LIFE after the EUA

By Alan Schwartz

YES, there will be a day when the US EUA, Emergency Use Authorization Act, will be lifted, the medical device industry goes back to reality and the FDA regains control of the medical approval process with the “a REAL” device review in place.

In my almost 5 decades of FDA experience, this is the first time I have ever seen an EUA put into practice — but, in real terms, what is an “EUA,” and why it is used so infrequently?

Because of the CORONA Virus (COVID-19) which became a global pandemic, the world supply of PPE devices (personal protection equipment) was thrown into a turmoil.

Under Section 564 of the Federal Food, Drug, and Cosmetic Act (FD&C Act), revised as the Pandemic and All-Hazards Preparedness Reauthorization Act of 2013 (PAHPRA), the FDA Commissioner is allowed to permit unapproved medical products, or unapproved uses of approved medical products, to be used in an emergency.  Such use of these products include diagnosis, treatment, or prevention of serious and/or life-threatening diseases or conditions caused by CBRN (chemical, biological, radiological, and nuclear) threat agents when there are no adequate, approved, and available alternatives.

The PAHPRA clarifies and enhances the FDA’s authority to support emergency preparedness and response and fosters the development and availability of medical products for use in the emergencies. These medical products, also referred to as “medical countermeasures” or “MCMs,” include drugs (e.g., antivirals and antidotes), biological products (e.g., vaccines, blood products, and biological therapeutics), and devices (e.g., in vitro diagnostics and personal protective equipment).

Before the FDA may issue a EUA, the HHS Secretary must declare circumstances that exist to justify the authorization of the EUA and include the following actions:

1. A determination by the Secretary of Homeland Security that there is a domestic emergency, or a significant potential for a domestic emergency, involving a heightened risk of attack with a CBRN agent(s);
2. A determination by the Secretary of HHS that there is a public health emergency, or a significant potential for a public health emergency, that affects, or has a significant potential to affect the national security or the health and security of United States citizens living abroad, and that involves a CBRN agent or agents, or a disease or condition that may be attributable to such agent(s);

After the Secretary of HHS issues an EUA declaration, based on one of these two determinations, and after consulting (to the extent feasible and appropriate given the applicable circumstances) with the Assistant Secretary for Preparedness and Response (ASPR), the Director of the National Institutes of Health (NIH), and the Director of CDC, the Commissioner may authorize the emergency use of an unapproved product or an unapproved use of an approved product, provided that other statutory criteria are met.

EUA candidate products include medical products and uses that are not approved, cleared, or licensed under sections 505, 510(k), and 515 of the FD&C Act or section 351 of the PHS Act.

After the requisite determination and declaration have been issued subsequent to feasible and appropriate consultations, FDA may issue a EUA only if the FDA concludes that the following four statutory criteria for issuance have been met.  If the product does not meet the statutory criteria for issuance or is not otherwise an appropriate candidate, an alternative regulatory mechanism (i.e., access under an IND or IDE, which can include expanded access protocols) may be an appropriate means to provide patients access to an unapproved use of a product in a CBRN emergency.

1. Serious or Life-Threatening Disease or Condition

For the FDA to issue a EUA, the CBRN agent(s) referred to in the HHS Secretary’s EUA declaration must be capable of causing a serious or life-threatening disease or condition.

1. Evidence of Effectiveness

The “may be effective” standard for EUAs provides for a lower level of evidence than the “effectiveness” standard that the FDA uses for product approvals. The FDA intends to assess the potential effectiveness of a possible EUA product on a case-by-case basis using a risk-benefit analysis, as explained below.  If, based on the totality of the scientific evidence available, it is reasonable to believe that the product may be effective for the specified use, the FDA may authorize its emergency use, provided that other statutory criteria for issuing a EUA also are met.

1. Risk-Benefit Analysis

In determining whether the known and potential benefits of the product outweigh the known and potential risks, the FDA intends to look at the totality of the scientific evidence to make an overall risk-benefit determination.  Such evidence, which could arise from a variety of sources, 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, available for FDA consideration.  The FDA will also assess the quality and quantity of the available evidence, given the current state of scientific knowledge.

1. No Alternatives

For the FDA to issue a EUA, there must be no adequate, approved, and available alternative to the candidate product for diagnosing, preventing, or treating the disease or condition.  A potential alternative product may be considered “unavailable” if there are insufficient supplies of the approved alternative to fully meet the emergency need.  A potential alternative product may be considered “inadequate” if, for example, there are contraindicating data for special circumstances or populations (e.g., children, immunocompromised individuals, or individuals with a drug allergy), if a dosage form of an approved product is inappropriate for use in a special population (e.g., a tablet for individuals who cannot swallow pills), or if the agent is or may be resistant to approved and available alternative products.

So, with the EUA in effect, what will happen when there is a termination of this EUA Declaration?

When a EUA declaration is terminated, then any EUA(s) issued based on that declaration will no longer remain in effect. The HHS Secretary’s EUA declaration will terminate earlier if:

(1) a determination by the HHS Secretary that the circumstances that precipitated the declaration have ceased (after consultation as appropriate with the Secretary of Homeland Security or the Secretary of Defense), or

(2) a change in the approval status of the product such that the authorized use(s) of the product are no longer unapproved (section 564(b)(2)).  For example, a EUA issued to allow an unapproved use of an approved product may no longer be needed if that product is later approved by FDA for the use permitted by the EUA.

Before an EUA declaration terminates, the Secretary of HHS must provide advance notice that is sufficient to allow for the disposition of an unapproved product, and of any labeling or other information provided related to an unapproved use of an approved product (section 564(b)(3)).

When this pandemic hit our shores, the United States was basically unprepared for what we were going to be needing to support the medical community let alone supplying the general population with PPE products. There was going to be a tremendous immediate need for medical devices such as PPE surgical masks, gloves, gowns, eye shields, as well as for ventilators. Besides the PPEs, the country was going to need IVD tests for the COVID-19 active infection and for the antibody tests. The FDA is also responsible for the approval for any drugs for the treatment of and prevention (vaccine) of this virus.

When the pandemic erupted in US, there was a surge for need of facial masks. Because of a major shortage of masks, one of the FDA’s first EUAs was for the NIOSH certified mask for medical use (this caused a tremendous amount of problems).

Basically, the National Institute of Occupational Safety and Health (NIOSH), had certified one mask, the 3M NIOSH mask. It was used by the construction industry for protecting workers from particles and dust during demolition and other operations. The FDA does mention that NIOSH certified masks are exempted from the FDA 510(k) and could be used as a medical surgical mask (21CFR878.4040).

This caused a tremendous amount of chaos  for the FDA and for the NIOSH offices. NIOSH was never set up to be a certification body like the FDA. When the FDA opened the window for NIOSH masks not requiring FDA approval to be sold as medical masks, everyone wanted to obtain NIOSH certification for their masks, including mask manufacturing companies from China, Korea, Vietnam, etc.

Because of this, NIOSH was over inundated with requests for certification (which require on-site inspections) to the extent that NIOSH stopped taking applications from foreign entities altogether.

China had a Chinese NIOSH mask as did Korea. The FDA had to outline how the EUA for masks would work and how to get on the CDC list, later called, the Appendix A.  This was  becoming increasingly complicated and the private labs conducting the testing were getting inundated with orders for testing, which added months to the backlog. The rush was on to be able to export masks to the US. There were rumors the US medical industry would need not millions of masks, but billions. The US Government, state governments as well as local governments were competing with the medical community to get masks for the present needs and to stockpile for the future.

Eventually, the FDA began testing the masks from importer companies to verify the test reports they submitted to the FDA.  Unfortunately, the results of the FDA’s own testing showed that many of the masks were subpar.  Understandably, the FDA removed many companies from the approved list, requiring these companies to resubmit verifiable lab reports. The FDA again tested the masks coming from overseas, and again many of these masks along with those manufacturers were refused to be put on the EUA approved list.

It appeared that the EUA process for masks was not working out how the FDA intended. In fact, it was working just the opposite. Masks shipped under the EUA could not be verified and confirmed for safety and effectiveness. It appeared that the FDA should have used a combination of EUA and 510(k) to get better certification on these PPE.

This situation may be repeated over and over again, especially since the FDA has been put into the position of making sure that the supplies of PPE are available to prevent the spread of the virus.

The FDA has repeatedly proven via their own testing, that various products imported into the USA under the EUAs were below standards,  giving the FDA had no choice but to keep adjusting the EUA requirements for products to be put on the approval lists.

As a reminder, the FDA’s basic tenet and the reason it was set up as an agency over 100 years ago, is to protect the American public.  The allowance of EUA in place of the standard pre-market clearance was based on the urgent PPE need superseding the normal FDA review process. However, the FDA still expects companies to accept the responsibility of personal safety and meet the product quality standards.

For US companies this was probably an accepted understanding. Unfortunately, for foreign companies, this was not the case. Look at the case of hand sanitizers contaminated with methanol where human deaths have occurred.

Currently, we are starting to see the FDA tighten the reins on the EUAs for various products such as COVID-19 diagnostic tests and face masks.  This was seen in the FDA’s recent webinar on how they visualize winding down the EUA for masks.

How do we see the EUA ending? There are many questions that need to be answered:

• Will the FDA allow companies who have been marketing EUA PPE devices (masks, gloves, gowns) and IR thermometers continue to market the devices they currently have in stock, in the USA? (this is dependent)
• Will the FDA allow companies to continue to export PPEs to the USA without a 510(k)? (highly unlikely)
• Will the FDA ask the companies to recall the EUA products, especially if they are below standards? (that is a possibility)

I can tell you that the FDA  cannot wait to  have the EUA shut down so that they  can return to the normal registration process with the FDA, proper device listing, and of course, obtaining the necessary 510(k) clearance. More importantly, the FDA wants to make sure all companies are in compliance with the QSR/cGMP which has basically be lost during this crisis (the FDA has not been doing any QSR/cGMP inspections during this pandemic).

Firms that have been proactive during this pandemic, in obtaining 510(k) clearances for their devices, while also marketing under the EUA, will appear to be in a better position to deal with eventual end of EUA and FDA compliance issues. Many new medical device-manufacturing companies were also addressing the QSR/cGMP compliance.

Be assured that the EUA conclusion will come as a big surprise for many of the companies who have been exporting under this temporary status. The bigger surprise may come if the FDA conducts their own testing and as a result, requests non-compliant products to be recalled.

Getting things back to normal for the FDA pre-market review is a necessity.  The public needs the assurance that the devices and drugs they are using are safe and effective.  But, how does the FDA ever balance the increasing supply demands with the required device and drug quality?  Consider what the new normal will be when millions, no, make that hundreds of millions of masks, gowns and gloves that are presently in circulation in the government, hospital, and medical supply chain do not meet the specifications.

Our government needs to find a way to properly wind down a EUA situation it has never experienced before.  Undoubtedly, the EUA served its purpose in the darkest of times and was instrumental in getting the necessary supplies to the front lines.  However, now the time had come for the EUA to take its place in the annals of COVID-19 history and clear the way for the FDA processes that are proven to work.

This is not the end of this story. Watch of updates on the Life After the EUA.

About the author: Alan Schwartz is Executive VP of mdi Consultants, Inc. He has been involved with FDA regulatory compliance since 1972, as a former US FDA Supervisory of Field Operations, and as a consultant to FDA regulated industries since 1978. He has worked with companies worldwide and has been an invited speaker as well as a writer for various conferences and publications. He can be reached at [email protected]