August 1, 2011 (Vol. 31, No. 14)
Jeffrey N. N. Gibbs
FDA Seeks to Better Define When and Where Research Use Only Designation Can Be Used
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On June 1, the FDA issued a draft guidance document that proposes both to define what products are eligible to bear the RUO label and how these products may be marketed. While much of the proposal is not controversial, several elements of the draft guidance document have raised significant concerns among manufacturers, laboratories, and researchers.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 The draft guidance document explicitly articulates concerns over the use of RUOs and IUOs in generating diagnoses.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patients, who are not aware that they are being diagnosed with research or investigational products, according to the draft guidance.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 The draft guidance narrows the class of products falling within that definition.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.
Intended Use Based on Actual Use
One of the most important regulatory concepts in the FDCA is that of “intended use.” That term plays a pivotal role in establishing the applicable regulatory requirements. Historically, intended use has been determined by the conduct of the manufacturer.
The intended use of a product is not based only on what words appear on the label, but what the manufacturer says about its product. A product would be regulated as a device if the manufacturer made diagnostic claims about it, even if the product itself was labeled RUO. The intended use of a product, though, has not been altered by the conduct of the purchaser. A manufacturer whose drug or device was approved for treating X does not face charges of off-label promotion because physicians use it to treat condition Y.
The draft document, however, states that the intended use of a product is altered by the conduct of its purchasers. According to FDA, “intended use may be shown by the circumstances surrounding the distribution of the product and the manufacturer’s knowledge that its product is offered and used for a purpose for which it is neither labeled nor advertised.”
Under the draft guidance, a company selling an RUO or IUO product that learns a customer is using a product for diagnostic purposes should “halt” sales of that product. This termination of sales to customers should take place even in the absence of actual knowledge, i.e., if the manufacturer has reason to know of the diagnostic usage.
This element of the draft guidance, if adopted, would have major repercussions for companies selling RUO or IUO products. Read literally, the policy would require the immediate cessation of sales to an RUO or IUO laboratory customer based on any diagnostic usage. No transition period is currently permitted under the draft guidance. This could be very disruptive to the manufacturer, the laboratory, and patients.
More broadly, this approach potentially represents a shift in FDA’s approach to offlabel use for FDA-regulated products. Drugs and devices are routinely used off-label. It is unclear what impact, if any, the approach adopted here toward RUOs and IUOs would have if applied to other FDA-regulated products in which off-label use occurs.
Guidance documents are not legally binding. Unlike statutes and regulations, guidance documents do not have the force and effect of law. FDA could not take enforcement action against a manufacturer on the ground that it “violated” a guidance document.
While FDA could cite a guidance document as evidence of the agency’s interpretation of the law, in an enforcement action FDA would need to establish a violation of a legally binding requirement, such as a statute or regulation. A draft guidance document has even less legal significance.
Nevertheless, the issuance of the draft guidance document does have consequences. It signals FDA’s intention to limit the sales of RUOs and IUOs. Taking this cue, some suppliers reportedly have already begun to restrict sales of RUO products to laboratories. If a final guidance document is issued in substantially the same form, FDA probably would send out letters to RUO and IUO companies alerting them to FDA’s position.
Certainly, the release of a final guidance document will cause many companies to change their behavior, regardless of the fact that the document is not itself enforceable. Issuance of a final guidance substantially curbing RUO products may also have a negative effect on investment in companies offering RUOs and, potentially, some of their customers.
The comment period for the draft guidance document closes on August 30, 2011. FDA has provided its views on how RUOs and IUOs should be regulated. It will be interesting indeed to see what comments are submitted in response.