FDA has issued a draft guidance that would limit the sale and distribution of “Research Use Only” (RUO) and “Investigational Use Only” (IUO) products. (A copy of the Federal Register notice announcing the guidance is available here.) While most of the restrictions set out in the policy are consistent with the current practices of many companies, in several key areas the agency’s proposals would substantially curb the sale of RUO and IUO labeled products.
Most significantly, FDA has departed from the well-established practice of determining intended use based on the manufacturer’s conduct, rather than how a customer uses a product. FDA states in the draft guidance that a manufacturer must stop sales of its RUO or IUO product to a customer once the manufacturer knows – “or has reason to know” – that the customer is using the product for a diagnostic use, even if the manufacturer makes no diagnostic claims or statements.
Long-standing Requirements for both RUOs and IUOs Retained
Several of the basic requirements to qualify as an RUO or an IUO have not changed. To be IUO, all labeling for “a product being shipped or delivered for product testing prior to full commercial marketing (for example, for use on specimens derived from humans to compare the usefulness of the product with other products or procedures which are in current use or recognized as useful)” must bear the statement, prominently placed: “For Investigational Use Only. The performance characteristics of this product have not been established.’’
Meanwhile, to be RUO, product must be in the laboratory research phase of development, and not represented as an effective in vitro diagnostic product. In addition, all labeling must bear the statement, prominently placed: “For Research Use Only. Not for use in diagnostic procedures.’’
The existing regulation has left the category “RUO” ill-defined. In the draft guidance, FDA explains that “the focus of manufacturer-initiated studies is typically to evaluate design, limited-scale performance, and issues such as usability of the test.” FDA provided the following examples of RUO products:
- Tests that are in development to identify test kit methodology, necessary components, and analytes to be measured;
- Instrumentation or other electrical/mechanical components under development to determine correct settings, subcomponents, subassemblies, basic operational characteristics, and possible use methods;
- Reagents under development to determine production methods, purification
- levels, packaging needs, shelf and storage life, etc.
FDA also recognizes that products “intended for use in non-clinical laboratory research with goals unrelated to development of a commercial product, such as discovering and developing novel and fundamental medical knowledge related to human disease and conditions,” (emphasis added) could qualify as RUO. The guidance provides as examples “instruments and reagents intended for use in research attempting to isolate a gene linked with a particular disease when such instruments and reagents are not intended to produce results for clinical use.”
This is a narrower interpretation of “research” than is commonly understood. It is not clear what is FDA’s basis in confining the category of research products to ones used to advance “novel and fundamental” objectives. It is clear that this limitation will be both difficult to apply and controversial.
Defining Intended Use Based on Actual Use
FDA states that in determining whether a product is properly marketed as RUO or IUO, it will consider the manufacturer’s statements and claims about its product. This is a well-established regulatory principle. However, FDA also said it would consider the manufacturer’s knowledge of the customer’s intended use.
FDA may consider a manufacturer’s knowledge of the purposes for which its customers offer and use its IVD product, and the manufacturer’s provision of technical support for those activities, to be evidence that the IVD product is intended to be used for such purposes. The weight of this evidence will vary with the circumstances.
Specifically, in addition to promotion by the manufacturer, FDA says it will consider the following factors as indicating that a device is not RUO or IUO:
- “[S]tatements in any labeling, advertising, or promotion of the IVD product that suggest that clinical laboratories can validate the test through their own investigational procedures and subsequently offer it for clinical diagnostic use as a laboratory developed test;”
- “Sales to clinical laboratories that the manufacturer knows, or has reason to know, use the IVD product in clinical diagnostic use in an investigation or otherwise, and support (including technical support) for those activities.”
- assistance “in the validation or verification of the performance of a test that the manufacturer know is used in clinical diagnosis.”
FDA also advises manufacturers of products labeled as RUO or IUO that if they discover that a clinical laboratory to which it sells its IUO or RUO device is using these IUO or RUO labeled products for a non-investigational diagnostic use, “it should halt sales for such use or comply with FDA regulations for IVD products, including premarket review requirements.” (Emphasis added). This position that a company should discontinue sales to a customer because that customer is using the product in a manner outside the labeling may be unprecedented. Significantly, the draft guidance includes no provision for manufacturers first to inform the customer that it must stop diagnostic use or take other measures to alter the manner of usage. Rather, FDA is apparently saying that the manufacturer has no option but to cease sales immediately.
Import of RUOs
Although IVD products intended solely for research use are generally exempt from most regulatory requirements, foreign manufacturers who import RUO IVD products into the U.S. are not specifically exempt from establishment registration and device listing requirements. FDA states in the guidance that it intends to exercise enforcement discretion “with respect to establishment registration and device listing requirements for persons who manufacture, propagate, compound, or process imported IVD products intended solely for research use.” The agency has established specific codes to use for import of RUO products. This information will provide FDA with more specific insights into which RUO products are being imported.
Many aspects of the draft guidance are not surprising, and are consistent with the practices adopted by many companies. However, FDA’s stance that RUO and IUO manufacturers must “halt” sales to a customer because its use of an RUO or IUO product for diagnosis is a major departure. Moreover, FDA’s reliance on customer conduct to define intended use has implications for other products beyond those labeled RUO and IUO, by determining intended use through customer behavior, not manufacturer’s conduct. In addition, the narrowed definition of RUO will be both difficult to apply and likely have unintended negative consequences.
Comments to this proposed draft guidance are due by August 30, 2011.