BACKGROUND AND PURPOSE
In the United States, the number of clinics offering “stem-cell therapy” is estimated to be well over 1000.1,2 Many clinics advertise unproven and unapproved regenerative medicine interventions for musculoskeletal conditions.1,2 A press release from the US Food and Drug Administration (FDA) in 2018 stated that, “The potential health benefits of regenerative medicine have spurred major progress in stem-cell biology over the past several decades. But we continue to see bad actors exploit the scientific promise of this field to mislead vulnerable patients into believing they are being given safe, effective treatments; when instead these stem-cell producers are leveraging the field's hype to push unapproved, unproven, illegal, and potentially unsafe products.”3
Many sports medicine physicians are currently considering the role of regenerative medicine in their practice. The purpose of this position statement created by the American Medical Society for Sports Medicine (AMSSM) is to provide sports medicine physicians with information regarding regenerative medicine terminology, a brief review of the basic science and clinical studies related to the musculoskeletal field (now commonly referred to as orthobiologics), regulatory considerations, and best practices for introducing regenerative medicine into clinical practice.4 This information will help sports medicine physicians make informed and responsible decisions about the role of regenerative medicine in their practice.
About the organization: AMSSM is a multidisciplinary organization of sports medicine physicians dedicated to education, research, advocacy, and the care of athletes of all ages. Most AMSSM members are primary care physicians with fellowship training and added qualification in sports medicine, who then combine their practice of sports medicine with their primary specialty. American Medical Society for Sports Medicine includes members who specialize solely in nonsurgical sports medicine and serve as team physicians at the youth level, National Collegiate Athletic Association, National Football League, Major League Baseball, National Basketball Association, Women's National Basketball Association, Major League Soccer, and National Hockey League, as well as with Olympic and Paralympic teams. By nature of their training and experience, sports medicine physicians are ideally suited to provide comprehensive medical care for athletes, sports teams, or active individuals who are simply looking to maintain a healthy lifestyle (www.amssm.org).
WRITING GROUP SELECTION AND PROCESS
The AMSSM Board of Directors established a Regenerative Medicine Task Force in 2019, with a subgroup charged to develop a regenerative medicine position statement. The Task Force submitted a recommended writing group that included sports medicine physicians and scientists who are recognized leaders in bioethics, research, and regenerative medicine clinical applications to the AMSSM Board of Directors. The position statement writing group, proposed timeline, and outline were approved by the AMSSM Board of Directors after their December 2019 meeting. The writing group communicated by conference calls and electronically to produce the final document that was reviewed and approved by the AMSSM Board of Directors on May 19, 2021.
The field of regenerative medicine is rapidly growing with terms and definitions that have not been standardized or may be overlapping especially in the subspecialty of orthobiologics. For the purposes of establishing a common understanding, regenerative medicine terms are described in Table 1.7–9
TABLE 1. -
Regenerative Medicine Terminology*
||A concentrate of BMA containing multiple cell types, including a small number of MSCs, typically created through a centrifugation process
|Cell-based medicinal product
||Medicinal product consisting of viable cells. These products may contain genetically modified human cells and can be combined with noncellular components
||Administration of living cells to a patient for the treatment of disease or condition
|Cell therapy product
||Biological product that contains or consists of substantially manipulated living cells/tissues that is administered to humans to treat, prevent, or diagnose a disease through the pharmacological, immunological, or metabolic action of its cells/tissues
|Embryonic stem cell
||Pluripotent cell derived from the undifferentiated inner cell mass of an embryo
||US FDA designation that permits the use of an investigational device in a clinical trial for the purpose of collecting safety and effectiveness data, which can be used to support a premarket approval application
||Request to the US FDA for permission to administer an investigational drug to humans as part of a clinical investigation or to administer an approved drug for a new indication or in a new patient population
||Nonhematopoietic multipotent adult stem cell identified in multiple tissues that can differentiate into specialized stromal cells
| Reported to be present in bone marrow, umbilical cord blood, adipose tissue, and muscle
| Has the capability to differentiate into specialized stromal cells of skeletal tissues such as tenocytes, osteoblasts, chondrocytes, and adipocytes
| Also referred to as mesenchymal stromal stem cells
||Use of biological substances to enhance biological healing of orthopedic injuries or alter the natural course of an orthopedic disease
||Perinatal-derived allogeneic biomaterials donated and recovered from healthy individuals
||Blood plasma enriched in platelets, which contains cytokines and growth factors in higher concentrations than in blood plasma
||Capable of developing into any of the 3 primary germ cell layers and therefore all cells of the adult body, but not extraembryonic tissue (ie, placenta)
||Hyperosmolar dextrose injection which triggers the inflammatory cascade and healing. The treatment targets fibroosseous junctions or entheses and well as intra-articular applications.5
||Interdisciplinary therapeutic approach that aims to repair, replace, regenerate, and/or rejuvenate lost, damaged, or diseased cells, tissues, or organs to restore or establish normal form and function.
||Any cell that makes up a multicellular organism that is not a germinal, reproductive, or undifferentiated cell
||Undifferentiated cell of multicellular organisms with the ability to carry out both self-renewal and asymmetric cell division and to provide cells that can differentiate into other cell types
||Nonhematopoietic connective tissue cell that indirectly influences and supports blood cell growth, typically derived from bone marrow.
||Injectable HA-based products that reduce pain through shock absorption and decreased inflammation by arachidonic acid and IL1 inhibition6
BMA, bone marrow aspirate; BMAC, bone marrow aspirate concentrate; FDA, Food and Drug Administration; HA, hyaluronic acid; IDE, Investigational Device Exemption; IL1, interleukin 1; IND, Investigational New Drug Application; MSC, mesenchymal stem cell; PRP, platelet-rich plasma.
BASIC AND CLINICAL SCIENCE
The understanding of the exact mechanisms by which regenerative medicine products have their therapeutic effect is evolving. The following is a brief discussion of the basic science, proposed therapeutic mechanisms of action, and clinical evidence related to regenerative medicine products. This is not meant to be an exhaustive or systematic review of the literature and should not be considered as an endorsement of any particular product or procedure. For the purposes of this position article, we have limited the references to those procedures that are commonly performed in the United States and do not require an Investigational New Drug Application or Investigational Device Exemption. Table 2 provides a summary of the literature search criteria used to create Tables 3-5 of this section.
TABLE 2. -
Summary of the Literature Search Criteria Used to Create Tables 3-5
in the Basic and Clinical Science Section
||Literature Search Criteria
||The literature search was performed using PubMed with the search terms (((PRP) OR (Platelet Rich Plasma)) AND ((Tendon) OR (Tendinopathy))) filtering for meta-analyses and systematic reviews in human subjects written in the English language between 2019 and 2020. Individual studies were reviewed for relevance.
||The literature search was performed using PubMed with the search terms (((PRP) OR (Platelet Rich Plasma)) AND ((Osteoarthritis) OR (OA) OR (Arthritis))) filtering for meta-analyses and systematic reviews in human subjects written in the English language between 2019 and 2020. Individual studies were reviewed for relevance.
||The literature search was performed using PubMed with the search terms (((BMAC) OR (Bone Marrow Aspirate Concentrate) OR (MSC) OR (Mesenchymal Stem Cell)) AND ((Osteoarthritis) OR (OA) OR (Arthritis))) filtering for meta-analyses and systematic reviews in human subjects written in the English language between 2016 and 2020. Individual studies were reviewed for relevance.
BMAC, bone marrow aspirate concentrate; MSC, mesenchymal stem cell; OA, osteoarthritis; PRP, platelet-rich plasma.
TABLE 3. -
Summary of Meta-Analyses and Systematic Reviews Evaluating the Efficacy and Major Adverse Events of Platelet-Rich Plasma Injections for Tendinopathy
From 2019 to 2020
||Treatment Mixed Efficacy
||Major Adverse Events
|Rotator cuff tendinopathy
TABLE 4. -
Summary of Meta-Analyses and Systematic Reviews Evaluating the Efficacy and Major Adverse Events of Platelet-Rich Plasma Injections for OA From 2019 to 2020
||Treatment Mixed Efficacy
||Major Adverse Events
TABLE 5. -
Summary of Meta-Analyses and Systematic Reviews Evaluating the Efficacy and Major Adverse Events of Bone Marrow Aspirate Concentrate Injections for OA From 2016 to 2020
||Treatment Mixed Efficacy
||Major Adverse Events
Platelet-rich plasma (PRP) is broadly defined as plasma with a platelet concentration higher than whole blood.77,78 The term PRP was coined by hematologists in the 1970s and was initially used as a transfusion product to treat patients with thrombocytopenia. It was almost 30 years later before its use in musculoskeletal medicine. Platelet-rich plasma can be further categorized based on its cellular composition, most commonly as leukocyte-rich PRP or leukocyte-poor PRP. Platelets participate in blood clot formation and in the modulation of inflammation and healing which are achieved through the release of various growth factors, cytokines, and chemokines from the platelet's mitochondria and all 3 granules (dense, alpha, and lysosomal).79 Generally, it is believed that 70% to 95% of the platelet's growth factors are released within 10 minutes of platelet activation, which occurs after exposure to connective tissue collagen or the addition of a platelet activator such as calcium chloride or thrombin, with the remainder being slowly released over a few days.77,80,81 Although the evidence for the clinical efficacy of PRP in a variety of musculoskeletal conditions is evolving, PRP is primarily used to treat tendinopathies and osteoarthritis (OA).78
Platelet-Rich Plasma for Tendinopathy
A summary of recent meta-analyses and systematic reviews evaluating the efficacy and major adverse events of PRP injections for tendinopathy is presented in Table 3.10–30,32,82,83 For tendinopathy, the most robust data supporting treatment with PRP injections are in lateral epicondylopathy. Multiple randomized controlled trials have demonstrated that lateral epicondylopathy responds positively to PRP injections.84–86 There have also been positive results seen in randomized controlled trials for the treatment of gluteus medius tendinopathy77 and plantar fasciopathy87 with PRP. The recent meta-analysis by Hurley et al88 suggests that PRP may augment rotator cuff repairs resulting in improved healing rates, reduced pain levels, and improved functional outcomes.88 In Achilles tendinopathy, well-designed, randomized controlled trials have found no difference between PRP and saline injections15,89,90 and results in patellar tendinopathy have been mixed.82,91,92
Platelet-Rich Plasma for Osteoarthritis
Table 4 summarizes recent meta-analyses and systematic reviews evaluating the efficacy and major adverse events of PRP injections for OA.11,12,33–54 The research suggests that PRP injections are more effective in reducing pain and improving function than steroid or hyaluronic acid injections for knee OA, particularly in those who are younger and have mild to moderate disease.71,93–97 Sufficient evidence has not been acquired to determine if PRP injections are an effective treatment for OA in other joints.
Platelet-Rich Plasma for Ligament and Muscle Injuries
The evidence for PRP in ligament injuries is limited. A few preliminary studies suggested PRP may facilitate improved outcomes in partial thickness ulnar collateral ligament injuries of the elbow,98,99 but a more recent large, retrospective controlled study of major league baseball players questioned these findings.100 Currently, the efficacy of PRP injections for muscle injuries is unknown as this area has not been well studied.101
The most commonly referred to cellular therapy involves mesenchymal stem cells (MSCs). The multipotent nature of these cells allows them to differentiate into various tissues in the mesenchymal lineage including bone, cartilage, adipose, and other soft tissues in vitro.102 However, the exact mechanism of action of MSCs in vivo is poorly understood. Many experts believe their primary mechanism of action is by paracrine activity because of their secretory function resulting in anti-inflammatory, immunomodulatory, proangiogenic, antiapoptotic, antifibrotic, and proliferative effects.103,104 Mesenchymal stem cells have also been shown to elicit differentiation of resident and nonresident cells to functional tissue, resulting in improved function of the degenerative tissue.105–107 Although there has been in vitro and animal data showing significant cartilage preservation and restoration, these results have not, so far, been demonstrated with any consistency in clinical studies using MSC treatments.108–111
Autologous Cellular Therapies for Osteoarthritis
At present, the literature supporting cellular therapies for musculoskeletal conditions consists of some basic science and animal studies along with case reports, case series, and cohort studies in humans. Human clinical studies have focused predominantly on the treatment of knee OA using bone marrow aspirate (BMA), bone marrow aspirate concentrate (BMAC), and adipose tissue. All the products have a small percentage of MSCs despite varying cellular composition.
Unfortunately, many studies used methods that are outside of the FDA regulatory considerations (eg, culture expansion and more than minimal manipulation), thus limiting their applicability to clinical practice in the United States. Since the most commonly used product is BMAC, a literature search was completed to provide a summary of recent meta-analyses and systematic reviews evaluating the efficacy and major adverse events of BMAC injections for OA. This information is presented in Table 5.43,46,55–70,72–76,112–116 The most methodologically sound study to date is the randomized controlled trial by Shapiro et al116 that compared BMAC with saline injections in patients with bilateral knee OA. Using a within-subjects design, they reported similar reductions in pain between the 2 interventions at both 6-month and 12-month follow-up.117 A few studies have shown that adipose-derived stem cells may reduce articular cartilage damage and degeneration, thereby reducing the progression of knee OA.118,119 Furthermore, well-designed studies are needed to determine the clinical efficacy of MSCs for OA.
Autologous Cellular Therapies for Tendinopathy
There have been few studies evaluating the efficacy of MSC injections for the treatment of tendinopathy, but there are some preliminary data to suggest that MSCs may lessen pain, improve function, and induce a healing response in tendon injuries.59 The most studied area is the rotator cuff. Hernigou et al120 demonstrated that patients who received a BMAC injection at the time of their rotator cuff repair had enhanced healing, improved repair quality, and less retears than a control group who did not receive a BMAC injection. In addition, those with a higher number of MSCs in their BMAC had a higher likelihood of treatment success than those with a lower number of MSCs.121 Although promising, it is difficult to extrapolate these results to other tendons. At this time, adipose-derived MSC products for tendons remain in the preclinical phase of inquiry or are moving toward clinical trials. No well-designed studies, systematic reviews, or meta-analyses have been completed. Based on the available evidence, the efficacy of MSCs in tendon pathology is still unknown and further studies are warranted.
Multiple perinatal products (umbilical cord blood, amniotic tissues, Wharton Jelly, etc) are being used in clinical practice. Currently available perinatal products that have been tested have been shown to contain biologically active molecules, but no viable human cells, MSC, or otherwise.122,123 Owing to regulatory restrictions and a lack of clinical data (see Regulatory Considerations section), they will not be discussed further in this section and are not recommended for clinical use at this time.
The use of human cells, tissues, and tissue products, commonly abbreviated HCT/Ps, such as blood products, stem cells, and adipose tissue, is regulated by the FDA under the authority of the federal Food, Drug, and Cosmetic Act and the Public Health Services Act.124,125 A thorough discussion of the regulatory landscape is beyond the scope of this position article; those considering introducing regenerative medicine into their clinical practice should review and have a thorough understanding of FDA guidance documents.126 Rossi et al127 have summarized current regenerative medicine products, their derivation, and regulatory considerations (Figure 1).
The FDA has released a developmental framework and guidance for developers and providers of regenerative therapies. Two key concepts for sports medicine physicians include homologous use and minimal manipulation.124,128Homologous use is defined by the FDA as the repair, reconstruction, replacement, or supplementation of a recipient's cells or tissues with an HCT/P that performs the same basic function(s). Minimal manipulation for structural tissue is processing that does not alter the original relevant characteristics of the tissue relating to the tissue's utility for reconstruction, repair, or replacement. Minimal manipulation of cells or nonstructural tissues is processing that does not alter the relevant biological characteristics of cells or tissues.
These 2 concepts determine whether a regenerative medicine product complies with the Code of Federal Regulations under Title 21, parts 1270 and 1271.124 All biologic products are regulated according to the current good tissue practice regulations, which ensure that HCT/Ps do not contain communicable disease agents and are not and do not become contaminated. The current preparation systems used to create PRP and BMAC are regulated under the 510 (k) pathway because they are considered “substantially equivalent” to a currently marketed device and therefore exempt from the traditional regulatory pathway. The products that they create are still regulated as HCT/Ps by the FDA. HCT/Ps that physically support, act as a conduit, connect, cover, or cushion are generally considered structural tissues and are regulated differently.
Despite the regulatory framework the FDA has put in place, uncertainty and controversy remains in orthopedic and sports medicine regarding whether a product (or procedure) will be regulated as a drug/device or whether it should be considered the practice of medicine.126 An additional guidance document on the Same Surgical Procedure Exception outlines the FDA's view on the use of HCT/Ps within a procedure as a part of the practice of medicine and not separate from it129; however, within this framework, the HCT/P should be minimally manipulated and not combined with another product or substance.
Given some degree of uncertainty regarding minimal manipulation and homologous use, some practitioners have sought to define this as it pertains to sports medicine procedures.130 Others have sought to challenge the FDA's oversight of orthobiologics with the most notable case in orthopedic and sports medicine being the United States versus Regenerative Sciences, 2012.131 The US Federal Court of Appeals confirmed the FDA's regulatory authority and stance on the use of cells in clinical practice.131
Currently, a physician is considered a “manufacturer” of HCT/Ps if they are involved in any step of HCT/P recovery, processing, screening, testing, storage, or distribution. Many of the procedures performed in regenerative sports medicine use these elements and can limit the procedures sports medicine practitioners can perform in practice for the time being or at least until commercially available therapies that have been given FDA-licensed approval become available on the market.125
A wide range of allogeneic cell and cell-derived products largely harvested from perinatal sources have also emerged in clinical practices that market regenerative therapies directly to patients. Owing to wide availability and ease of use (ie, no bone marrow or fat harvest required), these products present an additional layer of growing disagreement between regulators, industry, and providers. To date, no such product has been licensed for musculoskeletal pathology, and the FDA has been consistent that injectable perinatal tissues are considered nonhomologous use and more than minimally manipulated and should not be used in clinical practice until approved and licensed.126,128 There are some manufacturers who have engaged the FDA and have ongoing clinical trials using perinatal products for the purpose of bringing such therapies to market for orthopedic indications.132,133
American Medical Society for Sports Medicine advocates for the responsible use of regenerative therapies for the purpose of protecting patients, public health, and the individual practitioners. American Medical Society for Sports Medicine also advocates that sports medicine physicians keep up to date on regenerative medicine regulations. In addition, clinicians should use clear patient communication regarding science, research, and the benefits and harms of individual regenerative medicine options. Providers need to be cautious and truthful in marketing interventions that have limited clinical evidence and are yet unproven.
Sports medicine physicians play a crucial role in ensuring patient safety while protecting the legitimacy of regenerative sports medicine as it evolves into a subspecialty. The FDA believes that each practitioner is responsible for interpreting their guidance documents and determining how the information in those documents apply to their individual practice. Whenever in doubt, the FDA offers a “toolkit” to help practitioners and those developing regenerative medicine therapies such as the INTERACT (Initial Targeted Engagement for Regulatory Advice on CBER products)134 program that can help practitioners unsure of the regulatory status of a procedure that got guidance from regulators.125,135,136
Additional considerations include Federal Trade Commission oversight that regulates how physicians and their practices market regenerative therapies to protect patients (consumers) from deceptive, misleading, false, and fraudulent medical claims or practices.137 This applies not only to physician patient interactions but also physician claims, advertising, and websites about unproven regenerative therapies.126
Finally, although the discussion of regenerative therapy regulations often focuses on FDA authority, it is the state medical boards that regulate the practice of medicine. The Federation of State Medical Boards has published recommendations pertaining to regenerative and stem-cell therapy treatments that outlines best practices for physicians using treatments that remain unproven or unapproved.134,138
INTRODUCING REGENERATIVE MEDICINE INTO CLINICAL PRACTICE
Providers need to take a rigorous and structured approach when making the decision to introduce regenerative medicine procedures into clinical practice. Such an approach needs to consider the science and clinical evidence behind the product or procedure, feasibility of implementation, and regulatory considerations.
It is imperative that the procedure has a measure of scientific validity. Translation of novel therapeutics into clinical practice conventionally proceeds along a 4-phase clinical trial pathway to prove safety and efficacy. As discussed in the regulatory section, certain elements of regenerative medicine are not required to pass through such a development process. Despite this, it is incumbent on the provider to identify and review the relevant literature, including basic science, preclinical, and clinical studies to ensure such treatments meet the minimum criteria for evidence-based clinical standards. This review should be as free of influence of unsubstantiated claims and publicity regarding the treatment. The review should also demonstrate that there is at least clinical equipoise—a clinician's best judgment given a genuine uncertainty among the scientific community about whether the novel intervention is safer or more effective than the current treatment.
After making the decision to perform a regenerative medicine procedure, the sports medicine physician must then consider how this procedure fits into their algorithm of treatment for specific conditions. In general, treatments that are the least invasive, safest, most cost-effective treatment with the highest level of evidence are implemented first. Only after these treatment options are exhausted should more invasive and novel treatments, such as orthobiologics, be considered. For example, as was discussed in the basic and clinical science section of this article, treatment options, such as PRP, are relatively inexpensive, less invasive, and have more evidence in the treatment of specific musculoskeletal conditions (ie, OA and lateral epicondylopathy) than other orthobiologic options. This information should be considered when formulating a treatment algorithm.
Although there is strong interest among patients for regenerative medicine to treat orthopedic and sports-related conditions, the provider must explain the evidence-based rationale for such treatments and avoid patient motivations that are not supported by evidence.139 Similarly, the provider must guard against the potential to be unduly influenced by internal and external commercial motivations when completing their evaluation of the scientific support for a given procedure.
As with the potential introduction of any clinical procedure, the provider will need to consider several aspects to ensure that the procedure can be implemented in their practice environment. The provider will need to account for the availability, feasibility of purchase, upkeep and maintenance, and physical space needed for the equipment related to the procedure. Many clinicians who would like to provide these options to their patients will require additional training to become proficient in the relevant procedures.140 A plan should be developed to ensure appropriate training or certification of the provider and clinical staff to ensure the regenerative medicine therapy can be delivered in a safe manner in accordance with current research and manufacturer recommendations; these may include, but are not limited to, training related to cell or tissue harvest, material and equipment processing, biologic material assays, image guidance, and product delivery. Regenerative medicine treatments often require a multidisciplinary team and, in some practice environments, may require coordination with groups within or external to their organization. Setting standard operating procedures for communication between these groups is a key step toward successful and practical implementation.
Finally, the provider will need to have a firm understanding of how the regenerative medicine procedure fits into the existing regulatory landscape discussed above. Similar to the review of the scientific evidence in support of the procedure, so too should several sources be used during this assessment including internal and external regulatory and compliance personnel. The experiences and protocols of outside experts, institutions, and professional societies, such as AMSSM, may also be very helpful with this analysis. It is important to note that this review of the regulatory landscape is not a single static assessment. The regulatory environment is dynamic, and a plan should be in place to regularly reassess how new rules may impact the regenerative medicine therapies the practice offers. The provider may also communicate directly with the FDA as necessary.140 Clinicians also must remember that regulatory considerations are not limited to biological materials alone as the processing equipment may be novel or specific to the procedure and requires regulatory approval.
Procedures lacking clinical evidence on safety and efficacy should only be introduced under the internal review board oversight. Food and Drug Administration oversight may also be required. Even in cases where the regulatory environment is permissive, the provider should regularly assess patient outcomes, perform internal quality control, and improve their processes accordingly. If able, publishing their results to assist in the acquisition and dissemination of knowledge is recommended.
Knowledge and Training
Most regenerative medicine procedures are dependent on precise delivery of the product(s) to the affected location. As such, those performing regenerative medicine procedures must be proficient in image-guided procedures. These may include musculoskeletal ultrasound and fluoroscopy, alone or in combination with other image guidance techniques. The physician should have a full understanding of how to select the appropriate guidance technique for the regenerative medicine product being used as well as the anatomic target for the procedure given patient's characteristics (eg, body habitus) and its associated risks and costs.
The knowledge required in each of these areas is large and rapidly expanding. Sports medicine physicians may achieve and maintain competency in the field through a number of different pathways. Options include self-study, attending regenerative medicine courses and lectures, or attending courses related to ancillary skills development (such as musculoskeletal ultrasound courses). Industry-sponsored courses are common and may be a valuable adjunct for learning; however, to avoid potential bias, sports medicine physicians should not rely solely on these courses and avail themselves of a wide variety of learning opportunities. Orthobiologic principles and techniques are also taught in many sports medicine fellowships; however, this is not currently an Accreditation Council for Graduate Medical Education requirement, and the level of knowledge and competency provided during fellowship training varies significantly. Finally, rapidly evolving FDA rules and regulations will require those performing regenerative medicine procedures to engage in ongoing CME both in the form of self-study, formal courses, and symposia.
Informed consent is the process where patients (or their surrogates) are provided sufficient information so they can make an informed choice about their health care options. The ethical premise of informed consent is a respect for patient autonomy.141,142 Although many of the features of informed consent are common in both research and clinical care contexts, given the novelty of regenerative interventions, many of the elements of informed consent for research apply. Valid informed consent has 3 components: patients must be informed, consent must be obtained voluntarily, and consent must be given by a competent person (or surrogate).143
Clinicians are obligated to provide appropriate, understandable information to patients and address their questions so patients can make informed decisions about their care. The informed consent process should include the provision of information agreed on by professional standards or reasonable people143 and should be conveyed in verbal and written manner, with forms being written at a low-grade school reading level. The information should be discussed in an honest and balanced manner focusing on clinically indicated and scientifically justified options.144,145 In the context of orthobiologics where evidence of safety and efficacy is evolving, physicians should rigorously scrutinize the sources of scientific information to ensure a sound scientific rationale before presenting options to patients. Information should be offered without threat or coercion. Particularly egregious tactics include overemphasizing benefits or steering patients to a procedure after having been offered financial incentives such as a discount.143,146
A description of each care option should include the procedures involved, the risks, and potential benefits. The risk of infection, immune rejection, product/cell contamination, and other identifiable and unanticipated risks should be addressed.147 Benefits should be described accurately and not overemphasized, particularly in light of misinformation surrounding “stem-cell therapies” that may heighten patient expectations such that patients may not give adequate consideration to other treatment options.137,148–154
The patient should be informed that regenerative medicine interventions are not currently considered standard of care. The FDA approval status of the intervention being proposed should be provided, and if the intervention is being offered as part of a research protocol, the internal review board status of the research study should be discussed.126
The out-of-pocket costs for orthobiologic treatments should be clearly communicated to the patient. Relevant conflicts of interest by the physician, clinic, or employer should be clearly disclosed. The patient should be informed that they have the right to withdraw their consent from the procedure for any reason and at any time.
Quality control is defined as a system to maintain standards of manufacturing or procedures and to ensure they adhere to a defined set of criteria. Regarding regenerative medicine, quality control can take many forms. Acknowledging that the known and theoretical mechanisms of action for regenerative medicine products depend on the delivery and release of biologically active molecules that are “manufactured” by the clinician or practitioner, lack of precise control and biological characterization of the product can become an impediment to procedural validation and clinical outcomes. In addition, there are many opportunities for contamination during the formulation of many regenerative medicine products that may create safety issues. Therefore, although pharmaceutical grade good manufacture practice is not required for many office-based orthobiologic procedures because of the same surgical procedure exception, it is still important to implement and monitor quality control measures to ensure delivery of a safe and standardized product.
Documentation should include time and date of the procedure, patient demographics, condition being treated, medications, medical comorbidities, prior surgical history, social history (eg, tobacco use, alcohol consumption, and illicit drug use), regenerative medicine processing technique, equipment used, cellular composition of the final product in absolute terms and in relation to baseline parameters, how the product was delivered, where it was delivered to, amount delivered in the target location, activation of the product, and any associated procedures performed (eg, needle fenestration). With respect to PRP and other cellular products, baseline cellular count and differential, postprocessing cellular count and differential, changes in cellular concentrations, injectate volume, and total cells delivered (broken down by the cell type) should be recorded at least periodically if possible. Finally, to provide effective quality control, practitioners must familiarize themselves with test variability between laboratories, Clinical Laboratory Improvement Amendment regulations, individual state laws, and other regulatory bodies.
Patient-Reported Outcome Measures (PROMs) are an important part of medical practice. Practices performing regenerative medicine procedures should collect PROMs on their patients for multiple reasons including the following:
- The experimental nature of some regenerative medicine procedures
- Quality control and patient safety purposes
- Improving the informed consent process by discussing efficacy and safety outcomes among your patients
- Conducting clinical research
- Providing information that may assist with reimbursement of these procedures in the future
- Assisting regulatory bodies, such as the FDA, and third-party payers in examining the cost-effectiveness of these procedures
There are many relevant and validated musculoskeletal-specific PROMs that sports medicine physicians can use to assess physical function and pain of patients treated with regenerative medicine procedures.155 These PROMs are questionnaires that allow patients to report on their own health directly without interpretation from a medical professional.156 Currently, the FDA has stated that they will also consider real-world evidence (RWE) and outcomes (RWO) when reviewing information on regenerative medicine treatments.157 Real-world evidence and RWO are gathered outside of conventional clinical trials and includes data obtained from patient charts, laboratory reports, patient registries, pragmatic clinical trials, surveys, and mobile health devices.158 Real-world evidence and RWO complement evidence obtained from randomized controlled trials and provides information about the long-term safety and effectiveness in large populations in a more natural setting. Furthermore, RWE and RWO allow stakeholders and health insurance companies to assess the risk-benefit and economic value of medical interventions.158,159
The field of regenerative medicine, and the subclassification of orthobiologics, involves a variety of therapies and techniques focused on the repair or replacement of damaged or diseased tissue to restore function. Despite these novel therapies being very attractive to sports medicine physicians and patients alike, this is a complex and controversial topic as we have outlined above. This position statement provides sports medicine physicians with information on regenerative medicine terminology, a brief review of the basic science and clinical studies, regulatory considerations, and best practices for introducing the orthobiologic classification of regenerative therapies into their clinical practice. Armed with this knowledge, sports medicine physicians can make an informed and educated decision about whether to introduce certain regenerative medicine products and procedures into their clinical practice and as well as how to do so in a responsible manner.
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