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Clearer Final RUO/IUO Guidance Raises Concern Regarding FDA Regulation of LDTs

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Originally published Dec. 3.

In the final version of a guidance on research- or investigational-use in vitro diagnostic products, the US Food and Drug Administration has revised some language from a draft that didn't sit well with laboratories.

Nevertheless, industry players still believe that the document fails to address their broader concerns and is a potential harbinger of greater regulatory action from the agency on lab-developed tests.

In the final guidance, issued last month and entitled "Distribution of In Vitro Diagnostic Products Labeled for Research Use Only or Investigational Use Only," FDA has clarified language from a draft version that placed what manufacturers felt was an undue burden on them to regulate the appropriate use of such products. The latest document includes concrete examples of how the agency plans to establish the intended use of an RUO/IUO-labled product and the types of marketing or distribution activities that would place a device beyond the scope of the research-use category.

"The biggest change from the draft guidance was the removal of the provision which would have made the mere marketing or sale of an RUO product to clinical laboratories indication of an intended use that was inconsistent with the RUO/IUO labeling," Scott McGoohan, VP of reimbursement and scientific affairs at the American Clinical Laboratory Association, told PGx Reporter. "ACLA supports the removal of this provision, as it would have effectively prevented manufacturers of such products from selling them to laboratories, thereby putting patient access to these vital diagnostics at risk."

RUO or IUO products, including tests, instruments, software, and reagents, are still in the development phase and may be used in studies to advance knowledge about a particular disease, but aren't being commercially marketed for diagnostic use. Such products are exempt from certain regulatory requirements that devices intended for clinical diagnosis are subject to, such as premarket approval.

However, RUO/IUO products are still subject to labeling requirements that prominently inform researchers that the tests have not been validated for clinical diagnosis or patient management in the commercial setting. In order to qualify for an RUO/IUO label, the IVD product or component must meet certain criteria. For example, it has to be non-invasive and cannot be used for a diagnostic procedure without another medically established test confirming the diagnosis.

The FDA issued this guidance because it has grown concerned in recent years that IVD manufacturers are labeling products for research use to skirt regulatory oversight for tests actually intended for clinical use. Since RUO/IUO products aren't subject to regulatory controls, this means that their performance characteristics are unproven and their manufacturing may be inconsistent, the agency warns. This, the FDA worries, can mislead healthcare providers and harm patients. So, the agency intends to keep watch over how these types of tests and components are being sold.

"Mere placement of an RUO or IUO label on an IVD product does not render the device exempt from otherwise applicable clearance, approval, or other requirements," the agency informs industry players in the final guidance. "FDA may determine that the device is intended for use in clinical diagnosis based on other evidence, including how the device is marketed."

In contrast, in the 2011 draft guidance the FDA said the following: "The mere placement of an RUO or IUO label on an IVD product does not render the device exempt from clearance, approval, or other requirements, regardless of how it is marketed. Whether it bears an RUO or IUO label, or neither, an IVD product that is not intended for research or investigational purposes would not qualify for the applicable exemptions." The FDA further stated in the draft version that even if the manufacturer of RUO/IUO products did not make overt statements to encourage non-research use of such tests, but merely had knowledge that its tests were being used inappropriately by customers, that would be enough to warrant enforcement action.

'More enforceable'

Diagnostics firms and labs that provided testing services under the Centers for Medicare & Medicaid Services' Clinical Laboratory Improvement Amendments had a major problem with this guidance language. The use of RUO/IUO products for clinical diagnostic testing is a widespread practice, and manufacturers often have no way to monitor how such devices are being used by customers.

Earlier this year, Alberto Gutierrez, director of FDA's Office of In Vitro Diagnostics and Radiological Health hinted that the agency would tinker with the language in the final guidance to clarify its expectations for RUO/IUO IVD manufacturers. Gutierrez acknowledged at a conference in January that the agency "has created a bit of a storm in a teacup with the RUO draft guidance" by suggesting that marketers of RUO products may be held responsible for customers using these tools in a clinical setting. He ensured at the time that it's not the agency's intention to go after companies that truly aren't aware of how disparate customers are using their products.

At the same time, Gutierrez noted that in some instances an RUO/IUO manufacturer knows very well how its products are being applied by customers. For example, when one large company acquires another company and that acquired firm is using the parent firm's RUO products in a clinical setting, then it's obvious that the parent company was aware of how its products were being utilized, he noted. Gutierrez went on to suggest that FDA is keeping an eye on such a scenario after a prominent acquisition in the "prenatal testing space" this year.

Gutierrez did not mention the company by name at the January meeting. However, at the time, Illumina had announced plans to acquire prenatal testing firm Verinata Health, which markets a sequencing-based fetal trisomy test using Illumina's HiSeq platform. Verinata, now a subsidiary of Illumina, does use Illumina's RUO products in its tests, but so do a number of other Illumina customers. Illumina declined to comment for this article.

A few days before FDA issued the final RUO/IUO guidance, the agency granted premarket clearance for Illumina's MiSeqDx, the first sequencing platform to receive the agency's nod. Simultaneously, the FDA also cleared two cystic fibrosis assays that run on Illumina's MiSeqDx and a reagent kit that allows clinical labs to develop their own tests using the platform.

Before the FDA clearances, MiSeq was labeled RUO and the research-use version is still available through Illumina alongside the MiSeqDx, including the tests and reagent kit. The FDA cleared platform and reagent kit may provide a framework for other RUO/IUO IVD manufacturers, particularly those marketing next-generation sequencing based tests, to develop and commercialize a version for clinical diagnostic use from a research-use test. "These clearances, much like the [analyte-specific reagents] and general purpose reagents regulations, create a least burdensome path for manufacturers to provide laboratories with quality reagents, manufactured under good manufacturing practices, so that labs can create their own laboratory-developed sequencing tests with confidence in the reagents and instruments they use," Gutierrez told PGx Reporter.It remains to be seen how readily customers will adopt the FDA-cleared platform and reagents, however.

In the final guidelines, the FDA clarifies that in determining the true intended used of an RUO/IUO-labeled device it will look at the "objective intent" of the manufacturer based on the "totality of circumstances" in which the device is distributed. "Overt expressions by the manufacturer, such as those present in labeling and advertising, may be sufficient to determine that an IVD product is inappropriately labeled RUO or IUO, when such expressions demonstrate that the device is actually intended for clinical use despite the RUO or IUO labeling," the agency states in the guidance.

The FDA will also consider the design of the product and how it is sold or distributed on behalf of the manufacturer. For example, if a manufacturer only produces RUO products but its sales force routinely calls on clinical laboratories that don't perform research, this may tip off the FDA that the device is intended for clinical use. Also, if a manufacturer of an RUO/IUO-labeled IVD product helps another firm validate a clinical diagnostic test that incorporates the RUO/IUO-labeled IVD, "that assistance would be considered to be evidence of a non-research or non-investigational intended use," according to the final guidance.

According to Mya Thomae, CEO of IVD and companion diagnostic consulting firm Myraqa, the latest version of the guidance is more enforceable than its earlier iteration. "FDA has focused on intended use and has defined what the real limits of RUO labeling are," said Thomae. On a Myraqa blog post about the RUO/IUO guidance, Thomae elaborated that while the final version carries a stronger tone, very little has changed about the agency's underlying motivations. "FDA appears ready to get serious about RUO," she wrote.

"The previous document was really from the standpoint of how you keep your RUO labeling," she told PGx Reporter. "This document doesn't start with that premise. FDA seems to be communicating that the status quo is not the right place to start the discussion and has reset the baseline."

Impending LDT regulation?

For some in the industry, the RUO/IUO guidance is a sign that the FDA is sharpening its thinking on how to broadly regulate LDTs and may be readying to issue guidance in this area. "What remains now is the LDT guidance," said Lakshman Ramamurthy, director of the regulatory and policy practice at Avalere Health, an advisory firm focused on healthcare business strategy and policy. Ramamurthy, who until recently was a senior reviewer and policy advisor at FDA's Center for Devices and Radiological Health, noted that in the final guidance the agency shows a greater appreciation for the fact that it can't entirely hold the manufacturer responsible for how an RUO/IUO product is used on the market. "But certainly, the RUO guidance seems to be the step before releasing guidance on LDTs," he said.

The agency has long said that it intends to bring LDTs under its oversight in a risk-based manner. Although the FDA hasn't taken formal action on this front yet, Commissioner Margaret Hamburg in June reiterated the agency's commitment to bring LDTs under regulatory compliance.

"The agency is working to make sure that the accuracy and clinical validity of high-risk tests are established before they come to the market," she said at a major oncology conference in June. "The risk-based framework that we have under development will ensure that diagnostics used in cancer treatment will provide medical professionals with a critical baseline for confidence in the tests they order for their patients. Our intent in considering what to do about LDTs is to provide for safe and effective diagnostics while promoting innovation and patient access."

Shortly thereafter, ACLA, which has consistently pushed back against FDA's expressed intent to regulate LDTs, filed a citizen petition asserting that the agency lacked the legal authority for such oversight. In the petition, the interest group representing developers of lab tests suggested amending CLIA – the path through which LDTs have traditionally been overseen – to address regulatory gaps.

ACLA's McGoohan criticized that in the final RUO/IUO guidance the FDA still fails to address many of the group's major concerns. "Principally, the guidance fails to recognize the fact that CLIA, which regulates virtually all clinical laboratories performing testing, requires laboratories to establish performance specifications and validate any test that is not FDA-approved or cleared," he said. "Therefore, ACLA believes that where the laboratory has complied with the requirements of CLIA, the use of a properly validated RUO or IUO product should be permitted."

The Association for Molecular Pathology was also dissatisfied with the final guidance. "While the final guidance does provide some clarity on the scope of the guidance and examples of when a manufacturer is in noncompliance with the regulations, [it] fails to address AMP’s most significant concern to avoid the disruption of patient care," Mary Williams, AMP executive director, told PGx Reporter.

"The FDA should have provided accommodations to ensure continued patient access to critical tests as manufacturers come into compliance and/or instances where low test volume would deter a manufacturer from submitting an application to the FDA for that product," she said, adding that the agency should practice enforcement discretion or an alternative regulatory pathway in instances where no FDA cleared or approved products are available.

In Ramamurthy's view, just because FDA has historically exercised enforcement discretion over LDTs, leaving oversight activities to CMS under CLIA, doesn't mean the agency lacks this authority. "Enforcement discretion means that they have the discretion to enforce," he said. If the clinical labs just accepted that FDA will regulate LDTs in a risk-based manner, and started discussion with that understanding, the solutions would come faster, Ramamurthy suggested. "Everybody knows this is coming," he said. "So, to get all worked up about it doesn't make sense."

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