European Regulations for Companion Diagnostics (CDx): Navigating the CE Marking Pathway to Market

European Regulations for Companion Diagnostics (CDx): Navigating the CE Marking Pathway to Market

Companion diagnostics (CDx) play a big role in personalised medicine and are increasingly vital in modern medicine. In accordance with the European Union In Vitro Diagnostic Medical Devices Regulation (EU) 2017/746 (IVDR), CDx devices must undergo conformity assessment by a notified body to obtain CE marking for entry into the EU market. It’s advisable for applicants/manufacturers to plan CDx development as early as possible during drug development to ensure timely access to new medicines for patients.

It should be noted that devices manufactured and used only within health institutions established in the Union (“in-house devices”) are conditionally exempted from most of the requirements of the IVDR. The use of “in-house” devices is limited to within one legal entity.

What is the Definition of a CDx? 

Under article 2 of the IVDR now legally defines CDx for the first time as follows:

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

(i) Identify, before and/ or during treatment, patients who are most likely to benefit from the corresponding medicinal product; or

(ii) 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.”

Notably, other regulatory authorities already established the term companion diagnostics, which include Japan (PMDA) in 2012, the USA (FDA) and Canada (HCSC) in 2014. The only major difference between the IVDR definition compared to other regulatory authorities, is that IVDR specifically excluded devices that are used for treatment monitoring of a medicinal product.

 

What are the CDx Development Scenarios? 

For CDx development, there are usually three scenarios:

Co-developed CDx: A device that is developed in a clinical development program together with the concerned medicinal product, either in view of an initial marketing authorisation or a change of the indication.

Follow-on CDx: A device that seeks the same indication in its intended use as the co-developed CDx (hereafter, the original CDx). The follow-on CDx targets the same biomarker but is not developed in parallel with the clinical development program of the medicinal product and is not necessarily based on the same technology as the original CDx.

Devices that are already on the EU market under the In Vitro Diagnostic Medical Devices Directive 98/79/EC (IVDD) or that are transitioning to the IVDR as a CDx, fall under the co-developed or follow-on scenarios above, depending on how they were initially developed.

What Classification rules do CDx devices fall under?

The classification of a CDx depends on which legislation it currently complies but generally they fall under the following:

IVDD IVDR
CDx were classified as general IVDs (low risk) for which the manufacturer self-certifies conformity on the condition that the IVD meets the “essential requirements”.

The IVDR now applies rules and assigns each device to one of the four risk categories ranging from class A (lowest risk) to class D (highest risk).

CDx devices fall under rule 3(f), and most CDx are classified as class C devices (i.e., high individual risk and/or moderate public health risk).

CDx device under the IVDD is classed as a self-certified device which means the manufacturer could self-declare and place product on the market by registering with the competent authority with no Notified Body review.

For CDx devices under IVDR, the quality management system and technical documentation concerning the IVD are subject to a conformity assessment performed by a notified body. In addition, the medicines regulatory authorities, including European Medicines Agency (EMA) assume a responsibility in reviewing the “suitability” of the CDx in relation to the corresponding medicinal product.

Interaction amongst Manufacturers, Medicine Regulatory Authorities and Notified Body

IVDR introduces an important link between the assessment of a CDx by a notified body and the corresponding medicinal product by medicines regulators 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 EMA or National Competent Authority (NCA). 

  1. Initially, the CDx manufacturer shall send an application to the notified body for the assessment of the technical documentation.
    • Manufacturers can request a pre-submission meeting with both NCA/EMA and Notified body.
  1. The notified body will assess the CDx application which usually takes longer than standard conformity assessments for IVD’s.
    • The application shall enable the characteristics and performance of the device to be understood and shall enable conformity with the design-related requirements of the regulation to be assessed with regards to the suitability of the CDx device in relation to the medicinal product concerned.
  1. As part of conformity assessment, the notified body is expected to seek a scientific opinion on the suitability of the CDx with the concerned medicinal product(s) from the NCA/EMA.
    • The Notified body is expected to provide an “intention to submit letter” at least 3 months before the planned date of submission.
    • Summary of Safety and Performance (SSP) and Instruction for Use (IFU) will be submitted to NCA/EMA. g. The EMA expects manufacturers to use the SSP template provided in MDCG 2022-9 – Summary of Safety and Performance template.
    • NCA/EMA consulted shall provide its opinion, within 60 days of receipt of all the necessary documentation.
  1. The notified body gives due consideration to the scientific opinion by the EMA when making its decision. The notified body will convey its final decision to the medicinal products authority consulted.

As a general principle, early interactions between the NCA/EMA and the relevant notified body are recommended to enable timely access for patients to both the medicinal product and the CDx.

Tips to bring your CDx device to the EU market:

STEP 1: Define the Intended Purpose and the Classification

  • All CDx devices are in risk class C under Annex VIII, rule 3 of the IVDR
  • In case the intended purpose of a device includes several authorised medicinal products and indications, it is recommended to proceed with one single CDx consultation procedure to facilitate the assessment.

STEP 2: Quality Management System (QMS)

  • Set up the QMS according to Article 10 (8) – General obligations of manufacturers of the IVDR and the applicable clauses of ISO13485:2016, focusing on a risk-based approach.
  • Requirements for maintaining a risk management system (refer to Article10(2)) differs according to IVD class and must cover the entire lifetime of the device. Following ISO 14971-  Medical devices — Application of risk management to medical devices will assist with meeting the regulatory obligations of risk.
  • If there is an existing QMS, perform a gap analysis especially covering product design and development, post-market surveillance, risk management, and performance evaluation.

STEP 3: Technical Documentation and Performance evaluation

 The clinical evidence follows the same process for other IVDs: scientific validity, analytical performance and clinical performance.

  • The scientific validity should also clarify the clinical performance of the associated medicinal product in the patient population stratified/selected by the CDx device.
  • The analytical performance evaluation should be completed before the clinical trial of the medicinal product is started.
  • For the clinical performance, the manufacturer needs study data that shows that the CDx device is able to stratify or identify patients for a specific therapy based on a particular biomarker.
    • Adopting EN ISO 20916 – In vitro diagnostic medical devices. Clinical performance studies using specimens from human subjects, for clinical performance study design and conduct. Note: EN ISO 20916:2024 (European Standard) were released at the end of March 2024 harmonizing IVDR Performance Studies.
    • Ensure that all required EC and NCA study approvals for the medicinal product and the CDx study part are obtained.

STEP 4: Conformity Assessment:

  • Normally, the conformity assessment for class C devices is only carried out on one representative device per generic device group. However, it is different for CDx: Art. 48(7) – Conformity Assessment procedure of the IVDR states that each individual CDx device must go through the procedure. This means CDx manufacturers cannot take advantage of device groups.
  • However, if a device’s intended purpose includes several authorised medicinal products and indications, this can be proceeded with one single CDx consultation procedure. All concerned medicinal products should be listed in the ‘intention to submit letter’ by the Notified Body and in the application form.

Final Thoughts….

In summary, CDx devices play a vital role in modern medicine, requiring careful planning, adherence to regulatory standards, and collaboration among stakeholders to ensure safe and effective use in personalised healthcare.

Still unsure what to do? LFH Regulatory can help…

We can help you navigate European Regulations for Companion Diagnostics (CDx) and streamline your device to market. Contact us today phone +441484662575 or via info@lfhregulatory.co.uk. Alternatively, you can also simply complete the ‘Contact Us’ section below to see how we can help.

References:

  1. Frequently asked questions on medicinal products development and assessment involving companion
  2. Guidance on the procedural aspects for the consultation to the European Medicines Agency by a notified body on companion diagnostics
  3. MDCG 2022-10: Q&A on the interface between Regulation (EU) 536/2014 on clinical trials for medicinal products for human use (CTR) and Regulation (EU) 2017/746 on in vitro diagnostic medical devices  IVDR
  4. MDCG 2023-1: Guidance on the health institution exemption under Article 5(5) of Regulation (EU) 2017/745 and Regulation (EU) 2017/746
  5. MDCG 2022-9: Summary of safety and performance Template 


Written by Dr Yupei Xiao, Clinical and Regulatory Consultant. Dr Xiao has over 10 years of experience within the IVD and medical device industry. She has expertise in clinical and regulatory affairs for IVD product, medical and regulatory writing.

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