On July 6, 2016, the FDA announced two new draft guidances on the oversight of next generation sequencing (NGS)-based in vitro diagnostic tests.1 Following on the Agency’s recent release of a draft guidance regarding NGS methods for infectious disease,2 the two new draft guidances focus on additional uses of NGS testing approaches. Unlike most IVDs that typically detect a limited number of predefined analytes for diagnosing pre‑specified conditions, NGS-based tests can be used to detect millions of analytes related to numerous conditions in a single run. They also have the potential to detect previously unidentified variants, including rare variants that may be unique to a single individual. FDA has recognized the importance of developing appropriate regulatory frameworks for oversight of NGS-based tests. Building on three public workshops held in 2015,3 the new draft guidances outline a flexible and adaptive approach to the regulation of NGS-based tests.

The first draft guidance provides recommendations for NGS‑based tests for germline diseases and addresses the potential for using FDA-recognized standards to demonstrate analytical validity.4 The second draft describes an approach to using data from FDA-recognized genetic variant databases as part of the premarket review submission to support clinical validity.5 Both approaches were the topics of discussion in previous public workshops.

NGS Testing for Diagnosing Germline Diseases

The first draft guidance, entitled "Use of Standards in FDA’s Regulatory Oversight of Next Generation Sequencing (NGS)-Based In Vitro Diagnostics (IVDs) Used for Diagnosing Germline Diseases," offers recommendations to developers of NGS-based tests on the design, development, and validation of tests for rare hereditary diseases detectable within the reproductive cells (or “germline”).

Similar to the draft guidance for infectious disease NGS tests issued earlier this year, the scope of the draft germline disease NGS guidance is carefully crafted. According to FDA, the recommendations in this draft guidance are limited to targeted and whole exome sequencing (WES) NGS-based tests intended to aid in the diagnosis of individuals with suspected germline diseases, defined within the draft guidance as “genetic diseases or other conditions arising from inherited or de novo germline variants.” It does not apply to NGS-based tests intended for stand-alone diagnosis, screening, microbial genome testing, risk prediction, cell‑free DNA testing, fetal testing, pre-implantation embryo testing, tumor genome sequencing, RNA sequencing, or companion diagnostics. In addition, FDA notes that additional recommendations and controls could be needed for direct-to-consumer tests.

While there are no legally marketed NGS-based tests with a broad intended use for suspected germline diseases, the draft guidance indicates that such tests may be appropriate for classification into class II through the de novo process. FDA believes that there is a reasonable possibility that the risks associated with such tests may be sufficiently mitigated by general and special controls. FDA encourages applicants to use the pre-submission process to discuss with the Agency about anticipated de novo requests.

FDA further indicates that if such tests were classified in class II, the Agency would consider exempting them from premarket notification requirements. This is consistent with the Agency’s prior actions with regard to more traditional genetic tests not using NGS technology. In the de novo clearance of 23andMe’s Bloom Syndrome test, FDA exempted the new device category, autosomal recessive carrier screening gene mutation detection system, from 510(k) requirements.6 Regardless of whether an NGS-based test is exempted, however, FDA emphasizes that public availability of information about analytical and clinical validity data for specific tests is important to both users and patients. The mechanism whereby such information would be made publicly available is not addressed by FDA’s guidance.

Following the feedback received at previous NGS workshops, the draft guidance outlines an approach for supporting the analytical validation of NGS-based test through conformity with FDA-recognized standards. FDA, however, states in the draft guidance that the Agency “is unaware of any existing, comprehensive standard for analytical validation applicable to NGS-based tests for germline diseases that it believes could be used to help provide reasonable assurance of the safety and effectiveness of these tests.” Further, the draft guidance notes that FDA has not determined how conformity with standards should be demonstrated, and plans to discuss this in future guidance documents. Therefore, at least for now, test developers cannot rely on this new approach to support analytical validation of their NGS-based test without further discussion with FDA.

Nevertheless, the draft guidance outlines the requirements FDA has established for a future standard to be recognized, which include a description of the design activities that should be carried out and the performance characteristics that should be validated, as well as specific methodology, materials, and performance thresholds. The detailed requirements for the design, development, and validation activities are discussed at length in the draft guidance. Notably, FDA provides recommendations for minimum performance thresholds for some metrics, as listed in the table below.

Click here to view the table.

The second draft guidance, entitled "Use of Public Human Genetic Variant Databases to Support Clinical Validity for Next Generation Sequencing (NGS)-Based In Vitro Diagnostics," describes an approach where test developers may rely on clinical evidence from FDA-recognized public genetic variant databases to support clinical claims for their NGS tests and provide assurance of accurate clinical interpretation of results. Rather than focus on specific disease types, as was the case for infectious disease and germline NGS tests, this draft guidance focuses more broadly on the public sources of data against which NGS tests generally can be evaluated.

FDA defines the “public genetic variant database” as 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.” The draft guidance only applies to databases that contain human genetic variants, and does not apply to other types of databases, such as databases used for microbial genome identification and detection of antimicrobial resistance and virulence markers. Further, the draft guidance is limited to curated databases using human interpretation and does not apply to databases using software interpretation.

The draft guidance explains that if genetic variant databases are organized in accordance with the principles outlined in the guidance and FDA recognition is sought as provided in the guidance, then the data and assertions provided in the database may be used by test developers to support the clinical validity of a new test. This approach is proposed to encourage public deposition of variant information, reduce regulatory burden on test developers, and stimulate advancements in precision medicine.

The draft guidance outlines the requirements for a genetic variant database to be recognized by FDA. Key points are summarized below.

  • Database procedure and operation: Sufficient information regarding data sources and standard operating procedures (SOPs) should be made publicly available. SOPs should define how variant information is aggregated, curated, and interpreted.
  • Data quality: Information contained in the database should be of sufficient quality, and based on current scientific knowledge, so that the assertions linking specific genetic variants to diseases or conditions are accurate. Specifically, measures to ensure data quality include using consistent nomenclature, accompanying variant data with metadata, and confirming data uniqueness.
  • Curation and interpretation: Curation and variant interpretation of genetic variant databases should be based on well-defined SOPs and conducted by qualified professional. In addition, FDA recommends using publicly available decision matrices for variant interpretation.
  • Professional training and conflicts of interest: The personnel curating and interpreting variant should have adequate training and expertise. There should be methodologies, such as proficiency testing, to monitor the qualification of the personnel. Moreover, personnel of a genetic variant database should disclose and minimize any potential conflict of interest.

If a genetic variant database meets all the requirements outlined in the draft guidance, the administrator of the database can make a voluntary submission to FDA for recognition. As part of the review process, FDA may verify variant assertions to assure the quality of the database. It should also be noted that FDA will not publicly disclose the database prior to recognition. Therefore, a proprietary database can remain confidential if it is submitted for FDA recognition. The database administrator should make the information publicly available at the time of recognition. After recognition, FDA may review the recognized databases on a regular basis to verify that they continue to follow their SOPs and maintain transparency. In addition, FDA indicates that in the future, it may also consider using third-parties to assist with database recognition.

While the database approach outlined in FDA’s draft guidance does not allow for an immediate solution for test developers, because no databases have been recognized by FDA as of yet, it does propose a path to less burdensome clinical validation in the future.

In conclusion, the two draft guidances illustrate FDA’s intent to develop creative and flexible approaches for regulating genetic tests using the emerging NGS technology. FDA outlines the requirements for standards or databases to be recognized by the Agency, and intends to rely on these recognized standards or databases to evaluate the analytical or clinical validities, respectively, of the NGS-based tests.

FDA will accept public comments on these two draft guidances until October 6, 2016. Particular questions that the Agency seeks comments on are listed in the Federal Register.9