March 1, 2010 (Vol. 30, No. 5)
Jeffrey N. N. Gibbs
RUO Assays and Instruments Face Greater Scrutiny
The FDA actively regulates medical devices intended for diagnostic use. Diagnostic kits intended for diagnostic use face the full panoply of FDA regulation. In sharp contrast, research use only (RUO) products are essentially unregulated. In fact, although RUO products are often discussed as though they are a kind of medical device, RUOs are not devices at all.
A commercially important class of products, RUOs are defined very briefly by FDA regulations. RUO products are described as products “in the laboratory research phase of development and not represented as an effective in vitro diagnostic product.” This definition has created some uncertainty as to what products fall into the RUO category.
The same regulation establishing the RUO category requires that RUO products bear the following labeling statement: “For Research Use Only—Not for use in diagnostic procedures.” Although not authorized by the regulation, many companies have shortened the statement to just the first clause. FDA regulations do not prescribe any other restrictions or limitations on RUO products beyond this labeling statement. Thus, FDA regulations define the category and prescribe labeling, and nothing more.
Given that RUO products are not intended to diagnose “a disease or other condition,” it is not clear that they are even subject to FDA’s jurisdiction. The intended use of an RUO product—research, not diagnosis—presumptively removes it from the definition of a device and FDA’s authority.
In any event, aside from bearing the mandated statement, RUO products are not regulated by the agency. For example, they do not need to be listed with FDA or comply with the Quality System Regulation (QSR). They can be sold without any FDA clearance or approval. As a practical matter an RUO is essentially unregulated by FDA.
Over the years, the paramount regulatory issue for products bearing the RUO label has been whether or not they actually do belong within the RUO category. There have been multiple instances in which RUO products have become widely used by laboratories for clinical applications. There have also been a number of occasions where companies have labeled products as RUO but then promoted them for diagnostic use. In some instances, companies have made specific diagnostic claims for their assay or instrument but still labeled the product as RUO.
Biomarker kits are often labeled as RUO because it is not known whether the product has any clinical use or, if so, what that use might be. The assay’s developer may expect that a particular biological substance will be of some clinical value, but not be sure what that value is. Labeling a product RUO, allows it to get into the hands of researchers who can then evaluate whether the product may be potentially valuable for some specific diagnostic purpose.
Often, no clinical use is ever identified. Some assays maintain their true RUO status indefinitely. While the product may be helpful to researchers in understanding basic biological mechanisms, a diagnostic use may never be discovered.
FDA has initiated several attempts to try to regulate RUO products more tightly. In the early 1990s, FDA issued a draft Compliance Policy Guide (CPG) document that sought to significantly restrict the availability of RUO products. This guidance document went through several iterations but was never finalized. There is still no guidance document setting out FDA’s policy regarding RUO products, however, reports have recently surfaced that a new RUO policy may finally be released.
One of the elements set forth in the draft CPG was that the distributor of the RUO product should receive a certification from the laboratory customer that the product will be used for research purposes only. Although the CPG was not adopted, some vendors have asked laboratories to sign some type of acknowledgement form. While this will help support a vendor’s position that its product is intended only for research use, it is not currently required. FDA has, however, “encouraged” some instrument suppliers to adopt certification programs.
Concerned by the proliferation of RUO products, in 1997 FDA tried a different tack. That year, FDA promulgated the Analyte Specific Reagent (ASR) regulation. ASRs were broadly defined as the building blocks of diagnostic assays. Unlike RUOs, ASRs were subject to FDA requirements, including QSRs and Medical Device Reporting. This regulation was prompted, in part, by the belief that it would result in the availability of higher quality materials for laboratory tests and displace some of the lower quality RUOs.
To some degree, that plan succeeded. Many different products were offered to laboratories as ASRs. However, while many of these were basic chemical components, more complex products were also sold as ASRs. Ultimately, FDA concluded that the ASR regulation was being used as a vehicle for products that didn’t fit the intent of the regulation.
FDA therefore released a guidance document in 2007 that substantially curbed the availability of ASRs by prohibiting companies from combining more than one active component. With the advent of molecular diagnostics, selling a single component was often impracticable, e.g., a primer and probe pair need to be offered together. This narrow interpretation of ASRs has essentially precluded the sale of ASRs for use in molecular diagnostics. Somewhat predictability, a number of companies responded by relabeling their ASRs as RUOs. This has helped lead to a renewed focus on RUOs by FDA.
For years, the principal regulatory question for products labeled as RUOs has been whether they qualify for this classification and hence are not subject to regulation as devices. While FDA has not issued either a regulation or guidance delineating how companies can promote RUOs, the agency has taken enforcement action against a number of RUO companies.
Even absent regulations or guidance, it is apparent that in FDA’s view a product forfeits its RUO status if certain types of claims are made—claims that the product can diagnose a disease or condition, provide clinical sensitivity or specificity data, or offers a clinical benefit. Correspondingly, the instructions for use (IFU) accompanying the product need to be brief.
While the bulk of RUO products have been assays, the RUO category also encompasses instruments and equipment. This can present its own set of regulatory challenges, particularly when an IVD applicant has used an RUO instrument in conjunction with developing its assay, a situation that is now occurring with greater frequency.
The utilization of RUO instruments in assay development has led to the submission of applications that reference RUO instruments. This may result in naming the RUO instrument in the draft IFU, i.e., the applicant states that the assay is to be performed on an RUO instrument, or the data for the IVD were generated on an RUO instrument.
While FDA had accepted these practices, that has seemingly changed. Therefore, an IVD company that has tested and validated its assay on an RUO instrument or is using RUO assays in its test system should discuss with FDA at an early stage how to address the regulatory implications that may arise from this situation. Simultaneously, companies that are selling RUO-labeled instruments that are being widely used in diagnostics may find that they will be receiving more regulatory scrutiny from FDA.
Over the past few years, RUO products have received relatively little attention from FDA. That regulatory lull seems to be ending.
Jeffrey N. Gibbs ([email protected]) is a director at Hyman, Phelps & McNamara. Web: www.hpm.com.