FDA Final Order Moves Cancer-Drug ISH Tests to Class II, Ending PMA Requirement

The FDA on Monday issued a final order moving in situ hybridization (ISH) tests that are used to select patients for a corresponding approved cancer drug out of Class III, so that new tests of this type can reach the market through 510(k) clearance instead of premarket approval.

The final order, published in the Federal Register, reclassifies ISH test systems under product codes NYQ, MVD, OWE and PNK from Class III (premarket approval) into Class II (special controls) and creates a new classification regulation, 21 CFR 864.1890. It takes effect September 16, 2026. The agency first proposed the change on June 11, 2025.

The regulation describes the tests as prescription in vitro diagnostics made up of nucleic acid probes that detect specific nucleic acid sequences in clinical specimens to provide information related to the use of a corresponding approved oncology therapeutic product. The FDA said it acted on its own initiative and did not convene an advisory panel, which it said the law does not require for this kind of reclassification.

What changes for manufacturers

Under the order's implementation section, ISH tests that already hold premarket approval and were offered for sale before the effective date may stay on the market under that approval without a new submission. New tests will need 510(k) clearance before marketing. For tests already approved, the FDA said it expects a 510(k) when a manufacturer makes a change that could significantly affect safety or effectiveness, or a major change in intended use. The device type is not exempt from premarket notification.

The FDA wrote that the change "will decrease regulatory burden on industry," and that a 510(k) typically means a shorter premarket review than a PMA. The agency said it expects the reclassification to let more manufacturers develop these tests.

The special controls require, among other things, defined criteria for interpreting and reporting results, including the rationale for clinical cut-offs; data on analytical sensitivity and specificity; precision and reproducibility testing across reagent lots, operators, instruments and readers; and robustness testing. The order says general controls alone could not address risks such as false positive and false negative results, which it said may negatively influence treatment decisions for cancer patients.

Changes from the proposal

The FDA said it received comments from fewer than five commenters, mostly from the device industry, and that all supported the reclassification. In response, the final order allows surrogate samples that adequately represent the intended specimen types and biomarkers to supplement clinical specimens in precision studies, as determined by the FDA, and drops a proposed requirement for data on reagent stability.

The agency declined a commenter's request to rewrite the regulation's identification and labeling text, saying existing in vitro diagnostic labeling rules already cover the information. It also said it does not plan, for now, to issue a separate guidance on meeting the special controls. Responding to a question about artificial intelligence, the order notes that the FDA has not yet authorized any oncology ISH test that incorporates digital pathology devices, including AI-assisted ones, and points manufacturers to the agency's predetermined change control plan guidance and its Q-Submission program.

The order is part of a broader effort the FDA's device center announced on January 31, 2024, when it said it intended to begin reclassifying most Class III in vitro diagnostics, the majority of them infectious disease and companion diagnostic tests, into Class II.