[co-author: Gabrielle Simeck]
The U.S. Food and Drug Administration (FDA) has published final guidance on “Communications From Firms to Health Care Providers Regarding Scientific Information on Unapproved Uses of Approved/Cleared Medical Products” (SIUU Guidance), which describes permitted dissemination of scientific information on unapproved uses (SIUU) of approved/cleared medical products by firms to healthcare providers (HCPs). In short, this guidance covers FDA policy regarding manufacturer dissemination of off-label information about approved/cleared medical products. The updated guidance finalizes FDA’s proposed approach from its 2023 draft guidance, with notable revisions in response to industry and public criticism of the draft. Below we summarize the key changes implemented in the final guidance and consider what questions remain outstanding under the agency’s revised approach.
Background
FDA has allowed certain communications about unapproved uses of approved medical products primarily via policies elucidated in two guidance documents: 1) the 2014 “Revised Draft Guidance for Industry: Distributing Scientific and Medical Publications on Unapproved New Uses-Recommended Practices” (the Good Reprint Practices Draft Guidance, in itself a revision of a January 2009 guidance), and 2) the 2011 “Draft Guidance for Industry: Responding to Unsolicited Requests for Off-Label Information about Prescription Drugs and Medical Devices” (Unsolicited Requests Draft Guidance). The 2014 guidance permitted companies to disseminate certain publications about unapproved uses, while the 2011 guidance described how firms could respond to unsolicited questions about off-label information. Limitations on manufacturer communications spurred a number of First Amendment concerns. FDA responded by holding a public hearing soliciting stakeholder input on the issue in 2016 and publishing a 2017 memorandum outlining how its approach to regulating firm communications seeks to balance the interests of public health and safety with industry innovation and adherence to constitutional law.
In 2023, FDA updated the Good Reprint Practices Draft Guidance through the draft SIUU guidance, outlining SIUU communications that the agency would not consider to constitute evidence of manufacturer intent to promote a new intended use. (Review our analysis of the draft guidance here.) The draft SIUU guidance drew industry criticism for setting standards that were unclear and unduly restrictive of communications. The final SIUU guidance responds to some of these concerns, clarifying the scope of the policy and in some ways expanding the safe harbor for SIUU communications. A 2025 addendum to the FDA memorandum on First Amendment considerations was also published in conjunction with the final guidance, emphasizing that because the guidance provides a safe harbor for manufacturer SIUU communications, it is speech-enabling and for that reason does not run afoul of the First Amendment. Our analysis of notable takeaways from the final guidance follows.
Updating the standard for determining the appropriateness of a source publication to remove the “clinically relevant” requirement
Under the draft guidance, FDA created the “scientifically sound and clinically relevant” standard to determine whether a given article would be appropriate to rely on as a source publication for an SIUU communication. As we observed then, this standard was murky, leaving questions about how it would be applied in practice. Under the final guidance, a source must be “scientifically sound” to serve as the basis for an SIUU communication. While this updated language omits “clinically relevant” language from the standard, we note that the need for clinical relevance appears to remain and to simply have been incorporated as part of the “scientifically sound” standard. The definition of “scientifically sound” itself has not meaningfully changed from the draft guidance, stressing that the particular study or analysis must meet generally accepted design and methodological standards to ensure it is reliable; we note that FDA spends an entire page defining the term.
Reversing course on the acceptability of early-phase studies and non-traditional study designs
To further clarify this standard, FDA describes study design features that would generally meet the “scientifically sound” standard – i.e., a robust design and a prespecified statistical analysis plan. The agency appears to have addressed industry criticism that arose around the draft guidance by reversing course on statements that suggested that Phase 2 studies would not meet the SIUU source publication standard. In the final guidance, the agency expressly acknowledges that certain phase II studies could meet the “scientifically sound” standard when adequately designed and conducted. The guidance also acknowledges that less-conventional study designs, such as meta analyses, cohort or case-control studies, open-label studies, single-arm studies, externally controlled trials, and observational studies, can also meet the “scientifically sound” standard.
FDA also notes specific factors that companies should consider when evaluating whether source publications fall under the agency’s enforcement policy for SIUU, including reliability of the study, current scientific knowledge, and whether the conclusions reached in the source publication align with the articulated hypothesis or research question and are supported by the study’s results. Ongoing review of source publications may also be necessary to ensure continued reliability of the results.
For medical devices specifically, the agency notes that the “scientifically sound” standard for source publications aligns with “valid scientific evidence” on which FDA may rely in order to authorize a device for marketing. “Valid scientific evidence” is defined in 21 CFR 860.7 as including various sources ranging from well-controlled investigations to reports of significant human experience with a marketed device; FDA adds that specifically for medical device SIUU communications, single-arm studies with comparisons to external controls, non-interventional studies, meta-analyses testing a specific clinical hypothesis, and nonclinical research such as well-designed bench or animal studies may also be considered “scientifically sound.”
Expanding the permissible bases for firm-generated presentations of SIUU
Additionally, FDA appears to have responded to industry concerns that under the draft guidance firm-generated presentations could be based only on reprints. FDA clarified that appropriate source publications for firm-generated presentations extend beyond published scientific or medical journal articles (reprints) to also include clinical practice guidelines, scientific or medical reference texts, and digital clinical practice resources. Thus, a firm may use any type of source publication, so long as the source meets the “scientifically sound” standard described above
Maintaining Separation Between Permissible Off-Label Discussion and Promotional Communications
Consistent with the draft guidance, FDA stresses that the types of statements and presentations that are appropriate for SIUU differ from what constitutes acceptable promotional communications, because promotional communications accompany a marketing authorization (clearance or approval) that is supported by data that has been reviewed by FDA. The risk the agency aims to mitigate is that health care professionals may conflate approved and unapproved uses if they are presented together. The final guidance updates the draft guidance’s indication that SIUU and promotional communications must be “separate and distinct” to simply stating they must be “separate,” but the substance of the standard remains essentially the same. FDA emphasizes that companies should maintain dedicated channels/venues for discussion of approved versus unapproved uses – such as separate webpages, email messages, and physical spaces within a commercial exhibit booth. The final guidance includes a new example to practically outline what constitutes sufficient “separation” in a one-on-one context, noting that if a firm representative is sharing an SIUU communication with an HCP in an in-person visit, it should not be “attached to or intermingled with” any promotional communication that is shared during the same visit and should be clearly identified as an SIUU communication.
Clarification of “Persuasive Marketing Technique” Concerns
In the draft guidance, FDA prohibited the use of “persuasive marketing techniques,” defined to mean encouraging use of the product based on elements other than the scientific content of the communication. Industry constituents criticized this prohibition as being vague and overly sweeping if it applied to all SIUU communications. In response to these criticisms, FDA clarified that its concern about persuasive marketing is focused on firm-generated presentations of SIUU, because those inherently lack the independence of a peer-reviewed / third-party publication that meets the recommendations in the guidance and are also not generally available in the same way. To the previously listed examples of such techniques – celebrity endorsements, gifts, and premium offers – FDA added emotional appeals unrelated to scientific content, promotional tag lines, jingles, and “calls to value that “pre-judge the benefit(s) of the medical product for individual patients.” Here, the agency distinguishes a call to value that pre-judges the benefits of the product (e.g., “Call firm X now for more information about Product Y—it’s the best option for your patients!”) from one that does not pre-judge the benefit to individual patients (e.g., “Click here to access the full article for free!”)
FDA also explicitly notes that firm-generated SIUU communications can include visual elements such as tables and graphs that are consistent with the scientific content of a source publication, and graphic design techniques (e.g., contrast and white space) that enable clearly conveying the recommended disclosures.
Shoring up FDA’s Authority
In conjunction with the publication of the SIUU Final Guidance, FDA also released:
- An addendum to a 2017 FDA memorandum on public health interests and First Amendment considerations related to manufacturer communications on unapproved uses of medical products.
- An updated appendix to the 2017 FDA memorandum summarizing FDA’s premarket review and related authorities for medical products.
The 2025 addendum discusses the statutory framework, regulatory history, policy development, and FDA’s consideration of First Amendment and due process issues underlying its policy on communications related to unapproved uses of approved/cleared medical products. In the addendum, FDA responds to prior industry challenges, such as that the SIUU safe harbor is unconstitutionally vague, and tries to address potential First Amendment challenges to its SIUU safe harbor. The concerted effort to issue the final guidance and other policy documents in advance of the incoming pro-business, pro-speech administration may signal that FDA anticipates legal challenges.
[View source.]
