Building on last year’s public workshops related to Next-Generation Sequencing (NGS) and expanding its efforts to advance the Obama Administration’s Precision Medicine Initiative, the FDA late last week released two draft guidance documents on different aspects of NGS-based diagnostic tests. NGS is a term used to describe new technologies that allow rapid sequencing of large segments of an individual’s DNA or entire genomes, as we have described previously. The Agency’s stated goal is “to create a flexible and adaptive regulatory approach to the oversight of NGS-based tests,” given the rapid and innovative advancements being made in the technologies. 

The significance of this move by the Agency also is highlighted by the fact that a press release was issued to announce it, something that is typically not done for more “routine” guidance documents that come out of one or more of the FDA Centers on an almost daily basis. An earlier draft guidance on the use of NGS for infectious disease applications (released in May with an August 11 deadline for comments) did not receive nearly as much fanfare as these two new proposed guidelines.

Of the two new policies, the first draft guidance describes an approach to allow test developers to rely on clinical evidence from FDA-recognized public genome databases to support claims for their tests and to provide assurance of accurate clinical interpretation of genomic test results, potentially offering a streamlined path to approval. The second document provides recommendations for designing, developing, and validating NGS-based tests for rare hereditary diseases and addresses the potential for using FDA-recognized standards to show analytical validity. 

Use of Public Databases to Support Clinical Validity of NGS-Based Tests

The first draft guidance document, entitled “Use of Public Human Genetic Varian Databases to Support Clinical Validity for NGS-Based In Vitro Diagnostics,” sets forth how the Agency views the data and so-called assertions contained within a genetic variant database. An “assertion” is an informed assessment by qualified personnel about a genotype-phenotype correlation given the current state of knowledge for a particular variant. The key takeaways from this proposed approach by FDA are:

• Well-recognized professional guidelines for making assertions generally are expected to meet existing regulatory requirements for “valid scientific evidence” to support the analytical and clinical performance, and by extension the safety and effectiveness, of a device (in this case an in vitro diagnostic device or IVD).

• In order to serve this role as “valid scientific evidence” to support an NGS-based test, a curated database of human genetic variants must meet certain features intended to ensure high-quality procedures and data sets. 

• Those Agency recommendations are that a given database should “(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 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.”

• If a genetic variant database meets those quality requirements, as further fleshed out in FDA’s draft document, the Agency states that the database administrators could then request (voluntarily, of course) recognition from the Agency that the assertions contained within it be considered “valid scientific evidence” to support a future NGS-test premarketing review submission. The developer of an NGS-based test would then incorporate the recognized database’s assertions about specific genetic variants and the data supporting those assertions in its submission. FDA’s proposed Recognition Process for Genetic Variant Databases would, most critically, include a review of the policies, procedures, and other documentation from the database; such information would be expected to be made public by the database administrator after receiving FDA recognition as part of the transparency commitment. 

FDA’s goal in allowing developers of NGS-based tests to rely on assertions in carefully curated genetic databases is simultaneously to “encourage the deposition of variant information in such databases, reduce regulatory burden on test developers, and spur advancements in the interpretation and implementation of precision medicine.”

Use of Standards in FDA Oversight of NGS Tests for Germline Disease Diagnosis

“Use of Standards in FDA Regulatory Oversight of NGS-Based In Vitro Diagnostics Used for Diagnosing Certain Germline Diseases” is the name of the second draft guidance just issued by the Agency. The document provides recommendations to developers of NGS-based tests regarding the design, development, and validation of such tests for germline diseases only – that is, genetic diseases or other conditions are inherited or de novo mutations in egg or sperm cells (i.e., not mutations that arise from DNA damage after birth through exposure to environmental contaminants or as a result of other factors). It also does not apply to other types of NGS-based tests, such as fetal testing or tumor genome sequencing, among other applications of NGS expressly excluded from this proposed policy by the Agency. Accordingly, therefore, this initial foray by FDA into providing regulatory advice to NGS stakeholders is narrowly limited to a subset of the massive potential for the application of NGS-based technologies.

In addition, the key takeaways from this FDA proposed policy are:

• An NGS-based test for germline disease may be appropriate for classification as a Class II device, through the de novo classification process, because “there is a reasonable probability that the risks associated with [such tests] (e.g., those related to the consequences of a false positive or negative result provide to a patient) may be sufficiently mitigated by a combination of general and special controls, and that the safety and effectiveness of this type of test may be reasonably assured by such controls.” This discussion is practically an invitation by the Agency for someone, anyone, to submit a de novo classification request for NGS-based tests with this specific intended use.

• Once classification is established, even if as a Class II device, it is possible that FDA may exempt the NGS-based test for germline disease from premarket notification requirements of section 510(k) of the FD&C Act. Importantly, FDA would not alter any “limitations of exemption,” meaning that, according to prior guidance and regulation, the 510(k) exemption would be exceeded if there is a different intended use or technology. Exemption from the premarket notification requirements may be established based on conformance with FDA-recognized standards for analytical validity, although the guidance notes “FDA has not yet determined how conformity with standards…should be demonstrated and plans to discuss this in future guidance documents.”

• The remainder of the guidance delves into detailed recommendations for design, development, and validation of NGS-based tests for germline diseases. The detail reads much like other product specific guidances describing the content of premarket submissions. Initially, the guidance characterizes NGS-based tests for germline diseases so a test developer will be able to determine if their test is, in fact, captured by the guidance. If so, then specifics for indications for use, accuracy and performance, and test validation are described in detail.

• Content and format of Test Reports for the end users (health care professionals or consumers) are summarized, with requirements for such reports to include information about test limitations and information about any unknown variants.

Perhaps what is most telling in the draft guidance documents is what is missing or what is specifically carved out. Neither addresses how these policies will intersect with FDA plans for LDTs, and although we previously described FDA’s plans for a final LDT policy in early 2016, nothing has been finalized to date. Certainly there will be an intersection because the FDA policy set forth in these two guidance documents specifically focuses on the recommendations for preparing a premarket submission, leaving open the specific question of when enforcement discretion will be exercised, if at all, for NGS-based tests. The second guidance addressing “Use of Standards” importantly notes that while FDA is willing to recognize scientific standards, “FDA 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.” Maybe the title will be reconsidered before finalization of the guidance.

We will be posting further analysis and commentary on these proposed policies, and we plan to provide recommendations to potentially affected stakeholders who may want to submit their feedback to FDA. Public comments on these two NGS draft guidances are being accepted until October 6, 2016. A list of specific questions from the Agency to interested parties about the policies and regulatory approaches laid out in each document can be viewed in the July 8 Federal Register notices of availability – available here for “Use of Databases” and here for “Use of Standards.”