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In 2013, Regulatory, Professional Organizations and Payors Take Note of Clinical Sequencing

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Originally published Dec. 31, 2013

In 2013, next-generation sequencing received a vote of confidence from regulatory authorities as a technology appropriate for clinical use when the US Food and Drug Administration cleared Illumina's MiSeqDx and cystic fibrosis assays.

It is the first time the FDA has cleared a next-gen sequencing platform and assay for diagnostic use, but far from the first sign that the technology is increasingly being accepted in the clinic. In 2013, professional organizations issued a number of guidelines and recommendations seeking to establish best practices and standardize the field, and insurance companies are increasingly reimbursing for NGS-based tests.

A number of insurance companies openly stated their support of NGS tests for noninvasive prenatal screening of aneuploidy, and both the American College of Medical Genetics and Genomics and the European Society of Human Genetics issued guidelines addressing issues surrounding clinical sequencing.

Whole-genome sequencing as a means of predicting disease risk and developing individualized health profiles may still be a ways off, however, but it is clear that regulatory bodies and professional organizations are increasingly recognizing the technology's power to diagnose specific conditions.

FDA Clears MiSeqDx

The clearance of Illumina's MiSeqDx system and three assays marked a major milestone in the realm of clinical sequencing, as it was the first next-gen sequencing system to be cleared for marketing by the FDA.

While the MiSeqDx received clearance late this year, the FDA indicated it was considering regulating NGS-based tests as early as 2011 when it held a workshop to discuss the technology and strategies for assessing analytical validity of NGS platforms.

Since then, FDA officials have spoken at a number of conferences, including most recently at last year's Advances in Genome Biology and Technology meeting in Marco Island, Fla., where an official said the agency intends to regulate NGS-based tests, but highlighted the numerous issues that it must first address related to the technology.

To bring the MiSeqDx system through FDA clearance Illumina had to demonstrate the system's analytical validity, including its accuracy and reproducibility, the firm previously told Clinical Sequencing News.

One challenging aspect of determining analytical validity of next-gen systems is figuring out how to determine validity for each of the billions of bases in the human genome, given that certain regions of the genome are harder to assess than others. To do this, Illumina demonstrated the system's validity on various regions, including particularly troublesome regions such as repetitive areas, areas of high GC content, and homopolymers.

The clearance of the MiSeqDx system may pave the way for future next-gen sequencing instruments and assays now that the FDA is more comfortable with the technology. However, the practical impact of the designation still remains to be seen. At the very least, it could make it less burdensome for other laboratories to develop clinical sequencing tests now that there is a cleared system.

Illumina has said it plans to seek in vitro diagnostic approval for Verinata Health's noninvasive fetal aneuploidy test, Verifi. Sequenom has also said it has been in discussions with the FDA about developing an IVD version of its noninvasive fetal aneuploidy test, MaterniT21.

Insurance companies reimburse

In another sign that next-gen sequencing is becoming more accepted in the clinic, insurance companies have begun reimbursing for such tests. UnitedHealthcare and Aetna are two major national providers that this year issued policy decisions in favor of noninvasive sequencing-based tests to screen for fetal aneuploidy in certain cases.

Sequenom struck a broad agreement with the Blue Cross Blue Shield Association in May to offer its testing services to independent BCBS companies and has continued to add to its total number of covered lives under contract, 90 million as of November 2013. Nevertheless, the firm has still faced a number of challenges in obtaining reimbursement, especially from Medicaid, which it has said is due to changes implemented by the Centers for Medicaid and Medicare Services to the CPT coding system.

Two years ago, the American Medical Association came up with new CPT c odes for around 100 molecular diagnostics, and CMS is now in the process of determining pricing for those codes.

According to Sequenom, these changes caused some payors to initially deny payment simply because their systems did not recognize the new codes. The changes also spurred requests for additional information by payors to ensure that the test meets the guidelines, and that also has delayed payment.

Outside of the NIPT market, laboratories offering sequencing-based oncology tests, and even laboratories offering exome sequencing to diagnose rare childhood disorders, are increasingly being reimbursed for such tests.

For instance, the Genomics and Pathology Services Laboratory at Washington University has said that its NGS-based oncology tests are being reimbursed in around 80 to 90 percent of cases.

The lab attributes much of its reimbursement success to its strategy of being picky — its test assesses around 40 genes — and prioritizes genes that are currently reimbursed as single gene tests.

However, more comprehensive panels are also obtaining reimbursement. For example, Foundation Medicine, whose test screens more than 200 cancer-related genes, reported in November 2013 that insurance companies were reimbursing around $3,000 per test for its FoundationOne assay.

Insurance companies are also reimbursing for exome sequencing and whole-genome sequencing to diagnose rare disease, although typically on a case-by-case basis. Laboratories such as Baylor College of Medicine's Whole Genome Laboratory, the Medical College of Wisconsin's Human and Molecular Genetics Center, and Emory Genetics Laboratory have reported being reimbursed for such tests. Madhuri Hegde, EGL's executive director, previously told CSN that the lab is being reimbursed for between 50 percent and 90 percent of the test's $9,000 cost and is being paid on "almost every case."

ACMG recommendations spark debate

Professional organizations such as the American College of Medical Genetics and Genomics are increasingly making recommendations on best practices for clinical sequencing in order to establish standards in the booming field.

In 2013, ACMG issued recommendations for how clinical labs should deal with incidental findings from exome or whole-genome sequencing diagnostic tests. Currently, labs that offer exome or whole-genome sequencing tests all have slightly different policies and practices for how they return results and whether they return the inevitable findings that are unrelated to the patient's condition. ACMG convened a workgroup to look into the issue and to come up with best practices to try and standardize the practice between labs.

The workgroup delivered their results to ACMG, which issued the recommendations last spring. The organization now recommends that laboratories conducting clinical exome or whole-genome tests look for pathogenic variants in around 60 disease-related genes and return those results to the ordering physician along with the actual diagnostic findings.

The recommendations immediately sparked debate in the community, with some experts saying that the recommendations went too far and took away a patient's right to not know.

Some laboratories like Ambry Genetics and GeneDx quickly issued statements that while they report the variants suggested by the ACMG as a default for their exome tests, they would still allow patients to opt out of receiving those results.

Other labs, like ARUP Laboratories are following the recommendations. And the University of California, Los Angeles, which initially did not return any incidental findings for its exome test, has said it would revisit that policy.

Later in the year, ACMG also released guidelines for next-gen sequencing tests, addressing issues around deciding what genes to include on a panel, test ordering, reporting results, and how to deal with low-quality samples.

The recommendations essentially put into writing practices that early adopters of NGS-based tests have already grappled with and implemented. Rather than looking to get those labs to change their practices, the goal was to give guidance to labs just entering the field so that going forward there is more standardization.

The European Society of Human Genetics also issued recommendations of its own for clinical whole-genome sequencing, addressing issues such as when to use whole-genome sequencing clinically, informed consent, whole-genome sequencing in children, dealing with incidental findings, patient privacy, interpretation, and how to re-contact patients as new information becomes available.

Moving forward, there are still many issues to address and work out with regards to clinical sequencing, both from a regulatory and best practices aspect as well as on the reimbursement side. There is still debate in the community as to how to best perform these tests, in what situations, and when to use targeted panels versus more comprehensive sequencing. Additionally, while laboratories this year made significant progress in obtaining reimbursement, many are still feeling the effects of the CPT changes.

From a regulatory standpoint, the impact of FDA's decision to clear a next-gen system will likely begin playing out in the coming year, in terms of whether clinical laboratories switch to using the cleared instrument, whether the FDA steps in to more heavily regulate other aspects of clinical sequencing, and how laboratories will bring their own NGS tests through the FDA.

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