FDA Issues Proposed Rule Seeking to Clarify Evidence Relevant to Its Intended Use Determinations of FDA-Regulated Products

Footnotes for this article are available at the end of this page.

On September 23, 2020, the U.S. Food and Drug Administration (FDA) published in the Federal Register a proposed rule titled, “Regulations Regarding ‘Intended Uses.’” The goal of this proposed  rule is to amend the regulations defining “intended use” – for drugs and medical devices to provide better clarity regarding the specific types of evidence the agency may rely on when making a determination about the intended use of these FDA-regulated products.

“Intended Use” is a fundamental concept in the Federal Food, Drug, and Cosmetic Act (the “Act”), FDA regulations, and food and drug case law. Intended use determines whether a product is regulated as a drug or device, and has significant implications for how drug and device manufacturers communicate about and promote their products. Evidence that a firm intends its approved product for unapproved uses (often referred to as off-label promotion) can result in substantial criminal and civil penalties. The current action is the latest attempt by FDA to bring much needed clarity to regulations that are essential to how it regulates various products under its jurisdiction.

Background to the Currently Proposed Rule on Intended Use

In a proposed rule published in September 2015, which was primarily intended to address when tobacco products would be regulated as drugs, devices, or combination products, FDA announced that, in an effort to bring clarity to the matter, it was seeking to modify regulatory language describing how it determined the intended use of a medical product. Among other things, the proposed rule called for striking the last sentence from the intended use regulations of both drugs and devices which each conveyed that, if a manufacturer knows or has notice that its approved drug or device is used for unapproved uses, the manufacturer must provide adequate labeling for that use (the “knowledge sentence”). The final rule, published by FDA on January 2017, however, made an unexpected and significant second change to the previously mentioned regulations regarding intended use.

Although the “knowledge sentence” had been in the regulations for a long time, it had not been FDA’s policy to enforce it. Were FDA to enforce this provision, whenever a manufacturer knew its drug or device was prescribed or used off-label, the manufacturer would be required to include directions for that use in the product’s labeling, and the labeling would need to be FDA-approved. In the rulemaking, FDA stated that, absent extraordinary circumstances, the agency would not regard a firm as intending an unapproved use based solely on the firm’s knowledge that a product is prescribed or used off-label. Industry had expressed concerns about this “manufacturer’s knowledge” provision for many years, and FDA responded by making the regulation consistent with agency policy.

The second change to the regulations, however, was more controversial. FDA added a new last sentence to the final rule that was not in the original proposed rule, stating that, if the totality of the evidence establishes that a manufacturer intends a drug or device to be used for an unapproved use, the manufacturer is required to provide labeling for that use. FDA stated that it was codifying the agency’s longstanding position that, in determining a product’s intended use, FDA may look to any relevant source of evidence.

Regulated industry was concerned, however, that the “totality of the evidence” language expanded the types of evidence that could be considered in determining intended use. Several comments, and a Citizen Petition filed by several industry organizations, cited various legal concerns with the final rule and requested FDA to reconsider and indefinitely stay it. In addition to these legal concerns, several comments asserted that the final rule could have potentially negative health implications. The “totality of the evidence” standard would permit FDA to rely on non-promotional scientific exchange (e.g., company responses to unsolicited requests for information about unapproved uses, sponsorship of continuing medical education and other scientific or educational activities, dissemination of medical journals and scientific or medical reference publications) as evidence of intended use, thus chilling important communications between manufacturers and patients, healthcare professionals, and payors.

Accordingly, FDA delayed the effective date of the rule first until March 21, 2017, and, then again, until March 19, 2018.3  Then, on March 16, 2018, FDA, stating that it needed time to allow for additional consideration of substantive issues raised by comments to the final rule, delayed the implementation date of these specific, controversial aspects of the final rule indefinitely.4   If finalized, this rule would supersede the unimplemented proposals of prior rules on the matter.

Currently Proposed Rule on Intended Use

In a press release regarding the currently proposed rule on intended use, FDA Commissioner Stephen Hahn, M.D. pointed out that the actions being proposed “do not reflect a change in the FDA’s policies and practices” concerning the way the agency determines the intended use of a medical product, but rather are intended to “clarify the regulatory language describing the types of evidence [the FDA] considers relevant to determining a product’s intended use.” Importantly, Commissioner Hahn also noted that the proposed rule is also intended to “clarify an important point: 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 the products intended use.” Included in the actions intended to accomplish this, the proposed rule specifically:

  • deletes the last sentence from the intended use regulations for both drugs (21 C.F.R. § 201.128) and devices (21 C.F.R. § 801.4);
  • inserts a new clause in the intended use regulations for both drugs (21 C.F.R. § 201.128) and devices (21 C.F.R. § 801.4) stating: “provided, however, that a firm would not be regarded as intending an unapproved new use for an [approved drug / approved or cleared device] based solely on that firm’s knowledge that such [drug / device] was being prescribed or used by health care providers for such use.”; and
  • adds language to the intended use regulation for both drugs and devices to include “the design or composition of the article” as possible evidence of the responsible party’s intended use of the article.5

Additionally, the preamble to the proposed rule provides the types of evidence (including examples) the agency believes are relevant to determining a firm’s intended use of its product(s), as well as examples of evidence that, by itself, FDA believes would not be sufficient to determine a product’s intended use. The types of evidence that the agency believes would be relevant in determining a product’s intended use include:

  • express and implied claims about the product that are attributable to the responsible firm;
  • product characteristics, such as medical or recreational physiologic effects for which the product is unapproved;
  • product design or technical features, such as a device that includes software with a function or purpose not associated with an approved use of the device; and
  • circumstances of the sale or distribution of the product, such as a firm’s repeated and proactive detailing to a health care provider whose patient population does not fall within the product’s approved population.

Examples provided in the preamble of evidence that, by itself, would not be sufficient to determine a product’s intended use include:

  • as discussed previously, 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 (e.g., internal sales projections that include sales of the product for an unapproved use);
  • knowledge in combination with conduct that falls within an acknowledged FDA “safe harbor” (e.g., firm notes that one of its’ products, approved for adults, is being ordered by pediatric medical practices; firm distributes clinical practice guidelines, that recommend pediatric use, at medical conferences following all recommendations in the revised draft guidance “Distributing Scientific & Medical Publications on Unapproved New Uses – Recommended Practices.”);
  • certain instances when a firm, to minimize risk to patients, shares with health care providers safety and warning information about unapproved uses of it product;
  • information contained in required corporate submissions to the Securities and Exchange Commission; and
  • a ‘factual, balanced, and complete’ summary of clinical trial results that provides the summary solely to clinical trial participants; the summary includes relevant safety information and limitations of the study, but no conclusions about the safety or effectiveness of the unapproved product or unapproved use.
AGG Observations and Advice
  • We believe that FDA has tried to strike a happy medium in this proposed rule. On the one hand, industry should be pleased that (1) the original “knowledge” sentence has been removed from the codified language, and (2) the agency rejected the prior administration’s proposal to add a “totality of the evidence” test [although some might argue, that the preamble discussion stating that “any relevant source of evidence may be considered,” and the several types of evidence FDA will consider in determining intended use, is tantamount to the “totality of the evidence” standard]. On the other hand, FDA rejected the contentions that the agency should rely exclusively on firms’ claims to establish intended use, and rejected the argument that the 2017 rule could restrict dissemination of truthful and non-misleading information thereby raising First Amendment concerns.
  • Industry should keep in mind that, although knowledge alone, or in the context of an FDA “safe harbor,” would not be determinative of intended use, that “in some cases, knowledge that a product was being prescribed or used by health care providers for an unapproved use could be considered relevant to establishing a new intended use where there is additional evidence of intended use.”
  • It is interesting to note that, rather than adding additional language to the codified regulation, FDA chose to clarify the types of evidence relevant to establishing intended use in the preamble to the proposed rule. The preamble discussion is helpful to industry by providing detailed guidance and several helpful examples, however, it does not have the force and effect of the codified language.
  • As previously stated, FDA rejected comments submitted during the rulemaking regarding First Amendment considerations relating to how a product’s intended use is established.  However, surprisingly, FDA seemed to go much further in its’ First Amendment analysis by stating that (1) the government’s reliance on speech as evidence of intended use under the FD&C Act does not violate the First Amendment (citing to Wisconsin v. Mitchell, 508 U.S. 476, 489 (1993), a case relied on by the government in several First Amendment challenges brought during prior administrations), (2) the decision in United States v. Caronia, 703 F.3d 149 (2d Cir.2012), “left open the government’s ability to prove misbranding on a theory that promotional speech provides evidence that a drug is intended for a use that is not included on the drug’s FDA-approved label”. (citing to United States ex rel. Polansky v. Pfizer, Inc., 822 F.3d 613 n.2 (2d Cir. 2016), and (3) “Courts have long upheld the premarket review requirements of the FD&C Act and the PHS Act, and the role of intended use within that framework, as necessary to promote and protect the public health and as fully consistent with the First Amendment.”

FDA-regulated industry should carefully consider the implications presented by FDA’s current proposed rule regarding both the drug and device regulations relating to the intended use those products. Unless FDA grants an extension, comments on the proposed rule must be submitted to the agency by October 23, 2020.


[1] 85 Fed. Reg. 59718

[2] See: 21 C.F.R. Sec. 201.128 Meaning of “intended uses” and 21 C.F.R. Sec. 801.4 Meaning of intended uses.

[3] See, respectively: https://www.govinfo.gov/content/pkg/FR-2017-02-07/pdf/2017-02485.pdf and https://www.govinfo.gov/content/pkg/FR-2017-03-20/pdf/2017-05526.pdf

[4] See: https://www.govinfo.gov/content/pkg/FR-2018-03-16/pdf/2018-05347.pdf

[5] The proposed rule also adds to the intended use regulation for both drug and devices a reference to 21 C.F.R. § 1100.5.  This is for the purpose of clarifying the interplay between the medical product intended use regulations and the intended use regulation for tobacco, which describes when a product made or derived from tobacco that is intended for human consumption will be subject to regulation as a drug, device, or combination product.