On July 8, 2016, the FDA issued draft guidance on the subject of next generation sequencing (NGS) activities: (1) “Uses of Standards in FDA Regulatory Oversight of Next Generation Sequencing (NGS)-Based In Vitro Diagnostics (IVDs) Used for Diagnosing Germline Diseases” and (2) “Use of Public Human Genetic Variant Databases to Support Clinical Validity for Next Generation Sequencing (NGS)-Based In Vitro Diagnostics.” The first focuses on the FDA’s proposed use of standards to help establish the safety and efficacy of NGS-based tests. The second focuses on the importance of high quality and publicly accessible databases to provide robust scientific evidence for understanding genomic variation, to inform decision-making, and to assess the clinical validity of NGS-based tests. Guidance is not a formal regulation, but rather an agency’s statement about how it will interpret or apply a regulation in the future. Draft guidance is a proposed policy that means the agency is formulating a position, whereas a final guidance is a document that represents what the agency has settled on as its interpretive policy. In theory, guidance is intended to serve as additional instructions for complying with rules and not intended to serve as the rules themselves.
The premise underlying the draft guidance is the controversial and—as yet—legally untested assertion that genomic analyses of all kinds are “medical devices” that Congress has, by statute, authorized the FDA to regulate. If they are, then the FDA would have the power to bring them under its current risk-based classification scheme for medical devices or to create a new scheme for them. If they are not medical devices, then the effort to regulate them might exceed the FDA’s statutory authority and conceivably amount to an unconstitutional regulatory overreach. Both draft guidance documents avoid any mention of the overarching debate, a subject covered extensively on Genomics Law Report, surrounding FDA oversight of all laboratory developed tests (LDTs) and in vitro diagnostic multivariate index assays (IVDMIAs). As others have noted, it is impossible to consider these new pieces of draft guidance outside of that context. Nonetheless, even the FDA asserts (via Twitter and elsewhere) that the two new drafts are intended to facilitate the Precision Medicine Initiative (PMI) and are distinct from the agency’s expressed intention to regulate LDTs. These pieces of draft guidance also give a policy-based reason for pause, as they could be another example of governance by guidance, a highly problematic approach as highlighted recently by John Conley with regard to the HIPAA right to access lab data and results.
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The Cleveland Clinic’s Roger Klein responds to my previous GLR post:
The Office of Civil Rights’ interpretation of the requirements of 45 CFR § 164 could pose problems for clinical laboratories and the professionals who practice within them. Although the issue of providing benign variants for a single gene, at least prospectively, would be straightforward, a broad definition of the designated medical record set could result in considerable complexity when one considers large-scale sequencing. Some excluded data can be of variable reliability, may be prospectively filtered by software, or may otherwise be omitted from the patient report because of professional interpretation and judgment. One can legitimately argue that this interpretation and judgment, as reflected in the patient report, should serve as the gateway to the official medical record.
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UNC’s Karen Weck responds to my previous GLR post:
I agree in principle that patients have the right to access their genomic data; however, in practice it is much more complicated (as things often are). Giving a patient his/her raw sequencing data would be meaningless – it is the interpretation of the clinical significance of sequence data that is important when reporting results. This latter requires the expertise of molecular genetic laboratorians and clinical geneticists. We do not return all genomic sequence variants to individuals in exome sequencing, for example when we determine that they are unlikely to be contributory to their disease or medical health. It is important to those of us doing this that we retain the ability to use our professional judgement to determine what should be reported to patients as medically relevant, primarily so as not to dilute important medical information with irrelevant information.
Karen E. Weck, MD
Professor of Pathology & Laboratory Medicine and Genetics
Director, Molecular Genetics
University of North Carolina at Chapel Hill
Robert Cook-Deegan, MD
On September 5, the Federal Court of Australia (the appeals court) upheld a claim on isolated DNA from the BRCA1 gene. It dismissed Yvonne D’Arcy’s appeal of a case that has attracted international attention. Australian patent 686,004 has never been enforced, so the court decision has little real-world concrete impact. As Richard Gold and Julia Carbone explained in their classic case study, “Myriad Genetics: In the Eye of the Policy Storm,” the patent rights on BRCA1 and BRCA2 were exclusively licensed for use in Australia and New Zealand to Genetic Technologies, Ltd. (GTG), which in turn made them a “gift to the people of Australia.” When the CEO of GTG proposed taking back that gift in the summer of 2008, he provoked a firestorm and the company backed down in October, restating that it would not enforce its patent rights against laboratories offering BRCA testing. The Australian Senate held a series of hearings, and a bill proscribing DNA sequence patents was proposed, but the new government opposed it, and it lapsed. Instead, Australia enacted patent reforms in 2012 that raised the bar for utility and clarified the Australian law’s exemption from infringement liability for research and regulatory approval. Most of the provisions of that law took effect on April 15, 2013, the very day Association for Molecular Pathology v Myriad Genetics (AMP v Myriad) was argued before the U.S. Supreme Court.
A year ago, the American College of Medical Genetics and Genomics (ACMG) released its Recommendations for Reporting of Incidental Findings in Clinical Exome and Genome Sequencing. As I reported in a July 2013 post, the core recommendation was this: “The ACMG recommends that for any evaluation of clinical sequencing results, all of the genes and types of variants in the Table should be examined and the results reported to the ordering physician.” Specifically, the ACMG recommended that whenever a lab does whole genome or whole exome sequencing on a patient, it should examine all 57 [now 56] genes on the list included in the Recommendations and report any clinically significant findings to the ordering physician. It would then be the duty of that physician “to provide comprehensive pre- and post-test counseling to the patient.” Most controversially, the ACMG recommended that the test findings “be reported without seeking preferences from the patient and family and without limitation due to the patient’s age.” As I characterized it in the July post, “patients should be given the 57-gene screening whether they want it or not and told the results even if they say they don’t want them.”
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On November 19, 2013—three days before the highly-publicized warning letter to 23andMe (See here and here)—the U.S. Food and Drug Administration announced that it had given approval for the marketing of four Illumina MiSeqDX medical devices. They include two cystic fibrosis genetic assays as well as the Illumina MiSeqDX instrument platform and Illumina Universal Kit reagents. The FDA’s press release characterizes them as “devices that can be used for high throughput gene sequencing, often referred to as ‘next generation sequencing’” (NGS). These instruments, reagents, and test systems allow labs to sequence a patient’s DNA (deoxyribonucleic acid).
What does the FDA’s approval of the MiSeqDx platform for the clinical market mean for the DTC industry? For example, does this mean that 23andMe could just switch platforms from the Illumina HumanOmniExpress-24 format chip to MiSeqDx and be free from future FDA meddling? Could new companies enter the industry free from regulatory burdens by using Illumina’s MiSeqDx platform? Don’t bet on it.
It is likely that the FDA would take the position that its 510(k) premarket approval (a process John explained briefly on December 3) of the MiSeqDx instrument and MiSeqDx Universal Kit was not intended to be a blanket “go ahead” for DTC providers to offer a service like 23andMe’s Personal Genome Service®. Rather, it is more likely that the FDA would insist on review and pre-market approval of MiSeqDx as an next-generation sequencing in vitro diagnostic (or NGSIVD) if it were used for any purpose other than return of raw genomic data (i.e., if any interpretation were provided along with that raw data). It is also unclear to what extent these FDA approvals will allow future applicants to rely on the approved MiSeqDX products as “predicate devices” to clear some of the regulatory hurdles more easily. (Specifically, the future applicant would claim that its device was “substantially equivalent” to the already-approved device.)
The FDA’s own press release nowhere mentions a non-patient consumer. The press release emphasizes how next-generation sequencing technologies are “becoming more accessible for use by physicians,” underscoring the FDA’s continued insistence that clinicians be the gatekeepers for accessing information about one’s genome. The press release states front and center: “The new technology also gives physicians the ability to take a broader look at their patients’ genetic makeup and can help in diagnosing disease or identifying the cause of symptoms.”
The FDA’s approval of the MiSeqDx platform is thus intriguing, but the future regulation of DTC genomic testing remains uncertain. The 510(k) approval of the MiSeqDx platform may signal that raw data provided DTC might be acceptable to the FDA but that interpretation of that genomic data in any way related to health would still provoke FDA scrutiny and, possibly, hostility. Could a DTC provider use the MiSeqDx platform and successfully argue that its interpretation of raw data is a Laboratory Developed Test (LDT; a test manufactured and used within a single CLIA-certified lab) and, therefore, potentially outside the reach of the FDA? We can’t say for sure at this point. As for the implications of this for 23andMe, as I reported on December 6, current indications suggest that the company is still trying to gain FDA approval of its Personal Genome Service.
The GLR received some interesting comments on my recent post about the American College of Medical Genetics Gene Screening Recommendations. Here are two of the comments. As we are still in the early stages of what is likely to be a continuing and controversial story, we welcome others.
From an anonymous GLR reader:
Just read and am very intrigued by the new GLR piece. I think the potential for recommendations like those to be implicated in setting the standard of care in certain medmal cases is there, although I can’t imagine that these recommendations could seriously be argued (well, I’m sure they could be argued – but I don’t think the argument is at all a winner) as the standard of care now, since I don’t really expect that their adoption has yet been widespread. But it sure will be interesting to see somebody try at some point down the road. I just think, if and when that happens, it would have to be in a case where whole genome or whole exome sequencing was performed for a specific clinical purpose.
That brings me to the second thing I found interesting about your piece:
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In March, the American College of Medical Genetics and Genomics (ACMG) released its much-anticipated Recommendations for Reporting of Incidental Findings in Clinical Exome and Genome Sequencing. The ACMG describes itself as “an organization composed of biochemical, clinical, cytogenetic, medical and molecular geneticists, genetic counselors and other health care professionals committed to the practice of medical genetics.” Its brief mission statement includes a commitment to “Define and promote excellence in the practice of medical genetics and genomics in the integration of translational research into practice.” It publishes the journal Genetics in Medicine, and has previously issued “standards and guidelines” for clinical genetics laboratories and cystic fibrosis carrier screening.
The core recommendation is straightforward: “The ACMG recommends that for any evaluation of clinical sequencing results, all of the genes and types of variants in the Table should be examined and the results reported to the ordering physician.” Reading this in light of the definitions section and the rest of the report, it seems to mean this: Whenever a lab is requested to do any “clinical sequencing” (more below on what this means), it should examine the 57 genes listed on the Table and report any significant mutations it finds. It is the responsibility of the clinician who ordered the initial sequencing “to provide comprehensive pre- and post-test counseling to the patient.” In what has become the most controversial aspect of the Recommendations, the ACMG recommends the test findings “be reported without seeking preferences from the patient and family and without limitation due to the patient’s age.” In other words, patients should be given the 57-gene screening whether they want it or not and told the results even if they say they don’t want them—in effect, if you consent to any clinical sequencing, you automatically consent to this further screening and to hearing the results. The same holds true for the parents of minor patients.
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This morning, Gene By Gene, Ltd. – better known as the parent company of the popular genetic genealogy provider Family Tree DNA – formally announced a corporate reorganization that includes the debut of a new division, DNA DTC. (Apparently the news was also announced earlier this month at the Family Tree DNA Conference, although the company waited until today to launch press releases.)
The announcement from Gene By Gene is newsworthy for several reasons, including:
1. The Return of True DTC Whole Genome and Whole Exome Sequencing. According to DNA DTC, the company offers a range of products “utilizing next generation sequencing including the entire exome (at 80x coverage) and the whole genome.” The company’s website, while fairly spartan, appears to bear this out. Whole exomes ($695 at 80x coverage) and genomes ($5,495 at 30x coverage) are both listed as available products.
Now, Gene By Gene is not, as its Wikipedia page claims (as of this writing), “the first commercial company to offer whole genome sequencing tests.” Knome earned that honor more than four years ago, when it started selling whole genome sequences for $350,000; an astounding price, either low (given the cost of the first human genome was $3 billion) or high (given that, well, it was $350,000) depending on your perspective. Gene By Gene probably does represent, however, the only commercial company currently offering a whole genome sequence in a truly direct-to-consumer (DTC) manner.
Earlier this month, my colleagues John Conley, Robert Cook-Deegan, James Evans and I published a policy article in the European Journal of Human Genetics (EJHG) entitled “The next controversy in genetic testing: clinical data as trade secrets.”
The EJHG article is open access so you can read the entire article at the EJHG website, but here is the abstract: