Definition and classification

A companion diagnostic is defined in article 2(7) of Regulation (EU) 2017/746 (in vitro diagnostic medical device regulation, IVDR) as follows:

"companion diagnostic" means a device which is essential for the safe and effective use of a corresponding medicinal product to:

• identify, before and/or during treatment, patients who are most likely to benefit from the corresponding medicinal product; or
• identify, before and/or during treatment, patients likely to be at increased risk of serious adverse reactions as a result of treatment with the corresponding medicinal product

Whether an IVD fulfils the criteria of a CDx depends essentially on whether the detection of the biomarker status is absolutely necessary for the therapy decision in order to ensure the safe and effective use of the medicinal product. The analytical quality of detecting a certain biomarker only is not a sufficient criterion for a CDx.

Recital 12 of the IVDR also points out that devices used for "monitoring" are not included in the definition of a CDx:

Devices that are used with a view to monitoring treatment with a medicinal product in order to ensure that the concentration of relevant substances in the human body is within the therapeutic window are not considered to be companion diagnostics (recital 12, IVDR).

A classification system (classes A to D) was introduced when the IVDR came into force. This classifies CDx at least as class C device (IVDR, Annex VIII, rule 3f: Devices are classified as class C if they are intended to be used as companion diagnostics). For guidance on the interpretation of the individual classification rules including examples, see the MDCG 2020-16 guideline published by the Medical Device Coordination Group (MDCG) of the EU.

Areas with special regulatory requirements for CDx according to IVDR

CDx are subject to additional regulatory requirements in several areas.

Consultation

In the course of the conformity assessment of CDx, the notified body shall seek a scientific opinion from the competent authority responsible for the authorisation of the medicinal product (national authority or EMA) and shall give due consideration to the scientific opinion (article 48 IVDR). The EMA has published information and guidance on the consultation procedure in the form of a guideline and other documents on the EMA website under the subheading "Companion diagnostic":

EMA - Companion diagnostics

Contact persons for questions regarding the conformity assessment procedures are the notified bodies:

Notified Bodies IVDR

For general information on drug approval and contact persons see:

BfArM - Medicinal product licensing

Performance studies with CDx  

For the approval of performance studies for companion diagnostics (CDx performance studies), the same requirements apply in principle as for all IVD performance studies. According to the IVDR, interventional clinical performance studies are subject to approval. CDx performance studies in which only left-over samples are used are special: They must be notified to the competent authority (article 58 IVDR). Depending on the product, either the BfArM or the PEI is responsible in Germany (§ 85 MPDG).

The recitals of the IVDR also emphasise that all general requirements, and other additional requirements relating to data protection, as well as the requirements applicable to procedures conducted in accordance with national law - such as ethical approval - also continue to apply to all performance studies, including those using left-over samples (recital 73 IVDR). CDx performance studies with left-over samples that are notifiable in Germany thus require an evaluation by an ethics committee.

For more information and answers to frequently asked questions about performance studies, see the BfArM website of clinical investigations and performance studies.

Risk assessment for incident reports on CDx

According to the IVDR, the assessment of incident reports after the market placement of a CDx is basically carried out in the same way as for all other IVDs. In the case of CDx, the evaluating competent authority also informs the competent authority of the Member State or the EMA, depending on which body was contacted by the notified body in the course of the conformity assessment procedure (article 84, 6 IVDR).

Responsibilities at national level

The responsibilities of the two higher federal authorities, BfArM and PEI, are regulated at national level in the MPDG (§ 85 MPDG).

Table: Allocation of responsibilities to the higher federal authorities, BfArM and PEI, for class C CDx (rule 3f, Annex VIII, IVDR) according to Section 85 MPDG. The responsibility for the medicinal product is regulated in the German Medicines Act (Section 77 (2) AMG).

	BfArM	PEI
performance studies	Authorisation or, in the case of use of left-over samples, notification if responsible for medicinal products	Authorisation or, in the case of use of left-over samples, notification if responsible for medicinal products
consultation	Scientific opinion, if responsible for medicinal products (rapporteur)*	Scientific opinion, if responsible for medicinal products (rapporteur)*
vigilance	Risk assessment of all CDx	statement to BfArM if PEI is responsible for the medicinal product
classification / legal status	Decision	no competence
requirement to approve a performance study	Decision	no competence

* EMA-guidance on procedural aspects for the consultation to the EMA by a NB

Class C CDx fall under the responsibility of the BfArM. An exception is the approval of an application for a performance study involving a CDx. If the associated medicinal product falls within the responsibility of the PEI according to Section 77 (2) AMG, the application for approval of the corresponding performance study must be submitted to the PEI. Notifications of CDx performance studies in which only left-over samples are used are also notified to the higher federal authority responsible for the medicinal product.
BfArM is responsible for processing risk reports after the market placement of class C CDx. However, the MPDG stipulates that the BfArM must obtain an opinion from the PEI if the associated medicinal product is within the PEI's area of responsibility.

Further information: Dialogue

In May 2022, the two higher federal authorities PEI and BfArM invited to a joint dialogue to provide information on the changes to legal requirements and practical framework conditions for placing IVD on the market, approval and implementation of performance studies with IVDs, and product use risk assessment.   

Event of 11. May 2022: "IVDR: New regulations for IVDs and companion diagnostics (CDx)" - Joint dialogue event of PEI and BfArM, event language: German

Within the scope of its competence, the BfArM provides support through various advice procedures to discuss scientific or procedural issues.

Advice Procedures BfArM