Companion diagnostics: Best practices for effective collaboration
Keywords – companion diagnostic, co-development, in vitro diagnostic, FDA, EMA
Introduction
Target-driven drug development has ushered in a new era in precision medicine. Alongside these contemporary, target-driven approaches to developing therapeutics, there is a need to measure these targets with high sensitivity and specificity. Novel diagnostic tests and medical devices are increasingly being used as tools in clinical trials for purposes such as patient selection (e.g., inclusion and exclusion criteria), safety and monitoring, and surrogate endpoints.A companion diagnostic is defined by the US Food and Drug Administration (FDA) and EU regulators as a medical device, often an in vitro diagnostic, that is essential for the safe and effective use of a corresponding therapeutic product. CDx products help identify patients most likely to benefit from treatment, those at increased risk of adverse effects, or those who require treatment monitoring to support safe and effective use. FDA data indicate a significant increase in CDx approvals since 2017, reflecting their growing importance in precision medicine.1 Notably, this growth occurred during the COVID-19 pandemic, even as the agency and much of the industry were focused on developing tests to combat the SARS-CoV-2 virus.
Regulatory requirements for in vitro diagnostics (IVDs) and CDx are well established in many regions, including, but not limited to, the US, EU, Japan, China, and the UK. While regional definitions generally align on the need for a CDx to support the safe and effective use of a therapeutic, requirements for clinical trial initiation and market authorization differ across jurisdictions. It is essential to develop analytical validation and global submission plans in close collaboration with IVD partners to ensure regulatory compliance and timely authorization aligned with therapeutic asset development timelines.
The use of CDx tests as enabling technologies for therapeutic products is a broad subject with many nuances. This article focuses on market authorization for CDx tests in the US and EU, excluding clinical study authorization and implementation in other markets. This narrow scope was selected due to time and space constraints. However, the two topics not covered in this article – clinical study authorization of CDx tests (and the associated regulatory burdens) and differences in CDx policy across global markets – remain significant issues that warrant further discussion.
Effective collaboration among pharmaceutical companies, diagnostic companies, and health authorities is crucial for the development of CDx. Regulatory teams must align strategies for drug and diagnostic approvals, with support from agencies such as the FDA, including its Center for Drug Evaluation and Research and Center for Devices and Radiological Health, and from European regulators such as the European Medicines Agency (EMA) and notified bodies. This multistakeholder coordination is shown in the accompanying Figure 1.
Figure 1. Multistakeholder coordination for CDx development
Pharmaceutical company perspective
Biomarkers and diagnostics are used in many ways in therapeutic development. However, not all biomarkers used in clinical trials are subject to global IVD or CDx regulations. Given the diverse applications of biomarkers in clinical trials, it is essential to clearly define and categorize their intended use to ensure the appropriate regulatory requirements are identified and met. Figure 2 illustrates the levels of regulatory expectations according to the use of the biomarker within a clinical trial.Figure 2. Purpose of biomarker tests and related levels of regulatory expectation2,a
At the bottom tier, exploratory biomarkers, often used solely for research or discovery, carry low regulatory expectations because they are not involved in medical management or patient care decisions. In the next tier, biomarkers used for stratification or surrogate endpoints inform clinical trial design or subgroup analyses, or may be used to balance treatment arms. These applications are associated with moderate regulatory expectations. Although these biomarkers do not guide individual treatment decisions, they may indirectly influence patient management by shaping trial design. It is essential to note that health authorities may request data on these subgroup analyses and, in the interest of patient safety, may restrict the intended-use population of a drug, even if the subgroups are not statistically powered to draw definitive conclusions.
The next tier shows how regulatory expectations increase when biomarkers are used to monitor patient safety, screen patients, or provide prognostic information on the course or outcome of a disease or medical condition. Since these biomarkers support clinical decision making, they are subject to higher regulatory expectations and begin to fall under diagnostic regulations due to their direct impact on patient care decisions.
At the top tier, biomarker tests used for patient selection or predictive purposes require the highest level of regulatory oversight due to their essential role in ensuring the safe and effective use of therapeutic products. When investigational biomarkers are used to guide treatment decisions or identify patients for specific therapies, global IVD and CDx regulations should be considered to prevent noncompliance or delays in clinical trials.
Diagnostic company perspective
Companion diagnostics are critical to precision medicine. However, because CDx are fundamentally tools to enable patient selection for a precision therapeutic, developers are frequently subject to the timelines and goals of the drug sponsor. Diagnostic sponsors engaged in CDx development should be aware of several challenges that may arise during product development, approval, and postmarket activities.Product development
Drug sponsors may realize late in clinical development that a companion diagnostic is required or desirable. Early phase studies may have involved an all-comers approach, in which patients are enrolled regardless of biomarker status and without predefined specifications for a CDx assay. As such, CDx developers should be prepared to rapidly align with an already mature therapeutic development program. This requires diagnostic developers to be prepared to capture product requirements quickly and efficiently to enable assay deployment in a timely manner.
Drug sponsors also frequently initiate registrational studies without a clear strategy for collecting sufficient clinical samples during pivotal studies to support CDx validation. Clinical trial programs often do not collect any biomarker-negative samples and frequently retain only a fraction of samples from the enrolled patient population for diagnostic regulatory filing studies. This disconnect means that diagnostic sponsors should be prepared to procure relevant clinical samples from other sources, including biobanks, biomarker-negative samples from early clinical studies, and from routine clinical practice outside of the therapeutic development program.
Missing samples and discordance between the clinical trial assay used in pivotal studies and the CDx ultimately submitted for regulatory approval can complicate statistical analyses. Sensitivity analyses and the use of representative sample pools are essential to address these issues.
Regulatory approval and postmarket considerations
Regulatory review and approval timelines are not aligned between drug and diagnostic pathways in either the US or the EU. Therefore, the timing of the submission and review of a CDx must be carefully coordinated with the therapeutic sponsor, and any ambiguities in timelines should be clearly communicated. Because CDx are linked to the effectiveness of a therapeutic product, CDx claims generally come with increased risk classifications and longer review timelines than similar technologies not linked to a drug. This elevated risk classification can be extremely burdensome for the diagnostic sponsor in the postmarket setting.
In addition, reimbursement pathways for the CDx partners can be uncertain and lengthy. A study by Sexton and colleagues reported that only 44% of novel technologies were reimbursed after more than five years on the market, underscoring the need for diagnostic developers to implement patient access strategies both with and independent of the therapeutic partner.3
Health authority perspective: CDx in the European network
Perspectives from medicinal product sponsors, diagnostic partners, and health authorities emphasize the importance of collaboration and regulatory considerations. Effective co-development of therapeutic products and CDx requires close collaboration between pharmaceutical companies and diagnostic partners, with careful consideration of differing submission strategies.The EMA insights shared during the conference session include CDx aspects, regulatory pathways, challenges, and future directions, particularly in oncology and hematology. CDx are essential tools used to identify patients most likely to benefit from a specific medicinal product. In oncology and hematology, nearly a third of marketing authorizations in the EU between 2010 and 2024 were biomarker-driven indications, which required a diagnostic test for patient selection.4 Biomarkers such as PD-L1, EGFR, HER2, BRCA1/2, and KRAS are increasingly used to guide treatment decisions, highlighting the importance of robust and validated diagnostic assays.
Although the co-development of a personalized medicine and a CDx may be coordinated, the applicable regulatory pathways remain separate, both for clinical trial applications and for marketing authorization procedures. Multiple decision making bodies are involved within the EU, and notified bodies become engaged relatively late, after clinical and CDx development has been finalized.
As a general rule, applicants are referred to relevant guidance from the Medical Device Coordination Group and advised to consult with the relevant national competent authorities regarding in vitro diagnostics requirements in the context of clinical trials. The Q&A document on the interface between the Clinical Trials Regulation and the IVD Regulation provides clarity on applicable scenarios.5
The EMA’s consultation procedure for CDx
Before a notified body can issue a CE certificate, it must seek a scientific opinion from the EMA on the suitability of the CDx for the corresponding medicinal product. This assessment of suitability includes a review of the scientific rationale for the biomarker and the analytical and clinical performance of the CDx. The evidence requirements are provided on the EMA website.6
Alignment of marketing authorization applications
In vitro biomarker assays used for patient selection (for efficacy and/or safety) define the patient population investigated in clinical trials and considered for benefit-risk assessment, with direct impact on clinical practice. Evaluating the assay performance in terms of robustness and reliability to measure biomarker(s) is therefore key to understanding the benefit-risk of the product in the intended population. The applicant should provide sufficient data on the assay used in the clinical trial(s) to demonstrate their properties and robustness, and any uncertainties should be flagged in the assessment report.7,8
Coordination complexities
Collaboration among stakeholders in CDx development faces several regulatory and procedural difficulties. These include determining whether a biomarker requires a CDx or routine tests, and how this information is presented in the summary of product characteristics. Furthermore, pharma sponsors are encouraged to consult the European Commission on aspects related to CDx classification. In addition, optimizing submission timelines for consultation procedures on co-development devices remains a challenge for notified bodies.
In-progress EMA activities
The EMA has launched several initiatives to address the complexity of CDx development. For example, the agency’s Committee for Medicinal Products for Human Use (CHMP) convened the Companion Diagnostic Expert Group to provide input on procedures under evaluation by the CHMP.9 The group consists of individuals from the European regulatory network with expertise in in vitro diagnostics and companion diagnostics. It was created to support and enhance the EMA’s regulatory and scientific input into the evaluation process, with a focus on personalized medicines. The group may also provide input on other CHMP-relevant scientific issues related to CDx. Its role includes:
- Giving scientific and regulatory advice to EMA committees about IVDs, especially during consultations and application procedures;
- Updating guidelines and templates used during consultation procedures;
- Creating guidance for the CHMP on writing product information, specifically for IVDs used to identify patients suitable for a medicine; and
- Tracking how biomarker-related information is reviewed during both initial approval and subsequent updates to a medicine, to build knowledge.
Furthermore, the group may also serve as a forum for sharing knowledge on clinical trials involving medicines used in combination with IVDs, bridging multiple regulatory frameworks and stakeholders. To address procedural and technical issues linked to combination products and consultation procedures, the EMA is establishing an operational group to bring relevant stakeholders together. This forum is intended to support cross-sector dialogue among notified bodies and medicines and medical devices regulators, with separate streams for combination products and CDx. Interactions with industry stakeholders are planned on an ad hoc basis. The operational group will include representatives from medical devices authorities, notified bodies, the EMA, and the European Commission.10 Overall, the goal is to create a solid regulatory framework for CDx, encouraging innovation while safeguarding patient safety.
Conclusion
In summary, CDx are critical tools for advancing precision medicine, enabling targeted therapeutic approaches and improving patient outcomes. Their development and implementation require effective collaboration among pharmaceutical companies, diagnostic partners, and regulatory authorities. Despite challenges such as regulatory alignment, submission timelines, and reimbursement pathways, the co-development of CDx and therapeutic products remains essential for ensuring the safe and effective use of precision medicines.This article highlights the importance of early planning, robust analytical validation, and transparent communication between stakeholders to mitigate risks and streamline the regulatory process. Initiatives by regulatory agencies, such as the Combination Products Operational Group at the EMA, aim to strengthen the framework for CDx evaluation and foster innovation while prioritizing patient safety. By addressing procedural and technical challenges, the pharmaceutical and diagnostic developers can continue to advance the integration of CDx into therapeutic development, ultimately supporting the broader adoption of precision medicine.
Abbreviations
CDx, combination diagnostic; CHMP, Medicinal Products for Human Use; EMA, European Medicines Agency; FDA, Food and Drug Administration [US]; IVD, in vitro diagnostic.
About the authors
Joshua D. Levin, PhD, RAC-Device, is an IVD regulatory affairs and quality assurance leader at GSK, specializing in companion diagnostics and precision medicine at the pharma-IVD interface. He advises GSK on global precision medicine strategy and leads non-oncology CDx projects. At IronLine Consulting, ASELL, and PGDx, he led FDA interactions, marketing submissions, QMS and ISO 13485 implementations, and CDx and single‑site IVD strategies. As an FDA/CDRH reviewer and postmarket team lead, he worked with clinical labs, industry, and regulators to advance IVD development, commercialization, and compliance. He can be reached at [email protected]
Andrea Renninger, MS, is a regulatory affairs professional with over 20 years of experience integrating in vitro diagnostics into clinical development for precision medicine. Renninger holds a biology degree from Kutztown University and a master’s in exercise physiology from Temple University. Her career includes roles at Becton Dickinson, Schering Plough, Eisai, Bristol Myers Squibb, and now Daiichi Sankyo, where she leads global regulatory strategy for companion diagnostics. Renninger can be reached at [email protected]
Jennifer S. Dickey, PhD, RAC, is senior director and head of regulatory affairs, PGDx, at Labcorp. She specializes in IVDs that serve precision medicine applications in oncology. Prior to joining PGDx/Labcorp, Dickey was a senior reviewer at the Office of In Vitro Diagnostics (OHT7) at the FDA. She earned a bachelor’s degree in biology from the University of Kentucky, a PhD in biochemistry from Vanderbilt University, and served as a postdoctoral fellow at the National Cancer Institute. She has been a RAPS member since 2011 and can be reached at [email protected]
Ana Trullás Jimeno, PharmD, MSc, has been a senior scientific specialist at the EMA since 2003, currently serving as a product lead and companion diagnostic topic lead in the Oncology Office. She provides scientific and regulatory input throughout the lifecycle of medicinal products and acts as a point of reference on companion diagnostics at the agency. Trullás’s prior roles at the EMA include positions in the Procedure Management Department and the Quality of Medicines for Biologics Sector, and she has previously worked as a quality reviewer at the AEMPS. She holds a PharmD and MSc from the University of Alcalá, completed additional training in pharmaceutical technology at Utrecht University, and earned a master's degree in European registry. She can be reached at [email protected]
Acknowledgment This article was adapted from a presentation by the authors at the 2025 RAPS Convergence in Pittsburgh, PA, from 7-9 October 2025.
Citation Levin JD, et al. Companion diagnostics: Best practices for effective collaboration. RF Quarterly. 2025;5(4):14-20. Published online 15 December 2025. https://www.raps.org/news-and-articles/News-Articles/2025/12/Companion-diagnostics-Best-practices-for-effective
References
All references were last checked and verified on 5 December 2025.
- Jorgensen JT. The current landscape of the FDA approved companion diagnostics. Transl Oncol. Published June 2021. Accessed 20 September 2025. https://doi.org/10.1016/j.tranon.2021.101063
- Baker B, et al. Why diagnostic regulation matters in pharmaceutical development – and current best practices. Hanson Wade Intelligence website. Published 24 July 2025. Accessed July 2025. https://world-cdx.com/about/content-hub/
- Sexton ZA, et al. Time from authorization by the US Food and Drug Administration to Medicare coverage for novel technologies. JAMA Health Forum. Published 4 August 2023. Accessed 20 September 2025. https://doi.org/10.1001/jamahealthforum.2023.2260
- European Medicines Agency. Cancer medicines. Last updated 7 November 2025. Accessed 20 November 2025. https://www.ema.europa.eu/en/human-regulatory-overview/research-development/cancer-medicines
- European Commission. 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. Published 25 May 2022. Accessed 20 November 2025. https://health.ec.europa.eu/latest-updates/mdcg-2022-10-qa-interface-between-regulation-eu-5362014-clinical-trials-medicinal-products-human-use-2022-05-25_en
- European Medicines Agency. Medical devices: Companion diagnostics ('in vitro diagnostics') – The role of the EMA. Last updated 4 November 2025. Accessed 20 November 2025. https://www.ema.europa.eu/en/human-regulatory-overview/medical-devices#companion-diagnostics-in-vitro-diagnostics-13039
- European Medicines Agency. Assessment templates and guidance. Last updated 5 August 2025. Accessed 20 November 2025. https://www.ema.europa.eu/en/human-regulatory-overview/marketing-authorisation/assessment-templates-guidance
- European Medicines Agency. Frequently asked questions on medicinal products development and assessment involving companion diagnostic (CDx). Dated 23 December 2023. Accessed 20 November 2025. https://www.ema.europa.eu/en/documents/other/frequently-asked-questions-medicinal-products-development-and-assessment-involving-companion-diagnostic-cdx_en.pdf
- European Medicines Agency. Companion Diagnostic (CDx) Expert Group. Not dated. Accessed 20 November 2025. https://www.ema.europa.eu/en/committees/working-parties-other-groups/chmp-working-parties-other-groups/companion-diagnostic-cdx-expert-group
- European Medicines Agency. Combination Products Operational Group. Not dated. Accessed 20 November 2025. https://www.ema.europa.eu/en/human-regulatory-overview/medical-devices/combination-products-operational-group
