When a global pharma company runs a clinical trial for a new oncology drug that requires an NGS-based companion diagnostic to pre-screen patients, two regulatory worlds collide: the Clinical Trials Regulation governs the drug, while the IVDR governs the diagnostic. In Europe, these are legally separate submissions, with different portals, timelines and authorities. Operationally, however, they form one study, with shared patients, shared sites and shared deadlines.
At MDx CRO, we have supported over 20 companion diagnostic programmes in which the CDx clinical performance study runs in parallel with a pharma-sponsored drug trial. These combined studies, involving top-10 global pharmaceutical companies and IVD manufacturers across multiple EU Member States, have shown us what works, what fails and where regulatory friction most often arises.
This article reflects operational experience and interpretation of current regulatory frameworks under the CTR and IVDR. It shares what we have learned from supporting these studies in practice.
How to Run a CDx Performance Study Alongside a Drug Trial: Insights From 20+ Projects
When a global pharma company runs a clinical trial for a new oncology drug that requires an NGS-based companion diagnostic to pre-screen patients, two regulatory worlds collide. The Clinical Trials Regulation (CTR) governs the drug, while the IVDR governs the diagnostic. In Europe, these are legally separate submissions with different portals, different timelines, and different authorities, but operationally they are one study with shared patients, shared sites, and shared deadlines.
At MDx CRO, we have supported over 20 companion diagnostic programmes where the CDx clinical performance study runs in parallel with a pharma-sponsored drug trial. These combined studies, involving top-10 global pharmaceutical companies and IVD manufacturers across multiple EU Member States, have taught us what works, what fails, and where the regulatory friction points are.
This article shares what we have learned.
What is a combined study under IVDR and CTR?
A combined study is any study where two regulated product types, a medicinal product and an in vitro diagnostic, are investigated simultaneously. In practice, this is often referred to as a ‘combined study’. This typically means a Phase 2 or Phase 3 drug trial that uses a companion diagnostic to stratify or select patients based on a biomarker.
Under EU law, the drug trial falls under Regulation (EU) 536/2014 (the Clinical Trials Regulation, or CTR), and the CDx performance study falls under Regulation (EU) 2017/746 (the IVDR). There is currently no fully integrated EU submission pathway that covers both. Sponsors must file separate applications through separate systems: the drug trial via CTIS, and the performance study via national competent authority and ethics committee routes that vary by Member State.
The European Commission launched the COMBINE programme in 2023 to address this fragmentation, and a pilot coordinated assessment process began in mid-2025. However, for the foreseeable future, sponsors will need to manage dual submissions in parallel, and that is where complexity multiplies.
Why the CDx performance study gets underestimated
One of the most consistent patterns we see across combined studies is that the clinical performance study for the companion diagnostic is treated as secondary to the drug trial.
As Yaiza Benito, Clinical Project Manager at MDx CRO, explains:
“The clinical trial is always seen as the important one, and rightly so, there is enormous investment and pressure. But the companion diagnostic has to comply with IVDR on its own terms. Each product has its own requirements and each one has to meet them. You cannot undervalue the performance study.”
In our experience working with multinational pharma sponsors, this misalignment manifests in several ways. The IVD manufacturer and the pharma partner may not be fully coordinated on timelines, with the drug trial protocol advancing while the CDx documentation lags behind. Analytical validation, which must be completed before the CDx can be used in the trial, sometimes runs late because it was deprioritised in favour of the drug development programme. And the IVDR submission requirements, including the clinical performance study protocol, the investigator’s brochure for the IVD, and the risk management documentation, may not receive the same level of scrutiny as the CTR submission package.
The result is predictable: delays. Competent authorities and ethics committees issue Requests for Information (RFIs). Submissions stall. The drug trial start date slips, not because of the drug, but because of the diagnostic.
We have learned that the single most effective intervention in a combined study is treating the CDx performance study as an equal partner from day one, not an afterthought.
The regulatory landscape: two parallel submission tracks
Understanding the practical differences between the CTR and IVDR submission tracks is essential for anyone managing a combined study.
- The drug trial (CTR track): Applications are submitted centrally via CTIS. The process is harmonised across the EU, with coordinated assessment between the reporting Member State and concerned Member States. Timelines are defined: validation within 10 days, assessment within 45 days (Part I), with extensions possible. The framework is mature and well-understood by sponsors.
- The CDx performance study (IVDR track): Applications are submitted individually to each Member State’s competent authority and ethics committee, through national systems, which may include separate or partially coordinated submissions depending on the Member State. There is no central submission system yet, as EUDAMED’s performance study module is not expected before 2027-2028. Each country has its own templates, timelines, and review sequence. In some Member States, processes may be sequential (e.g., ethics review preceding competent authority assessment), while others allow parallel review.
This asymmetry creates a planning challenge. The drug trial submission is coordinated; the CDx submission is fragmented. When both need to be approved before the first patient can be enrolled at a given site, the slower of the two determines the timeline, and it is in many cases, the IVDR track becomes the critical path.
What MDx does in a combined study
Our involvement in combined studies focuses on the IVDR side of the equation. We support the CDx performance study across its full lifecycle, while the pharma sponsor or a drug-focused CRO manages the CTR clinical trial.
Review and development of technical documentation.
We review the IVD manufacturer’s technical documentation to ensure it meets IVDR requirements. In many cases, the CDx manufacturer is a US-based company whose documentation was initially built for FDA submission. We assess the documentation against IVDR General Safety and Performance Requirements (GSPRs) and identify the gaps that need to be addressed before European authorities will accept it. We can also develop documentation from scratch when the manufacturer provides the underlying data.
“Normally the bulk of the documentation is the same for FDA and IVDR, but IVDR tends to be more demanding on certain points. What we do is make sure it is 100% compliant with IVDR. That is our responsibility.”
Clinical performance study protocol development. We develop the Clinical Performance Study Protocol (CPSP) in accordance with ISO 20916 and IVDR Annex XIII requirements. The protocol defines study objectives, endpoints, specimen types, statistical methodology, site requirements, and monitoring plans. In a combined study, the CPSP must align with the drug trial protocol on key elements such as patient population, specimen collection procedures, and site selection, while remaining a standalone document for IVDR purposes.
Regulatory submissions to ethics committees and competent authorities. We manage the IVDR submission process across multiple EU Member States. This includes preparing country-specific documentation packages, managing communications with national authorities, and responding to RFIs. Each country has its own expectations, and our experience across 15+ EU Member States means we know what each authority prioritises before they ask.
Global sample monitoring under ISO 20916. We provide monitoring of testing sites, specifically the laboratories where the CDx is used to test patient samples. This includes site qualification (verifying the lab has the right equipment, QMS, and trained personnel), initiation visits, ongoing monitoring (on-site and remote), and close-out visits.
“For our current programmes with major pharma companies, we are monitoring all testing sites globally, not just the ones in Europe. We apply ISO 20916 across the board. This is where we are true experts.”
Clinical performance study reporting. At study close, we develop the Clinical Performance Study Report (CPSR), which feeds into the Performance Evaluation Report (PER) required for IVDR technical documentation and Notified Body review.
5 lessons from 20+ CDx programmes
Based on our experience managing the IVDR track of combined studies.
Start IVDR strategy at the same time as CTR strategy
Develop the IVDR regulatory strategy in parallel with the CTR strategy from Phase 2 onwards — not after the drug trial protocol is finalised.
Complete analytical validation before the CDx enters the trial
Engage the validation team early — expertise in NGS, IHC, and qPCR is critical.
Do not assume one submission package works for all countries
Cover letters, national forms, language and ethics requirements vary per EU Member State. Country-specific templates are essential.
Align the CDx manufacturer and the pharma sponsor
Different regulatory obligations, timelines, priorities. Someone must coordinate protocol details, specimen handling & submission timelines.
Risk-based monitoring must include CDx testing sites
CDx testing may happen at central labs, regional labs, or manufacturer facilities — these need qualification under ISO 20916 with remote monitoring capabilities.
Five lessons from 20+ CDx programmes
Based on our experience managing the IVDR track of combined studies, here are the five most important lessons we have learned.
1. Start the IVDR submission strategy at the same time as the CTR strategy, not after.
The most common mistake is treating the IVDR submission as something that can be figured out once the drug trial protocol is finalised. By that point, critical decisions have already been made about countries, sites, and specimen collection procedures that may not align with IVDR requirements. We recommend that the IVDR regulatory strategy is developed in parallel with the CTR strategy from Phase 2 onwards.
2. Analytical validation must be sufficiently established to support the safe and reliable use of the CDx in the clinical study
The CDx must be analytically validated before it is used to make patient selection decisions in a clinical trial. This seems obvious, but in practice we regularly see sponsors underestimate the time and resources required.
“Analytical validation is absolutely key. When it is incomplete or the documentation does not hold up, competent authorities flag it immediately, and the resulting RFIs can delay the study start by months.”
The analytical validation team, in our case a dedicated group with deep expertise in assay technologies including NGS, IHC, and qPCR, should be engaged early.
3. Do not assume one submission package works for all countries.
Each EU Member State has its own requirements for performance study applications. The core documentation may be the same, but cover letters, national forms, language requirements, and ethics committee expectations vary significantly. In some countries, you can submit in English; in others, key documents must be translated. Some authorities want the full Performance Evaluation Plan included; others do not. We maintain country-specific templates and relationship knowledge that allow us to submit with confidence across multiple markets simultaneously.
4. The CDx manufacturer and the pharma sponsor must be aligned, and someone needs to coordinate them.
In a combined study, the pharma company is typically the sponsor of the drug trial, and the IVD manufacturer is the sponsor (or legal manufacturer) of the CDx. These two entities have different regulatory obligations, different timelines, and sometimes different priorities. Someone needs to sit at the intersection and ensure alignment on protocol details, specimen handling procedures, site selection, and submission timelines.
“You have the pharma partner on one side and the IVD manufacturer on the other, and sometimes there is more than one CDx in the same study. There are a lot of stakeholders involved. What we bring is agility, strong organisational capacity, and the ability to move fast across all of them.”
5. Risk-based monitoring plans under ISO 20916 should include the CDx testing sites, not just the clinical trial sites.
Monitoring in a combined study often focuses on the clinical trial sites where patients are enrolled. But the CDx testing, where patient samples are analysed, may happen at different locations: central labs, regional labs, or the manufacturer’s own facilities. These testing sites need to be in line with ISO 20916 principles, including risk-based monitoring. We develop risk-based monitoring plans that cover both the clinical sites and the testing sites, with remote monitoring capabilities for global programmes.
The COMBINE programme and what it means for sponsors in 2026
The European Commission has initiated the COMBINE programme to explore and improve coordination between the Clinical Trials Regulation and the In Vitro Diagnostic Regulation for combined studies. The programme has identified several practical challenges, including misaligned timelines, fragmented national processes, limited coordination between competent authorities and ethics committees, and inconsistent documentation requirements.
In 2025, COMBINE activities included pilot work aimed at testing more coordinated approaches for multinational combined studies. These activities are intended to support better alignment between CTR and IVDR processes, including validation and assessment timelines, although the overall framework remains under development.
For sponsors planning combined studies in 2026 and beyond, the COMBINE programme is a positive signal. However, it is important to be realistic: the initiative is still evolving, and full harmonisation of IVDR submission processes is not expected until EUDAMED’s performance study module goes live, likely not before 2027–2028 at the earliest. In the meantime, sponsors should continue to plan for fragmented national submissions and invest in the country-specific expertise needed to manage them effectively.
Frequently asked questions
Not necessarily. Under the IVDR, whether a CDx performance study is classified as interventional depends on whether the test results influence patient management decisions. In many combined studies, the CDx is used for patient selection (screening), and the results do directly affect care, making it interventional. However, if the CDx study uses only left-over samples and does not influence treatment, it may qualify as non-interventional, with reduced submission requirements. The classification has significant implications for the level of regulatory review required.
In some cases, yes. When the studies are fully integrated, with the same patients, the same sites, and the same specimen collection, it is possible to use a single Subject Information Sheet (SIS) that covers both the CTR and IVDR components. However, it must be very clear to participants that they are consenting to both studies. In practice, whether a single or dual consent approach is used depends on the specific study design and the requirements of the individual ethics committees involved.
No. Our expertise is on the IVDR side: the CDx performance study, technical documentation review, regulatory submissions, and testing site monitoring. The drug trial is managed by the pharma sponsor or a drug-focused CRO. We work alongside them, ensuring the two tracks are coordinated and that the CDx programme does not become the bottleneck.
Timelines vary significantly by country. In our experience, from initial submission to final approval, sponsors should plan for 3 to 6 months per country, accounting for validation, assessment, RFIs, and any required translations. Countries with sequential review processes (ethics first, then competent authority) tend to take longer. Starting the submission process early and in parallel with the CTR application is critical.
Planning a combined drug-diagnostic study in Europe?
MDx CRO manages the IVDR track of combined studies, from CDx documentation review and protocol development to multi-country submissions and ISO 20916 testing site monitoring. We work alongside your drug CRO to keep both tracks aligned and on schedule.
