For the first time in almost 10 years, the U.S. Food and Drug Administration (FDA) released a draft guidance related to certain communications by firms to healthcare providers (HCPs) of scientific information on unapproved use(s) (SIUU) of approved or cleared medical products. The October 23, 2023, draft guidance, “Communications From Firms to Health Care Providers Regarding Scientific Information on Unapproved Uses of Approved/Cleared Medical Products Questions and Answers Guidance for Industry,” relates to communications including published scientific or medical journal articles (also known as reprints), published clinical resources such as clinical practice guidelines (CPGs), and firm-generated presentations of scientific information from an accompanying published reprint. Most notably, the draft guidance provides recommendations and considerations for digital publications and social media.

This guidance follows a February 2014 similar draft guidance, “Distributing Scientific and Medical Publications on Unapproved New Uses,” that was followed by a 2016 public meeting, 2017 memorandum with additional guidance, and 2021 preamble to the FDA’s final rule on “intended use.” The 2023 draft guidance responds to industry comments to all of these prior efforts and builds on the near decade of technology advancements and enforcement actions since the last draft guidance in 2014.

Background

As an initial matter, the term “firm” or “firms” applies to individuals or entities with legal responsibility for the labeling of medical products. This includes applicants, sponsors, requestors, manufacturers, packers, distributors of medical products, licensees of these entities, and individuals representing these organizations in their communications. HCPs, on the other hand, include licensed or legally authorized individuals, such as physicians, veterinarians, dentists, physician assistants, nurse practitioners, pharmacists, or registered nurses, who can prescribe, order, administer, or use medical products in a professional capacity.

The Federal Food, Drug, and Cosmetic Act, in conjunction with the Public Health Service Act, prohibits the introduction of medical products into interstate commerce that do not comply with premarket requirements or are misbranded or adulterated. This prohibition includes medical products intended for unapproved uses, even if they are approved for different purposes, as such actions can undermine important government interests, such as increasing the availability of medical products that have been shown to be safe and effective for a particular use and in preventing direct and indirect harm from uses of medical products that have not been shown to be safe and effective. However, the FDA has said that it recognizes that HCPs may require scientific information about unapproved uses for individual patient care decisions and aims to strike a balance between supporting HCPs’s access to such information and safeguarding government interests in this and past guidances.

The intended use of a medical product can be determined from various sources, including its label, accompanying labeling, packaging, promotional claims, and advertising. For example, claims or statements made by a firm or a firm’s sales representative that explicitly or implicitly promote a medical product for a particular use may be taken into account by HCPs in informing their treatment of a patient. HCPs prescribe and use approved/cleared medical products for unapproved uses when they determine that such unapproved use is medically appropriate for their individual patient. For instance, these patients may have unique characteristics and requirements that differ from the populations for which the use is officially approved.

Draft Guidance

As in prior guidances, the FDA states that SIUU communications must be: 1) truthful, non-misleading, factual, and unbiased; 2) “provide all information necessary for HCPs to interpret the strengths and weaknesses and validity and utility of the information in the SIUU communication”; 3) “scientifically sound”; and 4) “clinically relevant” (e.g., provide information “pertinent to HCPs engaged in making clinical practice decisions for the care of an individual patient”). Although the SIUU Guidance acknowledges that pharmaceutical and medical device companies have a valid concern in conveying accurate and non-misleading information regarding scientific advancements and clinical data, the FDA refrains from establishing a "safe harbor" for a company's non-commercial medical or scientific educational activities.

In pursuit of the balance between supporting HCP interest in scientific information about unapproved uses and the government’s interests in satisfying premarket requirements, the FDA stresses that SIUU communications must be truthful, unbiased, and comprehensive, providing HCPs with all necessary data to evaluate the information’s validity and utility. The draft guidance outlines four common considerations (and corresponding recommendations) regarding SIUU communications by manufacturers to HCPs—each is highlighted below.

1. Source publication considerations

• Source publications that serve as the foundation for SIUU communications should detail studies or analyses that are both scientifically sound and clinically relevant.
• A scientifically sound study or analysis will, at a minimum, meet generally accepted design (and other methodological) standards for the particular type of study or analysis performed, considering established scientific principles and existing scientific knowledge. Clinical relevance means that a study or analysis provides information that is pertinent to HCPs engaged in clinical decision-making for individual patients.
• Real-world data and real-world evidence about medical products may meet both of the above criteria, as may other types of well-designed and well-conducted studies and analyses. The FDA’s bottom line is that 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.
• Scientific data generated in early stages of product development, when used alone, are unlikely to be sufficiently reliable to allow for a determination of clinical relevance.
• Firms should delete SIUU communications that are based on studies or analyses that are no longer clinically relevant—for example, if subsequent research has made clear that the study’s findings are not reliable.

2. Information to include in SIUU communications

• SIUU communications should include:
  • FDA-required labeling;
  • FDA-approved use(s) and any limitations of use;
  • statement that the unapproved use(s) have not been approved by the FDA, and therefore the safety and effectiveness of the unapproved use(s) has not been established;
  • any limitations, restrictions, cautions, or warnings from the labeling related to unapproved use(s); and
  • statement identifying any author, editors, or contributors to the publication in the SIUU communications who were employees, consultants, or otherwise compensated by the firm.
• In addition to the above, SIUU communications based on a particular scientific study should also include:
  • all material aspects of the study design, methodology, and results;
  • all material limitations related to the study design, methodology, and results; and
  • any conclusions from other studies that are contrary to or cast doubt on the SIUU communications, including citations to such studies.

3. Presentational considerations to take into account

• SIUU Communications should:
  • clearly and prominently present all disclosures recommended in the guidance—e.g., use audio and visual components to help HCPs notice and comprehend the information;
  • not use “persuasive marketing techniques”—which would not appropriately serve the purpose of informing clinical practice decisions for individual care;
  • be separate and distinct from promotional communications about approved uses of medical products, including on social media or other digital channels—e.g., use a web page for SIUU communications and a separate web page for promotional communications about the approved uses; and
  • not be hosted on social media platforms that impose character-space limitations if the character-space limitations would prevent the firm from implementing the recommendations of the guidance. 
• Firms should consider using plain language in the content they develop for SIUU Communications to be more easily understandable, as HCPs may have difficulty understanding some types of scientific information, such as clinical trial data, or the design limitations of a study.

4. Additional recommendations

• If an SIUU communication is in the form a reprint, the reprint should:
  • be from a journal managed by an independent organization with an editorial board that has demonstrated expertise in the subject of the article;
  • be peer-reviewed by experts in the subject of the article;
  • be generally available through independent distribution channels;
  • describe studies or analyses that are scientifically sound and provide information that is clinically relevant; and
  • be unaltered/unabridged, in order to reduce bias or result in the omission of material information.
• If an SIUU communication is in the form of a clinical reference resource (e.g., CPG, reference text, materials from independent clinical practice resources), the resource 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, which may involve sharing multiple sections of the clinical reference resource that contain related or linked information; and
  • follow the other recommendations in the guidance with the following exceptions for unabridged CPGs or reference texts:
    • not required to disclose the FDA-approved use(s) and limitations of use;
    • not required to disclose limitations, restrictions, cautions, or warnings described in the FDA-required labeling;
    • not required to include a statement describing the contraindications in the FDA-required labeling; and
    • not required to include a description of the serious, life-threatening, or fatal risks that are in the FDA-required labeling or are known by the firm and that are relevant to the unapproved use(s).
• If an SIUU communication is in the form of a CPG specifically, the CPG should, in addition to the above:
  • be based on rigorous reviews of the existing evidence conducted according to a clear, established procedure and process that minimizes biases and conflicts of interest;
  • include ratings of the recommendations to reflect the quality and strength of evidence for each recommendation;
  • be revised when important new evidence warrants changes to existing recommendations; and
  • be generally available through independent distribution channels.
• If an SIUU communication is in the form of a reference text or independent clinical practice resource specifically, the text or resource should, in addition to the above:
  • be published by an independent publisher that is in the business of publishing scientific or medical educational content;
  • be 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;
  • be authored, edited, and contributed to by experts who have demonstrated expertise in the area; and
  • be generally available through independent distribution channels.
• If an SIUU communication is in the form of a firm-generated presentation, the presentation should:
  • be accompanied by the full reprint;
  • include all information material to the representations from the reprint;
  • identify any author, editors, or contributors to the presentation who were employees, consultants, or otherwise compensated by the firm;
  • identify what portions of the communication are firm-generated;
  • be consistent with the presentational considerations in this guidance; and
  • ensure the presentation of scientific information from the accompanying reprint is truthful, non-misleading, factual, and unbiased—meaning the presentation should not:
    • imply a study, analysis, or underlying data represents larger or more-general experience with the medical product than it actually does;
    • present quotes, conclusions, or excerpts out of context;
    • include suggestions about efficacy or safety that are inconsistent with the reprint;
    • present conclusions about safety or effectiveness for the unapproved use without attributing the statement to the reprint and with reference to contributors compensated by the firm;
    • use statistical analysis to indicate clinical significance of a finding that is unsupported by the reprint; or
    • distort or misrepresent the relationships, trends, differences, or changes among the outcomes evaluated in the reprint through tables, graphs, or other presentational elements.

Next Steps

Members of the industry can submit comments on the proposed rule here—comments are due by December 24, 2023. If you are interested in submitting comments to the FDA or have questions, please contact Georgia Ravitz, James Ravitz, Eva Yin, Andrea Linna, Paul Gadiock, Shawn Lichaa, Marissa Hill Daley, or any member of the firm’s FDA regulatory, healthcare, and consumer products practice.

Marissa Hill Daley contributed to the preparation of this alert.