The in vitro diagnostics (IVD) down-classification initiative

• A quick background on medical device regulation: In vitro diagnostics (IVDs) are regulated by the FDA as medical devices – meaning that tests and diagnostics typically go through the medical device market access pathways and comply with post-market regulations (e.g., quality system requirements). Under the purview of the FDA’s device regulations, IVDs (and all other medical devices) fall into three risk-based categories that determine their regulation: Class I (low risk); Class II (moderate risk); and Class III (high risk).
• The risk-based classification of the product will define which marketing application the sponsor should submit: a) 510(k) pre-market notifications for certain Class I and Class II devices; b) De Novo requests for moderate risk (Class II) devices without an established regulatory history or a relevant regulatory citation; and c) Pre-Market Approval (PMA) applications for Class III (high risk) products. The risk-based categorization of a generic device-type is determined when the first product of that type is authorized, which sets the precedent for additional products of that type.
• The framework defaults to a higher-risk category for a novel device; novel devices are typically considered Class III automatically and sponsors must make the case to the FDA that a product is Class II. However, the agency can up-classify (move a device type to a higher risk category) or down-classify (move a device type to a lower risk category) based on experience with the product or in response to a petition. The process for reclassification is set out in section 513(e) of the Federal Food, Drug and Cosmetic (FD&C) Act.
• CDRH is now looking to down-classify many IVDs. On January 31, CDRH announced that it was opening a reclassification initiative en masse to assess down-classification for “most in vitro diagnostic (IVD) tests that are currently class III (high risk) into class II (moderate risk).”
• What would this initiative entail? The medical device reclassification process is administrative, meaning it requires a proposed order, an advisory committee meeting, and a final order laying out the new citation. In the case of a down-classification from Class III to Class II, it would also require the establishment of special controls. CDRH’s announcement specifically states that it “intends to initiate the reclassification process.” This involves conducting a review of the current evidence and scientific literature in advance of “propos[ing] reclassification of devices for which we believe there is sufficient information to establish special controls” as a Class II device. CDRH Director JEFF SHUREN, speaking at a Friends of Cancer Research (FOCR) event the day after the announcement (February 1), acknowledged that reclassification is a “lengthy process, with rulemaking and advisory panels,” but that the agency “will proceed and move forward” with the reclassification initiative.
• Shuren explained the initiative like this: “Yesterday, we put out an announcement to express our intent to reclassify most of the in vitro diagnostics that are high risk, so essentially moving from a high-risk test to a moderate-risk class. The reason being – based on our experience – we think we can still assure those tests are safe and effectively or analytically and clinically valid with appropriate mitigations when we put special controls in place. And by having a more streamlined approach available, that can stimulate more innovation for those kinds of tests.” In effect: The agency seems to want to make it easier to develop, launch and market IVDs. As a reminder, the down-classification of existing IVDs which were approved under PMAs would open the 510(k) pathway for these device types. This would allow new market entrants under pre-market notification rather than under the more burdensome PMA process.
• IVDs implicated in this reclassification initiative: Companion diagnostics (CDx) and infectious disease. While there are a variety of IVDs that are currently Class III, these two categories of products are the largest – or as, the agency puts it, these areas make up “the majority of these tests.” Overall, while the FDA will still need to go through the different regulatory citations for each of these individual product types and issue proposed reclassification orders, the agency seems to be indicating that IVDs generally are not high-risk products in the device framework. Notably, the agency has already started the reclassification process for some infectious disease IVDs, convening a meeting of the microbiology devices panel of the medical device advisory committee (MDAC) in September 2023 to discuss a proposed reclassification of three types of infectious disease IVDs. In 2021, the FDA also finalized reclassifications of certain Hepatitis C virus tests to Class II.
• The agency also seems to be indicating that, going forward, it will be more willing to consider Class II for novel IVDs, including CDx. As noted above, novel devices are automatically considered high-risk products, and sponsors seeking a lower risk category (Class II or, as appropriate, Class I) must make that case to the FDA. Developers can seek feedback on their proposed risk classification in advance of planning for a De Novo request through the medical device Q-submission program, in a pre-submission (or “pre-sub”). The announcement for the down-classification initiative states that the agency “will continue taking a risk-based approach in the initial classification of individual in vitro diagnostic devices to determine the appropriate level of regulatory controls.” However, it goes on to state that, “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).
• Former FDA commissioner SCOTT GOTTLIEB also made the case for down-classification at the FOCR event. “I think it recognizes fundamentally that a test that is providing information to a treatment decision is fundamentally lower risk than a device that’s being implanted in a patient and has to perform over 15 years,” said Gottlieb. Notably, this represents a fairly common concern for IVD developers – that the medical device frameworks designed for more traditional medical devices do not apply well to IVDs and their context of use. “This information being provided to providers who are looking at a whole bunch of other information, it’s one element [of decision making] … and it does represent low risk and I think that CDRH has kind of recognized this over time,” he explained. He also cited the experience of the pandemic – in the context of down-classifying tests for infectious diseases – saying: “If you would have asked me 10 years ago ‘will CDRH ever approve an at-home diagnostic for a dangerous infectious disease, [where] patients can self-diagnose at home?’ [The response would be] nah, never gonna happen, you know, he’s crazy.” But given the pandemic experience, “I think the agency has really changed its view about how diagnostics are being used and the overall care continuum.”

This new initiative has significant implications for CDx policy and incentives

• This would represent a major shift in regulatory precedent, as a significant majority of all CDx currently FDA-authorized are Class III. Per  FDA definitions, CDx are “a medical device, often an in vitro diagnostic (IVD), which provides information that is essential for the safe and effective use of a corresponding drug or biological product.” Unlike combination products, CDx are authorized separately from their related drug/biologic product. The therapeutic is approved with labeling that “stipulates concomitant use of an IVD companion diagnostic when the use of the IVD is essential to the safe and effective use of the therapeutic product,” as explained in the  FDA’s 2014 guidance on CDx. Of the approximately 175 current FDA marketing authorizations for CDx (counting both individual and group indications), only three were granted marketing authorization under De Novo requests or the 510(k) pathway.
• As a reminder, moving current CDx into Class II would open up the 510(k) pathway, allowing additional developers to demonstrate substantial equivalence to the already approved (as a Class III, but down-classified to a Class II) CDx in order to gain market access, rather than going through the PMA pathway. As Gottlieb noted, this could have significant implications for the economics of CDx: “I think it’s going to change the commercial model there, and maybe more of the economics is going to have to be provided by the drug maker itself rather than the device/diagnostic lab that used to be able to get the monopoly around the provision of those tests.”
• What does this mean for developers of products that would currently be considered high-risk? At the FOCR meeting, representatives from industry were wondering about the implications for programs currently seeking to develop what would be considered “high-risk” diagnostics, including CDx. In fact, one meeting attendee said their firm had received feedback from CDRH on a Q-sub before this announcement which indicated that their proposed CDx product would be a Class III requiring a PMA. The attendee questioned whether they should “bring back” the -subs under the new initiative on down-classification. BRITTANY SCHUCK, deputy director of CDRH’s diagnostics office (OHT7), seemed to indicate that this would be an option: “Come ask us, come talk to us about that.” While she didn’t confirm that all CDx would now be considered Class II, she did indicate that the De Novo pathway could be appropriate moving forward, meaning that new CDx products could be more likely to be authorized as a Class II.

The down-classification initiative comes as CDRH is working on a variety of diagnostic-related reforms and projects

• It’s an extremely busy time in diagnostic regulation. In late 2023, the FDA released a proposed rule that would extend FDA regulatory oversight activities to a subset of IVDs known as laboratory developed tests (LDTs). While LDTs have historically been under “enforcement discretion” by the FDA, the proposed rule would treat all IVDs – including LDTs – as medical devices, updating the underlying regulations to clarify that IVDs are medical devices “including when the manufacturer of these products is a laboratory.” [ See AgencyIQ’s 2024 U.S./E.U. diagnostics landscape analysis here.]
• That proposal – which the FDA aims to finalize in the coming months – outlines a five-stage implementation period. Notably, the pre-market application requirements would be the last ones to come into effect, and vary based on the risk-based classification of products. Stage four (three and a half years into the transition) would end the enforcement discretion for pre-market review for Class III IVDs, while stage five (four years after the final rule) would require pre-market submissions for moderate and low-risk IVDs/LDTs. At the FOCR meeting, regulators tended to refer to the LDT rule as “the elephant in the room,” but declined to provide details about what a final version would look like or when it would be expected beyond the information available. Interestingly, however, multiple panelists at the meeting throughout the day called out a specific potential third-party reviewer – the State of New York. Third-party review is a core component of the FDA’s proposed rule that would help mitigate capacity issues at the agency. As Shuren explained, “there are a lot of similarities with the New York State program and ours” at FDA, as the state’s Department of Health “also perform a pre-market review on individual tests very similar to the FDA.”
• The down-classification policy, which defers to Class II, could be intended to ease the LDT transition. All LDTs are currently considered Class III by the FDA, as they are technically unauthorized products. The device framework’s deference to a higher-risk category could have required all LDTs for which there is not an established predicate device to submit a PMA or have a risk-based category determination by FDA to submit a De Novo. As AgencyIQ noted at the time, the intent of the proposed rule is that all products that would require a PMA will see the enforcement discretion terminated first, while all products that would require a 510(k) would be in the next phase. However, considering that those frameworks have historically not applied to these products, it will likely be confusing to effectively backfill risk categorizations. The new down-classification initiative and apparent adjustment to the way CDRH will view risk-based classification of IVDs going forward seem to indicate that the agency intends for most LDTs to go through the device pathways as Class II – as is, in fact, stated in the proposed rule. Notably, such a structure lowers the total cost of the rule itself; the laboratory industry pushed back strongly against FDA’s version of the economic impact analysis as published with the proposed rule.
• A key point of confusion about the LDT proposed rule: Implications for CDx. In the 2014 CDx guidance cited above, FDA acknowledges that CDx development is extremely challenging and that co-development (i.e., seeking CDx and therapeutic approval simultaneously) is sometimes infeasible. To address this, the agency built a workaround into that guidance document which allows drugs that would otherwise need a CDx to be approved without one, so long as certain criteria are met. Under this policy, LDTs typically fill the gap until a CDx can be authorized. The proposed rule did not provide clarification regarding the implications for CDx which are currently only available as LDTs for authorized drug products, or for future drug and CDx approvals. [See AgencyIQ’s analysis on the LDT proposed rule’s implications for CDx here.]
• Last year, the FDA announced a novel potential solution: Put LDT specifications on a drug label. In an effort to address the CDx gap, the FDA’s Oncology Center of Excellence (OCE) opened  a new pilot program in June 2023. As the agency noted at the time, “FDA has approved some oncology drug products that require use of in vitro companion diagnostics without contemporaneous marketing authorization of a corresponding in vitro companion diagnostic. In these cases, tests offered as [LDTs] are being used for patient treatment decisions.” The pilot intends to explore the potential for approval of certain CDER-regulated oncology drugs with the FDA signing off not on a CDx, but instead on the clinical validity of the developer’s clinical trial assay (CTA). This would then be posted online and referenced in the drug label.
• So far, no one has yet been accepted into the pilot – and Shuren, at least, doesn’t think it’s a broad fix. At FOCR, Shuren noted that the pilot itself, far from obviating the LDT proposed rule, “we sort of view for now as interim steps.” Currently, there are no participants in the pilot (which would accept up to eight developers), and “it’s kind of stuck in neutral for the moment, we’ll see if we’re able to move forward,” he explained. Further, he indicated that such an approach wouldn’t actually be a solution to the agency’s larger problems with LDT quality and performance variability: “At the end of the day, that’s not a solution. At all.”
• Even with no accepted applicants, there is interest in participation, as confirmed by LOXO@Lilly’s ANTHONY SIRECI, who indicated that his division (oncology) has been in touch with FDA about the pilot. Per Sireci, the pilot’s design “basically codifies what we’ve been trying to do, a lot. Which is to say [that] these tests exist … and we can’t ignore that.” Notably, Sireci also pointed to New York State approval as a key marker of quality during development.
• A key reminder of the larger context: “A bad quality test isn’t great, but no test is also not great,” said Sireci.

What’s next? CDRH’s capacity, an expanding pilot and a continued push for legislative action

• The announcement of the down-classification initiative comes as CDRH already has a packed schedule for 2024. In addition to the potential implementation of the LDT proposed rule, CDRH just finalized its proposal to overhaul the medical device quality system regulations. Implementation of that rule will involve significant legwork from the agency, including guidance updates, international program coordination and building (and training staff on) an entirely new inspections system. With a packed guidance agenda of regular work and a still-outstanding transition away from emergency authorities, CDRH was already set up for an extremely busy year, even without an en masse IVD reclassification initiative. The Center did obtain additional staffing authority under the current iteration of the medical device user fee program (MDUFA V); however, the sheer volume of work out of the Center raises questions about its capacity more broadly. It also raises questions for the diagnostics office, specifically, which is currently without a Director following TIM STENZEL’s retirement at the end of 2023. [See AgencyIQ’s 2024 landscape analysis on diagnostics policy here.]
• Per regulators at the FOCR meeting, novel diagnostics developers could also see some new policies come forward. In particular, Schuck and Shuren touted two specific policy areas and programs that will apply more broadly to diagnostics in the next year: Pre-determined change control plans (PCCPs) and the Total Product Lifecycle Advisory Program (TAP).
• First, PCCPs: Although these have traditionally been considered for artificial intelligence and machine learning (AI/ML) products, Schuck noted that the agency is looking to “encourag[e] and want to see more of” IVDs that are innovative and represent technological and scientific improvements, which could take the form of PCCPs. “This is having a plan upfront for changes that you would want to make to your test and telling us: how you would make that change, how you would validate that change, what would be the acceptable performance for that change? And then if we see that in a premarket submission, you can make that change [and] test developers can make that change … and not to come back for premarket review.” With CDRH set to release a new draft guidance on PCCPs for medical devices (i.e., beyond AI/ML) more broadly in FY2024, this could be a notable trend going forward.
• Second, TAP for diagnostics: The TAP pilot was a key priority for Shuren in the MDUFA V reauthorization, and is currently in its second programmatic year. During the FOCR meeting, Shuren provided some insight into the operation of the program, describing three components: 1) TAP advisors providing strategic advice; 2) CDRH’s “review team is engaging differently” with more “fluid” engagement and feedback, and 3) Connections with patient and provider groups. Currently, TAP participation is open to developers with products in two CDRH review offices – the cardiovascular devices office (OHT2) and the neurological and physical medicine devices office (OHT5). According to Shuren, “We will be expanding it in October to other parts of the center, and it will wind up including diagnostics” (emphasis added).
• And finally: A VALID longing. At the FOCR event, several stakeholders – including representatives from the FDA and industry – expressed continued support for a legislative approach to diagnostics reform, in particular the Verifying Accurate and Leading-edge IVCT [In Vitro Clinical Test] Development (VALID) Act. That proposal would have created a new classification of product type regulated by the FDA known as IVCTs – incorporating both IVDs and LDTs – with regulatory frameworks separate from the medical device system. However, the bill was not advanced as part of the 2023 omnibus and still has not been re-introduced in the Senate so far this year. Throughout 2023, regulators continued to make the case that a legislative solution to the challenges faced in diagnostic regulation (including challenges with the device pathways, risk categorization and LDTs) would be a “preferred approach.” According to remarks at FOCR, that continues to be the case. However, the bill still does not have a Republican co-sponsor in the Senate following the retirement of Senator Richard Burr (R-NC).

https://fda.agencyiq.com/article/0000018d-67bb-d66d-afed-efbb234c0000