The guidance document aims to provide interested parties in particular notified bodies, device manufacturers, and medicinal product applicants, with appropriate guidance on procedural aspects to facilitate the consultation procedure to the European Medicines Agency by notified bodies on companion diagnostics (CDx), as per Article 48(3), (4), (7), and (8) of Regulation (EU) 2017/746 (In Vitro 29 Diagnostic Regulation, IVDR).

In all cases, the notified body shall seek a scientific opinion on the suitability of the CDx with the concerned medicinal product(s), from either one of the competent authorities of medicinal products designated by the Member States in accordance with Directive 2001/83/EC or from the European Medicines Agency before issuing an EU technical documentation assessment certificate for the CDx.
 

The document gives practical guidance on what should be considered for:

• The initial consultation procedure to the European Medicines Agency by notified bodies on a companion diagnostic medical device and,

• A follow-up consultation in case of changes affecting the performance and/or the intended use and/or the suitability of the device in relation to the medicinal product(s) concerned for which the notified body considers there is a need for a supplement to the EU technical documentation assessment certificate and hence a further consultation with the European Medicines Agency.
 

Practical Recommendations

• Pre-submission activities:

The notified body will inform the European Medicines Agency of the start of a procedure for the evaluation of a CDx. In addition, the notified body is expected to provide an “intention to submit letter” at least 3 months before the planned date of submission. This letter should include the date of expected submission, the name of the concerned device, the device manufacturer, the classification, its intended purpose including specific medicinal product(s) related to the device, targeted indication(s) for the medicinal product(s), information about whether the submission is initial or a change and reference to parallel medicinal product(s) procedure, if applicable.

• Data Requirements and Format of the Application Dossier:

Each application for consultation for a CDx shall be submitted to the European Medicines Agency using the relevant application form, that can be found on the European Medicines Agency website and containing the information described in this document.

The consultation procedure by the CHMP/CAT should focus on the suitability of the CDx for use with the concerned medicinal product(s). The aspect of “suitability” relates to the use of a CDx with (a) particular medicinal product(s), given the performance and use claimed by the manufacturer.

The application dossier should contain sufficient information about the scientific validity and/or scientific rationale for the use of the biomarker, device measurement characteristics, device development characteristics, analytical and clinical performance. For co-developed devices, it is the expectation that a summary of the results/data in the SSP and IFU will be considered sufficient taking into account that an in-depth assessment is largely performed as part of the assessment of the marketing authorization application(s) for the concerned medicinal product(s).
 

Consultation Procedure to the European Medicines Agency

The applicant for the consultation procedure is the notified body in accordance with the legal provisions of Regulation (EU) 2017/746. The CAT/CHMP assessment will follow a 60-day timetable. In case issues that prevent the adoption of a scientific opinion are identified (i.e. justified grounds), there is a possibility for an extension of up to a maximum of 60 days. An opinion for the consultation procedure for the CDx will be issued at the latest by the end of the extension, taking into account where applicable clarification provided by the notified body. After the evaluation period, the CHMP/EMA will issue a scientific opinion on the suitability of the device in relation to the medicinal product concerned. The CHMP opinion is sent to the notified body. In the case of an ATMP, the CHMP opinion will be based on a draft CAT opinion. The notified body will give due consideration to the opinion of the European Medicines Agency when making its decision and will convey its final decision to the Agency. As regards to the time point to start the CDx consultation procedure vis a vis the medicinal product marketing authorization or extension of indication, there is no legal requirement that the medicinal product approval and the device certification are simultaneous. For co-developed devices, early interactions between the Agency and the relevant notified body are recommended to agree on the submission date for the CDx consultation procedure. For devices already marketed under Directive 98/79/EC which are transitioning to the IVDR and follow241 on devices, the start for the CDx consultation procedure can be at any time according to CAT/CHMP 242 timetable, as it is anticipated to be independent of a medicinal product procedure. In case the same existing test may be used for several authorized medicinal products, it is recommended to proceed with one single CDx consultation procedure.
 

Post-Consultation Phase

In accordance with point (f) of Section 5.2 of Annex IX of the IVDR, where changes are made to a CDx that affect the performance and/or the intended use and/or its suitability in relation to (a) medicinal product(s), the manufacturer must inform the notified body of the changes. The notified body must assess the changes and consult the Agency in case it identifies the need for a supplement to the EU technical documentation assessment certificate. The European Medicines Agency will give its opinion within 30 days of receipt of all the necessary documentation regarding the changes. In case the notified body considers that a new conformity assessment under Article 48 has to be followed, a new initial consultation will be required (i.e. 60 days)