skip to main content
Global Search Configuration

The 37 groups and individuals who submitted comments on FDA’s two draft guidances on next-generation sequencing issued in July expressed appreciation for the thinking behind the guidances, but found bones to pick with some details.


Trade groups and others responding to FDA draft guidance documents on next-generation sequencing (NGS) for diagnosing germline (inheritable) diseases praised the concepts, but questioned some of the specifics of the agency’s plans.


The first guidance document discusses how companies can design, develop and validate their tests that can identify millions of genetic variants relying in part on FDA-recognized standards, while the second explains how NGS developers can use public databases to validate their products. Both are geared toward a model that would let developers release their tests without conducting extensive new clinical studies. (Also see "FDA Maps Out Novel Path For NGS Market Access" - Medtech Insight, 6 Jul, 2016.)


FDA received 37 public comments on the guidance documents in all. The comment period ended Oct. 6, and the comments were posted about a week later.


The Biotechnology Innovation Organization (BIO) was one of several commenters to praise the thinking behind the guidances, saying the documents “demonstrate FDA’s strong commitment to be forward thinking in its approach to establish a regulatory framework that permits continued innovation in personalized medicine products and tools that improve the lives of patients.”


Standards Guidance Too Prescriptive, Some Say


But despite the rosy top-level view, stakeholders who commented on the documents had several disagreements with specifics. Most of the specific qualms from stakeholders concerned the guidance document on use of standards in test design and validation. The draft document was criticized for vague language as well as overly specific technical requirements that could make the guidances less useful or even constrain the industry’s growth, comments stated. They argued that expectations laid out in the guidance documents for such critical measurements as test accuracy were inappropriately stringent and could not be fairly applied to all tests.


“It’s inappropriate to use a one-size-fits all approach and as sequencing technologies evolve, it is also imperative that the standards evolve simultaneously” – Association for Molecular Pathology


“It’s inappropriate to use a one-size-fits all approach and as sequencing technologies evolve, it is also imperative that the standards evolve simultaneously,” the Association for Molecular Pathology (AMP) wrote. AMP also argued that the “performance standards outlined in the draft guidance are too restrictive and only applicable to limited technology platforms” that are not in use by not all labs.


As a solution, some commenters suggested that FDA recommend factors for test developers to consider, rather than setting minimum performance requirements. As with all guidance documents, FDA's draft does clarify that all of the contained provisions should be viewed as recommendations, and not legally enforceable responsibilities.


In addition, the Personalized Medicine Coalition said the final guidances would need to cut back on FDA’s revalidation suggestions. “Requiring revalidation of tests end-to-end for each additional modification, including aggregate validation of previous modifications, is impractical for many NGS-based diagnostic tests, and could have a significant chilling effect on innovation. The agency should devise new processes for reporting and validating modifications that do not impair performance of existing NGS-based tests,” the group wrote.


The Industry Pharmacogenomics Working Group (I-PWG) encouraged FDA to make the coverage depth threshold more flexible to accommodate the metrics of different sequencing technologies, as well as multiple types of mutation. I-PWG also asked that FDA clarify that laboratories may select the specific DNA extraction method used in testing, as long as it can be appropriately validated.


The Personalized Medicine Coalition noted that the document appears to assume all NGS diagnostics would be cleared via a 510(k) process, and asked for edits explaining how FDA would apply the guidelines to de novo pathway products. Similarly, the group said the guidances as written only apply to a minority of uses for NGS tests: Screening, microbial genome testing, and companion diagnostic uses would all be left out. PMC recommended FDA develop and release a timeline showing when it might release further guidances on these indications for use.


In addition, Roche Diagnostics Corp.

recommended that some NGS diagnostics that don't fit into the category of germline diseases targeted by the recent draft guidances might also be treated as class II exempt via a similar model. The regulatory approach “could and should be applied to other NGS-based test applications with similar risk profiles, such as testing for certain infectious diseases, noninvasive prenatal testing, and risk of disease testing,” Roche wrote.


Similarly, AdvaMed recommended that FDA consider applying the principles developed for the guidance documents to other IVD technologies, such as polymerase chain reaction, single nucleotide polymorphism, mass spectrometry and microarray technologies.


The industry trade association also suggested that FDA should develop an accreditation system for conformity assessment that would allow NGS test developers to be certified by FDA, and then periodically audited. “Such a model would afford certified NGS test developers the flexibility of bringing new and modified tests to the market quickly while providing the appropriate level of FDA oversight to support safety and effectiveness,” the group wrote.


Critics also took note of FDA’s statement there were no applicable standards for germline tests. "FDA is unaware of any existing, comprehensive standards for analytical validation applicable to NGS-based tests for germline diseases that it believes could be used to help provide a reasonable assurance of the safety and effectiveness of these tests," the first draft guidance states. Groups commenting on the document pointed out that guidelines have been developed by groups including the American College of Medical Genetics, the College of American Pathologists, the New York State Department of Health and the American Clinical Laboratory Association (ACLA).


“While these bodies may not be recognized by the FDA as ‘Standards Development Organizations,’ that does not negate the existence of their standards, nor diminish their value in ensuring high-quality NGS-based tests and services,” the American Medical Association wrote. “We urge the FDA to consider the collective expertise contained in these standards, and work with these groups to avoid unnecessary and/or duplicative requirements.” (Also see "

US FDA's Next-Gen Sequencing Guidances: One Stop On A Pathway

" - Medtech Insight, 26 Jul, 2016.)


However, in an interview with Medtech Insight in July, FDA device-center personalized-medicine chief Elizabeth Mansfield argued that there is a key distinction between clinical guidelines and standards that can be directly relied on to support product clearances.


"What's out there are recommendations, and some of them are very good, but they aren't standards," Mansfield said. "Most of them have been developed for laboratories and they address laboratory processes, certain things that go on in the laboratory. But generally, they don't completely address how you would design a test and how you would then develop it. We think they are probably not comprehensive enough to fill what we would need for regulatory purposes."


Less Attention On Database Document


Commenters had less to say about the guidance document describing how databases could be used, but seemed to feel it, too, needed some clarification.


For example, ACLA said the guidance document needs to better reflect the different responsibilities assigned to data administrators as opposed to test developers, and that the section on curation and variant interpretation is overly broad.


In addition, ACLA took issue with FDA’s use of the word “generally” to qualify database standards, feeling it could cause confusion as to whether the standard was met or not. The term “creates uncertainty and reduces predictability,” the group wrote.


From the editors of The Gray Sheet







Read also


Next steps

Whether you’re a small biotech start-up, research firm, generic manufacturer or a global pharmaceutical giant, you need focused, independent insight and opinion on market developments.

Our team is ready to hear from you for a particular request or area of interest. Please do not hesitate to reach out and discuss.

Contact us for product technical and account support.

  • US Toll-Free   : +1 888 670 8900 
  • US Toll             : +1 212-600-3520
  • UK & Europe : +44 (0) 208 052 0700

Have an immediate and specific information need?

Browse and buy from 1000s of analysis and research reports now: