• The FDA issued Revised Draft Guidance addressing communications by drug and device manufacturers about “off-label” uses of approved products.
• The Revised Draft Guidance supersedes FDA’s 2014 Draft Guidance on “Distributing Scientific and Medical Publications on Unapproved New Uses.”
• The Revised Draft Guidance expands the scope of permissible communications, yet limitations and restrictions remain.
• FDA continues to exercise enforcement discretion for communications that are consistent with the recommendations in the guidance.

On October 23, 2023, the U.S. Food and Drug Administration (FDA) issued a revised draft guidance, “Communications From Firms to Health Care Providers Regarding Scientific Information on Unapproved Uses of Approved/Cleared Medical Products.”¹ This revised draft guidance supersedes FDA’s 2014 draft guidance document, “Distributing Scientific and Medical Publications on Unapproved New Uses – Recommended Practices.”² The new guidance represents FDA’s latest attempt to regulate the ever-widening practice by drug and device manufacturers of communicating about “off-label” uses of approved products.

Background

Under the Federal Food, Drug, and Cosmetic Act (FDCA) and FDA regulations, manufacturers and other regulated firms (firms) are prohibited from introducing new drugs and most medical devices (medical products) into interstate commerce for any intended use that FDA has not approved or cleared (an unapproved or “off-label” use), even if that same medical product is approved or cleared by FDA for a different use.³

The intended use of a medical product can be established from, among other things, its label, accompanying labeling, promotional claims, advertising, and any other relevant source.⁴ Accordingly, a firm’s communications may be relevant in establishing whether its medical product is subject to regulation by FDA, and whether particular statutory or regulatory provisions apply to the medical product.

The revised draft guidance represents a continuation of FDA’s efforts to refine its policies and recommendations relating to communications by firms about unapproved uses of their approved/cleared medical products.

Revised Draft Guidance – Overview

The revised draft guidance provides specific recommendations regarding certain communications by firms to health care providers (HCPs) of scientific information on unapproved use(s) (SIUU communications) of approved/cleared medical products.

Three categories of SIUU communications are addressed:

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

FDA believes it is critical that SIUU communications be (1) truthful, (2) non-misleading, (3) factual, (4) unbiased, and (5) are provided with all information necessary for HCPs to interpret the strengths and weaknesses, and validity and utility of the information about the unapproved use. The revised draft guidance describes the information (disclosures) that should accompany an SIUU communication to help ensure it meets the requirements above. The bulk of these disclosures are similar to FDA’s recommendations in the 2014 draft guidance. In addition, according to FDA, SIUU communications should be based on studies and analyses that are scientifically sound and should provide clinically relevant information.

If a firm shares an SIUU communication with HCPs in a manner that is consistent with the recommendations in the guidance, FDA does not intend to use such communication, standing alone, as evidence of a new intended use (enforcement policy).

Important Differences Between the 2014 and 2023 Draft Guidance Documents

• Categories of Communications are Expanded – The newly revised draft guidance adds two categories of communications that were not included in the 2014 draft guidance: (1) materials from independent clinical practice resources, and (2) firm-generated presentations of scientific information from an accompanying published reprint. The first category refers to digital resources, typically searchable, that contain medical and scientific information on a wide range of topics developed by subject matter experts. The addition of the second category is particularly significant because it recognizes that firms often develop presentations to accompany distributed reprints (e.g., “reprint carriers”). FDA includes specific recommendations for the dissemination of firm-generated presentations, including that all information material to the representations made in the firm-generated presentation should be included with those representations within the firm-generated presentation.

• SIUU Communications Should Be “Clinically Relevant” – The revised draft guidance makes clear (and repeats several times in the document) that (1) the guidance is limited to communications by firms to HCPs engaged in making clinical practice decisions for the care of an individual patient, and (2) the study or analysis that is the basis for the communication should provide information that is “clinically relevant” to such HCPs. The guidance suggests that this new element (not addressed in the 2014 draft guidance) is intended to distinguish these communications from a firm’s communications with the payor/formulary committee/similar entity audience,⁵ and with HCPs in their capacities as researchers. In addition, the revised draft guidance clarifies that, in general, reprints that focus on nonclinical studies or analyses alone would not be clinically relevant, and thus not consistent with the revised draft guidance.

• SIUU Communications Should Not Use “Persuasive Marketing Techniques” – The revised draft guidance explains that the use of persuasive marketing techniques “suggests an improper intent to market the relevant products for unapproved uses.” Therefore, such communications are outside the scope of the enforcement policy outlined in the draft guidance. FDA explains that, “[s]ome of these marketing techniques influence use of the products based on elements other than the scientific content of the communication,” and provides three examples: the use of celebrity endorsements, premium offers, and gifts. However, the scope of FDA’s guidance on this point is not clear.

• Real-World Data – Unlike the 2014 draft guidance, the revised draft guidance provides that, “[r]eal-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 revised draft guidance recommends that analyses of real-world data should be prespecified, protocols and statistical analysis plans should be finalized prior to conducting the prespecified analyses, and data integrity should be carefully monitored and maintained.

• Online Platforms – The revised draft guidance recommends that SIUU communications should be shared through media and via platforms that enable firms to implement the disclosure recommendations in the guidance. For example, online platforms that impose character-space limitations or other presentational limitations that would not enable a firm to include within the communication all of the disclosures recommended in the guidance should not be used. However, such platforms could be used to direct HCPs to a linked SIUU communication, as long as the directional statement does not mention the name of any specific medical product (e.g., “New publication for HCPs – phase 3 trial results for an investigational treatment for disease X”).

• Plain Language – The revised draft guidance recommends that firms consider using plain language for any firm-generated portions of an SIUU communication to facilitate comprehension by HCPs.

Conclusion

FDA regulation of communications by firms regarding off-label uses of their products has been something of a work in progress over the years, iterating through First Amendment challenges,⁶ citizen petitions, and a variety of FDA guidance documents. The revised draft guidance represents the latest evolution of FDA’s thinking on this topic.

It is very significant that FDA has expanded the categories of acceptable communications covered by the revised draft guidance. First, the addition of materials from independent clinical practice resources is a recognition of the greater role that digital resources play in today’s medical practice. Second, the inclusion of firm-generated presentations from accompanying reprints is responsive to industry’s use of reprint carriers and its desire to summarize or highlight information that a very busy HCP might not have time to read if only presented with a copy of the reprint. Third, the statement that real-world data may be scientifically sound and clinically relevant is an acknowledgment of the growing role of real-world data in regulatory decision-making.

On the other hand, the revised draft guidance includes a number of notable limitations/restrictions that raise further questions in turn. For example:

• The revised draft guidance notes that (a) scientific data generated in early stages of medical product development are unlikely to be clinically relevant, and (b) a study may no longer be clinically relevant because subsequent research has questioned the reliability of the data. Will FDA object to SIUU communications based on such data as not clinically relevant?

• The revised draft guidance suggests that SIUU based on studies “without an adequate comparison or control group,” “isolated case reports,” “reports that lack enough detail to permit scientific evaluation,” and with weaknesses in study design are not scientifically sound. Will FDA object to SIUU communications based on such studies that are not scientifically sound?

• FDA’s recommendation for firm-generated presentations of scientific information is limited to presentations that accompany reprints. Will FDA object to firm-generated presentations of scientific information that are not accompanied by a reprint, or that present scientifically sound and clinically relevant information not contained in the reprint?

1. Available at: www.fda.gov/regulatory-information/search-fda-guidance-documents/communications-firms-health-care-providers-regarding-scientific-information-unapproved-uses
2. Available at: www.fda.gov/regulatory-information/search-fda-guidance-documents/distributing-scientific-and-medical-publications-risk-information-approved-prescription-drugs-and-devices
3. See, e.g., Sections 505(a), 515(a), 501(f)(1), and 301(a) and (d) of the FDCA (21 U.S.C.A. 355(a), 360e(a), 351(f)(1) and 331(a) and (d)).
4. See, e.g., FDA’s 2021 Intended Use Final Rule, 86 FR 41383 at 41386-41388.
5. See the FDA Guidance, “Drug and Device Manufacturer Communications With Payors, Formulary Committees, and Similar Entities – Questions and Answers.”
6. See, e.g., Washington Legal Foundation v. Henney, 202 F. 3d 331 (D.C. Cir. 2000); Unites States v. Caronia, 703 F.3d 149 (2d Cir. 2012).