As the number of cases of COVID-19 (coronavirus) grows in the U.S. and around the world, so too have questions regarding the potential impact of the pandemic on the medical device industry. At this time, projections of a deleterious impact on the U.S. health care system and supply of medical devices are becoming more of a reality. This is the first of two client alerts, which are developed to provide medical device manufacturers with resources and information regarding how to address an evolving pandemic in real time. Part I of this series covers the regulatory and business options available for companies to bring new (unapproved) products to market that are essential to address the public health need under Emergency Use Authorizations (EUA). Part II covers how medical device companies can plan for shortages and other challenges to their supply chains for both essential and non-essential devices.
Coronavirus public health emergency and medical devices
The U.S. Centers for Disease Control (CDC) has stated:
Widespread transmission of COVID-19 would translate into large numbers of people needing medical care at the same time. Schools, childcare centers, workplaces, and other places for mass gatherings may experience more absenteeism. Public health and healthcare systems may become overloaded, with elevated rates of hospitalizations and deaths. Other critical infrastructure, such as law enforcement, emergency medical services, and transportation industry may also be affected. Health care providers and hospitals may be overwhelmed. (Current as of March 5, 2020.)
U.S. authorities at the highest levels are already expressing a need for the development and release of new diagnostic tests for COVID-19 detection. As federal agencies have already declared coronavirus to be a public health emergency, there are pathways available for new diagnostic tests and essential medical devices to receive an expedited review by the U.S. Food and Drug Administration (FDA) for release and use as the pandemic spreads across the country.
Should the CDC projections come to fruition, the U.S. also could see a shortage in the supply of medical devices for multiple reasons. First, there is a strong likelihood that the demand for such products as facemasks, gowns, drapes, IV tubing and bags and other personal protective equipment will be in high demand and eventually in short supply. At its worst, due to the significance of respiratory symptoms (coughing, shortness of breath), there could be a shortage of critical devices such as respirators or oxygen delivery systems. There also could be shortages of other life sustaining/life supporting products necessary to maintain vital organ functions or for the delivery of drugs or fluids to sick patients, such as infusion pumps, IVs, or catheters. In short, due to overburdened health care systems, the supply of medical devices may well not be able to meet an overwhelming demand.
Under normal circumstances, the medical device industry would be challenged to meet the demand for products required to treat a pandemic. These challenges may well be exacerbated by challenges in the production and supply chain due to mandated shut downs of manufacturing facilities, or quarantine of production workers from a shuttered facility. Even if a production facility is open, the supply chain could be disrupted if downstream suppliers or critical parts, components, or raw materials are shut down or strapped for resources. These issues could lead to “critical” shortages of even the most basic class I medical devices, let alone class III life sustaining and life supporting devices. Supply chain issues, delays due to import controls and other challenges to production and distribution of medical devices are covered in Part II of this series.
Medical counter measures and emergency use authorizations for critical products
Declaration of public health emergency and FDA response
On February 4, 2020, Health and Human Services Secretary (HHS) Alex Azar declared a public health emergency based on the novel coronavirus (2019-nCoV, formally named SARS-CoV-2), the causative virus for COVID-19 disease. Since this date, there have been near daily communications from FDA regarding the Agency’s efforts and cooperation with other governmental departments and agencies regarding the government’s response to the situation. The HHS Secretary further declared that circumstances existed for justifying the authorization of emergency use of in vitro diagnostics for detection and/or diagnosis of the virus that causes COVID-19. Consequently, the FDA issued an “immediately in effect guidance” to swiftly expand testing for the novel coronavirus, also granting an Emergency Use Authorization (EUA) to two public health laboratories in New York for a diagnostic test to identify COVID-19. Additionally, at the request of the CDC, FDA has also released an EUA to allow for using respirators approved by the National Institute for Occupational Safety and Health but not reviewed or cleared by FDA for use in healthcare settings.
FDA has several tools at its disposal to address responses to public health emergencies to facilitate the introduction of medical counter measures (MCMs), including medical devices, drugs, and biological products, as follows:
- Issuing EUAs to allow for an MCM to be used in an emergency to diagnose, treat, or prevent serious or lifethreatening diseases or conditions caused by a chemical, biological, radiological, or nuclear (CBRN) agent, or by a product used to diagnose, treat, or prevent such diseases or conditions, when available data meet specified criteria to support such uses and there are no adequate, approved, and available alternatives.
- Extend the expiration date of an eligible FDA approved MCM stockpiled for use in a CBRN emergency, and establish appropriate conditions relating to such extensions, such as appropriate storage, sampling, and labeling;
- Waive otherwise applicable current good manufacturing practice requirements (e.g., storage or handling) to accommodate emergency response needs;
- Allow emergency dispensing of MCMs during an actual CBRN emergency event without requiring an individual prescription, or all of the information otherwise required, for each recipient of the MCM;
- Permit the Centers for Disease Control and Prevention to create and issue “emergency use instructions” concerning the FDAapproved conditions of use for eligible products;
- Ability to waive Risk Evaluation and Mitigation Strategy (REMS) requirements for drug products for CBRN emergencies; and
- Permission for Federal, State, and local governments to preposition (e.g., stockpile, forwarddeploy) MCMs in anticipation of FDA approval or clearance, authorization of an investigational use, or the issuance of an EUA.
Regarding the implementation of EUAs, FDA published a guidance document in January in 2017 entitled “Emergency Use Authorization of Medical Products and Related Authorities.” This guidance outlines the processes applicable to the authorization of the emergency use of medical products under Sections 564, 564A, and 564B of the Federal Food, Drug, and Cosmetic Act (FD&C Act), as amended by the Pandemic and All-Hazards Preparedness Reauthorization Act of 2013 (PAHPRA) and its implications. The EUA authority under Section 564 of the FD&C Act allows FDA to facilitate availability of MCMs, which could be new medical product products and unapproved uses of existing products, needed to prepare for and respond to public health, military, and domestic emergencies involving chemical, biological, radiological, and nuclear (CBRN) agents, including infectious disease threats. This may include issuance during an emergency to support a rapid public health response as well as when significant potential of an emergency exists to support preparedness planning.
FDA criteria for evaluating and granting EUAs
As the EUA process is a deviation from the standard medical device clearance or approval process, authorization of the use of a new unapproved device, or an approved device for an unapproved use, must meet defined criteria to permit access to and use of the device.
Initially, following a declaration by the HHS Secretary of a public health emergency, FDA may authorize the introduction of a medical product not approved, cleared, or licensed under sections 505, 510(k), and 515 of the FD&C Act or section 351 of the PHS Act into interstate commerce when the product is intended for use during an actual or potential emergency.
To issue an EUA, the product referenced in the EUA declaration must meet the following criteria:
- Serious or life-threatening disease or condition. The CBRN agent(s) referenced in the HHS Secretary’s EUA declaration must be capable of causing a serious or life-threatening disease or condition;
- May be effective. Medical products will be considered for an EUA if they “may be effective” to prevent, diagnose, or treat serious or life-threatening diseases or conditions that can be caused by a CBRN agent(s) identified in the HHS Secretary’s declaration of emergency, as well as those that may be effective in mitigating a disease or condition caused by an FDA-regulated product used to diagnose, treat, or prevent a disease or condition caused by a CBRN agent. Note that this is a far lower standard that the “effectiveness” standard FDA uses for product approvals outside of the EUA context;
- Risk/Benefit analysis. The Commissioner must determine that the known and potential benefits of the product, when used to diagnose, prevent, or treat the identified disease or condition, outweigh the known and potential risks of the product. This assessment is based on the totality of the scientific evidence, across multiple data sources, and considering the quality and quantity of evidence and the current state of scientific knowledge; and,
- No adequate alternatives. There must be no adequate, approved, and available alternative to the candidate product for diagnosing, preventing, or treating the disease or condition. The potential alternative product may be considered “unavailable” if there are insufficient supplies of the approved alternative to fully meet the emergency need.
Process of gaining approval for EUA products
FDA strongly encourages interaction with the appropriate agency Center about potential EUA products before submitting a formal request for an EUA. The process is akin to a pre-submission or Type B meeting request where the pre-EUA submission would summarize relevant information regarding the product, based on the criteria outlined above. However, given the emergency need, the process should be expected to move much more quickly. Assuming FDA is in general agreement with the pre-EUA process, the company would then proceed to requesting the EUA designation for the product.
FDA recommends providing the following information in any EUA request:
- A description of the product and its intended use (including how the product is anticipated to be used and by which population)
- A description of the product’s FDA approval status
- The need for the product, including identification of any approved alternative product(s) and their availability and adequacy for proposed use, and the unmet need the EUA would address
- Available safety and effectiveness information
- A discussion of risks and benefits
- Manufacturing information, including a list of each site where the product is or would be manufactured and current CGMP status of the manufacturing site(s). Importantly, FDA has indicated that in some circumstances, EUA products may receive waivers from requirements to comply with CGMPs (including the Quality System Regulation), as well as prescription requirements and Risk Evaluation and Mitigation Strategies (REMS).
- Quantity of finished product on hand and surge capabilities at the manufacturing site
- Labeling and a discussion of the level of information/guidance to be provided to health care professionals
- If seeking extension of labeled expiration date, any relevant information to support such an extension;
- Relevant data to support safety and effectiveness, particularly for the proposed use with the underlying disease or condition
FDA prioritizes the review of EUA requests based on a variety of factors, including the public health need for the product; the data to support use of the product; the seriousness and incidence of the clinical disease or condition; and the availability of the product. In urgent situations, FDA can issue EUAs in days, or even hours, when circumstances warrant. In some circumstances FDA may place conditions on the authorization of a EUA, such as labeling requirements, distribution requirements, and monitoring requirements for adverse events.
How companies can use this information
For those medical device manufacturers that have products either under development or currently manufactured that could have a direct impact on populations impacted by Coronavirus, ongoing communication with FDA would help raise awareness in case a EUA may be appropriate. In particular, those manufacturers that may have a product in advanced stages of development that could have a meaningful impact as relates to the ongoing Coronavirus concerns may want to consider the timeline and capacity for potential distribution and whether or not it may make sense to reach out to FDA and begin pre-EUA discussions. As FDA notes in the guidance, the agency has the ability to issue EUAs both during an emergency to support a rapid public health response as well as when significant potential of an emergency exists, to support preparedness planning. Thus, providing FDA with information about potential concerns that could arise as a result of coronavirus could help FDA obtain the relevant information to coordinate with HHS and have an emergency declaration issued that could directly impact a manufacturers’ ability to submit an EUA and get EUA status for a product.
For companies seeking to utilize the EUA pathway, pre-EUA communications should be sent as e-mails as follows:
- For an in vitro diagnostic device for which a current EUA declaration exists – CDRH-EUA-Templates@fda.hhs.gov
- For an in vitro diagnostic device for which there is not a current EUA declaration – Device@fda.hhs.gov and the Branch Chief for the review branch for the type of test (Microbiology, Virology, Molecular Testing, Chemistry, etc.)
- For any non-diagnostic medical device for which a current EUA declaration exists – CDRH-NonDiagnosticEUA-Templates@fda.hhs.gov
- For any non-diagnostic medical device - Device@fda.hhs.gov
- For any therapeutic (non-device ) product - EUA.OCET@fda.hhs.gov
FDA responds to pre-EUA contacts quickly, sometimes within the same day up to what is typically no more than 1 or 2 days. For Coronavirus concerns, we understand that FDA has responded to pre-EUA requests in as little as a few hours.
Once agreement is obtained with FDA, the EUA request should be submitted to the Center/Division/Branch with whom the pre-EUA discussions have occurred. FDA also is requiring the submission of a CDRH cover sheet (Form FDA 3514) to accompany any such EUA submissions, where the type of submission identified in Section A of the form is identified as “Other.” FDA is waiving the requirement to submit to the Document Mail Center and is allowing submissions to be sent directly to personnel at FDA via email. Specific instruction for recipients will be provided by FDA depending on the product type.
The content of this article is intended to provide a general guide to the subject matter. Specialist advice should be sought about your specific circumstances.