The World Health Organization’s Emergency Use Listing (EUL) provides an approach for assessing medicines, vaccines, and diagnostics that could help address an outbreak classified by the WHO as a Public Health Emergency of International Concern (PHEIC). Robyn Meurant, executive director, regulatory services, IVDs and medical devices for NSF International, describes the EUL as “akin to the U.S. FDA’s Emergency Use Authorization” and says it could help countries that are “without great means to do testing.” Before joining NSF International, Meurant acted both as a professional officer and an advisor to WHO and assisted with the development of the EUL for IVDs in 2014.
MD+DI asked Meurant a few questions about the WHO’s EUL and how it could help IVD and device manufacturers respond—and healthcare systems manage—the COVID-19 pandemic.
What is the Emergency Use Listing (EUL) for WHO and how would it pertain to diagnostics manufacturers?
Meurant: The World Health Organization’s Emergency Use Listing, or EUL, was developed in 2014 in response to the Ebola outbreak in three west African nations. Akin to the FDA’s Emergency Use Authorization (EUA), it’s an assessment for medicines, vaccines, and devices used to address an outbreak classified by the WHO as a Public Health Emergency of International Concern (PHEIC).
Because the countries affected by Ebola had large, systematic regulatory gaps, the market was flooded with unregulated products making spurious claims about product safety and assessment. This threat was compounded by a lack of local laboratory capability. Several international labs came in to assist with testing the affected population. However, it was apparent that there was an acute need for the rapid assessment of simple devices for use in regions where labs were either nonexistent, lacking in basic resources such as electricity, or managed by staff that had not been appropriately trained.
In terms of diagnostic tests (IVDs), these factors posed a genuine public health threat. With a virus like Ebola, there’s extraordinarily little tolerance for a wrong diagnosis. If a patient is provided with a false negative diagnosis, he or she may unwittingly spread the infection. Likewise, when a patient is provided with a false positive, that patient stands significant risk of being placed in close quarters with actual positives through transportation or quarantine and may end up being infected anyway. Either way, the result is the exact opposite of an IVD’s effective use in combating a viral outbreak: quickly and accurately diagnosing illness to forestall the spread of disease. The mandate for WHO was clear: create a mechanism that would give information to affected member states on the performance of IVDs often designed and manufactured in minimal development time.
The EUL for IVDs is based on the premise that a primary challenge in getting an IVD ready for market comes in obtaining the number of disease-specific specimens needed to conduct a thorough validation. Essentially, the WHO has told IVD manufacturers to step up with evidence of quality systems and preclinical work/analytical work that shows the manufacturer is detecting the right marker and that it is always negative when it should be and always positive when it should be, and so on. The WHO will then collaborate with the ministries of health and other bodies within the affected countries to organize the testing with real clinical specimens to help get products through the system quickly.
Would it also apply to medical device manufacturers?
Meurant: The WHO EUL has the potential to assess medical devices, but at present it does not. There will be devices that may be used in an emergency that may be specific to a disease, but the reality is the medical devices most needed to treat a disease outbreak like COVID-19 are essential medical devices such as stethoscopes and x-ray machines. Having quality equipment is fundamental, but the medical devices commonly supporting an emergency use are ones that should be in routine use. As such, the EUL currently addresses those medical products such as IVDs that are unique to the outbreak and as such are unlikely to be on the market already.
Would this listing impact the marketing of new products that have not yet been approved or would it also impact already approved products?
Meurant: We have an emergency right now with a virus that is novel—we have never seen it before, so every IVD on the market for COVID-19 is a new device. There are very few regulatory assessment mechanisms that would be able to approve something in a limited period with such a fast response. It usually requires an extraordinary assessment mechanism like the FDA EUA or WHO EUL.
For COVID-19, both the U.S. FDA and the Chinese Center for Medical Device Evaluation have approved some COVID-19 IVDs (the U.S. FDA through its emergency mechanism.) Thus, we know that there has been some form of independent assessment of these products. The same cannot be said for CE marked COVID-19 IVDs. Under the current regulatory scheme (the IVD Directive), these assays do not require independent assessment of conformity to be CE marked. The manufacturer self-certifies conformity. Therefore, a WHO EUL Listing of a CE marked product will provide a user with a level of assurance concerning the quality and performance of the device, and this indeed can assist in the marketing of the product.
What determines whether a product is added to the listing?
Meurant: Like FDA’s EUA, the EUL is specific to a disease that has caused an outbreak declared by WHO as a PHEIC. When there is a PHEIC, the WHO opens an EUL for products specific to that PHEIC. The first EUL eligibility requirement is that it is a medicine, vaccine, or IVD that looks like it can be used, and is appropriately used, in the setting where it will be used. IVD products should also be shown to have been manufactured under an effective Quality Management System (QMS), as indicated by appropriate quality systems certification and reports. Specific to COVID-19, WHO has published validation requirements for IVDs based on detection of specific nucleic acid. However, nucleic acid tests are just one tool in the toolbox of IVDs needed to respond to this crisis. There are other types needed, such as serological tests.
Because COVID-19 has been officially declared a pandemic, every country will need quality products. And we know that countries have varying abilities to take on more sophisticated tests, so the WHO will be looking particularly at those products that serve countries without great means to do testing. They will start with the simpler products and work up from there. The WHO’s emphasis is on assisting those countries that are both urgently affected by the virus and without the capacity to assist themselves.
How could this listing help healthcare systems manage the COVID19 outbreak?
Meurant: The public health benefit is twofold. During an outbreak, EUL products are focused on regions where the need is greatest. While COVID-19 is now a pandemic, those places remain hotspots, and regions without strong healthcare systems are always the most vulnerable. The EUL listing enables regions without the capacity to do this assessment themselves to access products that should work well. Additionally, they support the greater public health by providing increased epidemiological information such as case rates and case definitions, which WHO needs to provide an appropriate response to ongoing and future outbreaks.
Is there enough time to produce supplies for this outbreak?
Meurant: Supplies depend upon the critical, unique componentry requirements of any test, such as reactive reagents in an assay that makes it specific. The good news is that a lot of nucleic acid tests for COVID-19 will likely appear quickly because these are the easiest components to make. Reagents required for serological assays usually take longer to manufacture and unfortunately, they’re probably the ones we increasingly need. One aspect that is making life simpler for manufacturers in this outbreak, compared to others, is the availability of sufficient positive specimens to validate the assay. However, the need for reference materials persists, and these can take some time to develop. This virus has spread very quickly, revealing an immunity-naive global population. It is likely that even though the rate of spread will eventually slow, the need for good diagnostics to help rule in or out COVID-19 infection will not go away.
What should diagnostics manufacturers and medical device manufacturers do differently today?
Meurant: Manufacturers should be operating under the mindset that the next outbreak can come at any time. WHO has published an R&D blueprint to help determine which diseases and pathogens should be prioritized for research and development in the context of a public health emergency. The R&D Blueprint is a plan for readiness, but it’s limited by what diseases we know. For IVD manufacturers, a novel infection like COVID-19 is quite challenging. The best approach is the one used during the Ebola virus outbreak, when vaccine manufacturers cooperated to break down financial, national, and jurisdictional borders and worked together to address the public health crisis. In this way, if—and probably more accurately, when—there’s an outbreak, WHO can help coordinate the fast tracking of development of effective medical products. It’s an openness and transparency combined with the realization that we will all be losers if we don’t collaborate.
In terms of the EUL process, manufacturers already operating under independently audited effective Quality Management Systems with experience in creating well validated assays will be those with a high chance of being assessed efficiently and positively.