FDA Creates New Pathway for NGS Tests in Tumors under 510K Clearances

On November 15, 2017, the FDA and Memorial Sloan Kettering Cancer Center (MSKCC) announced a landmark new approach to NGS diagnostic test approvals.   The pathway will be a special 510(k) approval for genetic tests in tumors. 

Previously, FDA had declined to approve such tests under 510(k) because of the assumption, by the FDA, that the genes reported would serve as drug selectors, and must be approved under the PMA route.  For for the first time, tumor genetic tests will be certified on accuracy rather than requiring a direct correlation between the accurate gene analysis and a clinical outcome.   Just as glucose or sodium tests are approved based on accuracy, this is a positional outcome that was going to come sooner or later for the FDA, but the timing was unpredictable (whether 2014, 2017, or 2020).

The posture the FDA strikes is that the tumor gene analysis (e.g. finding an EGFR mutation or ALK rearrangement) is reportable to the doctor and cancer patient but "is not conclusive for use of a therapy" under a 510(k) test, whereas a PMA test of the same gene with same method and same result would be "conclusive" for therapy.   FDA has decided to live with the fact it has two nearly identical sounding product categories (PQM (of the PMA type) and PQZ (pf tje 510k type)).  Maybe someone at FDA used to say, "We couldn't do that," and now someone else has said, "Sure we can.  We just did."

• See press release at FDA, here.  
• See the FDA's new one-page "Fact Sheet," here.
• The Fact Sheet explicitly compares PMA clearance of Thermo Fisher Oncomine Target Dx and 510(k) clearance of MSKCC IMPACT.  
• Only the PMA test can make clinical companion diagnostic claims.  (Oncomine approved under Class III Product Code PQP, here.)
• Apparently, a 510(k) test can assert genes with "evidence of clinical significance" or the lesser "potential clinical significance."
• Regulatory Category is 21 CFR 866.6080, "NGS Tumor Test," and was created in April 2017.  To my eye, it's found at FDA.gov but not at the federal CFR, which is quirky.
• IMPACT uses "Product Code PZM," different than the Oncomine product code PQP.  
• For some deep dive comments and links on 866.6080, PQM, and PQZ, see side blog here.
• See news at OncLive, here.   At RAPS, here.  At Medscape, here.  At Endpoints News, here.  At Genetic Engineering & Biotech News, here.  At Fierce Healthcare here, including aspects of data sharing.
• See Genomeweb (subscription), here.   
• Second Genomeweb article with strategic analysis, here.
• The second Genomeweb article notes that MSKCC is working on clearance for CNV, dup/del, and total mutational burden (TMB).
• Specific to the IMPACT clearance and classification:
• The FDA immediately released its 57-page Decision Summary (here).
• At least part of the annotation used in IMPACT reflects the OnkoKB database; see article here.
• The De Novo 510(k) Classification Order (7p) is here.
• This legally downclassifies the product (and future product category) from PMA Class III to 510(k) Class II via the de novo reclassification and clearance method.

The newly reviewed test, IMPACT, includes 468 genes and MSI testing.  Earlier in November, MSKCC had highlighted its role in the first approval of a drug and gene combination based on a "basket trial," here. 

FDA recently announced a "precertification" approach to approval of genetic health risk germline tests (here) and a precertification approach to some digital health software (here).

The 510(k) clearance pathway is closely linked to New York State Department of Health approval.  FDA states:

Moving forward, laboratories whose NGS-based tumor profiling tests have been approved by NYSDOH do not need to submit a separate 510(k) application to the FDA. Instead, developers may choose to 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 full FDA press release is clipped below the break. 

The tumor sample is apparently run with a matched normal DNA sample "when available" (or else an "unmatched" normal DNA sample.)  The FDA intended use statement is:

The MSK-IMPACT assay 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 multi gene panel. The test is intended to provide information on somatic mutations (point mutations and small insertions and deletions) and microsatellite instability for use by qualified health care professionals in accordance with professional guidelines, and is not conclusive or prescriptive for labeled use of any specific therapeutic product. MSK-IMPACT is a single-site assay performed at Memorial Sloan Kettering Cancer Center.

Publications for the IMPACT test include Zehir et al. (May 2017, Nature Medicine), finding that 37% of 10,000 patients had an actionable mutation.   Mandelker et al. (September 2017, JAMA), conducted universal screening for germline risk mutations in 1000 patients who were undergoing tumor gene testing anyway.   They found many more germline risk genes than would have been found if only a subset of patients (getting tumor testing) had had guideline-based germline testing.

FDA
November 15, 2017

The U.S. Food and Drug Administration today authorized Memorial Sloan Kettering Cancer Center’s (MSK) IMPACT (Integrated Mutation Profiling of Actionable Cancer Targets) tumor profiling test (assay), an in vitro diagnostic test that can identify a higher number of genetic mutations (biomarkers) that may be found in various cancers than any test previously reviewed by the agency.

The IMPACT test uses next-generation sequencing (NGS) to rapidly identify the presence of mutations in 468 unique genes, as well as other molecular changes in the genomic makeup of a person’s tumor. Cancer profile tests are gaining wider acceptance. By identifying what genetic mutations are present in a particular tumor, the test results can provide patients and health care professionals with useful insight that may help inform how best to treat the cancer.
Today’s action advances a policy framework that paves the way for the efficient review and availability of other NGS-based cancer profiling tools.

The FDA is also announcing the recent accreditation of the New York State Department of Health (NYSDOH) as an FDA third-party reviewer of in vitro diagnostics, including tests similar to the IMPACT test. Moving forward, laboratories whose NGS-based tumor profiling tests have been approved by NYSDOH do not need to submit a separate 510(k) application to the FDA. Instead, developers may choose to 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. Other accredited, third-party FDA reviewers also may become eligible to conduct such reviews and make clearance recommendations to the agency.

“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. “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. We’ll continue to look for opportunities to create regulatory efficiencies where possible to drive broader access to tools that improve American health, while maintaining the safety and efficacy standards that patients should expect from their FDA-reviewed products.”

According to the National Cancer Institute at the National Institutes of Health, approximately 38.5 percent of American men and women will be diagnosed with a form of cancer at some point during their lifetime. Unlike many cancer diagnostics that are designed to detect one cancer biomarker for use with a single drug, the IMPACT test works by comparing tumor tissue to a “normal” sample of tissue or cells from the same patient to detect genetic alterations that might help guide treatment options. While the test is intended to provide information on cancer biomarkers, its results are not conclusive for choosing a corresponding treatment.

“NGS technologies can examine hundreds, if not millions, of DNA variants at a time; and we are only at the beginning of realizing the true potential for these devices to assist patients and their health care providers in learning about the genetic underpinnings of their disease,” said Jeffrey Shuren, M.D., director of the FDA’s Center for Devices and Radiological Health. “Recognizing the significant effect information about an individual’s biomarkers can have on their care planning and outcomes, the FDA worked closely with NYSDOH and MSK to help ensure that the IMPACT test is accurate, reliable and clinically meaningful. This collaboration is an excellent example of how the FDA can partner with the medical and development communities to review innovative tests as quickly as possible.”

The IMPACT test was reviewed by the FDA through the de novo premarket review pathway, a regulatory pathway for some low- to moderate-risk devices that are novel and for which there is no legally marketed device (predicate device). Its ability to detect genetic mutations (analytical performance) was evaluated for precision, accuracy and limit of detection. Results indicated that the assay is highly accurate (greater than 99 percent) and capable of detecting a mutation at a frequency of approximately 5 percent (range of 2-5 percent). Additionally, detection of certain molecular changes (microsatellite instability) using the IMPACT test was concordant more than 92 percent of the time across multiple cancer types in 175 cases, when compared to traditional methods of detection.

Specific to the IMPACT test’s authorization, the NYSDOH previously conducted its own review and approved it for use on samples coming from patients in the state of New York. However, MSK had not previously submitted the test for the FDA’s review because it is a laboratory-developed test, for which the agency has generally not enforced premarket review and other applicable requirements. MSK submitted a de novo application for the IMPACT test to the FDA, including and extending the information submitted for NYSDOH’s prior review, to inform and expedite today’s FDA authorization.

Along with this authorization, the FDA is also establishing a Class II regulatory pathway for the review of other NGS-based tumor profiling tests for use in patients diagnosed with cancer. Class II designation allows these types of tests to be eligible to use the FDA’s 510(k) clearance process, either by submitting the application to the FDA directly or through an accredited third-party reviewer, like NYSDOH.

The FDA granted marketing authorization for the IMPACT tumor profiling assay to Memorial Sloan Kettering Cancer Center.