The COVID-19 Pandemic has had a profound effect on people and industries worldwide. Without a doubt, one of the most heavily impacted areas of our society has been the healthcare sector which was inundated with patients and shortages of medical equipment.
In this article, we shall look at the impact on In-Vitro Diagnostic medical devices (IVDs), and how they are regulated in the EU.
In Vitro Diagnostic Medical Devices
Within the scope of the COVID-19 Pandemic, the most recognisable IVDs are those used in patient screening testing facilities, namely the Polymerase Chain Reaction (PCR) and Rapid Lateral Flow Tests (LFTs) or Rapid Antigen Tests (RATs), which have by now become household names. Collectively referred to as COVID-19 IVDs, there are various products which work using different principles for the detection or quantification of SARS-CoV-2 nucleic acid, antigens or antibodies against the virus.
Most of these tests have been introduced onto the market following the requirements of the EU IVD Directive 98/79/EC (IVDD). The IVDD is generally not considered to be a “strict” EU Directive; on the contrary, it seemingly allows relatively high-risk IVDs to enter the EU market with little oversight. The new IVD Regulation (which is applicable from 26 May 2022) puts the IVDD in check, increasing manufacturer obligations and requirements.
In accordance with the EU IVD Directive, devices capable of detecting SARS-CoV-2 (or its absence) qualify as General IVDs, and do not fall under the scrutiny of third-party assessment bodies referred to as Notified Bodies (NBs). That said, if the device is intended to be used as a self-test by laypersons, this would actually require assessment by a NB which will ensure that the product is up to scratch. NB assessments are notoriously expensive and may lead to delays in bringing products to the market (due to various factors including scheduling delays, lack of information or evidence of conformity on the manufacturer’s side). Therefore, it was no surprise that most of the tests being released in the early days (or was it months?) of the pandemic were all intended to be used by professionals; such devices had little to no external oversight and only required a self-declaration and registration in order to place on the market.
This all changes after 26 May 2022 with the application of new EU IVD Regulation 2017/746 (IVDR). The Regulation introduces a new device risk classification system to IVDs, in decreasing risk:
- Class D.
- Class C.
- Class B.
- Class A.
The Regulation is a massive improvement on the previous IVD Directive, outlining stricter requirements and obligations for manufacturers and other stakeholders in the EU to follow, bringing much needed oversight to the industry. Under this new Regulation, both self-test and professional-use COVID-19 IVDs are classified as Class C requiring external assessment by a NB.
In December 2021, the EU Commission agreed to a progressive roll-out of the IVDR. Through an amendment of Article 110 of this Regulation, manufacturers of General IVDs under the IVD Directive will be allowed to delay transition if their product has been ‘up-classified’ under the new IVDR rules and require NB intervention. Be sure to read our extensive article on this, above. In order to benefit from this additional grace period, manufacturers must have their General IVDs registered in the EU prior to 26 May 2022, in accordance with the IVD Directive. Otherwise, they will effectively “miss the boat” and would need to conform to all requirements of the IVDR and apply for Notified Body assessment. As expected, this has led to many manufacturers scrambling to get their SARS-CoV-2 detection IVDs registered under the IVD Directive prior to 26 May 2022.
Although not legally binding, the EU’s Medical Device Coordination Group (MDCG) have released several guidance documents to help the industry and to ensure that the IVDs entering the EU are of a high quality. One of the cornerstones of compliance with either the IVD Directive or Regulation is the documentation of a Performance Evaluation for the product, which effectively demonstrates whether or not the device functions as intended, and also to what extent it carries out its functions. This would typically involve a manufacturer providing their devices for performance testing to a participating laboratory or healthcare facility. Once this is complete, the manufacturer would put together documentation to document and interpret the results. The MDCG released guidance 2021-21 which specifically addresses performance evaluation of these devices and how they should be assessed. The EU also plans to publish Common Specifications for the manufacture of COVID-19 IVDs in 2022. This would be a specific set of requirements which will need to be met by manufacturers and their IVD in order to improve the standard and quality of such devices in use.
In a recent communication from the EU Commission to stakeholders within the EU, they request additional scrutiny on COVID-19 IVDs. The EU Authorised Representative is very often the “first line of defence” in identifying fraudulent or non-compliant devices, however, their role is limited to the review of documentation provided by the manufacturer, and they typically do not have any physical interaction with the device. On the other hand, importers and subsequently distributors will come into contact with the device packaging, and can furthermore ensure that nothing is amiss. However, for many of the professional-use tests currently on the market, their diagnostic performance has only been verified by the manufacturer. Therefore, it is important for all relevant stakeholders to ensure that the manufacturer has taken the correct steps in ensuring that the device will perform as intended.
Placing COVID-19 IVDs on the EU Market
Whether or not you are placing your COVID-19 IVD on the market prior to or after 26 May 2022, here are the steps you will need to take to place your product on the EU market:
- Perform performance evaluation and compile your technical documentation.
- If based outside of the EU, appoint an EU Authorised Representative.
- If applicable, select and begin application with a Notified Body. This will be required for COVID-19 detection IVDs under the IVDR, and for self-testing IVDs under the IVDD.
- Register your IVD device (If applicable, through EU Authorised Representative).
- Build your supply chain (Importer, Distributor).
Complementary information on this subject is also provided in MDCG 2022-1.
Technical Documentation and Performance Evaluation
One of the cornerstones of compliance is the compilation of a product’s technical documentation which will demonstrate that products conformity with EU legislation as well as the product’s performance. Under the IVD Directive, technical documentation requires are relatively sketchy and were, for the most part, drawn up with a similar structure as required in the Medical Device Directive. Historically, it was common to note General IVDs without any formal technical documentation in place due to the lack of well-defined requirements. Generally speaking, self-test IVDs were always held to a higher standard due to their assessment by Notified Bodies who would expect high quality performance evaluation to be conducted and reported within a structured technical file. As previously mentioned, the new EU IVD Regulation turns this on its head, providing well-structured and defined requirements with respect to what is required in terms of technical documentation. We would recommend using this structure, even for IVD Directive compliant products.
As the IVDR represents that state-of-the-art in terms of technical documentation structure, we would expect COVID-19 manufacturers under the IVDD to compile the following into a technical file:
- Device Description (Including a classification rationale).
- Information Provided to the User (Labels and IFU).
- Essential Requirements Checklist.
- Risk Management File (Plan, Analysis, Report).
- Validation and Verification (Relevant Test Reports).
- Performance Evaluation (Plan, Report).
- Post-Market Surveillance (Plan, and if applicable, Report).
- Declaration of Conformity with the IVDD.
Performance Evaluation of COVID-19 IVDs
However, there has recently been added scrutiny with respect to COVID-19 General IVDs too, especially with respect to performance evaluation. As previously mentioned, MDCG 2021-21 (August 2021) was released to specifically tackle Performance Evaluation of SARS-CoV-2 IVDs. The 17-page long document goes into Specific Considerations for the following types of IVDs:
- First-line assays (including rapid tests) for antibodies against SARS-CoV-2 (anti-SARS-CoV-2): IgG-only, IgG combined with IgM and/or IgA, and total antibody.
- Assays for detection of anti-SARS-CoV-2 IgM and/or IgA (including rapid tests).
- Confirmatory or supplementary assays for anti-SARS-CoV-2.
- Antigen SARS-CoV-2 tests, including rapid antigen tests.
- Nucleic acid amplification techniques (NAT) assays for SARS-CoV-2 RNA.
Specific Considerations include Diagnostic Sensitivity, Analytical Sensitivity, and Diagnostic Specificity for different specimen types.
In general, performance evaluation should be conducted in direct comparison to an already-marketed IVD detecting the same analyte and which reflect the state-of-the-art at the time of the performance study.
Furthermore, manufacturers of SARS-CoV-2 IVDs are required to continually assess the performance of their products in light of the emergence of genetic variants. Performance of your device may thus be affected by these new variants and would thus have an impact on the safety of patients, healthcare professionals or other individuals, with the infection going undetected.
It has been reported that the Omicron COVID-19 variant could affect the performance of some SARS-CoV-2 tests. Please refer to the following:
Preliminary study by FDA: SARS-CoV-2 Viral Mutations: Impact on COVID-19 Tests | FDA
Paper medRxiv.org: Discordant SARS-CoV-2 PCR and Rapid Antigen Test Results When Infectious: A December 2021 Occupational Case Series
With regards to the above two links we remind all relevant clients of MDCG notice 2021-7 regarding the manufacturers obligations to monitor the performance of their devices on any variants of SARS-CoV-2 and to take action as appropriate. MDCG 2021-7 requires manufacturers to document this approach which shall be made available upon request. Changes in the performance of your product which could result in direct or indirect harm shall be communicated to users through Field Safety Corrective Action, carried out in accordance with MEDDEV 2.12-1 rev.8. Performance limitations shall be identified within Instructions for Use.
For more information on the specifications of performance evaluation, please refer to MDCG 2021-21.
For more information on what is considered the state-of-the-art, and further considerations for performance evaluation, please refer to MDCG 2021-2.
Labels and Instructions for Use
All IVD products shall be accompanied by labels and Instructions for Use (IFU) and must be compliant with either Annex I section 8 of the IVD Directive or Annex I section 20 of the IVD Regulation. Furthermore, information provided to the user must be translated into all relevant languages for those countries where this product will be sold.
For rapid antibody tests, there are additional considerations to make as provided in MDCG 2021-2. For COVID-19 IVDs, it suggests that the following information on intended purpose is provided with the product, if and where applicable:
- The intended user.
- The target population,
- Window between infection and antibody detection.
- Result interpretation (including limitations of interpretation).
- Assay design (target antigen(s), antibody types).
- Limitations of the assay.
- Whether the assay is intended, for example, to detect the antibody response in individual patients’ recovery, to assess if the patient has been previously infected, to assess response to vaccination.
- The exclusion of antibody test use as first line test for diagnosis.
The IFU must then provide additional performance information for the relevant parameters above.
How Advena Ltd Can Help You
Advena Ltd has well over 25 years’ experience in the industry as an Authorised Representative and Regulatory Consultancy firm.
Our comprehensive Authorised Representative service and responsive team will provide you the peace of mind you need to get your product to market. After drawing up and agreeing on our mandate, we will verify that you have the appropriate documentation in place and we’ll be able to register your device with the relevant EU Competent Authority.
We also have a team of in-house experienced consultants who will be able to compile your technical documentation into the format required by regulators.
