Liquid Biopsy and Multi-Cancer Early Detection (MCED) Tests: FDA, IVDR Regulatory Pathway

Liquid Biopsy and the MCED Revolution

A liquid biopsy is a blood-based test that detects circulating tumor DNA (ctDNA), circulating tumor cells, exosomes, or other tumor-derived analytes shed into the bloodstream by tumors anywhere in the body. Unlike tissue biopsies, which require an invasive procedure and sample a single lesion, liquid biopsies capture a snapshot of the entire tumor genome from a simple blood draw — including hard-to-reach cancers and multiple primary tumors simultaneously.

The liquid biopsy market is projected to grow from $7.05 billion in 2025 to $22.69 billion by 2034, at a CAGR of 13.91%, driven by advances in next-generation sequencing (NGS), AI-powered mutation detection, and the clinical imperative to detect cancer earlier when it is most treatable. Over $2 billion has been invested in multi-cancer early detection (MCED) startups since 2020, making this one of the most capital-intensive segments of the IVD industry.

The clinical promise is clear: the five-year survival rate for cancers detected at Stage I averages 80–90%, compared to 10–20% for cancers detected at Stage IV. Yet in the United States, only about 14% of cancers are currently detected through organized screening programs — limited to breast, cervical, colorectal, lung, and prostate cancer. MCED tests aim to fill the gap for the majority of cancers that have no recommended screening method.

But the regulatory landscape for these tests is complex and still evolving. Liquid biopsy products span a wide range of intended uses — from screening asymptomatic populations (MCED) to companion diagnostics guiding therapy selection, minimal residual disease (MRD) monitoring, and recurrence surveillance — and each faces different regulatory requirements under both the FDA and EU IVDR.

This guide covers the complete regulatory framework for liquid biopsy and MCED tests in 2026: how the FDA classifies and reviews these products, the Breakthrough Device Designation pathway, companion diagnostic requirements, EU IVDR classification, clinical evidence expectations, and what the key market developments mean for regulatory strategy.

How Liquid Biopsy Tests Are Regulated

Liquid biopsy tests are regulated as in vitro diagnostic (IVD) devices in both the United States and European Union. But their regulatory treatment depends heavily on the intended use, the technology, the clinical evidence supporting the test, and the commercial model (FDA-approved IVD kit vs. laboratory-developed test).

The LDT vs. FDA-Approved IVD Divide

A critical distinction in the liquid biopsy market is between laboratory-developed tests (LDTs) and FDA-approved IVD kits:

• LDTs are designed, manufactured, and used within a single laboratory. Historically, the FDA exercised enforcement discretion over LDTs, meaning they were not subject to premarket review. Many liquid biopsy tests — including early versions of Guardant Health's Guardant360 and Grail's Galleri — launched as LDTs under CLIA laboratory certification.

• FDA-approved IVDs are test kits or systems that are manufactured and distributed to multiple laboratories. They require premarket submission (510(k), De Novo, or PMA) and FDA clearance or approval before marketing.

The regulatory landscape shifted significantly in 2024–2025. The FDA's final rule on LDTs, published in May 2024, phased out the enforcement discretion policy over four years. Under this rule, high-risk LDTs (Class III and certain Class II) will eventually require premarket approval. However, the implementation timeline has been subject to legal challenges and policy changes under new FDA leadership in 2026.

For liquid biopsy manufacturers, the strategic implication is clear: the market is moving toward FDA-approved IVD platforms. Guardant Health's transition of Guardant360 from LDT to FDA-approved CDx is a case study in this shift. When the FDA approved the expanded Guardant360 Liquid CDx on May 20, 2026, approximately half of Guardant360 testing volume was still running under LDT status. The approval creates a pathway for those users to transition to the FDA-authorized version, strengthening physician confidence and expanding payer coverage.

FDA Regulatory Pathways for Liquid Biopsy Tests

Classification: Which Pathway Applies?

The FDA classifies liquid biopsy tests based on intended use and risk level. The three primary pathways are:

Breakthrough Device Designation

The FDA's Breakthrough Device Program has become a central pathway for MCED tests. The designation is available for devices that provide for more effective treatment or diagnosis of life-threatening or irreversibly debilitating diseases, and that meet at least one of four criteria: breakthrough technology, no approved alternatives, significant patient benefit over existing options, or device availability is in the patient's best interest.

Breakthrough Device Designation does not confer marketing authorization. It provides:

• Prioritized review and interactive communication with FDA
• A dedicated FDA review team
• Senior FDA management involvement
• Expedited pre-submission meetings
• A prioritized queue for manufacturing and quality system inspections

The program has been heavily used in the liquid biopsy space. Recent examples include:

• Gene Solutions SPOT-MAS 10: On May 27, 2026, the FDA granted Breakthrough Device Designation to SPOT-MAS 10, a multi-omic blood test designed to detect cancer-associated signals across ten cancer types. SPOT-MAS became the first MCED blood test in Asia to complete a large prospective cohort validation (the K-DETEK study, published in BMC Medicine, evaluated over 9,000 asymptomatic participants). The test has since been used in more than 100,000 individuals in real-world practice. Gene Solutions is targeting U.S. launch readiness in late 2026.

• TCM Biotech CatCHimera: In April 2026, TCM Biotech received Breakthrough Device Designation for CatCHimera, a tumor-informed liquid biopsy MRD platform for hepatocellular carcinoma that uses patient-specific HBV-host genome integration junctions as the circulating tumor biomarker — a novel ctDNA biomarker class distinct from traditional somatic SNV/indel detection.

• Guardant Health Shield: Guardant Health's blood-based colorectal cancer screening test received FDA approval and Medicare coverage at $1,495 per test. On May 27, 2026, the American Cancer Society published updated screening guidelines that added the Shield blood test as an approved CRC screening option — a landmark for blood-based cancer screening.

Medicare Coverage: The Nancy Gardner Sewell MCED Act

A parallel legislative milestone has already been achieved. The Nancy Gardner Sewell Medicare Multi-Cancer Early Detection Screening Coverage Act (H.R. 842 / S. 339) was signed into law on February 3, 2026, establishing Medicare coverage authority for FDA-approved blood-based MCED screening tests beginning in January 2028. The legislation passed with strong bipartisan support and creates a pathway for CMS to determine coverage for MCED tests once they receive FDA approval and demonstrate clinical benefit. For the liquid biopsy industry, this is transformative — it removes the Medicare coverage barrier that would otherwise limit market access for the population that would benefit most (adults aged 50+).

PMA: The Pathway for Screening-Indication MCED Tests

MCED tests intended for cancer screening in asymptomatic populations are likely to be classified as Class III devices requiring PMA approval — the most rigorous FDA device pathway. Grail's Galleri test, which operates under Breakthrough Device Designation, is in the process of completing a PMA modular submission to FDA, with data from the PATHFINDER 2 study and the prevalent screening round of the NHS-Galleri trial. Grail also plans to submit a bridging analysis comparing the test version used in those studies to the updated version intended for commercialization. The PMA process requires:

• Analytical validation: Demonstrating accuracy, precision, sensitivity, specificity, limit of detection, and reproducibility of the test across the intended sample types and conditions
• Clinical validation: Prospective clinical studies demonstrating that the test detects cancer with clinically meaningful sensitivity and specificity, ideally with an outcome benefit (e.g., earlier stage at diagnosis, reduced late-stage cancer incidence)
• Clinical utility: Evidence that test-guided clinical actions improve patient outcomes — a growing expectation for screening tests
• Advisory panel review: FDA typically convenes an advisory panel for Class III screening devices
• Post-approval studies: Ongoing data collection requirements

The Grail Galleri MCED test illustrates the evidence bar. The NHS-Galleri trial — a prospective, randomized controlled trial involving over 140,000 asymptomatic participants aged 50–77 — was designed to demonstrate a statistically significant reduction in combined Stage III and IV cancer diagnoses. On February 19, 2026, Grail announced that the trial failed to meet its primary endpoint, sending shares plummeting by nearly 50%. The result underscores that generating definitive clinical outcome evidence for MCED screening is extraordinarily difficult and expensive.

However, Grail presented positive PATHFINDER 2 results at ASCO 2026 (May 31, 2026), showing that the Galleri test increased cancer detection 6.5-fold when added to recommended screenings, with 71% of newly detected cancers found at Stages I–III. The PATHFINDER 2 study — the largest interventional MCED study in North America with 35,878 participants — demonstrated robust performance and favorable safety in an intended-use population of adults aged 50 and older.

Companion Diagnostic (CDx) Pathway

Many liquid biopsy tests serve as companion diagnostics — IVD tests that identify patients who are likely to benefit from a specific therapeutic product. CDx tests are typically classified as Class II (requiring 510(k) or De Novo) or Class III (requiring PMA), depending on the risk profile.

Key CDx regulatory requirements include:

• Co-development: The CDx should be developed in parallel with the therapeutic product, with clinical evidence generated in the same pivotal trials
• Bridging studies: If the CDx is not used in the pivotal trial, a bridging study must demonstrate that the test identifies the same patient population
• PMA or 510(k): Most CDx tests for oncology therapies require PMA approval
• Labeling: The therapeutic product's labeling must reference the CDx test

Recent CDx milestones in liquid biopsy include:

• Guardant360 CDx for VEPPANU (vepdegestrant): On May 1, 2026, Guardant Health secured FDA approval for Guardant360 CDx as a companion diagnostic for Arvinas/Pfizer's vepdegestrant (VEPPANU) in ESR1-mutant ER+/HER2- advanced breast cancer — the first FDA-approved liquid biopsy CDx for a PROTAC degrader. VEPPANU is the first PROTAC (proteolysis-targeting chimera) therapy to receive FDA approval.
• Guardant360 Liquid CDx expanded panel: On May 20, 2026, the FDA approved the expanded Guardant360 Liquid CDx, the largest FDA-approved liquid biopsy panel integrating genomic and epigenomic data for comprehensive cancer profiling. The test is approved as a CDx for multiple therapies in non-small cell lung cancer, colorectal cancer, and advanced breast cancer, and is covered by Medicare and commercial insurers representing over 300 million lives

EU IVDR Classification for Liquid Biopsy Tests

Under the EU In Vitro Diagnostic Regulation (IVDR, Regulation 2017/746), liquid biopsy tests are classified based on the intended purpose and the risk profile of the clinical decision informed by the test results.

IVDR Classification Rules

Liquid biopsy tests typically fall under IVDR classification rules 3, 5, or 6:

• Rule 3: Devices intended to be used for screening, diagnosis, or staging of cancer are classified as Class C at minimum
• Rule 5: Devices intended for companion diagnostics are classified as Class C
• Rule 6: Devices intended to detect genetic variants that predict treatment response may be Class C or Class D depending on the clinical context

Class C devices require conformity assessment by a notified body, including review of clinical evidence, performance evaluation, and quality management system audit. Class D devices — the highest risk class — face additional requirements including consultation with an EU reference laboratory (EURL).

Clinical Evidence Requirements Under IVDR

The IVDR requires manufacturers to demonstrate:

• Scientific validity: The association between the analyte (e.g., ctDNA methylation pattern, genomic variant) and the clinical condition
• Analytical performance: Accuracy, precision, trueness, limit of detection, measuring range, interference, and stability
• Clinical performance: Clinical sensitivity, clinical specificity, positive predictive value, negative predictive value, and likelihood ratios — supported by clinical studies or peer-reviewed literature

For MCED tests marketed under IVDR, the clinical evidence bar is particularly high because:

1. The test must demonstrate performance across multiple cancer types (not just one)
2. The positive predictive value must be sufficient to justify follow-up diagnostic procedures
3. The test must not cause harm through false positives (unnecessary invasive procedures, anxiety) or false negatives (missed cancer diagnoses)

CE Marking Pathway

To obtain CE marking under IVDR, liquid biopsy manufacturers must:

1. Establish a quality management system (typically ISO 13485)
2. Appoint an EU authorized representative (if outside the EU)
3. Conduct a performance evaluation including scientific validity, analytical performance, and clinical performance
4. Prepare technical documentation demonstrating conformity with IVDR general safety and performance requirements
5. Submit to a notified body for conformity assessment (Class C and D)
6. Register the device in EUDAMED (mandatory from May 28, 2026)

Key Market Players and Regulatory Strategies

Guardant Health

Guardant Health is the market leader in FDA-approved liquid biopsy tests. The company's portfolio includes:

• Guardant360 CDx / Guardant360 Liquid CDx: The largest FDA-approved liquid biopsy panel (as of May 2026), integrating genomic and epigenomic insights. Approved as a companion diagnostic for multiple therapies in NSCLC, colorectal cancer, and breast cancer. The expanded Guardant360 Liquid CDx, approved May 20, 2026, offers 100x broader genomic coverage than its predecessor.
• Shield: An FDA-approved blood-based colorectal cancer screening test. Added to the American Cancer Society's CRC screening guidelines on May 27, 2026. Covered by Medicare at $1,495 per test.
• Guardant Reveal: A tissue-free liquid biopsy for MRD detection and recurrence monitoring in early-stage colorectal, breast, and lung cancers.
• Guardant Infinity: A combined tissue and liquid biopsy platform used in pharma collaborations for oncology trial support.

Guardant Health reported 38 abstracts at the 2026 ASCO Annual Meeting, demonstrating breadth across screening, therapy selection, and MRD monitoring. The company projects 27–30% revenue growth for 2026, with breakeven targeted by end of 2027.

Grail (Illumina)

Grail's Galleri MCED test detects methylation signatures in cell-free DNA to screen for over 50 cancer types from a single blood draw. Key developments:

• The NHS-Galleri trial (140,000+ participants) failed to meet its primary endpoint of reducing Stage III/IV cancer diagnoses, announced February 19, 2026
• PATHFINDER 2 results (presented May 31, 2026 at ASCO) showed the Galleri test increased cancer detection 6.5-fold when added to standard screenings, with 71% of new cancers detected at Stages I–III
• Grail announced a collaboration with Epic to embed Galleri ordering and results into Epic Aura, targeting broad availability across ~450 health systems by end of 2026
• The test is currently available in the U.S. as a physician-ordered LDT

Gene Solutions

Gene Solutions, a Singapore-based biotechnology company, received FDA Breakthrough Device Designation for SPOT-MAS 10 on May 27, 2026. Key facts:

• SPOT-MAS 10 is a multi-omic blood test detecting cancer-associated signals across ten cancer types
• The K-DETEK study (published in BMC Medicine) validated the test in over 9,000 asymptomatic participants
• The test has been used in more than 100,000 individuals in real-world practice
• Gene Solutions is targeting U.S. launch readiness in late 2026

Other Notable Players

• Exact Sciences: The company behind Cologuard/Cologuard Plus is advancing its own MCED platform
• Foundation Medicine (Roche): Competes in comprehensive genomic profiling with both tissue and liquid biopsy products
• Caris Life Sciences: Caris ChromoSeq received MolDX approval for myeloid cancers
• Precede Biosciences: Launched Precede Bio Insight, a research-use-only epigenomic liquid biopsy inferring genome-wide gene expression from cfDNA

Clinical Evidence Challenges Specific to MCED Tests

MCED tests face unique clinical evidence challenges that differentiate them from single-cancer screening tests:

1. The Multi-Cancer Sensitivity Problem

An MCED test must demonstrate adequate sensitivity across all target cancer types — not just one. The test may perform well for some cancers but poorly for others, and the aggregate performance statistic can mask important heterogeneity. Regulators will scrutinize per-cancer-type performance metrics, especially for cancers where no alternative screening exists.

2. Positive Predictive Value in Low-Prevalence Populations

In an asymptomatic screening population, even a highly specific test produces a substantial number of false positives when the prevalence is low. For example, a test with 99% specificity applied to a population with a 0.5% cancer prevalence yields approximately 2 false positives for every true positive. This has clinical implications: false positives lead to unnecessary imaging, biopsies, and patient anxiety.

3. Cancer Signal Origin Prediction

Many MCED tests predict the tissue of origin for detected cancer signals. The accuracy of this prediction directly affects the clinical workup — if the predicted origin is wrong, the patient may undergo inappropriate diagnostic procedures. Regulators evaluate tissue-of-origin prediction accuracy as a distinct performance metric.

4. The Outcome Endpoint Debate

The Grail NHS-Galleri trial used reduction in late-stage cancer incidence as its primary endpoint — a cancer outcome endpoint. Other trials, like PATHFINDER 2, focus on cancer detection performance metrics. The FDA has not yet established a definitive evidentiary standard for MCED screening approval, and the debate over what constitutes sufficient clinical utility continues.

5. Post-Market Surveillance

Given the population-level application of MCED tests, post-market surveillance is critical. Regulators will likely require:

• Long-term tracking of clinical outcomes for test-positive and test-negative individuals
• Monitoring of false-positive rates in real-world settings
• Assessment of interval cancer rates (cancers diagnosed between screening rounds)
• Ongoing performance monitoring across diverse populations

Regulatory Strategy Recommendations

For companies developing liquid biopsy and MCED tests:

For the U.S. Market

1. Engage FDA early through the pre-submission (Q-Submission) process: The regulatory pathway for MCED tests is not yet fully established. Early engagement with FDA CDRH is essential to agree on study design, endpoints, and analytical validation requirements.

2. Consider Breakthrough Device Designation: If the test addresses an unmet need in cancer screening or diagnosis, BDD provides significant benefits including prioritized review and interactive FDA communication.

3. Plan for PMA-level clinical evidence: MCED screening tests will almost certainly require PMA-level evidence, including prospective clinical studies with thousands of participants. Budget and timeline accordingly.

4. Develop a companion diagnostic strategy alongside screening: Companies like Guardant Health demonstrate that a CDx portfolio generates revenue and clinical evidence that supports a broader screening claim.

5. Build for the LDT-to-IVD transition: The regulatory trend is toward FDA oversight of all IVD tests, including LDTs. Companies should plan for FDA-approved IVD platforms rather than relying on long-term LDT status.

For the EU Market

1. Plan for IVDR Class C classification: Liquid biopsy tests for cancer screening or diagnosis will be classified as Class C at minimum, requiring notified body involvement.

2. Start EUDAMED registration early: EUDAMED is now mandatory (from May 28, 2026). All devices placed on the EU market must be registered, including legacy devices by November 27, 2026.

3. Prepare comprehensive performance evaluation: IVDR requires scientific validity, analytical performance, and clinical performance documentation. For MCED tests, the clinical performance dossier will be extensive.

4. Consider the EU AI Act: AI-powered liquid biopsy platforms (such as Guardant's InfinityAI) that qualify as high-risk AI systems under the EU AI Act will need to comply with additional requirements, including risk management, transparency, and human oversight obligations. The EU Digital Omnibus on AI (provisional deal reached May 2026) provides some mechanisms to reduce overlap between the AI Act and MDR/IVDR, but medical device AI systems will likely remain subject to both frameworks.

Conclusion

Liquid biopsy has moved from a promising research concept to a commercially validated clinical tool. Guardant Health's portfolio of FDA-approved tests, the addition of Shield to ACS screening guidelines, and Gene Solutions' Breakthrough Device Designation for SPOT-MAS 10 all signal that the regulatory infrastructure is maturing to support blood-based cancer diagnostics at scale.

But the field remains early. The Grail NHS-Galleri trial failure demonstrated that generating definitive clinical outcome evidence for MCED screening is extraordinarily challenging. The capital requirements are massive, the clinical trial timelines are measured in years, and the regulatory path is still being defined.

For regulatory professionals, the liquid biopsy space demands a new combination of skills: deep understanding of NGS analytical validation, companion diagnostic co-development, population-level screening trial design, and the intersection of emerging AI regulation with traditional IVD frameworks. The opportunity is enormous — but so is the evidence bar.

Related reading: For IVD analytical performance validation fundamentals, see our IVD Analytical Performance Validation Guide. For companion diagnostic regulatory requirements, see our Companion Diagnostics (CDx) Regulatory Guide. For the EU IVDR framework, see our Complete EU MDR and IVDR Guide.