On November 15, 2017, the FDA announced the clearance of a tumor profiling test under a novel, streamlined FDA premarket review pathway for certain next generation sequencing (NGS)-based tumor profiling tests. The creation of this pathway represents a significant, pro-industry shift with respect to the FDA regulatory requirements that might apply to tumor profiling tests. Nevertheless, substantial uncertainty remains regarding several aspects of the new pathway.
On November 15, 2017, the US Food and Drug Administration (FDA) announced the clearance of Memorial Sloan Kettering Cancer Center’s IMPACT tumor profiling test under a novel, streamlined FDA premarket review pathway for certain next generation sequencing (NGS)-based tumor profiling tests. Key elements of the streamlined pathway include the following:
Regulation as Class II medical device/eligibility for premarket notification (510(k)) pathway. The FDA’s enforcement discretion for most laboratory-developed tests (LDTs) has historically allowed—and continues to allow—clinical laboratories to offer many NGS-based tumor profiling tests without premarket review by the FDA. Insofar as a clinical laboratory voluntarily decides to submit an NGS-based tumor profiling test for FDA review, however, such test will be regulated as a Class II medical device subject to the FDA’s 510(k) requirement, and not as a Class III medical device subject to the agency’s premarket approval (PMA) requirement. The agency describes NGS-based tumor profiling tests as follows:
A next generation sequencing (NGS) based tumor profiling test is a qualitative in vitro diagnostic test intended for NGS analysis of tissue specimens from malignant solid neoplasms to detect somatic mutations in a broad panel of targeted genes to aid in the management of previously diagnosed cancer patients by qualified health care professionals.
Inclusion of mutations with evidence of clinical significance and potential clinical significance in FDA-cleared indication for use, but no companion diagnostic claims. Multiplexed tumor profiling tests assess many biomarkers that may have a range of clinical evidence associated with them that is consistently changing as new science emerges. As such, the agency assigns mutations detected by NGS-based tumor profiling assays to one of three levels, depending on the evidence available to support claims for such biomarkers:
Required Validation Data
Provide information that is essential for the safe and effective use of a corresponding therapeutic product (e.g., a drug or biological)
Analytical validation – data required for each specific biomarker
Clinical validation – clinical study establishing either: (a) the link between the result of the test and patient outcomes or (b) clinical concordance to a previously approved companion diagnostic
Cancer mutations with evidence of clinical significance
Enable health care professionals to use information about tumors in accordance with clinical evidence (e.g., professional guidelines)
Analytical validation – data on either on the mutation itself or via a representative approach (based on other mutations of the same type), where appropriateClinical validation – publicly available clinical evidence (e.g., professional guidelines, peer-reviewed publications)
Cancer mutations with potential clinical significance
Are informational or used to direct patients towards clinical trials for which they may be eligible
Analytical validation – principally through a representative approach (when appropriate)Clinical validation – clinical or mechanistic rationale for inclusion in the panel (e.g., peer-reviewed publications or in vitro pre-clinical clinical models)
Companion diagnostic (i.e., level 1) claims are explicitly excluded from the scope of the labeling for NGS-based tumor profiling tests cleared under the new pathway. Rather, tests that make companion diagnostic claims continue to be regulated Class III medical devices subject to the agency’s PMA requirement.
Ability to make certain modifications to the tests without requiring a new 510(k) from the FDA. Test developers will be permitted to add additional variants of the same type post-market in the panel for claims consistent with the clinical criteria established in the original submission without an additional submission. Moreover, as evidence of clinical significance becomes recognized by the clinical community, mutations can be moved from level 3 (potential clinical significance) to level 2 (clinical significance) without an additional submission, provided that the analytical validity of the test for such mutation was reviewed and established in a previous submission.
Recognition of the New York State Department of Health (Wadsworth Center) as a third-party reviewer. In conjunction with the IMPACT clearance announcement, FDA also announced the recent accreditation of the Wadsworth Center as a third party reviewer for in vitro diagnostics, including tumor profiling tests. Moving forward, laboratories whose NGS-based tumor profiling tests have been approved by Wadsworth do not need to submit a separate 510(k) application to the FDA. Instead, developers may choose to request that their NYS application, as well as Wadsworth’s review memorandum and recommendation, be forwarded to the FDA for possible clearance.
The clearance of a NGS-based tumor profiling test based primarily on the Wadsworth Center’s recommendation represents a significant, pro-industry shift with respect to the FDA regulatory requirements that might apply to such tests. Nevertheless, substantial uncertainty remains regarding several aspects of the new pathway, including the following:
Will clinical laboratories actually utilize the new pathway? FDA premarket review is currently required only insofar as an NGS-based profiling test is offered as a companion diagnostic. It is unclear whether the possible competitive and/or reimbursement advantages associated with offering an FDA-cleared test will be sufficient to encourage clinical laboratories to voluntarily request clearance from the agency.
Will reliance on the Wadsworth Center as a third-party reviewer actually speed the agency’s review? Or would laboratories be better off submitting directly to the FDA? The Wadsworth Center currently has a substantial backlog of test-specific applications for review. As such, clinical laboratories seeking FDA clearance may find it more expedient to work with the FDA itself as opposed to waiting for Wadsworth to complete its review of the file.
What information (if any) will FDA require beyond what Wadsworth requires? The press release announcing the clearance of the IMPACT assay stated that MSK’s submission to the FDA extended beyond the information made available to Wadsworth during its review of the test. The nature and extent of such additional information is unclear at this time.
Will laboratories be required to submit a new 510(k) each time they want to add a new gene to their panel? FDA explicitly calls out the addition of variants “within the existing analytically validated genes” as not triggering the requirement for a new 510(k). The agency does not, however, address the extent to which the addition of any individual gene would require a new 510(k) for the assay.