The stem cell market and policy options: a call for clarity

The field of regenerative medicine is widely viewed as having the potential to improve treatment options for a broad range of conditions. Stem cell research in particular has been celebrated for its considerable clinical promise. Although measured enthusiasm surrounding this area of research is warranted, it must be balanced by patience and set in the context of a long-term perspective that is cognizant of the many steps required to bring safe and efficacious therapies to market. Creating therapeutic applications of stem cell technologies is an intricate process involving complex biology. It will require careful scientific investigation and evaluation under responsible ethical frameworks and regulatory standards in order to safely maximize their potential. Alongside the many promising avenues of responsible research currently underway in countries throughout the world, a global market has emerged where a wide range of putative stem cell-based interventions are sold on a direct-to-consumer basis and marketed over the internet.1,2,3,4 In this paper, we discuss a number of concerns associated with this market that stem from a lack of clarity in several key areas, and propose approaches for how they might be remedied. Although we are not the first to identify many of these concerns, their persistence demonstrates the need for clear and concise actions. The market for unproven stem cell-based interventions engages varied interests and crosses different regulatory, research, and clinical domains. We draw on the considerable body of work in this area to highlight the contributing factors to this problem and to facilitate actions to ameliorate some of the most concerning issues. Engaging the different groups and entities that are involved in this space, and clarifying and coordinating their actions, will be critical to the success of policy efforts aimed at mitigating the risks of this market while promoting responsible progress in stem cell research.5 Numerous issues and concerns with the market for unproven stem cell-based interventions have been identified. Many for-profit clinics selling unproven stem cell-based interventions directly to patients take advantage of the hyperbole surrounding stem cell research6,7,8 to advertise their products and services. In many cases, interventions are sold that have no established biomedical or scientific basis (eg stem cell-based treatments for autism). In other instances, the interventions offered may be rooted in basic scientific findings and preliminary clinical experience, but currently have insufficient formal clinical testing to justify widespread clinical use (eg adipose derived stem cells for treatment of orthopedic injuries). At times, it appears that uncontrolled and non-standardized products are being administered, without credible evidence that the products contain active stem cells or have demonstrated any regenerative effects. In addition to other concerns (eg potential fraud and financial loss), when these unproven interventions are advertised and administered without an adequate evidence base, they risk causing serious injury to patients and violating professional and legal standards.9,10,11 For example, recent reports of adverse results include lesions of the spinal cord12 and retinal detachments following intraocular injection of adipose-derived stem cells.13 A comprehensive analysis of reported adverse events from patients who received unproven stem cell-based interventions published in 2018 details 35 cases of acute or chronic complications or death, emphasizing the potentially serious consequences of these unproven interventions.14 Early research investigating this global online direct-to-consumer marketplace for purported stem cell interventions revealed a preponderance of clinics in China, India, and Mexico.15,16 More recent research documents a growth of the market in such countries as the United States, Canada, Australia, and Japan.17,18,19,20 For example, one empirical study of the US direct-to-consumer marketplace for unproven stem cell interventions found over 350 businesses marketing putative ‘stem cell treatments’ for a wide range of diseases and injuries, and a recent update describes 716 clinics operating in 45 of the 50 US states.21 The risks associated with different supposed stem cell-based interventions available on the private market vary tremendously and depend on numerous factors including the source and type of cells used; the quality of harvesting and processing procedures and facilities; levels of procedural reproducibility and quality control; the manner and site of cell administration; the training and expertise of the health care team and the degree and quality of post-procedure care and follow-up. Leading scientific bodies such as the International Society for Stem Cell Research (ISSCR) have made important strides in developing voluntary guidelines for stem cell research and clinical translation pathways.22 However, as the global market for stem cell interventions continues to expand and diversify, it is increasingly difficult to draw sharp lines between what may constitute responsible and ethical instances of medical innovation,23,24 and activities that are clearly unethical because of the inappropriate personal financial burden they may create for the patient, the risks they pose, the uncertainties about their risks, or the lack of any potential benefits. This murkiness and the growing difficulties associated with identifying clear ‘red flags’ of problematic commercial activity creates challenges for prospective patients, health care providers, and regulators alike. We suggest that there is a need for policy makers and stakeholders to focus on achieving informational clarity about stem cell interventions in three key and interconnected areas, each of which carries different responsibilities for those involved: (i) with regulation that is clear and comprehensive, as well as consistently and robustly enforced; (ii) with scientific and clinical transparency, and (iii) with patient communication and engagement strategies that prioritize informed decision-making, accurate representations, and realistic expectations. Improvements in each of these domains depends on progress in the others. Effective regulation requires scientific and clinical precision. Similarly, truly informed decision-making by patients demands a clear understanding of scientific and clinical realities, while responsible scientific and clinical progress is facilitated by clear and consistent regulation that oversees the production of a high-quality product, thus improving reliability, patient confidence, and decision-making. We situate our analysis and recommendations largely in the Canadian and US contexts. In both countries, we see opportunity for timely, strategic interventions to restrict proliferation of the most egregious and concerning forms of this market. We also note however that the global nature of this market demands an important role for international cooperation and coordination. First and foremost, it is imperative that regulatory bodies maintain clear, comprehensive, and transparent governance frameworks for therapeutic cell-based interventions, and enforce those frameworks in a robust and consistent manner. Gaps in oversight and ambiguity regarding how regulations should be interpreted and applied can create regulatory gray zones. These gray zones then create space for the spread of potentially risky and/or ineffective interventions. We will address three key areas of regulatory authority and identify where there are opportunities to clarify how existing rules apply to unproven stem cell-based interventions. This clarification will be a critical component of regulatory certainty and effective enforcement. National regulators such as the US Food and Drug Administration (FDA) and Health Canada have a central role to play in governing drugs, biologics, and medical devices, including human cells and tissues.25 However, gaps have been noted regarding how current frameworks apply to some types of cell-based therapies. For example, in Canada there is ambiguity surrounding permissible applications of minimally manipulated autologous cell therapies for homologous use—a common application advertised in the private stem cell market—and how existing frameworks are monitored and enforced.26 In the USA, the FDA has been fairly public with its struggle to facilitate innovation while constraining high-risk interventions.27,28 It has recently released guidance on how minimal manipulation and homologous use29 and the same surgical procedure exceptions30 should be interpreted. Punctuated by reports of enforcement,31,32 including the FDA’s May 2018 decision to seek injunctions against two stem cell clinics,33 these efforts are promising and may provide much needed clarity. Nonetheless, their impact on the growing commercial marketplace for stem cell-based interventions in the US remains to be seen. Health Canada has yet to release any similar official policy on this issue, but is reportedly taking steps to investigate potentially problematic clinics.34 Although the fast-moving nature of this field may present regulatory challenges—including resource limitations that may influence regulators to focus enforcement efforts on particularly high-risk activities—such challenges are not unique to the stem cell context. Regulation by agencies such as the FDA and Health Canada is often rightly described as a means of protecting patients from unsafe or ineffective interventions. But it is important to note that such regulation is also a crucial framework for encouraging high-value innovation by requiring that rigorous research be conducted to study the effects of technologies.35 Although such research takes time, federal regulators have considerable expertise and experience in addressing questions of access to novel therapeutics and in facilitating patient access to promising unapproved products outside of clinical trials.36 Ideally, these expert regulators will accept the challenge of providing clear and unequivocal leadership in this field, helping to encourage the of truly therapies as the field continues to with such agencies such as the FDA and Health Canada this regulatory is For example, professional regulatory bodies such as the of and Canada and medical in the are of central when it to and standards of for medical and providing policy to their that by these bodies are in this there is a need for these to provide guidance to their regarding what is and is not when it to stem cell-based interventions, and to who include or of on the to which standards of have been and the rules of the particular In professional regulatory bodies in Canada and the have yet to take a to addressing the potentially problematic of their who are and/or providing unproven stem cell-based interventions. We also have yet to see take a leadership role in of providing or policy in to this In some cases, to the of and medicine medical may as for policy in this particularly where they focus on in and professional For example, the of and of addressing and medicine that must be informed by and of patients, requires to the of their and and in the of their clinical and that must or the potential therapeutic that can be or regarding therapeutic that are not by similar with to stem cell-based interventions provide clarity to in these In an of promising these the of in the recently the to and Stem Cell which has several recommendations for medical medical are to of existing and and governing clinical stem cell research and and to FDA and investigate such including the of marketing and about stem cell It remains to be how medical will in of these but they encouraging and standards are of enforcement with considerable Many countries, including Canada and the USA, have existing and that set standards regarding how products and can be advertised to For example, in Canada, that are or in a can to or there may be enforcement challenges associated with the and online nature of much of the of stem cell-based interventions available on the private efforts as which is by to online of and enforcement of existing standards play a role in potentially problematic marketing in this made on the of clinics operating in of (eg because their of or of being are and/or can require they be and This type of active enforcement not problematic from the public but as a to other similar we robust enforcement from the in Canada or the in the the of it may be that from stakeholders including medical will be required to this a a first the for example, a to provide clarity about the legal for of stem cell products and on what may be or with particular on online and potential official of this nature encourage those in this of marketing to their and as a to others. it may as a resource for health care and to provide accurate to informed decision-making by their patients, as in The and application of policy and regulatory for any field requires a clear and understanding of is being we will address and must be scientific and clinical and facilitated use of consistent and robust and and oversight of clinical These demands have both for and demands for how those are to scientific and regulatory it is that stem cell and those in responsible clinical translation and use accurate that and the active and products that are be the (eg and by the for the of and the to products stem and cells for the active component is similar in both other in the and this results in different provide important that scientific and clinical understanding and in some instances they are also complex and with gaps in and lack of It is important that those in providing stem cell interventions in a clinical context are as transparent as with the details of their treatment and and that they with the from to patients which are in the this scientific and clinical and with regulatory is critical both for with regulatory standards and for contributing to and in this Nonetheless, at present this degree of and is not common private market Many of the products such as adipose-derived cell products from are complex of cells with potential and regarding and to what degree the products contain active stem the reproducibility that products can and be and the of such interventions requires that be to identify the active cells and the activity of as well as and the to the It is any who to be in ethical to these that there may be no for businesses that from the of stem cell interventions to their current and transparency, it is also the of regulators to their of oversight to For example, private market may be to their medical at or they or other to federal regulatory oversight such as from Health Canada or the also have a role to play by regulatory bodies are that they can their and provide this not without its and in is the most and in scientific for promoting and reproducibility of study challenge to achieving in is the of to as that not provide or other in quality these can be as of scientific by of unproven interventions to the of their products and which lack robust quality standards are a to and in the scientific Although this challenge in this context the to the potential that patients including health care will be about the of the and its for clinical of scientific and clinical must their to this risk by being about their and by being to the of to or in addition to to enforcement activities by the US by several are a promising this growing problem and protecting the authority of such that it can be a resource for health care providers, patients, and their there is a need for quality standards clinical and The public and of the widely a resource by the US National of and the National of Health is increasingly by the of the of of scientific the of that not to with regulatory and of on the of study to be a public resource that be to credible clinical from other commercial in direct-to-consumer of unproven stem cell-based interventions are increasingly to clinical of and legal the US National of not clinical they are and on some businesses are clinical as marketing and to use as an to draw prospective to their has the of a that the not and on the the of of ethical and scientific it increasingly difficult for or their and their health care to providing access to stem cell interventions from businesses marketing and unproven stem cell lines need to be activities that are most as clinical research, and those in the of care for clinical The of these lines is a between regulators such as the FDA and Health Canada, professional regulatory bodies such as the of and in Canada or the medical in the USA, and research It will require and consistent enforcement. These actions are because in some cases, private market stem cell use the or nature of their work to they not have from the FDA or regulatory At the same time, to take the that they are not in research, and not require research but are selling established in the of robust evidence of and Research involving human must be to including Research and It is important these bodies provide truly scientific and ethical of clinical and of of scientific and ethical from the research treatments and procedures in clinical including stem cell-based interventions, should the standards of bodies as that use involved in the field as Similarly, the of these treatments and procedures should be reported to clinical that of and long-term are available as quality and the cell and that cell-based medical products are safe and when in a this not to be common of unproven stem cell-based interventions. The complex regulatory, and clinical challenges described to what has a and of from which patients have to difficult about their of the surrounding an market for stem cell-based interventions on the risks such commercial activity to the patient there are concerns to following reports of adverse and financial risks, the reported of (eg and risks to and It is often that with to health care have the to accept such risks, on the that they have accurate and have informed However, the of patients to in this can be by or For patients to and realistic they need from of stem cell-based interventions, adequate from their and the to the of available including patient We address each of these in with recommendations including strategies for communication and engagement The for informed a central role in health care decision-making in the and However, the to provide informed requires that have access to accurate to their It is particularly important that are informed about the risks and of any which also requires some understanding of what remains (eg to lack of the by clinics selling unproven stem cell interventions the for informed is the nature of on to which and as a stem cell a requiring health care to patients when the stem cell interventions they are not by the FDA and for to Although the and a similar in First challenges on the that they the of the may be to such challenges because they require and of their these are an encouraging to improve the and quality of available to prospective patients, but also suggest current in the of at some stem cell the with health care providing stem cell interventions, other health care (eg and who have care with have important and responsibilities as can be an important in unproven stem cell-based interventions, particularly where from or chronic for which effective and treatments not can be manipulated and by those who may from It is important that health care not difficult but realistic about the consequences of unproven therapies of about the potentially effects of or it is that with patients in unproven interventions to their legal and ethical including by providing about the risks and scientific uncertainties of unproven stem cell-based interventions. may to not the of informed where that providing a patient with they may not to guidance from professional and medical may be of considerable in clarifying in these professional medical patient and also have a role to play in helping informed and in promoting realistic on credible by about the therapeutic of stem cell interventions. patients in their decision-making process will about what is available as of the of care for their about what there for improving quality of in and of risk and and about what is offered on the private market. should be clear and to access and and to the and of that strategies are common in this the of quality online is Although some work has been in this field, research online about clinical translation of stem cells that for the most comprehensive is Stem cells in online including on but there is of widely For example, patient and have a role in the marketing of stem cell-based interventions and in which is concerning they are often of patients are to to seek financial in of their of an unproven stem cell-based These which often include personal from the prospective patients, that direct-to-consumer marketing including about the and of stem cell interventions are being by and in they are to as these for are on a marketing to be and without a balanced or accurate research for unproven stem cell interventions these often risks while and the use of personal may such also to draw on the marketing of the stem cell businesses that use purported to research and the and of regulatory bodies such as the FDA and the in the USA, in order to the and scientific of the stem cell These and other of or about the of stem cell research and its clinical applications can the and risk being for financial by of unproven stem cell-based of any communication aimed at informed decision-making by patients to include guidance for the quality and of different and of including have been with this in and of or to the quality of online health include the Health on the and to a Health care providers, patients, and their may from with and these health care care and an important role in their patients who may be unproven stem cell-based interventions to that they are to an informed In the research should to the of for including to how they are by the private market to both and about stem and to their role in health decision-making. In addition to that focus on informed and communication of and realistic stem cell interventions can be patients in stem cell patients in of research, from study to may their understanding of the research process and of the current of the and facilitate evaluation of interventions and The direct-to-consumer market for unproven stem cell-based interventions and the concerns it are well and have been the of considerable the and policy varied efforts to the of this market to be We suggest that many of the most challenges and risks associated with this market are by and We have that there is a need for clarity on at three interconnected scientific and clinical and communication or in any of these areas will progress in the others. In our clarity in of these domains is for the success of policy efforts at the spread of potentially and/or while encouraging translation of promising avenues of stem cell We also the of and international A global potentially with the leadership of bodies such as the Health will be for the long-term success of efforts to risk and problematic private market while promoting the health of the field of stem cell research and its to However, the of these not the of policy and governance work at the and For example, the of the market developing in Canada an important and opportunity to take a and informed to its oversight and efforts as for other to draw the US regulatory is currently being to the with on it to to the growing market its it to the it important and to global standards in this for clarity and efforts at a number of levels be by any one in it has for regulatory in areas including health care and and patient others. It is the and of those with interests and influence in stem cell research to in this important and take steps to the of patients, the public and the long-term clinical potential of this promising of the of to and Stem Cell has an expert on a of in against a stem cell This informed by a in in to potential policy to the growing private market for stem cell interventions. This in policy and stem cell and and with experience, a private market stem cell patients and patient The the Stem Cell for the and it to this We also to our to of the and for their time, and to this which directly informed the of this We note that this work and key from the but not or the and of of those or of their In addition to those as on this Cell and in Research Stem Cell Society of Health of cell for of of and of of Health

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