NEW YORK – A decision from the US Food and Drug Administration announced earlier this year may significantly reduce the burden of garnering regulatory approval for companion diagnostic developers and some infectious disease assay developers, according to industry experts.
At the Next-Generation Dx Summit in Washington, DC this week, multiple industry stakeholders discussed the potential impact of the decision announced in January by the FDA's Center for Devices and Radiological Health. The CDRH said in a press release that it intends to reclassify most high-risk in vitro diagnostic devices — known as Class III devices — as moderate-risk devices, or Class II. The majority of the tests included in this decision are companion diagnostic assays and microbiology tests, and the move would allow manufacturers to seek regulatory approval for their tests through a less-stringent regulatory pathway, the FDA said.
The reclassification would allow these tests to obtain clearance through the 510(k) or de novo pathways rather than the higher burden of premarket approval. Approximately 5 percent of in vitro diagnostic devices are Class III and 45 percent are Class II, Christine Bump, a principal at Penn Avenue Law and Policy, said in a talk at the summit. The majority of companion diagnostics, particularly those for cancer, are Class III devices, and the reclassification "has the potential to lessen the premarket and clinical trial burdens" on developers of these tests, Bump said.
A device's class is determined by the risk, intended use, and technology used and establishes the exact requirements that apply to a device and its manufacturer. Class I devices require general controls, such as the registration of the manufacturing facility, compliance with labeling requirements, and post-market compliance, Bump said. Class I devices are generally exempt from premarket review.
Class II devices require compliance with both general controls and special controls, and those special controls apply to all devices within that device type. Special controls include premarket data requirements, special labeling requirements, specific performance standards, and post-market surveillance. A key component of the de novo process is establishing the special controls, which any device following the 510(k) pathway can then use, citing the de novo device as a predicate device.
However, a Class III device exists in a "vacuum," meaning every device that goes through the premarket approval process is responsible for independently providing data and information to provide the reasonable assurance of safety and effectiveness.
Courtney Lias, director of the FDA's Office of In Vitro Diagnostics, said in a separate talk at the summit that the agency has learned enough about these test types to enable the FDA to craft special controls that can mitigate the risks enough to allow 510(k) approval. She added that the reclassification process may provide more incentive for smaller players in the industry to seek regulatory approval because it will be easier to manage allow for more predictability in the regulatory process, and lower costs.
The agency began the reclassification process in September 2023 with a panel of microbiology experts who were presented with three device types — assays for hepatitis B, Mycobacterium tuberculosis, and parvovirus B19 — and discussed the possibility of their reclassification. The panel found that there was enough evidence to proceed with reclassification of the latter two tests, Bump said.
To reclassify a test from Class III to Class II, the available scientific evidence must show that special and general controls are sufficient to provide reasonable assurance of safety and effectiveness, Bump said. The reclassification will apply to the broader device type and not an individual test, she noted.
Generally, the reclassification process requires the publication of a proposed administrative order in the Federal Register that includes details about each type of device the agency would like to reclassify and a summary of the scientific evidence that supports reclassification, Bump noted. The FDA will then convene a device classification panel meeting for every general category of devices it aims to reclassify. These meetings are open to the public and the panel then makes a recommendation to the agency, although the FDA is not required to follow the recommendation. The agency will also consider public comments from the proposed order and then publish a final administrative order in the Federal Register, Bump said.
The reclassification plan, despite being announced before the publication of the agency's final rule laying out its plan for overseeing laboratory-developed tests, likely is related to the FDA's LDT decision, Bump said. A large amount of LDTs would potentially be Class III devices, and having to move all of those through the premarket approval process would be "literally impossible," she said, adding that "onerously burdensome doesn't even begin to describe" the impact. If the LDT final rule remains in effect — which is not a guarantee, considering both the American Clinical Laboratory Association and the Association for Molecular Pathology have sued the FDA over the rule — the reclassification process would lessen the burden on both laboratories and the FDA, Bump noted.
The agency anticipates the reclassification process will be complete by November 2027, but historically, the process has taken a long time, and it is a "huge goal" to do all of this by that date, she added.
The FDA has also provided little additional information about how the process will work, particularly for complex companion diagnostic tests.
Kate Simon, senior director of global regulatory strategy for in vitro diagnostics at Bayer and a former FDA employee, said in a separate presentation at the summit that the level of burden for validation studies for a companion diagnostic is not driven by whether the device is submitting for premarket approval, de novo, or 510(k), but by the best practices for the performance characteristics of the device. "Since IVD devices that are currently regulated as PMAs tend to involve more complex clinical issues, the clinical studies tend to be more complex as well," she noted.
However, she noted for a PMA submission a sponsor must establish independent safety and effectiveness, whereas for a 510(k) submission a device can establish substantial equivalence to a predicate device. "How FDA will approach substantial equivalence for CDx [tests] versus safety and effectiveness in regards to validation data remains to be seen," she noted.
In addition, there is no option for modular submission under the 510(k) pathway, which CDx developers use to enable review of their submissions under tight timelines, Simon said. These submissions allow applicants to submit preclinical data and manufacturing information for review while still collecting, compiling, and analyzing clinical trial data. The move to 510(k) clearance for companion diagnostics may limit the FDA's ability to review submissions under accelerated timelines because the agency may not accept preclinical data before the device's clinical validation data, Simon added.