The field of companion diagnostics IVD (CDx) represents a confluence of technological innovation, regulatory compliance, and patient care. As personalized medicine becomes an integral part of healthcare, the regulatory framework governing CDx, including the In Vitro Diagnostic Medical Devices Regulation (IVDR), has become more complex. This scenario calls for a specialized companion diagnostics consultancy. MDx CRO is at the forefront of this arena, offering expertise and guidance in the process for CDx consultation with the European Medicines Agency (EMA), Notified Body preparation and IVDR compliance within the European Union (EU).

Companion Diagnostics IVD and their Role

CDx are in vitro diagnostic (IVD) tests designed to provide information that is essential for the safe and effective use of a corresponding medicinal product. Their applications could include:

• Identifying patients who are most likely to benefit from a particular therapeutic product.
• Determining patients’ suitability for specific treatments.
• Monitoring responses to ongoing treatments.

The Impact of IVDR on Companion Diagnostics

The IVDR sets out robust legal requirements for in vitro diagnostic medical devices, including CDx. Key aspects include:

• Enhanced Patient Safety: Ensuring the quality and reliability of CDx IVDs.
• Stricter Oversight: Increased scrutiny of the CDx development and approval process. Unlike the previous directive, CDx now require conformity assessment by a Notified Body, an independent organization designated to assess the compliance of medical devices and in-vitro diagnostics. In addition, CDx are also assessed by a medicines authority, most likely the EMA (European Medicines Agency), but a competent authority could also be involved .
• Comprehensive Technical Documentation: Increased clinical evidence requirements are particularly notable in the IVDR. MDx CRO can help CDx manufacturers and their drug partners gather the necessary data to support their CDx application. This data may include clinical trial data (clinical performance data), analytical data, and safety data. Manufacturers must provide robust clinical evidence to demonstrate the performance, safety, and clinical utility of the CDx.

There are a number of other factors that can affect the approval process for CDx in the EU. These factors include:

• The availability of data: Both the Notified Body and the EMA will need to have access to data from clinical trials that demonstrate the safety and effectiveness of the CDx.
• The complexity of the CDx: The more complex the CDx, the more difficult it will be to assess its safety and effectiveness.
• The novelty of the CDx: If the CDx involves new technologies or indications, the EMA and the Notified Body will need to take a more cautious approach to its approval. Different scenarios will play a role on the extent of scrutiny involved, including co-developed CDx scenarios, follow-on CDx, and CDx already on the market under the old IVD directive.

Understanding the EMA Companion Diagnostics Consultation Procedure

The consultation procedure is initiated by the notified body when it receives an application from a CDx manufacturer. The medicinal product involved could be a medicine already authorised for marketing in the EU or a medicine undergoing approval. Aligning drug and diagnostic development processes can help to ensure that the results of the clinical trials are accurate and reliable, and that the medicine is safe and effective when used with the CDx.

Upon application for a CDx IVD approval, the notified body will submit a letter of intent to the EMA, along with a technical dossier that describes the CDx and the medicinal product.

The EMA will then appoint a rapporteur, who will be responsible for reviewing the technical dossier and issuing a scientific opinion on the suitability of the CDx for use with the medicinal product. The rapporteur will also consider the views of any other interested parties, such as the applicant for the medicinal product, the manufacturer of the CDx, and patient groups.

The EMA will provide its scientific opinion on the CDx aspects that relate to the medicine to the notified body. The notified body will then use the EMA’s opinion to make a decision on whether to grant the CE mark to the CDx, in accordance with the regulatory requirements of the in vitro diagnostics regulation (EU IVDR).

EMA procedure timetables play a major role in the success of the consultation and turn around times for responses can be extremely short. Manufacturers should factor this in as they plan for their CDx submissions. There is the possibility to request a pre-submission meeting which will include representatives from Notified Bodies, EMA and could also include the drug manufacturer – this is used strictly to align on procedural and timing considerations (it is not used to provide feedback on study design or the content of the technical documentation).

One of the key documents used in the consultation and submitted by the notified body to the EMA is the SSP (Summary of Safety and Performance). The EMA expects manufacturers to use the SSP template provided in MDCG 2022-9. A lot more detail is expected in the SSP when compared to the information provided in the IFU. For example, detail on concordance studies is needed, particularly for co-developed CDx when different versions of a diagnostic have been used throughout the clinical development program.