1. Introduction
The sharing of knowledge, information and collaboration with external stakeholders is a powerful tool in science and medical research by translating ideas into innovation. Depending on the audience and context, legitimate scientific communications primarily seek to convey accurate information that may be important to predictive relevancy in terms of healthcare needs, building trust, and stimulating debates on contentious scientific issues.
Research and development of innovative medical products is increasingly challenging. In recent years, political, economic, regulatory, and scientific forces have converged to propel greater cost-efficiency, clinical relevance and patient-centricity in research and development programmes. Successful product developments will likely rely upon clinical insights, sourcing and communicating relevant data and deploying resources to support gathering such insights to guide an informed assessment of the safety and efficacy as well as the therapeutic value of an innovative product for its timely clinical adoption in the healthcare systems. In addition, outreach interventions to disseminate clinical research results can lead to changes in health policy, practice, and improvement in health outcomes.
In an increasingly patient-centric and cost-sensitive clinical delivery environment, national health systems, healthcare professionals (“HCPs”) and patients, as well as patient advocates, are demanding up-to-date information be communicated to support more equitable, inclusive, and evidence-based decisions. The concept of unmet medical need pervading various regulatory systems worldwide seeks to incentivise the development of new therapeutic methods and to identify a particular medical need as unmet to encourage innovation. There exists an enduring unmet medical need across multiple diseases affecting various demographic strata of the population, and such diseases may disproportionately affect the most vulnerable patient populations, such as the very old and the very young. Patients have unmet medical needs when treatment options are not or no longer adequate to manage the underlying conditions. When the end of a standard treatment trajectory comes into view, a discussion on non-standard treatment options between the treating physician and the patient will become inevitable. This discussion is guided by scientific data and clinical assessment of the patient’s individual circumstances to inform a decision on expanded access to unapproved treatment options, which are often experimental or investigational.
Moreover, clinical decision support systems, principally based upon digital tools, are designed to ensure that the right information is provided to the right person, in the right format, through the right channel at the right time to optimise healthcare delivery, health outcomes, and allocation of resources. In response to such a changing external environment, the industry understandably is required to gain greater insights into the treatment pathways, developing roadmaps, including those concerning therapy decision-making, to optimise the value of their products for market access.
As technology has evolved, the universe of media that medical product firms may use to engage in promotional and scientific communication with healthcare providers, patients, and other relevant stakeholders has expanded considerably. It is noticeable that dissemination of medical practice and scientific information through social media by medical and scientific communities is increasing. The scientific community justifies such broad exposure of information to promote connectivity, overcome barriers to access to sources, stimulate debate, and solicit layperson perspectives and preferences. On the other hand, misinformation may also be disseminated to promote practices lacking scientific evidence that may erode scientific integrity.
To keep up with this changing landscape, the regulatory rules and expectations governing promotional activities and communications in certain key jurisdictions are evolving in response. At a fundamental level, regulators are focused on making certain that information provided to the marketplace is truthful, non-misleading, and reliable to such an extent that it will not cause harm to treatment decision-making. In many instances, this requires the information underlying such communications to be scientifically sound, accurately characterised, and appropriately contextualised and disclaimed, as well as requiring that the risks and benefits of medical products are presented in a way that is understandable. In this way, HCPs can reliably use the information to support informed healthcare decisions.
This chapter seeks to explore recent regulatory developments involving scientific and medical communications, including for unapproved uses, historically deemed non-promotional, including scientific communications, as well as how regulators view such communications as impacting promotional issues. We will also address recent developments in three key geographical regions related to the regulation of advertising and promotion, particularly as it relates to the disclosure of product risks and limitations of promotional claims.
2. Dissemination of Non-Promotional, Scientific Communications
In October 2023, the United States Food and Drug Administration (“FDA”) released a non-binding draft guidance document related to firms’ communications regarding scientific information on unapproved uses (“SIUU”) of approved or cleared medical products (the “SIUU Draft Guidance”). The draft guidance, which represents the most significant development in FDA’s regulation of off-label communications in many years, is focused on communications that are non-promotional in nature, providing recommendations for dissemination and discussion of off-label reprints, clinical practice guidelines, and reference texts, among other sources. The scope of the draft guidance is limited to addressing communications directed to HCPs “engaged in making clinical practice decisions for the care of an individual patient”. Therefore, communications to HCPs acting in a payor or researcher capacity, as well as communications to non-HCP audiences, such as patients or caregivers, are out of scope. Though the scope of the SIUU Draft Guidance is cabined to non-promotional, scientific communications, FDA has made clear that it may still look to these communications as evidence of part of a broader inquiry into whether a company is promoting its product for a new or unapproved intended use.
The SIUU Draft Guidance, which FDA describes as a revision of a 2014 draft guidance focused on the distribution of scientific and medical publications, adheres to FDA’s longstanding position that firms can disseminate certain forms of truthful, non-misleading, factual, unbiased scientific information that relates to unapproved uses of medical products. However, it represents a significant departure from FDA’s prior position on dissemination of off-label scientific information in a number of ways. Perhaps most notably, the SIUU Draft Guidance expressly acknowledges that firms can develop their own presentations about off-label reprints to share with HCPs. Additionally, it recognises that social media can be an appropriate medium in some circumstances for the dissemination of SIUU of approved/cleared medical products.
It also introduces new and potentially complicated expectations and concepts surrounding SIUU communications. For example, the draft guidance introduces a new substantiation standard, recommending that SIUU communications only describe studies that are “scientifically sound” and “clinically relevant”. While FDA does provide some general concepts to inform the definition of these terms, it does not provide clear definitions, and examples that are offered indicate that this standard represents a restrictive, paternalistic approach to assessing the relevance of data. In particular, the draft guidance points to “randomized, double-blind, concurrently controlled superiority trials” as most likely to satisfy these standards and states that “early stage” data, such as data from Phase 2 studies, are “unlikely to be sufficiently reliable by themselves to allow for a determination of clinical relevance”. By creating this restrictive paradigm, FDA seems to substitute its own views of what constitutes “scientifically sound” and “clinically relevant” concepts for the views of practicing HCPs and may chill firms from sharing information that HCPs may have found valuable in informing clinical practice decisions. Additionally, the SIUU Draft Guidance does not address how this new standard should be understood to interact with existing substantiation standards in other contexts, such as the “scientifically appropriate and statistically sound” standard that FDA has established for promotional communications that are consistent with FDA-required labelling (“CFL communications”). This proliferation of varying standards for scientific communications may be difficult for firms to distinguish and manage.
Finally, the SIUU Draft Guidance provides numerous recommendations regarding presentation of communications materials and disclosures that should accompany SIUU communications. Though the SIUU Draft Guidance attempts to provide detailed recommendations, the extensive disclosure expectations that the draft guidance enumerates may be onerous in practice. For example, the draft guidance recommends including both a copy of the FDA-approved labelling as well as separate statements reiterating certain statements from the labelling, as well as a list of standard disclaimer-type statements providing extensive contextual information. Perhaps most onerous, however, is the draft guidance’s recommendation that SIUU communications also include a description of any conclusions from other relevant studies that are “contrary to or cast doubt on the results shared”, a phrase that is not then further clarified or defined.
EU pharmaceutical law expressly requires the advertising and promotional materials to be compatible with the approved particulars of a Summary of Product Characteristics (“SmPC”), which reflects the agreed conditions of use of an approved medicinal product. Consistent with the Council of Ministers’ position during the initial legislative procedure, the European jurisprudence requires the term “advertising of medicinal products” to be broadly interpreted with the focus on the promotional purpose of the message at issue. Advertising and promotion of an unapproved medicinal product and unapproved therapeutic use is expressly prohibited. The European jurisprudence distinguishes between promotional and non-promotional communications − including information communicated through digital and electronic means − by focusing on the effect of such communications on promoting the prescription, supply, sale, or consumption of medicinal products. However, material or communication that is purely informative, without promotional intent, is not covered by the provisions of the EU advertising and promotional rules for medicinal products. The European Federation of Pharmaceutical Industries and Associations (“EFPIA”) states in its Code of Practice that the Code is not intended to restrain or regulate the provision of non-promotional medical, scientific, and factual information. Nor is the Code intended to restrain or regulate activities directed towards the general public that relate solely to non-prescription medicinal products. Similarly, EU medical devices law prohibits: text, names, trademarks, pictures and figurative or other signs that may mislead the user or the patient with regard to the intended purpose, safety and performance characteristics of the medical device by ascribing functions and properties that the device does not have; creating a false impression regarding treatment of diagnosis, functions or properties that the device does not have; failing to inform the user or the patient of a likely risk associated with the use of the device according to its intended purpose; and suggesting uses for the device other than those covered by its approved intended purpose that has been the subject of the conformity assessment.
In addition, the EU heads of agencies representing all national competent authorities in the EU and the EEA, as well as the European Medicines Agency (“EMA”), have considered the need for regulatory authorities and industry to embrace an effective communication strategy to present information that is accurate, meaningful, and actionable to a varied audience such as the patient groups, general public and HCPs, to build trust in scientific developments and the regulatory systems. From a historical perspective, since 2010, the confidentiality paradigm began to shift towards transparency for either proactive or reactive disclosure of clinical trial data. The EMA’s policies were adopted with the primary objective of allowing developers, the scientific community, and other third parties access to detailed clinical trial data in order to learn from past successes and failures, develop new knowledge in the interest of public health, verify the original analyses and conclusions, and to conduct further analysis.
Asia, by comparison, has largely prohibited or limited off-label promotions generally. China, for example, has remained relatively stringent in its prohibition of off-label advertisement and promotion, and such regulations have remained unchanged. Companies may not promote products off-label. Similarly, Singapore’s Medicines Act holds that “unauthorised recommendations” (i.e., recommendations for off-label uses or purposes) are punishable offences. Japanese regulatory authorities have not provided regulations detailing exactly what information should be included in pharmaceutical advertising aimed at the general public, but the Ministry of Health, Labour and Welfare Standards state that if the advertising contains certain information such as names of the products, dosage, administration, or safety, then the advertising must follow certain rules, including a prohibition on using language that constitutes off-label promotion.
3. Risk Disclosures in Direct-to-Consumer (“DTC”) Advertisements
Unlike many other jurisdictions, the United States permits manufacturers of prescription drug products to market such products directly to consumers. However, given that the broader population may be less capable of assessing the risks and benefits of such products, the Federal Food, Drug, and Cosmetic Act has established specific requirements and regulations governing DTC advertising. Among these regulations is the requirement that DTC human prescription drug advertisements in television or radio format that state the name of the drug and its conditions of use also present the major statement relating to side effects and contraindications (the “major statement”) in a clear, conspicuous, and neutral manner. In November 2023, FDA published a long-awaited final rule amending its prescription drug regulations to reflect this requirement and to establish standards to help ensure that manufacturers understand how to comply with this requirement (the “Major Statement Rule”).
The Major Statement Rule establishes five standards for conveying the major statement in a “clear, conspicuous, and neutral manner”. These standards include:
- the major statement should be presented in consumer-friendly language and terminology that is readily understandable;
- the audio presentation of the major statement is at least as understandable as the audio in the rest of the ad;
- for ads in TV format, the major statement is presented concurrently in both audio and text and for long enough for the text to be read easily;
- for ads in TV format, text information is presented in easy-to-read format; and
- during the major statement, the ad does not include audio or visual elements, alone or in combination, that are likely to interfere with comprehension.
The five standards are aimed at addressing a longstanding concern by FDA and Congress that DTC advertisements may inadequately convey risk information to consumers. FDA has attempted to address this concern in the past by issuing numerous “untitled” letters to pharmaceutical companies for TV ads that contain attention-grabbing, distracting visual and audio elements (e.g., a person dancing to an upbeat song) and superimposed text slogans during the presentation of risk information that competed for the viewer’s attention and allegedly made it difficult to adequately process risk information.
While the Major Statement Rule represents a step toward clarity by FDA, some of the standards in the rule include broad and potentially subjective language, and FDA has yet to clarify how it will apply such standards in practice. For example, the terms “consumer-friendly” and “readily understandable” language are imprecise and have the potential to cause confusion, particularly in contexts where risk considerations are complex, and some “jargon” may be necessary to avoid oversimplifying such risk information. Similarly, the rule does not provide additional context for how FDA interprets the phrase “at least as understandable” with regard to, for example, volume, articulation, or pacing of audio. Additionally, the rule explicitly applies to prescription drug advertisements in “television and radio format” but does not provide clarity as to how broad the scope of that term is. The preamble to the rule acknowledges that “evolving technologies have allowed for DTC TV/radio ads to be presented on a broader range of devices and disseminated via a broader range of platforms” such as streaming platforms, podcasts, social media platforms, or other digital communications, but FDA has not provided an explicit view on whether these media are within or outside the scope of this rule.
The proposed legislative revisions to the EU pharmaceutical law were positively adopted by the European Parliament on 10 April 2024. The legislative proposal continues to restrict advertising of prescription medicinal products as well as medicinal products containing substances classified as psychotropic or narcotic to the general public. In addition, the proposed legislation imposes additional restrictions on advertising to the general public by requiring the advertising not to contain, among others, any material that: gives the impression that a medical consultation or surgical operation is unnecessary, by offering a diagnosis or by suggesting treatment by mail; refers to a purported recommendation by scientists, HCPs, or persons who are celebrities with the effect of encouraging the consumption of medicinal products; suggests the safety or efficacy of a medicinal product because it is ‘natural’; or refers to claims of recovery in improper, alarming, or misleading terms.
4. Enforcement on the Basis of False or Misleading Efficacy Claims
Though enforcement by FDA’s Office of Prescription Drug Promotion (“OPDP”) has waned in recent years – with OPDP issuing no warning or “untitled” letters in over a year from June 2022 to June 2023 – mid- and late-2023 saw a flurry of OPDP enforcement activity that has provided some insight into FDA’s enforcement priorities. Since June 2023, OPDP has issued six enforcement letters, including its first warning letter since February 2022, and a significant portion of OPDP’s relatively rare enforcement letters in recent years has focused on key issues raised by FDA’s guidance on CFL communications, which addresses communications regarding information and data that do not appear within a product’s approved labelling, but are nonetheless consistent with such labelling. OPDP’s recent enforcement letters indicate that, in addition to FDA’s continued focus on the presentation of risk information in promotional materials, FDA is taking a particularly close look at CFL communications.
In an August 2023 warning letter issued to AstraZeneca related to its promotion of BREZTRI AEROSPHERE – OPDP’s first warning and only warning letter since early 2022 – OPDP focused on promotional claims based on clinical trial data that did not appear in the labelling. In the letter, FDA stated that, among other things, the failure of the study to show significant results on endpoints higher in the analysis hierarchy, as well as potential compounding factors, made it such that “no conclusions … can be drawn from the … trial”. Similarly, FDA issued an “untitled” letter in January to Novartis related to its promotion of KISQALI in TV ads. Among the issues raised by FDA was Novartis’s inclusion of quality-of-life claims based on patient-reported outcome (“PRO”) data obtained during the course of a clinical trial because, among other things, the PRO data was considered an exploratory secondary endpoint. Given this, and due to other limitations associated with the PRO analysis, FDA took the position that the data did not support the quality-of-life claims. Notably, FDA also took issue with the way in which necessary contextual disclaimers were presented in the TV ad, noting that the presentation of material information about the product’s efficacy is “undermined by multiple, competing presentation aspects that distract the viewer”.
Given FDA’s recent focus on efficacy claims that do not appear in product labelling, manufacturers engaging in such communications should be particularly conscious to avoid claims or characterisations regarding CFL data, particularly where there are study design or statistical limitations, as in the case of post hoc analyses, failed material endpoints, and analyses not controlled for multiplicity. Additionally, manufacturers should take care when drafting disclaimers, ensuring that they are robust, prominent, and complete as it relates to disclosing limitations, and clear where conclusions cannot appropriately be drawn.
While advertising and promotion in the EU is governed by a harmonised regulatory framework, enforcement of the requirements is undertaken nationally by the national regulatory authorities or the national self-regulatory bodies. Consistent with the prevailing EU legislative framework, the enforcement regimes implemented at a national level must be proportionate, dissuasive, and effective. Enforcement actions can be judicially reviewed by the national courts, which can make a referral to the Court of Justice of the European Union (“CJEU”) for a preliminary ruling on a question of interpretation that is new and of general interest for the uniform application of EU law. The case law of the CJEU is instructive in guiding how the harmonised advertising and promotional rules ought to be interpreted and applied. The CJEU has held in various rulings that advertising of medicinal products is liable to harm public health in the sense that it may give rise to improper use or ill-conceived or irrational use of medicinal products. The CJEU has ruled that irrational and excessive use of medicinal products may also arise as a result of advertising material.
5. Conclusion
Conversion of scientific ideas and evidence-based medical practices can improve health outcomes to benefit patients. Building a culture of trust, transparency, accountability, and inclusion is increasingly essential to a vibrant life sciences ecosystem to propel the innovation agenda. Collaborations between the external stakeholders and industry are essential for advancing medical knowledge and improving patient care. Moreover, there is also an overall alignment among the international regulatory authorities as well as the industry trade associations to promote transparency in the clinical trial research process through improved and expanded disclosure of clinical trial data through publicly accessible portals.
In the world of greater transparency to gain trust in the scientific endeavours undertaken by medical researchers and industry, there is a greater demand by the scientific and medical community as well as patient advocacy groups for objective, unbiased research to be made available to inform individual clinical decisions, systematic reviews, meta-analyses, and development of clinical guidelines. Some have strongly argued that HCPs and the public deserve to be in a position to make informed choices about the benefit-risk of new medical interventions.
It is now widely recognised that patients are active partners in their personal healthcare and their views are increasingly sought in the planning for research and development for innovative medical interventions and effective allocation of healthcare resources to ensure that patients are put in the centre of clinical care pathways to improve health outcomes. Providing healthcare services that respect and meet patients’ and caregivers’ needs are essential in promoting positive care outcomes and perceptions of quality of care, thereby fulfilling a significant aspect of patient-centric care requirements. Effective communication between patients and healthcare providers is crucial for the provision of patient care and recovery. Hence, patient-cantered communication is fundamental to ensuring optimal health outcomes, reflecting long-held healthcare values that care must be individualised and responsive to patient health concerns, beliefs, and contextual variables.
Compliance with the globally diverse regulatory regimes for controlling advertising and promotion for healthcare products should evolve and adapt to ensure that good practices apply to external engagements and communications with the external stakeholders.
Production Editor’s Note
This chapter has been written by a member of ICLG’s international panel of experts,
who has been exclusively appointed for this task as a leading professional in their field by Global Legal Group, ICLG’s publisher.
ICLG’s in-house editorial team carefully reviews and edits each chapter, updated annually, and audits each one for originality, relevance and style,
including anti-plagiarism and AI-detection tools.
This chapter was copy-edited by Oliver Chang, our in-house editor.
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