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November 17, 2017

FDA Creates Pathway to Review Tumor Assays Based on Approval of MSK Panel

  • Memorial Sloan Kettering Cancer Center (MSK) has won the FDA’s first authorization for a first tumor-profiling laboratory-developed test (LDT)—an approval that has led the agency to create a regulatory pathway for reviewing similar assays.

    MSK-IMPACT (Integrated Mutation Profiling of Actionable Cancer Targets) is a 468-gene panel intended to detect gene mutations and other critical genetic aberrations in both rare and common cancers. Since 2014, pathologists in the Molecular Diagnostics Service of the cancer center’s Department of Pathology have used MSK-IMPACT to analyze the tumor DNA of essentially all patients with advanced solid cancers, MSK said.

    MSK-IMPACT is a qualitative in vitro diagnostic test that uses targeted next-generation sequencing of formalin-fixed, paraffin-embedded tumor tissue matched with normal specimens from patients with solid malignant neoplasms to detect tumor gene alterations in a broad multigene panel.

    The test is intended to provide information on somatic mutations such as point mutations and small insertions and deletions, as well as microsatellite instability (MSI). MSK cautions that the assay is not conclusive or prescriptive for labeled use of any specific therapeutic product. MSK-IMPACT is a single-site assay performed in the diagnostic molecular pathology laboratories at MSK.

    To date, more than 20,000 MSK patients with advanced cancers have had their tumors sequenced through MSK-IMPACT, MSK said.

    “This milestone authorization is a testament to MSK’s expertise in the rapidly expanding field of genome-driven oncology and will set the precedent for future approvals of this type,” MSK physician-in-chief José Baselga, M.D., Ph.D., said in a statement.

    Sequencing for MSK-IMPACT is performed in the clinical laboratories of the MSK Molecular Diagnostics Service, whose chief is attending pathologist Marc Ladanyi, M.D. According to MSK, he played a key role in implementing MSK-IMPACT sequencing clinically and oversees this effort with Maria Arcila, M.D., director of the cancer center’s diagnostic molecular pathology laboratory.

    MSK-IMPACT testing is carried out by a team that includes molecular pathologists, clinical bioinformaticians, genomic technology scientists, genomic variant curators, and clinical laboratory technologists. 

    “The valuable data obtained through the sequencing can guide treatment choices and, in some cases, identify patients who are candidates for a cancer clinical trial,” added David Klimstra, M.D., chair of the department of pathology and James Ewing Alumni Chair of Pathology at MSK.

  • Actionable Mutations

    The FDA based its authorization on research, including a study published in May in Nature Medicine ("Mutational Landscape of Metastatic Cancer Revealed from Prospective Clinical Sequencing of 10,000 Patients"). The study found that nearly 37% of the first 10,336 patients who had their tumors sequenced through MSK-IMPACT from January 2014 until May 2016 had at least one actionable mutation.

    The study also showed additional patients harboring mutation profiles suggesting they were more likely to respond to immunotherapy treatment, for which the test’s detection of MSI provided a means to select patients who may benefit from immunotherapy.

    In another analysis of DNA samples from 1040 patients whose tumors were sequenced by MSK-IMPACT, published in the Journal of the American Medical Association in September ("Mutation Detection in Patients with Advanced Cancer by Universal Sequencing of Cancer-Related Genes in Tumor and Normal DNA vs. Guideline-Based Germline Testing"), 182 patients (17.5%) had mutations indicating cancer susceptibility. Of the 182, 101 (55%) would not have had these mutations detected using traditional guidelines based on family history, age, and tumor type.

    MSK-IMPACT sequencing has been approved as a clinical test by the New York State Department of Health (NYSDOH), and is performed in the clinical laboratories of the MSK Molecular Diagnostics Service.

    The FDA reviewed data for MSK-IMPACT through its de novo premarket review pathway, designed to assess novel, low- to moderate-risk devices that are not substantially equivalent to an already legally marketed device. The FDA said it intends to allow future similar tests to come to the U.S. market as substantial equivalents.

  • Pathway Established

    In addition to authorizing MSK-IMPACT, the FDA said it was establishing a Class II regulatory pathway toward reviewing other NGS-based tumor profiling tests for patients diagnosed with cancer.

    The Class II designation qualifies such assays for the FDA’s 510(k) clearance process, either via submission of an application directly to the agency, or through an accredited third-party reviewer.

    NYSDOH is among the seven third-party reviewers accredited by the FDA as of November 13. The FDA said labs whose NGS-based tumor profiling tests have been approved by NYSDOH do not need to submit a separate 510(k) application to the agency—but can instead request that their NYSDOH application, as well as the state’s review memorandum and recommendation be forwarded to the FDA for possible 510(k) clearance.

    The other six accredited third-party reviewers are: AABB (formerly the American Association of Blood Banks), Regulatory Technology Services, TÜV SÜD America, Center for Measurement Standards of Industrial, NIOM (Nordic Institute of Dental Materials), and Third Party Review Group.

    “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,” FDA Commissioner Scott Gottlieb, M.D., said in an agency statement. “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.”

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