Originally published June 3.
By Turna Ray
The US Food and Drug Administration this week issued a new draft guidance on the marketing of research-use-only and investigational-use-only in vitro diagnostic products in an effort to close a regulatory loophole that has allowed companies to commercialize diagnostics by circumventing the agency's medical device rules.
However, given that RUO/IUO products are being marketed and used by life science players in numerous ways, the FDA's proposed restrictions will not be an easy task for industry to implement or for the agency to enforce.
In the document, available here, the FDA outlines the appropriate and inappropriate use, labeling, manufacturing requirements, and marketing of IVDs for research and investigational purposes. FDA's overarching stance is that products that manufacturers label as RUO or IOU, which in most cases haven't been approved or cleared by the FDA as medical devices, should only be used in research and not for clinical diagnosis of patients.
Mya Thomae, CEO of diagnostics consulting firm Myraqa, who previously worked with the FDA on developing regulation for microarray devices and establishing rules for parallel 510(k) submissions, believes the RUO/IUO guidance will be "a painful transition" for companies that have gotten used to conducting business under FDA's lax enforcement of such products.
While noting that "there are still many nuances to work out," Thomae told PGx Reporter that the FDA guidance "goes a long way to make previous gray areas a lot more black and white."
By issuing the document, "FDA is showing that they intend to put the 'only' back in research use only," she said. "There are many legitimate reasons to offer RUO and IUO products and companies that truly are engaged in research or are running investigations have very little to worry about."
However, the agency wants to make sure that the investigational device exemption, intended to excuse RUO and certain IUO products from having to garner pre-market approval or a 510(k) clearance, aren't being used by manufacturers to forego FDA regulation and introduce them commercially as laboratory-developed tests under the Centers for Medicare & Medicaid's Clinical Laboratory Improvement Amendments.
It is difficult for the FDA and industry players to quantify how prevalent this practice is. Stakeholders PGx Reporter has spoken to agree that RUO/IUO products are being used in non-research settings, but noted that in many cases, users aren't knowingly using such products as commercial tests with the intention of sidestepping FDA regulations. According to a spokesperson from an industry group representing molecular pathology test-makers, many labs are using RUO/IUO products as LDTs without knowing they are not meant to be used in this way.
In the draft guidance, the FDA informs manufacturers and distributors that RUO/IUO products, which can be tests, instruments, or reagents, may only marketed for use in research or as part of an investigation, and that a manufacturer's responsibility goes beyond merely slapping a RUO/IUO label on a product.
Indeed, the FDA said that it will not only be on the lookout for such "adulterated and misbranded" products, but that it expects manufacturers to not advise or provide support to customers that they know will use such technologies in the clinical setting. This restriction may have an impact on the way RUO/IUO product manufacturers are currently collaborating with other industry players in the advancement of personalized medicine products through drug/diagnostic co-development.
FDA notes in the document that manufacturers who label their IVD products RUO "should not sell such products to laboratories that they know use the product for clinical diagnostic use." In the case of IUO products, manufacturers "should not sell them to laboratories that they know use the product for clinical diagnostic use outside of a clinical investigation."
If a manufacturer learns that a customer is using an RUO/IUO-labeled product improperly, "it should halt such sales or comply with FDA requirements for IVD products, including premarket review requirements, if applicable."
The agency posted the draft document on June 1 on the Federal Register. Stakeholders may submit comments on the guidance for the next 90 days.
Assessing the Problem
The FDA has previously indicated that it intends to crack down on companies that are marketing RUO/IUO products for use outside of the research setting, a practice it has observed among industry players for some time (PGx Reporter 01/20/2010).
"The marketing of unapproved and uncleared IVD products for purposes other than research or investigation (for example, for clinical diagnostic use) has led in some cases to diagnostic use of laboratory tests with unproven performance characteristics and manufacturing controls that are inadequate to ensure consistent manufacturing of the finished product," the FDA states in the draft document. "Use of such tests for clinical diagnostic purposes may mislead healthcare providers and cause serious adverse health consequences to patients, who are not aware that they are being diagnosed with research or investigational products."
The FDA could not provide details on how common it is for RUO/IUO IVDs to be marketed as commercial tests, but the problem is clearly serious enough to have caught the agency's attention.
"We don't have a number, but we are aware that it is not uncommon for labs to use RUO-labeled products," Elizabeth Mansfield, director of personalized medicine at the Office of In Vitro Diagnostics in FDA's Center for Devices and Radiological Health, told PGx Reporter. According to Mansfield, the FDA has taken enforcement action against "a small number of companies" in this regard, but she could not name the companies due to confidentiality agreements.
Groups such as the Association of Molecular Pathology and the American Clinical Laboratory Association represent sectors of the life sciences industry that would be impacted by these guidelines. Both AMP and ACLA told PGx Reporter that they are mulling the draft document and plan to submit formal comments to the Federal Register.
"AMP members are dedicated to the development and implementation of molecular pathology testing in a manner consistent with the highest standards established by the Clinical Laboratory Improvement Amendments, the College of American Pathologists, the American College of Medical Genetics, and FDA," Mary Williams, director of scientific programs at AMP, told PGx Reporter. "The advent of analyte-specific reagents enabled laboratories to use commercial products for patient benefit that would otherwise not be available. However, some products necessary for laboratory tests are available only as RUOs," she noted
Williams added that the FDA's RUO/IUO guidance "may affect availability of certain tests, which, in turn, may limit a healthcare provider’s ability to manage patient care."
Reflecting on 20 years of experience with IVD regulation, Thomae said that the use of RUO reagents and instruments is pervasive in LDTs. "LDTs are not routinely reviewed by FDA and CLIA regulations do not speak specifically to the use of RUO materials," she said. "As a result, many LDTs have incorporated both RUO-labeled reagents and instruments into their products."
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Thomae said that the FDA's change in enforcement could have the biggest impact on oncology diagnostics. Since oncology clinical trials are inherently challenging in terms of demonstrating significant efficacy, even with the aid of biomarkers, "many of these [diagnostic] tests are only offered as LDTs and require the use of RUO materials from manufacturers."
One example of how FDA's new restrictions on RUO/IUO products might impact medical care can be considered with regard to Qiagen's KRAS PCR kits. The kits on Qiagen's website are clearly labeled as RUO products "not for use in diagnostics procedures" in the US, but it is possible that physicians and labs are using these tests for the diagnosis of patients without the company's knowledge.
Qiagen's KRAS Mutation Test Kit was developed by UK-based diagnostics firm DxS, which Qiagen acquired in 2009. When DxS was an independent firm, its test was being marketed as an LDT in the US by Exiqon subsidiary Oncotech. It is unclear if Exiqon still provides KRAS testing as an LDT in the US. Qiagen was unable to provide comments for this article, and a call to Exiqon's sales department was not returned.
Meeting the Criteria
In the draft guidance, the FDA explains that in order to be exempt from standard IVD labeling requirements, RUO/IUO tests must be noninvasive, not require invasive sampling, and not "introduce energy" into a person. In order for IUO tests to be exempt they cannot be used as diagnostic products in clinical investigations without the confirmation of the diagnosis by another medically established diagnostic.
In the personalized medicine space, noninvasive tests that would qualify as RUO products include diagnostics that require a blood sample, but may not include certain tests that require invasive tissue requisition. "Blood sampling that involves simple venipuncture is considered noninvasive, and the use of surplus samples of body fluids or tissues that are left over from samples taken for noninvestigational purposes is … considered noninvasive." Mansfield said. "So, collecting a blood sample would not be considered invasive, but collecting a tissue sample might be, depending on how it was collected."
Although FDA is generally practicing enforcement discretion over RUO/IUO tests, instruments, and reagents, these 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 the draft document, the agency also informs RUO/IUO manufacturers that these IVDs don't need to be developed under FDA's Quality System regulations if they meet conditions for an investigational device exemption, or IDE. IUO tests that aren't exempt would have to meet certain QS requirements, mainly the procedures controlling the design of the product.
"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," the FDA notes in the draft guidance. "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 states in the guidance that even if a 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.
In the process of deeming a RUO/IOU product misbranded, the agency will monitor written and verbal advertising and promotional materials from manufacturers suggesting the use of such IVDs as clinical diagnostics, as well as assess manufacturers' sales to clinical labs that they "know or [have] a reason to know" may be using such products to diagnose patients outside of research.
If FDA becomes aware that a manufacturer is promoting the use of an RUO/IOU IVD for use in an LDT for clinical diagnosis, the agency would deem that IVD misbranded.
While the draft guidance reads as if the burden is on manufacturers to ensure that their RUO/IUO products aren't being used in non-research settings, FDA's Mansfield said that the agency doesn't expect companies to be supercops when it comes to tracking how their customers are using investigational IVDs.
"We do not expect the manufacturers to police the labs' use of products," she said. "We do expect them to label and market their products appropriately."
Thomae believes that it may be difficult for manufacturers to determine exactly how far they need to go to assure FDA that their customers are truly using their RUO/IUO materials for research. However, she noted, "clinical labs aren't buying their materials at Costco. Manufacturers of all sizes typically know where their products are going and whether they are being incorporated into LDTs."
Personalized Medicine Impact
FDA's crackdown on RUO/IOU products will likely require life science industry players to change the way they ink Rx/Dx collaborations and become more cognizant of the types of technologies they're applying to their research.
Donna Roscoe, a scientific reviewer at the Office of In Vitro Diagnostics Device Evaluation and Safety at FDA's Center for Devices and Radiological Health, has previously warned against using RUO products in the development of companion diagnostics in drug trials.
At a conference in 2010, Roscoe said that device manufacturers should "avoid research-use-only components" in Rx/Dx co-development programs, since all systems used as part of a clinical trial involving human subjects need to be developed under good manufacturing practices and quality systems regulations. If RUO products are used, "then you'll have to work with the manufacturer of that particular instrument or make arrangements yourself to bring it in to your [quality systems regulations], which is not trivial," Roscoe noted at the time (PGx Reporter 09/22/2010).
In the draft guidance, FDA corroborates Roscoe's advice, noting that while RUO/IUO reagents or instruments may be used in the development of diagnostics that will be submitted to the FDA for regulatory approval under 510(k) or PMA, the sponsor should include data on the RUO/IUO products in the application package. "Once the IVD product is cleared or approved, the RUO- or IUO-labeled reagent and/or instrument should be relabeled to indicate that it is cleared or approved for use with that specific IVD product," the agency noted.
Outside of product development, however, the agency is pushing RUO/IUO IVD manufacturers to put up a wall between themselves and laboratories that might use their products outside of a clinical investigation. In the guidance, the agency restricts manufactures from helping clinical lab customers validate and verify the performance of LDTs that are intended for commercial use.
"If the manufacturer of an IVD product labeled RUO were to assist in the validation or verification of the performance of a test that the manufacturer knows is used in clinical diagnosis using its RUO-labeled IVD product, FDA would consider such assistance to be evidence of non-research intended use … [which] may render the device misbranded," the FDA states, adding that similar restrictions and consequences apply for IUO-labeled IVDs.
"This change in enforcement may dramatically affect development of LDTs, as well as availability of LDTs already on the market," Thomae said. "Given the growing importance of diagnostic information to personalized medicine, now may be the right time to enforce existing regulations more evenly."
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