After nearly a decade, the FDA released a revised draft guidance regarding three types of communications by companies to health care providers (HCPs) of scientific information on unapproved uses (SIUU) of approved or cleared medical products.

The new guidance, “Communications From Firms to Health Care Providers Regarding Scientific Information on Unapproved Uses of Approved/Cleared Medical Products Questions and Answers,” supersedes a 2014 draft guidance on distributing scientific and medical publications on unapproved new uses. The revised guidance expands the scope of the 2014 guidance by covering animal drugs and company-generated presentations. It also states that SIUU information must be “scientifically sound and clinically relevant.” The new guidance also adopts a question-and-answer format.

The four questions answered in the new guidance are:

• What should companies consider when determining whether a source publication is appropriate to serve as the basis for an SIUU communication?
• What information should companies include as part of SIUU communications?
• What presentational considerations should companies take into account for SIUU communications?
• What additional recommendations apply to specific types of SIUU communications?

The new guidance covers companies sharing:

• published scientific or medical journal articles (reprints);
• published clinical reference resources – clinical practice guidelines (CPGs), scientific or medical reference texts , and materials from independent clinical practice resources; and
• company-generated presentations of scientific information from an accompanying published reprint.

The guidance said the “FDA has sought to strike a careful balance between supporting HCP interest in scientific information about unapproved uses of approved/cleared medical products to inform clinical practice decisions for the care of an individual patient, and mitigating the potential that the government interests advanced by these statutory requirements will be undermined.”

“This includes the government interest in incentivizing the development of and satisfaction of applicable premarket requirements for medical products, which reduces the need to rely on unapproved use(s), and in protecting patients from medical product uses that have not been shown to be safe and effective,” the guidance said.

The “FDA believes it is critical that SIUU communications be truthful, non-misleading, factual, and unbiased and provide all information necessary for HCPs to interpret the strengths and weaknesses and validity and utility of the information in the SIUU communication,” the guidance said. “In addition, any study or analysis described in a source publication that serves as the basis for an SIUU communication should be scientifically sound. The study or analysis should also provide information that is relevant to HCPs engaged in making clinical practice decisions for the care of an individual patient.”

However, if companies “choose to use persuasive marketing techniques in communications regarding unapproved uses, this suggests an improper intent to market the relevant products for unapproved uses.”

If a company follows the guidance, the “FDA does not intend to use such communication standing alone as evidence of a new intended use.” However, the “guidance does not describe the only circumstances in which FDA does not intend to consider a firm’s dissemination of information about an unapproved use of its approved/cleared medical product to be evidence of the firm’s intent that the medical product be used for an unapproved use,” the guidance said, citing FDA’s guidance on Responding to Unsolicited Requests for Off-Label Information About Prescription Drugs and Medical Devices, and Industry-Supported Scientific and Educational Activities and Drug and Device Manufacturer Communications With Payors, Formulary Committees, and Similar Entities – Questions and Answers, noting that guidance has been superseded in part by Public Law No. 117-328.

“Furthermore, in amending FDA’s regulations regarding evidence of intended use in 2020–2021, FDA provided several examples of evidence that, standing alone, are not determinative of intended use,” the guidance said. “In addition, it has long been FDA policy not to consider a firm’s presentation of truthful and non-misleading scientific information about unapproved uses at the planned sessions and presentations at medical or scientific conferences to be evidence of intended use when the presentation is made in non-promotional settings and not accompanied by promotional communications.”

“Nothing in this draft guidance is intended to convey new policy regarding a firm’s existing obligations under the FDA Authorities to update FDA-required labeling to accurately reflect what is known about the safety profile of the drug, to ensure that the FDA-required labeling is not false or misleading, or for other reasons,” the guidance said.

Questions Answered

On the question of what companies should consider when determining whether a source publication is appropriate, the guidance said the publications “should describe studies or analyses that are scientifically sound and provide clinically relevant information. To be scientifically sound, the studies or analyses, at a minimum, should meet generally accepted design and other methodological standards for the particular type of study or analysis performed, taking into account established scientific principles and existing scientific knowledge.” To be clinically relevant, the studies or analyses, in addition to being scientifically sound, should provide information that is pertinent to HCPs engaged in making clinical practice decisions.

The FDA recommended that for human and animal drugs, randomized, double-blind, concurrently controlled superiority trials were regarded as the most rigorous design and informative to clinical practice, and “therefore the most likely to provide scientifically sound and clinically relevant information; however, other well-designed and well-conducted trials are also able to generate scientifically sound and clinically relevant information,” the guidance said.

For medical devices, studies 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.

In addition, “real-world data and associated real-world evidence about medical products may be scientifically sound and clinically relevant depending on the characteristics of the data and the nature of the analyses,” the guidance said.

Other types of well-designed and well-conducted studies and analyses also can be informative to HCPs, however, “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 and provides clinically relevant information. Certain studies without an adequate comparison or control group, isolated case reports about medical products, and other reports that lack enough detail to permit scientific evaluation would generally not be scientifically sound or clinically relevant and, therefore, use of such reports alone as the basis for an SIUU communication would not be consistent with the enforcement policy outlined in this guidance,” the guidance said.

In addition, “communications that distort studies as well as communications based on publications that distort studies or include fraudulent data would not be consistent with the enforcement policy and may also violate provisions of the FDA Authorities,” the guidance said. “In situations where flaws of a study or analysis render the data unreliable, such study or analysis should also be excluded from serving as the basis of an SIUU communication as 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,” the guidance said.

In addition, “scientific data generated in early stages of medical product development can produce results that are not borne out in later studies, as demonstrated by the failure of some clinical studies to support the use of a medical product for the treatment of a disease or condition for which the medical product initially appeared promising,” the guidance said. “Such scientific data generated in early stages of product development are unlikely to be sufficiently reliable by themselves to allow for a determination of clinical relevance. As a result, a communication based on this type of data alone is unlikely to be within the scope of the enforcement policy,” the guidance said.

It also would not be consistent with the enforcement policy to share an SIUU communication that is based on a study or analysis that is no longer clinically relevant. “A study or analysis may no longer be clinically relevant because, for example, subsequent research has established that the findings from the study or analysis are not reliable. Accordingly, when a firm has shared on the Internet an SIUU communication that is based on a study or analysis that is later determined to no longer be clinically relevant and the firm has the ability to remove their SIUU communication, we recommend the firm remove their SIUU communication,” the guidance said.

What Should Be Included in SIUU Communications

The FDA recommends that - as part of SIUU communications -  companies include:

• 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 the FDA-approved use(s) of the medical product, including any limitations of use specified in the FDA-required labeling.
• 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 a mechanism for obtaining the labeling).
• 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).
• 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 is based on a source publication that is 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 of study design, methodology and results; all material limitations related to the study design, methodology and results, and any conclusions from other relevant studies, when applicable, that are contrary to or cast doubt on the results shared, including citations for such studies.
• The publication date of any referenced or included publication(s) (if not specified in the publication or citation).

Through the guidance the FDA also recommended:

• SIUU communications should clearly and prominently present all disclosures recommended by the agency. “This helps to ensure that HCPs have the information necessary to interpret the scientific information and the SIUU communication as a whole.” The factors the FDA considers when determining whether information is clearly and prominently presented may include type size, font style, layout, contrast, graphic design, headlines, spacing, volume, articulation, pace and any other techniques to achieve emphasis or notice. “For SIUU communications that have both audio and visual components, to help HCPs notice and comprehend the information, FDA recommends that disclosures be presented in both the audio and in text at the same time using the same words (key terms and phrases or a full transcript).” In addition, for SIUU communications that have both audio and visual components, “it would be consistent with the disclosure recommendations of this guidance for both the audio and visual components to include a statement about how to obtain a copy of the most current FDA-required labeling for the medical product that is the subject of the SIUU communication,” the guidance said.
• SIUU communications should not use persuasive marketing techniques. The guidance noted some “marketing techniques influence use of the products based on elements other than the scientific content of the communication.” Examples include the use of celebrity endorsements, premium offers and gifts. In the context of communicating with HCPs in support of an unapproved use, a company’s “choice to use persuasive marketing techniques suggests an effort to convince the HCP to prescribe or use the product for the unapproved use, and FDA therefore considers such communications to be evidence of an intended use of the product,” the guidance said. “And because such communications attempt to influence HCPs to reach positive conclusions about the unapproved use based on elements other than the scientific content, such communications are outside the scope of the [guidance’s] enforcement policy.” The guidance added that “it is also important that the communication be presented in a manner that is unlikely to lead HCPs to base 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.”
• SIUU communications should be separate and distinct from promotional communications about approved uses of medical products. “Including information about unapproved uses in those promotional communications has the potential to undermine the government interests in the premarket requirements of the FDA Authorities,” the guidance said. “We strongly recommend that firms avoid sharing an SIUU communication for a medical product together with a promotional communication for that product for its approved use(s) because combining these two types of communications is more likely to lead to conflation of the approved use and unapproved use information,” the FDA said. “This conflation may lead HCPs to conclude that the firm’s medical product has been demonstrated to be safe and effective for all presented uses, including the unapproved use(s), or to conclude that all presented uses of the medical product are uses for which it may be approved/cleared.” The FDA also recommended that companies “use dedicated vehicles, channels, and venues for sharing SIUU communications that are separate from the vehicles, channels, and venues used for promotional communications about approved uses of medical products to reduce the risk of HCPs conflating the approved and unapproved use information. In cases where there is only one vehicle, venue, or channel available for the sharing of information, a firm should ensure that SIUU communications are clearly identified and distinct from promotional communications about approved uses.” For example, the FDA recommends SIUU communications be on a separate web page from a web page that hosts promotional communications about the approved uses of the medical product. The FDA also recommends that companies not include direct links from web pages that host promotional communications about approved uses to webpages that host SIUU communications. Similarly, FDA recommends that email messages used to share SIUU communications be separate and distinct from email messages used to share promotional communications about approved uses of the medical product. In addition, “when sharing information in commercial exhibit halls and similar venues where programming is not selected and determined by the conference organizers, firms should ensure that SIUU communications are clearly identified and distinct from promotional communications about approved uses. For example, in commercial exhibit halls, FDA strongly recommends that firms divide booth space to allow for a dedicated space where SIUU communications can be shared, separate and distinct from promotional communications about approved uses.
• SIUU communications should be shared through media and via platforms that enable companies to implement the FDA recommendations. The guidance noted that every “medium and platform may prompt unique presentational challenges and considerations. For example, certain online platforms may impose character-space limitations or other presentational limitations that would not enable a firm to include within their communications on that platform all of the disclosures that are recommended for an SIUU communication,” the guidance said. To be consistent with the FDA recommendations, “such platforms should not be used to host SIUU communications but could be used to direct HCPs to an SIUU communication. For example, it would be consistent with the recommendations for a communication on a character-space limited platform to direct HCPs to an SIUU communication through a statement that does not mention the name of any specific medical product, such as 'New publication for Health Care Providers – Phase 3 trial results for an investigational treatment for [disease X],' followed by a link to a website where the SIUU communication appears.” The guidance adds that companies “should carefully consider the limitations of different media types and platforms to ensure that the medium and platform used for sharing an SIUU communication allows the firm to include all information consistent with the recommendations.”
• Companies should consider using plain language in the content they develop for SIUU communications to aid comprehension. “Although HCPs have specialized training and experience in evaluating scientific information, research indicates that HCPs may nonetheless have difficulty understanding some types of scientific information, including clinical trial data, and the design and methodological limitations of studies,” the guidance said. “To aid in comprehension and encourage careful consideration of the information shared in an SIUU communication, firms should consider using plain language for any firm-generated portions of the SIUU communication, including recommended disclosures.” The guidance defined “plain language” as “language that is clear, concise, well-organized, and where possible, avoids complexities such as technical jargon, passive voice, and long sentences and paragraphs. Clearly explaining scientific or technical terms and avoiding or appropriately introducing acronyms and abbreviations can facilitate comprehension,” the guidance said.

The guidance also provided recommendations for reprints, saying all reprints should have all of the following characteristics:

• The article is published in a journal managed by an independent organization with an editorial board comprised of persons who have demonstrated expertise in the subject of the articles under review by the organization (through education or experience), and a publicly stated policy regarding the disclosure of conflicts of interest or biases for all authors, contributors or editors.
• The article is peer-reviewed by experts in the subject of the article, as established by education or experience.
• The article is generally available (or the journal from which the article is taken is generally available) through independent distribution channels (e.g., Internet sources, book retailers, subscriptions, libraries) where periodicals and reprints are sold or are accessible.
• The article describes studies or analyses that are scientifically sound and provides information that is clinically relevant, specifically to be scientifically sound and clinically relevant.
• Reprints should be unaltered/unabridged as the sharing of unaltered/unabridged articles is less likely to introduce bias or result in the omission of material information.

The guidance noted that “articles that misrepresent or overstate findings in light of the limitations of the study or analysis would not be consistent with the enforcement policy."

When companies share SIUU communications in the form of one or more individual sections of clinical reference resources, which include clinical practice guidelines (CPGs), reference texts and materials from independent clinical practice resources, the SIUU communication “should include all information from the clinical reference resource necessary for HCPs to interpret the strengths and weaknesses and validity and utility of the information. This may involve the sharing of multiple sections of the clinical reference resource that contain related or linked information,” the guidance noted.

In addition, the individual sections “should be unaltered/unabridged and extracted directly from the clinical 675 reference resource,” the guidance said. “When a firm shares an SIUU communication in the form of an unabridged CPG or reference text in its entirety that discusses a wide range of medical products and that discussion is not primarily focused on one or more of a firm’s medical products,” the FDA does not expect a company to include:

• A statement disclosing the FDA-approved use(s), including any limitations of use specified in the FDA-required labeling, for each of the company’s medical products mentioned.
• A statement disclosing any limitations, restrictions, cautions, or warnings described in the FDA-required labeling about the unapproved use(s) for each of the company’s medical products mentioned.
• A copy of or mechanism to obtain the FDA-required labeling for each of the company’s medical products mentioned.
• A statement describing the contraindications in the FDA-required labeling for each of the company’s medical products mentioned.
• A description of the serious, life-threatening or fatal risks that are in the FDA-required labeling or are known by the company and that are relevant to the unapproved use(s) posed by each of the company’s medical products mentioned, including whether a REMS has been established for any of the products.

Instead, the FDA recommended companies include a more general statement in the SIUU communication, such as – “This [CPG/reference text] describes some uses of medical products that are not approved by the FDA, and the safety and effectiveness of any unapproved use(s) have not been established.”

In addition, when companies share SIUU communications in the form of a CPG, the FDA recommended the CPG have all of the following characteristics:

• The CPG is based on rigorous reviews of the existing evidence conducted according to a clear, established procedure and following a transparent process that minimizes biases and conflicts of interest.
• The CPG include ratings of the recommendations to reflect the quality and strength of evidence that supports each recommendation.
• The CPG is revised when important new evidence warrants modifications of current recommendations.
• The CPG is generally available through independent distribution channels (e.g., internet sources, book retailers, subscriptions, libraries) where CPGs are sold or are accessible.

The guidance noted that when considering whether a particular CPG is appropriate to serve as the basis for an SIUU communication, a helpful resource is the National Academy of Medicine (NAM) standards for CPG “trustworthiness.” “CPGs that are consistent with the NAM standards would also be in alignment with the standards FDA has articulated,” the guidance said. The NAM standards recommend that CPGs:

• be based on a systematic review of the existing evidence;
• be developed by a knowledgeable, multidisciplinary panel of experts and representatives from key affected groups;
• consider important patient subgroups and patient preferences, as appropriate;
• be based on an explicit and transparent process by which the CPG is developed and funded that minimizes distortions, biases and conflicts of interest;
• provide a clear explanation of the logical relationships between alternative care options and health outcomes, provide clearly articulated recommendations in standardized form, and provide ratings of both quality of evidence and the strength of recommendations; and
• be reconsidered and revised when important new evidence warrants modifications of recommendations.

The guidance also recommended that reference text or material from an independent clinical practice resource have all the following characteristics:

It is published by an independent publisher that is in the business of publishing scientific or medical educational content.

It is 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.

It is authored, edited and contributed to by experts who have demonstrated expertise in the subject area(s) through education or experience.

It is generally available or sold through independent distribution channels, such as Internet sources, book retailers, subscriptions and libraries for medical and scientific educational content.

In regard to company-generated presentations of scientific information, the guidance said the material “should be truthful, non-misleading, factual, and unbiased and provide all information necessary for HCPs to interpret the strengths and weaknesses and validity and utility of the presented information.” The guidance recommended that:

• Full reprint(s) should accompany the company-generated presentation and should be consistent with the recommendations regarding reprints. However, the guidance cautioned that companies “should not rely upon the accompanying reprint(s) to provide information that is material to the representations made in the firm-generated presentation; all information material to the representations made in the firm-generated presentation should be included with those representations within the firm-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 recommended in the guidance and clearly disclose what portions of the communication are company-generated.
• Company-generated presentations should be consistent with the guidance recommendations regarding presentational considerations.
• Company-generated presentations should not: imply that the study, analysis, or underlying data or information from the reprint(s) represents larger or more general experience with the medical product than it actually does; present information (e.g., excerpts, quotes, paraphrases, conclusions) from the reprint(s) out of context, without the information necessary for HCPs to interpret the strengths and weaknesses and validity and utility of the information; include representations or suggestions about the safety or effectiveness of the medical product for the unapproved use(s) that are not consistent with the reprint; present conclusions or representations about safety or effectiveness for the unapproved use, even if an accurate reflection of the statements in the reprint, without attributing that statement expressly to the reprint and without immediately following it with the statement identifying any authors, editors or other contributors to the reprint(s) who were employees of or consultants to or who received compensation from the company at the time of writing, editing, or contributing to the reprint; use statistical analyses or techniques to indicate clinical significance or validity of a finding not supported by the data or information in the reprint; and use tables or graphs or other presentational elements to distort or misrepresent the relationships, trends, differences or changes among the outcomes evaluated in the reprint.

Submit electronic comments on the draft guidance to Docket No. FDA-2008-D-0053 on www.regulations.gov by Jan. 5, 2024.