By Robyn Meurant
As the COVID-19 pandemic spreads rapidly across the globe, public health organizations such as the World Health Organization (WHO) are moving as swiftly as they can to combat and control the disease. Because the virus is novel, every in vitro diagnostic device (IVD) on the market for diagnosing COVID-19 is a new device, and new devices require at least some measure of quality and safety assessment prior to deployment.
To bridge the gap between “no independent pre-market assessment whatsoever” and “adequate assessment in the case of an emergency,” WHO relies upon its emergency use listing, or EUL. Akin to the FDA’s emergency use authorization (EUA), EUL is a fast-tracked assessment pathway for medicines, vaccines, and devices used to address an outbreak classified by the WHO as a public health emergency of international concern (PHEIC). Indeed, WHO opened an EUL for COVID-19 diagnostics in January of 2020, and the FDA is taking similar steps to peel back regulatory red tape and expedite diagnostics availability.
The WHO EUL was developed in 2014 in response to the Ebola outbreak in three west African nations. Because the Ebola-affected nations had large, systematic regulatory gaps, the market was quickly flooded with unregulated products making spurious claims about product safety and assessment. This threat was compounded by a lack of local laboratory capability. Even with international support, 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.
When WHO officially classifies a crisis as a PHEIC, an EUL for products specific to that PHEIC is opened. 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 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 acids. 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.
The EUL is intended to provide a time-limited listing for products in an emergency context when limited data are available and the products are not yet ready for application for prequalification or even comprehensive regulatory approval. As part of the EUL, it is expected that the manufacturer will complete the development of the product and submit for routine pre-market regulatory assessment and WHO prequalification, as relevant.
Because COVID-19 has been officially declared a pandemic, every country will need quality products. And because countries have varying levels of laboratory sophistication and ability, WHO will be looking particularly at those products that serve countries without great means to do testing. When the choice is there, WHO will start with the simpler products and work up from there. WHO’s emphasis is on assisting those countries that are both urgently affected by the virus and without the capacity to assist themselves.
The EUL for IVDs is based on the premise that a primary challenge in getting an IVD ready for market comes from obtaining the number of disease-specific specimens needed to conduct a thorough validation. Essentially, through its EUL, 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.
WHO acknowledges that not all studies will have been completed when submitting to the EUL, including those that demonstrate clinical performance. When studies are still in progress or plans to commence such studies are in place, the manufacturer provides an update of progress or the study plan along with anticipated dates of completion. If more clinical data becomes available at a later time, this is submitted to WHO. It is a requirement that all studies will be finalized after listing.
For COVID-19, both the FDA and the Chinese Center for Medical Device Evaluation have approved some COVID-19 IVDs (the 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, although many CE-marked products will work. 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. This is important when products are developed by manufacturers without an established reputation for quality.
IVD manufacturing depends upon availability of materials, including 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 they have specific reagents that are the simplest 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 also 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 identify COVID-19 infection will not go away.
Having a Blueprint
In terms of non-IVD medical devices, having quality equipment is fundamental, but the medical devices commonly supporting an emergency use are ones that should already be in routine use. The medical devices most needed in response to a disease outbreak like COVID-19 are essential tools such as stethoscopes, thermometers, and x-ray machines. As such, the EUL currently centers its focus on those medical products, such as IVDs, that are unique to the outbreak and therefore are unlikely to already be on the market.
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.
Our current situation is, sadly, not unique, and recognition that novel disease outbreaks may become the “new normal” is a mindset that forward-thinking manufacturers need to adopt immediately. 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 such as 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 fasttracking the development of effective medical products. It’s openness and transparency, combined with the realization that we will all be losers if we don’t collaborate.
Robyn Meurant is executive director, regulatory services, IVDs and medical devices for NSF International. Before joining NSF International, she acted both as a professional officer and advisor to WHO. She assisted with the development of the EUL for IVDs in 2014. Questions and comments can be directed to 24×7 Magazine chief editor Keri Forsythe-Stephens at [email protected].