On January 7, 2025, FDA published a final guidance entitled Communications From Firms to Health Care Providers Regarding Scientific Information on Unapproved Uses of Approved/Cleared Medical Products - Questions and Answers (“SIUU Final Guidance”). The SIUU Final Guidance updates an October 2023 draft guidance of the same name, which we described in a prior Alert and podcast. In the SIUU Final Guidance, FDA describes recommendations for medical product manufacturers intending to disseminate or discuss scientific information contained in reprints, clinical practice guidelines, reference texts, or digital clinical practice resources about unapproved uses of approved or cleared medical products. The SIUU Final Guidance includes incremental clarifications regarding the contours of FDA’s enforcement policy and addresses some important issues that industry raised regarding the draft.
In conjunction with issuing the SIUU Final Guidance, FDA also released an addendum to its January 2017 memorandum, Public Health Interests and First Amendment Considerations Related to Manufacturer Communications Regarding Unapproved Uses of Approved or Cleared Medical Products (“Addendum”), which we also discussed in a prior Alert. The Addendum represents FDA’s latest defense of its legal framework governing manufacturer communications. It doubles down on FDA’s prior positions, citing heavily to the December 2023 First Circuit decision in United States v. Facteau,1 which was largely favorable to FDA and which we discussed in a prior Alert and podcast.
While the SIUU Final Guidance provides companies with some flexibility to communicate off-label scientific information under certain circumstances, it remains premised on FDA’s expansive view of its authority to regulate manufacturer communications. FDA’s publication of the SIUU Final Guidance and Addendum less than two weeks before a change in presidential administration likely reflects the outgoing administration’s desire to memorialize its views post-Facteau and to impact the agency’s regulatory approach going forward, whether to lay the foundation for renewed government enforcement efforts relating to off-label communications, or to defend against industry challenges relating to FDA’s regulatory regime. However, the precise impact of the SIUU Final Guidance and Addendum remains to be seen as the new Trump administration takes office.
This Alert summarizes key changes in the SIUU Final Guidance as compared to the 2023 draft, explains the significant updates to FDA’s First Amendment positions articulated in the Addendum, and describes important implications for industry.
The SIUU Final Guidance
The SIUU Final Guidance describes FDA’s recommendations for dissemination and discussion of off-label scientific information about approved products. Consistent with the 2023 draft guidance, FDA continues to recognize that firms can disseminate certain forms of scientific information related to unapproved uses, subject to the key tenets that the communication should be truthful and non-misleading and present all information necessary for health care professionals (“HCPs”) to understand and evaluate the strengths and weaknesses, validity, and clinical utility of the information. As in the draft guidance, FDA describes the SIUU Final Guidance as an “enforcement policy” and asserts that it does not intend to use communications consistent with the SIUU Final Guidance “standing alone” as evidence of a new intended use (i.e., an off-label use).
While the basic framework and many of the recommendations in the SIUU Final Guidance are unchanged from the draft, there are several important changes:
Removal of “Clinically Relevant” Standard. FDA has modified the substantiation standard for SIUU communications. Whereas the 2023 draft guidance recommended that source publications for SIUU communications be both “clinically relevant” and “scientifically sound,” the substantiation standard in the SIUU Final Guidance no longer refers to clinical relevance. Under the 2023 draft guidance, FDA described clinically relevant information as “pertinent to HCPs engaged in making clinical practice decisions for the care of an individual patient,” noting that “preliminary scientific data” and other data that may be generated in the “early stages of medical product development” would be unlikely to meet that clinical relevance standard. FDA also provided numerous examples of “clinically relevant” information suggesting that the agency viewed clinical relevance as a very high bar. In comments on the draft guidance, many stakeholders pushed back on the agency’s conception of clinical relevance, asserting that clinical relevance should be determined by HCPs rather than the FDA and that FDA’s description of clinical relevance, including its position with respect to early phase data, was overly restrictive.
While the SIUU Final Guidance no longer refers to clinical relevance, SIUU communications should still be “scientifically sound,” meaning that they “meet generally accepted design and other methodological standards for the particular type of study or analysis performed (e.g., provide a clear description of the prespecified hypothesis stated and tested, acknowledge and account for potential bias, and otherwise meet generally accepted scientific standards), taking into account established scientific principles.” The agency expressly acknowledges that certain early phase data could meet the scientifically sound standard and fall within the SIUU enforcement policy.
Changes Related to Firm-Generated Communications. The SIUU Final Guidance incorporates several important changes related to firm-generated communications of scientific information on unapproved uses, including:
- Expansion of Source Publications that Can Support Firm-Generated Communications. While the 2023 draft guidance contemplated firm-generated presentations only for accompanying reprints, the SIUU Final Guidance contemplates firm-generated presentations for any type of accompanying SIUU source publication described in the guidance. This includes not only reprints, but also clinical practice guidelines, reference texts, and digital clinical practice resources.
- Distinction from Source Publications. The SIUU Final Guidance adds substantial discussion of the distinction between firm-generated communications about source publications and the source publications themselves, which “are generally available from independent publishers and reflect at least some degree of editorial input by an independent publisher whose business interest is not tied to sales of specific medical product(s).” FDA therefore recommends more extensive disclosures for firm-generated presentations than for source publications.
- Tone and Presentation. The SIUU Final Guidance includes detailed recommendations regarding tone and presentational aspects for firm-generated communications, some of which were included in the draft guidance and some of which are new or clarified. The draft guidance had included an overarching recommendation against using “persuasive marketing techniques,” defined as marketing techniques that “influence use of the products based on elements other than the scientific content of the communication,” such as celebrity endorsements, premium offers, and gifts. While the SIUU Final Guidance does not use the term “persuasive marketing techniques,” it continues to assert that firm-generated communications involving techniques such as celebrity endorsements, emotional appeals unrelated to the scientific content (e.g., inspirational images like a “sunrise, a joyful family gathering, or a basket of puppies”), gifts, promotional tag lines, jingles, and premium offers would not fall within the enforcement policy described in the guidance. FDA also adds a new recommendation against “calls to value that pre-judge the benefit(s) of the medical product for individual patients,” such as a call to “Click here to start improving your patients’ lives today.” FDA’s rationale for these recommendations is that the use of these techniques “suggests an effort to convince the HCP to prescribe or use the product for the unapproved use” and “provide[s] particularly clear evidence of the firm’s intended use” for purposes of establishing an off-label intended use. FDA further rationalizes that without these boundaries on communication techniques, “there would not be a meaningful distinction between firm-generated presentations included in SIUU communications and promotional activities.”
No Expectation to Submit SIUU Communications to FDA. The guidance includes a new statement clarifying that FDA “does not expect” firms to submit SIUU communications that are consistent with the recommendations in the guidance to the Agency at the time the communication is initially shared with HCPs. FDA does not say so expressly, but is presumably referring to the regulatory requirement that all labeling or advertising devised for promotion of a drug must be submitted on Form 2253. The phrasing of this clarification could be read to suggest that FDA believes it could require SIUU communications to be submitted on Form 2253 because the agency considers all such communications to be promotional, but that it is choosing to exercise enforcement discretion for SIUU communications that follow all of the recommendations in the SIUU Final Guidance.
Separation of Promotional and SIUU Communications. The SIUU Final Guidance retains the recommendation from the draft guidance that SIUU communications should be separate from promotional communications about approved uses of medical products, though it no longer includes the recommendation that firms “use dedicated vehicles, channels, and venues for sharing SIUU communications” separate from those used for promotional communications. The final guidance also incorporates an additional example demonstrating the concept on separation in the context of in-person visits: “If a firm’s representative delivers an SIUU communication during an in-person visit with an HCP, that SIUU communication should be separate from (i.e., not attached to or intermingled with) any promotional communications about the approved use(s) of the firm’s medical product that are also shared during the in-person visit.” In an accompanying footnote, FDA states that personnel communicating about SIUU should have “specialized training in providing truthful, non-misleading scientific information about unapproved uses of the firms’ approved medical products” and should also be trained to handle potential questions or “know how to direct the questions to personnel who are best qualified to respond (e.g., medical or scientific/technical representative or department).” This new example suggests that, with appropriate guardrails in place, discussing SIUU information in the same HCP visit as promotional information could still be consistent with FDA’s recommendations. Like the draft guidance, the example in the SIUU Final Guidance is also silent as to which employees within a company may present the SIUU information and thus appears to leave the door open for SIUU communications by sales representatives so long as they have received the specialized training described above.
Clarifications Related to Recommended Disclosures. While the recommended disclosures are largely unchanged from the draft guidance, the SIUU Final Guidance includes one notable revision in the recommendation regarding disclosure of conflicting information. The draft guidance had recommended disclosure of “[a]ny conclusions from other relevant studies, when applicable, that are contrary to or cast doubt on the results shared, including citations for any such studies.” Industry raised concerns with the breadth and vagueness of this recommendation, which would seem to cover any study, regardless of its rigor, that merely casts doubt in some way on the SIUU communication. In contrast, the SIUU Final Guidance recommends disclosure of “any conclusions—from other scientifically sound studies that evaluated the same or similar hypotheses or research questions—that are in conflict with the conclusions from the studies or analyses described in the source publication(s).” Unlike the draft guidance, this limits the universe of studies that would have to be disclosed to those that are scientifically sound and that conflict with (rather than merely “cast doubt on”) the conclusions in the SIUU communication.
Continuing Review of SIUU Communications. The SIUU Final Guidance emphasizes that firms should not continue to disseminate a study or analysis that subsequent research has shown to be unreliable. The guidance builds this concept into its description of scientifically sound studies, recommending that “firms should take into account existing scientific knowledge to determine whether a source publication is appropriate to include in an SIUU communication, both when initially preparing the communication and at the time of each dissemination of that communication.” In addition to the example of subsequent research refuting a conclusion in the SIUU source publication, the SIUU Final Guidance provides several additional examples where continued dissemination of a source publication would be inappropriate, including where a publication has been retracted by the publisher due to discovery of scientific misconduct or error. Adhering to the SIUU Final Guidance’s direction to account for existing scientific knowledge “at the time of each dissemination” of an SIUU communication could present practical challenges for companies, and it will be critical to have mechanisms in place to monitor new publications and data proactively, flag any developments that may change the overall mix of data relating to an issue addressed in an SIUU communication, and periodically reassess the appropriateness of SIUU communications.
The First Amendment Addendum
In conjunction with its release of the SIUU Final Guidance, FDA also issued the Addendum to its 2017 memorandum outlining its First Amendment position vis-à-vis off-label promotion, as well as an updated Summary of Premarket Review and Related Authorities, which had been included as an appendix to the 2017 memorandum. FDA cites the Addendum multiple times in the guidance. The Addendum describes FDA’s position on its authority to regulate manufacturers’ off-label speech and refines the Agency’s arguments supporting the constitutionality of such regulation, with a particular focus on how FDA has accounted for First Amendment and due process considerations in the SIUU Final Guidance despite arguments by industry advocates to the contrary. The Addendum incorporates significant discussion of the First Circuit’s Facteau opinion. Key takeaways from the Addendum include:
- FDA contends, relying on Facteau, that the SIUU Final Guidance and the agency’s other “safe harbor” policies for manufacturer communications regarding off-label uses are “speech-enabling,” rather than “speech-restrictive.” Accordingly, FDA takes the position that these policies do not even implicate the First Amendment and therefore do not trigger any First Amendment scrutiny.
- Despite extensive discussion of the SIUU Final Guidance and numerous other FDA safe-harbor policies regarding manufacturer communications, the Addendum makes no mention of the concept of scientific exchange embodied in FDA’s regulations at 21 C.F.R. § 312.7. Nor is scientific exchange mentioned in the SIUU Final Guidance itself. These omissions call into question how FDA currently views scientific exchange, including whether the Agency acknowledges scientific exchange as a category of communications distinct from those specifically enumerated in current FDA guidance documents.
- FDA continues to assert its longstanding view, based on Facteau and earlier precedents, that the use of speech as evidence of intended use is constitutionally permissible and does not raise any First Amendment concerns. FDA also maintains its view that intended use can be determined from “any relevant source” of evidence, including “implicit promotion,” which may include dissemination of scientific research results. In conjunction with the lack of any mention of the scientific exchange regulation, this seems to suggest that FDA may be of the view that all speech is in play for establishing intended use, unless the speech fits squarely within a specific, FDA-recognized safe harbor policy.
- FDA argues that, even if the applicable legal framework were subject to First Amendment scrutiny, it would “easily” pass constitutional muster under the Central Hudson test for analyzing commercial speech and even under “more exacting levels of scrutiny.” As part of this discussion, FDA rejects alternative regulatory approaches, including, among others, the adoption of “industry group principles”—presumably referring to the PhRMA/BIO Principles on Responsible Sharing of Truthful and Non-Misleading Information About Medicines with Health Care Professionals and Payers. FDA asserts that the industry group principles are not sufficiently specific and would skew FDA’s “careful balancing” of competing public health interests relative to the policy FDA has adopted in the SIUU Final Guidance.
Medical products companies are likely to express continued concerns that the FDA’s positions have a chilling effect on truthful and non‑misleading speech, negatively affect public health, and rely on content- and speaker-based restrictions that are disfavored under the First Amendment. It remains to be seen whether FDA will continue to advance the arguments set forth in the 2017 memorandum and the Addendum under the Trump administration.
Conclusion
The SIUU Final Guidance includes some important clarifications to the 2023 draft guidance. As companies continue to develop their practices related to SIUU communications, including with respect to firm-generated communications describing reprints and other source publications, they should carefully consider the guardrails and recommendations provided in the guidance. On the whole, the SIUU Final Guidance may offer some additional flexibility for communicating scientific information on unapproved uses as compared to earlier iterations of the guidance. However, companies should exercise caution in light of the bullish stance reflected in the Addendum regarding the scope of FDA’s authority and various statements that raise questions about the concept of scientific exchange and suggest that dissemination of scientific information may be viewed as promotional and considered evidence of intended use by the agency unless fully consistent with the recommendations in the SIUU Final Guidance.
