COVID-19 has created an unprecedented situation around the world. Manufacturers have had to respond at lightening speed to develop tests to a disease that was first identified in December 2019. In most cases tried and tested technologies like PCR and immunoassay have been used, but there are limitations to the performance of the tests available. The main cause for concern is the performance of immunoassays used to detect patients who have had COVID-19 where the patient has raised antibodies to the virus and should therefore have some resistance to reinfection. This is primarily because the monoclonal and polyclonal antibodies used as tools in the tests themselves are still in their infancy. There has been insufficient time to select good antibodies and then grow sufficient stocks of antibodies because the disease is too new. It is the equivalent of expecting a new breed of plant to be created and grown so that it is available globally within 6 months. Until good antibodies are available the sensitivity and specificity of these tests will remain poor; however, once antibodies that are more specific to the virus become available the quality of the tests will rapidly improve.
Testing is an important part of most countries’ strategies to get back to normal. Whilst the quality of PCR tests to detect active infection is much better than serology tests, it is particularly important that users are aware of the capability of the tests they are using and that each batch performs to the declared specification. In an effort to ensure consistency across available tests and that tests meet needs, many countries are now creating guidelines detailing their expectations for the tests. These will vary between countries as their use may be different as each country is in a different place in their COVID-19 journey.
One final and very important factor is the intended purpose of the test should be clearly defined. The performance for a test used to screen healthcare workers for immunity could be different from a test for diagnosis of active infection. False negative results when detecting presence of the virus give a false sense of security for an individual but could create a super spreader giving rise to infected people mixing in the community or caring for vulnerable patients, whist a false positive could mean that keyworkers are in isolation and unable to work. Conversely, a false positive antibody test could make patients think they have immunity whereas they are not protected and still at risk of contracting the disease, in turn this provides the potential for the continued spread in the community. The performance of tests is therefore vital; however any testing may not be better than no testing.
The COVID-19 pandemic has required a rapid response and as a result a special legislation generally referred to as a humanitarian derogation has been utilized in the EU and the emergency Use Authorization (EUA) program in the US. In Europe, COVID-19 tests could today be placed on the market without the oversight of a Notified Body under the IVD Directive (98/79/EC) because they are not listed in Annex II. However, the same test would be classified as Class D, the highest risk category, under the IVDR (EU 2017/746) scheduled to become mandatory in 2022, which requires Notified Body oversight and individual batches to be tested by a reference laboratory before release. Because there is a shortage of data at present to prove total compliance to the requirements in Europe many manufacturers are using the humanitarian derogation route which is included in both the IVD Directive and the IVD Regulation to cover this type of emergency.
The details are described in Article 9 of the IVDD, which states:
Article 9 paragraph 12.
“By way of derogation from paragraphs 1 to 4, the competent authorities may authorise, on duly justified request, the placing on the market and putting into service, within the territory of the Member State concerned, of individual devices for which the procedures referred to in paragraphs 1 to 4 have not been carried out and the use of which is in the interest of protection of health.”
This means that under circumstances such as a pandemic each individual Member State can make a decision according to their own criteria to give special dispensation to place the device on the market. The CE mark provides market access throughout Europe; however, the humanitarian derogation does not provide a pan-European approval or a unified set or criteria. Access is limited to each Member State market separately.
Use of the humanitarian derogation is intended to be short-term during the emergency and once CE devices become available all devices will either have to be removed from the market or go through the CE marking process and expected performance will be defined in a Common Specification. It is therefore important to understand both the requirements for the humanitarian derogation and also the IVDD and the IVDR so that as technical documentation is created it is future proofed for CE marking to enable continued market access.
Europe has now issued a communication “Guidelines on COVID-19 in vitro diagnostic tests and their performance” 2020/C122I/01 outlining their expectation. The FDA in the US has also issued and revised their requirements and other countries such as the UK have issued detail requirements.
In the US, the EUA provisions are authorized by the FD&C Act and specifically in February 2020, FDA issued their policy for diagnostic testing for Coronavirus. FDA's Policy for Diagnostic Tests for Coronavirus Disease-2019, during the COVID-19 public health emergency, the FDA does not intend to object to the development and distribution by commercial manufacturers, or development and use by laboratories, of serology tests to identify antibodies to SARS-CoV-2 or test kits to detect the SARS-CoV-2 virus, where the test has been validated. The manufacturer is obligated to provide instructions for use of the test and post data about the test's performance characteristics on the their website. FDA believes 15 business days is a reasonable period of time to prepare an EUA submission for a test whose performance characteristics have already been validated.
Below is a summary of useful links that relating to the requirements for COVID-19 tests in the EU, UK, and the US. We will try to keep the list up to date as requirements evolve but it is rapidly changing.
If you have clinical trials in-progress impacted by COVID-19, see our article summarizing available guidance from health authorities in different regions for managing these through this difficult time.
If you have any links you would like to share please e-mail email@example.com. Many thanks for your help to share this information with the wider IVD community.
Qserve is working with a number of IVD manufacturers to help them compile the data needed to support humanitarian derogations and in turn support our communities.
MHRA in UK
FDA Guidance IVD