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FDA Increasingly Active in ‘Off-Label’ Space Despite Patchwork Regulatory Scheme
Tuesday, January 16, 2024

The U.S. Food and Drug Administration (FDA) has demonstrated increased interest in “off-label” communications in recent years. Together with uncertainty following recent FDA guidance changes and the agency’s increasingly broad discretion, this growing interest means greater regulatory risk for firms.

Go-To Guide:
  • FDA continues growing its interests in “off-label” communications.
  • Coupled with FDA’s expansive definition of “intended use,” recent guidance developments offer FDA significant discretion and pose a heightened regulatory risk for firms. 
  • In October 2023, FDA released “Revised Draft Guidance on Communications to Health Care Providers of Scientific Information on Unapproved Uses of Approved or Cleared Medical Products,” introducing uncertainty for firms.
  • FDA has become more aggressive in its enforcement of “off-label” communications related to its 2018 CFL (“consistent with the FDA-required labeling”) Guidance.
  • Constitutional challenges to FDA regulation of speech may become more difficult following the First Circuit’s recent ruling against former company executives.

FDA Discretion and Attention to ‘Off-Label’ Communications

Pursuant to the Food, Drug, and Cosmetic Act (FD&C Act), FDA regulates drugs and devices based on their “intended use.”1 Therefore, medical products intended or marketed for an unapproved or uncleared use (that is, “off-label use”) violate the FD&C Act. In 2021, FDA expanded its definition of “intended use” and broadened the types of evidence it can consider when determining a new intended or “off-label” use. Following the 2021 guidance, FDA considers “any relevant source of evidence” to establish intended use, including marketing and other communication materials.2 In 2018, FDA issued final “Medical Product Communications That Are Consistent With the FDA-Required Labeling” (the “CFL Guidance”) on medical product communications consistent with FDA labeling requirements but not contained in the FDA-required labeling. While this guidance is not new, since 2021, FDA has grown more aggressive in enforcing CFL-related drug efficacy claims that are inconsistent with labeling.

SIUU Communications Guidance Signals New Chapter of FDA Enforcement

Superseding and revising FDA’s 2014 draft guidance titled “Distributing Scientific and Medical Publications on Unapproved New Uses – Recommended Practices,” in October 2023 FDA announced revised draft guidance on communications from firms to health care providers (HCPs) regarding scientific information on unapproved uses (SIUU) of approved or cleared medical products (“revised draft SIUU Communications Guidance”), which made several significant changes that potentially grant FDA still more discretion and introduce greater uncertainty for firms. Because the revised draft SIUU Communications Guidance remains in draft form, there are few case study models. However, if the increased enforcement of the CFL Guidance is any indication of how FDA might approach the enforcement of a final SIUU Communications Guidance, industry should anticipate increased FDA enforcement action and should conduct risk assessments of all off-label communications and related compliance programs. Further, recent judicial rulings may make challenging FDA regulation of truthful, non-misleading “off-label” communications even more difficult.

Scientifically Sound and Clinically Relevant (SSCR)

According to the revised draft SIUU Communications Guidance, SIUU communications should be based on scientifically sound and clinically relevant information. This evidentiary standard differs from previous versions of the guidance, which used the longstanding “adequate and well-controlled studies” standard. “Scientifically Sound” means “the studies or analyses, at a minimum, should meet generally accepted design and other methodological standards for the particular type of study or analyses performed, taking into account established scientific principles and existing scientific knowledge.” “Clinically Relevant” means the information provided is “pertinent to HCPs engaged in making clinical practice decisions for the care of an individual patient.”

While this may be a more flexible standard, the standard remains ambiguous and affords FDA considerable discretion in its implementation and enforcement of the standard (discretion FDA could potentially exercise restrictively). In turn, significant uncertainty for firms remains, as it is unclear how FDA will interpret and enforce its guidance. Indeed, instead of providing precise definitions, FDA offers examples of what is “likely” and “unlikely” to satisfy the standard. Randomized, double-blind, concurrently controlled superiority trials are most likely to satisfy this standard, but “other well-designed and well-conducted trials” may also satisfy the standard. Moreover, the revised draft SIUU Communications Guidance, in contrast with the 2014 draft guidance, acknowledges real-world data but fails to provide actionable information about whether real-world data complies with this standard, stating that “[r]eal-world data and associated real-world evidence about medical products may be scientifically sound and clinically relevant depending on the characteristics of the data and the nature of the analyses.”

In addition to this ambiguity, the revised draft SIUU Communications Guidance likewise fails to define what does not satisfy the standard. Instead, it provides several examples of types of data that would not satisfy the standard (e.g., studies without an adequate comparison or control group, isolated case reports, reports that lack enough detail to permit scientific evaluation, communications that distort studies or include fraudulent data, and studies with weaknesses in study design) and data “unlikely” to be clinically relevant (e.g., scientific data generated in early stages of medical product development). FDA also notes that the SSCR status of a study can change, as a study may become no longer clinically relevant due to subsequent research questioning the reliability of the study’s data.

Expanded Communication Categories

The revised draft SIUU Communications Guidance also expands communication categories, adding (1) materials from independent clinical practice resources and (2) firm-generated presentations of scientific information from an accompanying published reprint. These materials should use plain language; include within the firm-generated presentation all information material to any representations; and have the full underlying reprint accompany the firm-generated presentation.

Coupled with significant new disclosure requirements, the ambiguous SSCR standard for firm-generated presentations may cause firms to pause before using these communications. Further, FDA has not oriented these communications on the scientific exchange-promotion spectrum. FDA did not mention scientific exchange, which is itself poorly defined, in the revised draft SIUU Communications Guidance, indicating that FDA considers it outside the scope of the guidance. However, as evidenced by the recommendations to segregate promotional material and SIUU communications (discussed below), FDA also seems to consider these communications distinct from promotional material. Hence, it is unclear how FDA will categorize these communications.

Communication Channels

FDA acknowledges that digital and online platforms as well as commercial exhibit halls are appropriate channels for communication with HCPs. The revised draft SIUU Communications Guidance provides that SIUU communications may be shared through media and platforms that enable the disclosures provided for in the guidance. Therefore, character-space-limited or other presentational-limited platforms should generally be avoided.

However, SIUU communications should not use “Persuasive Marketing Techniques,” such as celebrity endorsements, premium offers, and gifts, which “suggest[] an improper intent to market the relevant products for unapproved uses.” The precise scope of this prohibition remains unclear, in part because FDA has yet to define where SIUU communications fall on the scientific exchange-promotion spectrum and in part because FDA has yet to define who may present such information (e.g., medical personnel and/or sales and marketing representatives—express references to which were removed from the 2014 guidance). Therefore, it is unclear whether the revised draft SIUU Communications Guidance states that SIUU communications can come from both sales and marketing personnel and medical personnel or medical personnel only. FDA’s removal of any explicit references to sales and marketing personnel could evidence the former or the latter. As evidence of the latter possibility, FDA recommends SIUU information presentations be separate from promotional communications. Thus, FDA may view sales and marketing personnel as a promotional channel but not medical personnel. On the other hand, FDA may be indifferent about who disseminates the SIUU communication provided SIUU communications are delivered separately from promotional communications. Thus, uncertainty remains, and there is risk associated with using sales and marketing personnel to disseminate SIUU communications.

FDA Focus on CFL Enforcement

The revised draft SIUU Communications Guidance is not FDA’s only activity in the “off-label” space. FDA has also increased attention in the CFL space. In 2018, the FDA issued final guidance titled “Medical Product Communications That Are Consistent With the FDA-Required Labeling” (the “CFL Guidance”) on medical product communications that are consistent with FDA labeling requirements but that are not contained in FDA-required labeling. While clarifying that communications with information not contained in FDA-required labeling did not alone constitute “off-label,” the CFL Guidance provided a three-factor test for determining whether a communication was consistent with FDA-required labeling as well as an evidentiary standard for sources of support for claims made in such communications (the “Scientifically Appropriate and Statistically Sound” or “SASS” Standard).

The CFL Guidance left much to interpretation and, like the revised draft SIUU Communications Guidance, introduced uncertainty for firms. Regarding the SASS standard, the amount and type of evidence required remains a fact-specific inquiry that depends on the topic addressed by the communication; thus, there is considerable nuance when determining whether the standard is satisfied. Further, to date, it is unclear whether and to what extent real-world evidence can be used in communications and whether it complies with the SASS standard. FDA has found that real-world evidence is reliable when (1) used as natural history data and (2) supportive of efficacy. However, due to a dearth of details from FDA, industry generally must look to case studies to see how FDA has approached real-world evidence historically. For example, FDA found that, while not substantial alone, Pfizer’s use of real-world data from electronic health records and pharmacy claims data in its supplemental NDA for use of Ibrance in male breast cancer was supportive of its claims. In contrast, FDA found that a company’s use of data from an expanded access protocol enabling a broader indication than the clinical trial submitted for its radiopharmaceutical product was not supportive of its claims.

Recent Enforcement Trends

While the CFL Guidance is not new and uncertainties remain, FDA’s Office of Prescription Drug Promotion (OPDP) has become increasingly aggressive in its enforcement of alleged inconsistent communications. In fact, OPDP has issued five CFL letters since 2021, including two related to CFL in 2023 alone. Letters addressing efficacy included letters to:

  • A company regarding alleged inconsistent efficacy claims in sales aids for its inhaler product that purported to positively impact all-cause mortality and reduce risk of death when FDA stated the trial data did not support such claims.
  • A company regarding alleged misleading claims about findings of two clinical studies of its product for high cortisol, including claims FDA stated minimized serious risks.
  • A company regarding alleged efficacy overstatements in a brochure for a contraceptive gel product.
  • A company regarding a television advertisement for its product to treat depression.

However, there has been only one letter regarding promotional materials deemed scientifically unsound—purportedly sent to Althera Pharmaceuticals regarding its cholesterol drug, Roszet, where a firm-to-doctor communication claimed a reduction in cholesterol levels based on two unrelated studies.

Challenges Based on Constitutional Arguments

Industry has long challenged FDA’s regulation of truthful, non-misleading speech—speech subject to First and Fifth Amendment protection—on constitutional grounds. According to the revised draft SIUU Communications Guidance, if a firm communicates information to HCPs consistent with the guidance, FDA does not intend to use such communications, standing alone, as evidence of a new intended use. This “standing alone” language differs from the 2014 guidance and suggests that an SIUU communication, with other evidence, may be used as evidence of a new intended use. Similarly, in FDA’s CFL Guidance, FDA noted it does not intend to rely on consistent communications to establish a new intended use. However, FDA included a caveat: “product communications that are consistent with the FDA-required labeling may be part of the overall material that is evaluated in assessing the firm’s conduct.” The inclusion of the “standing alone” or equivalent language in these guidances still allows FDA to consider such communications when establishing a new intended use, broadly defined to include any relevant source including labeling, promotional claims, or advertising, if there is any other evidence of off-label intended use. This may temper firms’ use of certain communications and introduce regulatory risk.

To exacerbate matters, industry may face more difficulty in making constitutional arguments against this type of speech regulation following the First Circuit’s affirmation of former company executives’ 2016 convictions of misdemeanor adulteration and misbranding charges for their involvement in the off-label promotion of a purported steroid delivery device when the device was only cleared as a saline-eluting sinus spacer. The court, relying heavily on the Supreme Court’s Wisconsin v. Mitchell decision, reiterated that FDA can use truthful, non-misleading speech as evidence of an off-label intended use. Moreover, the court affirmed that intended use can be established using “any relevant source” of evidence. While the defendants may seek Supreme Court review and, hence, the full impact of the First Circuit’s holding is uncertain, the ruling, if upheld, is likely to pose challenges to future constitutional arguments against FDA regulation of truthful, non-misleading speech.

Ongoing and Future FDA Enforcement Trends

In the coming months, firms should anticipate FDA’s publication of final SIUU Communications Guidance and increased enforcement of that guidance alongside growing enforcement of the CFL Guidance. Firms should also monitor judicial developments, including the First Circuit’s ruling that is likely to be appealed to the Supreme Court. In the meantime, however, firms should carefully review their compliance programs and communications using the current guidance versions and determine their appetite for risk. Firms should review the revised draft SIUU Communications Guidance and determine what ways they wish to utilize firm-generated presentations, if at all, given the risk associated with the categorization of such communications as scientific exchange or promotional material. Moreover, firms should carefully consider who delivers the SIUU communications—medical personnel, sales and marketing personnel, or both, understanding that this ambiguity as to categorization coupled with the requirement that promotional material be segregated heightens the risk associated with having sales and marketing personnel disseminate these types of communications. Some firms, after conducting a risk analysis and accounting for their appetite for risk, may opt to only use medical personnel. Similarly, firms should carefully consider how such communications are delivered, as to ensure promotional materials are separate from SIUU communications and as not to violate the persuasive marketing prohibition. For instance, firms may establish dedicated promotional and SIUU communication streams, separate pamphlets, or even separate booths at conference exhibit halls to ensure these channels are distinct. Finally, firms may opt to develop internal compliance checklists to ensure studies or real-world evidence used to support information provided in SIUU communications are satisfactorily robust to meet the new SSCR standard, despite its ambiguity.

121 U.S.C. 321(g) (drugs) and (21 USC 321(h) (devices).
2 82 Fed. Reg. 2193, 2206 (Jan. 9, 2017); C.F.R. 201.128 and 801.4.
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