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FDA Warning Letter to Agena Bioscience a 'Shot Across the Bow' for RUO-Labeled Diagnostics


NEW YORK – The US Food and Drug Administration's recent warning letter to Agena Bioscience may have significant implications for clinical labs' ability to access research use only (RUO) diagnostic products, according to industry observers.

At the American Association for Cancer Research's annual meeting on Saturday, regulatory experts and diagnostics developers discussed a warning letter the FDA sent to Agena Bioscience stating that its iPLEX HS Colon Panel, which uses the MassARRAY4 (MA4) system and iPLEX HS chemistry panels, are "adulterated" medical devices under the Food, Drug, and Cosmetic Act, because they are developed for research use but being used by Agena's lab customers in clinical testing.

While manufacturers of RUO-labeled products and test kits commonly sell them to clinical labs, the FDA sent a "shot across the bow" for such practices in the lab industry, Sheila Walcoff, founder and CEO of regulatory consulting firm Goldbug Strategies, said during the webcast AACR session detailing the contents of the warning letter that the FDA posted to its website last week, but without mentioning Agena. "What's so significant about this is that most laboratories at least use some components that are labeled RUO," she noted. "The implications of this can be tremendous in terms of laboratory supply [of RUO products] if this is shaken up."

The FDA states in the warning letter that during an inspection of Agena's website, the company's director of regulatory and quality processes told the inspector that Agena sells the MA4 system to research and clinical diagnostics firms and that the system is labeled "For Research Use Only. Not for use in diagnostic procedures." The FDA also flagged language on Agena's website describing MA4 devices as RUO products. In addition, the MA4 product brochure states that the platform "is a benchtop MALDI-TOF mass spectrometer specifically designed for genomic research applications."

Despite being labeled RUO, "on numerous occasions your iPLEX HS Colon Panel and your MA4 were not being shipped or delivered for an investigation. And these devices were not for use in the laboratory research phase of development but rather were represented as effective IVDs," wrote Courtney Lias, acting director of OHT 7: Office of In Vitro Diagnostics within FDA's device division, and Shari Shambaugh, program division director, division 3 in FDA's Office of Regulatory Affairs.

Agency officials noted that while Agena has FDA clearance to run its Impact Dx Factor V Leiden and Factor II Genotyping Test on the IMPACT Dx system, inspectors learned from the company that it has since replaced that system with the MA4. As evidence that Agena is marketing the RUO-labeled MA4 and iPLEX HS Colon panel for clinical use, the FDA cited Agena's customer distribution lists; customers' experiences using the MA4 system featured on the firm's website; and claims on the site that the colon panel can enable tumor profiling studies and detect clinically relevant genetic variants. The agency even cited a 2021 customer alert to a hospital in Texas about "an increase in false-negative results" with certain reagent lots associated with the colon panel.

Agena is a subsidiary of Mesa Labs, which acquired the company in 2021. Emails to Mesa Labs executives seeking comment were not immediately returned.

The switch from a previous FDA-cleared test system to a new platform may be common practice in the world of laboratory medicine, but in the FDA's eyes, "you have just changed your test, and you are now offering a test that has not been appropriately validated," Walcoff said. Therefore, if a RUO manufacturer sells these products to a clinical lab with CLIA certification, at present, that lab might fall under FDA's enforcement discretion policy for lab-developed tests (LDTs). "But you, as developer of this [RUO] test kit or reagent package, you are considered [the developer of] a medical device," she underscored.

The FDA appears to have taken particular issue with Agena selling its RUO wares to labs with CLIA certification, which is not necessary for labs doing basic research but is required for labs testing human samples. The FDA focused on this, Walcoff noted, and interpreted it to mean that Agena's real intent is to sell RUO products for clinical use and not for research purposes.

In light of the latest warning letter, she advised RUO manufacturers to "be extremely careful" in how they describe their products, particularly on their websites. Naturally RUO manufacturers want to talk about the capabilities of their products so other labs will use them in the clinic, "but that's where you get caught," Walcoff said.

The warning letter comes at a time when the FDA is laser focused on bringing LDTs under its oversight. Although LDTs have traditionally been regulated by the US Centers for Medicare & Medicaid Services under CLIA, the FDA has long wanted to bring them under its regulatory framework, citing concerns that faulty LDTs are harming patients and last year proposed a rule describing its regulatory plans. Even though industry players have pushed back against this rule and continue to challenge the agency's statutory authority to regulate LDTs, experts like Walcoff and others expect the agency to finalize this rule quickly, ending its decades-long policy of enforcement discretion of LDTs and overlaying many new regulations that labs, particularly those within academic medical centers and hospitals, aren't used to.

Keith Ligon, a physician-scientist at Dana-Farber Cancer Institute, noted that academic labs in particular don't have internal expertise in FDA regulatory matters and don't typically interact with the agency much. "We don't have a plan for this," Ligon said, referring to forthcoming LDT oversight from the FDA.

Industry observers predict the FDA will try to push through the final LDT rule sometime in April and phase in risk-based regulations over the next three years, but they are also expecting lawsuits challenging the agency's regulatory authority in quick succession. It's an open question, Walcoff said, as to whether the courts will tell the FDA to stop implementing the LDT rule while lawsuits are ongoing or allow it to move ahead.

Carve outs and exemptions from FDA regulation for certain segments of the lab testing market, sometihng academic and hospital labs had hoped for, are also unlikely, according to Walcoff, who often feels like the "grim reaper" talking about the specter of FDA oversight with lab industry professionals. "It's hard to see where we're going to be a year from this," she reflected.

Meanwhile, "the FDA means business," Walcoff said, with the expectations it seems to be asserting for RUO manufacturers vis-à-vis the warning letter. Regardless of where the LDT rule lands, this is something that impacts the field right now, she stressed, and could result in a "double squeeze" of the industry. On one hand, labs are being told they have to establish clinical validity of LDTs through the FDA, but on the other hand, more stringent regulation of RUO products can significantly limit labs' access to the tools and materials they need to validate their tests.

Listening to the discussion at AACR from the audience, David Rimm, director of pathology tissue services at Yale University School of Medicine, estimated that his group uses 200 to 300 RUO components daily when performing immunohistochemistry tests for cancer patients. "How would the FDA handle that?" he wondered.

The FDA, back in 2013, issued guidance to industry on how RUO and investigational use only IVD products should be used, labeled, and marketed. Walcoff acknowledged that at present there is "no way to get around" using materials and tools that are only available as RUOs in clinical diagnostics, and the FDA seems more concerned these days with RUO-labeled kits than reagents. "The FDA is going to be looking for you to validate your whole test system [from sample collection to test report] and that can include RUO-labeled components," she said. "To the extent you're purchasing things [labeled RUO] and the FDA is going to put the squeeze on your supplier, that's a very big problem that's coming much more into the forefront."

Walcoff believes the FDA must address this problem and be more flexible toward RUO product suppliers as it brings LDT oversight under its aegis. "You can't have this double-edged [sword] of not getting your supply of [RUO materials] and … not being able to run validation studies," she said. "It's not a good situation."