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Translational Software to Submit PGx Software Platform for 510(k) Clearance

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NEW YORK – Translational Software, a company that provides decision support to integrate pharmacogenetics information into patient care, will seek regulatory clearance from the US Food and Drug Administration for certain components of its Precision Health Nexus software platform.

According to Translational Software CEO Don Rule, his company has been working "feverishly" for the last few months to put together a nearly 2,000-pages long 510(k) submission package. "We're hoping that this will provide some clarity for everybody on what the FDA considers valid [PGx] information" that can be reported in patient care, said Rule. The firm expects to submit the application with the agency in a couple of weeks.

The FDA has been prodding labs performing pharmacogenetic testing, and software firms providing reports from such testing, to undergo regulatory review. The agency issued a safety alert in October 2018, in which it called out unapproved PGx tests and software used to make clinical recommendations as a public health risk.

"Results from these tests may … indicate that the healthcare provider can or should change a patient's medication ... The FDA is also aware of software programs that interpret genetic information from a separate source that claim to provide this same type of information," the agency wrote in its safety alert. "However, clinical evidence is not currently available for these genetic tests or software programs and, therefore, these claims are not supported for most medications."

The agency followed up this safety alert with a warning letter last April to Inova Health System's genomics lab for conducting PGx tests without its blessing. Then, over the summer, the FDA began calling up labs in this sector and asking them to remove any mentions of drugs associated with PGx variants in reports.

Some in industry have pushed back, calling out the FDA's actions for lacking transparency and consistency. A group of stakeholders have formed a coalition to ask the agency to stop attempting to shut down PGx labs and to make any new, substantive changes in regulations through notice-and-comment rulemaking, as required by law.

However, the difficult regulatory environment and uncertainty created by the agency's actions is also moving some companies, among them Translational Software, to proactively seek approval or clearance for PGx-related products.

Based on its interactions with the FDA for the past year, Translational Software will seek FDA clearance for two components of its Precision Health Nexus software platform: PGxPortal and PGx API. After Translational Software's laboratory customers test patients' samples for genetic variants associated with drug response, they can run the detected variants through its PGxPortal to generate a report that assigns a diplotype and retrieves treatment recommendations based on those results. Translational Software's platform retrieves the clinical recommendations drawing on its knowledgebase, which contains information from FDA-approved drug labels, the published literature, as well as recommendations from expert groups, such as the Clinical Pharmacogenetics Implementation Consortium (CPIC) and the Dutch Pharmacogenetics Working Group.

According to Rule, the company's 510(k) application will describe how the company's software calls diplotypes and how it looks up clinical recommendations using its knowledgebase. The PGxAPI, meanwhile, is what Translational Software's customers use to integrate this PGx information into their own electronic systems, therefore the company will also need to demonstrate the validation of this application programming interface to the agency, Rule explained.

In its 510(k) filing, Translational Software will cite 23andMe's Personal Genome Service as the predicate device for its products. The FDA has authorized 23andMe's PGS in multiple settings, including for carrier screening and genetic health risk reports, as well as PGx reports for 33 variants. Rule noted that while his firm's software platform isn't exactly like 23andMe's offerings, in authorizing 23andMe's test reports, the FDA intended to create a more flexible path forward for other companies. "We're hoping to follow on that and use that as our predicate device," he said.

Translational Software started discussions with the agency about garnering approval for its software systems shortly after the FDA sent a warning letter to Inova's lab last April. The firm met with the FDA in June and held a pre-submission meeting with the agency on Nov. 4 to garner feedback on the parts of its system for which it would need to submit evidence. At the pre-submission meeting, the company learned that not only did the agency want to see data on its diplotype-calling process but also on its knowledgebase.

"They considered that the relationship between the changes in variants and the diplotype calls that we made was opaque enough that it constitutes a medical device," Rule said. In discussions with regulators, he and his colleagues tried to "make plain" how the company made those calls, but the agency had concerns that there was still room for error because a lab director may not evaluate every single call.

"It's not the answer we wanted, but I understand their point," Rule said.

The FDA has maintained that it has increased its regulatory scrutiny on PGx tests out of growing concern that unapproved tests were putting the public health at risk. Although the agency hasn't provided any recent examples of tests harming patients, Rule said that the agency has real cause for worry. He said he has seen companies make therapeutic recommendations based on "thin research," which could have led doctors to make inappropriate or harmful changes to patients' treatment regimens. 

"There are cases where some [labs] have gotten ahead of the science," Rule said. "We've seen it. We understand that's not good and if there is a regulatory pathway that keeps that from happening, then that's great."

However, the regulatory pathway for PGx labs and software companies isn't clear. For example, industry observers have questioned what the FDA considers sources of valid PGx information. Does the agency consider PGx recommendations in FDA-approved drug labels clinically valid? What about data from the published literature or recommendations from expert groups like CPIC?

Translational Software had to grapple with these questions in its 510(k) filing. "From our interactions with the agency, we know it's not sufficient to say we're just following CPIC guidelines," Rule said.

On the other hand, while it may seem straightforward to just provide the recommendations that are in FDA-approved drug labels, they don't always contain the most up-to-date information. "Sometimes, the phenotype of a patient [seen with a particular genotype] wasn't discovered at the time a drug label was written," Rule said. In some cases, new PGx information has come about that has led expert bodies to issue recommendations that are more appropriate than what's in a drug label. Although this is very rare, Rule noted that when it does happen, it's important.

In its submission, Translational Software will detail how its knowledgebase makes a determination that a genetic test result is clinically actionable. For example, the company has described what studies it considers when evaluating the clinical significance of genetic variants, what are the sizes and designs of those studies, the diversity of the sources, and how robust and repeatable the effect sizes have been. "We're documenting that this evaluation process occurred," Rule said. "We're hoping we can be in active dialogue with the FDA in the process of this submission and understand what they consider a clinically valid recommendation."

"No one has seen a playbook on what FDA considers valid on a [PGx] test report," he continued, adding that these concerns may be ameliorated after the firm gets some feedback on its submission. "We'll just have to see."

The company is also uncertain how the agency defines patient harm. The FDA appears to identify unapproved tests as a threat to public health, but lab industry players have pushed back against the idea that the FDA is the ultimate arbiter of lab test quality. The lab community has pointed out that FDA oversight can be a lengthy process, and by the time a test is approved or cleared, it may no longer be the best test for that setting or interrogate all the clinically important analytes associated with a condition.

Rule took particular issue with FDA's authorization of 23andMe's limited BRCA1/2 test for three mutations, which show up in those of Ashkenazi Jewish ancestry and are associated with heightened risk for breast, ovarian, and pancreatic cancer. However, BRCA1 and BRCA2 are highly variable genes and thousands of mutations have been identified as associated with a heightened risk for inherited cancers.

In authorizing 23andMe's test, the agency said that the test cannot be used to make clinical decisions, and that the results must be confirmed by follow-up testing. Rule agrees with other cancer geneticists who question the FDA's decision to allow direct-to-consumer access for this test, and worry that in granting marketing authorization the agency has actually increased the risk for harm, since people may get tested and not fully understand the limitations of 23andMe's report.  

Meanwhile, industry players have also criticized the FDA for putting the public health at risk by asking labs to remove any mentions of drugs from PGx test reports, since this would diminish physicians' ability to make sense of the reports and avoid drugs that might cause serious adverse events in patients, some of which may be life threatening. "There is a level of concern that the FDA may think of safety very differently than we do," Rule said.

Finally, if Translational Software is successful in achieving 510(k) clearance and its software becomes an FDA regulated product, another big unknown is whether that will impact the company's ability to work with lab customers that use its platform to produce reports for tests that aren't FDA approved. The majority of labs don't have FDA approval for their tests, and as such, it's not really an option for Translational Software to limit its business using that as a criteria, Rule said. "There are policies at issue here that are way outside of our domain," he said. "But our goal is to create an easy path for laboratories to provide a product that the FDA considers safe." 

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