With the emergence of cell-based therapies as viable treatment options readily accessible to patients, the scientific community and public have raised concerns regarding consumer accessibility and regulation enforcement. Opposing viewpoints regarding regulation have emerged, and efforts to maintain the balance between promoting scientific innovation and ensuring public safety has proved challenging. To further complicate matters, there is contradictory information regarding the clinical safety and efficacy of cell-based treatments. Herein, we outline the FDA’s regulatory framework for cell-based therapies and describe what we term the cutting edge, bleeding edge, and off the edge interventions. We conclude with a new classification system for regenerative cell-based therapies intended to further aid in delineating between the clinically and scientifically sound therapies to those that compel further scientific investigation.
There is controversy surrounding cell-based therapies. Patients have broad access to risky and unregulated stem cell therapies and this has raised concerns regarding regulation enforcement. Furthermore, there is contradictory evidence describing the clinical usefulness and safety of current therapies. Herein, we outline the FDA's regulatory framework for cellular therapies and describe what we define as the cutting edge, bleeding edge, and off the edge cell-based therapies. We describe a new classification system for regenerative cell-based therapies that stratifies interventions based on the supporting evidence and risk for harm. We intend to provide the scientific community with a systematic strategy to assess cell-based therapies and to further inform patients.
Two Sides to the Story
The efforts made to regulate stem cells and other cell-based therapies for regenerative approaches has engendered controversy and opposing points of view. From one perspective, the situation may draw comparisons to a “cowboy culture,”  where unregulated treatments are fully accessible to the public, and the system of checks and balances are askew. The flourishing direct-to-consumer marketplace has been widely reported, raising ethical and regulatory concerns, after a 2016 analysis identified 351 US businesses utilizing direct-to-consumer marketing strategies for therapies not approved by the US Food and Drug Administration (FDA) in 570 stem cell clinics. The advertised interventions encompass treatments for a wide range of conditions, including neurologic, orthopedic, pulmonary, immunologic, and cardiac diseases . A 2019 analysis focusing on three states previously determined to have the highest concentration of stem cell clinics – California, Texas, and Florida – found that many physicians provide stem cell treatments outside of their scope of training .
Businesses have attempted to evade FDA oversight by either claiming their interventions are within the scope of medical practice, and therefore not subject to FDA regulation, or their products meet criteria for an exception under the FDA’s regulatory framework and do not require premarket approval. Moreover, the rapid growth of stem cell businesses has prompted critique of the FDA’s response and has encouraged discussion regarding regulation enforcement .
On the one hand, the potential of cell-based therapies is tremendous. The full promise of cell-based interventions has not been realized. The reality is that the field remains in many ways in its infancy, which perforce demands ongoing preclinical and clinical research. Unfortunately, overstatements and exaggerations are rife throughout the public discourse and can be damaging to the field, as perceptions may not align with clinical reality. The promotion of cellular therapies as miracle cures without scientific evidence is not a minor transgression devoid of consequence. For desperate patients enduring chronic, debilitating, and even life-threatening conditions, the imagined potential of such treatments can offer a glimmer of hope that may remain unfulfilled, further encouraging frustration and grief .
The opposing argument suggests that the field is inundated with at the very least confusing and at most improper regulatory requirements that cripple legitimate efforts to develop regenerative therapies further and compete in the international arena. Stakeholders have suggested that the current framework requires necessary modifications. In 2015 a new regulatory pathway for cellular therapies was proposed and included a modified premarket approval process for autologous or allogeneic cells that do not induce an immune response . Proponents of deregulation have espoused the REGROW Act  and the Right to Try Act . The REGROW Act, proposed in 2016, promoted the accelerated approval of specific cellular therapies in which the requirement for large-scale clinical trials would not be necessary. Ultimately, the Act was not enacted during the 114th Congress. Nevertheless, the measure proposed an expedited approval process that received considerable support. In many ways, the Act led to the passage of replacement legislation in late 2016 known as the 21st Century Cures Act. The Act allows for expedited approval pathways for specific regenerative medicine therapies . Furthermore, the Right to Try Act was signed into law in 2018 and allows patients diagnosed with life-threatening conditions to have access to a selection of unapproved treatments when they have exhausted all other approved treatments and are unable to participate in clinical trials.
As has been alluded to earlier, there has been criticism of the FDA’s regulatory framework for cell-based therapies. Some have argued that the FDA has modified and adapted its already established framework for chemical drugs, vaccines, and biologics to establish regulation for cellular therapies. The argument is that drugs and cell-based therapies are fundamentally different, and therefore the regulation of such therapies requires a unique framework altogether . Also, criticisms further increased when the FDA changed its regulation and expanded its regulatory oversight in 2005  to now include autologous adult stem cell therapies. Prior, the FDA did not assert regulatory authority over these interventions as it was considered to fall within the scope of medical practice. The assumption was that the associated risk was low considering that patients were receiving their own cells back .
One may postulate that the side chosen in the discussion may be a direct consequence of one’s position as a stakeholder, from scientists and bioethicists to clinicians and CEOs of stem cell clinics. Nonetheless, a likely shared perspective is the promotion of scientific innovation to treat disease, but there is a risk of negating such efforts if they come at the cost of safety. There is a criticism of the FDA’s regulatory framework on both sides, where one asserts that there is not enough regulation enforcement, while the other asserts there is too much. A candid reminder is that the FDA maintains a federal mandate to ensure public safety.
The FDA has not had a tin ear to these issues. The agency has taken action to address some of the previously described criticisms. Central to this action has been the establishment of a unique discretionary enforcement period allowing manufacturers to achieve compliance with established regulatory standards. Additionally, the agency has adopted an expedited pathway for specific regenerative therapies, particularly those intended to treat life-threatening conditions.
Herein, we provide a brief outline of the most recent FDA regulation of cell-based therapies, a discussion intended to inform investigators as therapies transition from bench to bedside. Moreover, we highlight a recent federal court decision regarding a US stem cell clinic that is projected to set precedent for cellular therapies. Next, we describe the current cell-based interventions that represent what we term cutting edge, bleeding edge, and off the edge interventions. Finally, we describe a new classification system that categorizes regenerative cell-based therapies to address the balance between clinical treatment potential, clinical safety, and clinical efficacy. The overall goal is to establish further guidance that in the end will benefit the most important stakeholder, our patients.
The FDA described its regulation of human cells, tissues, and cellular and tissue-based products (HCT/Ps) as ‘highly fragmented” before the introduction and proposal of a comprehensive regulatory framework in 1997 . HCT/Ps are defined as “human cells or tissues that are intended for implantation, transplantation, infusion, or transfer into a human recipient,” and their regulatory framework was instituted under Title 21 of the Code of Federal Regulations (21 CFR), Part 1271 . The FDA maintains its regulatory authority under the communicable disease provisions of the Public Health Service Act (PHS Act) in which the agency is tasked with preventing the introduction and transmission of infectious disease through regulation enforcement in Section 361, and it maintains the authority to license biologic products under Section 351 .
The framework was implemented in 2005 and stratified products based on potential risk with the intended goal to prevent product contamination, prevent the use of products that can potentially transmit infectious diseases, and to ensure product safety and efficacy. Manufacturers are also required to register and list their products with the agency and adhere to donor suitability  and current good tissue practice requirements . The agency expressed that its’ intended goal is to provide the appropriate level of government regulation to protect public health without the unnecessary impedance of scientific advancements.
Under this framework, HCT/Ps that meet all of the criteria under section 361 of the PHS Act and regulation in 21 CFR Part 1271 are classified as “361 products” and therefore exempt from premarket approval requirements; manufacturers are required to register and list their products with the agency. These particular products are only subject to FDA regulation in order to prevent the transmission of communicable disease . If a product does not meet all of the established criteria and does not qualify for an exception, then it is subject to regulation under section 351 of the PHS Act, the Federal Food, Drug, and Cosmetic (FD&C) Act, and other applicable regulations. Therefore, such products are regulated as drugs, devices, or biologics, and the agency maintains the regulatory authority to subject such products to premarket approval requirements such as acquiring a biologics license .
The “361 products” must be minimally manipulated, for homologous use only, and not combined with another article except preserving or storage agents that do not change safety considerations. Furthermore, the product cannot exert a systemic effect, and it cannot rely on the metabolic activity of living cells to function. However, if the product has a systemic effect or is dependent on the metabolic activity of cells, the HCT/Ps must be intended for autologous use, allogeneic use (obtained from a first or second-degree blood relative), or reproductive use. Examples of these cells and tissue types include bone, ligament, cartilage, skin, vascular grafts, and hematopoietic stem cells derived from peripheral or umbilical cord blood. Products that do not meet the criteria of HCT/Ps and therefore are not considered in this regulatory framework include vascularized human organs for transplant, whole blood or blood components, secreted human products such as milk and cell factors, and minimally manipulated bone marrow intended for homologous use .
Historic Regenerative Medicine Policies
In November 2017, the FDA published a notice warning consumers about unapproved and unproven stem cell therapies . Within the same month, the agency released two guidance documents clarifying the criteria for the same surgical procedure exception and described policies further defining minimal manipulation and homologous use .
Same Surgical Procedure Exception
The same surgical procedure exception indicates that the FDA will not regulate cells or tissue-based products transplanted back into the same individual they were recovered from if this process occurs within a single surgical procedure. The rationale is that the process would not expose patients to more risks than what is typically associated with surgery. The same surgical procedure exception has heavy stipulations. These include the fact that the cells or tissues must remain in their original form and have not undergone any other processing, besides cleansing and sizing, that would increase the risk of transmitting communicable diseases .
Minimal Manipulation and Homologous Use
The FDA’s intent to clarify the definitions and criteria for minimal manipulation and homologous use  constitute essential guidance for industry as products must meet these criteria, among others, in order to receive classification as an HCT/P that does not require premarket approval.
A product is considered minimally manipulated if the manufacturing process has not altered the “original relevant characteristics” of structural tissues or the “relevant biological characteristics” of cells and nonstructural tissues. Characteristics of structural tissue include properties that contribute to its functions within the donor, such as strength, flexibility, and compressibility. Examples of these supporting structures include bone, skin, adipose tissue, blood vessel, articular cartilage, ligament, and amniotic membrane.
An example of structural tissue processing that exceeds more than minimal manipulation is the extraction of stromal vascular fraction (SVF), a source of adipose-derived stem cells. Its use is widespread in cell-based therapies. Adipose tissue is obtained via liposuction, and enzymatic digestion removes the adipocytes and surrounding structures to obtain a cellular extract. This process is considered more than minimal manipulation as it removes the contents of adipose tissue that provides support and cushioning, and therefore modifies the relevant characteristic of fat tissue.
The relevant biological characteristics of cells and nonstructural tissues relate to their biochemical roles in the body, such as within the blood, immune, and endocrine systems. Such cells and tissues include reproductive cells, hematopoietic stem cells, parathyroid glands, and pancreatic tissue. An example of more than minimal manipulation includes culturing hematopoietic stem cells to obtain terminally differentiated cells. This process alters the biological properties and the cells’ ability to differentiate into various cell types and maintain the capacity for self-renewal.
Homologous use suggests that cells and tissues will maintain their essential functions in the recipient as it would in the donor. For example, if adipose tissue is transplanted into the subcutaneous space of a breast for reconstruction or cosmetic purposes, it would meet criteria for homologous use as fat is intended to cushion and support other tissues. However, if an HCT/P derived from adipose tissue is used to regenerate cartilage for the treatment of osteoarthritis, then it would not meet criteria for homologous use as regenerating cartilage is not a primary function of fat.
Regenerative Medicine Therapies
In 2019, the FDA published guidance documents explaining the criteria for expedited programs for regenerative medicine therapies  with a particular emphasis on expedited approval pathways for therapies intended to treat serious diseases ineffectively managed with current treatments. Regulation for expedited therapies began in 1988, and accelerated pathways include fast track designation, breakthrough therapy, priority approval, and accelerated review.
Most notably, the 21st Century Cures Act established a new expedited program known as regenerative medicine advanced therapy (RMAT) for biologic products intended to treat severe and life-threatening conditions. The RMAT designation is distinguished from the breakthrough therapy designation as it only requires preliminary clinical data to demonstrate that the treatment addresses an unmet medical need. However, the breakthrough therapy designation requires preliminary clinical data to support that the treatment provides a substantial improvement over currently available treatments. The FDA will also allow cooperative development programs for regenerative medicine therapies that permit various sites that produce the same product with a similar manufacturing process the opportunity to collaborate on clinical trials and ultimately obtain a site-specific biologics license .
The FDA announced that it would apply enforcement discretion for the first 36 months after the release of their final guidance documents in November 2017 . The agency would allow manufacturers who market products that meet criteria for premarket approval but have yet to achieve compliance, the opportunity to ensure regulatory adherence within this timeframe. After the grace period, manufacturers would be subject to the full weight of the FDA’s regulatory authority. The FDA made it clear, however, that egregious violators of the regulatory rules would be subject to attention and action during this period. A recent federal court decision has invigorated the FDA’s attempts to stop clinics from administering unregulated treatments and perhaps heralds a new era in addressing groups that may pose a clear danger to the health and well-being of patients.
A Reality Check - Part 1
In 2019, the FDA announced a federal court’s decision to grant the government’s motion for summary judgment against a Florida-based stem cell clinic  and a permanent injunction that would prevent the company from manufacturing and distributing its product . The clinic used what was described as an unapproved stem cell product extracted from patients’ adipose tissue and injected back into the same individual to treat various diseases. The SVF product was determined to be adulterated, in which the manufacturing of the product does not meet current good manufacturing practice requirements, and misbranded, in which the product does not contain appropriate directions for use .
The company initially heard from the agency in 2017 when they received a warning letter  reporting a violation of good manufacturing practices and marketing of unapproved treatments. The clinic advertised treatments for heart disease, neurological disorders such as Parkinson’s disease and amyotrophic lateral sclerosis (ALS), and pulmonary conditions, including chronic obstructive pulmonary disease (COPD) and pulmonary fibrosis using SVF. The marketed SVF meets FDA criteria for classification as a drug, biologic, and an HCT/P and therefore required premarket approval. The federal court’s decision has already set a precedent and falls within the agency’s timeline of enforcement discretion.
The previously mentioned clinic has gained notoriety in recent years after three patients suffered vision loss after receiving intravitreal injections of an unclearly defined blend of autologous adipose-derived “stem cells” into both eyes for the management of age-related  macular degeneration (AMD). The incident has been compared  to the significant work of Mandai and colleagues who conducted a landmark study  in which a patient underwent transplantation of retinal pigment epithelium cells derived from induced pluripotent stem cells that were obtained from the patient’s skin fibroblasts for the treatment of AMD. At 1 year, that patient’s vision stabilized, and there was no indication of an adverse outcome.
A Reality Check - Part 2
Initially, the successful outcome in 2019 appeared to foreshadow a landslide victory in the charge against unregulated stem cell clinics. However, a recent and unanticipated drawback in early 2020 changed this perspective. A US federal judge denied the government’s motion for summary judgment against a network of California-based stem cell clinics. The ruling diverges from the federal court decision in Florida and perhaps portend unforeseen obstacles towards regulation enforcement .
Rodriguez and colleagues  propose that the current regulatory track for SVF may be inappropriate. The authors explain that SVF is a heterogenous collection of cells derived from lipoaspirate containing various cell types that can be lineage precursors, affect immune reactivity, and maintain vascular homeostasis. SVF is a different subpopulation of cells and thus has a distinct risk and safety profile in comparison to adipose-derived stem cells, a much narrower subpopulation of homogenous cells that are obtained via numerous passages in cell culture that undergo more than minimal manipulation. They present arguments against the current regulation that maintains SVF as an HCT/P that should require premarket approval. Furthermore, their work advocates for a collaborative effort in regulation that includes accreditation of facilities that provide treatments, developing a national registry for stem cell therapies, and entrusting state and professional societies to monitor physician practice. Nonetheless, the authors endorse a bipartisan view that some stem cell clinics may be overreaching by offering treatments without the appropriate technical training and doing so without the proper oversight.
There are numerous perspectives regarding the current issues surrounding cell-based therapies and thus lead into a discussion of the cutting edge, bleeding edge, and off the edge interventions.
Cutting edge technologies represent the latest advancements and are the by-product of progressive innovation. We define cutting edge therapies as treatments used in people with proven efficacy and reproducible results. Currently, the only FDA-approved stem cell-based therapy is hematopoietic progenitor cell transplantation (HPCT) for the treatment of hematologic disorders. There are also FDA-approved cell-based gene therapy products . Thus as of now, there is a limited number of cell-based therapies that meet cutting edge criteria.
CAR T cell therapy is a cell-based gene therapy used for the treatment of specific hematologic malignancies, and although it is not stem cell therapy, it appropriately fits the description of cutting edge therapy. It is an innovative immunotherapy that genetically engineers a patient’s T cells, or immune cells, to express receptors on its surface known as chimeric antigen receptors (CARs) to recognize a specific antigen on cancer cells to attack and destroy these cells. CAR T cell therapies fall under the broader category of adoptive cell transfer (ACT), an emerging immunotherapy. The process involves obtaining blood from a patient, isolating their T cells, and using an inactive virus to engineer the T cell to express the CAR on its surface. Next, the cells are expanded in the laboratory and infused into patients after they have undergone lymphodepleting chemotherapy . In 2010, Kochenderfer and colleagues were the first to report the regression of lymphoma using CAR T cell therapy .
There are two FDA-approved CAR T cell therapies available. The first cell-based gene therapy available in the USA, Kymriah (tisagenlecleucel), was approved by the FDA in August 2017. Kymriah is approved for the treatment of B cell precursor acute lymphoblastic leukemia in patients up to the age of 25 years who have refractory disease or experienced two or more relapses . By the following year, May 2018, the FDA approved the same therapy for the treatment of relapsed or refractory diffuse large B cell lymphoma in adults . The other CAR T cell therapy is known as Yescarta (axicabtagene ciloleucel) and was approved by the FDA in October 2017 for the treatment of relapsed or refractory diffuse large B cell lymphoma in adults .
Hematopoietic Progenitor Cell Transplantation
A notable multi-institutional study referred to as the Cord Blood Transplantation (COBLT) Study, sponsored by the National Heart, Lung, and Blood Institute, was conducted in the late 1990s and early 2000s  It was the first prospective multi-center clinical trial in the US established to assess whether banked umbilical cord blood from unrelated donors could provide a source of hematopoietic stem cells for hematopoietic reconstitution in the treatment of malignancies, immune deficiencies, inherited marrow failure, and inborn errors of metabolism in adults and children. There are numerous works in the field that have led to the established efficacy of HPCT . Currently, there are several cord blood products approved in unrelated donor transplantations for hematologic disorders that are acquired, inherited, or the result of myeloablative therapies . As of now, this therapy is the only FDA-approved stem cell-based product.
Bleeding edge technologies are new advancements in the investigational stage that have yet to demonstrate the efficacy and reliability established in cutting edge therapies. We define bleeding edge therapies as investigational therapies currently used in people with some evidence to support its utility, but data may be inconsistent and unevenly reproducible.
Bone marrow-derived stem cells (BMSC) are under investigation as a potential therapeutic intervention for patients suffering from ischemic heart disease (IHD) and heart failure (HF). Strauer and colleagues reported on the first clinical trial assessing the efficacy of stem cell therapy following an acute myocardial infarction (AMI). The intracoronary transplantation of autologous mononuclear bone marrow cells after standard therapeutic intervention was determined to be clinically safe and had a therapeutic effect of improved heart function and myocardial perfusion .
A systematic review and meta-analysis assessing the efficacy of autologous adult BMSC treatment for patients with IHD and HF concluded that there was a reduction in deaths and hospital readmission and an improvement over standard treatment . Furthermore, a systematic review determined that adult BMSC treatment is safe and moderately improves heart function in patients who have suffered an AMI. However, there is no evidence of a significant effect on morbidity and mortality over standard therapy . Gyongyosi and associates reported on a meta-analyses of randomized control trials assessing the efficacy of various stem cell therapies, including bone marrow mononuclear cells, bone marrow-derived mesenchymal stem cells, adipose tissue mesenchymal stem cells, bone marrow and peripheral blood progenitor cells, and cardiac progenitor cells. They concluded that the potential benefit of cell therapies for HF and AMI are inconclusive and statistically underpowered .
In 2017, the international consortium Transnational Alliance for Regenerative Therapies in Cardiovascular Syndromes (TACTICS) published a global position paper on regenerative therapies in cardiovascular conditions. They recounted that ischemic heart disease has become one of the most studied conditions for stem cell interventions. Thus far, studies indicate that cell therapies for IHD are both feasible and safe. Despite this, the clinical efficacy of regenerative therapies over standard-of-care treatments remains unproven. The field has faced challenges that have prevented implementation in clinical practice and includes an incomplete understanding of the regenerative mechanisms, lack of uniformity among study protocols, variable surrogate and clinical endpoints, and a lack of collaborative international initiatives to address these shortcomings .
The most commonly investigated cell type is the mesenchymal stem cell (MSC) and is thought to produce the mature cells that generate cartilage, bone, and adipose tissue. The proposed mechanism of action of stem cell therapies for the treatment of knee osteoarthritis (OA) is not fully elucidated but includes augmentation of inherent repair mechanisms via secretion of growth factors, providing cell support, as well as restoration of lost cartilage volume and immune modulation .
Systematic reviews analyzing the efficacy of MSCs for the treatment of knee osteoarthritis demonstrate some benefits but are inconsistent. Xia and colleagues suggest that MSC treatments may improve pain and physical function, but they ultimately concluded that the overall effects of MSC injections in knee OA were inconclusive . Pas and associates determined that there was level 3 to level 4 evidence in support of stem cell injections for knee osteoarthritis, but the analyzed studies had a high risk of bias . Yubo and colleagues concluded that MSC therapies showed great potential as a beneficial treatment. They concluded that before definitive statements could be made regarding safety and efficacy, more extensive and robust studies are needed . Jevotovsky and collaborators concluded that while studies support that MSC interventions positively affect patients, there is limited high-quality evidence and long-term follow-up. The current studies are inconsistent and lack reproducibility .
Most recently, the American Association of Hip and Knee Surgeons concluded that they cannot recommend stem cell therapies for the treatment of advanced knee OA. They recommend well-designed trials that assess safety, efficacy, and cost-effectiveness prior to widespread implementation .
Off the Edge
Off the edge technologies are in the very early stages of investigation and may represent borderline technologies that have questionable efficacy. We define off the edge therapies as those demonstrating promising results in preclinical models, and therefore have theoretical merit, but there is limited evidence to support clinical benefit.
Chronic Obstructive Pulmonary Disease (COPD)
Sun and associates report that preclinical studies have demonstrated a benefit of MSC therapies in COPD models. Exogenous MSC interventions demonstrated structural repair and functional improvement in injured respiratory systems of COPD models. The authors point out that preclinical studies simulate the mild-to-moderate condition of the disease. However, preliminary clinical trials have not reproduced these results. Studies utilizing MSC therapies in patients with moderate-to-severe COPD did not observe clear benefits in respiratory function. A possible reason for the lack of clear benefit may include inadequate immunomodulatory and anti-inflammatory effects of MSCs in people with advanced stages of the disease .
Amyotrophic Lateral Sclerosis (ALS)
A systematic review and meta-analysis conducted by Moura and colleagues assessing the efficacy of stem cell therapy for the treatment of ALS in preclinical studies demonstrated an improvement in survival. However, the authors concluded that there are an inadequate number of clinical studies to assess effectiveness . Furthermore, a 2016 systematic review did not find any completed randomized controlled trials assessing the effectiveness of stem cell therapy for the treatment of ALS .
A Spectrum of Evidence
A significant challenge regarding the regulation of cell-based therapies is that not all cell-based interventions are created equal, as evidenced by the discussion of the cutting edge, bleeding edge, and off the edge therapies. Therefore, the promotion of cure-all treatments further muddies the waters.
Furthermore, even therapies established as safe and effective can be promoted and used in ways that elicit ethical concerns. A most recent example of this is third-party marketing strategies offering T cell preservation services to consumers. Donor T cells are frozen for future treatments even in patients who are currently healthy yet anticipate that they may require the treatment in the future. The International Society for Cell and Gene Therapy (ISCT) issued a warning statement in 2019  to consumers regarding the impracticality of this intervention, along with the ethical concerns it raises. The unsettling reality is that these businesses are marketing a therapy with a limited scope of utility to the general population. CAR T cell therapies have only been approved for specific types of cancers where other standard treatments have failed. Besides, there would likely be numerous quality and regulatory concerns regarding the use of pre-stored cells.
In accordance with the growing pains of all emerging fields, the implementation of cell-based therapies with strong evidence has been slow to progress. The scientific community maintains the burden to demonstrate both the safety and efficacy of therapies before their adoption into clinical practice. However, disease-stricken patients may be unwilling to wait for what they may consider being a long and arduous process and the demand for new cell-based therapies outpaces currently approved treatments. Consequently, patients become consumers and thus provide incentive and demand for a lucrative and unregulated industry.
As previously stated, the currently approved cell-based therapies are limited. Thus, all other proposed treatments are technically “unproven” . Designating treatments as unproven and therefore unfit for use in people altogether, limits how we think about cell-based therapies that ultimately affects patients. Thus, the scientific community should broaden its classification system to accurately represent where we stand with establishing and utilizing potential therapies. Unproven treatments may fall into a spectrum , from therapies that have higher scientific reliability to those with lower scientific reliability. If we completely discount the unproven, then we will never be in a position to make new discoveries and establish new treatments. Therefore, if we plan to move ahead in advancing the field, then we must establish a method to classify these proposed therapies and address them accordingly.
Classification of Regenerative Cell-Based Therapies
We propose a classification system for regenerative cell-based therapies stratified by risk for harm and level of scientific reliability. This system will aid in categorizing proposed interventions to determine suitability for immediate clinical use or therapies that require further investigational studies prior to clinical use. We emphasize that we appreciate the heterogeneity of stem cells and cell-based therapies and this variability is influenced by numerous factors including the cell source and the manufacturing process. Therefore, we are not naive in assuming that the FDA's task in regulating cellular therapies is merely addressed with one simple solution. Nonetheless, our growth in the field has arguably remained stagnant and it is imperative that we critically examine where we stand and remain receptive to new and emerging ideas.
Harm is defined as damage to health . Adverse events are included in the classification of harm and may be defined as the untoward medical outcomes associated with an intervention such as the administration of a drug . Cell-based therapies may pose a potential risk to patients, and this potential for harm is influenced by the source of the cells (autologous vs. allogeneic), how they are processed (risk for introduction of contaminants), route of administration into the recipient (e.g., subcutaneous, intraarticular, intrathecal, and intracoronary injections), and how the cells function once transplanted into the recipient. Adverse outcomes can be graded based on severity and can include minor events such as swelling at an injection site to more severe outcomes associated with the carcinogenic potential of a treatment.
Scientific reliability is defined as the “ability to yield consistent, reproducible estimates of true treatment effect” . Therapeutic interventions considered in this classification system must meet prerequisite criteria including scientific plausibility. The plausibility of an intervention should be supported by the proposed mechanism of action as established via preclinical investigation. A controversial study that constestably has lower scientific plausibility will examine whether intrathecal injections of stem cells, bioactive peptides, lasers, and median nerve stimulation can effectively reverse death by neurologic criteria. Although the trial was not attempted in the USA, it was proposed by a US-based business and is registered in the National Library of Medicine website ClinicalTrials.gov as currently recruiting . The proposal has been highly criticized by the scientific community .
The findings in both preclinical and clinical studies will aid in determining the appropriate classification for a specific intervention. Our classification system emphasizes interventions with higher reliability as we cannot advise the use of therapies that have not demonstrated preliminary clinical benefit. Therapeutic procedures must be performed by board certified physicians with the appropriate training and adhere to current good tissue practices and other requisite standards.
Higher Scientific Reliability and Lower Chance for Harm: RT 1A
RT 1A therapies pose a lower risk of harm and demonstrate higher scientific reliability. Therefore, we recommend initiating clinical treatment with close clinical follow-up as well as registration with the FDA that includes submitting an investigational new drug (IND) application to conduct clinical trials in tandem. A regenerative intervention appropriate for this category is the intraarticular injection of autologous mesenchymal stem cells for the treatment of knee osteoarthritis. The therapy is scientifically plausible in which the proposed mechanisms of action includes immune modulation. Our discussion of bleeding edge interventions indicates that there is support for a clinical benefit. Furthermore, the treatment risks generally include pain, swelling at the injection site, difficulty with movement and possible risk of infection .
Higher Scientific Reliability and Higher Chance for Harm: RT 1B
RT 1B therapies pose a higher risk for harm but remain within the scope of higher scientific reliability. These therapies should follow the standard practice of registering with the FDA, conducting clinical investigations under an investigational new drug (IND) application and submitting a Biologics License Application (BLA) prior to marketing. We do not recommend concurrent clinical treatment in this category due to the increased potential for harm. An example of this intervention is the delivery of autologous bone marrow-derived stem cells directly into the coronary arteries via percutaneous coronary intervention for the treatment of heart failure. The treatment is scientifically plausible and is proposed to work due to paracrine mechanisms that promote cardiac repair and reduce fibrosis of the damaged cardiac muscle. Furthermore, there is evidence to support its utility. The therapy itself has a high chance for harm with serious adverse outcomes that include cardiac arrhythmias, pulmonary edema, visual disturbances, and perforation of the myocardium during direct infusion of the cells into the coronary arteries .
Lower Scientific Reliability and Lower Chance for Harm: RT 2A
Therapies that demonstrate lower scientific reliability with a lower chance for harm are RT 2A. These interventions will require more scientific evidence via basic science research efforts to support their use. This may be achieved via preclinical studies in animal models. Only in the case where the supporting evidence is clear can these therapies be considered for clinical investigation. Once adequate evidence has been obtained, then this therapy can potentially become RT 1A. An example of this treatment type is the use of mesenchymal stem cells for the treatment of full-thickness rotator cuff tears. In a rabbit model of full-thickness rotator cuff tear, umbilical cord blood-derived MSCs were injected under ultrasound guidance and resulted in partial tendon repair in 7 out of 10 rabbits. Three rabbits did not benefit from the treatment and continued to have full-thickness tears. No surgical repair or bioscaffold was used . In clinical practice, the risks of the procedure would generally include pain and swelling at the injection site and possible infection.
Lower Scientific Reliability and Higher Chance for Harm: RT 2B
Therapies that demonstrate lower scientific reliability with an increased chance for harm are RT 2B. They are not appropriate for clinical use and require basic science research to determine the appropriateness of utility. An example of this type of therapy is autologous stem cell transplantation to treat metastatic breast cancer, now described as ineffective, expensive, and risky . Studies in the 1980s reported encouraging outcomes for patients undergoing high-dose chemotherapy treatments followed by autologous hematopoietic stem cell transplantation in patients with chemotherapy-responsive metastatic breast cancer. The demand for hematopoietic stem cell transplantation increased although there were few investigations comparing stem cell transplantation with conventional-dose chemotherapy. The work of Stadtmauer and colleagues found that women with metastatic breast cancer who experienced a partial or complete response to standard chemotherapy and subsequently receive high-dose chemotherapy and an autologous stem cell transplantation do not survive longer or experience a longer time to disease progression than women who receive maintenance therapy with conventional-dose chemotherapy. Furthermore, patients who received high-dose chemotherapy combined with transplantation experienced serious adverse events . Therapies that meet criteria for this category may receive RT 1B designation if stronger evidence is developed.
Lessons for the Field of Regenerative Engineering
Regenerative engineering is defined as the convergence of Advanced Materials Sciences, Stem Cell Sciences, Physics, Developmental Biology and Clinical Translation for the regeneration of complex tissues and organ systems . Stem cells maintain a vital role in regenerative approaches for various organ systems, including musculoskeletal regeneration [66,67,68]. Ongoing collaboration is essential to addressing clinical grand challenges and the application of regenerative engineering principles are central to these efforts The use of regenerative engineering technologies continues to grow [69,70,71,72,73].
FDA approval of specific cellular and gene therapy products is a successful outcome that hopefully the field of regenerative therapies will continue to replicate for various diseases. One may even ponder what are the potential barriers that impede such a progressive field from achieving this critical milestone. Perhaps, the unregulated market of cell-based therapies has inadvertently contributed to this issue. Healthcare providers and businesses that offer unapproved treatments may consider their interventions a necessary service for patients who otherwise may not have access to such treatments. However, the lack of standardization has produced contradictory and inconsistent results, and an unregulated market may decrease the incentive to conduct and participate in rigorous clinical investigations. Therefore, we anticipate that continued regulation and widespread standardization will yield successful outcomes.
Our efforts to achieve innovative regenerative cell-based therapies have been imperfect. The FDA has attempted to establish regulation in a field where the demand is high, but the evidence is contradictory. Patients are incurring the health and financial risks associated with unregulated treatments, and the broad access to information has offered support for a range of technologies, from the scientifically sound to the scientifically questionable. To our knowledge, this is the first classification system that stratifies regenerative cell-based therapies based on scientific reliability and potential for harm. Future work will specifically focus on further quantifying standards for success. It is our hope that this new classification system will begin to help in systematically assessing potential therapies, a practice that will inform patients, aid in regulation, and encourage the scientific community to forge ahead.
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Support from NIH DP1 AR068147 and the Raymond and Beverly Sackler Center for Biomedical, Biological, Physical, and Engineering Sciences is gratefully acknowledged.
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Laurencin, C.T., McClinton, A. Regenerative Cell-Based Therapies: Cutting Edge, Bleeding Edge, and Off the Edge. Regen. Eng. Transl. Med. 6, 78–89 (2020). https://doi.org/10.1007/s40883-020-00147-1
- Stem cells
- Classification system
- Regenerative engineering