FDA Proposal to Reclassify CDx Assays May Broaden Opportunities for Dx Manufacturers, Experts Say

Original from: genomeweb

The US Food and Drug Administration's recent proposal to reclassify companion diagnostic assays as Class Il devices may lead to additional opportunities for diagnostic test manufacturers, diagnostic industry stakeholders claim.

The proposal, announced last month in the Federal Register, would reclassify certain Class Ill nucleic acid-based tests indicated for use with a corresponding approved oncology therapeutic into Class l devices.

Reclassifying a device to a Class Il device, or a device that poses a moderate risk to the public, from a Class Ill device, a device that poses a high risk to the public, would mean the device could go through a less rigorous regulatory process. In this case, it would allow companion diagnostic assays to go through the less rigorous 510(k) approval pathway rather than the premarket approval process, and loosening the requirements for approval could open the playing field for smaller companies to gain clearance for companion diagnostic assays, some stakeholders said.

The agency defines Class Il devices as devices for which general controls by themselves are insufficient, but for which there is sufficient information to establish special controls to assure safety and effectiveness. Some of those special controls include issuance of performance standards, postmarket surveillance, patient registries, and development and dissemination of guidelines.

The FDA's proposal encompasses in vitro diagnostic devices intended to detect specific genetic variants and/or other nucleic acid biomarkers in human clinical specimens using nucleic acid amplification technology and/or sequencing technology that are indicated for use with a corresponding approved oncology therapeutic product.

The FDA said in its proposal that the order, if finalized, would decrease the regulatory burden on industry by allowing manufacturers to go through the "generally more cost-effective" and less burdensome 510(k) pathway, which typically has a shorter premarket review timeline compared to premarket approval, it noted.

Ken Ruppel, VP of scientific and medical services at Diaceutics, noted that the proposal might encourage a more streamlined and less expensive approach for pharmaceutical companies to have diagnostics aligned with their therapies. It may also make it easier for laboratories to participate in companion diagnostic testing that would otherwise be sent out to another lab.

Making the pathway to clearance easier for other companies may also lead to "more players in the game," leading to the democratization of companion diagnostic development and potentially more innovation in the space, he added. The proposal lowers the barrier of entry "to a degree," particularly when it comes to financial concerns, although Ruppel noted that there is still a lot of analytical evidence that needs to be supported to move a test through the 510(k) pathway.

"For these other manufacturers that haven't been in the game for [companion diagnostics], it creates an opportunity for them to bring some of their science to the forefront," he said. "There may be things that we as a community missed out on because they ... don't have the regulatory support to take something through the FDA in a Class III status."

Jeffrey Jones, founder and chairman of diagnostics consultant firm The Deerborne Group, said that premarket approval is on a "completely different level" than the 510(k) clearance process.

For one, the time to approval is significantly different. Jones said that he has helped shepherd assays through the 510(k) process in 30 to 90 days, while premarket approval usually takes more than 180 days because the level of submission data required is so much more rigorous.

In Jones' view, the proposal is going to "open up the doors for maybe some smaller ... midcap companies to be able to dedicate resources to go after" companion diagnostic approval. For companies that already have premarket approval for companion diagnostic tests, such as Roche's Foundation Medicine or Guardant Health, Jones said he believes the process will go into "hyperdrive."

"I think it's going to allow them to move things forward a lot more quickly," he added.

However, one component of the FDA's proposal worries Ruppel - the requirement that device labeling be consistent with the information set forth in the corresponding therapy's product labeling. According to Ruppel, if laboratorians identify a better or more accurate tool and want to change the test or patient population, it won't be approved because it's not consistent with the original label. The only way to ensure that test's approval would be to get the pharmaceutical company involved to change the drug label, which "creates this whole business aspect to patient care," Ruppel said.

There are times when changing the assay to make it more accurate might limit the number of patients who can receive a certain drug, which could be a deterrent for pharmaceutical companies, according to Ruppel.

"Based on the science, that would be a good thing because the science might show that these patients simply don't benefit," he said. "But pharma wants to be able to give their drug to as many patients as they possibly can."

As a result, the labeling issue may create a "sticky situation [in which] those decisions [are made] based on business [considerations] and not so much on the science," he said.

Joe Saad, chair of the College of American Pathologists' Council for Government and Professional Affairs, noted that at the time of 510(k) approval manufacturers can request a predetermined change control plan that allows for certain changes to be made to the test without having to go through the full approval process again. He hoped that the option will allow more tests to be offered and more effective tests to be developed, as well as allowing for consistent improvement of tests that have already been approved.

Jones considered that naysayers may believe the proposal will "open up a floodgate" and inundate the FDA with manufacturers and tests clamoring for approval, which could lead to longer turnaround times for those approvals. However, he said he doesn't see that happening because the evidence requirements in the proposal are still "very rigorous" and the FDA's 510(k) clearance process is a "well-oiled machine."

In all, this is the "most consequential shift in [companion diagnostic] policy in over a decade," Jones said.

Laboratorians, clinicians, and pathologists would also benefit from the change, Saad said. Currently, companion diagnostic assays are approved on a certain platform for a certain test, so clinicians who want to order those tests need to go to a laboratory that can offer that one companion diagnostic. According to Saad, it becomes very confusing for pathologists and clinicians who are trying to determine what laboratory a test order should go to depending on which treatment is on the table, and it's complicated for laboratorians to ensure the right test is being run on the right equipment with the right reagents.

The FDA's proposal may provide alternative options for labs to perform companion diagnostic tests since they may not be as limited by the FDA's requirements, Saad noted.

"Hopefully with a 510(k), it'll be a simplified way to get the test done and for patients to get the appropriate treatment," he said.

Saad also noted that cost of tests may come down as competition in the space increases.

Reimbursement implications

According to healthcare consultant Bruce Quinn, the proposal also has implications for reimbursement of companion diagnostic assays. Coverage under the national coverage determination forext-generation sequencing-based tests from the US Centers for Medicare and Medicaid Services is for premarket approval or FDA-cleared tests, so companion diagnostics manufacturers will now be able to use the 510(k) pathway to get coverage under that NCD.

In addition, the Advanced Diagnostic Laboratory Test designation provided by CMS that coordinates payment for certain assays also requires premarket approval or FDA clearance. If companion diagnostic tests are cleared through the 510(k) pathway, that expands the types of tests that might receive ADLT status.

A sole-source companion diagnostic test that receives 510(k) clearance would get guaranteed coverage under the NCD as well as the guaranteed list price payment under the ADLT designation - something that's currently not available to companion diagnostic assays unless they receive premarket approval.

"You can get both of those things only by crossing the 'cleared' bar, rather than spending a zillion dollars and crossing the [premarket approval] bar," Quinn said.

He, like Ruppel, noted that the labeling requirement "potentially could be tricky for some applications," but said that he doesn't see many downsides to the proposal. The only downside may be for companies that already went through the premarket approval process and "thought they had a very wide, very deep moat around their approval," he added.

One company that has been through the premarket approval process and is a major player in the companion diagnostic space is Roche's Foundation Medicine, which requested the FDA proposal.

A Foundation Medicine spokesperson said via email that the company appreciates the FDA's recognition that clinically validated companion diagnostics are important to accurately and reliably identify patients who are most likely to benefit from an FDA-approved therapy."

The firm's petition was in response to the agency's previously stated intent to reclassify most companion diagnostic tests that are currently Class Ill into Class Il by November 6, 2027, the spokesperson added.

In a statement via email to GenomeWeb, the FDA said that in addition to the reclassification process, "we 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 and whether a new test may be classified into Class Il through de novo classification (and special controls established), rather than being Class Ill and subject to the PMA pathway."

The agency added that "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 I| devices."

Overall, the goal for the proposal - to ensure patients have access to safe, necessary testing - is appreciated by stakeholders, despite possible concerns. "If we can get more patients access to some of these tests that could provide potential access to game-changing therapies, it's a win," Ruppel said.

Source: FDA Proposal to Reclassify CDx Assays May Broaden Opportunities for Dx Manufacturers, Experts Say