The FDA released final guidance on communications from companies to health care providers (HCP) regarding scientific information on unapproved uses (SIUU) of approved/cleared medical products.

“In summary, this guidance strives to balance HCP interest in scientific information about unapproved uses of approved/cleared medical products to inform clinical practice decisions for the care and management of individual patients and the various government interests in incentivizing the development of and satisfaction of applicable premarket requirements for medical products,” the guidance said.

The “FDA is issuing this guidance to provide reassurance to firms that, if they choose to provide communications consistent with the recommendations in this guidance, FDA does not intend to use the firm’s dissemination of such communication standing alone as evidence of a new intended use,” the agency said in announcing the guidance. “Additionally, FDA does not expect a firm to submit such a communication to the agency at the time the communication is initially shared with HCPs. We acknowledge that firms communicate in other ways and with other audiences, and this guidance neither speaks to nor intends to convey any views on communications that are not within the scope of the enforcement policy outlined in this guidance.”

“A key tenet underlying this enforcement approach is that, to promote the public health, any individual firm-initiated communication of scientific information about unapproved use(s) of that firm’s approved/cleared medical product(s) should be truthful and non-misleading, and provide and appropriately present all information necessary for HCPs to understand and evaluate the strengths and weaknesses, validity, and clinical utility of the scientific information on unapproved use(s) in that specific communication,” the FDA said.

The guidance provides recommendations for companies initiating the sharing with HCPs of:

• Source publications that are published scientific or medical journal articles (reprints) or published clinical reference resources: clinical practice guidelines (CPGs); scientific or medical reference texts (reference texts); or materials from digital clinical practice resources.

• Company-generated presentations of scientific information on unapproved use(s) provided with a source publication.

The guidance finalizes a revised draft guidance issued in October 2023. Changes from the draft include:

• reorganizing the guidance to include dedicated glossary and policy sections;
• revising the recommendations for source publications to provide additional specificity and examples to illustrate the recommendations;
• refining language around presentational considerations to provide additional clarity and an additional example; and
• updating the section on company-generated presentations to specify that the recommendations apply to company-generated presentations of scientific information from any of the source publications addressed in the guidance.

The new policy section states that “it is critical that SIUU communications be truthful and non-misleading and also provide and appropriately present all information necessary for HCPs to understand and evaluate the strengths and weaknesses, validity, and clinical utility of the scientific information on unapproved use(s) in the SIUU communication.”

The guidance said “SIUU communications that include firm-generated presentations give rise to considerations that are different in some ways from the considerations that arise from a firm’s distribution of SIUU communications that consist of source publications and the recommended disclosures.”

The guidance noted that source publications “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), in contrast to the firm that has chosen to draw attention to that source publication. These characteristics of a source publication help to explain why a firm’s choice to draw HCP attention to such a source publication is less likely, on its own, to upset the careful balance of competing public health interests. By contrast, firm-generated presentations lack that independence and generally come to an HCP’s attention because of the firm’s initiative to create and share them.”

The guidance added that in company-generated presentations, a company’s use of communication techniques “to encourage the unapproved use of its medical product based on elements other than the communication’s scientific content does not appropriately serve the purpose of informing clinical practice decisions for the care and management of individual patients and therefore does not counterbalance the important government interests discussed in this guidance. For these reasons, those communications are outside the scope of the enforcement policy outlined in this guidance.”

In addition, “an SIUU communication that includes a firm-generated presentation should be truthful and non-misleading and should provide and appropriately present all information necessary for HCPs to understand and evaluate the strengths and weaknesses, validity, and clinical utility of the presented scientific information on unapproved use(s).”

The guidance advises that:

• The company-generated presentation should be limited to the scientific information on unapproved use(s) from one or more source publications.
• Companies should provide the source publication(s) with the company-generated presentation.
• Companies should include all information material to the representations made in the company-generated presentation with those representations within the company-generated presentation. “For example, if a firm-generated presentation includes information about study results, the firm-generated presentation should include all material aspects of and limitations related to the study design, methodology, and results necessary to interpret the presented information directly with the presented information.”
• Company-generated presentations should include the disclosures including a statement that the unapproved use(s) of the medical product has not been approved by the 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, warnings or precautions described in the FDA-required labeling about the unapproved use(s); a copy of the most current FDA-required labeling (or a mechanism for obtaining this labeling, as appropriate); a statement describing any contraindication(s) in the FDA-required labeling for the medical product; a statement describing 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 company and that are relevant to the unapproved use(s) – if a risk evaluation and mitigation strategy (REMS) has been established the statement should disclose that fact and should describe the goal(s) of the REMS; a statement identifying any authors, editors or other contributors to publication(s) included in the SIUU communication who were employees of or consultants to or who received compensation from the company at the time of writing, editing or contributing to the publication, to the extent a company acting reasonably would know of such relationship; in the case of an SIUU communication that includes one or more source publications primarily focused on a particular scientific study or studies, for each such study where the following information is not included in the source publication, provide a description of: all material aspects of study design, methodology and results; all material limitations related to the study design, methodology and results; 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). The citations for any such studies should also be included. The publication date of any referenced or included source publication (if not specified in the source publication or citation).
• Company-generated presentations should be consistent with the guidance recommendations including: SIUU communications should clearly and prominently present the disclosures; SIUU communications should be separate from promotional communications about approved uses of medical products; SIUU communications should be shared through media and via platforms that enable companies to implement the FDA’s recommendations.

Additionally, to ensure a company-generated presentation is truthful and non-misleading, the company-generated presentation should not, for example:

• imply that the study, analysis or underlying data or information from the source publication represents larger or more-general experience with the medical product than it actually does;
• include representations or suggestions about the safety or effectiveness of the medical product for the unapproved use(s) that are not consistent with the source publication;
• present conclusions or representations about safety or effectiveness for the unapproved use, even if they are an accurate reflection of the statements in the source publication, without attributing that statement expressly to the source publication and without immediately following it with the statement identifying any authors, editors or other contributors to the source publication who were employees of or consultants to or who received compensation from the company at the time of writing, editing or contributing to the source publication;
• present information (e.g., excerpts, quotes, paraphrases, conclusions) from the source publication out of context;
• use statistical analyses or techniques to indicate clinical significance or validity of a finding not supported by the data or information in the source publication;
• use presentational elements to obscure or distort the scientific content, such as by using textual features and graphic design elements to emphasize only positive information or distract attention from unfavorable information, or by using tables or graphs to distort or misrepresent the relationships, trends, differences or changes among the outcomes evaluated in the source publication.

The guidance noted that “nevertheless, it is consistent with the enforcement policy outlined in this guidance for firm generated presentations to use presentational elements and other communication techniques to help explain or illustrate the scientific content in an accurate way or to help ensure clear and prominent presentation of the recommended disclosures. For instance, a communication that includes a firm-generated presentation that is otherwise consistent with the recommendations of this guidance and includes an accurate reproduction of tables or graphs from a source publication, or otherwise makes use of color, typeface, font style, contrast and white space to, for example, ensure a clear and prominent presentation of the recommended disclosures, would be consistent with the enforcement policy,” the guidance said.

“In contrast, firm-generated presentations that use communication techniques to encourage the unapproved use of the medical product based on elements other than the communication’s scientific content are outside the scope of the enforcement policy outlined in this guidance,” the agency said.

“Furthermore, in FDA’s experience, when the following communication techniques are used, in most cases, that use is to influence decisions based on elements other than the communication’s substance: celebrity endorsements, emotional appeals unrelated to the scientific content, gifts, promotional tag lines, jingles, and premium offers. For this reason, the enforcement policy outlined in this guidance does not extend to firm-generated presentations of scientific information on unapproved use(s) that use any of the foregoing communication techniques,” the guidance said.

The enforcement policy also does not extend to company-generated presentations of scientific information about an unapproved use of the company’s approved/cleared medical product that include calls to value that pre-judge the benefit(s) of the medical product for individual patients. Examples of these calls include: “Call FIRM X now for more information on [Medical product X] — it’s the best option for your difficult-to-treat patients!” and “Click here to start improving your patients’ lives today.”

“In contrast, inclusion of a call to value that does not pre-judge the benefit(s) of the medical product for individual patients would not alone cause a firm generated presentation to fall outside the enforcement policy outlined in this guidance. Examples of calls to value that do not pre-judge the benefit(s) of the medical product for individual patients include ‘Click here to access the full article for free!’ or ‘Read now to learn more about this new data on Medical product X,’” the guidance said.

The guidance noted that “without this boundary regarding communication techniques in firm-generated presentations, there would not be a meaningful distinction between firm-generated presentations included in SIUU communications and promotional activities. As with SIUU communications that include firm-generated presentations, a firm’s promotional communications about approved uses are also firm generated, and, particularly when directed to an HCP audience, frequently present scientific content to encourage use of the medical product. Dissolving this distinction between these types of communications would undercut the incentives for firms to develop scientific evidence and engage in the premarket review process in order to promote their medical product.”

The guidance added that because an SIUU communication may be used to inform clinical practice decisions about whether to expose an individual patient to an unapproved use of a medical product, “without the assurances of safety and effectiveness provided by premarket review, it is critical that the communication be presented in a manner that is unlikely to lead HCPs to base those decisions on conclusions about the safety or effectiveness of the unapproved use that are not in alignment with or that go beyond what is justified by the underlying scientific information.”

The guidance said that because SIUU communications are company-initiated communications directed to HCPs engaged in prescribing or administering medical products to individual patients, “it is critical that the source publications that firms choose to share in their SIUU communications are not likely to lead to direct or indirect patient harm when HCPs rely upon the communication to inform clinical decisions. Accordingly, FDA recommends”:

Source publications included by companies in SIUU communications should describe studies and analyses that are scientifically sound.

• To be scientifically sound, the studies or analyses should 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. Statistical rigor is generally necessary, but not sufficient, for a study or analysis to be scientifically sound. Any study or analysis described in a source publication should be evaluated in light of its limitations to determine whether the study or analysis is scientifically sound. In situations where flaws of a study or analysis render it unreliable, such study or analysis would not meet generally accepted design and methodological standards and should not be included in an SIUU communication because even full disclosure of the limitations of such study or analysis would not permit interpretation of results or attribution of the results to an effect of the medical product. Further, disseminating source publications that distort studies or analyses (e.g., by inaccurately describing or reporting results) or that include fraudulent data would not be consistent with the enforcement policy outlined in this guidance and may also violate provisions of the FDA Authorities, such as section 502(a) of the FD&C Act.
• For human and animal drugs, randomized, double-blind, concurrently controlled superiority trials are usually regarded as the most rigorous design and therefore the most likely to provide scientifically sound information. However, other studies also may be scientifically sound when adequately designed and conducted (e.g., data sources are reliable and relevant, protocols and statistical analysis plans are finalized prior to conducting the analyses, data integrity is carefully monitored and maintained). For example, a scientifically sound study could include an early-phase, randomized, double-blind, parallel assignment clinical study with a prespecified statistical analysis plan comparing the pharmacokinetics, pharmacodynamics, safety and immunogenicity of two prescription drug products. Other examples of studies that could be consistent with this recommendation include meta-analyses, cohort or case-control studies, open-label studies, single-arm studies, externally controlled trials and non-interventional (observational) studies.
• For devices, the types of studies, information and analyses that are considered valid scientific evidence are described in 21 C.F.R. §860.7 and may include well-controlled investigations, partially controlled studies, studies and objective trials without matched controls, well-documented case histories conducted by qualified experts, and reports of significant human experience with a marketed device. For devices, these types of studies, information and analyses are most likely to be scientifically sound. Additionally, in the case of devices, 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 also may be scientifically sound.

Companies 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.

• A more recent study that generated a different outcome than a previous study does not necessarily make the previous study obsolete or inappropriate to disseminate. However, each time a company considers disseminating an SIUU communication that includes particular source publication(s), the company should consider whether existing scientific knowledge has, for example, refuted a conclusion from a study described in that source publication or has corrected a long-held misunderstanding that informed a study described in that source publication. The act of disseminating a communication based on a source publication that describes such a study would not fall within the enforcement policy, the guidance said. “If, for example, a firm were to disseminate a source publication that predated the scientific knowledge that Medical Product X causes a severe adverse event in a specific population of women (e.g., severe birth defects when administered to pregnant women) and the source publication suggested Medical Product X was an appropriate treatment for all women, that would not be consistent with this recommendation.”
• In addition, it would not be consistent with this recommendation that companies take into account existing scientific knowledge if a company continues to share an SIUU communication that has been retracted by the publisher because, for example, findings from the study are no longer trusted due to discovery of scientific misconduct or error. Additionally, in a case where understanding of a disease has advanced and shown that certain outcome measures used in studies do not reflect an effect on the disease, sharing source publications that are based on studies that used those outcome measures would not be consistent with the recommendation that companies take into account existing scientific knowledge when determining whether a source publication should be included in an SIUU communication. “Accordingly, when a firm has shared on the Internet an SIUU communication that includes a source publication that is no longer consistent with the recommendation that firms take into account existing scientific knowledge, and the firm has the ability to remove its SIUU communication, we recommend the firm remove its SIUU communication,” the guidance said.

Any conclusions articulated in a source publication should align with the prespecified hypothesis or research question from the described study or analysis and be supported by the results from that study or analysis.

The guidance also noted that Clinical Practice Guidelines that “misrepresent or overstate findings from a study or analysis in light of the limitations of such study or analysis would not fall within the enforcement policy.” In addition, “reference texts or material(s) from digital clinical practice resources that misrepresent or overstate findings from a study or analysis in light of the limitations of such study or analysis” also do not fall within the enforcement policy.