NEW YORK (GenomeWeb) – Illumina broke ground in late 2013 when it successfully brought its MiSeqDx system through US Food and Drug Administration 510(k) clearance.
Over the last year, regulatory agencies and payors alike have continued to indicate their acceptance of next-generation sequencing-based clinical tests.
Thermo Fisher and Vela Diagnostics have both listed NGS systems with the FDA, and the two firms, along with Illumina, all have CE-IVD markings for their respective platforms.
In addition, the China FDA — which initially forced BGI, Berry Genomics, and other providers of NGS-based noninvasive prenatal tests to stop offering tests — has cleared two NGS-based tests offered by BGI on Thermo Fisher's Ion Proton and the Complete Genomics technology.
In March, the American Medical Association said it accepted new CPT codes for genomic tests, including NGS-based tests, and in October the Centers for Medicare and Medicaid Services released its preliminary clinical laboratory fee schedule determination for CPT codes.
Some companies now have unique identifiers with which to bill insurance companies, which they have said is helping secure reimbursement. Even labs that offer clinical exome testing have reported increased success in gaining reimbursement for such tests to diagnose rare disorders.
Cleared NGS products
Illumina's FDA clearance paved the way for other companies to bring their platforms through regulatory clearance. In September, Thermo Fisher listed its Ion PGM Dx as a Class II medical device with the FDA. Because the system was for the same intended use as MiSeqDx, the company did not have to go through the entire 510(k) clearance process or submit an assay along with the system.
Then in November, Vela Diagnostics listed its sequencing system as a Class II medical device with the FDA. VelaDx's NGS system includes the Sentosa ST401 instruments, which provide an automated solution for template preparation and enrichments; the Sentosa SQ301 sequencer and server, which is based on Thermo's Ion Torrent sequencing technology but designed under VelaDx's specifications; and the Sentosa SQ Reporter for data analysis and report generation.
Illumina now plans to submit its Verifi NIPT on the HiSeq 2500 to the FDA and plans to bring its NextSeq 500 system through FDA clearance. The company is also working with Chinese genetic testing firm Berry Genomics and the China FDA to bring Berry's noninvasive Bambni test for fetal aneuploidy through the regulatory process in China. As of July, the test, which runs on a customized version of the NextSeq 500, was in late stage review in the CFDA's medical device registration process, according to Illumina.
The clinical market in China is considered to be more stringent than the US because it does not have the equivalent of CLIA certification and CAP accreditation for laboratory-developed tests. And, this year, the China FDA said that genetic tests must pass regulatory approval. That initially halted testing by BGI, Berry Genomics, and potentially other firms.
In July, BGI received CFDA approval for two sequencing systems, BGISEQ-100 and BGISEQ-1000, which are based on Thermo's Ion Torrent semiconductor sequencing technology and Complete Genomics' sequencing technology, respectively. The CFDA approved the systems with BGI's noninvasive prenatal test NIFTY, which screens for fetal aneuploidies in chromosomes 21, 18, and 13.
Oncology and companion diagnostics
Clearing an NGS system and assay in the oncology field will not be as simple as registering the specific NGS system. Because the MiSeqDx received 510(k) clearance to analyze germline mutations from blood samples, an NGS system and assay that looks at somatic mutations from tumor or formalin-fixed paraffin-embedded samples would not have the same intended use, so would have to go through its own clearance process.
Illumina plans to develop NGS-based oncology panels, including one product as part of its Actionable Genome Consortium and a universal companion diagnostic test in conjunction with AstraZeneca, Jannsen Biotech, and Sanofi. The firm plans to leverage the MiSeqDx in order to develop an oncology test kit that includes the NGS system, bioinformatics capabilities, and the reagents necessary to target single nucleotide variants, indels, copy number variants, and gene fusions. In a separate deal with Amgen, it plans to bring a CDx through FDA clearance for Amgen's colorectal cancer drug Vectibix (panitumumab).
Additionally, Illumina struck an agreement with Sequenta to develop an in vitro diagnostic based on Sequenta's minimal residual disease monitoring technology. Sequenta already offers an LDT, ClonoSight, which measures MRD in leukemia and lymphoma patients.
Thermo Fisher is also looking to develop an NGS-based CDx test. In September, the company said it was collaborating with GlaxoSmithKline and Pfizer on the Ion PGM Dx. This assay will be based on Thermo Fisher's Oncomine Cancer Research Panel, which includes all targets that exist for drugs on the market today, as well as targets for over 500 compounds in Phase II and III trials, and will also be used in the National Cancer Institute's MATCH trial.
The NCI has been working with the FDA to design the MATCH trial and validate the panel it will use to ensure that it meets the agency's requirements, and plans to file a pre-submission to the FDA for the assay.
Foundation Medicine also hopes to bring a CDx test through FDA premarket approval through an agreement it struck with Clovis Oncology in 2013 and expanded on this year.
Although reimbursement is still a hurdle for NGS-based tests, progress is being made. The NIPT field is perhaps the area where NGS tests are most likely to be reimbursed due to recommendations from professional organizations such as the American College of Obstetrics and Gynecologists that such tests be offered to women with high-risk pregnancies.
Sequenom most recently reported that it has over 140 million lives under contract by both commercial payors and under Medicaid, while Illumina has said that it has 130 million lives under contract for its Verifi test. In addition, in January, new molecular diagnostic codes specific to NGS-based fetal aneuploidy tests will be implemented.
Payors are reimbursing for tests in other fields, as well. Foundation Medicine recently inked its first contract with Priority Health for FoundationOne and FoundationOne Heme in 2014 and Google has also said that employees will have covered access to the cancer profiling tests.
Even in cases where Foundation Medicine's tests aren't formally covered, the company has said that it receives an average per-test reimbursement of $3,600.
Also this year, the company received unique identifiers for its tests from the online test registry McKesson Diagnostics Exchange, which Foundation said would help in obtaining reimbursement.
Academic laboratories, too, are seeing reimbursement pick up. Washington University's Genomics and Pathology Services Laboratory offers an NGS cancer panel, and has said that approximately 90 percent of the tests it runs are reimbursed. John Pfeiffer, vice chair of clinical affairs, pathology, and immunology, has said that the reason why the test is reimbursed at such a high rate is because it is a more limited panel that looks primarily at the genes that are already reimbursable as single-gene tests.
Intermountain Healthcare has reported nearly as high reimbursement rates for its 100-gene cancer panel.
The year ahead is likely to bring even more progress on the regulatory and reimbursement sides of clinical sequencing. The AMA's new CPT codes for NGS-based tests will kick in, making submitting claims more straightforward, and a number of NGS-based tests and new platforms are likely to be submitted to the FDA.
Several groups have also been working on developing standards for clinical sequencing, including the National Institute of Standards and Technology's Genome in a Bottle consortium and the Actionable Genome Consortium, which Illumina spearheaded this year.
Such standards will help guide smaller laboratories looking to develop tests and should help engage stakeholders with the technology and will help set the bar in terms of quality of test.
Stakeholder groups have also formed to help address issues around specific types of NGS-based clinical tests, such as companion diagnostics.
Finally, as cost effectiveness and clinical utility studies continue to be published, laboratories will have a better idea of the types of tests that make the most sense for different conditions and they will increase their chances of getting buy-in from regulators, payors, and physicians alike.