FDA’s Two Big Moves on NGS-Based Tumor Panels May Offer Clues for Alternative Pathways for LDT Approval

In late November the U.S. Food and Drug Administration (FDA) authorized Memorial Sloan Kettering Cancer Center's Integrated Mutation Profiling of Actionable Cancer Targets tumor profiling test assay (MSK-IMPACT) and approved FoundationOne CDx (F1CDx), Foundation Medicine's comprehensive, next-generation sequencing- (NGS-) based companion diagnostic (CDx) test for solid tumors. While personalized medicine advocates can certainly hail these regulatory wins as progress towards greater adoption and reimbursement of comprehensive molecular panels in routine cancer care, the FDA's actions may also offer some more subtle clues for potential innovative regulatory pathways the agency may be exploring for laboratory-developed tests (LDTs).

In the case of MSK-IMPACT, the FDA not only authorized the panel, but it also established a lighter regulatory pathway for the review of subsequent NGS-based tumor profiling assays, including the appointment of a third-party reviewer for such tests. In approving F1CDx through the Parallel Review Program in concert with the Centers for Medicare & Medicaid Services, the FDA is furthering regulatory mechanisms that enable faster reimbursement and adoption of emerging, innovative technologies.

The Two Panels
MSK-IMPACT is a 468-gene panel intended to detect genetic mutations in both rare and common cancers. The test uses formalin-fixed, paraffin-embedded tumor tissue matched with normal patient specimens. MSK (New York) says the test intends to provide information on somatic mutations (point mutations, as well as small insertions and deletions) and microsatellite instability (MSI).

Data submitted to the FDA demonstrated that the MSK-IMPACT assay is highly accurate (more than 99 percent) and capable of detecting a mutation at a frequency of approximately 5 percent (range, 2 percent to 5 percent). Additionally, the test could detect microsatellite instabilities 92 percent of the time across multiple cancer types in 175 cases, when compared to traditional detection methods. However, the FDA says the test is intended to provide information on cancer biomarkers, but its results are not conclusive for choosing a corresponding treatment, as a CDx would be. MSK says that more than 20,000 patients with advanced cancers have had their tumors sequenced using the test.

Unlike previous FDA CDx approvals that match one test to one drug, Foundation Medicine's F1CDx enables matching of patients with five different tumor types to 15 different approved, targeted treatments, including those for nonsmall cell lung cancer, melanoma, breast cancer, colorectal cancer, or ovarian cancer. Foundation Medicine (Boston) estimates that the test could aid in the clinical management of one in three cancer patients.

F1CDx can detect genetic mutations in 324 genes and two genomic signatures in any solid tumor type. Data submitted to the FDA demonstrated the test's ability to detect select mutation types (substitutions, as well as short insertions and deletions) with 94.6 percent accuracy. The company says F1CDx results are delivered in an integrated report that identifies alterations matched to FDA-approved therapies; additional alterations in genes known to drive cancer growth; information about other genomic biomarkers, including microsatellite instabilities and tumor mutational burden; relevant clinical trial information, and s interpretive content on solid tumors developed in accordance with professional oncology guidelines.

Overview of MSK-IMPACT and F1CDx

The Assays' Regulatory Pathways and Implications
MSK-IMPACT became the first comprehensive tumor-profiling LDT to receive FDA authorization through the de novo premarket review pathway. It had previously been approved by the New York State Department of Health as a laboratory- developed clinical test. The FDA authorized MSK-IMPACT as a Class II, moderate-risk device, which enables subsequent, similar types of tests to use the FDA's less onerous 510(k) clearance pathway.

Aside from the size of the panel, the authorization is noteworthy because it highlights a new, efficient pathway for authorization in the future. In addition to the Class II designation, the FDA also announced the recent accreditation of the New York State Department of Health as an FDA third-party reviewer of in vitro diagnostics, including for NGS-based tests similar to MSK-IMPACT test. The agency says that, moving forward, laboratories whose NGS-based tumor profiling tests have been approved by the New York State Department of Health do not need to submit a separate 510(k) application to the FDA. Instead, test developers can choose to forward their NYSDOH application, as well as the state's review memorandum and recommendation, to the FDA for possible 510(k) clearance.

"The goal of allowing NGS-based tumor profiling tests to undergo review by accredited third parties is to reduce the burden on test developers and streamline the regulatory assessment of these types of innovative products. As this field advances, we are modernizing the FDA's approach to the efficient authorization of laboratory tests from developers that voluntarily seek 510(k) clearance," said FDA Commissioner Scott Gottlieb, M.D. in a statement. "This is another example of where the FDA is working to find creative and flexible approaches to regulation that spurs development and efficient delivery of innovative technology."

Private-sector regulatory experts believe the FDA's action may provide important insight for how the agency will handle LDTs in the future. They note that use of accredited third parties is in line with steps the FDA has taken to respond to rapidly evolving technologies, such as in digital health.

"This is really a clever sleight-of-hand in a way," Carol Pratt, an FDA regulatory attorney with Lee & Hayes PLLC in Portland, Ore., told Bloomberg Law. "It appears that the FDA is announcing a new, low-burden regulatory pathway for IVD devices, when it is really about a voluntary 'authorization' process for LDTs."

Pratt stresses that the word "voluntary" in Gottlieb's statement is "critical" because it acknowledges that 510(k)s aren't required for LDTs. While many see this action as providing a new pathway for developers wanting their tests cleared, clarification is still needed over if and how the agency will exert its authority over LDTs.

The FDA reviewed F1CDx under its Breakthrough Device Program. The FDA says this program enables the agency to provide "intensive interaction and guidance" to companies, assisting them with efficient device development and expedited evidence generation for devices that provide for more effective treatment or diagnosis for life-threatening conditions. F1CD qualified as it represents a significant advantage over the existing standard of care because F1CDx effectively consolidates multiple CDx into a single test.

The FDA and the Centers for Medicare & Medicaid Services (CMS) simultaneously reviewed F1CDx under their Parallel Review Program, enabling the test to receive approval and secure an immediate proposed Medicare coverage determination. The Parallel Review Program is open to certain premarket approval applications for new device technologies that fall within Medicare's Part A or Part B benefit categories. A final coverage decision is expected in the first quarter of 2018, at which time F1CDx will be made commercially available.

It is noteworthy that the draft coverage determination is not just for the F1CDx, but would also provide coverage for other FDA-approved companion diagnostic claims, as well as a pathway for additional coverage with evidence development as the company adds claims for other solid tumor types.

Analysts are optimistic that FDA approval and Medicare coverage could have a positive impact on future private reimbursement decisions. Foundation Medicine's CEO Troy Cox said that Medicare's coverage determination will represent a "significant expansion" of coverage for Medicare beneficiaries nationwide, as approximately 40 percent of the company's testing volume consists of Medicare and Medicare Advantage patients. Ultimately, though pricing will be determined under the Protecting Access to Medicare Act, company officials said.

Earlier this year, Foundation Medicine reported it had received its first payments for Medicare patients from Palmetto for its LDT FoundationOne test, at an allowable rate of $3,416. However, overall, payments for the LDT appear to have been significantly lower. In a November earnings call with investors the company said that the average revenue for each test in the third quarter was $2,600.

Takeaway: Recent FDA action related to two comprehensive NGS-based oncology panels may accelerate adoption and reimbursement for these types of tests. Additionally, these actions reveal emerging, alternative pathways for future approval of complex LDTs.