On Oct. 23, 2023, the U.S. Food and Drug Administration (FDA) issued draft guidance in the form of questions and answers (Q&A) regarding manufacturers’ (Firms) dissemination of scientific and medical information on unapproved uses of approved/cleared drugs and medical devices to health care professionals (HCPs). The draft guidance, if finalized, is intended to supersede the FDA’s 2014 guidance titled Distributing Scientific and Medical Publications on Unapproved New Uses – Recommended Practices.
The new draft guidance provides the FDA’s current thinking regarding communications involving scientific information on unapproved uses (SIUU). It requires such communications to be truthful, non-misleading, factual and unbiased, and to provide all information necessary for HCPs to interpret the strengths, weaknesses, validity, and utility of the information in the SIUU communication. The guidance suggests that if an SIUU communication is shared with HCPs in a manner consistent with the guidance, the FDA does not intend to use such communication, standing alone, as evidence of a new intended use.
As described below, the draft guidance addresses requirements for SIUU communications, including the adequacy of supporting data, required disclosures, format, layout, and other presentational considerations, and recommendations for certain types of SIUU communications, such as reprints, published clinical reference resources, and Firm-generated presentations. It is important to note that the FDA issued the draft guidance for comment purposes only, and that it is nonbinding and is labeled “not for implementation.” Comments to the draft guidance are due Jan. 5, 2024.
1. Determining Whether a Source Publication Is Adequate and Appropriate to Support SIUU Communications
The draft guidance provides that communications regarding SIUU of approved or cleared medical products must be scientifically sound and clinically relevant. Specifically, the guidance provides that the study or analysis supporting the communication should meet generally accepted design and/or methodological standards for the particular type of study or analysis, taking into account established scientific principles and existing scientific knowledge.
For drugs, the FDA considers randomized, double-blinded, concurrently controlled superiority trials to be scientifically sound and clinically relevant. If the communication is based on real-world data and associated real-world evidence about medical products — such as electronic health records, medical claims data, or product or disease registries — the guidance suggests that the analytical methods, protocols, and statistical analysis plans should be finalized prior to conducting the analysis and that data integrity should be carefully monitored and maintained.
The FDA has previously raised concerns regarding promotional communications that are based on a retrospective analysis of real-world data where the analytical methods are not appropriately validated. For example, in an untitled letter from July 2021, the FDA noted concerns regarding promotional communications for Neulasta® based on a retrospective real-world study. The FDA raised concerns that the unvalidated algorithm used to retrospectively identify study participants may have misclassified patients and indicated that it had not received any information regarding the performance characteristics (e.g., sensitivity, positive predictive value) of the algorithm or the diagnostic codes that were used. The FDA also raised concerns that the study was not designed to ensure that the respective patient populations were adequately balanced or controlled for bias.
In another untitled letter from March 2022, the FDA raised concerns regarding claims made on a webpage regarding DUOBRII™ lotion. Specifically, the FDA alleged that stating that the product had superior efficacy when compared to the aggregated results of two monotherapies created a misleading impression. The statements were based on a post hoc analysis of a single phase two trial of limited sample size that compared DUOBRII™ to its aggregated components. The FDA took the position that, as a post hoc analysis, the trial failed to include a prespecified statistical procedure that would control for false positives (type 1 error rate).
The draft guidance also provides that the FDA will not consider isolated case reports, other reports that lack sufficient detail to permit scientific information (including abstracts), or studies without an adequate control group to be scientifically sound or clinically relevant. The FDA also will not consider information based on studies that may have appeared promising in early stages, but was not borne out in later studies, to be scientifically sound or clinically relevant.
2. Determining What Should Be Included in SIUU Communications
The draft guidance recommends that Firms include additional information in SIUU communications to provide HCPs with adequate information to determine the strengths, weaknesses, validity, and utility of the presented information. The draft guidance specifies a number of disclosure statements that Firms should include as part of SIUU communications, including: (i) indicating that the suggested uses are not FDA approved; (ii) indicating that the safety and effectiveness of the product for the proposed use have not been established; (iii) identifying the FDA-approved uses of the product; (iv) disclosing any applicable limitations, restrictions, cautions, or warnings regarding the unapproved use; and (iv) including additional information regarding the supporting studies if certain information is not included in the supporting source publication.
Specifically, to the extent not included in the source publication, the FDA recommends including a description of (i) all material aspects of study design, methodology, and results; (ii) all material limitations related to the study design, methodology, and results; and (iii) any conclusions from other relevant studies, when applicable, that are contrary to or cast doubt on the results shared, including citations for any such studies.
The draft guidance also provides that SIUU should include information regarding serious risks posed by the medical product that are in the FDA-required labeling for the medical product or known by the Firm and relevant to the unapproved use(s). The FDA historically has raised significant concerns when key risks were either downplayed or omitted from such communications.
For example, in an untitled letter from October 2018, the FDA raised concerns regarding a sales representative who promoted Fycompa® tablets for a new unapproved use at a lunch meeting with healthcare providers. In addition to off-label promotion issues, the FDA raised significant concerns that the representative minimized serious, life-threatening risks associated with Fycompa® that were identified in the product’s Boxed Warning.
3. Presentational Considerations for SIUU Communications
The draft guidance addresses certain format, layout, and other presentational considerations for company-prepared presentations (such as PowerPoint presentations) that include SIUUs to ensure that the information presented is not only truthful and non-misleading, but factual and unbiased.
The disclosures described in the draft guidance should be clearly and prominently presented, taking into consideration the type size, font style, layout, contrast, graphic design, headlines, spacing, volume, articulation, pace, and any other techniques necessary to achieve required prominence and should utilize plain language that is clear, concise, well-organized, and minimizes the use of technical or complex language. The draft guidance also recommends that, for communications with audio and visual components, disclosures should be presented simultaneously in audio and text using the same words. The FDA also cautions Firms against using platforms that do not allow the Firm to display all of the information required by the guidance.
The FDA will not consider SIUU communications that utilize persuasive marketing techniques — such as celebrity endorsements, premium offers, and gifts — to qualify for the enforcement policy set forth in the draft guidance. Accordingly, SIUU communications that include persuasive sales and marketing techniques may expose Firms to significant civil and criminal liability. The FDA strongly recommends that Firms (i) avoid sharing SIUU communications together with promotional communications for approved uses and (ii) use separate channels and venues to communicate SIUU (e.g., separate web pages and emails without links to each other and segregated booth space at a conference) to reduce the risk that HCPs may conflate the approved and unapproved use information.
4. FDA Recommendations for Specific Types of SIUU Communications
The FDA draft guidance also provides specific recommendations for disseminating reprints, clinical reference resources, and Firm-generated presentations to HCPs. These recommendations include new guidance for the use of clinical practice guidelines (CPGs), such as ensuring that CPGs include ratings of the recommendations to demonstrate the quality and strength of the evidence supporting each recommendation.
The draft guidance also includes recommendations for Firm-generated presentations, such as ensuring that all information material to the representations made in the Firm-generated presentation is included in the presentation, even if it also is included in the accompanying reprint. Firms should consider the recommendations set forth in the draft guidance regarding specific types of SIUU communications when developing such communications.
However, as the draft guidance is not currently intended for implementation, Firms should exercise caution before taking steps to amend their current scientific exchange programs in reliance on the FDA’s proposed SIUU position.
McGuireWoods’ cross-functional team of life sciences attorneys routinely assists clients with addressing regulatory, transactional, and litigation matters and navigating the ever-evolving landscape of FDA regulation. For assistance with SIUU communications or other promotional matters, please contact one of the authors of this article.