On October 23, 2023, the Food and Drug Administration ("FDA") released a draft guidance for industry entitled "Communications From Firms to Health Care Providers Regarding Scientific Information on Unapproved Uses of Approved/Cleared Medical Products – Questions and Answers" ("SIUU Draft Guidance"). The SIUU Draft Guidance provides recommendations for dissemination and discussion of off-label reprints, clinical practice guidelines, and reference texts, among other sources. FDA describes the SIUU Draft Guidance as a revision of FDA's 2014 draft guidance entitled "Distributing Scientific and Medical Publications on Unapproved New Uses–Recommended Practices" ("2014 Draft Guidance"), which itself was a revision to a 2009 final guidance entitled "Good Reprint Practices for the Distribution of Medical Journal Articles and Medical or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" (see this prior Ropes & Gray Alert for more history).

The SIUU Draft Guidance represents a significant departure from the 2014 Draft Guidance. For example, it expressly acknowledges that firms can develop their own presentations about off-label reprints to share with HCPs, and it recognizes that social media can be an appropriate medium for dissemination of scientific information on unapproved uses of approved/cleared medical products. It also would introduce a new substantiation standard for communications to fall within the scope of the guidance's enforcement policy, conveying an expectation that any studies or analyses described in source materials (e.g., reprints) be "scientifically sound" and "clinically relevant." Like the 2014 Draft Guidance, and FDA's regulatory framework for manufacturer communications in general, the SIUU Draft Guidance raises significant constitutional questions under the First and Fifth Amendments, advances a broad view of the concept of "intended use," leaves key questions unanswered, and, if finalized, may be challenging and confusing for FDA-regulated companies to interpret and implement.

This Alert summarizes key principles from the SIUU Draft Guidance, highlighting some departures from the 2014 Draft Guidance, and describes implications and considerations for industry.

Overview

Consistent with the 2014 Draft Guidance, the SIUU Draft Guidance recognizes that firms can disseminate certain forms of truthful, non-misleading, factual, unbiased scientific information that relates to unapproved uses of medical products. The SIUU Draft Guidance also reflects FDA's expectation that extensive disclosures are necessary for health care professionals ("HCPs") to assess the validity and utility of such information to a prescribing or treatment decision for an individual patient.

FDA characterizes the SIUU Draft Guidance as an enforcement policy and asserts that it does not intend to use communications consistent with the SIUU Draft Guidance "standing alone" as evidence of a new intended use (i.e., an off-label use). The addition of the phrase "standing alone," which did not appear in the 2014 Draft Guidance, is a significant caveat, apparently intended to preserve the government's ability to consider communications that fully satisfy the recommendations in the SIUU Draft Guidance as evidence of a new intended use whenever there is other evidence that the government considers relevant to that new use. Given that FDA asserts broad authority to consider "any relevant source" of evidence when determining intended use and has not clarified when safe-harbored speech, including certain forms of scientific exchange, may be relevant to an intended use determination (see prior Ropes & Gray Alert), FDA's caveat could chill manufacturers from conveying the very scientific information FDA purports to allow in the SIUU Draft Guidance.

The chilling effect of FDA's regulatory framework governing manufacturer speech has long been described by industry stakeholders, who have asserted that the agency's approach to regulation is overbroad, restrictive, and ambiguous in ways that violate the First and Fifth Amendments and adversely impact the public health. In the SIUU Draft Guidance, FDA cites repeatedly to its 2017 memorandum addressing First Amendment issues, titled "Manufacturer Communications Regarding Unapproved Uses of Approved or Cleared Medical Products" (see prior Ropes & Gray Alert) and refers generally to a "careful balance" of interests the agency believes the SIUU Draft Guidance strikes. Yet FDA makes no attempt to explain how the specific approach proposed in the SIUU Draft Guidance would pass constitutional muster. The SIUU Draft Guidance, like FDA's past guidance documents in this area, is grounded in content- and speaker-based restrictions strongly disfavored under First Amendment principles, and it incorporates undefined terms and unclear concepts that raise questions under the Fifth Amendment, which requires that the government establish precise boundaries for the regulation of speech.

Scope of the Draft Guidance

  • Audiences. The SIUU Draft Guidance is expressly limited to manufacturer communications directed to HCPs "engaged in making clinical practice decisions for the care of an individual patient." Communications to HCPs acting in a payor or researcher capacity, and communications to non-HCP audiences such as patients and caregivers, are out of scope.
  • Products. The SIUU Draft Guidance only addresses communications on unapproved uses of approved/cleared medical products, which include human and animal drugs and medical devices. Communications about investigational medical products that are not yet approved/cleared for any use or about uses of medical products made available under an emergency use authorization ("EUA") are out of scope.
  • Uses. The SIUU Draft Guidance applies only to communications about an "unapproved use," defined in the SIUU Draft Guidance as a use that is not lawfully included as an indication or use in the FDA-required labeling of an approved or cleared medical product. This definition differs from FDA's description of what is not "consistent with the FDA-required labeling" ("CFL"), as described in its 2018 final guidance Medical Product Communications That Are Consistent With the FDA-Required Labeling — Questions and Answers ("CFL Guidance"). It is not clear whether that distinction is intentional, and if so, why FDA has chosen to take a different approach here.
  • Forms of Communication. The SIUU Draft Guidance covers five types of SIUU communications:
    • Scientific or medical journal articles (i.e., reprints)
    • Clinical practice guidelines
    • Scientific or medical reference texts
    • Materials from independent clinical practice resources, defined as "a digital resource that contains medical and scientific information on a wide range of topics developed by subject matter experts in various medical specialty fields [that] is typically searchable by topic or keyword and produces materials in response to the HCP's search terms"
    • Firm-generated presentations of scientific information from an accompanying published reprint

    Two of these categories —"materials from independent clinical practice resources" and "firm-generated presentations of scientific information from an accompanying published reprint"— were not included in the 2014 Draft Guidance. The inclusion of firm-generated presentations is a particularly welcome change for medical products manufacturers from the 2014 Draft Guidance, which stated that companies should not summarize, characterize, or emphasize information on unapproved uses from reprints. That said, it is not clear why FDA only addresses firm-generated presentations related to reprints and seemingly excludes presentations related to CPGs, reference texts, or other clinical practice resources.

  • Communications out of scope. For those communications outside the scope of the SIUU Draft Guidance, FDA states that it "do[es] not intend to convey any views on such communications in issuing this draft guidance." Accordingly, while the SIUU Draft Guidance does not address other types of communication of scientific information on unapproved uses and unapproved products, it also does not foreclose such communications through scientific exchange (see 21 C.F.R. § 312.7), or in accordance with other FDA enforcement policies or safe harbors.

Sources That Can Support SIUU Communications

In the SIUU Draft Guidance, FDA introduces a new substantiation standard, recommending that SIUU communications describe studies that are "scientifically sound" and "clinically relevant." This substantiation standard has evolved since the 2014 Draft Guidance, which stated only that reprints related to drugs should describe "adequate and well-controlled clinical investigations" and that reprints for devices could describe "significant investigations other than adequate and well-controlled studies," such as certain meta-analyses and significant non-clinical research.

  • Scientifically Sound. To be "scientifically sound," studies or analyses should "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." In a footnote, FDA also states that "statistical robustness" is generally necessary to satisfy the "scientifically sound" standard.
  • Clinically Relevant. To be clinically relevant, FDA states that the studies or analyses should "provide information that is pertinent to HCPs engaged in making clinical practice decisions for the care of an individual patient." Importantly, FDA expressly states that "preliminary scientific data" and other data that may be generated in the "early stages of medical product development" would be unlikely to meet the clinical relevance standard.

FDA acknowledges that different types of "well-designed and well-conducted" studies and analyses could be scientifically sound and clinically relevant and provides various examples that could potentially satisfy the standard, including real-world evidence and meta-analyses "if these studies and analyses meet generally acceptable design and other methodological standards for the type of study or analysis being performed and take into account any limitations of the selected design and methodology." For drugs, the agency suggests that "randomized, double-blind, concurrently controlled superiority trials . . . are the most likely to provide scientifically sound and clinically relevant information." For devices, FDA states that the types of studies and analyses considered "valid scientific evidence" pursuant to 21 C.F.R. § 860.7, which includes, e.g., well-controlled and partially controlled studies, studies and objective trials without matched controls, and well-documented case histories by qualified experts, are the most likely to be scientifically sound and clinically relevant. However, FDA asserts that generally a non-clinical study or analysis alone would not be considered "clinically relevant" and would not fall within the enforcement policy described in the SIUU Draft Guidance. This is a change from the 2014 Draft Guidance, which said that articles describing significant non-clinical research with a medical device could be consistent with the guidance.

FDA's expectation that SIUU communications be scientifically sound (including statistically robust) and clinically relevant is likely to generate substantial confusion and controversy among regulated industry. For one, it is not clear how this substantiation standard stacks up against the "scientifically appropriate and statistically sound" standard FDA has established for promotional communications that are consistent with FDA-required labeling. This proliferation of varying standards for scientific communications may be difficult for firms to distinguish and manage. Given that SIUU communications are expected to be clinically relevant in addition to scientifically sound and statistically robust, it could be that FDA intended to establish a higher standard for non-promotional communications under the SIUU Draft Guidance than for promotional claims. Yet FDA does not make this point clear, nor, if that is the intention, does FDA provide a rationale for it. Furthermore, even though FDA repeatedly underscores in the SIUU Draft Guidance that SIUU communications are shared with HCPs engaged in making clinical practice decisions for the care of an individual patient, the agency nevertheless assumes that early-stage clinical data are unlikely to be clinically relevant. This restrictive and ambiguous substantiation standard would potentially chill firms from conveying truthful and non-misleading scientific information to HCPs.

Presentation and Disclosure Considerations

The SIUU Draft Guidance provides numerous recommendations regarding presentation and disclosures that should accompany SIUU communications in general, as well as recommendations specific to the five different types of SIUU communications. Generally, SIUU communications should:

  1. Clearly and prominently present all disclosures recommended in the SIUU Draft Guidance.
  2. Not use "persuasive marketing techniques." FDA defines these as marketing techniques that "influence use of the products based on elements other than the scientific content of the communication," and provides as examples use of celebrity endorsements, premium offers, and gifts. FDA did not address this issue in the 2014 Draft Guidance and does not explain why it has done so in the latest draft guidance. It is not clear, for example, whether FDA has observed instances in which firms have used these types of tactics in communicating SIUU.
  3. Be separate and distinct from promotional communications about approved uses of medical products. FDA recommends that firms use "dedicated vehicles, channels, and venues" for sharing SIUU communications that are separate from those used for promotional communications about approved uses of medical products. Although FDA describes how to separate promotional and SIUU communications, the SIUU Draft Guidance does not define what communications FDA would consider "promotional." The ambiguity of this critical distinction is a long-standing concern for industry, and one that gives rise to important First and Fifth Amendment questions.
  4. Be shared through media and via platforms that enable firms to implement the recommendations in the SIUU Draft Guidance. FDA notes that if a platform has character space or other presentational limitations that would not enable inclusion of all disclosures recommended in the SIUU Draft Guidance (implicitly referring to social media platforms like "X"), that platform should not be used directly for SIUU communications. Rather, FDA suggests that firms could use these platforms to direct HCPs to an SIUU communication through a statement that does not mention the name of any specific medical product, such as "New publication for Health Care Providers—phase 3 trial results for an investigational treatment for [disease X]," followed by a link to a website where the SIUU communication appears.
  5. Use plain language when feasible for firm-developed SIUU communications.

In addition to these recommendations on presenting SIUU communications, the SIUU Draft Guidance includes extensive recommended disclosures that should accompany an SIUU communication, which may be onerous in practice. These include, for example, statements disclosing that the SIUU communication describes an unapproved use and information on approved use(s), various safety-related considerations, any conflicts of interest, the study design and its limitations, and any contrary conclusions from other relevant studies. While the recommended disclosures are similar to those in the 2014 Draft Guidance, one notable change relates to the disclosures of author conflicts of interest. Although both the 2014 Draft Guidance and SIUU Draft Guidance recommend disclosure of author conflicts of interest, the SIUU Draft Guidance omits the recommendation in the 2014 Draft Guidance that publications should not be "edited or significantly influenced by a drug or device manufacturer or any individuals having a financial relationship with the manufacturer."

The SIUU Draft Guidance also includes recommendations about disclosures and presentation specific to the different types of communication contemplated under the guidance. For example, for firm-generated SIUU communications, FDA states that when presenting conclusions about safety or effectiveness of an unapproved use, firms should attribute the statement expressly to the reprint and "immediately follow" it with the statement identifying any authors, editors, or other contributors to the reprint who were employees of or consultants to or who received compensation from the firm. Given that FDA already expects such statements regarding safety and effectiveness to be truthful, non-misleading, presented in the context of the study and its limitations, and to come from a peer-reviewed reprint describing a "scientifically sound" and "clinically relevant" study, it is unclear why FDA also recommends this specific placement for conflict of interest information.

Conclusion

The SIUU Draft Guidance represents a substantial revision of the 2014 Draft Guidance. While some of the changes appear to be helpful from the perspective of drug and device manufacturers, particularly the inclusion of firm-generated communications, the SIUU Draft Guidance ultimately carries forward FDA's restrictive regime governing off-label communications. It remains to be seen whether the changes FDA proposes in the SIUU Draft Guidance will in practice provide meaningful flexibility or lead to additional scrutiny over manufacturer communications regarding truthful, non-misleading information about unapproved uses for approved or cleared products.

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