On September 23, the U.S. Food and Drug Administration (FDA) published a proposed rule to modify its intended use regulations to clarify the types of evidence FDA will consider when determining the “intended use” of a medical device, drug, or combination product. The proposed rule’s preamble says that certain types of evidence, standing alone, are not dispositive of intended use, while reserving the ability to look to other relevant sources of evidence that might inform a product’s intended use. This is consistent with FDA’s longstanding practice and with the agency’s January 2017 final rule, which we summarized here. FDA delayed the effective date of that final rule due to concerns expressed by industry stakeholders over the regulation’s requirements around whether a manufacturer is required to update labeling if it has knowledge of unapproved, or “off label” use, leaving in effect text indicating that such knowledge does trigger this manufacturer responsibility.

Proposed revisions to the intended use regulations

The intended use of a product, as interpreted by FDA under the regulations in 21 C.F.R. §§ 801.4 (covering devices) and 201.128 (covering drugs), determines whether that product meets the statutory definition of a device or a drug, or whether it is being marketed for a use that exceeds its existing clearance or approval. FDA says the proposed rule aims to eliminate longstanding confusion created by the view that the last sentences of 21 CFR §§ 201.128 and 801.4 indicate that a manufacturer’s mere knowledge of an unapproved use of its approved product automatically triggers a requirement for updated labeling. The proposed rule clarifies that while knowledge is one element FDA may consider in determining a product’s intended use, this knowledge alone on the part of a manufacturer does not render illegal the distribution of that approved product based on current labeling.

Toward this end, FDA has proposed to delete the last sentences of 21 CFR §§ 201.128 and 801.4, which currently state:

“But if a manufacturer knows, or has knowledge of facts that would give him notice, that a [drug or 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 [drug or device] which accords with such other uses to which the article is to be put.” (Emphasis added).

The deleted sentence, which had previously been modified by the 2017 final rule that was never implemented, would now be replaced with a new clause in the regulations to qualify that a manufacturer’s objective intent and corresponding responsibilities with respect to labeling will not be determined solely based on knowledge:

“provided, however, that a firm would not be regarded as intending an unapproved new use for an [approved or cleared] [drug or device] based solely on that firm's knowledge that such [drug or device] was being prescribed or used by health care providers for such use.”

The proposed rule also sets forth a few other changes to the text of the intended use regulations “to clarify and reinforce that intended use can be based on any relevant source of evidence, including a variety of direct and circumstantial evidence.” For example, the proposed regulation would specifically state that intent may be shown by “the design or composition of the article.” In addition, as in the stalled 2017 final rule, the proposed rule would insert into CFR §§ 201.128 and 801.4 a reference to § 1100.5, which states:

“If a product made or derived from tobacco that is intended for human consumption is intended for use for any of the purposes described in paragraph (a) or (b) of this section, the product is not a tobacco product as defined in section 201(rr) of the Federal Food, Drug, and Cosmetic Act and will be subject to regulation as a drug, device, or combination product.”

The preamble to the proposed rule also addresses, at length, stakeholders’ concerns that the agency’s approach to determining “intended use” could implicate the First Amendment, stressing that this is not the case.

Any relevant source of evidence may be considered to establish “intended use”

The proposed rule maintains FDA's longstanding position that, in evaluating a product's intended use, “any relevant source of evidence” may be considered (See, e.g., proposed rule at 59721), including “a variety of direct and circumstantial evidence.” This includes, but is not limited to “express claims and representations” such as labeling claims and representations, advertising matter, and oral or written statements by persons responsible for the labeling. In addition to these express claims, the following may be evidence relevant to establishing “intended use”:

• Any claim made by or on behalf of a firm that implicitly represents a product for a particular use is also relevant to intended use, including:

  • suggestive product names, such as “e-Cialis,”

  • statements implying an intended use, such as “For best results use approximately 30-45 minutes prior to engaging in sexual intercourse,” and

  • representations that a product contains a particular ingredient to imply a physiological effect, such as inclusion of the word “aspirin”;

• Characteristics of the product and its design, including:

  • the known use (recreational or medical) of a product that is unapproved for any medical use, such as 2,4-Dinitrophenol being used for weight loss,

  • the known physiological effects (medical or recreational) of a product that is unapproved for any medical use, or

  • a stent that is specifically sized for a use that differs from the purported use (e.g., to allow use in a different anatomical area than that for which it was cleared/approved); and

• Circumstances surrounding the distribution of the product and the context in which it is sold, including:

  • To whom and for whom the products are offered, such as a firm's repeated proactive detailing and delivery of large amounts of complimentary product samples to a health care provider whose patient population does not fall within the product's approved population, and

  • Context surrounding the sale, such as the repackaging of bulk product into smaller plastic bags and using personal (not business) emails and addresses for communications and deliveries.

Types of evidence that are not dispositive of “intended use”

In the proposed rule, FDA describes several examples of evidence that, standing alone, are not determinative of intended use. The proposed rule emphasizes multiple times that “a firm will not be regarded as intending an unapproved use of an approved product based solely on that firm’s knowledge that the product is being prescribed or used by health care providers for such use.” This underscores the agency’s stated desire to refrain from interference with the professional judgment of health care providers in prescribing legally marketed medical products for unapproved uses for individual patients.

In addition, the proposed rule provides a non-exhaustive list of types of evidence which, standing alone, are not determinative of intended use:

• Dissemination of safety information by a firm to health care providers about an unapproved use to minimize risk to patients;

• A firm's official social media account “following” – without commenting on or otherwise endorsing – the social media account of a non-profit entity supporting patients with a condition for which the firm is currently investigating an approved product;

• An internal document reflecting potential sales for an unapproved use that is widely recognized as the standard of care;

• Corporate filings or SEC submissions that include required disclosures of development activities or potential or actual sales for an unapproved use; and

• Clinical trial summary information, provided solely to participants, that includes a conspicuous and prominent statement that the product or use has not been approved, cleared, or licensed by FDA.

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In a statement announcing the proposal, FDA Commissioner Stephen M. Hahn, M.D., said that it does “not reflect a change” in policies and practices; however, given the centrality of “intended use” to FDA’s regulation of medical products, this proposed rule merits close review by manufacturers.

Comment on the proposed rule will be accepted until October 23. 

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