On September 1, 2021, the long-awaited U.S. Food and Drug Administration (“FDA”) final rule amending the medical product “intended use” regulations at 21 C.F.R. § 201.128 and 21 C.F.R. § 801.4 took effect. See 86 Fed. Reg. 41383 (Aug. 2, 2021). The final rule serves as a conclusion of a nearly six-year rulemaking odyssey aimed at answering the question: How does FDA determine a product’s intended use?
The intended use of a drug or medical device (collectively, “medical products”) has long been central to FDA’s regulatory oversight of medical product promotion. FDA clears and approves medical products for particular indications under certain intended use conditions. Manufacturers are generally prohibited from promoting, either directly or impliedly, the use of their medical product for uses other than those cleared or approved by FDA. The Federal Food, Drug, and Cosmetic Act of 1938 (“FDCA”) prohibits placing medical products into interstate commerce where labeling—defined broadly to include advertising and promotional materials—is “false or misleading in any particular,” designating medical products so labeled as “misbranded.” See 21 U.S.C. § 352(a).
Whether a manufacturer’s promotion of a medical product is for a use other than its cleared or approved intended use, generally termed “off-label promotion,” is based on the manufacturer’s objective intent as demonstrated “by labeling claims, advertising matter, or oral or written statements by” the manufacturer or its representatives. 86 Fed. Reg. at 41401. If FDA can demonstrate that a manufacturer is marketing a medical product for a new intended use, it is authorized to initiate enforcement action against the manufacturer for the distribution of misbranded product.
How We Got Here
Historically, as codified in 1976, the determination of a manufacturer’s objective intent to establish a new intended use and the attachment of an obligation to provide adequate labeling for such intended use could be based on its “mere knowledge” of off-label use:
[I]f a manufacturer knows, or has knowledge of facts that would give him notice, that a [medical product] 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 [medical product] which accords with such other uses to which the article is to be put. 41 Fed. Reg. 6911.
Based on this provision, manufacturers ran the risk of FDA enforcement based on mere knowledge of off-label use of their medical products, despite a lack of showing of the manufacturer’s objective intent. In 2015, FDA proposed the elimination of this provision and thus, the risk of enforcement based on mere knowledge. However, in 2017, FDA withdrew this proposed revision and instead issued a Final Rule (82 Fed. Reg. 2193 (Jan. 9, 2017) (2017 Final Rule)) replacing the mere knowledge standard with a new “totality of the evidence” standard to determine a medical product’s intended use.
The 2017 Final Rule was met with significant industry pushback, challenging the new, and arguably vague, standard on practical as well as constitutional grounds. Implementation of the 2017 Final Rule was twice delayed, and in September 2020, FDA issued a proposed rule (85 Fed. Reg. 59718 (Sept. 23, 2020) (2020 Proposed Rule)) withdrawing aspects of the 2017 Final Rule, eliminating both the historical “mere knowledge” standard as well as the unimplemented “totality of the evidence” standard, and attempting to clarify once-and-for-all the factors considerable by FDA in determining a medical product’s intended use. The heavily commented 2020 Proposed Rule was issued with minimal changes on August 2, 2021 (2021 Final Rule).
Four Key Issues
Despite the fact that the 2021 Final Rule represents no sweeping changes to FDA’s policy regarding medical products’intended use, there are several key takeaways to be gleaned, particularly from FDA’s extensive commentary contained in the rule’spreamble. Dominating our clients’ questions and concerns about the rule are the following four key issues.
1. Known Off-Label Use
Despite occasional enforcement discretion being exercised by FDA, the risk of enforcement action based on a manufacturer’s mere knowledge of off-label use of its medical products loomed based on the text of the intended use regulations. The 2021 Final Rule removes this provision, which arguably would have required manufacturers whose products are used off-label to either:
(1) continually update labeling based on known off-label uses; or
(2) implement certain activities to prevent the off-label use of their products by health care professionals in the practice of medicine in order to avoid new labeling obligations.
In removing this provision, FDA clarified that knowledge of off-label use alone does not create a new intended use. The 2021 Final Rule provides, in part: “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.” 21 C.F.R. § 201.128; see also 21 C.F.R. § 801.4 for medical device corollary.
This provision creates some assurance that, provided that a manufacturer does not proactively encourage or facilitate off-label product use, knowledge alone of the product’s off-label use will not draw FDA enforcement. Note however that, while mere knowledge of an unapproved use cannot, standing alone, constitute evidence of a new intended use, FDA may still consider such knowledge, along with other factors, as evidence of a new intended use. See 86 Fed. Reg. at 41397.
“What other factors,” you may ask…
2. “Any Relevant Source”
Industry has long lobbied for the exclusive use of a manufacturer’s advertising and promotional claims about its product as the basis for establishing a new intended use or FDA enforcement action for misbranding of product. To that end, the 2021 Final Rule landed with a disappointing *thud* for many. Replacing the “mere knowledge” and “totality of evidence” standards as the focus of industry’s ire may well be the 2021 Final Rule’s “any relevant source” provision.
FDA clarifies in the 2021 Final Rule—most notably in response to commenters’ challenges of FDA’s authority to evaluate factors other than manufacturers’ own promotional claims—that “intended use of a product may be determined from its label, accompanying labeling, promotional material, advertising, and any other relevant source.” 86 Fed. Reg. at 41386. (emphasis added). Of particular note, 21 C.F.R. § 201.128 and 21 C.F.R. § 801.4, as amended, includes “the design or composition of the [product and] the circumstances surrounding the distribution of the [product]” in its determination of a manufacturer’s objective intent.
This change appears to make clear that the design of a product in a way that encourages or facilitates a new intended use, or business practices in the distribution of a product that encourage or facilitate a new intended use, may be applicable to FDA’s analysis of whether a medical product has a new intended use. This statement is critical to manufacturers in evaluating and mitigating risk associated with actual or potential off-label use and makes clear that FDA may evaluate nearly any evidence relevant to a product’s promotion or distribution in evaluating a product’s intended use.
3. Safe Harbors
In addition to industry’s pleas that FDA limit the scope of its evaluation of products’ intended use to manufacturers’ promotional and advertising claims, industry has fervently pushed for FDA’s formal, codified adoption of “safe harbor” communications (some of which FDA has acknowledged and addressed in sub-regulatory guidance (see, e.g., FDA Guidance for Industry, “Medical Product Communications that Are Consistent with the FDA-Required Labeling – Questions and Answers” (June 2018)).
In particular, industry has argued that communications amounting to medical or scientific exchange of information should be excluded from FDA’s analysis of a medical product’s intended use. In response to commenters in the 2021 Final Rule’s preamble, FDA declined to exclude such communications, to the extent such communications with health care professionals relate to investigational or otherwise off-label use, as safe harbors to its intended use analyses, deeming that to be action outside of the scope of this rulemaking.
While FDA states that it will continue to accept comments on and consider this topic, FDA specifically addressed the possibility of a scientific exchange safe harbor to be used to perverse effect: “the Agency notes that if all scientific exchange were excluded from determinations of intended use, companies might have an incentive to create and promote new intended uses for marketed products based on incomplete or otherwise flawed data.” 86 Fed. Reg. at 41396.
As a result, while FDA does not disturb the acknowledged safe harbors it addresses in guidance, industry may not rely on a codified safe harbor removing scientific exchange communication from FDA’s analysis of a medical product’s intended use.
4. Constitutional Considerations
Finally, in the 2021 Final Rule’s preamble, FDA addressed industry stakeholders’ numerous and vehement constitutional challenges to the proposed rule. The comments and responses preview the potential arguments of future legal challenges to the 2021 Final Rule.
Most notably, industry challenges the 2021 Final Rule on First Amendment grounds, arguing that it is suspect under First Amendment jurisprudence based on its regulation of truthful and non-misleading speech. See, e.g., U.S. v. Caronia, 703 F.3d 149 (2012). FDA’s stance is that the First Amendment is not implicated by the 2021 Final Rule because the intended use regulations do not directly regulate speech – they merely “describe evidence that may be relevant to establishing intended use[.]” 82 Fed. Reg. at 41391.
Citing the Supreme Court’s opinion in Rumsfeld v. Forum for Academic and Institutional Rights, FDA argues that “it has never been deemed an abridgment of freedom of speech . . . to make a course of conduct illegal merely because the conduct was in part initiated, evidenced, or carried out by means of language, either spoken, written, or printed” (547 U.S. 47, 62 (2006)) and goes on to say that “the First Amendment does not prevent restrictions directed at commerce or conduct from imposing incidental burdens on speech.” 86 Fed. Reg. at 41392, citing Barr v. Am. Ass’n of Political Consultants, 140 S. Ct. 2335, 2347 (2020).
While FDA attempts to close the door on First Amendment challenges, its response appears to leave the door open to future challenge of intended use regulation’s enforcement being more restrictive than necessary to protect the Agency’s governmental interest. See Central Hudson Gas & Elec. Corp. v. Pub. Serv. Comm’n of New York, 447 U.S. 557, 566 (1980).
Industry commenters also raised the Fifth Amendment due process issues implicated by the 2021 Final Rule, arguing that it is impermissibly vague and lacks adequate specificity in clarifying the boundaries between permissible and impermissible communications. FDA cites to courts’ repeated rejection of due process challenges to the FDCA as unconstitutionally vague or ambiguous and states that “[o]ver nearly seven decades, medical product manufacturers have shown little difficulty in understanding how the regulations are applied.” 82 Fed. Reg. 41395.
In so arguing, FDA acknowledges that, while ‘laws must give a “person of ordinary intelligence a reasonable opportunity to know what is prohibited,’ ‘meticulous specificity’ is not required.” Id., citing Grayned v. City of Rockford, 408 U.S. 104, 110 (1972). If effective in defending a Fifth Amendment due process challenge, FDA’s statements stand to support its broad exercise of enforcement discretion in evaluating manufacturers’ objective intent and levying enforcement actions for the establishment of a new intended use.
Having traveled this nearly six-years-long (and winding) road (hat-tip to Lennon and McCartney), what is a manufacturer’s takeaway?
The 2021 Final Rule certainly stands to disappoint those desiring additional clarity on specific, permissible activity regarding the development and commercialization of a medical product. While FDA has made clear that mere knowledge of a medical products’ off-label use will not be, used alone, evidence of a new intended use, the other types of evidence applicable to FDA’s analysis appear to have grown to encompass a universe of anything-that-is-relevant.
As a result, FDA continues to construe the assessment of a product’s intended use broadly, and manufacturers—particularly those who, despite careful curtailing of their advertising and promotional speech, were hoping to rely on implied or inferred uses of their product—should consider themselves on notice. And while we do not consider the constitutional challenges to be definitively resolved in the same way that FDA does, the time and cost associated with such legal challenges will continue to preclude most manufacturers from inviting FDA’s scrutiny.
Therefore, in evaluating its business practices regarding its medical products – from R&D to postmarket promotional activities – a manufacturer should be mindful of the evidence of its objective intent to establish a new intended use it may be creating and the resultant FDA enforcement implications.
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