Regulatory Landscape - Overview

Next Generation Sequencing (NGS) based In Vitro Diagnostic Tests (IVD) Regulatory Landscape: Product Overview:

Next generation sequencing (NGS) is a high throughput technology that allows for rapid sequencing of entire genomes, targeted regions or transcriptomes. In vitro diagnostics (IVDs) using NGS have transformed disease detection, diagnosis, prognosis, treatment selection, specially in oncology, infectious diseases and genetic disorder.

Next Generation Sequencing based IVD Tests Types:

Next generation sequencing based In vitro Diagnostics test include various types intended for diagnosis for various health conditions, some of which are as follows: Germline testing. Somatic mutation testing, liquid biopsy, infectious disease testing, prenatal testing, pharmacogenomics, rare disease diagnosis.

Next Generation Sequencing based In Vitro Diagnostic Tests Applications:

Next Generation Sequencing (NGS)-based In Vitro Diagnostic (IVD) tests is a transformative advancement in clinical diagnostics, offering advanced options for genetic analysis. These tests are capable of analysing millions of DNA sequences simultaneously, enabling the detection of a wide array of genetic variations in a single assay.

One of the most impactful applications of NGS-based IVDs is in the diagnosis of inherited genetic disorders, where they allow for the simultaneous examination of multiple genes associated with complex conditions such as cystic fibrosis, muscular dystrophies, and hereditary cancers.

 In oncology, NGS is used to profile tumors at the molecular level, identifying mutations that can guide personalized treatment strategies and predict therapeutic responses. Additionally, NGS plays a important role in infectious disease diagnostics by enabling the identification and characterization of pathogens, including their resistance profiles, which is essential for managing outbreaks and tailoring antimicrobial therapies.

In prenatal and neonatal care, NGS-based tests are employed for non-invasive prenatal testing (NIPT) to detect chromosomal abnormalities and for newborn screening to identify rare genetic disorders early in life. Pharmacogenomics is another key area where NGS informs drug selection and dosing by analysing genetic factors that influence drug metabolism and response.

Next Generation Sequencing based In Vitro Diagnostic Tests Regulatory Landscape:

There are several key regulatory agencies who oversee the approval and monitoring of Next Generation Sequencing based In Vitro Diagnostic Tests to ensure their safety, efficacy, and quality.

Next Generation Sequencing based In Vitro Diagnostic Tests Guidelines:

These tests are designed for the diagnosis of suspected inherited (germline) or acquired (somatic) genetic disorders. They are also used in cancer diagnostics and screening, helping to identify patients suitable for targeted therapies (such as personalized medicine), guide treatment decisions (e.g., monitoring minimal residual disease or assessing relapse risk), and assist in disease staging.

Next Generation Sequencing based In Vitro Diagnostic Tests Regulatory Process Overview, By Country:

The U.S. Food and Drug Administration (FDA) finalized two key guidance’s, aimed at accelerating the development of reliable next-generation sequencing (NGS) tests for genetic diseases and precision medicine. These guidelines provide a modern and flexible framework to support developers in creating and validating NGS-based in-vitro diagnostics (IVDs).

1. Use of Public Human Genetic Variant Databases to Support Clinical Validity

This guidance allows test developers to use clinical evidence from FDA-recognized public databases, such as ClinGen, to support clinical claims for their tests. By using these databases, developers can provide assurance of the accurate clinical evaluation of genomic test results, facilitating a more efficient path for marketing clearance or approval of new tests.

2. Considerations for Design, Development, and Analytical Validation of NGS-Based IVDs for Germline Diseases

The second guidance outlines recommendations for designing, developing, and validating NGS-based tests intended to aid in the diagnosis of suspected germline diseases. It provides insight into the FDA’s current thinking on what data is needed to determine the analytical validity of these tests, including how well the test detects the presence or absence of a particular genomic change.

So far, the FDA has approved only a limited number of targeted, single-gene NGS-based tests for specific diseases, such as the Illumina MiSeqDx Cystic Fibrosis 139-Variant Assay (k124006) and the Illumina MiSeqDx Cystic Fibrosis Clinical Sequencing Assay (k132750). However, the FDA has not yet established a classification for NGS-based tests intended for broader use in diagnosing suspected germline conditions. Since there are no existing legally marketed devices of this type to serve as a predicate for a 510(k) submission under the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 360(k)), these tests are automatically designated as Class III devices by law, so they undergo the more strict and extensive Premarket Approval (PMA) process.

When no suitable predicate device exists, low- to moderate-risk devices, like certain NGS-based tests for diagnosing suspected germline diseases, may be eligible for the FDA’s De Novo classification process. The FDA believes the risks of these tests could be managed through general and special controls. If a De Novo request is approved, the test would be classified as a Class II device, allowing it to be marketed and used as a predicate for future 510(k) submissions. These future tests would then need to comply with the established general and special controls, such as performance standards and Labeling requirements. The FDA encourages developers to use the Pre-Submission process to consult with the Agency before submitting a De Novo request.

Under section 510(m) of the FD&C Act, the FDA can exempt certain Class II devices from 510(k) premarket notification if it determines that such review isn’t necessary to ensure safety and effectiveness. As the FDA gains more experience with NGS-based tests for diagnosing suspected germline diseases, it may eventually establish special controls that would allow these tests to be exempt from 510(k) requirements under specific conditions.

These guidelines are part of the FDA's efforts to streamline the regulation and review of NGS tests, promoting innovation while ensuring patient safety and test reliability.

Analytical Performance of NGS Tests – FDA Perspective

The FDA has approved the Illumina MiSeqDx system and its cystic fibrosis assays by evaluating a representative subset of genetic variants, rather than requiring data for every possible variant. This approach shows that adequate analytical performance for this subset can provide reasonable assurance and proving that test would identify relevant variants in the genome without need for the company to submit data for every possible variant the test could identify.  Going forward, the FDA plans to continue using this subset-based evaluation for NGS platforms. Additionally, the agency is exploring new, efficient methods for assessing analytical performance of lab-developed NGS tests that use FDA-cleared components.

One proposed strategy is to develop methodological quality-based standards that labs can follow to demonstrate test performance. These standards could include:

• Defined technical metrics (e.g., error rates, coverage, depth)
• Computational methods for performance validation
• Quality system requirements for labs
• Best practices for quality assurance and proficiency testing
• Change control processes to manage technology updates

These standards can be developed by expert committees, the FDA, or organizations like the Clinical Laboratory and Standards Institute (CLSI). If developed by a recognized Standards Development Organization (SDO), the FDA would review and recognise those standards using its already established Standards Programs.

Clinical Performance Assessment of NGS Tests- FDA Perspective

FDA evaluate the clinical performance of the NGS based IVD test based on a sponsor’s submission of adequate data or information submitted in premarket application for their device or device platform. This data can come from clinical studies, trusted databases, published research, or other solid scientific sources.

When the FDA approved Illumina’s cystic fibrosis tests, they faced a challenge: some genetic variants are so rare that it’s hard to study them directly. Instead of requiring new studies, the FDA allowed the company to use a well-maintained third-party database that combined evidence from many sources to show which variants are linked to the disease.

Now, the FDA is asking for public feedback on how this kind of approach (using trusted databases instead of new studies) could be used more widely to help doctors get accurate and timely genetic information for patient care.

Next Generation Sequencing based In Vitro Diagnostic Tests updates:

February 2025, Roche has introduced its breakthrough technology of Sequencing by Expansion (SBX), marking a significant improvement in next-generation sequencing (NGS). SBX uses a novel biochemical process which encode DNA or RNA sequences into measurable polymers called Xpandomers, which are 50 times longer than the original molecules. These Xpandomers produce high signal-to-noise outputs, enabling highly accurate single-molecule sequencing. The technology is integrated with a CMOS-based sensor module that supports parallel processing, allowing for ultra-rapid, scalable, and flexible sequencing. SBX reduces the time of genome sample processing, from days to just hours, still making it ideal for both research and clinical applications. It is especially promising for decoding complex diseases like cancer, immune disorders, and neurodegenerative conditions. Roche positions SBX as a transformative solution that overcomes the limitations of existing sequencing technologies by offering unmatched speed, accuracy, and adaptability.

April 2025, Pillar Biosciences announced that its FDA-approved oncoReveal CDx pan-cancer solid tumor IVD kit has received nationwide Medicare coverage from the Centers for Medicare & Medicaid Services (CMS). This next-generation sequencing (NGS) kit uses Pillar’s proprietary SLIMamp technology to detect genetic mutations—such as single nucleotide variants, insertions, and deletions—in 22 cancer-related genes from tumor tissue samples. It is designed to help healthcare professionals profile tumors in patients with solid cancers and guide treatment decisions.

The kit is also approved as a companion diagnostic for identifying patients who may benefit from targeted therapies like EGFR TKIs in non-small cell lung cancer (NSCLC) and ERBITUX or VECTIBIX in colorectal cancer (CRC). Cleared for use on the Illumina MiSeq Dx platform, the test is now more accessible and reimbursable, potentially improving outcomes by enabling faster, localized, and cost-effective genomic testing.

Next Generation Sequencing based In Vitro Diagnostic Tests Regulatory Challenges and possible risk in development:

All the countries have their own regulatory framework used for approval of healthcare products; this makes difficult for the manufacturers to develop the product which will show compliance to all the regulatory frameworks for different countries allowing its marketing in those countries. And NGS based IVD test are new advanced diagnostic technology for which regulatory bodies are still not clear about how to regulate them effectively.

NGS based test may face technological challenges in development since it is a very complex technique, therefore its regulation will also be very strict, which can take longer time in its approval and may cause product launch delay, keeping patients away from getting such a advanced treatment.

High cost in developing and validating the NGS based IVD test as it involves use of expensive equipment, bioinformatics infrastructure and skilled personnel for the research and development. There can be ethical issues as NGS based test involves sequencing of genome of the patient raising ethical concerns about disclosure of unexpected genetic information of patient.

Next Generation Sequencing based In Vitro Diagnostic Tests Competitive Landscape Dashboard:

Companies With Marketed Next Generation Sequencing based In Vitro Diagnostic Tests:

• Thermo Fisher Scientific
• Pacific Biosciences
• QIAGEN
• Roche
• BGI Group
• Illumina
• Danaher Corporation
• PerkinElmer
• Agilent Technologies
• Array Biologicals
• Myraqa
• Oxford Nanopore Technologies
• Microsynth
• Genesis HealthCare