Companion vs Complementary Diagnostics: Differences & Examples

Companion vs Complementary Diagnostics: Differences & Examples

Two tests can measure the same biomarker, on the same tissue, with the same antibody chemistry, and still have very different regulatory weight. One is written into the drug’s indication and must be used before a patient is treated. The other is described in the label as useful context, but a physician can prescribe without it. That is the difference between a companion diagnostic and a complementary diagnostic.

The distinction matters well beyond terminology. It decides whether a test result gates access to a therapy, how the drug and device labels are written, what evidence the diagnostics partner has to generate, and how much commercial leverage the test carries once the drug launches. PD-L1 immunohistochemistry is the clearest case study: four assays, several drugs, and examples of tests that started as complementary and later became companions.

Key takeaways

• A companion diagnostic (CDx) provides information that is essential for the safe and effective use of a corresponding drug. Its use is stated in both the device labelling and the drug labelling.
• A complementary diagnostic identifies a biomarker-defined subgroup that may benefit more, and can inform benefit-risk discussions, but testing is not required before prescribing.
• FDA began using the “complementary” term publicly in 2015, and PD-L1 IHC 28-8 pharmDx for nivolumab in non-squamous NSCLC (October 2015) is generally cited as the first test approved as one.
• The EU IVDR defines companion diagnostics in Article 2(7) but has no formal complementary category.
• Tests move between categories. VENTANA PD-L1 (SP142) and PD-L1 IHC 28-8 both gained companion claims after drug labels were restricted to biomarker-defined populations.

What is a companion diagnostic?

FDA describes a companion diagnostic as a medical device, often an in vitro diagnostic, that “provides information that is essential for the safe and effective use of a corresponding drug or biological product”. According to the FDA companion diagnostics page, a CDx can be used to:

• identify patients who are most likely to benefit from a particular therapeutic product;
• identify patients likely to be at increased risk of serious side effects;
• monitor response to treatment so that treatment can be adjusted for safety or effectiveness.

The governing documents are FDA’s August 2014 final guidance, In Vitro Companion Diagnostic Devices, and the April 2020 guidance on developing and labelling companion diagnostics for a specific group of oncology therapeutic products, which supports broader class labelling. The practical consequence is in the labels. The drug’s indication refers to the biomarker “as determined by an FDA-approved test”, and the device’s intended use names the drug. FDA keeps a public list of authorised companion diagnostic devices that records each test, drug, indication and biomarker cut-off.

Because the drug cannot be used safely and effectively without the test, FDA generally expects the CDx to be approved or cleared at the same time as the drug. Most oncology CDx are class III devices that go through premarket approval (PMA). The full pathway is covered in our FDA companion diagnostic approval guide.

What is a complementary diagnostic?

A complementary diagnostic identifies a biomarker-defined subset of patients who tend to respond differently to a drug, and helps physicians and patients weigh benefit and risk, but it is not a prerequisite for receiving the drug. The drug’s indication covers the whole population; the biomarker data sit in the label as additional information, typically in the clinical studies section.

The term is newer than “companion diagnostic” and has never had the same formal footing. FDA’s Elizabeth Mansfield, then Deputy Director for Personalized Medicine in the device centre, said in mid-2015 that the agency would focus on complementary as well as companion diagnostics, describing them as tests that give additional information about how a drug might be used, as Covington reported at the time. FDA had not yet labelled any test that way.

That changed with PD-L1. On 2 October 2015, PD-L1 IHC 22C3 pharmDx was approved as the companion diagnostic for pembrolizumab in NSCLC, because the pembrolizumab indication was restricted to PD-L1-expressing tumours. A week later nivolumab was approved in previously treated non-squamous NSCLC for all patients, regardless of PD-L1 status, on the basis of CheckMate 057. Dako’s PD-L1 IHC 28-8 pharmDx, which had been used in that trial and showed an association between PD-L1 expression and survival benefit, was approved as a complementary diagnostic. It is generally cited as the first.

A complementary diagnostic is not a lighter device: 28-8 pharmDx went through PMA like a CDx. Only the claim differs.

Companion vs complementary diagnostic: side by side

Companion diagnostics examples in oncology

The examples below are taken from the FDA list of authorised companion diagnostic devices. The list is long and growing; these are chosen to show the range of biomarker types and technologies.

One instructive exception: when pembrolizumab received the first tissue-agnostic approval for MSI-H or dMMR solid tumours in May 2017, no FDA-approved test existed for that claim, and developing one was a post-marketing requirement. FoundationOne CDx was approved as the CDx for that indication in February 2022.

Complementary diagnostics examples (and where they went next)

Complementary diagnostics are far fewer, and nearly all well-known oncology examples are PD-L1 assays from the first wave of checkpoint inhibitor approvals. PD-L1 enriches for response without cleanly separating responders from non-responders, so some drugs were approved for all-comers with PD-L1 data as supporting information. For the biology behind that, see our guide to PD-L1 as a predictive biomarker.

How a test moves between categories

The category is not a property of the assay. It is a property of the claim, and the claim follows the drug label. A test can be a companion diagnostic for one drug and indication and a complementary diagnostic for another, as 28-8 pharmDx is today.

Complementary to companion

The usual trigger is new evidence that the biomarker-negative population does not benefit, or is harmed. Urothelial cancer is the textbook case. In 2018, early data from first-line trials showed decreased survival with pembrolizumab or atezolizumab monotherapy compared with platinum chemotherapy in patients with low PD-L1 expression. FDA restricted both labels in cisplatin-ineligible patients to PD-L1-positive tumours, as determined by an FDA-approved test. SP142 was approved as the CDx for atezolizumab (IC ≥5%) in July 2018, and 22C3 for pembrolizumab (CPS ≥10) in August 2018. A test that had been optional context became a gate overnight.

A new indication, a new claim

The second route is a new trial that enrols or analyses by biomarker. Nivolumab plus ipilimumab in first-line NSCLC was approved for PD-L1 ≥1% tumours, so 28-8 pharmDx gained a companion claim for that combination in May 2020 while remaining complementary in earlier settings. HER2-low is the same pattern for a companion test: trastuzumab deruxtecan created a new population, and the existing 4B5 assay needed a new claim, new scoring guidance and new reader training.

Companion to less essential

Movement the other way is rarer, because removing a test requirement means showing the drug is safe and effective without selection. More often the indication is withdrawn or replaced, as with several checkpoint inhibitor urothelial claims, and the CDx claim goes with it. Diagnostics partners should treat any CDx claim as only as durable as the drug indication it serves.

The EU position: IVDR companion diagnostics, no complementary category

Regulation (EU) 2017/746 defines a companion diagnostic in Article 2(7) as a device essential for the safe and effective use of a corresponding medicinal product to identify patients most likely to benefit, or patients at increased risk of serious adverse reactions. Unlike the FDA definition, it does not include monitoring response to adjust treatment, and Recital 12 excludes devices that monitor drug levels within the therapeutic window. BfArM’s guidance puts the practical test simply: what matters is whether detection of the biomarker is absolutely necessary for the therapy decision.

Under Annex VIII, rule 3(f), CDx are at least class C, and the notified body must consult the EMA or a national medicines authority on the suitability of the device for the medicinal product before issuing a certificate. There is no “complementary” category in the IVDR. A test that informs but does not determine treatment is classified under the general rules, without the medicines-authority consultation. That creates real divergence: an assay that is a complementary diagnostic in the US may face a different classification analysis in Europe, and vice versa. Our IVDR companion diagnostics guide covers the consultation procedure and transition timelines in detail.

What this means for co-development and diagnostics partners

• Decide the intended claim early, and revisit it. Whether a test will be a companion or complementary diagnostic depends on how the pivotal trial enrols and how biomarker-negative patients perform. Pharma and diagnostics teams should agree in the development plan what data would push the claim either way.
• Enrol biomarker-negative patients where you can. All-comer data are what make a complementary claim possible, and they protect the drug from a later label restriction. Enrichment designs are faster but lock the test in as a CDx.
• Bank samples and lock the assay. The 2018 urothelial restrictions show that a CDx claim may be needed years after launch. Retained tissue and a clinical trial assay that matches the final device make that possible without a new study.
• Build the commercial difference into the partnership. A CDx guarantees testing volume; a complementary claim depends on guideline adoption and payer coverage. Contracts should cover what happens if the category changes. Our piece on structuring pharma-diagnostics co-development partnerships goes into deal terms.
• Plan for US and EU divergence. A single global intended use is rarely possible when one jurisdiction has a complementary category and the other does not.

Discuss CDx strategy with peers at ImmunoMark London

These questions are on the agenda in Stream 2: Biomarkers & Companion Diagnostics at the biomarker and immuno-oncology conference in London on 3–4 March 2027. Sessions include “Regulation of Companion Diagnostics from a Pharma Perspective”, “Panel: Global CDx Approval Pathways – EMA, FDA & MHRA Perspectives” and “Companion Diagnostics Co-development Strategies”. The 2nd annual London edition expects 400+ attendees across two parallel streams, with keynotes, panels, case studies, pre-arranged 1:1 meetings and a Day 1 drinks reception. The March 2026 London edition brought together 300+ attendees from 100+ companies, 70% of them senior decision-makers.

Register for ImmunoMark London 2027

If your company wants to meet this audience directly, whether you develop companion diagnostics, run CDx-grade clinical assays or support regulatory submissions, see the London 2027 sponsorship opportunities or our overview of the companion diagnostics conference in London.

FAQs

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

A companion diagnostic provides information that is essential for the safe and effective use of a drug, so the drug’s indication requires the test. A complementary diagnostic identifies a biomarker-defined subgroup that may benefit more and can inform benefit-risk decisions, but the drug can be prescribed without it.

Does the FDA formally define complementary diagnostics?

Not in the way it defines companion diagnostics. FDA has guidance documents and a public list for companion diagnostics, but the complementary category has been established through individual approvals, starting with PD-L1 IHC 28-8 pharmDx for nivolumab in non-squamous NSCLC in October 2015.

What are examples of companion diagnostics in oncology?

Examples include PD-L1 IHC 22C3 pharmDx for pembrolizumab, PATHWAY HER2 (4B5) for trastuzumab deruxtecan in HER2-low breast cancer, THxID BRAF for BRAF inhibitors in melanoma, the cobas EGFR Mutation Test v2 for EGFR inhibitors in NSCLC, FoundationOne CDx for pembrolizumab in TMB-high and MSI-H solid tumours, and VENTANA CLDN18 (43-14A) for zolbetuximab.

Can a complementary diagnostic become a companion diagnostic?

Yes. VENTANA PD-L1 (SP142) was approved as a complementary diagnostic for atezolizumab in urothelial carcinoma in 2016 and became a companion diagnostic in 2018 after FDA restricted the indication to PD-L1-positive patients. PD-L1 IHC 28-8 pharmDx gained a companion claim for nivolumab plus ipilimumab in NSCLC in 2020.

Does the EU IVDR recognise complementary diagnostics?

No. The IVDR defines companion diagnostics in Article 2(7), classifies them as at least class C and requires the notified body to consult a medicines authority. There is no separate complementary category, so such tests are classified under the general IVDR rules.