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Stem Cells Transl Med
Stem Cells Transl Med
stcltm
Stem Cells Translational Medicine
2157-6564
2157-6580
Oxford University Press US

39045646
10.1093/stcltm/szae050
szae050
Concise Reviews
AcademicSubjects/MED00770
AcademicSubjects/SCI00960
The evolution and ongoing challenge of unproven cell-based interventions
Brinsfield Taylor N School of Public Policy, Georgia Institute of Technology, Atlanta, GA 30332-0345, United States

Pinson Noah R School of Public Policy, Georgia Institute of Technology, Atlanta, GA 30332-0345, United States

https://orcid.org/0000-0002-1037-8408
Levine Aaron D School of Public Policy, Georgia Institute of Technology, Atlanta, GA 30332-0345, United States
Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA 30332-0363, United States

Corresponding author: Aaron Levine, School of Public Policy, Georgia Institute of Technology, 685 Cherry Street, Atlanta, GA 30332-0345, USA (aaron.levine@pubpolicy.gatech.edu).
Taylor N. Brinsfield and Noah R. Pinson contributed equally to the paper.

9 2024
23 7 2024
23 7 2024
13 9 851858
18 12 2023
23 6 2024
© The Author(s) 2024. Published by Oxford University Press.
2024
https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.

Abstract

Unproven cell-based interventions (CBIs) emerged early in the 2000s as a particularly problematic form of unproven therapy and remain a vexing policy problem to this day. These unproven interventions can harm patients both physically and financially and can complicate the process of developing a rigorous evidence base to support the translation of novel stem cell or other cell therapies. In this concise review, we examine the emergence of unproven CBIs and the various policy approaches that have been pursued or proposed to address this problem. We review the evolution of this field over the last 2 decades and explore why these policy efforts have proven challenging. We conclude by highlighting potential directions that the field could evolve and urging continued attention to both current and future forms of unproven CBIs to minimize future risks to patients and the field and to promote the development of evidence-based cell therapies.

stem cells
bioethics
health policy
medical tourism
National Science Foundation 10.13039/100000001 EEC-1648035
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pmcSignificance Statement

Unproven cell-based interventions (CBIs) pose substantial risks to patients and to the broader field of translational cell therapy research, yet efforts to regulate this market have proven challenging. In this concise review, we examine past developments and highlight emerging trends related to unproven CBIs. This review should help inform and support efforts by both scientists and policymakers to address the challenges posed by unproven CBIs and promote evidence-based translational cell therapy research.

Introduction

While unproven medical interventions have a long history, unproven cell-based interventions (CBIs) emerged early in the 2000s as a particularly problematic form of unproven therapy and remain a vexing policy problem to this day. These unproven interventions can harm patients both physically and financially and can complicate the process of developing a rigorous evidence base to support the translation of novel stem cell or other cell therapies. In this concise review, we examine the emergence of unproven CBIs and the various policy approaches that have been pursued or proposed to address this problem. We review the evolution of this field over the last, approximately, 2 decades and explore why these policy efforts have proven challenging and what options remain for regulators and scientific leaders seeking to minimize the risks of unproven CBIs and, thus, support responsible translation of cell and stem cell research into safe and effective therapies.

Early history of unproven cell therapies

Initial reports of unproven CBIs were found primarily in the mass media, as journalists tracked the stories of individual patients seeking care for conditions that lacked approved options. This growth coincided with increased excitement and, in some cases, hype, around the potential of pluripotent stem cell research, following the report of the first successful isolation of human embryonic stem cells in 1998.1 During the early 2000s, stem cell science received substantial public attention as well as high-profile interest from policymakers, and companies around the world took advantage of this environment to market CBIs, ostensibly based on stem cells, to patients in the absence of appropriate evidence of safety and efficacy.2 Because most of these early reports of patients accessing unproven CBIs involved traveling to access a therapy not available in the patient’s home country, this practice became known as “stem cell tourism.”

As stem cell tourism increased in profile and scientific societies, including the International Society for Stem Cell Research (ISSCR) and International Society for Cell and Gene Therapy (ISCT), raised concerns about the impact of these unproven CBIs on patients and legitimate translational research, numerous scholars turned their attention toward this practice. Two groups used internet search strategies in 2007 to identify providers of unproven CBIs.3,4 In Lau et al,3 the authors identified 19 clinics offering unproven CBIs and analyzed the websites of these clinics, comparing the claims made versus the published clinical literature. They concluded that “the portrayal of stem cell medicine on provider websites is optimistic and unsubstantiated by peer-reviewed literature.” In Regenberg et al,4 they identified 23 providers with accessible websites and inquired via email with each provider about the interventions, receiving 10 replies. Their analysis provided information on the conditions “treated,” the costs of these interventions, the sources of the cells ostensibly used, and any information provided about the benefits or risks of these interventions. Overall, they concluded that they found “content that strains credulity and almost no evidence of SCBIs being delivering the context of clinical trials,” and recommended efforts to increase patient education and global oversight of this emerging practice. In 2013, a group of scholars compared historical (ca 2008) information with newer clinic websites and found that relatively little had changed.5 Notably, while descriptions on clinic websites were more detailed and descriptive, they remained “overly optimistic.”5

Data on the patients pursuing unproven CBIs have generally been scarcer than that available about the clinics themselves. One exception is a 2010 study examining patients who blogged about their experiences receiving unproven CBIs.6 While acknowledging limitations associated with studying patient blogs, this paper reported rapid growth in the number of patients blogging about their experiences receiving unproven CBIs around the world.6 A 2012 paper reporting on a small series of qualitative interviews with patients who received unproven CBIs provided insight into how patients learned about these options, how they made decisions to pursue them, and to what extent, if any, they interacted with home country physicians in their decision-making processes.7 Ethnographic methods, including participant observation, have also been applied to the study of unproven CBIs. In a series of papers, Margaret Sleeboom-Faulkner et al8-10 have examined experimental stem cell research, including the provision of unproven CBIs in several Asian countries. Among their findings is the pervasive use of recruiter-patients—“a group of patients who either have already received or are in the process of receiving the therapy and, importantly, are used by service providers as mediums or tools to attract desperate yet novice therapy seeking patients to the ambit of the stem cell therapy enterprise.”11 Other ethnographic work has stepped back from the condemnation of unproven CBIs common in the medical ethics literature to focus on understanding how patients navigate these journeys of hope.12,13 Cumulatively, these and other studies of the early development of the unproven CBI industry painted a picture of a global practice that varied across jurisdictions and cultures but that nearly universally raised concerns about physical and health risks to patients and called out for greater regulation and coordination.

From stem cell “tourism” to cell “therapies” everywhere

While unproven CBIs first received attention in the context of international travel, the industry grew in many jurisdictions, changing the narrative from one of stem cell tourism to one where unproven CBIs were readily available in many countries around the world. The US context is instructive. Initially, when unproven CBIs grew in prominence, a small number of providers in the United States were identified,14,15 often when they rose to the interest of the legal system.16 Still, most attention was on patients traveling from the United States to other jurisdictions, including China, India, and Mexico. Notably, clinics that did operate in the United States either took advantage of ambiguities in the Food and Drug Administration (FDA) oversight rules for cell therapies to claim they were compliant with the regulatory framework or operated in defiance of FDA rules entirely. While FDA enforcement action led some of these early clinics to close or move their operations offshore,17 large numbers of clinics rapidly took their places, both testing the limits of the FDA’s authority and overwhelming their relatively small enforcement division. The development of this industry in the United States context has been tracked most diligently by Leigh Turner and Paul Knoepfler. Using systematic web search and scraping techniques, between September 2015 and February 2016, they identified 351 businesses offering “stem cell interventions” at 570 clinics across the United States.18 These clinics were distributed across the United States with clusters in Florida, Southern California, and Colorado and claimed to use a variety of different stem cell types in their interventions.18 This analysis was updated by Leigh Turner19, finding that by early 2021 there were at least 1480 businesses operating 2754 clinics across the United States. Turner and Knoepfler did not analyze individual clinics to assess whether they were compliant with FDA rules, but given the small number of approved cell therapies and increasingly clear FDA guidance documents (discussed below), it is likely that the vast majority of these clinics were marketing and providing unproven CBIs directly to patients.

A portion of this recent growth reflects the emergence and expansion of the market for unproven allogeneic perinatal stem cell products. Turner et al20 recently assessed the US market for these interventions. They found more than 300 businesses offering such products, typically claiming to use stem cells derived from umbilical cord blood or amniotic fluid.20 Given the relative clarity of FDA regulations for these products and the end of the enforcement discretion period (discussed below), most, if not all, of these clinics were likely offering products without required regulatory approvals.20 Some evidence suggests that FDA has targeted enforcement in this area, at least relative to other forms of unproven CBIs,21 but this effort remains limited.

Similar, if less dramatic, growth of the unproven CBI industry has been observed in other countries around the world. Indeed, by 2016, when the most comprehensive attempt to map the global (English speaking) market for unproven CBIs to date was published, the authors found that the online marketing of unproven CBIs was skewed toward developed countries, with relatively well-regarded regulatory systems, including the United States, Germany, and Australia.22 In-depth studies of individual countries tell a similar story. In the United Kingdom, for instance, a 2020 study found 71 businesses operating out of 106 facilities that appeared to offer CBIs directly to patients.23 This was up from 12 UK-based clinics identified in the 2016 analysis.22 In 2018, 2 studies provided insight into the unproven CBI industry in Canada, documenting and analyzing 15 clinic websites24 and 30 businesses, providing services at 43 clinics.25

The strategies driving this growth and establishment of the unproven CBI industry varied across countries due to the specifics of the rules on advertising and providing novel therapies to patients. Yet these clinics consistently took advantage of ambiguous rules and used clever marketing efforts to suggest to potential patients that they were offering legitimate or at least very promising medical interventions. These marketing tactics, which came to be known collectively as “tokens of scientific legitimacy,” included filing patent applications, listing clinical trials on government directories, publishing related papers in predatory journals, etc.26 As discussed in the sections that follow, this combination of plausibly scientific marketing content, when paired with demand from patients for therapies for a wide range of conditions that are not well treated today, and a willingness by clinics to aggressively exploit regulatory uncertainty or weakness, led to a thriving industry that has proven challenging for regulatory authorities or the broader legitimate research enterprise to control.

Distinguishing the growing unproven CBI industry from evidence-based cell therapy development and translation has proven challenging for patients, clinicians, and regulators alike because of the relatively limited clinical track record for cell therapies (outside of hematopoietic stem cell transplantation), rapid technological advances, and the wide diversity of cell types and therapeutic targets. As a result, clinics offer evidence of various forms and quality as they market their offerings and “tokens of scientific legitimacy” can be persuasive marketing tactics. As a result, multiple scholars27,28 have highlighted the need to view and address the challenge of unproven CBIs on a spectrum that ranges from products that are provided with no evidence and should, in some cases, be viewed as outright scams to products that are undergoing clinical research in the hopes of generating sufficient evidence to warrant approval and market access, but for which this bar has not yet been (and may never be) met. Although the marketing of unproven CBIs anywhere on this spectrum raises concerns, views of potential patients and clinicians as well as appropriate regulatory action may differ for providers on different portions of this spectrum.

Raising awareness

As reports about patients seeking unproven CBIs proliferated and the number of clinics offering these therapies grew, scientific societies grew concerned about the risks these unproven interventions posed to patients as well as the potential impact of unproven CBIs on the ongoing effort to develop and translate evidence-based cell therapies. To help educate their members, as well as the broader research and health care communities and the public, several scientific societies, most notably the ISSCR and ISCT, created a series of reference guides and resources (Figure 1).

Figure 1. Timeline of key scientific society and regulatory activity.

The creation and distribution of these resources served a variety of purposes. They allowed those interested in, or pursuing, stem cell therapies credible information and access to expert scientific opinion to help inform their decisions. In addition, they provided information for those treating patients or conducting research on key ethical considerations relevant to their work. An early example of this genre of reports is the ISSCR’s 2006 “Guidelines for the Conduct of Human Embryonic Stem Cell Research.”29 This document, developed by an ISSCR Task Force, laid out a set of ethical guidelines to help guide research using human embryonic stem cells. This report was followed in 2008 by the ISSCR’s “Guidelines for the Clinical Translation of Stem Cells.”30 Notably, this document articulated a specific ISSCR position on unproven CBIs. With the exception of small-scale medical innovation,31 the “ISSCR condemns the administration of unproven uses of stem cells or their direct derivatives to a large series of patients outside of a clinical trial, particularly when patients are charged for such services.”30(p5). This report was complemented by the ISSCR’s “Patient Handbook on Stem Cell Therapies,” an 8-page document containing a variety of questions and accompanying information regarding stem cell therapies. This handbook not only informs potential patients of the potential risks, costs, and benefits of stem cell treatments, but also provides information on what they should expect from, and ask of, those conducting trials and offering treatments. The ISSCR updates its guidelines as the field advances, but similar statements condemning the administration of unproven CBIs remained in its 2016 and, current, 2021 reports.32,33 In addition to reports, the ISSCR has attempted to call out clinics more explicitly. In June 2010, the ISSCR launched their “Submit a Clinic” website to help patients identify clinics promoting unproven cell therapies by providing them with “fact-based, on-demand analysis” of the treatments offered by these clinics. However, after receiving numerous threats from clinic’s lawyers, ISSCR quickly backed down and deleted the website, unable to risk litigation.34

In addition, the ISCT has published a series of statements and reports aiming to raise awareness of and minimize risks associated with unproven CBIs. This effort started with ISCT’s 2010 publication, “Cell Therapy Medical Tourism: Time for Action.”35 This report reviewed the state of the field and articulated a key role for scientific societies in helping address the challenges posed by unproven CBIs. It also kicked off a long-term effort, led primarily by the ISCT’s Presidential Task Force on the Unproven Cellular Therapies (now renamed the Committee on the Ethics of Cell and Gene Therapy). These included the 2015 report, “Positioning a Scientific Community on Unproven Cell Therapies,"36 (translated into 10 languages), as well as an extensive reference guide examining various facets (eg, definitions, manufacturing, regulation, communication, etc.) of the unproven CBI industry.37 More recently, the ISCT released an updated position paper, titled, “Key considerations to support evidence-based cell and gene therapies and oppose marketing of unproven products” designed to empower ISCT members to take steps to address the ongoing challenges posed by unproven CBIs.38

Unfortunately, a series of adverse events reported by patients who received unproven CBIs have added urgency to the ISSCR and ISCT’s calls for increased awareness of the risks of unproven CBIs. An initial report of these adverse events, published in 2018, identified a total of 35 cases of “acute or chronic complications or death following an alleged SCI administration” through searches of the peer-reviewed literature and the mass media.39 A more recent assessment, led by the Pew Charitable Trusts, identified 360 adverse event reports through searches of the scientific literature, mainstream media, and the FDA adverse event reporting system.40 The earliest of these cases, reported in the scientific literature in 200941 was linked to a 2001 treatment of a young boy with ataxia telangiectasia with intracerebellar and intrathecal injections of a putative mixture of neural stem cells at a hospital in Moscow. Several years after receiving an unproven CBI, the patient was diagnosed with a multifocal brain tumor that was shown to be of donor origin.41 At times, reports of adverse events have triggered enforcement actions by regulatory agencies, medical boards, or similar. For example, a controversial German clinic was closed by authorities in 2011, shortly after the death of an 18-month-old following an injection of bone marrow-derived stem cells into the brain.42 Similarly, in the United States, a high-profile report of vision loss in multiple patients with age-related macular degeneration following intravitreal injection of autologous adipose-derived stromal cells at a clinic in Florida,43 led to intensified regulatory attention on the field.17 Unfortunately, many clinics offering unproven CBIs have little incentive (and perhaps ample disincentive) to closely follow patient outcomes and especially to report adverse events, suggesting that the accounting of adverse events reported to date is almost certainly an undercount.40

Regulation and enforcement activities (and struggles)

Better data on the practice of unproven CBIs, as has been called for repeatedly,44,45 would help physicians, patients, and policymakers understand the risks and could help inform decision-making. Yet, even in the absence of additional data, the harms associated with unproven CBIs are abundantly clear and justify regulatory action to protect patients and support the responsible translation of safe and effective evidence-based cell therapies.26 Regulators in countries around the world have responded by clarifying and enhancing their regulations and, at times, increasing their enforcement efforts. Reviewing regulatory advances (and associated struggles) is beyond the scope of this review, but we briefly highlight the evolution of regulatory oversight in the US context as an illustrative and important example (Figure 1).

In the late 1990s, the US FDA embarked on a multiyear policy process that led to the promulgation of a series of regulations for human cells, tissues, and cellular and tissue-based products.46 Several years later in 2014, the FDA won a key lawsuit—US vs Regenerative Sciences Inc.—establishing its authority to regulate autologous cell therapies that were more than minimally manipulated. This case amply illustrates the challenges of regulating unproven CBIs in a global environment. Although the US FDA was victorious in this case, the company it was seeking to restrain simply moved its operations for the specific procedure at question in the litigation to the Cayman Islands, where it continues to operate today.47 In 2017, the FDA announced a new “comprehensive regenerative medicine policy framework,” building upon its existing regulatory authority and issuing guidance documents to clarify several key terms, including “minimal manipulation,” “homologous use,” and “same surgical procedure,” to help clinics better understand which products were subject to premarket authorization requirements and which were exempt from these requirements. These documents aimed to close key loopholes that clinics offering unproven CBIs in the United States were using to operate with relative impunity. Along with the publication of these documents, the FDA announced that it would offer a 36-month period of enforcement discretion to allow manufacturers time to comply with the guidelines. This enforcement discretion ended in mid-2021 (following a pandemic-induced extension). According to an FDA presentation at the Association for the Advancement of Blood & Biotherapies48 annual meeting in October 2023, FDA compliance activities in this area include 28 warning letters (typically issued following inspections finding significant violations of good manufacturing practice requirements) since August 2017 and over 40 untitled letters since August 2018. In addition, since December 2018, the FDA issued more than 600 letters to manufacturers, health care providers, and clinics, notifying these entities that they appear to be marketing a product in violation of FDA regulations. Most of these latter categories of letters appear to be based on FDA review of provider websites or marketing materials. These less formal notification letters may prompt entities to change their business practices or may be precursors to more intensive compliance activity. To date, however, evidence of these effects is limited and the market for unproven CBIs continues to thrive.19

This environment is impacted by legal questions that have been raised about FDA’s regulatory authority. In 2021, the FDA won a key case in Florida (US v US Stem Cell Clinic), with the 11th District Court of Appeals affirming a lower court’s decision that stromal-vascular fraction (SVF) cells isolated from a patient’s adipose tissue and reinjected into the same patient fell under FDA authority. Yet the FDA lost a similar case in California (US v California Stem Cell Treatment Center) with a district court judge ruling that SVF cells were excluded from the FDA’s regulatory authority because they fell under the same surgical procedure exception. As of July 2024, FDA is appealing this decision to the Court of Appeals for the 9th Circuit. The ISSCR and ISCT submitted a cosigned amicus brief in support of the FDA’s position. While this case is pending, the FDA’s authority to regulate at least some unproven CBIs is uncertain and it seems plausible that this might limit their enforcement actions. In addition, the FDA faces other challenges to its authority, both specific to stem cells and regenerative medicine (eg, the proposed but not passed federal Regrow Act,49 state-level stem cell laws,50 etc.) and as part of a larger deregulatory agenda (eg, Right to Try laws at the state and federal level,51 ongoing legal challenges to Chevron Deference,52 etc.). Thus, even if the FDA succeeds in its current appeal, it will face a difficult regulatory challenge and an uphill struggle to regulate the 2700+ clinics operating across the country. Despite these challenges, however, the FDA remains the cognizant regulator for novel medical products in the United States and should explore various options, including reprioritizing its existing compliance activities, requesting additional funding to expand enforcement and compliance activities, and partnering with other federal and state agencies to help address the challenges posed by the rapid expansion of unproven CBIs.

Other policy options

Given the challenges of addressing unproven CBIs under drug regulations, substantial attention has been given to the question of whether other policy tools could help. These include laws addressing the advertising of unproven CBIs as well as enforcement actions by medical authorities (eg, state medical boards or similar) that credential health care providers. In Australia, concerns over unproven CBIs led to a change in advertising rules in 2018, explicitly banning the marketing of stem cell products directly to consumers.53 In the US context, where such a ban would not be legal, truth in advertising laws provides an alternative approach. One example occurred in 2021 when the Federal Trade Commission (FTC) took joint action with the Attorney General of the State of Georgia against a group of clinics for “marketing stem cell therapy to seniors nationwide using bogus claims that it is effective in treating arthritis, joint pain, and a range of other orthopedic ailments.” Given the readily accessible marketing materials produced by many providers of unproven CBIs, this approach appears promising, yet it remains to be seen how highly it is prioritized by the FTC. More broadly, action by state attorneys general, both in collaboration with federal agencies and independently, offers a promising alternative with efforts in New York54 and Washington55 among others serving as potential templates for action in other states.

Credentialing authorities (eg, state medical boards in the United States, colleges of physicians and surgeons across Canada, etc.) provide another option for potential oversight. These and similar bodies set and potentially enforce standards for medical professionals and could use this authority to discourage their members from engaging the direct-to-consumer marketing and provision of unproven CBIs.56 Yet, with a small number of exceptions in particularly egregious cases, they have not taken such action. The Federation of State Medical Boards in the United States has produced a report on the issue,57 which could potentially be used to justify more aggressive action in the future. In the Canadian context, scholars have argued that colleges of physicians and surgeons have the authority to take action against members providing unproven CBIs yet have not taken significant action.58 One possible route forward might be for these boards, which do not specialize in stem cell or cellular therapy, to collaborate more directly with scientific societies, such as the ISSCR and ISCT, in this area.59

Increased public/patient education has also been posited as a strategy to minimize the risks associated with unproven CBIs.59-61 This approach has the benefit of not relying on action by any particular regulatory body or government agency, yet is certainly a long-term project and it is far from certain that providing patients with a better understanding of stem cell research, cell therapies, and their limitations would dampen demand for unproven CBIs. Indeed, science communication practitioners have increasingly rejected the so-called deficit model of scientific communication, suggesting that a more inclusive and intensive program of public and patient engagement (rather than simply education) may be called for.62

Open questions and future directions

While the policy environment remains in flux for unproven CBIs, both in the United States and around the world, science continues to advance and providers of unproven inventions continue to identify opportunities to market their wares. This was the case during the early days of the Covid-19 pandemic, for instance, with numerous clinics offering unproven CBIs that they claimed provided protection against or helped treat the symptoms of Covid-19.63,64 We conclude this concise review with a short discussion of 3 emerging issues in the field: (1) the emergence of unproven exosome-based therapies as an alternative or complement to unproven cell therapies, (2) the development of an unproven cell banking industry, and (3) the possibility for clinics to emerge that offer unproven or unregulated chimeric antigen receptor T (CAR-T) cell therapies.

As exosomes have gained prominence in research as a potential therapeutic tool,65 clinics offering unproven CBIs have increasingly added unproven exosome therapies to their offerings. This led the International Society for Extracellular Vesicles to issue a patient advisory in August 2020 about the marketing of unproven exosome therapies. Indeed, in Turner’s 2021 report, 99 businesses listed exosomes among their offerings.19 A more recent study explored the emerging global market for unproven stem cell secretome-based therapies, including those that claimed to offer treatments based on exosomes, or extracellular vesicles.66 In this paper, the authors identified 114 companies marketing these therapies in 28 countries. This highlights the challenge of a rapidly evolving industry. Indeed, even as regulators struggle to provide appropriate oversight for, as an example, unproven autologous stem cell-based interventions, an emerging industry is growing that may also prove difficult to regulate or control.

Concerns have also been raised over the potential emergence of an unproven cell banking industry.67 Cell banking capitalizes on the potential future applications of stem cells by providing a preservation system for cells that may one day prove medically useful. These firms find a model in cord blood banking, a well-established industry that banks hematopoietic stem cells isolated from placental tissue and cord blood (otherwise discarded as medical waste after birth) for potential medical use. Both public and private cord blood banks exist, although private banks have been criticized on ethical grounds, typically over misleading marketing or the low chance that cells could actually be used.68,69 Despite this criticism, cord blood banking has a plausible justification in the established use of hematopoietic stem cells to treat certain hematologic malignancies. More recently, cell banking firms have offered to preserve cells for highly speculative future uses. Ethical concerns with this practice have been articulated67 and the ISCT developed a statement of concern about the practice that was signed by 10 additional scientific societies.70 While it is uncertain how many unproven call banking firms exist, this industry merits observation to ensure that cell banking initiatives are designed to maximize patient benefit.

As cell and gene therapies continue to advance, personalized CAR-T cell therapies have emerged as a success story.71 Unlike most of the unproven CBIs discussed in this review, CAR-T cell therapies were approved through traditional regulatory pathways in the United States, Europe, and a number of other jurisdictions. Yet these therapies are expensive and face capacity constraints in some settings with companies unable to manufacture the personalized product quickly enough to meet demand. As a result, the possibility exists that a market for unproven and/or unregulated CAR-T cell therapy will emerge in parallel to the market for approved regulated products. Indeed, in August 2022, an “immunotherapy” institute in Mexico announced it would begin offering CAR-T cell therapy to “American, Canadian, and other international patients” at their facility in Mexico. While it is unclear how many patients, if any, have traveled to Mexico to receive CAR-T cell therapy, the marketing harkens back to the early days of stem cell tourism and suggests that both the scientific community and cognizant regulators in countries around the world should remain vigilant to ensure that CAR-T cell therapies are administered to patients in contexts where safety and efficacy have been appropriately established and avoid the emergence of an industry offering these powerful treatments directly to patients in potentially unsafe conditions.

As the history of unproven CBIs and these 3 examples illustrate, the unproven CBI industry continues to evolve and is likely to continue doing so well into the future. As long as patients have unmet medical needs, there are likely to be providers who are willing to treat them, even if doing so requires skirting or deliberately ignoring existing rules and norms. Despite these challenges, however, the scientific community and the medical community can and should take steps to encourage ethical evidence-based medical practice and should partner with regulators and other relevant authorities to reduce the availability of unproven CBIs and reduce the risks posed to patients and the broader field. Such collaborative efforts offer the best hope to continue advancing evidence-based cell therapies to meet the health care needs of patients worldwide.

Author Contributions

Taylor N. Brinsfield, Noah R. Pinson: Collection and/or assembly of data, Data analysis and interpretation, Manuscript writing, Final approval of manuscript. Aaron D. Levine: Conception and design, Financial support, Data analysis and interpretation, Manuscript writing, Final approval of manuscript.

Funding

This material is based upon work supported by the National Science Foundation under Grant No. EEC-1648035. This award supports the NSF Engineering Research Center for Cell Manufacturing Technologies (CMaT), which has the mission of “Transforming the manufacture of cell-based therapeutics into a large-scale, lower-cost, reproducible, and high-quality engineered process, for broad industry and clinical use.”

Conflict of Interest

A.D.L. declared compensation to teach in an ISCT Workforce Development Course and travel costs reimbursed to attend the ISCT Regulatory Summit. The other authors declared no potential conflicts of interest.

Data Availability

No new data were generated or analyzed in support of this research.
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