Regulatory approval of medical devices for COVID-19

For newly developed medical devices to be able to make a difference in current COVID-19 pandemic, development and regulatory approval needs to be fast. However, regulatory processes are generally not known for their speediness. Developing an efficient and safe product can take years, followed by a regulatory approval process which generally requires up to months, even years if clinical trials are required. Luckily the FDA and similar regulatory bodies provide alternative routes-to-market for crisis situations. How do these regulatory pathways work? For which medical devices are they relevant? And what can we expect in the near future to make it to the finish line of these processes?

The FDA’s COVID-19 adjusted regulatory pathway

Over the past few weeks, the FDA has been putting a lot of effort into enabling fast regulatory processes for COVID-19 related medical devices. This started with the declaration of an emergency on February 4th 2020 by the US Department of Health and Human Services. The declaration states that it “provides liability immunity to certain individuals and entities […] against any claim of loss caused by, arising out of, relating to, or resulting from the manufacture, distribution, administration, or use of medical countermeasures”.1 In other words, for products that might help counter the COVID-19 pandemic, it might be easier and faster to get a regulatory OK than under usual circumstances.

For the FDA, this declaration opened the door to the Emergency Use Authorization process or EUA for short. This is an accelerated regulatory pathway, enabling products that require pre-market notification to get the green light for distribution in a few days instead of the usual months an approval process may require. The process is specifically meant for emergency situations that rapidly need additional devices to improve the health protection of the public, hence it only applies to products that are able to help us solve a specific situation.2 In the case of the COVID-19 pandemic examples include oxygen ventilators, personal protective equipment such as mouth masks, and in vitro diagnostics to test for COVID-19 and support the search for a treatment.3

An EUA may be only open for devices that fit the scope of the COVID-19 pandemic. This includes products that are currently unauthorized for the USA, but also the unauthorized use of products that do already have an approval for a different type of use. For example, the drug hydroxychloroquine for off-label use,4 the modification of medical devices to generate ventilators, and many newly developed in-vitro tests.5

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The EAU regulatory pathway for COVID-19, how does that work?

There are four criteria that will be assessed for products that are being submitted for an EUA. 

  1. Seriousness of the agent
    The FDA commissioner has to assess whether the agent subject of the declaration of emergency can “cause a serious or life-threatening disease or condition”.
  2. The scientific evidence available
    It is unlikely that the available scientific evidence suits all requirements set by regular FDA approval processes. After all, why turn to an EUA pathway if everything is in place for an everyday route to approval? For this reason, the FDA commissioner also has to assess scientific evidence proving the product’s worth by checking the likelihood that “the product may be effective in diagnosing, treating or preventing” the disease. This gets assessed on a case-by-case basis. What this basically comes down to, is that they will work with what is available
  3. Risk benefit analysis
    This is as straightforward as it sounds. When the FDA is checking a product’s eligibility for an EUA, it has to assess whether the chances of it doing good are greater than the chances of it doing harm. In this case the FDA will go beyond the available scientific evidence as discussed under 2. This includes, for example, information stemming from animal models, but also conclusions drawn from in-vitro research.
  4. Available alternatives
    Lastly, the FDA will see whether there are any approved alternatives on the market that would actually be able to diagnose, prevent or treat the disease adequately. For if there is a product that has successfully gone through the full FDA approval process, then why approve another product using a more shortcutted route.

Important to realize is that an EUA pathway is not something like a carte blanche to quickly get products approved so they are commercially available until the end of time. An EUA will only be in effect for the duration of the declaration under which it was issued.2 Hence, the FDA also poses a strong disclaimer that the quality of the review is much less stringent than it would be for a regular approval process. EUA claims made on safety and effectiveness are generally phrased using words such as might and could instead of the stronger ‘is’ alternative.6

What other COVID-19 regulatory measures did the FDA take?

In addition to activated EUAs, the FDA rolled out a special program geared towards acceleration of the approval of treatments for COVID-19. This program has already proven beneficial by clearing two potential therapeutics for trial.7

Another action undertaken by the FDA is to relax requirements for certain product groups. This means three things: 1) Certain non-510(k) cleared products, that are cleared in other jurisdictions, may also be allowed in the US, 2) some products may be allowed to be modified (for example for remote monitoring), and 3) products may be used outside their intended shelf live to increase stocks.8

How does regulatory Europe respond to COVID-19?

First, let’s clarify that we should generally differentiate between the three classes of medical devices the EU adheres to. Class I contains a large subgroup of devices that are both non-sterile and not re-usable. For these reasons the products are considered “low risk devices” and they can be self-certified. Hence, the impact of the COVID-19 pandemic on this process is limited.

For all the other devices that require involvement of a notified body for CE marking – that is a specific group of class I and the whole group of class II and class III devices – there might be implications as a result of current situation. The exact implications, however, depend on the country where the medical device is produced.

Why is this the case? In Europe, laws concerning approval of medical devices are defined on European level, however, regulation is controlled on a national level by the national competent authorities. This means, that in the COVID-19 situation, taking initiative when it comes to adjusting the way the European law is implemented and enforced, to certain limits, is up to each country by itself. This leads to significant differences between European countries in their approach of allowing novel COVID-19 related medical devices to the (national) market.

For example, in The Netherlands and Ireland, authorities allow companies to bring medical products of all classes to the market without CE marking, that is, if a healthcare institution indicates they require this product as soon as possible and no alternative is available.9 Other countries, such as Belgium, have adjusted rules for reuse of facial masks, and, fun fact, France even went as far as to adjust regulation concerning stool transplantation to limit chance of contamination.10,11

Is nothing happening at European level then? No, definitely not nothing. Some initiatives have been initiated such as the Joint Procurement Agreement, which enables all participating member states to purchase face masks and other personal protective equipment together. Other efforts include increasing production of and improving availability of medical equipment through close contacts with industry, regulated exports and stimulated free circulation of goods and people.12

Additionally, the EU has made all relevant harmonized standards freely available. Harmonized standards are standards which the industry can use to demonstrate that their products or services are compliant with European legislation. Usually companies have to pay a good number of euros per standard. Combined with an updated version of these harmonized standards, the EU has made development and production of class I medical devices more accessible.13

Furthermore, the EU aims to implement article 59 of the Medical Device Regulation 2017/745 immediately instead of the planned date of May 26, 2020. This article specifies that member states, in exceptional cases, are allowed to approve certain products themselves and, in case of a public health emergency, this approval is valid throughout the whole EU.14 Realize though, that that this is only effective after acceptation and publication of the proposed legislation, something that is usually not done within a week.

So, which drugs and devices can we expect to fuel the fight against COVID-19 soon?

Let’s get ahead of the question asked and answer what kind of drugs and devices are already okay-ed by the authorities to help us battle COVID-19 right now. The FDA issued several EAUs over the past few weeks including almost 20 types of ventilators and accessories,15 a set of Chinese respirators,16 and a whole list of diagnostic tests.5 In Europe these efforts are more scattered across the different countries due to the fact that National authorities are responsible for allowing unauthorized products or uses. To relieve some of the pressure of current situation the European Committee has reduced regulatory and administrative burden and provided European-wide coordination to prevent shortages of drugs (coordinated by the European Medicines Agency), medical devices and personal protective equipment. Additionally, they develop guidances for Notified Bodies and National Competent Authorities on how to respond adequately and fast to this crisis situation.

Furthermore, it is encouraging to see how relaxed regulations open up the door for a variety of sectors to work towards providing additional medical equipment. Dyson has added clinical ventilators to their regular portfolio of household appliances,17 Ford is joining efforts with GE to produce respirators,18 and there are many examples of smaller organizations such as 3D printing companies that open source their designs to support faster production of face shields.19

Altogether, the authorities set up many initiatives to get medical devices to the clinics faster to get COVID-19 under control. We will never know what would have happened, if measures would have been otherwise, however, it is without a doubt that joined efforts improve and accelerate our battle against this pandemic. 

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Bibliography

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