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This guest post is from Reed Smith‘s Matt Jacobson, who is keeping us up to date with the FDA’s initiatives concerning pharmacogenomics and personalized medicine.  It is 100% his work, as Matt deserves all the credit (and any blame).


This blog, or at least Bexis and this guest blogger, try to be on the forefront of products liability implications of new technologies. See, e.g., here, here, and here.  So when the FDA issued two guidances on next generation DNA sequencing, we thought we would let you know since this new technology plays an important role in genetic-based personalized medicine, and in turn, prescription medical product liability litigation.

Now for some background.

The Human Genome Project is said to be, at least according to the National Human Genome Research Institute, “one of the great feats of exploration in history.” It was a large collaborative project that mapped out the sequence of essentially the entire human genome.  And, a little less known fact, in addition to the human genome, it mapped out the genomes of brewers’ yeast, the roundworm, and the fruit fly, among other things.  While the project was a huge accomplishment, it was slow—taking over a decade to complete in 2003—and expensive, costing billions of dollars.

Next generation sequencing or “NGS” is a newer technology that allows researchers to sequence DNA quicker and cheaper. Using NGS, an entire human genome can be sequenced within a single day.   This is remarkably faster than the Sanger sequencing technology that was used in the Human Genome Project.   Because NGS is capable of quickly identifying a person’s genome and much cheaper (on average under $1000), it can help physicians and researchers find genetic variants, which will help them personalize medicine to treat an individual’s condition.

Although in genome research NGS has mostly superseded the conventional Sanger sequencing, the U.S. Food and Drug Administration (“FDA”) had yet to issue any final guidances on the new technology. That was until recently.  And the FDA did not release just one guidance, it released two.  Both of which had been published in draft forms previously and submitted for comments.  The joint purpose of the guidances is to streamline the regulatory process for NGS tests.

FDA’s press release said that it released the final guidances “to drive the efficient development of a novel technology that scans a person’s DNA to diagnose genetic diseases, which are usually hereditary, and guide medical treatments.”  The FDA went on to say that “[t]he guidances provide recommendations for designing, developing, and validating tests that use the technology, called next generation sequencing (NGS), and will play an important role in the continued advancement of individualized, genetic-based medicine.”

The first guidance is entitled “Use of Public Human Genetic Variant Databases to Support Clinical Validity for Genetic and Genomic-Based In Vitro Diagnostics.”  In the guidance, the FDA states that NGS can help speed up the clinical use of “a variety of diagnostic purposes, including risk prediction, diagnosis, and treatment selection for a disease or condition.”  It provides FDA’s thoughts on whether a publically accessible genetic database “is a source of valid scientific evidence that could support the clinical validity of genetic and genomic-based tests in a premarket submission, regardless of the type of technology for the test.”  The short answer is yes, as long as the database conforms to the FDA’s recommendations.  Those recommendations are split into four categories:  1) database procedures and operations, 2) data quality, 3) variant evaluation and assertions, and 4) professional training and conflicts of interest.  For example, the FDA provides the following assistance as to what a genetic database should contain:

  • the database’s information regarding data sources and standard operating procedures should be publically available
  • clear guidelines on how genetic information is aggregated, curated, and evaluated
  • processes in place related to backing up and preserving the data
  • compliance with all federal laws and regulations, including the Health Insurance Portability and Accountability Act, the Genetic Information Nondiscrimination Act, the Privacy Act, and the Federal Policy for the Protection of Human Subjects
  • privacy protection security measures
  • commonly accepted nomenclature and formats are used
  • metadata should detail numerous types of useful information to assure that linking specific genetic variants to diseases or conditions are accurate
  • each variant evaluation should be performed by at least two qualified and trained professionals to lessen the risk that any single assertion could be incorrectly made
  • types of evidence used for evaluating variants, and their corresponding strengths, should be defined and combined in a protocol

Assuming a database follows the FDA’s recommendations, the FDA then plans to implement a recognition process on a voluntary basis. The FDA hopes that this will help streamline premarket review of genetic and genomic-based tests, including NGS.

The second guidance issued by the FDA is entitled “Considerations for Design, Development, and Analytical Validation of Next Generation Sequencing (NGS)–Based In Vitro Diagnostics (IVDs) Intended to Aid in the Diagnosis of Suspected Germline Diseases.” This guidance describes FDA’s intent to “create a flexible and adaptive regulatory approach to the oversight” of NGS.  It is directed particularly towards “germline diseases”—a fancy way of denoting medical conditions caused by mutations in the DNA of either egg or sperm cells that result in the genetic error being present in every cell of a offspring’s body.

The NGS guidance is based in part on comments that the FDA received at four of its public workshops held in 2015. FDA states that “[t]his guidance document provides recommendations for designing, developing, and validating NGS-based tests intended to aid clinicians in the diagnosis of symptomatic individuals with suspected germline diseases.”  The FDA also lists numerous categories to which the guidance does not apply.  The FDA spends considerable effort outlining the proper regulatory pathway for a NGS based test.  It then turns to providing recommendations for designing, developing, and validating NGS tests used to diagnose individuals with suspected genetic diseases.  It describes what the FDA will look for in premarket submissions in order to guide those submitting such applications for NGS-based tests.

Personalized medicine is the next frontier. NGS will help speed up the process and the guidances from FDA may help speed up the regulatory part of it.  Certainly, the FDA realizes that its approach to reviewing these innovations needs to keep up with the rapid evolution of the technology.  As FDA commissioner Dr. Scott Gottlieb said about the guidances, “they provide a modern and flexible framework to generate data needed to support the FDA’s review of NGS-based tests.”  That does sound promising.

Now if you made it this far and are wondering how this applies to products liability, Bexis and I recently gave a presentation on pharmacogenomics or how genes affect a person’s response to drugs.  NGS tests will only help advance pharmacogenomics.  You can register and watch the presentation here and I promise will be more entertaining than this post.