Companion Diagnostics: The Complete Guide to Development, Approval & Co-Development

Companion Diagnostics: The Complete Guide to Development, Approval & Co-Development

Companion diagnostics sit at the point where a targeted therapy meets the patient who should receive it. For clinical development, regulatory affairs and diagnostics teams, the companion diagnostic (CDx) strategy now shapes a drug programme’s timeline as much as its pivotal trial design does.

A CDx decision made at Phase 1, such as which assay to use, where samples are tested or what consent is collected, can decide years later whether the drug and its test reach patients on the same day. The rules also differ across markets. The FDA, the EU under the In Vitro Diagnostic Medical Devices Regulation (IVDR) and the UK’s MHRA each treat companion diagnostics in their own way.

This guide brings the essentials together: what the FDA calls a companion diagnostic, how the US approval pathways work, what the IVDR requires in Europe, where the UK stands, how drug and diagnostic co-development fits together, which oncology CDx are already approved, and what changed for laboratory-developed tests in 2025.

Key takeaways

• The FDA defines a companion diagnostic as a device that provides information essential for the safe and effective use of a corresponding therapeutic product. If a test is essential, both the drug and the device labelling must say so.
• Most US companion diagnostics are Class III devices approved through premarket approval (PMA). The FDA has also authorised CDx through 510(k) and De Novo, and in August 2026 it moved oncology in situ hybridisation (ISH) CDx into Class II.
• Under the EU IVDR, every companion diagnostic is class C. A notified body must consult the EMA or a national medicines authority before it issues a certificate.
• Legacy class C IVDs can stay on the EU market until 31 December 2028 under Regulation (EU) 2024/1860, but only if the manufacturer met the application and notified body agreement deadlines.
• A US court vacated the FDA’s laboratory-developed test (LDT) rule on 31 March 2025, and the FDA formally rescinded it in September 2025.
• The choice of trial assay is the biggest single driver of CDx timing risk. If the trial runs on a test other than the final CDx, a bridging study is likely.

What is a companion diagnostic?

The US definition comes from the FDA’s 2014 final guidance, In Vitro Companion Diagnostic Devices. An IVD companion diagnostic is an in vitro diagnostic device that provides information essential for the safe and effective use of a corresponding therapeutic product. The FDA’s current wording also covers imaging tools, so a companion diagnostic does not have to be an IVD.

The definition sits in guidance rather than in a stand-alone regulation. Its legal force comes from labelling: the drug label under 21 CFR 201.57 and the IVD label under 21 CFR 809.10 must both reflect the requirement to use the test.

What “essential” means in practice

That single word carries legal weight. The FDA describes several uses that can make a test essential:

• Patient selection: identifying patients most likely to benefit from the therapy
• Safety exclusion: identifying patients at increased risk of serious adverse reactions
• Treatment monitoring: monitoring response so that treatment (schedule, dose or discontinuation) can be adjusted for better safety or effectiveness

The EU definition in Article 2(7) of the IVDR is narrower. It covers devices essential for the safe and effective use of a medicinal product to identify, before or during treatment, the patients most likely to benefit or the patients at increased risk of serious adverse reactions.

Companion vs complementary diagnostics

A complementary diagnostic gives clinically useful information about a drug’s benefit and risk, but the drug can be prescribed without it. A companion diagnostic is a prerequisite: the label restricts use to patients selected by the test.

The FDA began using the “complementary” label in 2015. The best-known early example is PD-L1 IHC 28-8 pharmDx with nivolumab (Opdivo) in non-squamous NSCLC: PD-L1 expression was associated with greater survival benefit, but testing was not required before treatment. The FDA has not published a formal regulatory definition of a complementary diagnostic, and the IVDR has no equivalent category.

The distinction matters commercially. A companion claim makes the test part of the prescribing pathway. A complementary claim informs the decision but does not gate access. We will cover complementary diagnostics in more depth in a separate article.

How CDRH, CDER and CBER share CDx review

Every IVD companion diagnostic programme touches more than one FDA centre. Regulatory teams that treat it as a single-centre process tend to find the coordination gap at the worst possible time.

The FDA requires separate marketing applications for the therapeutic and the companion diagnostic, even when one sponsor develops both. Letters of Authorization let each application cross-reference the other’s proprietary data without sharing confidential submissions directly.

The FDA encourages early joint meetings with all relevant centres, ideally before the IND. Teams that wait until the NDA or BLA stage to engage CDRH usually face longer reviews and more deficiency letters.

FDA approval pathways for companion diagnostics

PMA: the default route

Premarket approval under section 515 of the FD&C Act has been the main route for companion diagnostics in the US. The FDA has generally classed CDx as Class III because a wrong result directly decides whether a patient receives, or is denied, a targeted therapy.

A PMA must show reasonable assurance of safety and effectiveness. The FDA favours a modular PMA for many CDx, where sponsors submit sections as data become available rather than in a single package.

A pre-submission (Q-Sub) with CDRH before the first module is standard practice. Use it to agree the table of contents, the content expected in each module and the review timelines. The statutory review period for a PMA is 180 days, although advisory panels and major deficiency letters can extend it. User fees are significant, so build them into the programme budget early.

Supplemental PMA for new indications

When an already-approved CDx gains a new drug indication, the usual mechanism is a PMA supplement (sPMA). It focuses on the analytical and clinical validation for the new claim rather than re-establishing the whole device. This is how platforms such as FoundationOne CDx and Guardant360 CDx have built long lists of claims.

510(k) and De Novo

Not every CDx is Class III. The FDA’s list includes a 510(k)-cleared CDx (the MRDx BCR-ABL Test, for nilotinib) and De Novo-authorised CDx outside oncology. Where no predicate exists but risk is moderate, De Novo can be the right route.

Down-classification of oncology CDx

The FDA is moving some oncology CDx from PMA to 510(k):

• In situ hybridisation (ISH) tests: a final order published on 17 August 2026 reclassified ISH test systems used with an approved oncology therapeutic into Class II (special controls), under a new 21 CFR 864.1890. It took effect on 16 September 2026. The proposal dates from June 2025.
• Nucleic acid-based tests: a proposed order of 25 November 2025 would move nucleic acid-based oncology CDx (including NGS and PCR tests) into Class II under a new 21 CFR 866.6075. Comments closed on 26 January 2026. At the time of writing, no final order has been published.

Special controls would still require strong analytical and clinical validity data. What changes is the submission architecture: substantial equivalence to an existing device rather than a full PMA. IHC-based CDx are not covered by either action. Programmes in active development should plan on the current pathway and track the docket rather than assume the nucleic acid order will be finalised.

The FDA’s CDx list and oncology group labelling

The FDA keeps a public list of FDA-authorised companion diagnostic devices, including imaging tools, with the drug, biomarker and PMA or 510(k) number for each claim. It is the best single source to check whether a test is a CDx for a given drug.

The FDA’s April 2020 final guidance, Developing and Labeling In vitro Companion Diagnostic Devices for a Specific Group of Oncology Therapeutic Products, allows a CDx to be labelled for a group of oncology drugs (for example, EGFR tyrosine kinase inhibitors in NSCLC) rather than one named product, where the evidence supports it. Current group claims on the FDA list cover EGFR TKIs in NSCLC and BRAF inhibitors (alone or with MEK inhibitors) in melanoma, on tests such as cobas EGFR Mutation Test v2, FoundationOne CDx and FoundationOne Liquid CDx.

IDEs, study risk and contemporaneous approval

Investigational device exemptions

An investigational test that selects patients or assigns treatment in a drug trial is a device under investigation. Under 21 CFR 812, a significant-risk use needs an approved IDE before the trial starts. A test is often significant risk when a wrong result could lead to a patient receiving an ineffective or harmful treatment, or missing an effective one.

For oncology trials, the FDA’s October 2019 final guidance, Investigational In Vitro Diagnostics in Oncology Trials: Streamlined Submission Process for Study Risk Determination, lets the drug sponsor include the IVD information in the IND and get a study risk determination without a separate submission. If the test is judged significant risk, an IDE may still be needed.

Contemporaneous approval

The FDA’s stated aim is contemporaneous approval: the CDx is approved or cleared at the same time as the drug, so the labels match from day one. Achieving it requires:

• Joint regulatory strategy sessions from the pre-IND stage
• Coordinated pre-submission meetings with CDRH and the drug review centre
• Contract terms that stop either partner from advancing or withdrawing an FDA submission without the other’s knowledge

For serious or life-threatening conditions with no satisfactory alternative, the FDA may approve the drug before the CDx is ready. The drug label then refers to an appropriate test generically until the CDx is authorised. Treat this as a contingency, not a plan: the decisions that cause approval lag are made years before their effects show.

The two kinds of validation evidence in every CDx submission

FDA validation requirements for a companion diagnostic work on two separate axes. Mixing them up is a common source of deficiency letters.

Analytical validation

Analytical validation shows that the assay accurately and reliably measures the analyte it claims to measure. FDA reviewers look at:

• Accuracy and precision
• Analytical sensitivity and specificity
• Limit of detection (LoD)
• Reproducibility across sites, operators and reagent lots
• Justification of the analytical cut-off
• Linearity and interference

Studies are usually designed to CLSI standards. For molecular assays, the FDA expects documentation for every part of the testing chain: extraction, reagents, the instrument platform and the bioinformatics pipeline.

Clinical validation

Clinical validation shows that the test result predicts the clinical outcome for which the drug is indicated. Biomarker-positive patients should benefit; biomarker-negative patients should not, or should face a documented safety risk.

The FDA generally expects clinical validation data to come from the pivotal trial, using samples from the intended-use population. For rare biomarkers, the FDA has accepted alternative sample sources such as archival, retrospective or commercially acquired specimens. Agree that approach early through a Q-Submission. For more on study design, see our guide to validating an IO biomarker in a clinical trial.

The bridging study decision

The assay used in the pivotal trial decides whether a bridging study is needed after the trial ends.

A bridging study must show that patients selected by the clinical trial assay have equivalent outcomes when retested on the final CDx. That means banking both biomarker-positive and biomarker-negative samples from all screened patients, with confirmed analyte stability. Consent for retesting must be collected at enrolment. Trying to collect it retrospectively rarely works.

Companion diagnostics in the EU: IVDR requirements

The IVDR (Regulation (EU) 2017/746) has applied since 26 May 2022. It created the first formal EU link between the approval of a medicine and its companion diagnostic.

Classification: CDx are class C

Annex VIII, Rule 3(f) classifies every device “to be used as companion diagnostics” as class C. Under the old IVD Directive most CDx were self-certified. Under the IVDR, a notified body must assess the technical documentation.

Notified body plus medicines authority consultation

Before issuing a certificate for a CDx, the notified body must seek a scientific opinion on the suitability of the device for the medicinal product:

• from the EMA where the medicine falls within the centralised procedure, or is already authorised or under assessment centrally
• from the relevant national competent authority (or the EMA) in other cases

The authority must give its opinion within 60 days of receiving all the necessary documentation. This may be extended once by a further 60 days on justified grounds. The notified body must give due consideration to the opinion. Changes that affect the CDx’s performance, intended use or suitability with the medicine trigger a further consultation.

In practice, the drug’s MAA and the CDx conformity assessment run on separate tracks, with different reviewers. Aligning them is the EU version of the contemporaneous approval problem.

Transition timelines

Regulation (EU) 2024/1860 extended the IVDR transition for legacy devices (those with an IVD Directive declaration or certificate):

The extensions apply only if the device continues to comply with the Directive, has no significant change in design or intended purpose, presents no unacceptable risk, and the manufacturer had an IVDR quality management system in place by 26 May 2025. For legacy class C devices, including CDx, both the application and agreement deadlines have now passed. New CDx must go through full IVDR conformity assessment.

The same regulation added a duty (Article 10a) to give at least six months’ notice of an expected supply interruption or discontinuation that could seriously harm patients, applicable since 10 January 2025.

The European Commission published a proposal for a targeted revision of the MDR and IVDR on 16 December 2025. It is still going through the European Parliament and Council and is not yet law, so the dates above remain in force.

The UK position: MHRA and IVDs

The UK picture is still in transition, so it pays to separate what is in force from what is proposed.

In force now (Great Britain):

• IVDs are regulated under the UK Medical Devices Regulations 2002, which are based on the old EU IVD Directive. That framework has no separate companion diagnostic class, so most CDx are treated as general IVDs.
• CE-marked IVDs remain accepted in Great Britain: IVD Directive devices until the earlier of certificate expiry or 30 June 2030, and IVDR devices until 30 June 2030 (MHRA guidance).
• IVDs must be registered with the MHRA before being placed on the GB market.
• Strengthened post-market surveillance requirements came into force on 16 June 2025.

Proposed, not yet in force:

• The MHRA published draft Medical Devices (Amendment) Regulations 2026 for comment in May 2026. They would align IVD classification with International Medical Device Regulators Forum (IMDRF) principles and create an international reliance route for devices already approved in Australia, Canada and the USA.
• The MHRA consulted between February and April 2026 on recognising CE-marked devices, including IVDR-compliant IVDs, indefinitely. At the time of writing, we have not seen a published government response.

Northern Ireland: the EU IVDR applies, and CE marking is required.

For CDx sponsors, the practical message is that IVDR conformity currently also secures GB market access until mid-2030. Watch the final text of the GB pre-market regulations for how companion diagnostics will be classified and assessed.

Drug–diagnostic co-development timeline

Co-development works when the diagnostic plan runs in step with the clinical plan. The table below shows the usual milestones. Our article on structuring pharma–diagnostics co-development partnerships covers the commercial and contractual side in more detail.

Data sharing and Letters of Authorization

The diagnostic sponsor needs clinical outcome data from the drug trial to support clinical validation. The drug sponsor needs the diagnostic’s performance data to complete its NDA or BLA. Neither party can finalise its FDA submission without the other.

When the drug sponsor and the diagnostic manufacturer are separate companies (the most common set-up in oncology), the contract has to settle data rights, specimen flows, Letters of Authorization and submission timing before the pivotal trial begins.

Companion diagnostics examples: approved oncology CDx

The table shows a selection of FDA-approved oncology companion diagnostics and some of their drug claims, taken from the FDA’s CDx list. Many of these tests carry further claims not shown here.

Two patterns stand out. First, broad NGS panels, in tissue and in plasma, now collect claims through supplements rather than separate devices. Second, IHC remains central for antibody-drug conjugates and other protein targets, where the scoring algorithm and cut-off become part of the claim. For background on two of the most-used biomarkers, see our articles on PD-L1 as a predictive biomarker and tumour mutational burden.

LDTs and companion diagnostics after the 2025 court ruling

Laboratory-developed tests are designed, made and used within a single laboratory. In the US they have historically been overseen under CLIA, with the FDA exercising enforcement discretion.

In May 2024 the FDA issued a final rule stating that LDTs are devices and phasing out that enforcement discretion. On 31 March 2025, the US District Court for the Eastern District of Texas, in consolidated challenges brought by the American Clinical Laboratory Association and the Association for Molecular Pathology, vacated the rule in its entirety. The court found that the FDA lacked statutory authority to regulate LDTs as devices. The FDA did not appeal. In September 2025 it issued a final rule removing the 2024 amendment and restoring the earlier wording of 21 CFR 809.3(a).

What this means for CDx:

• LDTs are not FDA-authorised companion diagnostics. Drug labels that require a test still point to FDA-authorised CDx, and the FDA’s CDx list remains the reference.
• In practice, many patients are still tested with LDTs in clinical laboratories, especially in oncology. Without the rule, there is no FDA premarket review of those tests.
• LDTs remain common as clinical trial assays. That brings the bridging risk described above.
• The FDA’s June 2023 final guidance on a voluntary oncology pilot programme (Oncology Drug Products Used with Certain In Vitro Diagnostic Tests) aims to make clear the performance characteristics that tests for certain oncology biomarkers should meet.

In the EU, the nearest equivalent is the in-house exemption for health institutions under Article 5(5) of the IVDR, which comes with its own conditions.

Practical CDx checklist for pharma and diagnostics partners

Pharma and biotech sponsors

• Decide by the end of Phase 1 whether a CDx, a complementary diagnostic or no test is the likely outcome
• Choose the diagnostic partner and technology before the pivotal trial design is locked
• Use the final CDx, or a central assay that can be bridged, in the pivotal trial
• Collect retesting consent and bank biomarker-positive and biomarker-negative samples from all screened patients
• Include CDRH in pre-IND and end-of-Phase 2 meetings
• Plan the EU notified body route and the EMA consultation alongside the MAA timeline

Diagnostics partners

• Agree the intended use, cut-off and scoring algorithm in writing with the drug sponsor
• Lock the analytical validation plan (to CLSI standards) before pivotal samples are tested
• Settle data rights, specimen access and Letters of Authorization in the contract
• Choose the US pathway (PMA, 510(k) after down-classification, or De Novo) and confirm it in a Q-Submission
• Confirm IVDR class C notified body capacity early, and plan for GB requirements once the new regulations are final
• Plan post-approval supplements for new indications, specimen types and software updates

Both parties

• Set up a joint governance committee with a single regulatory lead for FDA communications
• Agree that neither party can file, change or withdraw a submission without notifying the other
• Align drug and device labelling language before submission

FAQs

What is a companion diagnostic?

A companion diagnostic is a medical device, usually an in vitro diagnostic test, that provides information essential for the safe and effective use of a corresponding drug or biologic. It is typically used to identify patients most likely to benefit or patients at increased risk of serious side effects, and its use is written into both the drug and device labels.

What is the difference between a companion and a complementary diagnostic?

A companion diagnostic is required before the drug is prescribed, because the label restricts use to patients selected by the test. A complementary diagnostic gives useful information about benefit and risk, but the drug can be used without it. PD-L1 IHC 28-8 pharmDx with nivolumab is an early example of a complementary diagnostic.

Are FDA companion diagnostics always approved through PMA?

No. Most have been Class III devices approved through PMA, but some have been cleared through 510(k) or authorised through De Novo. In August 2026 the FDA reclassified oncology in situ hybridisation CDx into Class II, and a November 2025 proposal would do the same for nucleic acid-based oncology CDx.

How are companion diagnostics regulated under the EU IVDR?

All companion diagnostics are class C under the IVDR. A notified body assesses the device and must consult the EMA or a national medicines authority on its suitability for the medicine. That authority has 60 days to give its opinion, which can be extended once by a further 60 days.

What are some examples of companion diagnostics?

Examples include FoundationOne CDx and Guardant360 CDx (NGS panels in tissue and plasma), PD-L1 IHC 22C3 pharmDx for pembrolizumab, the therascreen EGFR and KRAS PCR kits, and Roche’s VENTANA ALK (D5F3), CLDN18 (43-14A) and MET (SP44) immunohistochemistry assays.

Meet the CDx community at ImmunoMark Summit

Companion diagnostic partnerships are built in rooms where pharma, biotech and diagnostics leaders meet, not in inboxes. ImmunoMark Summit runs two parallel streams, and Stream 2, Biomarkers & Companion Diagnostics, runs at every edition, alongside pre-arranged 1:1 meetings, case studies and panels.

• San Diego (West Coast Edition), 10–11 February 2027: 300+ senior attendees
• London, 3–4 March 2027: 400+ target attendees at our immuno-oncology conference in London
• Boston (East Coast Edition), June 2027: 300+ attendees

London 2026 brought together 300+ attendees from 100+ companies, 70% of them senior decision-makers, with more than 200 meetings across the two days and 15–25 meetings per sponsor. Participating companies included GSK, Roche, Merck, AstraZeneca, J&J and BMS. For the wider biomarker context, see our IO biomarker trends article.

If your company wants to meet this audience of pharma, biotech and diagnostics decision-makers, see the London 2027 sponsorship opportunities. At London 2026, title sponsors had 55+ pre-scheduled 1:1 meetings.

Explore London 2027 sponsorship

Planning for the US? See the San Diego sponsorship opportunities or the Boston sponsorship opportunities. To attend, register for ImmunoMark London 2027.