Companion diagnostics (CDx) are essential tools in personalized medicine, enabling the safe and effective use of specific drugs. These diagnostic devices help identify patients that are most likely to benefit from a particular treatment, assess their suitability for therapies, and monitor their responses. Clinically validated CDx play a crucial role in determining a patient’s likelihood of responding to targeted treatments.

The In Vitro Diagnostic Regulation (IVDR 2017/746), which fully replaced the In Vitro Diagnostic Directive (IVDD 98/79/EC) in May 2022, introduced stricter requirements for all in vitro diagnostic devices (IVDs), including CDx. The new regulatory framework significantly impacts the development, approval, and commercialization of CDx, posing new challenges for manufacturers.

This article explores the key regulatory changes introduced by IVDR and their impact on CDx manufacturers.

Key Timelines

To support the continued availability of IVDs, the European Commission extended the IVDR transition period. This extension applies only to legacy devices: those placed on the market before May 26, 2022 with a valid IVDD certificate or declaration of conformity.

• Class A devices (except sterile Class A) are not eligible for the transitional period and were required to comply with IVDR requirements beginning on May 26, 2022.
• All new IVDs placed on the market after May 26, 2022 must fully comply with the IVDR.

1. IVDD certified devices: Devices with a IVDD certification from a notified body (NB) issued before May 26, 2022.

2. IVDD self-certified devices: IVDs on the market that did not require an NB certification under IVDD.

Key Changes Introduced by IVDR That Impact CDx

The IVDR represents a significant shift from the IVDD, requiring manufacturers to adapt to a more stringent regulatory landscape. The transition involves more rigorous certification processes, closer alignment with the medicinal product regulatory framework, and continuous compliance obligations. As this is a relatively new process, manufacturers and regulators are still navigating the complexities, making the transition period particularly challenging.

Certification Process and Notified Body Involvement

Under the IVDD, most CDx were self-certified by manufacturers. However, under the IVDR, CDx are now classified as Class C devices, requiring involvement from an NB for certification. To obtain the CE mark, CDx manufacturers must submit a technical package to the NB and undergo a conformity assessment procedure.

Interaction With the European Medicines Agency and Medicinal Products Regulatory Framework

Since CDx are closely linked to specific medicinal products, their regulatory assessment must align with the drug approval process. The IVDR requires the NB to submit a letter of intent to the European Medicines Agency to obtain a scientific opinion confirming that a CDx is appropriate for its intended use with the corresponding medicinal product. For successful approval, CDx manufacturers must navigate both the IVD and medicinal product regulatory frameworks, ensuring alignment throughout product development. This dual compliance introduces challenges in interpreting and applying both sets of regulations.

Stricter and Continuous Compliance Requirements

The IVDR raises the bar for clinical evidence, demanding rigorous validation:

• Analytical validity to confirm that the test accurately and reliably detects the biomarker
• Scientific validity to show that the biomarker is scientifically linked to the disease or therapy
• Clinical validity and utility to prove that the CDx provides clear benefits in guiding treatment decisions

Once approved, CDx manufacturers must conduct post-market surveillance to monitor performance and detect potential issues. Post-market surveillance data must be regularly reported to NBs as part of the Performance Evaluation Procedure, ensuring continuous compliance with IVDR.

Conclusion

The IVDR introduced a more stringent regulatory framework for CDx, impacting approval processes, compliance obligations, and interaction with medicinal product regulations. While these changes aim to enhance patient safety and diagnostic reliability, they also present significant challenges for manufacturers navigating the evolving regulatory landscape.

Manufacturers must coordinate with pharmaceutical companies to ensure regulatory alignment and timely submissions.  A meticulously planned and executed regulatory strategy is key to generating robust validation and data that will lead to simultaneous CDx-drug market access approval.