Late last year, the FDA proposed a sweeping change to the regulation of certain cancer-linked tests, regulating them as Class II devices. The proposal was open for comment through January 2026, and industry has weighed in with a list of priorities for the agency, including choosing the right pathway and airing long-standing concerns about validation approaches for cancer-linked tests.
FDA’s push to re-classify diagnostic products and its cancer test announcement
- Background: Device pathways are designed around regulatory precedence and risk. In the U.S., in vitro diagnostics are regulated as medical devices, follow the medical device regulations, and use the medical device regulatory pathways. The FDA categorizes medical device products, including IVDs, into three risk-based categories: Class I (low risk); Class II (moderate risk); Class III (high risk). The Class I-II pathways are the most utilized, in particular the 510(k) pre-market notification pathway. Under a 510(k), a sponsor must demonstrate that the product is “substantially equivalent” – in performance, safety, and intended use – to an existing marketed device, which is known as a “predicate.” If there is no available predicate but the sponsor believes its product should not be considered a Class II product, the sponsor can submit a De Novo classification request to seek authorization as a novel moderate or low risk product; the granting of a De Novo establishes a new regulatory classification for the type of device. High risk products must submit a Pre-Market Approval application for market access, and demonstrate safety and performance of the device for its intended use. The regulatory classification of a medical device impacts not just its market access pathway, but also post-market oversight and reporting. Class III products, as the highest risk products, face the highest level of regulatory scrutiny.
- In early 2024, FDA’s Center for Devices and Radiological Health announced a new project with big impacts for diagnostics regulation: the downclassification initiative. The announcement, posted Jan. 31, 2024, said that the agency was opening a project to downclassify “most in vitro diagnostic (IVD) tests that are currently class III (high risk) into Class II.” In effect, seek to move “most” high-risk IVDs into the moderate risk category – which impacts the applicability of different regulatory pathways and oversight and compliance requirements. At the time, the agency noted that CDx and IVDs for infectious disease make up “the majority of these tests” that would be subject to potential reclassification.
- At the time, the downclassification initiative was seen as part of CDRH’s bigger plans for diagnostics reform. The agency’s now-rescinded rule to expand oversight over laboratory developed tests, or LDTs, would have required additional products to seek FDA authorization for marketing and comply with FDA regulations. Under the standing system for IVD regulation, all LDTs are technically considered high risk products. Under the downclassification initiative, the agency indicated that it was more willing to consider Class II categorizations for novel IVDs, including CDx. This means the agency would not only seek to downclassify existing CDx into Class II but allow new CDx pathways to use the De Novo (or 510(k), as applicable) marketing pathway instead of the Pre-Market Approval pathway. The notice said: “Based on our experience, we believe that special controls could be developed, along with general controls, that could provide a reasonable assurance of safety and effectiveness for most future companion diagnostic and infectious disease IVDs. As such they would be regulated as class II devices” (emphasis added).
- While the LDT rule is no longer moving forward, the downclassification initiative is. In her first public remarks after taking the mantel of CDRH’s diagnostics office, known as OHT7, as permanent director in mid-2024, COURTNEY LIAS said the reclassification initiative was one of her priorities. The LDT rule was struck down in federal court in March 2025, and formally rescinded by the FDA in September 2025. However, the agency has continued to work to downclassify some high risk IVDs; for example it issued a final order to downclassify several types of Hepatitis B tests in September 2025.
- The process to downclassify existing products is complex. Formal regulatory classification of a product type under FDA regulations is done through an administrative process. To reclassify an existing product type, the agency must issue a proposed notice to do so, take comments, convene an Advisory Committee meeting, and then issue a final notice.
- At the end of 2025, the agency issued a new downclassification proposal: Cancer-linked tests. On Nov. 24, 2025, the FDA released a new proposed reclassification order which would move certain nucleic acid-based tests systems for use with a corresponding approved oncology therapeutic product into Class II. These include both product codes for CDx and for test systems referenced in therapeutic product labeling where the product is not considered “essential” for use with the corresponding therapeutic – these are sometimes known as “complimentary” diagnostics. The product codes for which the reclassification is being proposed are OWD, PJG, PQP, and SFL. [See AgencyIQ’s full analysis of the reclassification proposal here.]
- The proposed classification order also includes a new proposed regulatory classification for these products, which would be “Nucleic Acid-Based Test Systems for Use with a Corresponding Approved Oncology Therapeutic Product,” including both the CDx and non-CDx functions. The new regulation would be found in 21 CFR 866, which warehouses the regulatory citations for immunology and microbiology devices, and would be 21 CFR 866.6075. The proposed device classification would be: “Nucleic acid-based test systems indicated for use with a corresponding approved oncology therapeutic product are identified as prescription IVD devices intended for the detection of specific genetic variant(s) and/or other nucleic acid biomarkers in human clinical specimens using NAAT and/or sequencing technology to provide information related to the use of a corresponding approved oncology therapeutic product. These test systems provide information that is essential for the safe and effective use of a corresponding approved oncology therapeutic product and/or are test systems that, while not essential to the safe and effective use of the corresponding approved oncology therapeutic product, provide information about known benefits and/or risks related to the use of the corresponding approved oncology therapeutic product.”
The comments are in: What industry thinks of a downclassification approach
- The proposed order sought feedback on the proposal to move cancer-linked tests to Class II. As AgencyIQ has previously noted, there currently isn’t a good roadmap for test developers to follow as to what a Class II pathway would look like for cancer-linked tests. Therefore, the reclassification offers a unique opportunity for industry to weigh in on what would be important as far as regulatory guardrails. Several of the commenters highlighted this point, acknowledging the opportunity to weigh in on what special controls would look like for complex test products – and urging the FDA to expand the approach to additional test types and technologies, including novel technologies.
- Overall, the comments expressed significant support for the approach, with Bayer writing that the move was “a critical advancement in the regulatory framework governing cancer diagnostics.” Friends of Cancer Research wrote that the move was an “important step toward realigning regulatory requirements with accumulated scientific and clinical experience for these devices.”
- Still, commenters had a bevy of practical questions for the FDA about how the approach would work. AgencyIQ grouped these into two areas: understanding evidentiary expectations and practical concerns about the Class II process compared to the Class III system. The full docket of comments is available here.
A topline theme: Understanding evidentiary expectations and airing existing concerns about CDx development
- The proposed downclassification order listed a series of “special controls” the agency would require for Class II submissions of these products. Special controls are the types of regulatory requirements that the agency would maintain for these products, related to evidentiary expectations and risk management. However, the language in the order is high-level, as it would appear in a regulatory classification, rather than in-depth as described in a guidance or presented in a submission, albeit with a few examples described narratively in upfront sections. (For example, “For example, a requirement to provide a device description that includes a description of relevant limitations with regard to target/genomic regions(s) that cannot be targeted and/or detected by the test system, as applicable.”)
- A key theme in the comments was seeking more information about the specific parameters of the special controls. Nearly every commenter asked for more information on what the agency would be looking for under the different components of the special controls. Bayer, for example, questioned what the agency would expect on verification and validation, while GSK cited the need for more specific in clinical validation expectations and analytical/technical performance expectations. Guardant Health, which expressed less outright support for the proposed reclassification, sought for significantly more information about the various aspects of special controls, including clinical performance specifications, transparency and lifecycle management of Class II CDx and complementary tests, labeling and post-market expectations. Illumina requested that the FDA align its regulatory expectations, including language about “analytical accuracy” or “biomarker classification” with guidelines from the CLSI. As Tempus asserted, the agency’s goals of reducing regulatory burden and onus on developers would be stymied by a lack of clarity around what information, exactly, the agency was hoping to see in a submission.
- Foundation Medicine, developer and manufacturer of FDA-approved CDx, cited its own list of special controls requests. In 2024, Foundation submitted a Citizen Petition to the FDA asking for the agency to downclassify tests regulated under PQP (one of the product codes included in the FDA’s reclassification proposed order), citing the downclassification initiative. As would be expected, the description of the special controls in the petition extends beyond what would typically go into a regulatory citation but reflects what the firm has asked for in its comments.
Another main theme: Sources of evidence
- Throughout the comments, multiple stakeholders flagged ongoing challenges with CDx and complementary test development, using the reclassification proposal as a forum. This includes questions about whether and when developers can use alternate sample types, challenges with accessing the reference or innovator test, and the potential use of reference datasets. Biocartis further pointed to the need for clear evidentiary guidelines when, for example, the proposed test is used in the clinical trial of the corresponding therapeutic (and is therefore a clinical trial assay, or CTA), compared to when a CDx is developed under a different program design, while Illumina likewise flagged this question about different evidentiary expectations depending on the development framework. Several commenters requested that the agency clarify that real-world evidence would be acceptable to support certain regulatory submissions for tests under Class II.
- Analysis of this comment theme: Much of what was submitted on this topic are areas that would generally be expected in guidance, rather than specified in a regulatory citation for a product type or spelled out in a new De Novo summary for a novel device-type. Further, many of the commenters used the opportunity to flag longstanding, existing challenges with the development of CDx, which has long been a pain point for both industry and the agency – this includes access to samples, the challenges of working a CDx development program into a therapeutic trial (a method known as “co-development”), and questions about how to transition a CTA to a CDx. This highlights that even if the agency moves to downclassify these cancer-linked tests, the existing development challenges are likely to remain. The agency would have a bevy of guidance to either draft or update, such as its policy on CDx or its guidance on seeking authorization as a CDx to a class a therapeutics rather than an individual product. In general, for Class II products, the documents published (albeit often at a delay) as part of a De Novo authorization can help provide some insight into how the FDA is interpreting the specifics of the special controls that are spelled out in that granted authorization, which establishes the new generic device-type. However, for reclassified products, developers wouldn’t necessarily be able to refer back to PMA packages as implementing documents for the newly-established special controls – which would mean that FDA would either face significant questions directly from developers, or be expected to put out new guidance to interpret the regulatory requirements for these technology types.
Several commenters flagged operational challenges with the Class II pathways for cancer-linked tests
- Conditions of approval and post approval studies: Several commenters, including Bayer, Hyman, Phelps and McNamara, and Foundation, all called out one key limitation of the 510(k) pathway: It does not have an option for COAs. Under the PMA pathway, the FDA can impose postapproval conditions known as COAs; this allows the agency to approve an application even if there is additional information needed. “As a condition of approval the sponsor agrees to abide by advertising and final printed labeling requirements and to submit adverse event reports, annual reports, and PMA supplements for certain changes,” the FDA states on its PMA Review Process webpage. As commenters on the proposed reclassification noted, the COA process allows some flexibility for test developers to receive FDA approval even if the agency has questions, which can be addressed through a COA. For example, a COA can include a Post-Approval Study, which “is typically intended to gather specific data to address questions about the postmarket performance or experience with an approved medical device.” Commenters cited the benefit of having this flexibility under the PMA pathway and questioned the FDA about any alternative approaches that would be available under the 510(k) pathway. Notably, the COA/PAS system is not available under that market access pathway.
- Another practical issue: Modular submissions. The PMA process allows for “modular” submissions, in which “the complete contents of a PMA are broken down into well-delineated components (or module) and each component is submitted to FDA as soon as the applicant has completed the module, compiling a complete PMA over time.” However, the 510(k) process does not offer such an approach – something flagged by commenters as potentially a challenge.
- How to consider a predicate and a De Novo. The Class II pathways are based in part on regulatory precedent. Several commenters had questions about scenarios that would potentially create a new device-type, which would therefore require a De Novo submission, versus seeking new indications in an existing device-type, and how to draw the line between when a De Novo would be appropriate versus a 510(k) submission. Further, as Tempus noted, the existing landscape of CDx creates some challenges for the selection of and access to a predicate, especially as tests may be either single-site or limited to only a few sites. Under the 510(k) pathway, the existing test would be the predicate, and “when the existing test … is a single-site assay, the follow-on developer typically has no way to access the single-site assay to perform concordance testing.”
- A practical point: User fees. As flagged in comments from HPM, the user fees for Class III products are significantly higher than those for Class II products; while De Novo fees are higher than 510(k) fees, there are significantly fewer De Novo submissions than 510(k)s, by design. The downclassification, HPM flagged, could impact the FDA resources in this area: “These fees are at least in part responsible for the significant support provided by robust teams at FDA during the course of the review of these tests. To avoid the potential for reduced reviewer support for these types of tests, which could lead to uncertainty and delay in access to oncology therapeutic products and corresponding Nucleic Acid-Based Companion Diagnostic Tests, our client requests additional clarity from FDA as to how it will maintain staffing levels and support for these reviews with substantially lower user fees.”
- Analysis of this comment theme: The Class II pathways have a reduced level of regulatory burden but also have their own limitations. Several commenters pointed to the existing flexibility for the FDA to shift certain pre-market expectations into the post-market setting as a key point for diagnostics developers, which would need to be addressed by the agency. While the agency’s Pre-Determined Change Control Plan framework could help fill some of these gaps, and the agency has long touted the potential for PCCPs to be leveraged more widely in diagnostics regulation, the PCCP system is intended to allow for updates in post-market settings, rather than shifting expectations to post-market. The question about selecting appropriate predicates has been an ongoing debate beyond test regulation in recent years, with the agency seeking to update its recommendations on best practices for selecting a predicate. However, that work remains ongoing. Finally, the current medical device user fee program reauthorization negotiations, which will be MDUFA VI, have pointed to the challenges with the De Novo process, including a lack of options for “second place finishers,” or firms for which a De Novo has been accepted by the FDA but are not granted by the time another De Novo, which could serve as a predicate, is granted. These issues are not unique to the diagnostics space, but if the FDA moves forward with the reclassification, they will need to be addressed for these test types.
Key documents and dates
- Immunology and Microbiology Devices; Reclassification of Nucleic Acid-Based Test Systems for Use With a Corresponding Approved Oncology Therapeutic Product; Proposed Amendment; Proposed Order; Request for Comments (Comment period ended Jan. 26, 2026)
- AgencyIQ Analysis: FDA moves to downclassify certain companion diagnostics and oncology test systems