Dr. Shankar Pattabhiraman, clinical flow cytometry senior technical product manager, Beckman Coulter Life Sciences, discusses the implications the regulations will have on IV device manufacturers and labs and how they can make progress to hit the May 2024 deadline.
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Regulations and laws
The European Union announced the In Vitro Diagnostic Medical Devices Regulation (IVDR) in May 2017, a robust, transparent regulatory framework that raises diagnostic assay standards and reflects technological and medical advances since the 1998 IVD Directive. Long term, IVDR is intended to ensure greater compliance, as well as improved consumer safety and efficacy. Optimised product portfolios, better design, and an effective quality management system can benefit manufacturers and laboratories. The CE mark also helps laboratories and manufacturers compete globally, even influencing other countries to consider IVD regulations, such as the VALID Act in the United States.
A roadmap towards compliance
The IVDR entails a multi-year compliance marathon, with the goal of increasing consistency, quality, safety, and traceability of in vitro diagnostic products in the European market. Manufacturers must first decide which products to CE mark and which to discontinue, and then notify customers of their intentions. As soon as a manufacturer decides to certify a product, they should file an initial application with notified bodies. The products are classified based on their risk to individual and public health, ranging from Class A (low) to Class D (extremely high). The class A device deadline was in May 2022, and the journey for the remaining risk classes will last until May 2027.
Unlike the previous IVD directive, the new regulation will include in-house IVD tests performed by the laboratories. This means that laboratories must follow standards that are, in many ways, similar to those of manufacturers. As a starting point, laboratories should audit all tests performed in the lab and ask questions such as:
1) Are CE-marked IVDs, modified IVDs, or laboratory developed tests (LDTs) lab tests?
2) Are any of the CE-marked IVDs provided by companies that do not appear to be ready to transition to IVDR?
3) Which of the modified IVDs or LDTs can be easily replaced with CE-marked IVDs?
4) Is there a CE-marked IVD supplier who can provide all (or a majority) of the tests?
5) Are there tests where a rationale for continuing to use an LDT (without being identified as a manufacturer) can be provided?
6) Is the laboratory considered a European health institution?
7) Is the lab adequately resourced, and is the laboratory management team willing to assume responsibility for all IVDR requirements (if LDTs are to be continued in the absence of CE-marked alternatives)?
The first deadline for laboratories to comply with Annex I General Safety and Performance Requirements was also in May 2022. The next important deadline is in May 2024 for laboratories to meet the Article 5.5 requirements and decide whether to continue the path of LDTs.
Manufacturers, on the other hand, must race ahead of labs in the compliance race. To meet the May 2024 LDT deadline, laboratories need the complete IVDR product list and details from manufacturers in order to evaluate the CE status of their LDTs. The manufacturers' deadline may be later, in 2026, but they must provide this information to the laboratories as soon as possible. For example, in flow cytometry-based assays, the antibody conjugates used to compose an LDT assay panel fall under class C, with a deadline of May 2026; however, the deadline for article 5.5 compliance for LDTs is May 2024, so manufacturers must either release the IVDR antibody conjugates early or provide detailed information from the manufacturer, or, at the very least, provide detailed information from the Instructions for Use well ahead of the May 2024 deadline.
Lab workflows
After auditing their IVDs and LDTs and answering the above questions, laboratories should contact manufacturers, distributors, and importers. They should then consult with notified bodies and regulators before approaching stakeholders for assistance.
Laboratories will also have to make decisions for each LDT, such as whether to find a commercially available CE-marked substitute, make an LDT despite the availability of a commercially available substitute (acting as both manufacturer and laboratory), or make a test and justify it by demonstrating that no commercially available substitutes meet the needs of the patient group.
Each option generates a unique workflow and challenge, but the latter two necessitate the use of a Quality Management System (QMS). After deciding which devices to CE mark, laboratories that want to also be manufacturers (e.g. continue with LDTs) should put in place an effective QMS that includes:
1) Compliance strategies for conformity assessment and device modification processes
2) Appointing a regulatory compliance officer
3) A general safety and performance requirement system
4) Product development
5) Resource management and supply chain management
6) Creating a risk management strategy
7) A system for reporting serious incidents and corrective actions
Laboratories that choose to manufacture LDTs due to a lack of a viable alternative must develop a QMS and face scrutiny from a national regulatory agency. Monitoring and recording test performance, maintaining documentation about the test's manufacture and use, and justifying why omitted requirements are not applicable, are all part of the QMS.
Clinical laboratories that use LDTs with CE-marked alternatives should work with manufacturers to ensure full IVDR compliance, such as adopting a QMS that covers all diagnostic phases and meets quality and competence requirements.
Managing data and documentation
Aside from a greater emphasis on the QMS, notified bodies examine a technical documentation file for manufacturers that includes product design and supplier information, data product verification, product validation, pre-clinical and clinical data, a post-market surveillance plan, and reports. Meanwhile, manufacturers should prepare a performance evaluation report that includes clinical performance evaluations that show scientific validity and clinical evidence.
The IVDR requires a post-market follow-up performance report that includes a follow-up plan and a review of the performance evaluation report, as well as current research and device status. The post-market surveillance report necessitates the collection, recording, and analysis of risk-related data. It includes information on design and manufacturing, a performance evaluation on safety and performance, post-market surveillance of any relevant devices, and an incident report, making it useful in detecting design or manufacturing problems.
Considering timelines and staff support
Manufacturers must race ahead of labs in the compliance race. Manufacturers and labs should start the application process immediately to meet the first deadline in May 2024. Delays only put manufacturers at risk, as they disrupt lab workflows and leave the market without critical diagnostics. According to a survey conducted by 2023 MedTech, the initial application process can take anywhere from several months to more than a year. It also takes time to establish a notified body (NB) relationship. In terms of staffing, there should be a designated regulatory compliance employee (full-time) at large IVD companies and a contracted employee at smaller companies who is responsible for reviewing core processes and maintaining a strong QMS. Manufacturers may need to hire and train additional clinical study personnel in order to meet scientific validity and clinical evaluation requirements. In the face of commercially viable alternatives, laboratories that take on the role of manufacturer and manufacture LDTs will need to hire staff to help document and manage the QMS.
Navigating costs: The value of preparing now
Manufacturers will be required to pay notified bodies a fee for initial certification and ongoing monitoring. Many manufacturers have discontinued products due to high prices, according to the 2023 MedTech survey.
Because there are no commercially available substitutes for LDTs, IVDR can increase costs and daily workflows in flow cytometry labs. Hiring personnel and purchasing equipment for QMS and documentation can also be costly.
Nonetheless, the long-term benefits outweigh the initial costs. Once manufacturers' technologies have been CE marked, they will be able to more closely link reagents, tests, and equipment and address gaps caused by the IVDR. To enable continuous workflow, laboratories can work with manufacturers and invest in CE-marked reagents, equipment, and technology.
While there are many unknowns about what the IVDR will entail, manufacturers who provide affordable technology, all-in-one products, technical support, or resource platforms to assist labs in becoming compliant will gain new market opportunities and keep up with demand.
IVDR has the potential to improve clinical care precision and become the global standard. Manufacturers and laboratories must prepare now to avoid costly delays or shutdowns.
