By: Daniel Dwyer
On September 23, 2020, FDA published a proposed rule that would amend its medical product “intended use” regulations. This proposal raises some interesting questions about what “intent” means.
By way of background, a product is subject to regulation as a “drug” or “device” under section 201(g) and (h) of the Federal Food, Drug, and Cosmetic Act if it is “intended for use” in the diagnosis, cure, mitigation, treatment, or prevention of disease, or (unless it is a food) “intended” to affect the structure or any function of the body. How does FDA determine “intended use?”
FDA answered this question in a regulation that dates back to 1976 (41 FR 6911, Feb. 13, 1976) and is still in effect today: 21 CFR 201.128. This regulation says:
The words intended uses or words of similar import … refer to the objective intent of the persons legally responsible for the labeling of drugs. The intent is determined by such persons’ expressions or may be shown by the circumstances surrounding the distribution of the article. This objective intent may, for example, be shown by labeling claims, advertising matter, or oral or written statements by such persons or their representatives. It may be shown by the circumstances that the article is, with the knowledge of such persons or their representatives, offered and used for a purpose for which it is neither labeled nor advertised. The intended uses of an article may change after it has been introduced into interstate commerce by its manufacturer. If, for example, a packer, distributor, or seller intends an article for different uses than those intended by the person from whom he received the drug, such packer, distributor, or seller is required to supply adequate labeling in accordance with the new intended uses. But if a manufacturer knows, or has knowledge of facts that would give him notice, that a drug introduced into interstate commerce by him is to be used for conditions, purposes, or uses other than the ones for which he offers it, he is required to provide adequate labeling for such a drug which accords with such other uses to which the article is to be put.
The device version of this rule is at 21 CFR 801.4 and is worded similarly.
The final sentence in this regulation was troubling for many manufacturers because it suggested that mere knowledge of off-label use of a product by a healthcare provider could trigger a requirement for a labeling change that could itself require FDA approval. In other words, knowledge was equated with intent.
In 2015, FDA was prompted by the Family Smoking Prevention and Tobacco Control Act, which gave the agency the authority to regulate tobacco products, to clarify its definition of “intended use” so as to clarify when products would be subject to regulation as drugs or devices rather than as tobacco products. As part of this process, it decided to revise section 201.128 (and 801.4) by eliminating the last sentence (80 FR 57756, Sept. 25, 2015). This solution turned out to be too simple, however, because, when it published its final rule, FDA decided to amend the last sentence so that it no longer suggested that a firm’s mere knowledge that its approved or cleared product is being prescribed or used for an unapproved use would, on its own, trigger the requirement to provide adequate labeling. FDA’s final rule changed the last sentence (and poetically began it with “And”) to:
And if the totality of the evidence establishes that a manufacturer objectively intends that a drug introduced into interstate commerce by him is to be used for conditions, purposes, or uses other than ones for which it is approved (if any), he is required, in accordance with section 502(f) of the Federal Food, Drug, and Cosmetic Act, or, as applicable, duly promulgated regulations exempting the drug from the requirements of section 502(f)(1), to provide for such drug adequate labeling that accords with such other intended uses.
82 FR 2193, 2217 (Jan. 9, 2017).
Although FDA had tried to undo the “knowledge = intent” problem, vociferous opposition nevertheless resulted due to the addition of the “totality of the evidence” language. Various stakeholders argued that the regulation violated the First Amendment by regulating truthful speech regarding lawful activity; violated the due process clause of the Fifth Amendment to the extent that the types of evidence to be considered were not clearly defined; unlawfully interfered with the practice of medicine; departed from relevant statutory text, legislative history, case law, and FDA past practices; and was issued in violation of the notice requirement under the Administrative Procedure Act based on the inclusion of the new “totality of the evidence” language. In response, FDA delayed the effective date of the final rule indefinitely. 83 FR 11639 (March 16, 2018).
FDA’s September 23, 2020, proposal is its latest attempt to fix this regulation: it proposes to abandon the approach in its 2017 final rule, delete the last sentence of the current regulation, and replace the fourth sentence with:
Objective intent may be shown, for example, by circumstances in which the article is, with the knowledge of such persons or their representatives, offered or used for a purpose for which it is neither labeled nor advertised; provided, however, that a firm would not be regarded as intending an unapproved new use for an approved drug based solely on that firm’s knowledge that such drug was being prescribed or used by health care providers for such use.
In the press release that accompanied the proposed rule, FDA states that its “longstanding position is that, in evaluating a product’s intended use, any relevant source of evidence may be considered.” FDA states that while this position remains unchanged, the proposed rule is intended to clarify that a firm’s knowledge that a health care provider has prescribed or used an approved or cleared medical product for an unapproved use, standing alone, is not sufficient to establish a product’s intended use. FDA’s preamble includes some other examples of when knowledge would not equal intent. For example, FDA says that the fact that a pharmaceutical firm that knows that one of its products, approved for use only in adults, is being ordered by and distributed to many medical practices that treat exclusively pediatric populations would not be deemed to intend such use – assuming that it does not direct its sales or marketing staff to disseminate samples or information about this product to these pediatric practices. FDA also states that disseminating medical and scientific publications in accordance with “safe harbors” established in guidance would not be deemed to be intended use.
In general, FDA’s examples show that, if a firm is not affirmatively promoting its products for unapproved uses, then mere knowledge of off label use will not be deemed to change the intended use of the product. Thus, although FDA says that “knowledge can be within the types of evidence that are relevant to establishing intended use,” it relies on actions, not knowledge, to establish intended use. As such, it is difficult to see why the revised fourth sentence is needed in the regulation at all, or why FDA insists on keeping alive an argument that knowledge = intent.
Comments on the new proposed rule are due by October 23, 2020.