Alert April 19, 2018

FDA Streamlines Regulatory Approaches for Next Generation Sequencing-Based Tests and Investigational In Vitro Diagnostics In Oncology Drug Trials


On April 12, 2018, the U.S. Food and Drug Administration (FDA) announced the finalization of two guidances that describe regulatory approaches intended to streamline oversight of next generation sequencing (NGS)-based tests and other genetic and genomic-based tests. Additionally, on April 11, 2018, the FDA announced the availability of a draft guidance that introduces a streamlined submission process for obtaining a study risk determination for an investigational in vitro diagnostic (IVD) used in a clinical trial for an oncology therapeutic. As NGS and other IVDs continue to rapidly evolve, including in the growing field of precision medicine, so too has the FDA evolved its approach to regulating such diagnostics. In this alert, we provide an overview of recent regulatory developments in this field.

The ability of NGS-based tests to yield vast amounts of information in a single test has posed novel challenges to applying the traditional framework for IVDs that test a single disease or condition. In an effort to provide for more flexible and efficient oversight of this rapidly evolving technology, on April 12, 2018, the FDA announced the finalization of two guidances that set forth approaches intended to streamline the submission and review of data, and therefore, accelerate the path to market for NGS-based tests:  

  • The first guidance issued, entitled “Considerations for Design, Development, and Analytical Validation of FDA Next Generation Sequencing (NGS)–Based In Vitro Diagnostics (IVDs) Intended to Aid in the Diagnosis of Suspected Germline Diseases,” provides insight into the FDA’s current thinking on what data the FDA is looking for to determine the analytical validity of a subset of NGS-based tests. The guidance further envisions leveraging the expertise of the community to collaboratively develop consensus standards for analytical validation of NGS-based tests that can then be relied upon by individual test developers and the FDA. While the scope of the guidance is directly applicable to only a subset of NGS-based tests as described in the guidance, the principles described in the guidance may be applicable to NGS-based tests more broadly.  [Guidance
  • The second guidance issued, entitled, “Use of Public Human Genetic Variant Databases to Support Clinical Validity for Genetic and Genomic-Based In Vitro Diagnostics,” describes the FDA’s vision whereby evidence of clinical validity is crowdsourced through the aggregation of genetic variant data into publicly accessible databases that can then be relied upon by individual developers of NGS-based tests and other genetic and genomic-based tests (e.g., Sanger sequencing and polymerase chain reaction (PCR)) should the FDA recognize such databases as sources of valid scientific evidence. The guidance sets forth the FDA’s current thinking on the appropriate characteristics for databases that can become FDA-recognized and, therefore, relied upon as sources of valid scientific evidence.  [Guidance

The issuance of these guidances follows several major regulatory developments concerning the development and regulation of genetic-based tests, including:

  • Introduction of the FDA’s three-tiered approach for streamlined review of tumor profiling NGS tests, such as the Memorial Sloan Kettering Cancer Center’s IMPACT tumor profiling assay, and the FDA’s increased reliance on third-party reviews by the New York State Department of Health (NYSDOH) for assessment of such tests. [FDA Fact Sheet] [Press Release]
  • The FDA’s approval of the first breakthrough-designated NGS-based test for detection of genetic mutations in 324 genes and two genomic signatures in any solid tumor type. This approval also marked the second IVD to be approved and covered after overlapping FDA and Centers for Medicare & Medicaid Services (CMS) review under the Parallel Review Program. CMS’s proposed national coverage decision (NCD) was finalized on March 16, 2018, and notably, provides that only diagnostic laboratory tests using NGS for patients with advanced cancer that have received marketing authorization from the FDA as a companion diagnostic would automatically receive full coverage under the final NCD. [Press Release – FDA Approval] [Press Release – CMS NCD]
  • Finalization of standardized criteria for direct-to-consumer autosomal recessive carrier screening tests that allows for marketing without prior FDA premarket review. [Classification Regulation][Exemption Order]
  • The establishment of standardized criteria for direct-to-consumer genetic health risk tests and a proposal to allow their marketing following a one-time agency review of a representative test or tests. [Classification Regulation] [Exemption Notice]

Additionally, on April 11, 2018, the FDA issued a draft guidance entitled “Investigational In Vitro Diagnostics in Oncology Trials: Streamlined Submission Process for Study Risk Determination.” This draft guidance introduces a voluntary streamlined submission process for determining whether an investigational IVD in a clinical trial for an oncology therapeutic is considered significant risk (SR), nonsignificant risk (NSR), or exempt. IVD and drug developers partnering to co-develop a therapeutic product and companion diagnostic may in certain circumstances utilize the new streamlined pathway to avoid some of the administrative burden of the traditional submission pathway. [Draft Guidance]

This draft guidance follows an earlier draft guidance issued in 2017 entitled “Investigational IVDs Used in Clinical Investigations of Therapeutic Products.” In the 2017 draft guidance, the FDA expressed concern that sponsors and investigational review boards (IRBs) may not appreciate that investigational IVDs used in clinical trials can pose significant risk to patients by affecting important aspects of the treatment they are receiving in the study. In addition, the FDA draft guidance highlights that in such circumstances, the investigation may be subject to the FDA’s Investigational Device Exemption (IDE) requirements in addition to the Investigational New Drug (IND) regulation. [Draft Guidance]

* * *

Developers and sponsors of new technologies should carefully review and incorporate the FDA’s latest thinking in their product development strategies. Additionally, with the continued growth of the field of precision medicine and the IVD technologies underlying the discovery of novel, targeted therapies, we expect to see continued collaboration between the FDA and its stakeholders in industry, laboratories, academia, and patient and professional societies in the years to come to explore new approaches that further foster the development of these critical diagnostic tests.