FDA recently published two draft guidance documents related to the development of devices that utilize next generation sequencing (NGS) technologies. These two draft guidances support the Administration’s Precision Medicine Initiative (PMI), which is intended to promote technologies that use genetic, environmental, and other data to tailor health care tools to unique needs of individual patients.  FDA had previously held public workshops addressing NGS technology in February and November 2015.  According to FDA, when finalized, the guidance documents “will provide a flexible and streamlined approach to the oversight of tests that detect medically important differences in a person’s genomic makeup.”

NGS technology holds the promise of furthering the goals of the PMI, given that it is capable of providing a wealth of information about genetic variants that may be relevant to medical decisions, such as the early detection of diseases, a patient’s risk of developing health conditions, or the choice of drugs or biologics. Unlike most traditional diagnostic tests that are focused on a specific or small set of biomarkers or genetic variants, NGS allows researchers or clinicians to obtain data across an entire genome, thereby providing information on a multitude of diseases or conditions.  The complexity and promise of NGS is leading FDA to consider new and innovative regulatory approaches for this technology.  The two guidances describe a conceptual framework for germline tests.

FDA’s first draft guidance, titled “Use of Standards in FDA’s Regulatory Oversight of Next Generation Sequencing (NGS)-Based In Vitro Diagnostics (IVDs) Used for Diagnosing Germline Diseases” provides recommendations for designing, developing and validating NGS-based tests for hereditary diseases, and addresses the potential for using FDA-recognized standards to demonstrate analytical validity.  Analytic validity refers to how well a test predicts the presence or absence of a particular genomic marker.  To demonstrate analytic validity, test developers should first define the indications for use statement of their test, which establishes the disease or condition, target population, and clinical use.  Developers should prospectively determine the performance needs, including the types of studies that should be conducted (e.g., accuracy) as well as the thresholds that should be met for each in the form of a minimum and target value.  After design and development of the test, validation studies will indicate if the predefined performance is met.  FDA’s draft guidance provides recommendations on each step for establishing analytic validity, including FDA-recommended minimum performance thresholds.

In addition, the draft guidance suggests that one approach for supporting the analytical validation of NGS-based tests may be to comply with one or more FDA-recognized standards or special controls. While FDA does not currently recognize any standards for NGS tests, the draft guidance sets forth considerations for a standard to be recognized by FDA.

The second draft guidance, titled “Use of Public Human Genetic Variant Databases to Support Clinical Validity for Next Generation Sequencing (NGS)-Based In Vitro Diagnostics” describes an approach wherein test developers may rely on clinical evidence from FDA-recognized public databases to support clinical claims for their tests.  According to the draft guidance, a “genetic variant database” is a publicly accessible database of human genetic variants that aggregates and curates reports of human phenotype-genotype relationships to a disease or condition with publicly available documentation of evidence supporting those linkages.  Once a database is recognized by FDA, a test developer could rely on the relationships between a genomic marker and a disease or condition reported by that database to support clinical validity claims.  The test developer would still need to demonstrate analytical validity, but would not have to independently assess the clinical validity of that relationship.  To be recognized by FDA, a database should do the following:

  1. operate in a manner that provides sufficient information and assurances regarding the quality of source data and its evidence review and variant assertions;
  2. provide transparency regarding its data sources and its operations, particularly around how variant evidence is evaluated and interpreted;
  3. collect, store, and report data and conclusions in compliance with all applicable requirements regarding protected health information, patient privacy, research subject protections, and data security; and
  4. house sequence information generated by validated methods.

The draft guidance describes a process by which a database could be recognized by FDA, which would include: (1) a voluntary submission of detailed information about the database; (2) FDA review of genetic variant database policies and procedures for obtaining and maintaining data and making variant assertions; and (3) maintenance of FDA recognition of a database. Once recognized, evidence contained in a genetic variant database would generally constitute valid scientific evidence that can be used to support the clinical validity of an NGS-based test.

NGS technology and testing is advancing at a rapid pace. Given the myriad applications for NGS, researchers and clinicians are developing and employing novel NGS approaches that address critical health issues.  It is important, therefore, for FDA to provide its current thinking on the regulation of this dynamic technology.  FDA’s draft guidance documents are a helpful step, but only a step.  To avoid FDA regulation slowing the development of NGS-based tests, the agency will need to demonstrate a willingness to recognize consensus standards and databases, so that test developers may appropriately leverage prior research.  Such standards and databases already exist.  Numerous organizations have been established to curate evidence of clinical validity of genomic assays, many of which are administered by federal agencies.  Additionally, FDA’s guidances have been criticized as an attempt to regulate laboratory-developed tests (LDTs) before FDA issues final LDT guidance and before questions about FDA’s regulatory authority over LDTs is resolved.  Stakeholders will want to review these two NGS draft guidances and submit comments to FDA by the October 6, 2016, deadline.