How to secure reimbursement / Cancer National Genomic Test Directory 2025/26

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A Quiet Revolution in Genomic Medicine

On 6 May 2025, NHS England quietly published the new National Genomic Test Directory 2025/26, a document that may seem administrative but in reality reshapes the foundations of precision oncology and rare-disease diagnostics in the UK.

Amid hundreds of line-item codes and eligibility tables lies a single but transformative update: The National Genomic Test Directory 2025/26 introduces Code M4.14, a multi-target circulating tumour DNA (ctDNA) panel specifically designed for non-small-cell lung cancer (NSCLC).

This update is more than a new line of text; it’s the first formal NHS endorsement of liquid biopsy as a reimbursed clinical testing strategy. With it, England’s national health system signals that the era of minimally invasive, real-time genomic medicine has truly begun.

The M4.14 code allows a multi-gene NGS-based ctDNA test that looks for important cancer-related genes, including EGFR, ALK, BRAF, KRAS, ROS1, RET These molecular alterations govern eligibility for a growing list of targeted and tumour-agnostic therapies—from osimertinib and alectinib to entrectinib and tepotinib—linking genomic information directly to therapeutic decision-making.

For the NHS, inclusion in the Test Directory is synonymous with funded implementation through Genomic Laboratory Hubs (GLHs). For patients, it means faster access to treatment when tissue is unobtainable or biopsy is unsafe. For industry, it defines reimbursement visibility—the threshold between an investigational assay and an NHS-backed diagnostic service.

This update consolidates the NHS Genomic Medicine Service as a global model of publicly funded precision medicine, bridging scientific innovation, operational delivery, and health-economic governance.

NHS England’s 2025 Genomic Test Directory Code M4.14 multi-target NGS panel includes liquid biopsy with circulating tumour DNA (ctDNA).

Table of Contents (SEO Internal Anchors)

1. What’s New in the 2025/26 NHS Genomic Test Directory
2. Understanding ctDNA and Its Scientific Foundation
3. The relevance of Code M4.14 for NSCLC and the NHS is important to understand.
4. The clinical and economic impact includes turnaround time, cost, and access.
5. The NHS Genomic Laboratory Hub Network interconnects with reimbursement processes.
6. Implications for Industry: IVD, Pharma, and Digital Health
7. Rare Disease Eligibility Updates: The Quiet Revolution Continues
8. The Future of NHS Genomic Medicine: From Tissue to Plasma
9. References and Key Links

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1. What’s New in the 2025/26 NHS Genomic Test Directory

On 6 May 2025, NHS England released the latest version of its National Genomic Test Directory, a framework that determines which genomic tests are publicly funded, under what conditions, and through which laboratories.

Three updated components were published:

• Cancer Test Directory (v12)
• Rare and Inherited Disease Directory (v8)
• Eligibility Criteria for Rare and Inherited Diseases (v8)

The major headline: introduction of Code M4.14, a multi-target circulating tumour DNA (ctDNA) panel for non-small cell lung cancer (NSCLC)—marking the first official reimbursement inclusion of a liquid biopsy test within the NHS cancer genomics service.

2. Understanding ctDNA and Its Scientific Foundation: The Role of Circulating Tumour DNA in Cancer Diagnosis

Circulating tumour DNA (ctDNA) refers to fragments of DNA shed by cancer cells in the bloodstream. Through next-generation sequencing (NGS), clinicians can detect key mutations and fusions associated with tumour biology, treatment response, and resistance.

Scientific relevance:

• Sensitivity: Advanced digital PCR and NGS techniques can detect variant allele frequencies below 0.1%.
• Comprehensiveness: Multi-gene panels identify SNVs, CNVs, and structural variants across EGFR, ALK, BRAF, KRAS, MET, ROS1, RET, and NTRK1–3.
• Dynamic monitoring: ctDNA allows repeated testing to track response to targeted therapy, detect minimal residual disease (MRD), and monitor acquired resistance mutations.

This approach is backed by pivotal trials such as NILE (Aggarwal et al., JCO 2019) and TRACERx (Abbosh et al., NEJM 2017), which validated the use of ctDNA for detecting actionable variants and tracking tumour evolution in NSCLC.

3. Why Code M4.14 Is relevant for NSCLC and the NHS {#why-m414-matters}

The inclusion of M4.14 – multi-target ctDNA combined with the multi-target NGS panel – represents a strategic alignment between clinical evidence and policy adoption.

Actionable drivers covered include:

• The actionable drivers covered by this test include the following genes: EGFR, ALK, BRAF, KRAS, ROS1, RET, MET exon 14 skipping, and NTRK1-3.

These genes correspond to approved targeted therapies reimbursed under NHS England and NICE Technology Appraisals.
By embedding this test in the National Genomic Test Directory, NHS England ensures:

• Standardised access for NSCLC patients across all 7 Genomic Laboratory Hubs (GLHs)
• Direct reimbursement under NHS specialised commissioning
• Faster turnaround times (liquid biopsy ~7 days vs tissue biopsy ~21 days)
• Improved equity for patients unable to undergo invasive biopsy

4. Clinical and Economic Impact: Turnaround, Cost, and Access {#clinical-economic-impact}

From a health economics perspective, liquid biopsy offers both efficiency gains and value for money:

Parameter	Traditional Tissue Biopsy	ctDNA Liquid Biopsy
Turnaround time	21–28 days	5–10 days
Sample adequacy failure rate	10–20%	<2%
Repeatability	Limited	High
Cost per test (average NHS rate)	£900–£1,200	£700–£1,000
Clinical utility	Mutation identification only	Mutation + resistance + MRD

When linked to earlier treatment initiation and reduced hospitalisation, this translates to potential budget impact savings of £1,200–£1,800 per patient episode, particularly in cases where re-biopsy is avoided (NHS England data modelling, 2024).

5. Reimbursement and the NHS Genomic Laboratory Hub Network

Under the Genomic Medicine Service (GMS), all tests listed in the Genomic Test Directory are centrally funded via Specialised Commissioning and delivered through seven regional Genomic Laboratory Hubs (GLHs).

Each GLH is responsible for:

• Test ordering and logistics
• Quality assurance and interpretation
• Data integration into the National Genomic Research Library (Genomics England)

Inclusion = reimbursement.
If a test isn’t listed, it cannot be invoiced or commissioned by the NHS.
The M4.14 ctDNA panel therefore unlocks funding for hospitals and laboratories, making liquid biopsy a reimbursable diagnostic pathway rather than a research tool.

6. Implications for Industry: IVD, Pharma, and Digital Health

For IVD manufacturers, pharma-companion diagnostic partnerships, and digital health data platforms, inclusion in the Test Directory signifies market access legitimacy.

Strategic implications:

• ctDNA assays must demonstrate analytical validity under IVDR (EU 2017/746) or MHRA transitional regulations.
• Companion diagnostic (CDx) partnerships (e.g., AstraZeneca–Guardant Health, Roche–Foundation Medicine) will now align commercial access with NHS reimbursement.
• Digital and AI analytics platforms can link ctDNA results to clinical decision support tools under DTAC and NHS AI Lab frameworks.

7. Rare Disease Eligibility Updates: The Quiet Revolution Continues

While less publicised, the Eligibility Criteria for Rare and Inherited Diseases (v8) includes refinements that can dramatically affect testing access for rare disease patients.

These updates clarify:

• Who qualifies for funded testing
• Referral protocols for clinicians
• Inheritance pattern-based eligibility (autosomal dominant/recessive, de novo, mosaic)

By removing ambiguity, NHS England shortens diagnostic timelines for families navigating rare disease pathways—potentially reducing the average 5-year diagnostic odyssey.

8. The Future of NHS Genomic Medicine: From Tissue to Plasma

The inclusion of ctDNA heralds a systemic evolution in NHS precision medicine.
Liquid biopsy may soon expand to:

• Colorectal, breast, and prostate cancers
• Minimal residual disease (MRD) detection
• Treatment monitoring and recurrence prediction

As real-world evidence (RWE) accumulates through NHS GLH data and Genomics England integration, the UK is poised to lead in evidence-based adoption of plasma-based precision diagnostics.

9. References and Key Links {#references}

• NHS England. National Genomic Test Directory 2025/26 – Cancer (v12), Rare and Inherited Diseases (v8). https://www.england.nhs.uk/genomics/test-directory/
• Aggarwal C. et al. “Clinical Utility of Plasma NGS Testing in NSCLC (NILE Study).” J Clin Oncol, 2019.
• Abbosh C. et al. “Phylogenetic ctDNA Analysis in Early-Stage Lung Cancer.” NEJM, 2017.
• NICE Technology Appraisals: https://www.nice.org.uk/guidance/ta
• NHS Genomic Laboratory Hubs overview: https://www.england.nhs.uk/genomics/genomic-lab-hubs/
• Genomics England Research Library: https://www.genomicsengland.co.uk

Frequently Asked Questions (FAQ) — NHS England Genomic Test Directory 2025/26 and ctDNA Integration

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1. What is ctDNA, and how does it differ from traditional tissue biopsy?

Circulating tumour DNA (ctDNA) consists of small fragments of DNA shed by tumour cells into the bloodstream. Unlike tissue biopsy, which requires invasive sampling, ctDNA testing (liquid biopsy) uses plasma from a blood draw to identify actionable mutations such as EGFR, BRAF, or ALK.
This allows minimally invasive, real-time genomic monitoring and supports treatment adaptation over time.

📚 Reference: Abbosh et al., NEJM 2017; Aggarwal et al., JCO 2019.

2. Why is the inclusion of Code M4.14 in the NHS Genomic Test Directory significant?

Code M4.14 represents the first NHS-backed multi-target ctDNA NGS panel for Non-Small Cell Lung Cancer (NSCLC).
Its inclusion signals full reimbursement through Genomic Laboratory Hubs (GLHs) and recognition of ctDNA as a validated diagnostic pathway, not merely research.

3. Which mutations and biomarkers are covered under Code M4.14?

The M4.14 panel includes:

• EGFR, ALK, BRAF, KRAS, ROS1, RET, MET exon 14 skipping, and NTRK1–3 fusions.
  These biomarkers enable access to tumour-agnostic therapies such as osimertinib, entrectinib, and tepotinib, aligning directly with NICE Technology Appraisals.
  

4. What are the turnaround times for ctDNA testing compared to tissue biopsy?

Average tissue biopsy turnaround time in the NHS: 21–28 days.
ctDNA testing: typically 5–10 days.
Rapid turnaround allows earlier therapy initiation, especially crucial for rapidly progressing NSCLC.

📚 Reference: NHS GLH performance data (2024).

5. How is ctDNA testing reimbursed within the NHS Genomic Medicine Service?

All tests listed in the National Genomic Test Directory are centrally funded under Specialised Commissioning.
Once listed, the test becomes reimbursable via GLHs, meaning hospitals and labs cannot charge patients directly.

📚 Reference: NHS England Genomic Test Directory Policy 2025.

6. What role do the NHS Genomic Laboratory Hubs (GLHs) play in ctDNA testing?

The seven GLHs act as the operational backbone of the NHS Genomic Medicine Service.
They handle test logistics, bioinformatics pipelines, and result interpretation, ensuring uniform quality and turnaround across regions.

📚 Reference: NHS England GLH overview.

7. How does ctDNA improve equity of access for NSCLC patients?

Many NSCLC patients cannot undergo tissue biopsy due to comorbidities or inaccessible tumours.
Liquid biopsy provides a safer, repeatable, and equitable diagnostic option, expanding access to precision medicine for underserved groups.

8. Is ctDNA testing as reliable as tissue biopsy for mutation detection?

Modern NGS-based ctDNA panels achieve >90% concordance with tissue-based assays for key actionable mutations (EGFR, BRAF, KRAS).
While sensitivity may vary with tumour burden, ctDNA offers higher repeatability and lower sample failure rates.
📚 Reference: Aggarwal et al., JCO 2019 (NILE Study).

9. How does ctDNA enable real-time treatment monitoring?

By detecting emerging resistance mutations (e.g., EGFR T790M, MET amplification), ctDNA testing supports longitudinal monitoring and early therapy adaptation.
This allows oncologists to modify treatment before clinical relapse occurs.

10. What is the role of ctDNA in minimal residual disease (MRD) detection?

ctDNA enables ultra-sensitive detection of MRD, identifying recurrence months before imaging.
This is a key research frontier in NHS oncology pilots, potentially guiding adjuvant therapy decisions.

📚 Reference: Reinert et al., JCO Precision Oncology 2023.

11. How does the NHS evaluate the cost-effectiveness of ctDNA testing?

NHS England uses Budget Impact Analysis (BIA) and Cost-Utility Analysis (CUA) models incorporating turnaround time, treatment delay costs, and hospitalisation rates.
Early estimates suggest £1,200–£1,800 savings per patient episode when ctDNA replaces re-biopsy.

📚 Reference: NHS Genomic Evaluation Model, 2024.

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12. How does this update align with NICE Technology Appraisals?

NICE appraisals for EGFR, ALK, NTRK, and ROS1-targeted therapies require verified biomarker detection.
By listing ctDNA-based panels in the Directory, NHS ensures compliance with NICE TA-linked testing requirements, enabling national reimbursement alignment.

13. How does ctDNA testing integrate with digital and AI diagnostic tools?

Digital pathology and AI-driven variant calling are increasingly integrated within NHS GLH workflows.
ctDNA datasets contribute to AI training for predictive analytics in treatment response and mutation evolution.

14. What are the regulatory requirements for ctDNA assays under IVDR or MHRA?

Under EU IVDR 2017/746 (or MHRA transitional provisions in the UK), ctDNA assays must demonstrate:

• Analytical validity (precision, limit of detection)
• Clinical performance
• Real-world evidence (RWE) for intended use
  

15. How does NHS England’s update compare internationally?

The UK joins France, Germany, and the US in formally integrating liquid biopsy into national reimbursement frameworks.
While the US CMS covers Guardant360 and FoundationOne Liquid CDx, the NHS M4.14 inclusion positions the UK as a publicly funded leader in plasma genomics.

16. What does this mean for pharmaceutical companies with companion diagnostics (CDx)?

Pharma-CDx alliances (e.g., AstraZeneca–Guardant Health, Roche–Foundation Medicine) gain a direct reimbursement pathway for biomarker-linked drugs.
This encourages joint submissions and integrated CDx approval with NICE and MHRA.

17. How will real-world evidence (RWE) strengthen ctDNA adoption?

Data from the NHS GLH network and Genomics England Research Library will generate real-world evidence on outcomes, cost, and workflow integration.
This RWE will guide future expansion of ctDNA testing into other tumour types.
📚 Reference: Genomics England Annual Report 2025.

18. How does this update affect rare disease testing in the NHS?

The 2025 update also refines Eligibility Criteria for Rare and Inherited Diseases (v8), clarifying genetic inheritance pathways and referral criteria.
It ensures faster diagnostic turnaround and better utilisation of genomic sequencing in rare disease management.

19. What’s next for ctDNA and NHS genomic innovation?

NHS England’s next focus areas include:

• ctDNA in colorectal and breast cancers
• Minimal residual disease (MRD) monitoring pilots
• Integration with national cancer screening and early detection initiatives
  

20. How can diagnostic companies or researchers engage with the NHS Genomic Medicine Service?

Companies can:

1. Align assays with NHS Directory evidence requirements.
2. Collaborate with GLHs and Genomics England for pilot evaluation.
3. Submit data via NICE’s Diagnostic Assessment Programme (DAP) or HealthTech Connect.
   
   📚 Reference: NICE HealthTech Connect Portal; NHS England GMS Guidance 2025.