When the original In Vitro Diagnostics Directive was put in place in 1998, the products it covered were very different to those now on the market. Technological innovation, advances in genetic markers and other innovations meant the IVDD was no longer fit for purpose. The In Vitro Diagnostics Regulation (IVDR), which went into force in 2017 and was implemented in May 2022, is a response to the advances in the market and brings significant change to how devices are classified. The IVDD list-based classification approach became outdated over time and a risk based classification system for IVDs ensures a preapproval process involving NBs has been put in place that is appropriate for the device type.
The IVDR establishes four product classes – from A to D, with D being the highest risk. Under the IVDR, only class A products can be self-certified, whereas, in the past, around 80% of products were self-certified. All other products must be assessed by a notified body.
The problem that exists for manufacturers is that the capacity of notified bodies is now very limited. Previously there were around 40 notified bodies working in the IVD space, but currently there are only seven designated under the EU IVDR, with another two awaiting designation by end of 2022.
Given the importance of the notified body in bringing or keeping products on the market, manufacturers must first secure a contract with an appropriate notified body for their product types, then build the relationship with this key stakeholder and ensure that they are always following the IVDR guidelines. The notified body does not consult, but they will likely provide regular feedback through the assessment process.
Manufacturers should try to select a notified body that is suitable for their company, but this is understandably more difficult for small and medium sized companies that may find their previous notified body does not have EU IVDR designation.
With fewer notified bodies, planning is crucial. The reviewers of these files will likely have significant expertise in the diagnostic products under review, so it’s important ensure your regulatory affairs teams have the expertise to help build the technical files and manage expectations and timelines. Timely delivery will be key, given the workload for the small number of notified bodies to facilitate their scheduling for their teams.
Those technical files need to be clear and concise, with easy navigation to make reviewers’ jobs easier. Meaningful file names and ensuring sufficient detail are simple ways to assist the review process.
There will often be questions during the review process. The goal is to provide as comprehensive a file as possible to limit the number of rounds of questions, and to respond to those questions in a timely manner.
How long does approval take?
Technical file approval time varies significantly and will depend on the quality of the technical file itself. According to an EU Commission survey of notified bodies, almost 70% of applications take between 13 and 18 months to reach final certification, compared with 6 to 12 months for most tests under the IVDD. The timelines are expected to become less onerous over time and will likely be closer to between six and nine months in future. However, companies should be in regular contact with the notified body to establish expectations and manage resources.
Recent figures from conferences are that there have been 648 applications with 125 IVDR certificates issued so far. That contrasts significantly with 1300 certificates issued under the IVDD. Not surprisingly, conformity assessment takes the longest time for Class D products, which are the highest risk products. So far, very few certifications for those products have been completed. To our knowledge, there have been no certifications for companion diagnostics.
So, it’s important to build in time for certification in the overall route-to-market process.
The review process under the IVDR is new for both industry and the notified bodies, so it will take time and there will be a period of adjustment as all stakeholders develop and refine their processes.
The process does, however, align more closely with that of the US, where most IVD products in Class B/C/D go through as a Class II 510K submission. This process requires premarket notification and clearance by FDA prior to placing the product on the US market.
While there are many new requirements, there is also plenty of guidance to help manufacturers understand what is required of them. The Medical Device Coordination Group (MDCG) has issued many useful and endorsed documents and guidances and will continue to do so[i]. Key guidances to follow include:
- MDCG 2022-10 — Q&A on the interface between Regulation (EU) 536/2014 on clinical trials for medicinal products for human use (CTR) and Regulation (EU) 2017/746 on in vitro diagnostic medical devices (IVDR)
- MDCG 2022-6 — Guidance on significant changes, which is key for manufacturers wanting to make significant changes to devices already on the market
- MDCG 2022-9 — Summary of safety and performance template
- MDCG 2022- 2 — Clinical evidence is another key document, since notified bodies want to see how the product works in the user environment with real samples
- MDCG 2022-3 — Class D, with guidance on ensuring the product conforms to relevant requirements based upon objective evidence and analysis
In addition to the guidances above, the MDCG has developed guidance on classification rules to help manufacturers with how their product will be determined; guidance on the European Medical Device Nomenclature for registering devices, on the notified bodies, on unique device identifier (UDI) requirements.
There are also many harmonized standards published in the Official Journal of the European Union that can be followed, and compliance with these standards will facilitate notified body review and approval of submission documents[ii].
Ensuring a proper understanding of the requirements by following the guidance and adopting harmonized standards will facilitate review and approval process by the notified bodies. This, in turn, will help companies ensure their products make it to market.
About the author:
Sean O’Dowd is Director Medical Devices and IVD at PharmaLex