PerspectiveStem Cells

Marketing of unproven stem cell–based interventions: A call to action

See allHide authors and affiliations

Science Translational Medicine  05 Jul 2017:
Vol. 9, Issue 397, eaag0426
DOI: 10.1126/scitranslmed.aag0426

Abstract

Commercial promotion of unsupported therapeutic uses of stem cells is a global problem that has proven resistant to regulatory efforts. Here, we suggest a coordinated approach at the national and international levels focused on engagement, harmonization, and enforcement to reduce the risks associated with direct-to-consumer marketing of unproven stem cell treatments.

INTRODUCTION

The growth of the industry engaged in direct-to-consumer online marketing of unproven stem cell interventions has become impossible to ignore (1, 2). Effective measures for regulating this sector both nationally and internationally are urgently needed. Despite the lack of compelling evidence from well-designed studies to support their efficacy (3), or even in some cases in the absence of a plausible biological rationale, providers aggressively promote the use of stem cells for a wide range of indications. Such practices first emerged in the peripheries of international biomedical research and development (4), but providers have been making inroads in some leading global markets, including Japan (5), Australia (2, 6), and the United States (1, 7). Public warnings by scientific and medical groups (8, 9), government organizations (10), and the media (11) have not slowed the global expansion of an industry based on inappropriate marketing of unproven stem cell treatments. The success of this industry has adverse implications for patients’ health and the integrity of health care markets, as well as potential repercussions for legitimate biomedical endeavors. It also provides an unsettling glimpse of what may lie ahead for other emerging biomedical technologies, such as mitochondrial replacement therapy and gene editing (12).

Efforts to ensure that stem cell–based interventions rest on a foundation of scientific evidence have not all been in vain. Authorities in Germany were successful in closing a private clinic that marketed stem cell treatments primarily to overseas patients, but only after several reports of serious adverse events, including the death of an infant (13). The Chinese Ministry of Health has made significant strides in curtailing an industry in which hundreds of clinics promoted purported stem cell therapeutics over the Internet (14). More recently, the resolution of the Stamina Foundation controversy in Italy provides an excellent example of academic researchers and regulatory officials successfully pushing back against a highly publicized provider of unproven stem cell treatments (15). In this case, a private foundation aggressively promoted purported therapeutic uses of mesenchymal stem cells, and gained national attention by rallying support from some media and advocacy groups around a narrative of patients’ rights and demands for accelerated testing and approval. Following a several-year public debate and scientific review, the “Stamina method” was unanimously rejected and deemed unworthy of further study by a Ministry of Health expert panel. This was an important victory in the fight to ensure that unsupported therapeutic claims about stem cell–based interventions do not go unchallenged. The Stamina Foundation case, in particular, provides critical insights into how promoters of unproven stem cell treatments harness and manipulate popular sentiments and misconceptions and how scientists and physicians can help to inform both representations by the media and public policy (16). By mobilizing support from international scientific organizations and engaging with the public through traditional and social media, scientists were able to exert a positive influence on national policies that initially appeared to be veering toward state support for pseudomedicine (17).

In this perspective, we draw on the mounting body of literature describing the growth and characteristics of direct-to-consumer marketing of stem cell–based therapies (1, 2, 18, 19) to highlight a number of key features and challenges for broad-based efforts to regulate this industry. We also examine how past successes in countering the premature commercialization of stem cell–based therapies in medicine can inform coordinated responses to this phenomenon nationally and internationally (Fig. 1).

Fig. 1. Ways to counter the premature commercialization and deregulation of unproven stem cell therapies.

Approaches will require both national and global action by the scientific, medical, and regulatory communities. Advocacy, monitoring, public outreach, rule-making, and enforcement at the national level are necessary activities. These can be complemented by international standard setting, coordination, engagement, and harmonization, which may benefit from support by authoritative international bodies such as the World Health Organization.

CREDIT: A. KITTERMAN/SCIENCE TRANSLATIONAL MEDICINE

Defining the problem

The online marketing of stem cells takes place within a context of heightened direct-to-consumer marketing activity in the health sector. Direct-to-consumer advertising of medical products and services reflects the increasingly commercialized and consumer-oriented nature of the health sector. The growth of the Internet and social media has provided new outlets for the marketing of both licensed and unlicensed therapeutics and offers sellers the ability to reach worldwide audiences, amplifying the difficulties of enforcing national laws in a global marketplace (20). Critics have cautioned that such unmediated forms of drug advertising may evade regulatory oversight and provide unreliable or incomplete information regarding risks, efficacy, and treatment alternatives (21).

Many professional organizations, including the largest international academic societies in cell therapy (3) and stem cell research (9), have adopted a staged approach to determining what constitutes sufficient evidence of efficacy to justify routine clinical uses of stem cells. These approaches hold that such decisions should typically be based on results from independent, randomized, controlled clinical trials, a view broadly consistent with the norms of evidence-based medicine. Nevertheless, it is important to recognize that study designs and evidentiary standards continue to evolve, and there is a diversity of viewpoints on the nature and quality of evidence needed to support widespread clinical adoption. For this reason, there is inevitably a gray zone between the extremes of strong scientific support and quackery (22). Nonetheless, requiring new stem cell–based interventions to be carefully evaluated for safety and efficacy prior to entering widespread clinical use is consistent with best practices in biomedical research and development, for which there is substantial agreement across many jurisdictions. The steps involved in conventional clinical translation of new therapies include a compelling scientific rationale, well-defined and validated standards for ex vivo processing to achieve cellular product quality and potency, substantial evidence from rigorously designed independent clinical studies demonstrating safety and efficacy in the context of a specific medical indication, and the provision of information from such studies to inform clinical decision-making (23).

Stem cell–based interventions are classified under diverse and potentially incompatible national regulatory frameworks. Many countries have defined a wide spectrum of treatments using human cell and tissue as medical products, which require the oversight of the U.S. Food and Drug Administration (FDA) in the United States or an equivalent authority, such as the European Medicines Agency in the European Union. Other countries, including Australia and Japan, allow physicians’ broad discretion in using autologous cells in the course of medical procedures (24). In the majority of nations, however, clear rules governing the clinical use of stem cell–based interventions are absent. Cell-based interventions may be categorized as “products,” which are subject to oversight by national regulatory authorities, or as “procedures” conducted within the scope of medical practice. These distinct regulatory philosophies have direct implications for how stem cells can be advertised in different jurisdictions. Evidence standards in the context of commercial advertising, market authorization, and standard of care often vary considerably, as do the enforcement options available to national regulators.

Inflated messages

Much of the coverage of stem cells in the popular press to date has been unjustifiably optimistic, both in terms of the potential clinical benefit and the time frame in which such treatments would reach routine clinical application (25). This positive messaging is leveraged by some providers to market unproven stem cell–based interventions. Indeed, the term “stem cell” has been used broadly in promises of youth, rejuvenation, and good health, as well as in the branding of cosmetics, dietary supplements, and sports products (26). Such hyperbole carries with it not only an increased risk of exploitation of vulnerable patients and their families desperate for a cure but also of significant damage to the health of those subjected to these unproven interventions. In the longer term, unfulfilled promises may bring regenerative medicine research and development into disrepute.

In parallel to the hyping of the clinical utility of stem cells, providers of unproven stem cell interventions often display tokens of scientific legitimacy in their marketing messages (Table 1). Such tokens of scientific legitimacy include publications in journals with weak or nonexistent peer review and the registration of pay-to-participate clinical trials on public databases. It can be difficult even for professionals, let alone patients, to determine whether these tokens demonstrate true compliance with the evidentiary standards for developing and testing stem cell therapies.

Table 1. Co-opted tokens of scientific legitimacy.
View this table:

Misrepresentations of the safety and efficacy of stem cell interventions by providers may build on exaggerated accounts of the state of the science in the popular media and research publications. Media accounts may uncritically report statements about the efficacy of stem cell–based treatments. Such articles are then re-posted on clinic websites, cited in social media, and used in crowd-funding efforts, which may further consolidate public expectations and arouse the curiosity of patients. However, the presumption of the efficacy of stem cell–based interventions is not simply a media issue. The pressure to publish, patent, promote, and commercialize research results, as well as to secure funding for future research, are all contributors to the hyping of stem cell science (27).

Regulatory turmoil

National regulatory authorities have been challenged in recent decades by calls for faster access to medical products, even in advance of the completion of rigorous clinical trials. This may reduce the willingness or ability of policy makers, patient groups, and regulators to take a stand against the commercial promotion of unproven stem cell interventions. In the United States, for example, in the face of a strong push for deregulation by providers and patient activists, the FDA is reviewing its regulations on human cell and tissue products. This comes at a time when so-called “right to try” laws designed to weaken federal oversight of the sale of products to terminally ill patients have been passed in the majority of U.S. states (28), and the newly enacted federal 21st Century Cures Act has included provisions for accelerating approvals of cell biologics (29). New laws passed in Japan to stimulate the regenerative medicine industry through the introduction of conditional approvals (effectively shifting efficacy testing to a postmarket context) (30) have also had a major impact on discussions of how new stem cell–based products should be regulated.

Current trends toward ever greater acceleration of medical approvals are a cause for concern given the limits they inevitably impose on premarket testing and the new ethical and legal questions they raise. Whereas medical product deregulation may promote access to interventions via a market model, there are accompanying risks to the health and economic well-being of patients. In under-regulated markets or those in which direct-to-consumer marketing goes unchecked, patients are obliged to make health care decisions without access to reliable information. Furthermore, providers may not be held accountable for the validity of their therapeutic claims, thereby increasing physical, emotional, and financial risks to patients and their families. When individuals spend their limited resources on ineffective therapies, such expenditure come at the cost of alternative effective therapies and other activities that could improve their quality of life; thus, patients purchasing inefficacious treatments might forego effective care. Further, under-regulated markets make it difficult for experts and non-experts to seek and evaluate information about competing claims. Even within regulated markets, health care is characterized by a high degree of information asymmetry, in which consumers must rely on providers’ expert knowledge. Under-regulated health markets, in contrast, permit a lack of reliable information on both sides of the equation that can be profitable to sellers without conferring utility to buyers. Such deficits severely limit both the opportunity for patients to make informed decisions and the incentives for investment in the development of definitive clinical evidence. Deregulation exacerbates these problems and thus increases the likelihood of the wasteful allocation of limited health care resources.

Time to act

What, then, is to be done? Clearly, mutual engagement across a broad range of stakeholders is needed to foster regulatory frameworks that facilitate progress in medical research and ultimately affordable clinical benefit. Uncontrolled advertising and delivery of stem cell interventions for which no evidence or proven rationale exists risks stem cell medicine becoming identified as just another instance of commercialization outpacing evidence. The situation is further complicated by jurisdictional limits on the ability to control cross-border trade in health services (31). If the enormous public investment into stem cell research and development, and indeed its real therapeutic potential, is not to be squandered, it is important that health care systems are structured in ways that incentivize scientifically grounded, clinically meaningful and valuable innovation while curtailing exploitative practices.

Recent history provides several examples of successful responses against direct-to-consumer stem cell marketers. Journalistic pressure has in some cases been effective in exposing predatory stem cell clinics, leading to the closure of clinics in the United States (32) and Germany (13). Medical specialties, such as plastic surgery (33) and respiratory medicine (34), have issued position statements highlighting the lack of sufficient evidence to justify routine use of stem cells in these fields, and state licensing boards have taken action in a small number of instances (35). The Stamina Foundation incident is a case in point where scientific experts worked with, and sometimes confronted, the media to get the facts straight on the actual state of the science with respect to the cells purportedly used by the clinic in question.

National efforts, while critically important, cannot alone succeed in countering the activities of a transnational industry. The effectively borderless nature of the Internet, the ease of international travel, and the jurisdictional limits on extraterritorial enforcement all create windows of opportunity for clinics targeting patients across national borders. International research and medical organizations can play vital roles in supporting the work of local colleagues but also in setting consensus regulatory and practice standards, driving evidence development, and facilitating the exchange of information among stakeholder groups (Fig. 1). To date, organizations dedicated to stem cell and cell therapy research have taken the lead in global coordination, but recent surveys of the global stem cell marketing industry suggest that much work remains to be done. Proactive efforts should now be implemented by organizations with broad constituencies, such as the World Health Organization.

We propose a cooperative model in which stakeholder groups at the national and international levels work together. In their respective national contexts, stakeholder organizations can contribute by advocating for appropriate regulations and accurate media representations and by supporting regulatory agencies through monitoring and outreach efforts. They can also play a role in developing national guidelines to protect patients and human research subjects. This latter function is particularly important in countries that have yet to formalize rules governing clinical research and use of human stem cell–based products. Similarly, advice from international stem cell research and medical organizations on the development of regulations appropriate to individual nations’ specific circumstances could make a significant impact on efforts to harmonize the current patchwork of national regulatory systems.

Approaches for international regulation not only need to develop consistent rules over the commercialization of medical practices and products but also need to give them teeth by developing cross-border partnerships for compliance. Consensus building may best be facilitated by global agencies with the breadth of perspective and authority to coordinate and reconcile divergent interests. We note that international harmonization by professional, industry, and other stakeholder groups has been broadly effective in the regulation of small-molecule drugs and biotechnologies, but this remains underdeveloped with respect to cellular therapeutics, which could similarly benefit from consensus medical practice standards, harmonization of market approval pathways, and resource-building for the development and enforcement of local regulations. In the pharmaceuticals arena, the International Council for Harmonization has been successful in developing and promulgating global drug quality standards. A similar international effort in the field of stem cells and regenerative medicine could help to reduce the heterogeneity and incompatibility of the various national systems governing stem cell products. Additionally, for medical practice, the World Health Organization could contribute through developing guidelines on the responsible clinical use of human cells and tissues and could advise countries seeking to develop local practice standards. Importantly, the success of this model depends on cooperation among relevant national and international organizations around public engagement, harmonization, and enforcement activities (Fig. 1). However, the need for global conformity should not preclude local action where the opportunity arises. Given the time it takes to achieve consensus on policy issues, this would allow local jurisdictions to provide protections while subsequently bringing them into line with a more globally harmonized framework. The globalization of health markets and the specific tensions surrounding stem cell research and its applications have made this a difficult challenge. However, the stakes are too high not to take a united stance.

REFERENCES AND NOTES

  1. Funding: We received funding from the Brocher Foundation for a 3-day residential workshop in Hermance, Switzerland, on the subject of marketing unproven stem cell therapies. Competing interests: D.S. is a member of the Ethics and Public Policy Committees of the International Society for Stem Cell Research. T.C. is a member of the Ethics Committee of the International Society for Stem Cell Research. M.D.L. is a Board Member and Scientific Director of Holostem Terapie Avanzate, Modena, Italy. C.B. is a Coordinator of the EuroStemCell public engagement project, which receives funding from the European Union’s Horizon 2020 research and innovation program under grant agreement no. 652796. M.M. is a member of the advisory committee of the Australasian Society for Stem Cell Research, International Society for Stem Cell Research, and International Society for Cellular Therapy. J.S. serves on the Merck KGaA Bioethics Advisory Panel and Stem Cell Research Oversight Committee and on the Quintiles Ethics Advisory Panel and is a member of the Ethics and Public Policy Committees of the International Society for Stem Cell Research. J.E.J.R. is a Director of Pathology at Genea, an IVF company, is a Scientific Patron of FSHD Global Research Foundation, is a committee member of New Directions in Leukemia, is a Director of Cure The Future Foundation, and is President-elect of the International Society for Cellular Therapy. J.E.J.R. is also chair of the Royal Prince Alfred Hospital Institutional Biosafety Committee and Gene Technology Technical Advisory Committee of the Office of the Gene Technology Regulator, Australian Government.
View Abstract

Navigate This Article