Companion Diagnostic (CDx) Regulatory Challenges in the EU

What are companion diagnostics (CDx)?

The success of several drug developments requires an in-vitro diagnostic medical device (IVD). In a laboratory setting, this IVD can be used to determine if a drug target is present in the patient. In hospitals, physicians can use the analysis from this IVD to identify suitable patients for certain therapies. Companion diagnostic (CDx) is a type of IVD used with a medicinal product to ensure safe therapy development and patient management.

Presently, clinical practice relies heavily on the in-vitro analysis of biological specimens derived from patients to support and guide diagnosis, therapeutic monitoring and decisions. CDx plays a crucial role in personalised medicines, which aim to determine a customised therapy for each patient according to their genetic makeup. Precision or personalised medicine translates patient-specific genetic, clinical, and environmental information into patient-specific therapeutic interventions. This shifts the focus from traditional trial-and-error medicines to more personalised therapeutic strategies.

Patients’ blood and tissue biomarkers can be tested and characterised using companion diagnostic (CDx). In oncology practice, CDx is a biomarker-based assay that enables the selection of appropriate therapeutic interventions, thus optimising disease outcomes ^[1].

Typically, CDx platforms include:

• Immunohistochemistry (IHC)
• Quantitative and qualitative polymerase chain reaction (PCR)
• Next-generation sequencing (NGS)
• Fluorescent or chromogenic in-situ hybridisation (FISH/CISH)

Previously, under the EU In-Vitro Diagnostic Medical Device Directive (IVDD), CDx was not officially defined nor recognised. Before the IVDR, CDx were considered low-risk devices, meaning they could be self-certified by manufacturers^[2]. The new EU In-Vitro Diagnostic Medical Device Regulation (IVDR) officially defines ‘companion diagnostic’ (Article 2) as “a device which is essential for the safe and effective use of a corresponding medicinal product to:

1. a) Identify, before and/or during treatment, patients who are most likely to benefit from the corresponding medicinal product; or
2. b) identify, before and/or during treatment, patients likely to be at increased risk for serious adverse reactions due to treatment with the corresponding medicinal product” ^[3].

Who are CDx relevant for?

Both medicinal product and IVD sponsors should familiarise themselves with the regulatory basics of IVDs and specific requirements for the authorisation of CDx. Understanding the interdependencies between the IVD and the medicinal product(s) is also important.

What are the key regulatory features of the IVDR regarding CDx?

The IVDR establishes a new risk-based classification system which consists of Classes A, B, C, and D in order of lowest to highest risk (for individual and public health risk). This results in up-classifying up to 90% of IVDs currently marketed in Europe. Accordingly, CDx is considered a Class C device. This translates into a need for Quality Management Systems (QMS) and the extensive revision of Technical Documentation (TD). Consequently, CDx must also undergo conformity assessment procedures, in which the Notified Body (NB) is required to consult the respective Competent Authority (CA) for medicinal products according to the 2001/83/EC directive or the European Medicine Agency (EMA)^[3].

Requirements for clinical evidence of CDx are similar to those of IVDs, where the performance evaluation must demonstrate scientific validity, analytical performance, and clinical performance. Specifically for clinical performance, CDx manufacturers must show that the CDx under evaluation can identify patients for a specific therapy based on a particular biomarker.

Three main factors that can affect the approval process for CDx in the EU:

• Data availability: The NB and the EMA will need access to data from clinical trials demonstrating the safety and effectiveness of the CDx.
• CDx complexity: The more complex the CDx, the more difficult it will be to assess its safety and effectiveness.
• CDx technology novelty: If the CDx involves new technologies or indications, the EMA and the NB will need to take a more cautious approach to its approval. Different scenarios will play a role in the extent of scrutiny involved, including co-developed CDx scenarios, follow-on CDx, and CDx already on the market under the old IVDD (In Vitro Diagnostic Directive).

The regulatory interplay of companion diagnostic and medicinal products in the EU

In the past decades, advances in molecular diagnosis technology, such as PCR and NGS, have enabled researchers and physicians to determine the genetic information of tumours quickly and inexpensively. In clinical oncology, CDx is a key diagnostic tool that facilitates the development of personalised therapies that can target specific abnormalities in each patient’s cancer. Consequently, developing biomarker-based assays, or CDx, is often linked to developing and validating the corresponding medicine(s)^[1].

In the EU, the legal basis of the certification for CDx is different and independent from that required for medicinal products. Thus, synchronising these procedures is not legally required^[4]. The IVDR requires that the Summary of Safety and Performance (SSP) and Instructions for Use (IFU) of the CDx mention the International Nonproprietary Name (INN) of the associated medicinal product for which it is a companion. In contrast, the medicinal product legislation does not differentiate between a predictive biomarker test and European conformity (CE)-marked CDx and currently does not include any specific provision for communicating information on a diagnostic test in the medicinal product information^[4].

On 17th June 2022, the EMA published the “Guidance on the procedural aspects for the consultation to the European Medicines Agency by a notified body on companion diagnostics”. The guidance aims to provide NBs, device manufacturers, and medicinal product applicants with practical guidance for the consultation procedures regarding CDx^[5]. Before issuing the CE marking, the NB shall consult with the EMA for the scientific opinion regarding the suitability of the CDx device to the concerned medicinal product. The scientific opinion is based on the draft instructions for use (IFU) and draft summary of safety and performance (SSP). The time frame for the consultation is 60 days, with the possibility of an extension for another 60 days^[5].

Other guidelines for CDx

• The Medical Device Coordination Group (MDCG) has recently updated the SSP template^[6]. This updated template aims to ensure that consistent information is provided in the SSP of CDx, thus facilitating the assessment of the suitability of CDx during the consultation procedures.
• To address issues related to CDx and to facilitate co-development of CDx and medicines, the MDCG published “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)”. This document aims to clarify certain interfaces between the CTR and the IVDR and to support the conduct of clinical trials using diagnostic assays, including combined trials for the development of CDx^[7].
• MedTech Europe published “Clinical Evidence Requirements for CE Certification under the In-Vitro Diagnostic Regulation in the European Union.”
• MedTech Europe and the European Federation of Pharmaceutical Industries and Associations (EFPIA) released a document regarding unclear regulatory issues and suggestions for solutions.
• EMA’s “Concept paper on predictive biomarker-based assay development in the context of drug development and lifecycle.”

Concluding remarks

The development of CDx presents significant potential to advance personalised medicines, thus improving patient access to innovative pharmaceutical products and diagnostic methods. To meet the complicated regulatory requirements of IVDs, collaboration is needed between medicine and CDx developers from an early development stage onward. This means that early planning and effective communication is crucial. Close dialogue among stakeholders (NB and the EMA, CDx and drug sponsors) will have to be established to clarify the scope of assessments performed by the different parties to align the timing of assessment procedures for both medicinal products and CDx. Thus, this will ensure transparency and consistency regarding the level of information provided on the CDx in the product information of the medicine. Successful development and certification of CDx will provide significant patient benefits and facilitate access to innovative therapeutic interventions.

How can PLG help you?

PLG has a strong and specialised regulatory and compliance team that can accommodate you throughout the product life cycle from CDx development and approval to post-market surveillance (PMS):

• Guidance on IVDR requirements: Identify the specific requirements of the CDx based on its intended use (e.g. patient selection for a certain therapy versus monitoring of a patient’s response to therapy) and support for lab-developed tests (LDTs) requirements.
• Market access strategy: Health Technology Assessment (HTA), pricing and reimbursement option per country.
• Pre-clinical and clinical support: gap analysis, design and/or review of the Performance Evaluation (PE) plan, selection and management of the Contract Research Organization (CRO).
• Quality compliance: Assess QMS needs to set up the QMS following the risk-based approach.
• Support for NB assessment: Thanks to our privileged access to 6 NBs, PLG can assist you with compiling and submitting TD and quality-related documents for your CDx.
• Device registration: IVDR compliant CE marking and 510(k) FDA’s approval.
• PMS support: implement PMS processes, evaluate Post-Market Performance Follow-up (PMPF), and monitor and analyse CDx’s performance in clinical settings, thanks to our networks with strong CROs.

Contact us at [email protected] to learn how we can help you get your CDx ready for the IVDR full implementation by May 2026 (the extended deadline for Class C IVDs). See our recent publication, “New IVDR Transition Periods,”  for more information regarding the transitional provisions of the IVDR.

Sources

[1]        V. Valla, S. Alzabin, A. Koukoura, A. Lewis, A. A. Nielsen, and E. Vassiliadis, “Companion Diagnostics: State of the Art and New Regulations,” Biomark. Insights, vol. 16, pp. 1–14, Jan. 2021, doi: 10.1177/11772719211047763.

[2]        A. M. M. Hermans, M. Maliepaard, W. P. C. Boon, and A. M. G. Pasmooij, “Impact of the new European Union In Vitro Diagnostics Regulation on the practice of hospital diagnostic laboratories,” Expert Rev. Mol. Diagn., vol. 22, no. 5, pp. 583–590, May 2022, doi: 10.1080/14737159.2022.2087508.

[3]        “Regulation (EU) 2017/746 of the European Parliament and of the Council of 05th April 2017 on in vitro diagnostic medical devices and repealing Directive 98/79/EC and Commission Decision 2010/227/EU.” Official Journal of the European Union, 05th May, 2017.

[4]        Ciska Verbaanderd et al., “Biomarker‐Driven Developments in the Context of the New Regulatory Framework for Companion Diagnostics in the European Union,” Clin. Pharmacol. Ther., vol. 114, no. 2, pp. 316–324, May 2023.

[5]        “Guidance on the procedural aspects for the consultation to the European Medicines Agency by a notified body on companion diagnostics.” European Medicines Agency, 17th June, 2022.

[6]        “MDCG 2022-9 Summary of safety and performance (Template).” Medical Device Coordination Group, May 2022.

[7]        “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).” Medical Device Coordination Group and Clinical Trials Expert Group, May 2022.