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MSKCC to Seek CDx Status From FDA for Markers on Cancer NGS Panel

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WASHINGTON, DC (GenomeWeb) – Memorial Sloan Kettering Cancer Center is pursuing national Medicare coverage for its MSK-IMPACT next-generation sequencing cancer profiling test by filing with the US Food and Drug Administration to garner companion diagnostic status for at least one marker on the multi-gene panel.

The move is precipitated by the Centers for Medicare & Medicaid Services' final national coverage determination (NCD) released in March, which extended coverage for FDA-cleared or -approved NGS companion diagnostics for certain advanced cancer patients, but left it up to Medicare contractors to review such tests without FDA clearance/approval through the local coverage determination process.

In the aftermath of the final NCD, many test providers are contemplating which path to pursue, since the FDA review pathway for an NGS test is a resource intensive one.

MSK, for its part, garnered FDA authorization for the MSK-IMPACT test last November for gauging somatic mutations in 468 genes and microsatellite instability — information that doctors can use along with other tools to inform treatment strategies for cancer patients. However, the label also makes clear that the test "is not conclusive or prescriptive for labeled use of any specifictherapeutic product," in other words it is not a companion diagnostic.

"[MSK] had a lot of data on its biomarkers, but none that would tie any one of them to a companion diagnostic," Alberto Gutierrez, former head of FDA's Office of In Vitro Diagnostics and Radiological Health, said at the Next Generation Dx Summit held here this week. Gutierrez oversaw the review of MSK-IMPACT but left the agency last fall shortly before the de novo class II market authorization of the tumor profiling test was announced.

Not having a CDx distinction presented a difficulty for MSK-IMPACT once CMS released the final NCD for next-generation sequencing cancer panels. In order to meet the criteria for national coverage, "we are at this point assembling a package … [to gain] companion diagnostic approval for one or more biomarkers," Marc Ladanyi, chief of the molecular diagnostics service at MSKCC, said at the conference.  

The NCD was triggered by Foundation Medicine's bid for parallel review from the FDA and CMS for FoundationOne CDx, which analyzes 324 genes, microsatellite instability, and tumor mutational burden. "We were a little bit blindsided that Foundation Medicine got the class III approval at the same time we got class II clearance," Ladanyi admitted. "But so be it. We're certainly working toward a class III [CDx] approval at this time."

During a separate talk, Gutierrez noted that the NCD suggests the agency can use the 510(k) pathway to clear a Class II test as a companion diagnostic. For example, MolecularMD filed a 510(k) premarket notification to garner authorization for its MRDx BCR-ABL Test as a tool for identifying Philadelphia chromosome positive chronic myeloid leukemia patients treated with the drug Tasigna(nilotinib), who may be candidates for treatment discontinuation and for monitoring of treatment-free remission.

In taking its test through the FDA, MSK also charted a new regulatory pathway for NGS tumor profiling tests. Along with authorizing MSK-IMPACT, the FDA also accredited the New York State Department of Health as a third-party reviewer of in vitro diagnostics, and said that laboratories that gain approval for their NGS tumor profiling tests through NYSDOH won't need to file a separate 510(k) application to the FDA, but have the state regulator forward its review and recommendation to the agency.

With the MSK-IMPACT decision, the FDA also outlined a three-tier biomarker framework, in which it designated markers with CDx status in the top tier, having to meet the highest bar in terms of analytical and clinical validity (via concordance studies with another FDA-approved CDx). It designated a second tier for "cancer mutations with evidence of clinical significance," which doctors can use in the care of cancer patients in line with guidelines and other information.

In the third tier are "cancer mutations with potential clinical significance," which can help direct patients to clinical trials. "This is actually an amazing development for the agency," Gutierrez explained. "Now you can have a device that has several tiers, and one of the tiers [of biomarkers] can be for investigational use."

Although the markers on MSK-IMPACT fall in the second tier, the cancer center is hoping to apply as soon as this fall to garner top-tier, companion diagnostic status for HER2 amplification for identifying best responders to HER2-targeted treatments for breast and gastric cancer. MSK has tested 30,000 patient samples on MSK-IMPACT to date. Ladanyi explained that MSK has a lot of data on patients tested on FDA-approved HER2 companion diagnostics, which can be used to demonstrate concordance with MSK-IMPACT.

But for all the work MSK has already put in to carve out a new regulatory framework for NGS tumor-profiling tests, some industry observers felt the cancer center was short changed on the Medicare reimbursement front. A number of stakeholders at the meeting questioned the incentive for test developers to even pursue the third-party review pathway charted by MSK given CMS's parameters for national Medicare coverage.

Gutierrez pointed out that during the parallel review process for FoundationOne CDx, the FDA and CMS had envisioned that national Medicare coverage criteria would align with the regulatory framework for biomarkers. This intent was reflected in the proposed NCD, which included coverage with evidence development (CED) provisions for FDA-approved or -cleared NGS panels without CDx status when patients were enrolled in a registry, and for lab-developed tests without FDA's blessing that were utilized within a National Cancer Institute study.

The draft NCD came out last November, a few weeks after FDA authorized MSK-IMPACT. "The way it was written, MSK would have been pleased, because MSK-IMPACT fit into that category that put them in the CED segment," said Robert Dumanois, manager of reimbursement strategy for Thermo Fisher Scientific. "Fast forward to the final NCD, and there was no CED. It disappeared."

During the comment period on the NCD, many industry stakeholders complained to CMS that the extensive data collection requirements outlined under CED would be too costly to implement. Even though CED were something that FDA and CMS appeared to agree on initially, according to Gutierrez, CMS decided to do away with it in the final version.

"The idea was that one could use this as an incentive to get the biomarkers into the market, get some data on patients, so we would know if those biomarkers were clinically useful or not," he said. "It is now up to the companies to do so."

Foundation Medicine, meanwhile, has interpreted the final NCD as extending coverage for its test in all solid tumors, because CMS specifically stipulated it would cover NGS panels for advanced cancer patients under the following conditions: When tests are FDA cleared or approved as a companion diagnostic; and when the panel had an FDA-approved or -cleared indication for use in a patient's cancer; and when the results could be used by the treating physician to specify therapy options.

FoundationOne CDx meets the first clause of the NCD since the FDA approved eight genetic markers as companion diagnostics that can predict response to 17 treatments across five solid tumors. Because the FDA also approved the other markers on the panel broadly for tumor mutational profiling, a doctor could apply those to direct therapy for patients who have cancers outside of the CDx indications.

Foundation has reasoned that by meeting all three clauses the NCD enables Medicare coverage for the test for all solid tumors, an interpretation has created some confusion among industry players and policy experts. Foundation has said it has assurance from CMS that its interpretation is correct. At the conference this week, Joseph Chin, deputy director of CMS's Coverage Analysis Group, confirmed that FoundationOne CDx is indeed covered for all solid tumors.

Katherine Szarama, lead analyst within CMS's evidence and analysis group, acknowledged that the FDA's focus in reviewing FoundationOne CDx for regulatory purposes was different than CMS's focus in reviewing the test for coverage purposes. "The FDA's level of granularity … is at the level of an individual biomarker," Szarama said at the meeting. "The level of granularity that CMS chose to perform their analysis was at the level of the diagnostic test."

"The other level of scope … is the applicability to a population with cancer," she continued. "In the final national coverage determination, CMS decided that the relationship between the test and the diagnosis would be at the stage of the patient's cancer, not the specific area of the cancer in the body, for example."

Then, in practice, if one FDA-approved/cleared CDx marker allows Medicare coverage for a panel of several hundred investigational genes, some questioned if CMS will eventually have to structure pricing so test developers will still be motivated to invest in generating the evidence and filing with the FDA to garner CDx status for those markers. "Theoretically, if we add a new CDx marker, is the test worth $5 more, $50 more, or $500 more? No one knows the answer to that yet," Dumanois said.

While it's currently unclear what incentives test developers will have from a Medicare coverage and pricing standpoint, CDx status has implications for test labeling and how biomarker information is presented in the test report, which may influence physician adoption. "Coverage and reimbursement is one facet we look at in terms of determining if something is valuable or not, but test content is another one," Dumanois said. "If you get lapped by other tests because they have 10 markers in a specific indication and you have three, that's another competitive differentiator."  

Thermo Fisher does have national Medicare coverage for its FDA-approved Oncomine Dx Target Test, which gauges 23 genes, but it also has CDx indications for assessing EGFR mutations, ROS1 rearrangements, and BRAF mutations in advanced non-small cell lung cancer patients most likely to benefit from three treatment regimens. Dumanois said the company plans to file supplemental premarket-approval applications to grow the test's CDx biomarkers in NSCLC and in other tumor types.

The NCD also seems to be having a positive impact on Foundation Medicine's business. John Truesdell, senior director and life cycle lead at the firm, said during the conference this week that the FoundationOne CDx has been "doing very well in the Medicare population."

In 10-Q filings with the US Securities and Exchange Commission earlier this month, Foundation reported revenues from tests ordered by physicians totaled $23.8 million in the second quarter, an 84 percent increase from the year-ago period, partly driven by an increase in tests reported for US patients and to the commercial launch of FoundationOne CDx after the final NCD was released. The company also recently achieved advanced diagnostic laboratory test status and starting July 1 began reimbursing the test at a rate of $3,500 per test, in accordance with pricing under the Protecting Access to Medicare Act.

It remains to be seen the extent to which commercial payors will follow CMS's lead with regard to coverage and payment of NGS cancer panels. Commercial payors are required to abide by the NCD for patients covered under Medicare Advantage plans, but not their commercial plans.

At the meeting, Eugean Jiwanmall, senior research analyst at Independence Blue Cross, said that the insurer is carefully considering the terms of the NCD, but suggested that it will arrive at its own conclusions for its commercial plans. "We try to see where we agree and disagree," Jiwanmall said. "I wouldn't say we're completely misaligned with it."

Independence Blue Cross does require precertification of genetic tests for coverage under commercial plans. When Independence Blue Cross evaluates companion diagnostics for coverage, Jiwanmall said, it's a simpler process for FDA-approved, single-gene tests compared to FDA-approved NGS panels that have CDx markers and hundreds of other markers with varying levels of evidence, which require much more consideration.

Although currently only a few labs qualify for national coverage for NGS cancer panels, he expects more labs will come forward and seek national coverage for large panels, as Foundation and Thermo Fisher have done, and now MSK is doing. This could lead to over-utilization, Jiwanmall said. "Right now there is no gatekeeper in place."