For decades, products labeled for research use only (RUO) have been widely sold and used in the United States, playing a pivotal role in the development of new diagnostic tests. During this period, neither the definition of this class of products nor the marketing restrictions have been well-defined. (See GEN April 1, 2011).
On June 1, the FDA issued a draft guidance document that proposes both to define what products are eligible to bear the RUO label and how these products may be marketed. While much of the proposal is not controversial, several elements of the draft guidance document have raised significant concerns among manufacturers, laboratories, and researchers. The proposal, through its expansive definition of “intended use,” also has implications for drug, device, and biologic companies.
For a number of years, FDA officials have publicly expressed reservations about the use of RUO and Investigational Use Only (IUO) products by laboratories. In particular, FDA officials have worried about the use of RUO and IUO products both in lieu of in vitro diagnostic (IVD) products that had been reviewed by FDA, and also the use of RUO products to create laboratory developed tests. The draft guidance document explicitly articulates concerns over the use of RUOs and IUOs in generating diagnoses.
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patients, who are not aware that they are being diagnosed with research or investigational products, according to the draft guidance.
FDA does not cite any specific examples of misdiagnosis stemming from the use of RUOs or IUO products. Nor does FDA acknowledge that laboratories have been able to provide better diagnostic information by using an RUO or IUO than if they had no access to those products.
What Is an RUO?
The RUO regulation broadly defines the products falling within the RUO classification as “in the laboratory research phase of development.” The draft guidance narrows the class of products falling within that definition.
Products that are sold to laboratories for the purpose of refining or improving an assay's performance qualify as RUOs. For example, a manufacturer may retain its RUO label when providing an assay in order to “identify test kit methodology, necessary components, and analytes to be measured.” A manufacturer may use an RUO label when providing an instrument in order to “determine correct settings, subcomponents, subassemblies, basic operational characteristics, and possible use methods.”
In addition, products intended to be used for scientific research qualify for an RUO label. Somewhat surprisingly, apparently FDA does not state that all scientific research falls within the universe of “research use only” products. Rather, FDA says such research “includes” research that is “novel and fundamental.” The draft guidance does not elaborate on what those terms mean, or what criteria would be used to evaluate whether research is “novel and fundamental.” It is clear, though, that this qualifying language will create confusion and uncertainty if retained in any final document.
Marketing RUOs and IUOs
Under the Federal Food, Drug, and Cosmetic Act (FDCA), products intended to be used in “diagnosis” are subject to regulation as devices. FDA makes it clear in the draft guidance that simply labeling a product RUO or IUO is not sufficient to avoid regulation as a device. A product may bear an RUO or IUO label but be regulated as a device if it is marketed improperly. In that situation, FDA will deem the product to be an RUO IVD or IUO IVD.
This newly created—and somewhat confusing—nomenclature presumably describes products containing an RUO or IUO label that are, in fact, intended for diagnostic purposes.
A product intended for diagnostic use is an IVD, not an RUO or an IUO. Therefore, neither a product labeled RUO nor one labeled IUO may be promoted for diagnostic applications. While FDA has long made it clear that companies could not promote RUO and IUO products for diagnostic uses, the agency had never laid out specific parameters. The draft guidance document helps fill that void.
Under the draft guidance, a range of marketing activities can cause an RUO to forfeit that status. For example, companies selling an RUO product cannot make written or oral statements “that claim or suggest that the IVD product may be used in a clinical investigation or for any clinical diagnostic use” or that a laboratory can validate the product and “subsequently offer it for clinical diagnostic use as a laboratory developed test.” Furthermore, an RUO/IUO product can become an IVD because of “product names” (presumably this refers to a name implying diagnostic utility) or “clinical information” provided by the manufacturer.
FDA also says that it will consider the manufacturer's actions, not just its words. For example, “FDA may consider a manufacturer's knowledge of the purposes for which its customers offer and use its [RUO] product, and the manufacturer's provision of technical support for those activities.” Given that suppliers of RUO products are often asked by laboratories to provide product support, this statement by FDA could have significant practical ramifications both for laboratories and companies that sell laboratories RUOs. The restrictions enumerated on the marketing of IUO products essentially parallels the limits set out for RUO products.
To a large degree, these limits by FDA are consistent with the procedures many companies have adopted. This draft document reinforces the importance of carefully crafting marketing materials, including statements made by sales representatives, and of controlling technical support activities for laboratories. Diagnostic claims must be avoided. However, while the restraints on manufacturer-sponsored words and activities should not generate much controversy, that is not the case for another proposed restriction.