What Are RUO's?
However, saying RUOs are not devices leaves open a major question: What, then, are RUOs? A product that is intended to be used diagnostically is not an RUO. For what purposes are RUOs intended to be used?
Decades after FDA issued the RUO regulation, the answer to that fundamental question is still not entirely clear. A product that is intended by the manufacturer to be used by researchers in understanding basic biology would qualify as an RUO. Similarly, an assay whose clinical relevance is unknown should also be eligible for RUO status.
For example, a monoclonal antibody that is being sold because it has biologically interesting characteristics but no known diagnostic use could fall into the RUO category. Instruments or assays that are intended to enable biological discovery or basic research could also be positioned as an RUO product.
In practice, FDA’s approach to regulatory RUOs has been based on exclusion, rather than on affirmatively defining the characteristics of an RUO. That is, FDA essentially has focused on what products are not RUOs, rather than identifying what attributes make a product an RUO.
Given this, it is not surprising that FDA’s enforcement activities involving RUOs have been directed at the claims made for the products. For example, a product labeled RUO but advertised “as an aid in diagnosing lung cancer” would forfeit its RUO status and be regulated as an in vitro diagnostic. Conversely, a product labeled as RUO could be used by researchers to determine whether it might have utility in the detection of lung cancer.
Making matters more complicated, the product might be considered an “investigational device” if the manufacturer intended for the antibody’s clinical performance for a specific diagnosis to be evaluated. Once the intended use shifts from evaluating whether the analyte might potentially have diagnostic utility to evaluating its diagnostic performance for a specific disease, the product’s regulatory status may move from RUO to investigational.
FDA has never adapted a list of terms that companies should not use when promoting RUO products. The agency has, however, intermittently sent warning letters or taken other enforcement actions against companies selling RUOs. Based on these actions, certain principles can be derived.
For example, companies selling RUOs should not claim diagnostic utility. An assertion of diagnostic usefulness is not compatible with the RUO designation. Similarly, companies should not make claims relating to clinical sensitivity, clinical specificity, negative predictive value, or positive predictive value. Nor should the company compare the performance of its RUO product to that of an assay or instrument marketed for diagnostic use, since that would constitute an implicit diagnostic claim.
RUO products are, in fact, used diagnostically. Laboratories buy products labeled as RUO and then use the results in generating diagnoses. Historically, from an FDA prospective, that use did not alter the regulatory status of the RUO product. One well-established regulatory principle is that the regulatory classification of a product hinges on the manufacturer’s objective intent for the product rather than how it is ultimately used. This is a fundamental principle when it comes to devices, biologicals, and drugs that have been cleared or approved by FDA. It is the use intended by the manufacturer that controls the regulatory classification, not the use to which the product is put.
There are some indications that FDA personnel would like to adopt a more restrictive approach for RUOs. In a few instances, FDA officials have stated that a product labeled as RUO loses that status if a laboratory uses it diagnostically. That approach would be at odds with one of the basic tenets of FDA law. The RUO status of a properly promoted product should not be altered simply because a laboratory chooses to use an RUO product diagnostically.
In earlier draft guidance documents, FDA proposed that companies selling RUO products obtain a signed certificate from the laboratory stating that it would not use the product for diagnostic purposes. There is currently no requirement that manufacturers obtain a certificate from a laboratory customer. However, to reinforce the product’s intended use as RUO, some manufacturers do ask laboratories to sign a form acknowledging that the product is not intended to be used diagnostically. At a minimum, the materials sent to customers and potential customers, including invoices and purchase orders, should reiterate the RUO designation of the product.