FDA Issues Revised Draft Guidance On

Key Takeaways:

On October 23, 2023, the Food and Drug Administration (FDA) published a draft guidance, Communications From Firms to Health Care Providers Regarding Scientific Information on Unapproved Uses of Approved/Cleared Medical Products, Questions and Answers. This draft guidance, if finalized, will supersede FDA's 2014 draft guidance document, Distributing Scientific and Medical Publications on Unapproved New Uses — Recommended Practices.
This version discusses FDA's evolving policy surrounding "Scientific Information on Unapproved Uses Communications" ("SIUU Communications"), which builds upon the 2014 draft guidance but includes a handful of key differences.
The revised draft guidance provides explicit recommendations and examples for SIUU Communications to help firms comply with statutory prohibitions against introducing (or causing the introduction) into interstate commerce a medical product that is intended for a use that has not been approved or cleared by FDA and related regulations and policies. The draft guidance includes specific recommendations regarding the appropriate types of media and content for such communications.

Background

On October 23, 2023, FDA published a draft guidance document to provide detailed recommendations to industry regarding the communication of unapproved uses of approved or cleared drugs and medical devices to health care providers (HCPs) in a manner that complies with applicable laws, regulations, and policies surrounding the promotion and commercial marketing of medical products. This draft guidance is the latest in a series of efforts, including:

In 2008–2009, FDA issued a draft, and then final, guidance on "good reprint practices" for firms distributing "journal articles" or "scientific or medical reference publications. "
In 2014, the agency issued a revised draft guidance (the "2014 Draft Guidance") expanding the scope of communications with specific recommended standards to include clinical practice guidelines, as well as further guidance on reprints and other issues.
The agency held a public meeting in 2016 to solicit comments on its guidelines for communications regarding unapproved uses. In 2017, following the hearing, FDA published a new memorandum with additional guidance, which was accompanied by a public docket for comment on the issue.
In the preamble to FDA's final rule on "intended use" in 2021, the agency discussed unapproved use communication at length. The preamble included responses to comments to the proposed rule which cited litigation challenging the agency's ability to bring enforcement actions against firms that are allegedly promoting off-label uses.

The 2023 SIUU Communication Draft Guidance (or "2023 Draft Guidance") provides FDA's interpretation of how unapproved uses of approved or cleared medical products can be communicated by firms in a compliant manner. In addition, the guidance expands the scope of regulated communications to include firm-generated presentations.

This latest draft guidance supplements the agency's other notable guidance documents on preapproval communications and communications about unapproved uses including, Responding to Unsolicited Requests for Off-Label Information About Prescription Drugs and Medical Devices and Drug and Device Manufacturer Communications With Payors, Formulary Committees, and Similar Entities – Questions and Answers. These guidance documents, while different in scope, similarly address extra-label communication of scientifically supported product information.

Return of "FDA-required labeling" Definition

One of the key defined terms in the SIUU Communication Draft Guidance, "FDA-required labeling," recently appeared in another draft guidance document, Regulatory Considerations for Prescription Drug Use-Related Software (PDURS). In the PDURS draft guidance, FDA stated that it generally recognizes two broad categories of prescription drug labeling: (1) FDA-required labeling or (2) promotional labeling. The PDURS draft guidance defines "FDA-required labeling" as "the labeling reviewed and approved by FDA as part of a new drug application (NDA), an abbreviated new drug application (ANDA), or a biologics license application (BLA), as well as supplemental applications ...". According to the PDURS draft guidance, any labeling that falls outside of "FDA-required labeling" would be considered "promotional labeling."

The SIUU Communication Draft Guidance defines "FDA-required labeling" as labeling "reviewed and approved by FDA as part of the medical product premarket review process." The draft guidance provides some examples for "FDA-required labeling" including prescribing information for prescription drug and biologics, the "labeling approved during the review of a premarket approval application or De Novo classification" for devices, and the labeling that must be provided for nonprescription drugs. The SIUU definition (which also covers animal drugs) covers more products and includes a more specific application than the PDURS draft guidance definition of "FDA-required labeling."

Both guidance documents include "labeling reviewed and approved by FDA" in their definitions of "FDA-required labeling," but it is conceivable that FDA would consider certain materials to be "FDA-required" in one context, but not in another. If that is the case, manufacturers and sponsors will have to navigate what constitutes "promotional labeling" on a situational basis unless the agency creates a uniform definition upon finalization of the draft guidance documents. Nonetheless, FDA is putting firms on notice that it will continue to view labeling that it approves under a different lens than labeling it does not review pursuant to a product approval.

SIUU Communications

The 2023 Draft Guidance defines a new term, "Scientific Information on Unapproved Uses Communications" ("SIUU Communications"), which may have been motivated in part to differentiate this guidance from FDA's 1997 guidance regarding scientific exchange. While the 2014 Draft Guidance did not define key terms, the 2023 Draft Guidance provides a detailed scope for SIUU Communications. Such communications are defined as "specific types of communications from firms to HCPs of scientific information on unapproved uses of approved/cleared medical products in combination with the disclosures recommended in this guidance." An "unapproved use" is defined as "a use that is not lawfully included as an indication or use in FDA-required labeling of an approved/cleared medical product," using the definition of "FDA-required labeling" discussed above.

Notably, the 2023 Draft Guidance specifies that the SIUU standards described do not apply to products authorized for emergency use under Section 564 of the Federal Food, Drug, and Cosmetics Act (FDCA), a distinction necessary due to the substantial increase in EUA devices, vaccines, and drugs that were authorized during the COVID-19 pandemic.

Sources that discuss unapproved uses of approved/cleared medical products are grouped into the following three categories of SIUU Communications:

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

These categories of communications are broader than the categories discussed in the 2014 Draft Guidance, which included reprints, CPGs, and reference texts, but not independent clinical resources or firm-generated presentations of scientific information accompanying a reprint. (The 2014 Draft Guidance contained some guidelines that may have been relevant and therefore reasonably interpreted to govern those categories of communications.)

Presentational Considerations for SIUU Communications

The agency provides examples of acceptable media and communication standards for SIUU through a Q&A format. FDA outlines five principles that sponsors should consider when communicating SIUU:

SIUU Communications should clearly and prominently present all disclosures recommended in the guidance.
SIUU Communications should not use "persuasive marketing techniques."
SIUU Communications should be separate and distinct from promotional communications about approved uses of medical products.
SIUU Communications should be shared through media and via platforms that enable firms to implement the recommendations in this guidance.
Firms should consider using plain language in the content they develop for SIUU Communications to facilitate comprehension.

Most of these recommendations were expressed or implied in the 2014 Draft Guidance, but the revised draft guidance elaborates further on the agency's recommendations regarding the use of certain types of media, formatting of text and graphics, and elements that should be present in specific types of communications. For example, the 2023 Draft Guidance explains that the limitations of some platforms (e.g., character counts, size restrictions) might interfere with the ability to clearly and prominently present all recommended disclosures, thereby making them inappropriate for SIUU Communications. The revised draft guidance also details the agency's rationale for advising against the use of persuasive marketing techniques (i.e., marketing techniques that influence the use of medical products based on elements other than the scientific content of the communication) in SIUU Communications and for recommending that firms maintain appropriate separation between SIUU Communications and communications about approved uses.

Key Differences Between the 2014 and 2023 Draft Guidance Documents

The 2023 Draft Guidance repeatedly emphasizes that SIUU Communications should be relevant to the "care of an individual patient," as opposed to information that is typically shared with HCPs in the context of population-based coverage or reimbursement decisions or for research purposes. The distinction suggests that the agency looks less favorably on a firm's dissemination of off-label information to HCPs if the information is derived from published sources that are too general to provide meaningful guidance for clinical practice.

Also, of note, is the 2023 Draft Guidance's repeated emphasis on the balancing act of 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 preserving the various government interests in incentivizing the development of and satisfaction of applicable premarket requirements for medical products—potentially signifying that FDA will likely scrutinize SIUU communications more closely.

The 2023 Draft Guidance provides new, specific guidelines for all SIUU Communications, including a recommendation that any communication focused on a particular study or set of studies also include "any conclusions from other relevant studies, when applicable, that are contrary to or cast doubt on the results shared, including citations for any such studies," as compared with the 2014 Draft Guidance's narrower recommendation that reprints be "disseminated with a representative publication, when such information exists, that reaches contrary or different conclusions regarding the unapproved use—especially when the conclusions of articles to be disseminated have been specifically called into question by another publication."

The most significant changes for a specific category of SIUU pertains to reprints. The 2023 Draft Guidance stresses that reprints and other communications should be "clinically relevant," meaning "the studies or analyses, in addition to being scientifically sound, should provide information that is pertinent to HCPs engaged in making clinical practice decisions for the care of an individual patient."

The 2023 Draft Guidance establishes new recommendations for reprints that are stricter than those in the 2014 Draft Guidance, including the following:

New, stricter standards for journals used for reprints: Rather than just being "peer-reviewed and published in accordance with the peer-review procedures of the organization" (2014), reprints should be "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" (2023), and the peer reviewers should be "experts in the subject of the article, as established by education or experience. "
Stricter specifications for determining that a publication is "scientifically sound" and "clinically relevant": Where the 2014 Draft Guidance, for instance, stated that, "in the case of devices, significant investigations other than adequate and well-controlled studies, such as ... journal articles discussing significant non-clinical research (such as well-designed bench or animal studies) may be consistent with this guidance," the 2023 version states that "sharing articles focused on a nonclinical study or analysis alone would not be consistent with the enforcement policy outlined in this guidance because this nonclinical study or analysis alone is unlikely to provide information that is clinically relevant." The 2023 draft guidance also specifically notes concerns about SIUU relaying or being based on studies "without an adequate comparison or control group," "isolated case reports," and "scientific data generated in early stages of product development."

The 2023 Draft Guidance also provides specific recommendations for SIUU characterized as "firm-generated presentations" that are consistent with those provided for SIUU in general and communications explicitly discussed in the 2014 Draft Guidance. For example, FDA advises that presentations should avoid suggesting a study "represents larger or more-general experience with the medical product than it actually does." In addition, presentations should not "rely upon the accompanying reprint(s) to provide information that is material to the representations made in the firm-generated presentation," even if the reprint includes that material information itself.

Conclusion

The 2023 Draft Guidance reveals the evolution of FDA's position regarding communications to HCPs by firms regarding unapproved uses of their approved or cleared medical products and aims to take into consideration current promotional trends. The agency's use of the term "FDA-required labeling" and focus on information relevant to the treatment of an "individual patient" may be worth monitoring. The revised draft guidance's recommendations appear more responsive to industry activities than its 2014 predecessor and the draft guidance's focus and detail may signify that FDA is paying close attention to SIUU communications. Furthermore, this extra-label communication guidance document revision may be just the first of other draft guidance revisions to come. FDA's draft guidance Drug and Device Manufacturer Communications With Payors, Formulary Committees, and Similar Entities – Questions and Answers was superseded, in part, through legislation in 2022 and is set to expire by August 2024, making it a potential candidate for revision following this updated SIUU Communications draft guidance.

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