[co-author: Priya Sinha]

In its 1997 hit song “Don’t Go Away,” the rock band, Oasis, sang, “Say what you say . . . ’cause I need more time . . . just to make things right.” The lyrics must have been playing in the hallway when the Food and Drug Administration recently issued a draft guidance titled “Communications From Firms to Health Care Providers Regarding Scientific Information on Unapproved Uses of Approved/Cleared Medical Products: Questions and Answers” (“SIUU Draft Guidance”). The Draft attempts to find the balance of dissemination of off-label uses while encouraging companies to submit new applications to include this information on an approved product label.¹ The guidance describes certain communications by firms to healthcare providers (“HCPs”) of scientific information on unapproved uses (“SIUU”) of approved or cleared medical products.² The SIUU Draft Guidance focuses on the following types of communications:

• Published scientific or medical journal articles (reprints)
• Published clinical reference resources, such as:
  • Clinical practice guidelines (“CPGs”)
  • Scientific or medical reference texts
  • Materials from independent clinical practice resources
• Firm-generated presentations of scientific information from an accompanying published reprint

FDA will accept comments on the SIUU Draft Guidance until December 24, 2023. When finalized, the SIUU Draft Guidance will supersede the 2014 draft guidance on dissemination of scientific information titled “Distributing Scientific and Medical Publications on Unapproved New Uses–Recommended Practices,” which revised a 2009 draft guidance titled “Good Reprint Practices for the Distribution of Medical Journal Articles and Medical or Scientific Reference Publications on Unapproved New Uses of Approved Drugs and Approved or Cleared Medical Devices.” The Draft is in a question-and-answer format.

This Bulletin summarizes key points from the Draft.

Highlights

• Reprints are copies of an article originally published by a medical or scientific journal.
• CPGs are statements or documents from a professional or academic organization that include recommendations focused on a specific disease or condition intended to help HCPs make decisions for individual patient care, including decisions in circumstances where there are few or no approved medical products indicated for the patient’s condition, or the approved medical products have not proven successful for the individual patient.
• Scientific or medical reference texts are medical or scientific textbooks that typically discuss a wide range of topics.
• Materials from independent clinical practice resources are digital resources that contain medical and scientific information on a wide range of topics developed by subject matter experts in various medical specialty fields. The information is typically searchable by topic or keyword and produces materials in response to the HCP’s search terms.
• Because SIUU may be used to inform clinical decisions, the SIUU must be truthful, non-misleading, factual, and unbiased. It should provide all information necessary for HCPs to interpret the strengths and weaknesses and the validity and utility of the information. SIUU must be based on scientifically sound studies and provide clinically relevant information.
• If a firm shares an SIUU communication that follows the Draft, FDA will not use the communication as stand-alone evidence of a violation of law (with other evidence, this could possibly change).
• FDA addresses what firms should consider when determining whether a source publication is appropriate to serve as the basis for an SIUU communication.
  • The source publication should describe studies or analyses that are scientifically sound and provide clinically relevant information.
    • To be scientifically sound, the studies and analyses should use generally accepted design and other methodological standards for the particular type of study or analysis performed.
    • To be clinically relevant, the studies or analysis should provide information that is relevant to HCPs engaged in making clinical practice decisions.
  • For drug products, FDA notes that randomized, double-blind, concurrently controlled superiority trials are most likely best to demonstrate scientifically sound and clinically relevant information.
  • For medical devices, the agency states that companies should consider well-controlled investigations, partially controlled studies, objective trials without matched controls, well-documented case histories conducted by qualified experts, and reports of significant human experience with a marketed device.
  • Scientific data generated in early stages of product development are likely not a reliable basis.
• The agency discusses what information firms should include as part of SIUU communications.
  • A statement that the unapproved use of the medical product has not been approved by FDA, and the safety and effectiveness of the product for the unapproved use has not been established.
  • A statement disclosing the FDA-approved use of the medical product, including any limitations of use in the FDA-required labeling.
  • A statement disclosing any limitations, restrictions, cautions, or warnings described in the FDA-required labeling about the unapproved use.
  • A copy of the most current FDA-required labeling (or a way to obtain it).
  • A statement describing any contraindications in the FDA-required labeling.
  • A statement describing any serious, life-threatening, or fatal risks of the product that are in the FDA-required labeling or that are known by the firm and relevant to the unapproved use.
  • A statement identifying any authors, editors, or other contributors to publications included in the SIUU communication who were employees or consultants of the firm or received compensation.
  • All relevant information for a scientific study that is the basis for an SIUU communication, including design, results, limitations of study designs, and contrary studies (if not included in the publication).
  • The publication date of any referenced or included publications.
• FDA describes what presentational considerations firms should take into account for SIUU communications.
  • Firms should clearly and prominently present all disclosures recommended in the Draft.
    • For example, a company should use type size, font style, layout, contract, graphic design, headlines, and spacing for emphasis purposes.
    • For SIUU components that have both audio and visual components, the company should provide disclosures in both the audio and in text at the same time using the same words.
  • Firms should not use “persuasive” marketing techniques (e.g., celebrity endorsements, premium offers, and gifts), which are not based on the scientific content of the communications.
  • Firms should separate SIUU messaging from promotional communications about a product’s approved use.
    • FDA recommends using vehicles, channels, and venues for sharing SIUU communications that are separate from those used for promotional communications. For example, on a website, SIUU communications should be on a separate web page from the web page that promotes an approved use.
    • At medical conferences, firms should divide booths so that there is a dedicated space for SIUU communications, separate from promotional messaging for the product’s approved use.
  • Firms should share SIUU communications through platforms that allow firms to implement the Draft’s recommendations. For example, platforms that limit word and character count should not be used to host SIUU communications, but can be used to direct HCPs to an SIUU communication (but without identifying a specific product, e.g., “new publication for Healthcare Providers – phase 3 trial results for an investigation treatment for [disease x]” and then link to the website where one can find the SIUU communication).
  • Firms should use plain language for SIUU communications to facilitate comprehension. Plain language should be clear, concise, and well organized — avoid technical jargon, passive voice, acronyms, long sentences, and paragraphs.
• FDA provides additional recommendations that apply to specific types of SIUU communications.
  • Reprints
    • When sharing reprints, FDA recommends that firms ensure that the reprints are:
      • published in a journal managed by an independent organization with an editorial board of experts on the subject matter, and have a publicly disclosed policy concerning conflicts of interest or biases for all authors, contributors, or editors;
      • peer reviewed by experts on the subject matter;
      • generally available through independent distribution channels where periodicals and reprints are sold or are accessible (e,g., book retailers, subscriptions, libraries);
      • describe studies that are scientifically sound and provide information that is clinically relevant (discussed above); and
      • unaltered or unabridged.
  • Clinical reference resources
    • CPGs
      • When firms share a CPG as an SIUU communication, FDA advises that firms should ensure that CPGs:
        • are based on rigorous reviews of existing information that follow established procedures and follow transparent processes;
        • include ratings of the recommendations to reflect the quality and strength of evidence that supports each recommendation;
        • are revised when new evidence requires modifications to the recommendation; and
        • are available through independent distribution channels where CPGs are sold or accessible.³
    • Reference texts and independent clinical practice resources
      • When firms share SIUU communications in the form of a reference text or an independent clinical practice source, FDA recommends that they are:
        • published by an independent company in the business of providing scientific or medical educational content;
        • published in a manner consistent with current standards for medical content creation, such as following a publisher’s specific peer-review procedures;
        • authored, edited, and contributed to by experts with a demonstrated expertise in the subject area; and
        • generally available or sold through independent distribution channels for medical and scientific educational content.
      • When a firm shares an SIUU communication in the form of an unabridged CPG or reference text in its entirety that discusses a range of medical products and that discussion is not primarily focused on one or more of a firm’s medical products, FDA does not expect a firm to include the types of aforementioned disclosures.
        • FDA suggests a more general statement about SIUU communications, 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.”
  • Firm-generated presentations of scientific information from an accompanying published reprint
    • For firm-generated presentations of scientific information from an accompanying reprint, FDA recommends that:
      • the full reprints should accompany the firm-generated presentation, but all information material to the representation should be included with those representations; and
      • firm-generated presentations should include the required disclosures under the Draft and clearly disclose what portions of the presentation are firm generated.
    • Firm-generated presentations should not:
      • imply that a study, analysis, or the underlying data from the reprints represents larger or more general experience with the medical product than it actually does;
      • present information from the reprints out of context;
      • include representations or suggestions about the safety or effectiveness of the medical product for the unapproved use that are not consistent with the reprint;
      • present conclusions or representations about safety or effectiveness for the unapproved use, even if it is an accurate reflection of the statements in the reprint, without attributing the statement directly to the reprint and immediately following it with a statement identifying the authors, editors, or other contributors to the reprints who were employees of or consultants to or who received compensation from the firm 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
      • use presentational elements to distort or misrepresent the data.

AGG Observations

• The SIUU Draft Guidance is broader than the 2014 guidance in many ways: (1) the new Draft adds the category of “materials from independent clinical practice resources” to clinical reference resources; (2) it includes a new category of communications — “firm-generated presentations of scientific information from an accompanying published reprint;” (3) it discusses new “presentational considerations;” (4) it requires substantive disclosures, where appropriate; and 5) the “SIUU” term is new.
• The Draft introduces a new standard for SIUU communications — “scientifically sound” and “clinically relevant.”
• The definition of “FDA-required labeling” differs from the definition of “FDA-required labeling” in another recently issued draft guidance titled “Regulatory Considerations for Prescription Drug Use-Related Software.”⁴
• The Draft focuses on communications by firms to HCPs, compared to researchers or patients.
• FDA continues to balance the need for allowing companies to provide SIUU-type information to HCPs while requiring companies to seek approval for new uses. “Say what you say” to educate HCPs, but try to “make things right” by seeking marketing authorization for the new uses.

AGG Food & Drug co-chair Alan Minsk would like to recognize AGG law clerk Priya Sinha as a co-author of this Bulletin.

[1] https://www.fda.gov/media/173172/download.

[2] For simplicity, we will use the term “approved” for all types of products.

[3] FDA recommends reviewing the National Academy of Medicine standards for “trustworthiness” when evaluating whether a particular CPG is appropriate: https://nap.nationalacademies.org/catalog/13058/clinical-practice-guidelines-we-can-trust.

[4] AGG prepared a Bulletin on this issue, which can be accessed here: https://www.agg.com/news-insights/publications/fda-issues-new-draft-guidance-on-regulatory-considerations-for-prescription-drug-use-related-software/.