On October 23, 2023, the Food and Drug Administration (“FDA”) published a new draft guidance, titled Communications From Firms to Health Care Providers Regarding Scientific Information on Unapproved Uses of Approved/Cleared Medical Products, Questions and Answers (the “2023 Draft Guidance”). The 2023 Draft Guidance is a revision to, and builds upon, FDA’s 2014 draft guidance on the same issue, Distributing Scientific and Medical Publications on Unapproved New Uses — Recommended Practices, which itself was a revision to FDA’s 2009 guidance, Good Reprint Practices for the Distribution of Medical Journal Articles and Medical or Scientific Reference Publications on Unapproved New Uses of Approved Drugs and Approved or Cleared Medical Devices. Drug and device manufacturers (“firms”) will note that in the 2023 Draft Guidance, FDA introduces multiple new concepts. Addition of terms such as “SIUU Communications” and “Firm-Generated Presentations” appear to broaden the possibilities for firms’ communications with healthcare providers (“HCPs”) while inclusion of concepts such as “scientifically sound” and “clinically relevant” can be read as imposing certain limitations on what can be included in SIUU Communications. FDA’s inclusion of these new concepts provides both guidance and guardrails for firms to ensure SIUU Communications with HCPs stay in line with FDA regulatory requirements. With the 2023 Draft Guidance, FDA continues to be thoughtful and intentional with its views on communications between firms and HCPs, and demonstrates to industry that the agency will continue to evolve its thinking with the advent of new technologies, advancements in science, medicine, and the delivery of care, and in light of the ever-changing modes and methods of communication.
Background
Building on the 2009 draft guidance, the 2014 draft guidance reflected FDA’s then-current recommended practices for firms distributing to HCPs scientific or medical journal articles (also known as “Reprints”), scientific or medical reference texts, or clinical practice guidelines (“CPG”) that discuss unapproved new uses for approved or cleared drugs and medical devices (“medical products”) marketed in the United States. In the background to the 2014 draft guidance, FDA emphasized the public health concerns surrounding the safety and efficacy of unapproved drugs and medical devices. FDA emphasized how new intended uses that have not undergone the appropriate approval processes can pose similar public health concerns as a determination of the safety and efficacy of a drug or medical device for one intended use does not assure its safety and efficacy for other uses.
With this in mind, FDA sought to provide general recommended practices for firms – essentially a “do” and “don’t” list for the distribution of Reprints, scientific or medical reference texts, and CPGs. The 2014 draft guidance laid out how firms should disseminate these texts, what information should be included or excluded, and where certain disclosures should be made to ensure appropriate qualification of statements are prominently displayed with respect to a medical product’s unintended uses. With the 2014 draft guidance, FDA provided industry with a framework intended to balance the public health concern regarding the safety and efficacy of the using medical products for unintended purposes with the public health benefit of arming HCPs with truthful and non-misleading scientific or medical information on unapproved new uses of existing medical products. It was evident that FDA did not want to suppress firms’ sharing of information that could better equip HCPs who would in turn make more informed decisions on whether to use or prescribe a medical product for an unapproved use based on their medical judgment.
The 2023 Draft Guidance
FDA’s most recent guidance builds on the 2014 draft guidance and includes several changes, most notably in scope, including an expansion and clarification of defined terms used in the guidance, and in the format of the guidance, which reflects a question and answer presentation.
As a starting point, the 2023 Draft Guidance does not address communications where a firm is responding to unsolicited requests, which is addressed in another FDA guidance document.[1] Instead, the agency starts the 2023 Draft Guidance by introducing clear definitions, starting with SIUU, which stands for “scientific information on unapproved uses of a medical product.” Communications related to SIUU are called “SIUU Communications” and FDA uses the term “source publication” to refer to published reprints, CPGs, reference texts, or material from an independent clinical practice resource that serves as the basis for a firm’s SIUU Communication. FDA then uses a Questions and Answers format to guide firms through their approach to formatting and disseminating SIUU Communications.
Taking a deeper dive into the 2023 Draft Guidance, the analysis below seeks to identify and discuss the new concepts adopted by FDA in this 2023 Draft Guidance and provide some context behind and insight into FDA’s recommendations.
“Scientifically Sound” and “Clinically Relevant” Considerations for Source Publications
FDA emphasizes—unsurprisingly—that SIUU Communications should be “truthful, non-misleading, factual, and unbiased” so that a HCP has all the information necessary to “interpret the strengths and weaknesses, and validity and utility of the information” provided in such communications. To satisfy this requirement, firms are tasked with two broad goals: (1) to ensure that any study or analysis discussed in a source publication that serves as a foundation for an SIUU Communication is “scientifically sound” and (2) to provide information that is pertinent to HCPs making clinical practice decisions for the care of an individual patient or “clinically relevant.”
Though this is not the first time FDA has recommended that scientific or medical journals be scientifically sound as a predicate for distribution, FDA leans into this dual standard of “scientifically sound” and “clinically relevant” to meter the type of source materials that can serve as the underlying support for SIUU Communications. By setting-up a second subjective standard, FDA has either broadened or narrowed the scope of appropriate content for distribution under the guidance. But that would depend on who you ask.
The emphasis on “scientifically sound” is centered on firms’ use of source studies, analyses, and publications that have gone through rigorous and thorough scientific analyses. As described by the agency in both regulation and guidance in the past, randomized, double-blind, controlled trials are the prime example of scientific analysis that supports the dual standard of being scientifically sound and capable of providing information that is clinically relevant. FDA notes that depending on the data and analyses, real-world data and associated real-world evidence about medical products may also be scientifically sound and capable of providing information that the agency deems to be clinically relevant. Well-designed and well-conducted trials, that at minimum meet generally accepted design and methodologies and take into account scientific principles and existing scientific knowledge, may also satisfy FDA’s new dual standard of “scientifically sound” and “clinically relevant.”
So, firms will want to make a decision on whether each of the source publications relied upon in their SIUU Communications is scientifically sound and can provide clinically relevant information. To be clear, firms should ensure that SIUU Communications are “clinically relevant” in that all such communications should contain clinically relevant information pertinent to HCPs who are making clinical practice decisions for each individual patient’s care. As noted by FDA, ensuring information provided is “clinically relevant” may mean firms will need to (1) make an effort to rely less on preliminary results or scientific data generated in the early stages of drug or medical device development (as initial results may not be reflective of final results); (2) ensure that studies underlying SIUU Communications do not make use of fraudulent data or are otherwise inaccurate in the descriptions or interpretations of study results (even where firms are fully disclosing the limitations of such a study or analysis); and (3) confirm that results relied upon from source studies and analyses are not superseded by findings from subsequent studies and analyses.
Information Firms Should Include in SIUU Communications
SIUU Communications must be truthful, non-misleading, factual, and unbiased and must also provide all information necessary for HCPs to fully assess the strengths and weaknesses, and the validity and utility of the information disseminated in such communications. To satisfy this standard, FDA encourages including the following information:
- A statement disclosing the FDA-approved use(s) of the medical product, including any limitations of use specified in the FDA-required labeling.
- A statement that the unapproved use(s) of the medical product has not been approved by FDA and that the safety and effectiveness of the medical product for the unapproved use(s) has not been established.
- A statement disclosing any limitations, restrictions, cautions, or warnings described in the FDA-required labeling about the unapproved use(s).
- A copy of the most current FDA-required labeling (or information on how to obtain labels).
- A statement describing any contraindication(s) as well as any serious, life-threatening, or fatal risks posed by the medical product that are in the FDA-required labeling for the medical product or known by the firm and which are relevant to the unapproved use(s).
- A statement identifying any authors, editors, or other contributors to publication(s) included in the SIUU communication who were employees of, consultants to, or who received compensation from the firm at the time of such persons contributed to the publication.
- In the case of an SIUU communication that is based on a source publication primarily focused on a particular scientific study or studies, for each such study where the following information is not included in the publication, provide a description of all material aspects and limitations of a study’s design, methodology, and results; 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; and the publication date of any referenced or included publication(s), if such information is not specified in the publication.
Presentation Considerations in SIUU Communications
FDA also provides context on the manner in which the communications are presented as well as the methods of presentation which FDA considers to be acceptable for SIUU Communications. In doing so, the agency seeks to strike a “careful balance” between, on the one hand, supporting HCPs interest in obtaining scientific information about unapproved uses of medical products that inform their clinical practice decisions and, on the other, ensuring that firms are not emboldened to promote or advertise off-label uses of medical products. FDA heavily regulates off-label use of medical products due to the potential that such use could result in patient harm. This is especially relevant given the continued advancements in technology, as evidenced by FDA’s references to the use of different media types and platforms beyond traditional paper pamphlets where firms can share information. The 2023 Draft Guidance suggests that firms can disseminate SIUU Communications in a variety of methods including but not limited to the provision of approved and unapproved uses of medical products at medical or scientific conferences and conference commercial exhibit halls, via online platforms, and on websites. Further, while presentation considerations are discussed in the 2014 draft guidance for each individual type of communication, the 2023 Draft Guidance separately engages with these considerations as its own category, setting forth standard presentation guidelines applicable to SIUU Communications.
- First, all SIUU Communications should “clearly and prominently present” the disclosures FDA recommends in its answer to Question 2 taking into account factors such as type size, font style, layout, contrast, graphic design, headlines, spacing, volume, articulation, and pace. This can limit the sources of communication that firms use. Specifically, if a communication medium is intended for short-form communications, firms should consider whether the communication will sufficiently satisfy FDA’s recommendations under the 2023 Draft Guidance. For example, if firms will use both audio and visual components in SIUU Communications, any relevant disclosures should be presented simultaneously in audio and visual form, such as a transcript to accompany audio communications or accurate closed captions to accompany a video communication.
- Second, SIUU Communications should not include persuasive marketing techniques. This follows FDA’s recommendation that SIUU Communications should not be presented in a manner that can lead HCPs to base clinical practice decisions on conclusions about the safety or efficacy of the unapproved product that is not supported by the underlying scientific information. Reliance on persuasive marketing techniques can influence how products are used based on elements outside of the scientific content of communications. Firms should heed FDA’s guidance here as the use of persuasive marketing techniques in SIUU Communications will be considered by FDA as outside the scope of the 2023 Draft Guidance and evidence of promoting an intended use of the product.
- Third, SIUU Communications should be provided to HCPs in a manner that is separate and distinct from any promotional communications about the approved uses of medical products (“Promotional Communications”). FDA strongly recommends that firms separate Promotional Communications from SIUU Communications to avoid the potential that HCPs can conflate approved use versus unapproved use information about a medical product. Abiding by this recommendation can look like separate and dedicated communication streams, such as distinct web pages for SIUU Communications and Promotional Communications, clearly labeled and separate pamphlets for Promotional Communications and SIUU Communications, or setting up separate booths in a conference exhibit hall to ensure the clear identification and distinction between SIUU Communications and Promotional Communications about a medical product.
- Fourth, firms should ensure that SIUU Communications are shared via platforms that will allow firms to abide by the 2023 Draft Guidance and should consider the limitations of various platforms and mediums of communication. For example, if a firm is aware that a platform will not allow for the inclusion of both SIUU Communications and appropriate disclosures due to space restrictions, the firm should not use that platform or that specific limiting format and should instead consider a platform or format that has sufficient space to accommodate FDA’s recommended disclosures.
- Finally, as with all firm communications, SIUU Communications should use plain language to aid in the accurate comprehension and careful consideration of scientific information shared in SIUU Communications. To minimize any misunderstanding of such scientific information, firms are encouraged to use clear, concise, and well-organized language that effectively communicates the information to the HCP as quickly, easily, and comprehensively as possible.
Other Considerations Of Note
The 2023 Draft Guidance addresses various types of SIUU Communications and each type of SIUU Communication has different considerations. Firms should review the 2023 Draft Guidance carefully to familiarize themselves with the considerations applicable to Reprints and Clinical Reference Resources, which include CPGs, Reference Texts, and Materials from Independent Clinical Practice Resources.
For CPGs, FDA recommends that (1) the CPG is based on rigorous reviews of existing evidence conducted according to a clear, established procedure and following a transparent process that minimizes biases and conflicts of interest; (2) the CPG includes ratings of recommendations to reflect the quality and strength of evidence that supports each recommendation; (3) the CPG is revised when important new evidence warrants modifications of current recommendations; and (4) the CPG is generally available through independent distribution channels (e.g., internet sources, book retailers, subscriptions, libraries). Firms can look to the National Academy of Medicine (“NAM”) standards for CPG “trustworthiness” as FDA considers CPGs consistent with NAM standards to be in alignment with the FDA standards articulated in the 2023 Draft Guidance.
For Reference Texts and Independent Clinical Practice Resources, FDA recommends that texts and resources are (1) published by an independent publisher in the business of publishing scientific or medical educational content; (2) published in a manner consistent with current standards for medical content creation and review that are generally accepted by the medical publishing industry and in accordance with any specific peer-review procedures of the publisher; and (3) authored, edited, and contributed to by experts who have demonstrated expertise in the subject area(s) through education or experience. The texts and resources should also be generally available or sold through independent distribution channels (e.g., internet sources, book retailers, subscriptions, libraries) for medical and scientific educational content.
Firm-Generated Presentations. FDA provides recommendations and guidance for a new form of SIUU Communications, namely on firms’ sharing of information on unapproved uses of medical products and Firm-Generated Presentations, which were not discussed in prior guidances on Reprints.
While not specifically defined, Firm-Generated Presentations are described as presentations of scientific information accompanying a published reprint. As with all SIUU Communications, Firm-Generated Presentations of scientific information should be truthful, non-misleading, factual, and unbiased and should provide HCPs with all the information needed to accurately assess the strengths and weaknesses, and validity and utility of any presented information. Additionally, Firm-Generated Presentations should be presented alongside the full reprints on which they rely. All information that is material to the representations made in Firm-Generated Presentations should be included in the Firm-Generated Presentation and not simply in the accompanying reprints, and firms should clearly indicate and disclose the portions of the communications that are firm-generated. FDA guidance here can be summarized as such: any firm-generated presentations should follow the same guidelines as other forms of SIUU Communications.
Intended Use. FDA is careful to clarify that while compliance with the 2023 Draft Guidance allows firms to communicate scientific information of unapproved uses of a medical product, firms should also ensure that SIUU Communications abide by other applicable FDA guidance, including FDA’s Rule on Intended Uses.[2] While FDA has stated that it will not use compliant SIUU Communications with HCPs as standalone evidence of a new intended use, the analysis does not end there.
In fact, FDA has referenced case law in prior guidances that stated intended use of a medical product depends “on the manufacturer’s objective intent in promoting and selling the product”[3] and takes into account an objective evaluation of the totally of circumstances surrounding a product’s distribution including labels, promotional claims, advertisements, written statements, and actual use of the product, among other relevant sources.[4] For firms, this means that compliance with the 2023 Draft Guidance alone does not mean that firms are off the hook for promoting a new intended use of a medical product. FDA will continue to look at other sources and circumstances in determining whether firms are promoting a new intended use of a medical product, including but not limited to how an SIUU Communication is discussed in the industry and among medical experts, and any related labels, advertisements, written statements, and promotional materials discussing the information provided in an SIUU Communication. Industry should take note of FDA’s commentary on this issue and be diligent in separating SIUU Communications from a medical product’s labels, promotional claims, advertisements, and other documentation and discussion surrounding the approved use(s) for such approved or cleared medical products.
Moving Forward
By issuing this 2023 Draft Guidance, FDA seeks to provide firms with more detailed recommendations for and examples of SIUU Communications. FDA takes care to distinguish between permissible and impermissible content and actions for firms seeking to proactively communicate scientific information on unapproved uses with HCPs, solidifying the agency’s commitment to “strike a careful balance” between addressing public health concerns and encouraging public health benefits that can result from dissemination of such information.
While FDA reiterates existing concepts surrounding Reprints and scientific and medical publications in this guidance, FDA also discusses new concepts surrounding firms’ dissemination of information to discuss unapproved uses of medical products. This 2023 Draft Guidance is especially timely in light of the advances in technology, medicine, and the delivery of care to patients. Introduction of new concepts like the term “SIUU Communication”, firms’ use of “scientifically sound” and “clinically relevant” studies, and “Firm-Generated Presentations” reflects FDA’s attempts to explore the potential and possible forms of acceptable SIUU Communications. At the same time, FDA’s approach to Intended Use seeks to keep firms from taking the same SIUU Communications too far. All together, the 2023 Draft Guidance contains FDA’s evolving thought process on communications which will hopefully guide firms as they continue exploring new and different methods of communication with HCPs that can further the goal of sharing information that can assist HCPs with providing patients with better individualized care.
FDA is soliciting comments from industry up to December 26, 2023 with the intention of finalizing this guidance on SIUU Communications. The docket for submissions and comments can be found here. In the meantime, firms that are already following the recommendations in this revised guidance can take some comfort in FDA’s assertion that SIUU Communications consistent with the 2023 Draft Guidance will not, on its own, be seen by FDA as evidence of a firm promoting a new intended use.
If you have any questions on this new guidance, please contact the authors of this article or your Sheppard Mullin attorney.
FOOTNOTES
[1] Responding to Unsolicited Requests for Off-Label Information About Prescription Drugs and Medical Devices (December 2011).
[2] Final Rule: Regulations Regarding “Intended Uses” (2021 Intended Use).
[3] Id, citing United States v. 789 Cases, More or Less, of Latex Surgeons’ Gloves, 799 F. Supp. 1275, 1285 (D. Puerto Rico 1992)