Background on “intended use” regulations
The “intended use” regulations have been the subject of industry focus since September 2015, when FDA issued a proposed rule (summarized here) to amend the existing regulations. At that time, FDA proposed to remove a provision requiring a manufacturer that “knows, or has knowledge of facts that would give him notice that” its product is to be used for an unapproved [“off label”] use, the manufacturer would be required to “provide adequate labeling” to account for such use.
The 2017 final rule (summarized here) removed the provision but also required a manufacturer to incorporate an unapproved use into the labeling if the “totality of the evidence” establishes that the manufacturer objectively intended to introduce the product for that use. This “totality of the evidence” clause prompted significant concern in the industry and led FDA to delay the 2017 final rule’s effective date.
In September 2020, the agency issued a new proposed rule (discussed here) that among other things, clarified that (1) knowledge of off-label use of a product by a physician cannot by itself establish a manufacturer’s intended use for the product, and (2) the scope of evidence that FDA may rely on to establish a manufacturer’s objective intent is not limited to promotional claims and may include multiple types of evidence that do not involve speech.
Any relevant source of evidence may be considered to establish “intended use”
The recently published final rule aims to address key industry concerns while maintaining FDA’s flexibility to consider all relevant information in determining the intended use of a product. The final rule reflects FDA's longstanding position, stated in the 2020 proposed rule, that in evaluating a product's intended use, the agency may consider “any relevant source of evidence,” including “a variety of direct and circumstantial evidence.”
In the preamble to the final rule, FDA rejects the notion (advanced in several comments to the 2020 proposed rule) that evidence of intended use should be limited to promotional claims. The agency says nothing in the Federal Food, Drug, and Cosmetic Act (FDCA) or implementing regulations requires such a narrow interpretation, and cites numerous examples to show that FDA frequently takes into consideration a broader scope of evidence in establishing intended, including in enforcement actions and import determinations. The preamble also asserts FDA’s view that a broader basis for evaluating a product’s intended use “helps ensure that [the agency] can help curb the distribution of dangerous and fraudulent products.” The agency made a point of addressing commenters’ First and Fifth Amendment concerns via discussion and citation to numerous court decisions.
Requirement for updated labeling and the role of "knowledge" in determining intended use
The 2020 proposed rule expressed FDA’s intention to eliminate longstanding confusion created by the view that, in their then-current form, the regulations indicated that a manufacturer’s mere knowledge of an unapproved use triggers a requirement to update a product’s labeling. The final rule similarly clarifies that a manufacturer will not be deemed to have intended an off-label use based solely on knowledge that its approved product is being used or prescribed off-label. This also reflects the longstanding “practice of medicine exemption,” whereby FDA will not regulate off-label use of a lawfully marketed drug/device by a licensed health care practitioner in the context of caring for an individual patient.
The final rule language also addresses another highly contested issue by preserving the ability of laboratories to develop laboratory-developed tests (LDTs) using either in vitro diagnostic (IVD) or research use only (RUO) components, as long as such LDTs comply with Clinical Laboratory Improvement Amendments (CLIA) regulations in their development and are offered on the order of a health care provider.
Design or composition of an article
The new final rule also includes a new potential source of evidence of intended use, as proposed in 2020; as revised, the regulation states that “the design or composition of the article” may also be used by FDA as evidence of the manufacturer’s objective intent regarding a product’s intended use. FDA identifies as an example a stent that is designed to be specifically sized for a use that differs from the purported and labeled use. Although this principle is new to the regulation, it reflects existing agency practice, because FDA has often held that a product’s inherent characteristics can influence how it is regulated. By way of example, FDA has said in guidance that “[u]nder the Agency’s interpretation of the device definition, a product exhibits ‘chemical action’ if it interacts at the molecular level with bodily components (e.g., cells or tissues) to mediate (including promoting or inhibiting) a bodily response, or with foreign entities (e.g., organisms or chemicals) so as to alter that entity’s interaction with the body.”
In response to comments opposing the addition of product design or composition to the regulation as possible evidence of intended use, FDA characterized this element as an example of non-speech evidence that can properly contribute to establishing a manufacturer’s intent.
Relevant to device manufacturers specifically, the revised regulation also clarifies that the rule applies equally to devices granted marketing authorization (thus covering those brought to market via the de novo pathway) and those brought to market through 510(k) clearance or PMA approval, as well as to those exempt from premarket notification.
FDA also left in place a complimentary provision under which a third party may be held liable for furthering an off-label use. Under this provision, a person (e.g., distributor, seller) who receives an article and furthers its commercialization for a different, unapproved purpose is required to supply adequate labeling for that use, or else be liable for marketing a misbranded article.
Although the revised regulation does not materially change FDA’s policies or approach to off-label-related enforcement, it captures additional nuances in how FDA classifies a product and/or determines its intended use. In particular, clarifying that a manufacturer’s knowledge of how health care providers are using a product is not by itself sufficient to establish a manufacturer’s “intended use” of the product offers some additional defenses to companies. At the same time, the new “design and composition” language codifies an additional method by which FDA may establish the objective intent of the manufacturer in placing a device into commerce.
 86 Fed. Reg. 41,383 at 41,390-01 (Aug. 2, 2021)