Ethical and Practical Considerations for Integrating Cellular (“Stem Cell”) Therapy into Clinical Practice

Abstract

Purpose of Review

Cellular therapies, also known as “stem cell” interventions (SCI), have undergone a rapid popularization in the USA and worldwide. The current review aimed at outlining (1) the ethical challenges facing the implementation of SCI; (2) the applicability of the currently available SCI; and (3) recommendations to achieve ethical, well-regulated incorporation of SCI in the clinical setting.

Recent Findings

Concerns regarding the inadequate characterization, poor adverse effects disclosure, and unorthodox, often inappropriate, market practices have engendered a genuine concern regarding the SCI compliance with ethical standards. Six instances of litigation on the basis of misrepresentation or inappropriate informed consent were recorded between 2012 and 2018. Such concerns have been furthered by the loopholes in the regulatory aspect governing the use of SCI coupled with the unclear literature-reported efficacy and diverse spectrum of profess indications. Similarly, the application of SCI in the clinical field is yet to prove its value. The uncertain efficacy, coupled with obscure true-costs of utilization, impedes a value-based assessment.

Summary

A multidisciplinary approach involving legislative and medical professional societies should continue to advance regulations that govern SCI. A well-regulated system that allows for the ethical integration of SCI with appositely evidenced-based described benefits and risks should be sought.

Introduction

The use of cellular therapies oftentimes referred to as “stem cell interventions” (SCI) has exponentially increased for the treatment of orthopedic and musculoskeletal conditions such as osteoarthritis [1, 2]. In the context of a 98.6% appreciation from 2012 to 2016, the global stem cell market is projected to reach a market valuation of $14.8 billion US dollars by 2022 [3•]. Given the significant burden of musculoskeletal diseases, with osteoarthritis alone costing an estimated $87.1 billion annually and affecting 27 million Americans, there exists a significant need for regenerative disease-modifying biologics such as stem cell therapy [4, 5]. Although the majority of current SCI utilize autologous preparation such as the bone marrow aspirate concentrate (BMAC), or adipose-derived cells, there are reports of other “stem cells” currently being tested for a variety of indications [6, 7]. Therefore, SCI can be segregated into proven vs. unproven interventions. Proven interventions require further evidence in the form of well-conducted randomized controlled trials and post-marketing registries within centers offering such therapeutics. Conversely, minimally processed unproven SCI should be designated as “cellular therapies” and require appropriate characterization and scrutiny.

Despite the significant hype surrounding the potential benefits of SCI [8•], current clinical evidence supporting its use is of low quality and limited to small cohorts with considerable methodological variability [9–12]. Therefore, care must be taken to balance the promise of “stem cell” regenerative potential against the lack of established clinical efficacy and high out-of-pocket patient costs associated with them [2, 13, 14••, 15••]. To date, most of the clinical claims being made are substantiated on basic science studies and not on clinical research. Furthermore, there is even a lack of basic science studies that enlighten the mechanism of action of several of the clinically offered SCI [13, 14••, 15••],. In short, the demand for regenerative intervention should be regulated by an intricate balance of ethical guardianship/regulation and the subsequent practicality/limitations of implementation.

Ethical Challenges of SCI

SCI have become a frequent target of scrutiny, owing to its questionable alignment with cornerstone ethical principles [16]. Indeed, Horner et al. [17] reported nine major class-action lawsuits between 2012 and 2018, targeting the application of unapproved autologous SCI for arthritis and various autoimmune derangements, cosmetics, and ophthalmologic disorders. Six of the nine class actions cite claims of misrepresentation, false advertisement, or the lack of proper informed consent. The aforementioned pattern highlights a discrepancy between patient perception and the available evidence. Such discrepancy could be attributed to the novel nature of the field in addition to the occasional unethical marketing practices [18••]. Therefore, the current ethical dilemmas facing the application of SCI can be identified as (1) the lack of clarity regarding the nature of SCI, their indications, and expected outcomes; and (2) the phenomenon of direct-to-consumer marketing which compounds, and often benefits, from the poor characterization.

The term “stem cell therapy” for musculoskeletal disorders has often been stretched beyond its capacity, to encompass an array of heterogeneous uncharacterized cell sources in variable concentrations, obtained from the bone marrow, adipose tissue, blood, umbilical, and placental tissues being the most commonly utilized cell sources [15••, 19–22]. In addition, extracted substrates undergo highly variable degrees of alteration ranging from density separation (centrifugation), mechanical disgregation, and even culture-expansion prior to reinjection, all the while being presented as “stem cell treatment” to prospective patients [14••, 15••, 16, 23, 24].

Scientific literature has not gone unscathed from the inadequate characterization of SCI, with only 30% of the available studies providing the number of nucleated cells delivered after processing [14••, 18]. Furthermore, the available clinical trials are, in the most part, early-stage Phase I/II clinical trials with significant limitations, including small patient size, diversity of cell preparation techniques, and lack of long-term follow-up [25–29]. In addition, while there is evidence indicating SCI are safe, these are never without risk and include the possibility of infection, swelling, and bleeding [25, 28, 30]. Similarly, the lack of established standard of care to serve as controls to compare SCI is concerning, considering the importance of the placebo effect of intraarticular injections for knee osteoarthritis, which demonstrates significant efficacy in reducing pain, improving functional outcomes, and stiffness [31, 32]. Therefore, the currently available cell products can be grossly divided into proven vs. unproven SCI [14••]. The International Society for Cellular Therapies has proposed criteria in an attempt to regulate these therapies. Proven stem cell therapies are defined as well-characterized SCI that have undergone duly authorized clinical trials with sufficient documentation and reporting of outcomes for a specific indication. Conversely, unproven stem cell therapies generally exhibit an unclear scientific rationale to suggest efficacy, insufficient data from in vitro assays, animal model experiments, and clinical studies as well as a significant lack of standardization and consistency in cell extraction and alteration [33].

Over 716 clinics in the USA drive the direct to consumer marketing of often uncharacterized and unproven SCI, with claims of effectiveness exceeding 80% for an array of heterogeneous disorders [18••, 19, 34]. Frow et al. [19] investigated the direct to consumer “stem cell” marketing patterns in 169 operational “stem-cell” clinics in the Southwestern USA as of May 2019. The authors described a spectrum of marketed indications for “stem cell therapy”, including autism, cancer, cosmetic, gastrointestinal, hepatic, dystrophic, neurodegenerative, urological, inflammatory, and orthopedic disorders, with the latter having the biggest share of the marketed indications. Furthermore, they highlighted that 25% of businesses offered more than one source of utilized cellular therapy, while 40% of businesses offered more than one cell type for the marketed interventions, adding to the complexity of adequate substrate characterization. Knoepfle et al. [35] furthered this by illustrating the unfounded claims of, superior safety compared with the standard of care absence of potential adverse effects, and attainment of FDA approval being routinely made in advertisement or so-called “educational seminars.” Such claims are often received by vulnerable patients with serious medical conditions, which, coupled with the poorly characterized nature of the intervention, poses significant concerns. Similarly, Piuzzi et al. [2] studied the marketing patterns of 273 businesses offering SCI for knee OA. The authors outlined that an average of 82% efficacy was claimed by the studied businesses, a rate that is significantly dissonant from published literature.

The stem cell market is fraught with conflated messages that over-emphasize potential benefits and trivialize established risks of SCI. Additionally, advertisement utilized in direct-to-consumer marketing may describe a treatment that is inconsistent with that provided to the patient. Marketers of unproven SCI often misuse terminology, in addition to engaging in predatory practices. Such behavior includes the dissemination of publications in journals with little to no peer-review in addition to seeking scientific legitimacy by renting laboratory spaces within credible scientific institutions, followed by claims of an unfounded affiliation.

While certain businesses may be implicated in initiating the SCI marketing hype, both mainstream and social media are clearly implicated in its widespread [14••, 15••, 16]. Media practices tapped into the public fascination with a perceived revolutionary regenerative potential that is yet to be established. Early research findings are often trumpeted by media outlets as breakthroughs that are expected to be clinically implemented in a so-called near future [36]. In addition, “stem cell” marketers are, with or without deliberation, portrayed as the good mavericks who side with patients in their search of an unorthodox but effective cure despite the efforts of the “misguided” medical institutions and the big pharma [14••, 36]. Such marketing strategies, whether intentional or unintentional, have the potential for misguiding patients who are often cornered between sever pain and the dread of surgical interventions.

The Applicability of SCI

The applicability of SCI in clinical practice is contingent upon (1) the provision of equivalent or superior value (cost vs. effectiveness) compared with the current standard of care and (2) establishing appropriate regulations governing the implementation of novel therapeutics ensuring patient safety.

The value of SCI is yet to be asserted owing to a lack of studies exploring true-cost coupled with the lack of high-quality evidence supporting the efficacy of the various forms of SCI for a range of musculoskeletal indications including joint osteoarthritis, rotator cuff pathology, healing of fractures, and long bone defects, osteonecrosis of the hip and the knee, tendon regeneration, and the regeneration of osteochondral defects [37]. Piuzzi et al. [2] investigated the average cost of SCI for knee osteoarthritis, one of the most common SCI applications in orthopedics. The authors reported the mean price of a single unilateral stem-cell injection in the USA to be $5156 ± 2446, which is significantly under the $29,488 cost of a unilateral total knee arthroplasty (TKA) recently described by Palsis et al. [38] However, the current body of literature is devoid of an overall comparison of cost between both interventions that take into account the added expenses of complications, the need for reinjection, conversion to TKA, or reoperation. Furthermore, the extent to which the absence of insurance coverage of SCI impacts the patient-perceived cost is yet to be determined [2]. Similarly, the vagueness of the SCI efficacy is closely tied to the absence of high-quality evidence comparing the outcomes of SCI to those of the standard of care [18••, 39].

Achieving a balance that avoids overtly lax or strictly prohibitive regulatory measures over SCI has been a notoriously precarious aspect of legislation [40]. The marketing of uncharacterized and unproven SCI poses a controversy based on medical ethics [16, 34]. While the “right to try” act may provide a legislative escape clause for the use of unproven “stem cell” therapies in certain fields, musculoskeletal disorders rarely satisfy the conditions of posing a threat to life and the exhaustion of alternative therapies [14••, 41]. Therefore, despite the pervasiveness of its regulatory complexity, musculoskeletal disorders stand to benefit the most from regulations with clear definitions and robust inclusion/exclusion criteria regarding the type and indication of SCI [14••, 15••]. However, it is also important to present a fair recreation of the status of knowledge in the field, so that patients can also gain access to early-stage novel treatment that has the potential to provide ailment to their pain and limitations.

Recommendations for Safe and Ethical Incorporation in Practice

To date, there is a limited amount of high-quality clinical evidence supporting the use of “stem cell” therapies for musculoskeletal conditions [10, 29]. Adequately powered randomized controlled studies should be conducted with the standard of care as the control to assess the superiority, or lack thereof, of SCI. Furthermore, studies should utilize validated patient-reported outcome measures and tests for the attainment of a minimal clinically important difference (MCID), in order to maintain the clinical relevance of potential findings [10–12, 25, 28–30, 42]. An active, interdisciplinary, and well-coordinated approach involving physicians, legislators, and professional communities as well as media and market stakeholders is required. Medical licensing boards could effectively curb the spread of the unindicated use of SCI through disciplinary actions ranging from issued warnings to revoking of licensure [16, 34, 43]. Civil litigation, including the aforementioned class-actions, could act as a deterrent against bland violations in the form of misrepresentation that invalidates informed consent [40]. The Federal Trade Commission (FTC) has instituted a campaign to halt the deceptive health claims by certain SCI businesses advertisement. The FTC recommendations for appropriate marketing of SCI include the avoidance of “cure” claims without statistically and clinically significant results in addition to the proper use of medical terminology. Moreover, the FTC has enforced federal injunctions on deceptive SCI advertisement with a recently recorded $3.31 million judgment for infractions committed by an amniotic stem cell business.

Professional societies as the International Society for Cellular Therapy and the American Academy of Orthopaedic Surgeons (AAOS) have issued recommendations regarding the use of SCI for musculoskeletal disorders. The AAOS issued a consensus in 2018 recommending that practitioners appreciate the “untested and uncharacterized nature of these treatments”, and that this nature is “clearly communicated within the profession, to patients, and to the public.” [15••]. The American Association of Hip and Knee Surgeons (AAHKS) recommendations are consistent with those of AAOS, and state “It is our position that biologic therapies, including stem cell and PRP injections, cannot be currently recommended for the treatment of advanced hip or knee arthritis [44].” Of note, given the need for novel nonsurgical therapies to manage OA and the potential promise of biologics such as “stem cell” therapies, the AAOS recommends standardization of study design/reporting, the establishment of registries for postmarket monitoring, and the organization of a multicenter knee OA clinical trial consortium that includes randomized controlled trials assessing MCID [15••].

Conclusion

SCI are being popularized as a regenerative therapeutic intervention for multiple musculoskeletal disorders. Upholding the principles of ethical medical practice requires clear disclosure of the specific nature of the intervention and a proper informed consent of the potential risk and benefit. The poor characterization of SCI, as well as irresponsible marketing practices, compromise the transparency of SCI thereby jeopardizing patient safety along with the potential of developing meaningful cell-based therapeutics and their routine application in the musculoskeletal field. It is especially important for clinicians to properly educate patients on the risks and benefits of “stem cell” injections. Furthermore, a multifaceted intervention that encompasses all stakeholders is essential to prevent further abuse.

Compliance with Ethical Standards

Institutional Review Board approval was not required for the current study.

Conflict of Interest

Nicolas S. Piuzzi has the following declarations: ISCT: board or committee member; Journal of Hip Surgery: editorial or governing board; Journal of Knee Surgery: editorial or governing board; Orthopaedic Research Society: board or committee member; RegenLab: research support; Zimmer: research support. Ahmed K. Emara has no conflict of interest. Jorge Chahla has the following declarations: Arthrex, Inc.: unpaid consultant; CONMED Linvatec: unpaid consultant; Smith & Nephew: unpaid consultant. Bert R. Mandelbaum has the following declarations: AJSM, cartilage: editorial or governing board; Arthrex, Inc.: IP royalties; paid consultant; Chairman CONCACAF Medical Committee: board or committee member; DePuy, A Johnson & Johnson Company: paid consultant; Exactech, Inc.: PAID consultant; Kerlan Jobe Institute: board or committee member.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.