The final rule purports to amend the codified regulatory text in significant respects. The final rule changes the language of the regulations in an extraordinarily consequential respect: It abandons the general rule that intended use means “objective intent,” which “is determined by” the manufacturer’s “expressions.” Under the revised regulations, intended use continues to mean “objective intent,” but such intent now “may be shown” by such expressions and many other types evidence. As a result, promotional claims — “expressions” — by the manufacturer are no longer the linchpin of intended use determinations.
According to the preamble accompanying the final rule, promotional claims are not required to establish a new intended use for a lawfully marketed product and FDA “may look to any relevant source of evidence, including a variety of direct and circumstantial evidence.”3 FDA does not discuss (or even acknowledge) all of the specific changes that the final rule makes to the codified regulations but rather asserts that the action merely aligns the regulations so that they “better reflect” the agency’s “current practices.”4
Under the amended regulations, FDA asserts that many activities long regarded as safe harbored, such as responses to unsolicited requests, are no longer categorically protected. Protections for manufacturers’ ability to share information about off-label uses under appropriate circumstances have been well established in the law and in FDA policy for decades and have been repeatedly affirmed by the agency in litigation briefs and other pronouncements. The final rule preamble identifies five “safe harbor” guidance documents describing circumstances in which manufacturers are permitted to disseminate information that is not directly taken from product labeling, including information about “off-label” uses:
- Communications consistent with FDA-approved labeling
- Payor communications
- Industry-supported scientific and educational activities
- Responses to unsolicited requests (draft)
- Distribution of scientific and medical publications (scientific or medical journal articles, scientific or medical reference texts, and clinical practice guidelines) (draft)5
Although the preamble asserts that nothing in the final rule reflects a change in these policies,6 it also states that FDA can point to safe-harbored communications as evidence of a new intended use. The preamble asserts that under FDA’s approach to intended use, these types of firm communications “ordinarily would not, on their own,” establish a firm’s intent that a lawfully marketed medical product be used for an unapproved use.7 But those communications would be relevant to the manufacturer’s intent that a medical product be used off-label.
The situation is even more complex with respect to responses to unsolicited requests and the dissemination of scientific and medical publications. The guidance documents relevant to these categories of communication are in draft and do not reflect current FDA policy. Indeed, FDA acknowledges the different status of communications undertaken in reliance on a draft safe harbor guidance, noting that a guidance reflects current agency policy only after it has been finalized.8
The final rule does not explicitly preclude reliance on knowledge as evidence of a new intended use. FDA began proceedings to amend the regulations in 2015, in response to an industry petition asking FDA to remove language ostensibly defining intended use with reference to a manufacturer’s knowledge that its drug or medical device was being used off-label.9 Under the final rule, a firm would not be regarded as intending an unapproved new use “based solely on that firm’s knowledge that such drug was being prescribed or used by health care providers for such use.” According to FDA, the word “solely” is used to convey that FDA does not intend to consider a firm’s knowledge of off-label use, by itself, as sufficient to establish intended use.10 That means a firm’s knowledge of off-label use can be used to establish a new intended use even if FDA has concluded that knowledge alone is insufficient. Thus, “relevant sources” of evidence “may include” a firm’s knowledge that a healthcare provider has used or prescribed the firm’s medical product for an unapproved use.11 Accordingly, although mere knowledge of off-label use, without more, is not sufficient to establish a new intended use, under the final rule such knowledge is relevant to intended use determinations.
The final rule reduces the level of clarity in the regulatory and enforcement scheme. The preamble asserts that the final rule is intended to provide “clarity and direction” regarding the types of evidence relevant to determining a product’s intended uses.12 In reality, the final rule purports to transform the regulatory definition of intended use from an objective standard based primarily on claims into a much broader and potentially standardless concept based on an unexplained notion of “relevance.” According to the codified text, “intended use” means “objective intent,” which “may be shown” by (1) “expressions,” such as “labeling claims, advertising matter, or oral or written statements,” (2) product “design or composition,” (3) “the circumstances surrounding ... distribution,” or (4) the circumstance that a manufacturer knew that its product was being “offered or used for a purpose for which it is neither labeled nor advertised.” FDA asserts that “determining a product’s intended use is a fact-specific inquiry” in which “FDA may consider all relevant sources of evidence,” which are not limited to the sources identified in the codified text.13 Beyond “relevance,” the preamble sheds no light on a governing principle applicable to intended use determinations. The preamble, instead, states that in fulfilling its mission to protect the public health, FDA will evaluate the “individual and unique circumstances of each case” in determining a product’s intended use.14 The preamble notes, further, that in some cases, “a single piece of evidence may be dispositive,” while in others, “several elements combined may establish a product’s intended use.”15
The final rule purports to amend foundational regulatory definitions in significant ways not adequately explained or even recognized by the corresponding preamble. Drug and medical device manufacturers should not rely on the usual regulatory intelligence procedures to evaluate the implications of the final rule for operational impacts. Instead, a cross-functional, senior team representing the key risk management functions of the organization, along with appropriate input from the medical and commercial functions, should consider the degree to which FDA’s approach to intended use potentially affects nonpromotional communications of the type that historically have been regarded as categorically permissible when conducted in accordance with recommendations set forth in FDA guidance documents and other policy statements. Companies that have relied on the safe-harbored status of particular activities to inform risk analyses should revisit those assessments in view of the final rule.
1 86 Fed. Reg. 41,383 (August 2, 2021), codified at 21 C.F.R. §§ 201.128 and 801.4.
2 21 U.S.C. § 352(f)(1). See also id. §§ 355(a), 351(f)(1)(B), 352(o).
3 86 Fed. Reg. at 41,386, 41,388. The preamble accompanying the final rule accurately notes that the knowledge prong of 21 C.F.R. §§ 201.128 and 801.4 has been removed and that those regulations now include a proviso under which “a firm would not be regarded as intending an unapproved new use ... based solely on that firm’s knowledge” of off-label use.
4 86 Fed. Reg. at 41,383, 41,384; see also id. at 41,390 (“[T]he amendments to the intended use regulations are intended to describe the types of evidence relevant to determining a product’s intended use based on FDA’s current practices”). The preamble states that the only change effected by the rule is the deletion of language defining intended use solely with reference to a manufacturer’s knowledge of off-label use. Id. at 41,391 (citing 82 Fed. Reg. 2,193, 2,207 (2017) (withdrawn final rule)). Moreover, FDA contends, the final rule would not “impose costs,” id. at 41,384, but would “reduce ... uncertainty” among regulated entities, id. at 41,400.
5 86 Fed. Reg. at 41,396 (citing 85 Fed. Reg. 59,718, 59,725)).
6 86 Fed. Reg. at 41,393.
7 Id.(emphasis added); see also id. at 41,396 (the final rule “does not reflect a change in FDA’s policies and practices regarding the types of firm communications that ordinarily would not, on their own, establish a new intended use”).
8 FDA has not directly addressed whether activities undertaken in accordance with a draft guidance will be accorded the same (albeit limited) protection as those undertaken in accordance with a final guidance (see 85 Fed. Reg. at 59,723 n.7 (describing even the draft guidances as “recognized”)).
9 80 Fed. Reg. 57,756 (Sept. 25, 2015); Citizen Petition from the Medical Information Working Group, Docket No. FDA-2013-P-1079 (Sept. 3, 2013).
10 86 Fed. Reg. at 41,397 (emphasis in original).
11 Id. (emphasis added); see also id. (“although the healthcare provider’s use is not under the firm’s control, what may be relevant to intended use is the firm’s knowledge that the article is being used by the healthcare provider”).
12 Id. at 41,384.
13 Id. at 41,397 (emphasis added); see also 82 Fed. Reg. at 2,207 (listing additional “relevant” sources of evidence, such as “consumer intent” and “evidence of claims that were never communicated to the public”).
14 86 Fed. Reg. at 41,387 n.3; see also 85 Fed. Reg. at 59,724 (same).
15 86 Fed. Reg. at 41,387 n.3; see also id. at 41,397 (“Each scenario described in the preamble is fact-specific, and, under other circumstances or in other contexts, similar material may be evaluated differently”); 85 Fed. Reg. at 59,724 (“Each scenario is fact-specific, and, under other circumstances or in other contexts, similar material may be evaluated differently”).