Updated
65% of EMA and FDA drug approvals involved a biomarker. By 2025, roughly half of all new oncology molecular entity approvals in the US had an associated companion diagnostic (CDx) listed as required in the label. These are not marginal tools — they are now the default architecture of targeted therapy development.
Yet in practice, companion diagnostic programmes fail — not because of science, but because of structure. The pharmaceutical team and the diagnostics team work on disconnected timelines. The IVDR or FDA submission is treated as a late-stage add-on rather than an integrated workstream. The assay evolves after pivotal data has been collected. These are avoidable failures, and they are the failures this article is designed to address.
What Is a Companion Diagnostic? The Definition That Drives Everything Downstream
When a regulatory authority (FDA, EMA, or a Notified Body under IVDR) determines that a diagnostic result is essential, the labelling of both the drug and the diagnostic must reflect that link. This creates a codependency between two separately regulated products that must coordinate at every stage of development and approval.
| The CDx result can serve four functions |
| Patient selection — identifying patients most likely to benefit from the therapy |
| Safety exclusion — identifying patients at elevated risk of serious adverse reactions |
| Dose optimisation — monitoring therapeutic or toxic effects to guide dose adjustment |
| Response monitoring — tracking treatment response after initiation |
In oncology, the most common application is patient selection — confirming that a specific mutation, protein expression level, or genomic signature is present before initiating a targeted therapy. EGFR, ALK, KRAS, BRAF, HER2, and PD-L1 are among the best-known examples. But the CDx architecture is now expanding into immunology, rare diseases, and gene therapy, where biomarker prevalence is lower and sample availability is more constrained.
Pharma and IVD sponsors most commonly underestimate the extent to which CDx CRO support is an integrated strategic function rather than simply an executional resource. It is often assumed that internal regulatory and clinical operations teams can manage the core programme internally. In practice, the greatest complexity lies in integrating these disciplines into a coherent regulatory and clinical development strategy from the very beginning.
Callum Pickett | MDx CRO
CDx Development Partner vs. CDMO: A Distinction That Shapes Regulatory Outcomes
This distinction causes significant problems in early-stage programmes and it is worth clarifying before anything else.
CDx development partner such as a CRO with IVD regulatory expertise, is engaged from the beginning to define what the diagnostic should be, guide R&D, manage analytical and clinical validation, ensure IVDR and FDA regulatory compliance throughout the development lifecycle, and advise on pathway strategy.
Contract Development and Manufacturing Organisation (CDMO) is engaged to manufacture a device that has already been defined. The CDMO can only produce what has already been designed and validated. It cannot assume responsibility for the regulatory fate of the product.
A CDx development partner helps determine what the diagnostic should be from the ground up — including R&D, manufacturing, analytical and clinical validation, IVDR compliance during development, and the regulatory strategy. A CDMO is purely a partner to support manufacture of a device that has already been defined. Sponsors who engage a CDMO without first engaging a CDx development partner often discover, late in development, that their device lacks the analytical validation infrastructure or regulatory documentation needed to support an FDA or IVDR submission.
Callum Pickett | MDx CRO
How CDx Co-Development Actually Works: The Integrated Model
The co-development model, where a drug and its companion diagnostic are developed in parallel under a shared governance framework, is FDA’s and EMA’s preferred approach. In practice, a realistic integrated programme from biomarker confirmation to regulatory approval of both products takes four to six years. Aggressive programmes with mature biomarker readiness may compress to around three and a half years.
| Development Phase | Timeframe | CDx Workstream |
|---|---|---|
| Biomarker discovery and confirmation | Months 0–12 | Define intended use; select assay technology; pre-analytical controls |
| Prototype assay and fit-for-purpose validation | Months 12–24 | Develop CTA; first regulatory pre-submission (FDA Q-Sub or NB pre-sub) |
| Clinical trial assay deployment | Months 18–36 | IDE/IVDR submission strategy; IRB; GLP analytical validation |
| Commercial assay lock and analytical validation | Months 24–42 | Design controls; assay bridging if needed; first PMA modules (FDA) or Annex XIV planning (EU) |
| Pivotal clinical performance study | Months 36–54 | Clinical validation in the therapeutic trial; specimen banking; co-development governance |
| Regulatory submission, review, and approval | Months 48–72 | Complete PMA/Annex XIV; dual-label alignment; contemporaneous approval target |
The Three Structural Failure Modes of Co-Development
The same failures recur across programmes, regardless of sponsor size or indication:
- Assay lock too late. Every major assay change after pivotal data collection has begun creates the potential for a bridging study. Bridging studies add 12–24 months and six-figure costs to a programme. The fix is simple: lock the commercial assay version before the pivotal trial enrols.
- The diagnostic is treated as the diagnostic manufacturer’s problem. Under Article 2(57) of the IVDR and FDA’s CDx guidance, the pharmaceutical sponsor is often responsible for the performance study or IDE submission. When the drug team assumes the diagnostic team owns this entirely, regulatory submissions are disconnected, timelines diverge, and RFI responses become incoherent.
- Biomarker prevalence is misestimated. Low enrolment due to unexpectedly low biomarker positivity rates collapses statistical power in the pivotal trial, making it impossible to calculate diagnostic sensitivity and specificity within the planned timeline. This is particularly acute in rare disease and gene therapy programmes.
Most Expensive Mistake
The single most expensive mistake is treating the IVDR performance study as an afterthought. In one programme, the sponsor had not engaged with IVDR requirements until three months before planned first-patient-in. At that point they discovered a PSA was required in multiple Member States, that documentation requirements were not harmonised, and that each required different local forms and certified translations. The result was a nine-month delay and an estimated €800,000–€1.2 million in additional costs. This is not an outlier, industry data shows a significant proportion of sponsors experience 6–12 months of IVDR-related delay in combined programmes.
Callum Pickett | MDx CRO
Assay Technology Selection: IHC, NGS, PCR, and ELISA
Technology selection for a companion diagnostic is not a pure technical decision — it is a regulatory and commercial one. The technology determines the scope of analytical validation, the plausibility of a 510(k) vs. PMA pathway, the level of software and algorithm documentation required, and the ease with which the assay can be standardised across clinical sites.
When selecting a CDx technology, the first consideration must be the science behind the biomarker. If the analyte is DNA- or RNA-based, NGS or PCR should be considered. If it is protein-based, IHC or ELISA. The current state-of-the-art for detecting that analyte in clinical practice should be reviewed, the technology chosen should reflect how the biomarker is already measured in the real world. Analytically, the technology must be sufficiently sensitive and specific around the diagnostic cut-off, because for a CDx the performance around the cut-off directly influences patient management decisions.
Callum Pickett, MDx CRO
| Technology | Biomarker Type | Key CDx Considerations |
|---|---|---|
| NGS (Next-Generation Sequencing) | DNA/RNA — genomic alterations, fusions, TMB, MSI | Bioinformatics pipeline must be validated and version-controlled. Nov 2025 FDA proposed reclassification to Class II applies to NGS-based oncology CDx. |
| PCR (Polymerase Chain Reaction) | DNA/RNA — specific mutations, gene expression | Highly sensitive and specific. Simpler validation path than NGS. Well-established in regulatory submissions. |
| IHC (Immunohistochemistry) | Protein expression (e.g. PD-L1, HER2) | Subjective scoring — inter-lab variability requires extensive standardisation. Not covered by Nov 2025 reclassification proposal. |
| ELISA | Protein — serum/plasma biomarkers | High throughput. Specimen type and stability are primary regulatory concerns. |
Regulatory Frameworks: What IVDR and FDA Each Require
EU IVDR: Class C, Annex XIV, and the Combined Study Problem
Under the EU IVDR, companion diagnostics are classified as Class C IVDs, requiring mandatory Notified Body involvement, a clinical performance study under Annex XIV, and EMA consultation where the CDx is co-developed with a medicinal product subject to centralised authorisation.
When the CDx is used in a drug clinical trial, which is the norm in co-development, the study is a combined study: simultaneously regulated under the Clinical Trials Regulation (CTR) for the drug and under the IVDR for the diagnostic. These are separate submission tracks with different portals, different national requirements, and different timelines. The practical complexity of managing both in parallel is the dominant operational challenge in European CDx development.
As Callum mentioned, in one combined programme, three Member State competent authorities gave three completely different answers about whether a Performance Study Application was required, all for the same protocol, same device, same samples, same patient population. One said no submission required; a second required full PSA authorisation; a third hadn’t decided. No harmonised consensus was reached. The sponsor ultimately prepared three country-specific strategies. This divergence introduced 4–6 months of delay to the diagnostic component of the trial.
FDA: PMA, Q-Submissions, IDE, and the November 2025 Reclassification
In the US, most companion diagnostics are Class III devices requiring Premarket Approval (PMA). FDA’s preferred submission format is the modular PMA, with four modules filed sequentially as data become available. A Pre-Submission (Q-Submission) to CDRH before Module 1 is standard practice — it aligns the intended use statement, the analytical validation plan, and review timelines before any significant evidence generation has begun.
When a CDx is used in a therapeutic trial, the sponsor must determine whether the study device is significant risk (SR) or non-significant risk (NSR) under 21 CFR 812.3(m). This determination affects whether an IDE application to FDA is required, separate from IRB approval.
Why Pharma-IVD Partnerships Break Down — and How to Prevent It
The most structurally important failure mode in CDx co-development is not regulatory, it is contractual and operational. The pharmaceutical partner and the IVD developer want different things, operate on different timelines, and frequently lack formal governance structures that force early alignment.
Pharma partners see the drug as the main asset and the IVD as enabling infrastructure. The IVD partner sees the diagnostic as an independently regulated product carrying substantial technical and regulatory risks. The right approach is for both partners to understand both development pathways and the intended outcomes from the programme so that direction can be finalised as early as possible. The healthiest partner relations work when both sides understand that the drug cannot launch without the diagnostic, and the diagnostic has limited value without the associated therapeutic.
Four governance elements must be established before pivotal evidence generation begins:
- Data sharing and Letters of Authorisation. The diagnostic sponsor needs access to clinical outcome data from the drug trial. The drug sponsor needs the diagnostic sponsor’s performance data for the NDA or BLA. Neither can finalise its submission without the other. These agreements must be in place before the pivotal trial enrols.
- Assay lock and version control. The commercial assay version must be locked before pivotal evidence generation begins. Any post-lock change — reagents, software, cut-off, specimen criteria — triggers a bridging study. This decision point must be contractually governed, not left to informal agreement.
- Contemporaneous approval planning. FDA’s preferred model is the CDx PMA and the drug NDA or BLA approved on the same day. Achieving this requires coordinated Pre-Submission meetings with CDRH and the drug review centre from the pre-IND stage.
- Named joint workstream owner. Someone must own the diagnostic regulatory workstream inside the master trial timeline. Not the drug team. Not the diagnostic team. A jointly accountable function with visibility into both submission tracks.
CDx in Rare Disease and Gene Therapy: Why These Programmes Are Structurally Different
Rare disease and gene therapy CDx programmes present a set of challenges that standard CDx regulatory guidance does not adequately address. The difficulties are epidemiological before they are regulatory.
The most common problem with gene therapy and rare disease programmes is the availability of patients. During analytical development, the limited patient population means that specimens positive for the biomarker may be genuinely scarce. This limits options if the intended use needs to be extended for the purpose of validating new sample types. Similarly, due to low enrolment numbers in the associated clinical trial, there are often too few samples to achieve the statistical power needed to calculate diagnostic sensitivity and specificity. For this reason, the objectives and endpoints of the CDx must be carefully reconsidered, often built around clinical utility endpoints rather than conventional accuracy metrics.
What to Look for in a CDx Development Partner: The Questions That Separate Capable from Credible
Evaluating a CDx development partner requires questions that go beyond credentials and prior submission counts. The questions that most reliably separate capable partners from those that present well are:
- Does the team assigned to the CDx project understand the science behind the device and the clinical setting, not just the regulatory requirements?
- Does the partner have a regulatory intelligence system for continuous improvement, incorporating feedback from FDA and Notified Bodies to increase submission success?
- What is the partner’s average number of RFIs received per performance study application, and how long does it take to resolve them? (A low RFI rate with fast resolution reflects pre-submission preparation quality, not just team availability.)
- Does the partner have tried-and-tested QMS templates that can be deployed quickly across new programmes?
- If programme workload increases, can the partner scale the team with CDx-experienced personnel, not generalists redeployed from other areas?
A global biopharma partner needed to launch Performance Study Applications across multiple EU countries for an upcoming Phase 3 clinical trial. During setup, safety events necessitated genetic testing in a related Phase 1 study, and required a complete IVDR Annex XIV technical package within weeks, not months. In six weeks, the MDx team reviewed all device documentation, analysed the Phase 1 protocol, and developed the complete Annex XIV package including the clinical performance study plan. All submissions were accepted; the Phase 1 study proceeded on schedule.
Frequently Asked Questions: Companion Diagnostics in Precision Medicine
A companion diagnostic is required for patient access to the associated therapeutic — the drug label mandates its use. A complementary diagnostic is recommended but not required; clinicians may use it to guide therapy selection, but it is not a labelled prerequisite. Regulatory requirements differ significantly: companion diagnostics require Notified Body involvement (EU) or PMA/510(k) (US); complementary diagnostics may follow a less intensive pathway.
From Day 1. The intended use statement, assay technology selection, and pre-analytical strategy should be established at the same time as the drug development plan. The most expensive mistake in CDx development is initiating the diagnostic regulatory workstream after the clinical trial has already started.
If the CDx will eventually be marketed in the EU, IVDR will apply to its development and CE marking regardless of where clinical data is generated. However, a US trial using EU specimens may need to justify population equivalence to the EU intended-use population. Early engagement with the Notified Body and FDA on cross-jurisdictional sample use is strongly recommended.
