA in response to the COVID-19 pandemic to the Centers for Disease Control and Prevention (CDC), authorizing use of the CDC 2019-nCoV Real-Time RT-PCR Diagnostic Panel for the presumptive qualitative detection of nucleic acid from 2019-nCoV specimens.⁶ It should be noted the agency’s focus on medical device product categories has evolved during the course of the pandemic response. At a high level, the HHS declaration and FDA’s EUA issuance can be summarized in four phases:

• Phase 1: In vitro diagnostic (IVD) products. FDA issued two EUAs for RT-PCR‒based COVID-19 IVD tests in February, first to the CDC, and then to the New York State Department of Public Health (Wadsworth Center NYSDOH). As of 11 May 2020, more than 60 EUAs had been issued to public and private labs, including IVD manufacturers, for the distribution of COVID-19 diagnostic tests. In addition, 25 clinical laboratories have been included in the EUA of molecular-based, laboratory-developed tests.⁷
• Phase 2: Personal protective equipment (PPE). Because of the shortage of hospital PPE supplies, FDA issued a number of EUAs for air-filtering respirators, approved by the National Institute for Occupational Safety and Health (NIOSH) and non-NIOSH bodies, for use in health care settings. Further, devices that assist in reuse of PPEs through decontamination and sterilization have also been considered in the PPE category for emergency authorizations.⁷
• Phase 3: Ventilators and components. Severe forms of SARS-CoV-2 infection may develop into acute respiratory distress syndrome.⁸ A large proportion of hospitalized COVID-19 patients experience shortness of breath and low oxygen saturation and require breathing support,⁸ including mechanical ventilation, extracorporeal membrane oxygenation, and extracorporeal blood purification (EBP) technology to assist in reducing pro-inflammatory cytokine levels. FDA has issued EUAs for ventilators and accessories, as well as other respiratory devices, such as EBP, renal replacement therapy, and diaphragmatic pacing stimulator systems, for weaning patients off ventilators.⁷
• Phase 4: Other relevant medical devices. Although the HHS declaration was specific to certain categories of medical devices in the early days of the pandemic response ‒ IVD COVID-19 tests, PPEs, and ventilators ‒ the FDA has issued EUAs to devices that may assist in reducing PPE usage and provide better care. For example, on 5 May, FDA issued an EUA for a remote ECG-monitoring device in response to complications related to treatment of COVID-19 with drugs that may cause life-threatening arrhythmia.⁹

 
Regulatory considerations for medical device manufacturers
It is important for medical device manufacturers pursuing an EUA in response to COVID-19‒related health care efforts to consider both the short- and long-term impacts of this regulatory statute. Working alongside the FDA, device companies may strive to help health care workers tackle the newfound challenges of treating patients with a novel infectious disease by expediting the availability of premarket products and technologies to health care professionals.

Regulatory professionals should carefully evaluate the FDA’s position on specific product types and plan EUA strategies accordingly. For product types for which an EUA has been issued, manufacturers may follow FDA instructions in the letter of authorization on how to add an authorized device to a list (e.g., a list of ventilators and breathing devices authorized under the ventilator EUA). For devices that do not meet the criteria for issuance of a device type EUA, the manufacturer may request an individual EUA per FDA’s guidance document, Emergency Use Authorization of Medical Products and Related Authorities.⁴
 
Pre-EUA discussions
FDA recommends having pre-EUA discussions with the agency about a potential EUA product. Such discussion could include the available safety and effectiveness data the manufacturer intends to use to demonstrate the device “may be effective” to prevent, diagnose, or treat COVID-19, or to mitigate conditions caused by an FDA-regulated product used to diagnose, treat, or prevent COVID-19. As with a premarket application, FDA uses a risk-benefit analysis to assess the totality of available scientific evidence to determine whether the proposed EUA product may be effective in its intended purpose.
 
Device manufacturers should understand that FDA will issue an EUA only if there are no adequate, approved, or available alternatives to the candidate product. This also means that, should an EUA be issued, the demand for the product may increase rapidly and outpace the availability of supply ramp-up. FDA may also consider potential demand when issuing a product type EUA to ensure that multiple manufacturers are able to supply the product type to meet the demand of the public health emergency.
 
Statutory limits
Regulatory professionals should also consider that the statutory limit of the EUA ends when the HHS declaration of public health emergency ends. Receiving a product type or individual EUA does not preclude the FDA’s requirement for premarket approval or clearance for the device to be legally marketed after the public health emergency. It is, therefore, imperative to fully consider the appropriate regulatory pathway for the EUA candidate product and any potential impact of the clinical evidence during the emergency use period. It may be advisable to plan and propose controlled clinical studies that could be conducted in parallel with an EUA to pursue premarket submissions during the COVID-19 emergency.
 
Finally, regulatory professionals may consider other pathways for enabling medical device uses in response to the COVID-19 pandemic. To date, FDA has issued 15 guidance documents on enforcement policy for specific device types in response to COVID-19, ranging from infusion pumps to telemedicine technologies. Manufacturers should evaluate whether a candidate product is a better fit for EUA or expanded use under enforcement discretion by the FDA.
 
Abbreviations
2019-nCoV, the 2019 novel coronavirus; CBRN, chemical, biological, radiological, and nuclear; CDC, Centers for Disease Control and Prevention; COVID-19, coronavirus disease 2019; EBP, extracorporeal blood purification; EUA, emergency use authorization; FDA, US Food and Drug Administration; FD&C, Food, Drug, and Cosmetic [Act]; HHS, [US Department of] Health and Human Services; IVD, in vitro diagnostic; NIOSH, National Institute for Occupational Safety and Health; PPE, personal protective equipment; PHS, Public Health Service [Act]; RT-PCR, reverse transcriptase polymerase chain reaction.
 
References

1. Holshue ML et al. First case of 2019 novel coronavirus in the United States. N Engl J Med. 2020;382(10):929-36.
2. US Department of Health and Human Services. Determination that a public health emergency exists. https://www.phe.gov/emergency/news/healthactions/phe/Pages/2019-nCoV.aspx. Published 31 January 2020. Accessed 16 June 2020.
3. Federal Register. A notice by the Health and Human Services Department on 02/07/2020. https://www.federalregister.gov/documents/2020/02/07/2020-02496/determination-of-public-health-emergency. Published 7 February 2020. Accessed 16 June 2020.
4. US Department of Health and Human Services. emergency use authorization of medical products and related authorities: Guidance for industry and other stakeholders. https://www.fda.gov/media/97321/download. Published January 2017. Accessed 15 June 2020.
5. US Food and Drug Administration. Emergency use authorization (EUA) information and list of all current EUAs. https://www.fda.gov/emergency-preparedness-and-response/mcm-legal-regulatory-and-policy-framework/emergency-use-authorization. Last updated 16 June 2020. Accessed 16 June 2020.
6. Hinton DM [US Food and Drug Administration]. Emergency use authorization of the CDC 2019-nCoV RT-PCR diagnostic panel [Letter]. https://www.fda.gov/media/134919/download. Published 15 March 2020. Accessed 15 June 2020.
7. US Food and Drug Administration. Emergency use authorizations for Medical Devices. https://www.fda.gov/medical-devices/emergency-use-authorizations-medical-devices/coronavirus-disease-2019-covid-19-emergency-use-authorizations-medical-devices. Last updated 17 June 2020. Accessed 18 June 2020.
8. Berlin DA, Gulick RM, Martinez FJ. Severe Covid-19. N Engl J Med. 2020 May 15. doi: 10.1056/NEJMcp2009575.
9. Hinton DM [US Food and Drug Administration]. Emergency use authorization of the PhysioGuard ECG-QT Analysis System. https://www.fda.gov/media/137693/download. Published 5 May 2020. Accessed 15 June 2020.

 
Additional reading
Centers for Disease Control and Prevention. Information for clinicians on investigational therapeutics for patients with COVID-19. https://www.cdc.gov/coronavirus/2019-ncov/hcp/therapeutic-options.html. Updated 25 April 2020. Accessed 18 June 2020.
 
About the authors
Ginny Hu, PhD, is the manager of regulatory affairs at Dexcom, where she leads a team to provide regulatory strategy and filing support for Dexcom’s new market initiatives. Hu has more than 8 years of experience in the medical device industry, having had roles in research and development, marketing, and regulatory affairs leadership. She has a PhD in neurobiology from the University of Wisconsin, Madison, and is the author of numerous peer-reviewed research publications. Hu can be contacted at ginny.hu@dexcom.com.
 
Neeta Sharma, MS, is the vice president of global regulatory affairs at Dexcom. She oversees all regulatory affairs activities for Dexcom’s continuous glucose sensing technology. Sharma has 15 years of strategic and executive regulatory leadership experience at leading medical device companies, including DJO, Philips, Edward Lifesciences, and Medtronic, and across multiple fields, such as diabetes management and cardiovascular and orthopedic devices. She graduated from the University of Southern California with a dual master’s degree in biomedical engineering and regulatory sciences. Sharma can be contacted at neeta.sharma@dexcom.com.
 
Citation Hu G, Sharma N. Regulatory considerations for EUA during the COVID-19 public health emergency for medical device manufacturers. June 2020. Regulatory Focus. Regulatory Affairs Professionals Society.