A determination of “intended use” is fundamental to the U.S. Food and Drug Administration’s (FDA) regulation of drugs and medical devices under the Federal Food, Drug, and Cosmetic Act (FDCA). It is a primary basis for determining if an article is regulated by FDA, and if so, what regulatory requirements apply.
FDA has now proposed to amend the regulation “to provide direction and clarity to regulated industry and other stakeholders.” 85 FR 59,718, 59,718 (Sept. 23, 2020). This proposal modifies a 2015 proposal to amend the regulation, which ultimately was not finalized. The saga of the 2015 proposal and the events leading to this new one are set forth in the preamble to the new proposal. We blogged on the prior proposal here and here. Our own proposal for reforming the regulation is here. In today’s post, we will provide some initial thoughts on the new proposed rule.
In the “intended use” regulations, FDA defines the term and describes the evidentiary basis for determining the intended use of articles that are being marketed. There is one regulation for devices and another for drugs, but they are in substance the same (21 C.F.R. §§ 201.128, 801.4).
For reference, the current regulation (device version) reads as follows:
The words intended uses or words of similar import . . . refer to the objective intent of the persons legally responsible for the labeling of devices 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 devices, 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 device 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 device which accords with such other uses to which the article is to be put.
In FDA’s proposal, the agency would entirely delete the last sentence of the regulation: “But if a manufacturer knows, or has knowledge of facts that would give him notice that a device 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 device which accords with such other uses to which the article is to be put.” This deletion was, in fact, the heart of FDA’s original proposal back in 2015.
The sentence to be deleted has always been problematic. As we stated five years ago:
This ‘knowledge’ provision for many years has hung like the Sword of Damocles over the heads of manufacturers who have any knowledge of off‑label uses of their products. The possibility was always present that FDA could deem such knowledge to create a new intended use. If so, a manufacturer could find itself in trouble for failing to provide adequate directions for this imputed intended use. FDA also could deem the intended use an unapproved use outside the scope of the existing clearance or approval, opening the manufacturer up to criminal and civil liability for past sales and the burden of developing a new marketing application to bring the imputed use on‑label.
This change is, therefore, a welcome one. It would have been a good stopping point. But FDA’s proposed amendment has two substantive additions to the intended use regulation as well.
Addition #1. In the second sentence, FDA would add that objective intent can be inferred from “the design or composition” of the article. The sentence currently states: “The intent is determined by such persons’ expressions or may be shown by the circumstances surrounding the distribution of the article.” The revised sentence would include the phrase shown in italics: “The intent is determined by such persons’ expressions, the design or composition of the article, or may be shown by the circumstances surrounding the distribution of the article.”
This change is a significant departure from the historical focus of the intended use regulation on communications. The regulation has never before expressly specified that the physical attributes of an article may underlie an intended use determination. Significantly, the new language does not say that the design or composition will exclusively determine intended use. Nor does it say that the design or composition overrides a firm’s labeling or advertising in determining intended use. If the regulation were applied in that way, it could potentially be contrary to law.
For example, in Section 513(i)(1)(E) of the FDCA, FDA is required to limit the determination of intended use in premarket review to the proposed labeling. If FDA believes based upon a device’s design that an off-label is possible and could cause harm, it may require certain cautionary labeling statements. The agency may not require that the company obtain clearance or approval of the off‑label use.
Given the proposed new language, would FDA be authorized to infer solely from the design of the device once it is on the market that an off‑label use is intended? It seems likely that this application of the proposed new language would contradict Section 513(i)(1)(E), at least in the absence of communications from the firm promoting the off‑label intended use.
At a minimum, the proposed rule should be amended to clarify that it does not override Section 513(i)(1)(E). (Even if it is not amended, in a clash between the statute and the regulation, the former must prevail.) More fundamentally, the proposed rule should be amended to clarify that, with respect to drugs/devices that have a clearance or approval, only post‑market alterations to the design or composition may be considering whether the company has created an unapproved new intended use. If the design or composition has been cleared or approved after FDA’s premarket review, then the proposed rule should not authorize FDA to invoke the same design or composition as evidence of an unapproved new intended use. The current proposed language improperly authorizes FDA to do so.
Addition #2. FDA also proposes to add a proviso. The regulation currently states: “It [objective intent] 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 amendment would add: “provided, however, that a firm would not be regarded as intending an unapproved new use for an approved or cleared device based solely on that firm’s knowledge that such device was being prescribed or used by health care providers for such use.”
A couple of comments on the proviso.
First, the proviso should be extended to devices that are 510(k)‑exempt. There is no reason not to include them.
Second, this language moves the intended use regulation in the direction of recognizing the important distinction between (i) articles without any clearance or approval from FDA versus (ii) articles that have a clearance or approval from FDA but also may be put to additional unapproved uses in the practice of medicine. Under the current regulation as now in effect, in both scenarios (i) and (ii), FDA may consider the offeror’s knowledge of the use to which the article in the determination of intended use. In contrast, with the amended language, in scenario (ii), FDA could not rely “solely” on the seller’s knowledge of the off‑label use to determine intended use.
As argued here, FDA should be much more constrained in applying the intended use regulation in scenario (ii) (where an article has at least one cleared or approved use) versus scenario (i) (where an article has not been cleared or approved for any use). This proviso is a small step toward at least acknowledging the distinction. That is the silver lining.
At the same time, unfortunately, FDA’s proposed proviso is limited by “solely.” This word implies that knowledge of off‑label use could be an element in determining intended use in scenario (ii). That implication undermines the proposed deletion of the “knowledge” sentence and seemingly brings it back into play. It also creates obvious lack of clarity and open‑endedness about the role of knowledge of off-label use in this determination. This potential for greater uncertainty is quite ironic considering the amendment is touted as a “clarification” of the intended use regulation. The word “solely” should be struck from the proposal.
The preamble to the proposed rule (85 FR 59,718) has a summary of how FDA and the courts have historically determined intended use. Id. at 59,721‑724. It also has a number of examples of how FDA would apply the rule with the proposed amendments. Id. at 59,724-726. Finally, FDA argues that the regulation, both currently and once the proposed revisions are implemented, is consistent with the First Amendment. Id. at 59722.
There is little in the preamble that breaks new ground. It is an interesting question whether the courts should give deference to FDA’s legal arguments and examples of how the regulation might be applied, simply because they have now been incorporated into the preamble. Typically, a preamble is entitled to weight or deference from a court in explaining or interpreting ambiguous language in a regulation. But this regulation is not so much ambiguous as vague and open‑ended. It gives some notice of how FDA may evaluate statutory intended use, but it mainly notifies firms that almost any evidence may be used.
As FDA seems to acknowledge (id. at 59,723), the agency must still justify its position in any specific case. In this context, a legal justification or an example of how the regulation might be applied does not gain persuasiveness or authority just because it was anticipated in the preamble. The chief value of the preamble is in providing guidance to firms that seek as a practical matter to avoid FDA enforcement action. This guidance does not appear to resolve significant ambiguities in the regulation. Therefore, although the preamble is grossly self‑serving, it potentially may not have a great impact in specific cases.
On the whole, FDA’s proposed rule would do more to clarify intended use if the agency simply deleted the knowledge sentence. That would resolve a long‑standing contradiction between the regulation and the statutory scheme. The proposed add‑ons do not, on net, do not appear to add value and actually are likely to sow more confusion than they reap. FDA’s stubborn insistence on retaining maximum leeway in intended use continues unabated, even at the expense of greater clarity and certainty for industry.