FDA Updates Off-Label Communications Guidance
On October 23, the U.S. Food and Drug Administration (FDA or Agency) released a much anticipated draft guidance entitled, “Communications From Firms to Health Care Providers Regarding Scientific Information on Unapproved Uses of Approved/Cleared Medical Products Questions and Answers Guidance for Industry” (SIUU Guidance).1 Per FDA, “nothing in this draft guidance is intended to convey new policy” regarding manufacturer communications about scientific information on unapproved use(s) (SIUU).2 Instead, the SIUU Guidance represents FDA’s current recommendations and considerations for firms engaged in sharing SIUU communications with healthcare providers (HCPs) and supersedes FDA’s 2014 revised draft guidance, “Distributing Scientific and Medical Publications on Unapproved New Uses — Recommended Practices” (2014 Guidance).3 Notably, the SIUU Guidance does not replace FDA’s 2011 draft guidance on unsolicited requests for off-label information.4 Comments on the SIUU Guidance are due December 26 and should be submitted to Docket No. FDA-2008-D-0053.5
The SIUU Guidance was informed by industry feedback from FDA’s ongoing efforts related to SIUU communications, including comments FDA received from the 2014 Guidance.6 In issuing the SIUU Guidance, FDA sought to balance the Agency’s “substantial government interests” regarding premarket requirements for medical products, while addressing the First Amendment commercial speech protections of industry and “supporting HCP interest” in receiving SIUU to inform “clinical practice decisions for the care of an individual patient.”7 Overall, the revised guidance reiterates, clarifies, and expands on the following SIUU principles:
- In light of recent First Amendment jurisprudence, FDA has moved away from using the term “off-label,” and instead, now uses SIUU.
- The SIUU Guidance addresses human drugs, devices, and animal drugs.
- Consistent with FDA’s 2009 draft reprints guidance and the 2014 Guidance, the SIUU Guidance applies to “SIUU communications with HCPs.” The SIUU Guidance defines HCPs to mean “individuals” licensed or authorized to prescribe, order, administer, or use medical products in a professional capacity and are “engaged in making clinical practice decisions in the care of an individual patient.”8 Thus, the SIUU Guidance does not apply to SIUU communications to other audiences, such as patients, payors, and other healthcare stakeholders. SIUU communications, as described by FDA, are focused on HCPs “when they judge that the unapproved use is medically appropriate for their particular patient — whose characteristics and needs may differ” from the approved use or population.9
- The SIUU Guidance largely provides the same recommendations for dissemination of: (1) clinical practice guidelines (CPGs); (2) scientific or medical reference texts (reference texts); and (3) published reprints as outlined in the 2014 Guidance. However, the SIUU Guidance adds two new categories of SIUU communications: (1) “[f]irm-generated presentations of scientific information from an accompanying published reprint” and (2) “[m]aterials from independent clinical practice resources.” Collectively, FDA refers to these as the “source publication” for the SIUU communication.
- 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”).10
- FDA recommends that SIUU communications be “separate and distinct from promotional communications about approved uses of medical products,” including on social or digital media channels, and should not use “persuasive marketing techniques.”11
- FDA recommends that firms use digital or social media platforms that do not have space-character limitations that “would not enable a firm to” comply with the SIUU Guidance.12
- FDA reiterated (in a footnote) the Agency’s longstanding position that the Agency will not “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.”13
- While the SIUU Guidance recognizes that pharmaceutical and medical device companies have a legitimate interest in presenting truthful, non-misleading information about scientific developments and clinical information, FDA stops short of recognizing a “safe harbor” for a company’s non-commercial medical or scientific education function. When read against the context of the other active guidance documents, including Responding to Unsolicited Requests, the SIUU Guidance seems to leave open the possibility that FDA would bring enforcement against a company that communicates proactively to HCPs about non-CFL information that falls outside the “trustworthiness” criteria established in the draft, regardless of whether it is communicated in a truthful and non-misleading manner. FDA’s ability to sustain this position is questionable.14
SIUU Guidance: Four Common Questions
The SIUU Guidance outlines four common questions regarding SIUU communications by manufacturers to HCPs. FDA states that, if a company shares an SIUU communication “with HCPs” in a manner consistent with the SIUU Guidance, “FDA does not intend to use such communication standing alone as evidence of a new intended use.”15 Below we have highlighted key recommendations and considerations from FDA for each question.
What should firms consider when determining whether a source publication is appropriate to serve as the basis for an SIUU communication? (Q1)
FDA recommended that firms consider several factors when evaluating source publications that “serve as the basis for SIUU communications”:16
- Does the source 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”? Did the source have statistical robustness?
- FDA states that, for human and animal drugs, “randomized, double-blind, concurrently controlled superiority trials” are “most likely to provide scientifically sound and clinically relevant information.”
- For medical devices, the types of studies, information, and analyses that FDA considers valid scientific evidence are described in 21 C.F.R. 860.7, and could 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.”
- FDA acknowledges that real-world data (RWD) and associated real-world evidence (RWE) about medical products may be scientifically sound and clinically relevant depending on the characteristics of the data and the nature of the analyses, citing FDA’s recent guidance on RWE/RWD.
- Consistent with FDA’s 2009 and 2014 Guidances, examples of sources that, if used alone, would not comply with the SIUU Guidance include: (1) studies without adequate comparison or control group; (2) isolated case reports about medical products; (3) communications that distort studies or include fraudulent data; and (4) other reports that lack enough detail to permit scientific evaluation.
- FDA contends that sources based on a “flaw[ed] study or analysis” that “render the data unreliable” (e.g., fail to control for confounding factors; fail to enroll the appropriate spectrum of patients; fail to include clear definitions of study endpoints)17 should be entirely “excluded from serving as the basis of an SIUU communication” because even “full disclosure of the limitations of the study or analysis” would not mitigate the risk of misinterpretation of the study results.
- The SIUU Guidance notes that “scientific data generated in early stages” of product development used alone “are unlikely to be sufficiently reliable by themselves to allow for a determination of clinical relevance.”18
- Finally, FDA notes that SIUU communications cannot be based on a source that “is no longer clinically relevant” (e.g., subsequent research shows the study or analysis is not reliable). FDA recommends that, if a firm “has the ability,” it should “remove” such sources from applicable SIUU communications.
What information should firms include as part of SIUU communications? (Q2)
Consistent with the 2009 and 2014 Guidances, FDA recommends that SIUU communications be accompanied by certain information, including:
- A copy of the FDA-required labeling
- A statement that the unapproved use(s) of the medical product has not been approved by FDA and that the safety and effectiveness of the medical product for the unapproved use(s) has not been established
- The FDA-approved use(s) of the product and any limitations of use
- Any limitations, restrictions, cautions, or warnings from the labeling about unapproved use(s)
For SIUU communications focused on a particular study or studies, the communication should also include a description of:
- All material aspects of the study design, methodology, and results
- All material limitations related to the study design, methodology, and results
- Any conclusions from other studies that are contrary to or cast doubt on the SIUU communications, including citations to such studies
In addition, the SIUU communication should include a statement identifying any author, editors, or contributors to the publication(s) in the SIUU communications who were employees, consultants, or received compensation from the firm.
What presentational considerations should firms take into account for SIUU communications? (Q3)
FDA notes the importance of SIUU communications being conveyed in a manner that “enhances and does not interfere with HCP understanding and evaluation” of the SIUU communication, including limitations. To that end, FDA makes five specific recommendations:19
- SIUU communications should clearly and prominently present all disclosures, including by presenting disclosures in both audio and text at the same time using the same words (as applicable).20
- As noted, SIUU communications should not use “persuasive marketing techniques,” such as “celebrity endorsements, premium offers, or gifts” because FDA considers such techniques to: (1) suggest a firm’s effort to convince the HCP to prescribe or use the product for the unapproved use and (2) influence HCPs “to reach positive conclusions about the unapproved use based on elements other than the scientific content.” FDA, thus, would consider such communications to be “evidence of an intended use” outside of the SIUU Guidance. SIUU communications should also be “presented in a manner unlikely to lead HCPs to base" clinical decisions on "conclusions about the safety or effectiveness of the unapproved use" that are not supported by or go beyond the "underlying scientific information."
- SIUU communications should be separate and distinct from promotional communications about approved uses of medical products to avoid HCPs “conflating the approved use and unapproved use information.” FDA recommends that firms use “dedicated vehicles, channels, and venues for sharing SIUU communications” that are separate from vehicles, channels, and venues used for promotional communications. For example, FDA recommends: (1) a separate webpage for SIUU communications; (2) no “direct links from web pages that host promotional communications about approved uses to webpages that host SIUU communications;” (3) separate SIUU and promotional emails; and (4) divided or separate booth spaces at scientific meetings.
- SIUU communications should be shared through media and via platforms that enable complying with the SIUU Guidance and not platforms that impose character-space limitations or other presentational limitations that prevent firms from including recommended disclosures.
- SIUU communications should use plain language for any firm-generated portions.
What additional recommendations apply to specific types of SIUU communications? (Q4)
The last section of the SIUU Guidance provides specific recommendations on: (1) reprints; (2) clinical reference resources (e.g., CPGs, reference texts, and materials from independent clinical practice resources); and (3) firm-generated presentations. FDA’s recommendations in the first two categories are similar to the 2014 Guidance. Below we have highlighted key considerations for each type of source publication.
Reprints: FDA acknowledges that meta-analyses, cohort or case-control studies, open-label studies, single-arm studies, or epidemiological studies could be “scientifically sound” and comply with the SIUU Guidance if the studies and analyses meet generally acceptable design and other methodological standards for the type of study or analysis being performed, taking into account study limitations. FDA notes that using a “nonclinical study or analysis alone” would not comply with the SIUU Guidance because such information is unlikely to be “clinically relevant.”21
Clinical Reference Resources
- General Principles: FDA reiterates that when sharing one or more individual section(s) of a clinical reference resource, firms should include all information from the resource “necessary for HCPs to interpret the strengths and weaknesses and validity and utility of the information” (e.g., sharing multiple sections).22 FDA does not expect many of the required disclosure statements outlined in Q2 when a firm shares CPGs or reference texts that: (1) are unabridged and in their entirety; (2) discuss “a wide range of medical products”; and (3) are not “primarily focused on one or more of a firm’s medical products.”23
- CPGs: In addition to the principles from the 2014 Guidance, FDA recommends that CPGs: (1) include ratings of recommendations to reflect the quality and strength of evidence and (2) are revised when important new evidence warrants modification. FDA notes that CPGs that are consistent with the National Academy of Medicine standards would comply with the SIUU Guidance. FDA acknowledges the “proliferation of professional organizations promulgating CPGs and the variations in scope and evidence used,” and thus, recommends that firms carefully consider FDA’s recommendations.
Firm-Generated Scientific Presentations From an Accompanying Reprint
The SIUU Guidance expands on FDA’s 2014 Guidance to include “firm-generated presentations of scientific information from an accompanying reprint.” Using several principles from FDA’s promotional regulations, FDA recommends that firm-generated presentations:24
- Comply with other principles of the SIUU Guidance (e.g., truthful, non-misleading, etc.)
- Be accompanied by the full reprint(s), which should be consistent with item 1 in Q4
- Should include “all information that is material to the representations made in the firm-generated presentation” (e.g., study design, methodology, results necessary to interpret the information presented)
- Should: (1) include the disclosures recommended in Q2 and (2) clearly disclose what portions of the SIUU communications are firm-generated
- Should be consistent with the recommendations in Q3 regarding presentational considerations (e.g., audio/video disclosures; no persuasive marketing techniques)
- Should not: (1) imply a study, analysis, or underlying data represents larger or more-general experience with the medical product than it actually does; (2) present information (e.g., excerpts, quotes, conclusions) from a reprint out of context; (3) include suggestions about safety or efficacy that are not consistent with the reprint; (4) 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 the statement to the reprint and immediately following it with a statement identifying any contributor to the publication(s) in the SIUU communications who were employees, consultants, or received compensation from the firm; (5) use statistical analysis or techniques to indicate clinical significance or validity of a finding not supported by the data or information in the reprint; (6) 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
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The SIUU Guidance represents FDA’s current thinking on SIUU communications based on almost a decade of learnings, enforcement, litigation, and industry comments. FDA claims that it sought to strike a balance in the revised guidance by using new terminology, along with updated principles and considerations to address industry concerns under the First Amendment, the Agency’s interest in protecting and maintaining the premarket product approval process, and an HCP’s ability to make individual patient treatment decisions.
While the SIUU Guidance does not represent a significant shift in FDA’s longstanding policies around SIUU communications, it does provide recommendations and considerations across a wide variety of areas, particularly digital and social media activities. If manufacturers have questions about how the SIUU Guidance applies to their own specific circumstances, please do not hesitate to connect with us.
© Arnold & Porter Kaye Scholer LLP 2023 All Rights Reserved. This Advisory is intended to be a general summary of the law and does not constitute legal advice. You should consult with counsel to determine applicable legal requirements in a specific fact situation.
FDA Draft Guidance for Industry: Communications From Firms to Health Care Providers Regarding Scientific Information on Unapproved Uses of Approved/Cleared Medical Products Questions and Answers Guidance for Industry (Oct. 23, 2023), available here (SIUU Guidance). The Federal Register notice is available here. 88 Fed. Reg. 73031.
See also FDA Draft Guidance for Industry: 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 (2009).
FDA held a public hearing and requested comments on the topic of “Manufacturer Communications Regarding Unapproved Uses of Approved or Cleared Medical Products” in 2016. 81 Fed. Reg. 60299 (Sept. 1, 2016), available here. In response to comments at the hearing, FDA developed a memorandum to provide additional background on issues related to communications by firms regarding unapproved uses of cleared medical products and the First Amendment. FDA Memorandum: Public Health Interests and First Amendment Considerations Related to Manufacturer Communications Regarding Unapproved Uses of Approved or Cleared Medical Products, 82 Fed. Reg. 6367 (Jan. 19, 2017), available here.
SIUU Guidance at 8. FDA noted that such practice is “most common in patients with diseases for which there is no medical product that is a proven treatment or in patients who have exhausted all approved uses of medical products.” SIUU Guidance at 8.
Such an enforcement policy would raise serious concerns under the First Amendment. See, e.g., Amarin Pharma, Inc. v. U.S. Food & Drug Admin., 119 F. Supp. 3d 196 (S.D.N.Y. 2015) (citing United States v. Caronia, 703 F.3d 149, 155-56 (2d Cir. 2012)) (explaining Caronia’s holding that “the FDCA's misbranding provisions cannot constitutionally criminalize, and therefore do not reach, the act of truthful and non-misleading speech promoting off-label use.”). The Amarin court further noted that Caronia “did not limit this holding to a subset of truthful promotional speech, such as statements responding to doctors' queries or statements by non-sales personnel.” The Amarin court explained that Caronia construed the FDCA’s misbranding provisions not to reach any “truthful off-label promotion of FDA-approved prescription drugs,” 703 F.3d at 168-69, and that the reasons given in Caronia for that holding “apply across-the-board to all truthful and non-misleading promotional speech.” 703 F.3d at 155-56. Thus, the Amarin court held that distinctions between proactive and reactive communications, and distinctions based on medical versus commercial functions or backgrounds, have no applicability under the First Amendment.
Other reasons a source could be flawed include: “poorly extracted data or data that is transferred with errors, is not source verified, or is inaccurately collected and documented would not provide reliable information.” SIUU Guidance at 11.
FDA notes that such data would not be consistent with the SIUU guidance because the results are not always “borne out in later studies,” citing a study that showed that over 95% of new prescription drug development studies fail. SIUU Guidance at 11.
FDA notes that, “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.” SIUU Guidance at 15.