Abstract
Introduction
There are for-profit private stem cell clinics that promote using stem cells to treat a variety of diseases and conditions. This is very enticing for some patients who pursue such treatments, including putative untested stem cell–based therapies. Some patients are even willing to travel overseas to get these so-called treatments, known as transnational stem cell tourism. While there is promising research carried out on stem cells in the laboratories, an ever-growing industry targets vulnerable patients all over the world. Alarmingly, there have been accounts of claims of miracle cures and adverse medical events, including fatalities. 1
Accordingly, it is imperative such untested stem cell therapies are stringently regulated. Currently, there are Guidelines for Stem Cell Research and Clinical Translation issued by the International Society for Stem Cell Research (ISSCR Guidelines). 2 This article provides a critical analysis of the guidelines. I argue that while the ISSCR Guidelines are comprehensive and exemplary, they are not entirely effective and much more efforts are required to address this serious problem. 3
The Various Risks of Undergoing Innovative Stem Cell Therapies
While research involving stem cells holds the promise for the medical treatment of a wide-ranging variety of illnesses and conditions, much work is needed to translate the research into safe and effective therapies. During these stages, these treatments may not work and they could also cause adverse effects. Currently, most stem cell-based therapies are novel and experimental. The clinical translation of cell therapy, especially stem-cell-based interventions, is in the early phase. 4 The range of diseases and conditions from which there are proven treatments based on stem cells is minimal, 5 e.g., disorders of the blood and immune system could be treated with stem cell transplantation.
An accepted medical treatment is peer-reviewed, its safety proven through large-scale clinical trials, and is strictly overseen by regulatory bodies. Often, medical breakthroughs require years of rigorous research which entails a costly and elaborate process that advances from fundamental research to clinical research and finally clinical trials. 6 Similar to the development of a new drug, stem cell therapies must be evaluated and fulfil strict criteria before receiving approval from the regulatory groups to be used to administer in humans.
Stem cell clinics are an international phenomenon and some patients are willing to go abroad and pay a high cost to obtain these medical procedures. 7 Some governments, regulatory bodies, and medical associations even support these clinics, and thus they remain in business. 8 Private clinics proffering these services advertise the procedures on the internet, including via websites and social networking.
With legal loopholes and weak enforcement, it is concerning that stem cell treatments are advertised all over the world before they have been demonstrated safe and effective. In 2008, a study led by Professor Timothy Caulfield examined websites advertising so-called stem cell therapies. 9 The findings of this research noted that direct advertisements were made to patients on a variety of sites. The authors enquired whether the claims made on the websites were substantiated by peer-reviewed reports published in the literature and found that many of these clinics overpromised results and underestimated the potential risks of the treatments they offered. Disturbingly, a follow-up analysis found that those unscrupulous practices remain unchanged. 10 The study aimed to determine whether increased awareness and scrutiny of stem cell tourism has led to changes in the claims by private clinics that provide unproven stem cell treatments. The team compared past and present versions of clinics' websites and their findings were that there were parallels between previous and current stem cell treatment offerings, claims, accounts of risk, benefits, and efficacy.
A more recent study was conducted on websites selling autologous stem cells in both Australia and Japan. 11 Their findings revealed more evidence of the fast international growth of private clinics offering unproven stem cell treatments. The marketing practices they adopt to promote their procedures appear on their face to align with evidentiary and ethical standards of science, research, and medicine. These “tokens of legitimacy” include clinical study registration, ethics review, certification/accreditation, claims to expertise/membership of professional organizations, rationales to justify clinical application, testimonials/endorsements, and publications.
Some clinics advertise stem cell-based treatments for a wide range of diseases. 12 A serious concern is that there may be adverse events arising after getting the treatment. There are multiple kinds of harm that resulted in patients after having treatments. 13 For instance, a patient had bone fragments developing in her eye after a cosmetic stem cell treatment a few months earlier. 14 Other adverse effects included meningitis, 15 brain tumor growth, 16 autoimmune disease, 17 and deaths. 18 In a Canadian case, a 38-year-old man developed a tumor on his spinal cord (intramedullary cervical spinal mass). 19 His doctors linked this to a stem cell treatment he underwent in Portugal 12 years ago. This man injured his spine during an accident several years ago when he was 20. He underwent a stem cell procedure that involved transplanting cells from his nose (olfactory mucosal cell autograft) onto the spot of his spinal cord injury. In an analysis, there were 35 cases of complications, including fatalities, following untested stem cell–based treatments. 20 These problems include loss of vision, infections, cardiovascular complications, and cancer. According to the report, while the surgical technique might have caused some of these problems, others are linked to stem cell treatments.
Only a few websites contain warnings about the risks of undergoing innovative stem cell treatments. 21 However, there are multiple useful scientific resources for patients available on the internet, e.g., the ISSCR website.
There is also the concern about the lack of efficacy of innovative therapies; a patient with urinary incontinence sued the hospital as the treatment did not improve his condition. 22 Further, there are exorbitant expenses associated with treatment (and possible repeat procedures), and there are also costs associated with travelling, accommodation, caregiver aid, etc. 23 In the Canadian case, the olfactory mucosal autograft surgery was around C$50,000. 24
The advertising and provision of unproven stem cell treatments are scientifically and unethically unacceptable. Not only has the damage done to patients dented public confidence, but it also undermines the legitimacy of promising stem cell science. In the following parts of this article, I will critically analyse the key provisions of the ISSCR Guidelines to determine to what degree it is effective to curb this complex problem.
The ISSCR Guidelines for the Clinical Translation of Stem Cells
This section explores the essential recommendations of the ISSCR Guidelines. 25 The ISSCR's objective is to guide the proper and responsible translation of stem cell research to safe and appropriate applications. The ISSCR released the Guidelines for the Clinical Translation of Stem Cells (ISSCR Guidelines) in 2008 and it was updated in 2016. 26
The ISSCR Guidelines provide comprehensive guidance for the future development of responsible stem cell therapies from research to the clinic. The guidelines build on commonly shared ethical principles in science, studies with human participants, and medicine, such as the Nuremberg Code, 1949. Ethical practice standards to be applied in preclinical translational applications of stem cell technology are established by recommendations made to institutions, review committees, and investigators.
The ISSCR Guidelines Updates Task Force drafted the guidelines. The task force is a multidisciplinary group comprising scientists, ethicists and regulatory officials from various countries. Feedback was provided on the drafts from private individuals and organizations including regulators, funding bodies, editors, patient groups, researchers, and the general public before the guidelines were published.
The chief aim of biomedical research and its clinical translation is to prevent, mitigate, or eliminate human suffering caused by injury and sickness. The guidelines encourage an efficient and sustainable research enterprise for stem cell research and interventions that will advance human health. The primacy of patient welfare, respect for research subjects and transparency are the fundamental ethical tenets of the ISSCR Guidelines. 27
Researchers must promote open and timely sharing of ideas, methods, data, and materials on the state of the art, including the uncertainties about the safety, reliability, or efficacy of the stem cell applications. There should be prompt communication with the stakeholders, including the patient communities.
It is essential that the subjects participating in clinical research are confident that the projects are scientifically justified and the risks are reasonable in relation to the benefits. Physicians must be convinced that the medical evidence they rely on to make crucial decisions is robust and rigorous. As they owe a duty of care to the patient/research subject, they must not put their patients at risk. Application of stem cell-based interventions must be evidence-based and also subject to independent peer review. Novel techniques should be evaluated early and before use in larger populations. To apply stem cell-based interventions to a large patient community before receiving a rigorous and independent peer review of safety and efficacy amounts to a breach of professional ethics.
Patients/research participants should give informed consent to researchers, clinicians, and clinics. Accordingly, it is crucial to communicate precise and detailed information about the risks and the state of evidence for stem cell–based interventions to the subjects before providing treatment to them. The next few sections of this article further elaborate the ISCCR Guidelines.
Precise Communication of Stem Cell Science
Often, the general public is confused over contradictory messages presented to them. While stem cells are often described as an innovative breakthrough therapy, society is then told that the treatments may not necessarily work. The guidelines stipulate that the stem cell community should provide precise and balanced information about stem cell research. 28 In this connected world, the portrayal of the stem cell field places it under the spotlight in the media. The intense interest in the stem cell field is not unexpected, given its clinical potential. The risks to the clinical application are often toned down, whereas the potential benefits are exaggerated. 29 Forums on stem cell-based medical therapies have been positive, “lending an air of legitimacy to stem cell therapy that hasn't been validated by research.” 30 Inaccurate, incomplete, and partially correct information could harm the entire community. For-profit clinics exploit misrepresentations and oversell by aggressively promoting stem cells for untested clinical uses.
Confusions and distorted perceptions could be formed about the current state of the science of stem cells, including its potential for application, risks, and uncertainties. 31 Thus, consistent and regular engagements with the general public are recommended. The research community could be more proactive through outreach efforts. Scientists could inform their work in several ways, including giving public talks and sharing via social media. These engagements provide understanding for their technical work among laypeople. And scientists also receive acknowledgment, recognition, and respect for their significant contributions to society.
However, as a matter of caution, it is essential to avoid making aspirational declarations on uncertain new developments during these engagements with the public. Well-intentioned scientists may prematurely publish their work, 32 including claims in regard to clinical application, the probability of product approval, or speculation on the future economic impact of unrealized technologies. Researchers should be wary about announcing research findings that have not passed peer review. Premature reporting can affect public confidence if conclusions are subsequently disproven. And if there are errors, inaccuracies, or misleading statements in their research, they must make prompt corrections.
Researchers could consider liaising with communications experts at their institutions. Media departments exist at established organizations with vast resources, and collectively they could produce materials that are intelligible without oversimplifying and which do not understate risks and uncertainties. Research-sponsoring institutions and communications specialists, including editors and journalists, have an ethical responsibility to ensure that the informational materials adopt these values. The lead scientist(s) must check through the content thoroughly before release. It may also be necessary to receive feedback from independent experts. Scientists, clinicians, communications experts at institutions, and industry spokespersons must make sure that risks and benefits of the science of stem cells are not misrepresented to the general public. Adequate care should be practiced for the communication process. These include the use of social networking and traditional print media.
Formulating Standards Development
Researchers, industry, and regulators should work together on the development of standards concerning design, conduct, interpretation, and reporting of research in stem cell science. The ISSCR Guidelines has recommended a way to address untested stem cell treatments through the development of standards in stem cell science. 33 It has designed a donor consent form template to promote uniform standards for consent and procurement of biomaterials.
Standards development will encourage the clinical application of stem cells, and it will also encourage collaborations among the actors, e.g., scientists, clinics, industry, regulators, and patients. Not only would these steps reduce uncertainties, they could also create trust among patients. The articulation of standards includes manufacturing regulations, consent, procurement, the design and reporting of clinical trials, method of delivery, recruitment of recipients for stem cell-based interventions, reporting of animal experiments, reference materials for calibrating scientific instruments, and minimally acceptable changes during the cell culture process.
The guidelines should be regularly reviewed and, if necessary, updated to accommodate scientific innovations, new ethical challenges, and evolving social priorities. 34 The field of stem cell science is not static and evolves speedily. The ISSCR Guidelines are not intended to be the final word. Ethical issues in the conduct of stem cell research should be addressed promptly. Revisiting the guidelines is needed when there are reviews, debates, and amendments. 35 With periodic reviews and revisions of the guidelines, stem cell science can progress and evolve in a responsible and ethically acceptable manner. This good practice could also increase the probability that a standard set of principles will dictate the global scientific research community. However, this recommendation does not provide how regularly the review should be held. 36 It is also noted that reviewing and revising guidelines is a cumbersome and time-consuming task which involves the presence of numerous actors.
The analysis above suggests that the ISSCR recommendations that propose precise communications of stem cell science and the articulation of standards development could address the ethical issues arising from unapproved stem cell treatments.
Are the ISSCR Guidelines Effective?
In my assessment, while the ISSCR Guidelines are comprehensive and commendable, they are not very effective. The guidelines were released in 2008 and revised in 2016. In spite of its existence, the number of stem cell clinics continue to increase all over the world. 37 In the Caulfield follow-up study, it found that the increased scrutiny of stem cell tourism has not had much bearing on the claims of those private clinics that proffer untested stem cell therapies. 38 There is cynicism voiced about the effectiveness of the ISSCR Guidelines. 39 Therefore, many efforts are needed to address this serious problem.
Guidelines are a set of guidance that promote the conduct of responsible and ethical stem cell research and clinical applications. Thus, the ISSCR Guidelines are not legally binding. No guidelines can be the final word. 40 In sum, nation-states are not obliged to adopt the ISSCR Guidelines.
Medical tourism is vital to the economies of developing nations, and their governments may support or condone unproven stem cell treatments. And countries that have established legislation and policies may override the ISSCR Guidelines. Moreover, different societies may have diverse notions of right and wrong, and no state can enforce its laws on another. Indeed the ISSCR Guidelines are not going to filter every charlatan. Also, it is entirely the decision of the patient whether to pursue an untested stem cell therapy. Despite not being legally binding, I argue that the ISSCR Guidelines are very significant. Not only do they set high ethical standards and robust mechanisms for the conduct of stem cell research and its clinical application, but the guidelines are also supported by compelling evidence and logical reasoning. 41
Indeed, the ISSCR Guidelines are an essential first step in raising awareness about the critical issues of unproven stem cell treatments in the international community. The guidelines set the norms regarding pre-clinical evidence and clinical trial design. They do not supersede local laws, but they could assist in the interpretation of domestic laws and they can also guide research practices not covered by the law. 42 Also, the guidelines enable a structured basis in settlement of disputes. They may be tendered as proof of professional conduct to the courts. 43
The ISSCR Guidelines provide scientists with high ethical standards for the responsible conduct of research. They were drafted in broad language and their proposed ethical standards can apply to diverse settings. While one could aspire to their recommendations, it is also crucial to exercise appropriate judgment in specific circumstances. While the guidelines are highly aspirational, they are intended to set an excellent benchmark for researchers in clinical trials in less regulated countries.
The ISSCR Guidelines may encourage governments to adopt appropriate regulations within their borders. 44 For instance, countries, medical establishments, and funding organizations could promote a culture of compliance by integrating the guidelines into their official policies. 45 With support given by ISSCR, it is suggested that governments in countries with less-developed regimes for the regulation of stem cell research and clinical trials must establish effective regulatory frameworks to govern the research and trials conducted within their borders like Australia (see the next section).
Australia's New Tga Regulation
A few countries have taken steps to address unproven stem cell treatments, including Australia. 46 Australia's Therapeutic Goods Authority (TGA) held two consultations with various stakeholders to gather their submissions to establish an appropriate regulatory regime to oversee autologous human cell and tissue products. 47 After the meetings, TGA announced that there would be amendments to the biologicals regulatory framework. 48 These revisions will bring Australia into greater alignment with other jurisdictions, such as the U.S. and the European Union. The changes are intended to bring about graduated regulatory oversight of the products which is commensurate with the safety risks to patients. A higher proportion of the autologous cell products, including stem cells, will now be subject to TGA regulation. 49
Autologous cell products that are more than minimally manipulated, 50 non-homologous, 51 and manufactured and used outside an accredited hospital will be regulated entirely under the Biologicals Regulatory Framework. Products that are minimally manipulated and for homologous use are also controlled subject to exemptions. Access to some unapproved therapeutic goods, such as through clinical trials and the special access schemes, will continue to be available to patients. However, cell products that are manufactured and used in an accredited hospital by a medical practitioner for a patient in the care of the same doctor are exempted from TGA's regulation.
Similar to the prohibition of the promotion of prescription medicines, direct advertising to consumers of the autologous cell products will not be allowed. 52 As the advertising should be generally drafted, no specific reference can be made to the autologous product. For instance, advertisers cannot use abbreviations, acronyms, and colloquial terms like stem cells. The prohibitions apply to all kinds of media including conventional (tv, radio, print media, posters, etc.) and electronic (websites, social media, YouTube, blogs, discussion forums, e-mails, etc.). Testimonials given by patients on websites are considered as advertising. The requirements apply to physicians, media outlets, commercial ventures, and professional groups.
There are other strict conditions imposed on the autologous product. Before being supplied, TGA's approval is needed and applicants who do not show compliance with the regulation will be refused access. The manufacturer and the facilities that perform testing on the product must obtain a TGA-issued license/certification. The cell product must be entered in the Australian Register of Therapeutic Goods (ARTG) where TGA must be satisfied as to the safety, efficacy, and quality of the product. TGA has powers to recall the cell product. It also can suspend and cancel the inclusion of the product in the ARTG. There is compliance with all applicable standards and compliance with matters concerning record keeping and reporting. In cases where a patient experiences an adverse event after the medical treatment, this would have to be reported to TGA.
Finally, TGA has monitoring powers concerning the safety, quality, and performance of therapeutic goods to confirm continuous compliance with the regulatory obligations and resort to enforcement where a breach of the requirement is found. For instance, when a complaint about the noncompliant advertising is made to TGA, the advertiser will be contacted and TGA will educate and assist advertisers in complying with the requirements. If this does not materialize, it will then escalate to other steps by TGA to achieve compliance, and fines could be imposed for noncompliance (up to $840,000 for private individuals and up to $4,200,000 for companies).
However, it is uncertain as to how effective the new TGA regulation is likely to be. Currently, TGA is drafting guidance documents, with the involvement of stakeholders, which will assist in the construction and enforcement of the legal rules. A transition period will enable providers some time to adapt to the new requirements. Indeed, the Australian government's decision to change the law is a progressive move and other nations could consider taking similar measures. At the time of writing, some states in the U.S. have stepped up to address this situation and the latest is Vermont. 53 Vermont lawmakers will introduce legislation to regulate stem cell clinics located in the state.
Conclusion
It is essential patients and their caregivers are given precise, up-to-date, and trustworthy facts on stem cell science. Often they lack the context to comprehend the risks and benefits of purported treatments. Given the current state of scientific knowledge about stem cells, patients should be advised against opting for untested stem cell-based treatments. With sufficient efforts, the comprehensive ISSCR Guidelines could create awareness of the critical issues surrounding unproven stem cell therapies. The guidelines must be widely disseminated to doctors, patient, patient advocates, institutions, review committees, regulators, and investigators all over the world. These groups are then encouraged to collectively inform, caution, and better educate the broader community. They could also exercise their influence to deter patients from seeking unproven stem cell therapies.
Governments must acknowledge and address this serious problem of private clinics providing unproven stem cell treatments to patients. Local lawmakers need to establish an effective regulatory regime to regulate these therapies. The regulation, together with strict enforcement, could be in the form of legislation and guidelines. A legal mechanism is required to ensure that unproven stem cell therapies are not marketed to patients. It is recommended that countries that are considering adopting a strict regulation to mitigate and control the problem could adopt the ISSCR Guidelines, which are based on bedrock principles.