Pharmacogenomics and IVDR: Overcoming transition challenges

In recent years, the in vitro diagnostics (IVD) regulatory landscape in Europe has changed and we are now in the transition from IVD Directive 98/79/EC (IVDD) to In Vitro Medical Devices Regulation (EU) 2017/746 (IVDR).

Historically, IVD devices could be self-assessed under the 1998 Directive, meaning that manufacturers could declare that the device was entirely safe for use without a great degree of direct external scrutiny. After several high-profile scandals surrounding medical devices, where irresponsible manufacturers’ malpractice in cutting corners showed how easy it was to abuse the Directive, the IVDR came into force in 2017.

The IVDR is a risk-based regulation, and its key mandate is patient safety. To underpin this, the IVDR requires an expanded collection of evidence to be collated by the manufacturer and will now be assessed by the Notified Body (NB) prior to being placed on the market.

The biggest change for manufacturers of IVD devices (who were previously in the self-declared space under IVDD) is that the majority of their technical files will now be scrutinised by the NB for the first time. This is akin to Submission of a Centralised Authorisation Procedure to the European Medicines Agency (EMA) for pharmaceuticals. Clinical device manufacturers must comprehensively demonstrate scientific validity, analytical and clinical performance, as well as a robust and appropriate intended purpose. They must also show sufficiently diligent post-market surveillance (PMS) of devices; activities similar to those of the Pharmacovigilance Risk Assessment Committee (PRAC) in the EU.

IVDR challenges in pharmacogenomics

One of the main challenges of transitioning from CE-IVD products to IVDR is aligning with the everchanging clinical guidelines for diagnostic devices. Under IVDR, manufacturers must generate a cumbersome amount of data, which is a real challenge in a world where clinical guidelines and best practices can change frequently and rapidly. Hence, it is essential that IVDR allows for this flexibility.

For example, the Clinical Pharmacogenomics Implementation Consortium (CPIC) guidelines¹ were last updated in January 2024, which can be an issue for manufacturers who have already submitted their device to IVDR and cannot make any significant changes until it has been approved. Consequently, there may be a delay in getting devices that meet the most recent guidelines to market, due to the time it takes to complete the review.

If, for instance, manufacturers added new variants to an existing pharmacogenomic assay, they would have to design an experiment with a large data cohort to justify the new variants for inclusion. Expanding mutational coverage is relatively straightforwards from a technical perspective. However, updates that broaden the intended use of the device require a new dataset, which can be burdensome and complex. The cohort must be representative of the risk; therefore, this can take time, due to a lack of availability of rarer sample types. Data must then be presented and approved before the updated testing kit can be released.

A challenge of IVDR is the ability to keep up with research advancements and allow manufacturers to make improvements to kits easily. The pharmacogenomics sector is constantly changing. For example, in March 2024, the FDA² made labelling changes to injectable 5-fluorouracil (5-FU, capecitabine (Xeloda)) warning clinicians that treatment comes with a strong risk of severe side effects. The FDA issuing new recommendations has an immediate impact on the pharma company comprising a label change. Providers of the diagnostic tests that help direct this treatment, such as Yourgene Health which manufactures an IVDR-certified DPYD genotyping assay, also saw the aforementioned CPIC guidelines updated in January 2024.

For device manufacturers, maintaining the utility of their test to reflect a guideline update can be a slower process now under IVDR than it was under IVDD. This largely comes down to the requirement for each significant change made to a device on the market remaining safe first and foremost. Manufacturers must demonstrate that the performance and reliability is not compromised, and beyond generating the substantiating data required for this, each significant change must also be submitted for approval to the NB.

Additionally, R&D teams design robust validation processes, but as the market changes rapidly, the speed that manufacturers have to adapt has been encumbered by the administrative bottleneck following the transition to IVDR. Ultimately, manufacturers may not be able to adapt devices as fast as the market demands.

Having an experienced regulatory team is, therefore, critical in device manufacturers’ successful implementation of IVDR. Beyond the significant effort required to implement the whole-organisation changes needed to robustly adopt the regulations, a company that has already achieved IVDR status for its products also has the foresight to act early; this means beginning the journey to IVDR months and often years ahead of the projected deadlines. Users can, therefore, have confidence that a highly competent regulatory team has overseen the transition of a device from IVDD to IVDR.

Burden of post-market surveillance data

Obligations have also increased with respect to PMS activities. IVDR ensures manufacturers have to submit an annual report to the NB demonstrating an ongoing and proactive effort to gather customer feedback and review academic papers, to ensure the safety and efficacy of the device is being monitored in the field.

Having an insight into how your devices are performing in the field is critical. It’s also essential to monitor what other assays on the market are doing and the issues they’re facing to prevent it happening to others, too. Information on this is now visible thanks to IVDR, making it easier to prepare for regulatory adjustments.

Despite often being perceived as a burden, PMS is essentially about best practice and being able to horizon scan and have insight into how the assay is performing, thereby ensuring that the assay is meeting customer needs and giving accurate results that users can have confidence in.

Ensuring patient safety

Regulations within pharmacogenomics naturally have an impact on pharma because molecular diagnostic devices can be used to direct therapy to patients. Despite facing hurdles and tighter restrictions with IVDR, its enforcement ensures confidence in the devices available on the market, further prioritising patient safety. This, alongside appropriately labelled drugs, helps clinicians direct safe and effective treatment, with the knowledge that the device being used has undergone robust scrutiny and validation.

About the authors

Jennifer Golding has eight years’ NHS experience in cellular pathology, having attained the Certificate of Competence in Cervical Cytology in 2011 and pursued her special interests in HPV testing and male fertility analysis. Now, with four years’ commercial experience as a product manager in the molecular diagnostics industry, Golding has worked with medical devices including NGS, FISH probes, PCR assays, and NIPT technology. She has a BSc in Medical Biochemistry from the University of Birmingham and is an HCPC registered biomedical scientist.

Sophie Fairhurst has three years’ experience in life sciences marketing, working for Yourgene Health as marketing manager. Following her interests in studying science and psychology, she has worked in marketing within the biotechnology and life sciences sector, particularly in molecular diagnostics. Fairhurst has a BSc in Psychology from the University of Nottingham and two professional diplomas in marketing.