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Regenerative Medicine and Cell Therapy in Orthopedics—Health Policy, Regulatory and Clinical Development, and Market Access

Spinner, Daryl S. PhD, MBA*; Faulkner, Eric C. MPH*,†,‡; Carroll, Marissa C. MPH§; Ringo, Moira C. PhD, MBA*; Joines, John W. BPharm, RPh, RAC

doi: 10.1097/BTO.0000000000000413
Symposium
Free

Orthopedic indications collectively represent a large clinical and economic burden, especially given the aging world population. To meet this area of unmet need, a wave of regenerative medicine therapies, including stem cells and other cell-based therapies, is currently in clinical development and anticipated to inundate the global market over the next few years. Although intended to be transformative, orthopedic cell therapies face several practical opportunities and challenges. Such therapies could reduce the health care burden, in part by replacing traditional drug therapies and highly-invasive surgical interventions with single-dose treatments. However, therapy developers and providers must address hurdles from regulatory to reimbursement to commercial challenges before successful orthopedic cell therapies are available to patients. Regulatory policies, reimbursement processes, and commercial requirements for orthopedic cell therapies differ across markets, and key health care stakeholders must address these differences well before a product launch. Pricing and reimbursement models for innovative therapies, like cell-based therapies in orthopedics, grow unclear, especially how health care systems will absorb potentially transformative and highly-needed, but costly, therapies. Single administration therapies with relatively high upfront cost require more evidence to support their value for pricing and reimbursement than other health care products, and orthopedic cell therapies must do so based on patient quality of life and health care resource use, as opposed to improved survival, which is especially challenging. In addition, alternative financing and reimbursement models may be needed to support ongoing patient access and innovation. In the current article, we discuss global health policy issues and considerations for orthopedic cell therapy development and adoption.

*Evidera | PPD

PPD, Morrisville

Institute for Pharmacogenomics and Individualized Therapy, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC

Genomics, Biotech, and Emerging Medical Technology Institute, National Association of Managed Care Physicians, Glen Allen, VA

§Evidera | PPD, Waltham, MA

The authors declare that they have nothing to disclose.

For reprint requests, or additional information and guidance on the techniques described in the article, please contact Daryl S. Spinner, PhD, MBA, at or Eric C. Faulkner, MPH at or by mail at Real-World Value and Strategy, Center of Excellence for Precision and Transformative Medicine, Evidera | PPD, 3900 Paramount Parkway, Morrisville, NC 27560. You may inquire whether the author(s) will agree to phone conferences and/or visits regarding these techniques.

Online date: October 31, 2019

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RELEVANCE AND POTENTIAL IMPACT OF CELL THERAPIES IN CLINICAL ORTHOPEDICS

The goal of medicine and biomedical science has always been to cure ailing patients through disease-modifying therapies, not simply treating patients for symptom control. Given rapid expansion in scientific knowledge and biomedical discovery over the past 30 to 40 years, innovative new therapies have exploded in clinical development and on the market as a result of the intent to develop transformative therapies that aim to cure or substantially modify the course of disease has resulted in the current explosion of innovative new therapies in clinical development and on the market. Many such therapies are either cell therapies or gene-modified cell therapies that intend to regenerate or otherwise repair, replace, and/or supplement cell and tissue defects that cause or contribute to disease.

Musculoskeletal conditions represent a ∼$900 billion economic burden to the US health care system,1 with osteoarthritis alone being a $373 billion (direct costs only) area of unmet medical need.2 Orthopedic indications are growing in global prevalence given the aging world population3,4 and are increasingly targeted by current regenerative therapies in development and/or on the market (including cell, gene-modified cell, and gene therapies).5–10

As of September 2018, there were ∼892 regenerative medicine companies distributed across 6 continents (Fig. 1).11 The pipeline of the cell-modified, gene-modified cell, and tissue engineering-based therapies includes a total of 652 clinical trials, with 60 in phase III studies, indicating the final stage in development before seeking market approval.11 This represents a 5.8% growth in the number of companies and a 7.4% growth in the number of clinical trials in regenerative medicine from 1 year earlier.12 As of September 2018, 5.8% of all regenerative medicine clinical trials (58/1003) focused on musculoskeletal disorders, including orthopedic indications such as osteoarthritis, cartilage disorders, and bone fractures and disorders,11 which represents a 7.4% increase in the number of trials targeting this disease area.12 This consistent investment and market growth in the regenerative medicine space, and orthopedic applications, in particular, signals a promising but competitive future landscape of new orthopedic regenerative medicine treatments where differentiating product value will be key to their success.

FIGURE 1

FIGURE 1

Unlike conventional orthopedic therapies, cell and gene-modified cell therapies (heretofore referred to as “cell therapies”), of which stem cells are a subset having the ability to replace a broader range of cell types in the body, are expected to deliver profound disease-modifying and durable benefit, often following a single administration. This gives cell therapies great potential to transform the treatment of orthopedic disease and affect downstream health care costs, especially when provided with rehabilitative medicine to optimize both structural and functional healing.13 Indeed, there is substantial interest among orthopedic surgeons and clinical experts for safe and effective regenerative therapies for patients.14

To provide this potentially transformative impact on health outcomes and health economics, health care provider acceptance is required, as well as the ability to use cell therapies when treating patients who need it. Granting patients access to cell therapies requires aligning health care policies and coordinating with an array of delivery stakeholders and decision-makers. Given stakeholder expectations for transformative cell therapy and its overall value to the health care system, mitigating risks and maximizing the potential for a successful product is necessary to help satisfy the needs of all health care stakeholders and help ensure that new therapies make it to patients (Fig. 2).15–17 This is particularly true for cell therapies developed by biotechnology and pharmaceutical companies, which require a return on investment to embark on their development.18–20 Actualizing their return on investment requires a commercially successful product, and repeated failure to achieve required success across a portfolio of products increases the cost of all therapies.21–23 In the case of regenerative medicines such as innovative cell therapies, the commercial environment is especially complex and fraught with numerous barriers that often require novel approaches to reimbursement and access.1,18,20,24–32

FIGURE 2

FIGURE 2

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ETHICAL CONSIDERATIONS AROUND CELL THERAPY: STEM CELLS

The clinical and regulatory landscape of regenerative stem cell therapy is rife with ethical challenges, particularly around the use of human embryonic stem cells in clinical therapeutics.33–36 More recently, the ethical debate has shifted to issues concerning patient safety and consent14,37–40 and cell therapy generation and use (eg, electively enhancing human performance or introducing unnecessary desirable traits vs. preventing or ameliorating disease), especially when genetically modifying cells.41–43 Although the ethics of cell therapy have been a concern for policymakers, theologians, and academics for some time, as a practical matter ethical consideration may not be top of mind for the community of cell therapy researchers, clinicians, and commercial stakeholders as explicit ethical concerns did not surface in a recent study exploring these stakeholder perspectives on barriers to cell therapy adoption.44

Outside of the direct ethics of human embryonic stem cells use and genetic modification/gene editing, stakeholders’ ethical considerations may focus instead on sufficient evidence for cell therapy efficacy, safety, and economic value before their administration to patients. Cell therapy stakeholders, including clinicians, believe that evidence of efficacy, cost-effectiveness data, and reimbursement are the biggest challenges to cell therapy adoption.44 To demonstrate the value of specific regenerative and advanced therapies (including cell therapies), a recent survey of US payers indicates the most important aspects include safety, cost/economic impact, magnitude of treatment effects as measured by “hard” outcomes (eg, objective endpoints such as survival, disease progression), and duration of effect.26 The acceptance of such therapies by US payers is influenced by the uncertainty in the magnitude and duration of therapeutic effect, ability to discontinue other treatments once initiating the therapy, and the overall budget impact of adopting the therapy.26 Regarding the duration of therapeutic effect, >70% of US payers indicated anticipating regenerative and advanced therapies (eg, orthopedic cell therapies) to provide a therapeutic benefit for >3 years, and >30% anticipate a benefit lasting >5 years.26 In a move toward defining/aligning evidence standards for musculoskeletal/orthopedic regenerative medicines away from “sham” controls, the Osteoarthritis Research Society International (OARSI) recently issued guidance on appropriate clinical trial comparators to be used by therapy developers based on existing standards of care.45 Therefore, the burden of evidence for acceptance and adoption of regenerative medicine therapies is high.

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DEFINING THE VALUE OF ORTHOPEDIC CELL THERAPIES

The most common orthopedic indications targeted for cell therapy include osteoarthritis, cartilage disorders or injuries, bone fractures, degenerative bone diseases (eg, osteonecrosis), and ligament or tendon injuries,46–49 which are the clinical orthopedic uses currently with the strongest supporting evidence.50 Transformative cell therapies often target rapidly progressing rare and/or life-threatening diseases, such as blood cancer or rare genetic disorders of childhood, for which therapeutic value could easily be measured by extending the life and improving survival [eg, tisagenlecleucel (Kymriah) in hematologic malignancy, Strimvelis in adenosine deaminase-deficient severe-combined immunodeficiency].51,52 Although the most prevalent orthopedic disorders are not life-threatening or associated with high mortality, they do impose a heavy burden on patient quality of life in terms of pain management, ability to perform normal/daily activities, ability to remain physically active, and/or the need for costly surgeries requiring prolonged postsurgical rehabilitation and other health care resources. Therefore, instead of the impact on survival outcomes comprising evidence of therapeutic value, orthopedic cell therapies must demonstrate transformative value relative to current standards of care based almost entirely on patient quality of life and health care resource use. This is a challenging endeavor and one which regenerative medicine and cell therapy developers often get wrong.

For cell therapies subject to high degrees of regulatory and clinical scrutiny, such as those currently being developed by regenerative medicine companies, the process to align health care policies, delivery stakeholders, and decision-makers must begin early. Developing and commercializing a transformative cell therapy product, particularly one regulated as a biologic drug (as opposed to a medical device or one that is exempt from regulatory approval), is illustrated in Figure 3. The process entails preclinical development, clinical development, which includes regulatory approval/marketing authorization, and market access, which includes removing reimbursement and commercial barriers for patients to access the therapy. In this review, we will focus largely on regulatory and clinical development and touch briefly on demonstrating value for the money required to achieve market access (sometimes referred to as the “fourth hurdle” to drug commercialization)53,54 as these represent the key challenges to implementing cell therapies in orthopedic clinical practice. We also touch on cell therapies that are exempt from the process of regulatory approval/marketing authorization.

FIGURE 3

FIGURE 3

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CLINICAL DEVELOPMENT AND REGULATORY APPROVAL OF ORTHOPEDIC CELL THERAPIES

Global Development and Regulatory Landscape for Cell Therapies

Several orthopedic cell therapies have been approved by global regulators over the past 20 years, with a rapid rise in approvals over the past 5 to 10 years (Table 1). The clinical use and marketing of cell therapies, regardless of the therapeutic area in which they are applied, are governed by national-level regulatory authorities (or multi-national level, eg, in the case of the European Union). Each regulatory authority sets specific guidelines on what constitutes regenerative medicine, advanced therapy, cell therapy, and gene therapy, and how they are regulated for use in patients (Table 2). Most regulatory authorities assess cell therapies based on the level of risk associated with the specific cell preparation with the level of risk characterized by the following criteria:

  • Donor source of cells (eg, autologous, related allogeneic, nonrelated allogeneic, xenogeneic).
  • Level of manipulation (eg, cell expansion in culture, exposure to chemicals/biological materials, genetic modification).
  • Therapeutic use (eg, reproductive, replacing metabolic or structural function, homologous use).
  • Same surgical procedure (eg, reimplantation/transplantation during the same procedure, the extent of temporal separation between cell/tissue removal from and reintroduction into the patient).
  • Mechanism of action (eg, cells having systemic vs. local effects).
TABLE 1

TABLE 1

TABLE 2

TABLE 2

Most regulatory authorities have exempted/excluded cells that are minimally manipulated and/or autologous or related allogeneic from formal regulatory oversight and do not require research and development activities outlined in Figure 3. As a result, there has been a proliferation of independent stem cell therapy clinics offering autologous cell therapies for a variety of indications, with orthopedics being one of the primary therapeutic areas.39,77–80 Given the lack of formal regulatory requirements and rigorous oversight, many of these clinics are offering orthopedic cell therapies and services that are not supported by a body of evidence demonstrating their efficacy and/or safety. Some clinics have actively marketed the therapies and services with unsubstantiated claims of benefit and used improper cell processing techniques, which caused some patients harm as a result.37,38,80–83

To address the spread of virtually unregulated autologous cell therapies whose safety and efficacy is unknown, some regulatory agencies [eg, the US Food and Drug Administration (FDA), Australian Therapeutic Goods Administration (TGA)] have begun to crack down on independent clinics that inappropriately market cell therapies and conduct unauthorized clinical trials. In addition to regulatory actions, patients, providers, medical societies, politicians, and industry groups have also taken aim at these practices.40,78,79,82,84–87

The US FDA recently issued warnings to the general public about unproven cell therapies and the risk of participating in clinical trials without an approved Investigational New Drug (IND) application.88 The FDA is also targeting providers who have been caught violating various marketing and cell processing regulations.89–92 In Australia, the TGA recently updated requirements for autologous cell therapies outlining the current marketing, reporting, and donor testing guidelines for exempt, nonapproved cell therapies. For example, only the service can be marketed without directly mentioning or providing claims for the cell therapy “product” itself93–95; all adverse events must be reported to the TGA93; and cell therapies must comply with standard screening and testing requirements applicable to fully-regulated cell therapies as outlined in Therapeutic Goods Order No. 88.96 The Canadian national regulatory authority, Heath Canada, recently issued a policy paper on autologous cell therapy products to clarify risks, existing standards, and requirements for efficacy, safety, and quality, with plans to provide further guidance and oversight on such therapies.97

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Regulation of Orthopedic Cell Therapies: A Deep Dive into the United States

The US FDA has issued several regulatory guidance documents over the past few years on human cells, tissues, and cellular and tissue-based products (HCT/Ps), including those relevant to trials of orthopedic regenerative medicines (eg, knee cartilage repair or replacement),98 some of which we review in this section. For additional review, the authors refer readers to recent articles providing more detail.15,73–76 For a comprehensive listing of regulatory guidance documents on HCT/P regulation, the FDA website is an excellent resource.99,100

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Regulatory Guidance on Cellular Manipulation

The 2 main guidance documents that provide FDA policy framework for stem cell manipulation are:

As outlined briefly in Table 2, Sections 351 and 361 of the Public Health Service Act (PHSA) provide the authority for the FDA to establish regulatory requirements for marketing traditional biologics and HCT/Ps. As discussed below, in terms of autologous cell therapies, these 2 pathways differ markedly in terms of the time, effort, and expense required. The ultimate determinant of which one is relevant to a particular HCT/P comes down to the degree of manipulation experienced by the cells and whether they are removed from and implanted into the same patient within a single operation performed at the same establishment (see Table 3 for additional detail).

TABLE 3

TABLE 3

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Minimal Manipulation

According to the FDA, in 21 CFR (Code of Federal Regulations) 1271.10, the regulations identify the criteria for regulation solely under section 361 of the PHS Act and 21 CFR Part 1271. An HCT/P is regulated solely under section 361 of the PHS Act and 21 CFR Part 1271 if it meets all of the following criteria [21 CFR 1271.10(a)]101:

  • The HCT/P is minimally manipulated.
  • The HCT/P is intended for homologous use only, as reflected by the labeling, advertising, or other indications of the manufacturer’s objective intent.
  • The manufacture of the HCT/P does not involve the combination of the cells or tissues with another article, except for water, crystalloids, or a sterilizing, preserving, or storage agent, provided that the addition of water, crystalloids, or the sterilizing, preserving, or storage agent does not raise new clinical safety concerns with respect to the HCT/P.
  • Either:
    • (i) The HCT/P does not have a systemic effect and is not dependent upon the metabolic activity of living cells for its primary function.
    • (ii) The HCT/P has a systemic effect or is dependent upon the metabolic activity of living cells for its primary function.
  • (a) Is for autologous use.
  • (b) Is for allogeneic use in a first-degree or second-degree blood relative.
  • (c) Is for reproductive use.

HCT/Ps that are marketed under section 361 are not required to obtain premarket approval/clearance from the FDA and are considered exempt from approval. Distributors and marketers of HCT/Ps are permitted to self-designate the tissue products as meeting the criteria set forth under 21 CFR Part 1271. Examples of orthopedic HCT/P treatments in clinical use and subject to regulation under section 361 include autologous platelet-rich plasma (PRP) for knee and chronic tendon injuries103 and autologous bone and cartilage implantation.

If an HCT/P does not meet the criteria (ie, does not meet the 4-part test under minimal manipulation) set out in 21 CFR 1271.10(a), and the establishment that manufactures the HCT/P does not qualify for any of the exceptions in 21 CFR 1271.155, the HCT/P will be regulated as a drug, device, and/or biological product under the Federal Food, Drug, and Cosmetic (FD&C) Act, Section 351 of the PHS Act (42 U.S.C. 262), and other applicable regulations, including 21 CFR Part 1271.102 Premarket review and approval are required before the HCT/P can be legally marketed in the United States. HCT/Ps, including stem cells, intended for implantation, transplantation, or infusion are regulated under 21 CFR 1270 and 21 CFR 1271. A product will only be regulated under 21 CFR 1271 and will not require a regulatory pathway for approval if all requirements above are met.

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Approved Cellular Products

Concentrated autologous stem cells do not require approval by the FDA as described in the definition above. There are examples of commercialized demineralized bone matrix (DBM) products for orthopedic use that are marketed as containing or intending to be mixed with viable stem cells (eg, mesenchymal stem cells, bone marrow aspirate), some of which are exempt from regulatory clearance processes, and others that have been cleared by the FDA through a nondrug pathway, specifically via the 510(k) (device) process.104,105Table 4 lists examples of FDA-exempt and cleared products in the United States.

TABLE 4

TABLE 4

According to the FDA, there is a limited number of currently approved cell therapies in the United States—including ones involving bone marrow for transplants in cancer care and cord blood for specific blood-related disorders. No products using engineered or expanded stem cells have been approved by the FDA for orthopedic applications.106

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Recent Regulatory Updates Relevant to Orthopedic Cell Therapy: The 21st Century Cures Act

In December 2016, the 21st Century Cures Act (Cures Act) was signed into law in the United States.107 The Cures Act created a new regulatory designation for regenerative medicines and advanced therapies (including cell and gene therapies), called Regenerative Medicine Advanced Therapy (RMAT), which was created for adoption by the FDA. An RMAT designation facilitates clinical development and accelerates regulatory approval of (and ultimately patient access to) regenerative medicines and advanced therapies for serious conditions and/or diseases with high unmet need,73,75,108 which adds potential benefits for regenerative medicine sponsors on the regulatory path to market. The RMAT designation is similar to a Breakthrough Therapy designation (BTD) established in 2012 (see US Congress/FDA Administration Safety and Innovation Act of 2012 [FDASIA] Section 902),109 providing for ongoing advice from the FDA on study design and, relevant to cell and other regenerative medicine therapies, manufacturing issues.73,75,108,110 To accelerate time to regulatory approval, an advantage over BTD and similar to the Accelerated Approval pathway established in 1992, the RMAT designation allows for potential approval based on surrogate or intermediate endpoints and eligibility for priority and accelerated FDA review.73,75,108,110 Another advantage of an RMAT designation versus BTD for product developers is that obtaining an RMAT does not require a product to demonstrate substantial improvement relative to already available products.73,75,108,110

For a product to obtain an RMAT designation it must be a “regenerative medicine” as defined by the Cures Act. Specifically, regenerative medicine is a “cell therapy, therapeutic tissue engineering product, human cell, and tissue product, or any combination product using such therapies or products intended to treat, modify, reverse, or cure a serious or life-threatening disease with preliminary clinical evidence demonstrating the potential to address unmet needs”.110 Key terms relevant to defining regenerative medicines in the Cures Act are shown in Table 5.

TABLE 5

TABLE 5

The FDA does not disclose which regenerative medicine therapy products in development have been granted an RMAT designation,75 thus the products with RMAT designations are only identifiable through sponsor/developer disclosures. As of September 2018, whereas 7 of 73 requests for RMAT designations (9.6%) were for orthopedic products,113 only 2 orthopedic cell therapies that received RMAT designations have been disclosed in the public domain73,114 (Table 6).

TABLE 6

TABLE 6

Although regulatory approval pathways and processes have been more amenable to larger sponsors given the need for centralized regenerative medicine manufacturing to support the conduct of clinical studies, the FDA seeks to facilitate product development by smaller sponsors/investigators in the regenerative medicine draft guidance issued in November 2017.74,110 A key component articulated in the framework relates to new guidance on how, in the context of a single regenerative medicine trial, smaller investigators can meet regulatory hurdles for expedited clinical development and product approval. Specifically, the FDA intends to allow sponsors of multi-site clinical trials to develop a standardized protocol for manufacturing the therapy (eg, stem cells) at each site to treat trial patients enrolled at their own site.74,110 In the context of the broader clinical trial, efficacy and safety data from all participating investigator sites would be pooled and submitted as part of the Biologic License Application. This “decentralized manufacturing” with “data pooling” approach would most likely be limited to products requiring low complexity manufacturing and simple trial designs,74 including those using manipulated autologous cells without genetic modifications (eg, autologous chondrocyte or osteoblast therapy, autologous bone marrow or adipose-derived mesenchymal stem cell therapy).

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Accelerated Regulatory Pathways and Associated Challenges

It is important to note that while accelerated approval is possible for regenerative medicines based on surrogate or intermediate endpoints, which could be considered beneficial in some ways (eg, requiring shorter pivotal study, shorter regulatory review period for approval, compressed time to product launch), their reliance for product approval could also present potential obstacles to postlaunch market access and uptake that could be addressed if adequately accounted for in clinical development planning. One potential obstacle from a regulatory approval perspective is the impact of surrogate or intermediate endpoints on labeling in a way that could affect the uptake of the therapy. To clarify this point, on January 2019 the FDA issued guidance on labeling for products including biologics (eg, cell therapies) that clarifies how accelerated approval pathways and use of surrogate or intermediate endpoints could influence regulatory labeling at approval.116,117 Specifically, product approval based on a surrogate or intermediate endpoint that has not been sufficiently validated to correlate with survival or disease-related symptoms will generally result in a statement within the “Indications and Usage” section of the regulatory label indicating the product’s accelerated approval based on a surrogate endpoint, including any specific limitations/cautions advised for prescribing given lack of a more accepted regulatory endpoint.116

Another potential obstacle presented by accelerated product approval is the abbreviated timeline to develop sufficient efficacy and safety evidence, as well as other aspects of value that are important to regenerative medicines in orthopedics. For instance, the duration/durability of therapeutic benefit is often a critical aspect scrutinized by health technology assessors, payers, and other policymakers, particularly in the context of therapies that promise transformative impact at a commensurate cost.15,26,29,118–120 Access decision-makers often deny reimbursement due to insufficient evidence of long-term comparative therapeutic benefit of a regenerative medicine/cell therapy product.121–124 In the next section, we briefly discuss challenges in securing reimbursement and market access for regenerative medicine and cell therapies in orthopedics.

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GLOBAL MARKET ACCESS OF ORTHOPEDIC CELL THERAPIES

As mentioned earlier, implementing any health care product or service requires aligning key stakeholder and decision-maker perspectives, along with health system processes that permit provider adoption and enable affordable access for patients. For many cell therapies, stakeholder expectations are higher (Fig. 2), raising the bar for what cell therapy developers must meet to ensure patients ultimately receive these treatments after regulatory approval. Key health care decision-makers include payers, health technology assessment (HTA) bodies, providers, patients, and product manufacturers. The specific players within each of these categories often vary by country and/or market (Fig. 4A) with different incentive-driven decision criteria (Fig. 4B), creating a complex path for health care product developers to achieve global reimbursement, market access, and sustained commercial availability (Fig. 4). Oftentimes when referring to health care stakeholders, budget holders, benefits managers, and HTA bodies are collectively called payers (Fig. 4A; a–c), and include, for example:

  • National and sub-national government departments of health and funding organizations (eg, the Centers for Medicare and Medicaid Services125 in the United States, the National Health Service in the United Kingdom, regional and pan-regional sickness funds in France and Germany).
  • Commercial insurers/managed care organizations (eg, Aetna, Anthem, Cigna, Humana, United Healthcare, and others in the United States).
  • Healthcare plan self-funding groups (eg, employer self-funded plans).
  • High-risk reinsurance carriers (eg, stop-loss carriers, benefit carve-out insurers).
  • Integrated delivery networks, which are payers with a connected provider network/health system under the same corporate structure (eg, Geisinger Health, Intermountain Healthcare, and Kaiser Permanente in the United States).
  • Healthcare benefit managers (eg, pharmacy benefit managers, radiology benefit managers).
  • HTA bodies that evaluate and strongly influence whether, and in what form, health care technologies are paid and provided to patients [eg, National Institute for Health and Care Excellence124 in the United Kingdom, French National Healthcare Authority/Haute Autorité de Santé (HAS) in France, Canadian Agency for Drugs and Technologies in Health (CADTH) in Canada, German Institute for Quality and Efficiency in Healthcare (IQWiG) in Germany, and Health Insurance Review and Assessment Service (HIRA) in South Korea].
FIGURE 4

FIGURE 4

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Global Reimbursement of Orthopedic Cell Therapies

Payment for health care treatments relies on reimbursement mechanisms that apply to each treatment or treatment component. Health care products and services are typically reimbursed based on the applicable reimbursement codes, payer acceptance, and payment as well as pricing arrangements specific to the product, service, setting of care, and patient scenario. Payer acceptance may be formalized differently by market, such as within payer-specific coverage policies in the United States and health technology guidance, treatment guidelines, and government, private payer, or institutional formularies in many ex-United States markets.

In general, for reimbursement of a health care product or service to be granted, it must have an associated reimbursement code or tariff description that adequately and compliantly describes it, agreement with the payer that the product or service is covered under the specific patient scenario and accepted as reimbursable, and an associated payment rate that is typically agreed upon between the payer and the product manufacturer and/or the service provider. The process of achieving these 3 reimbursement components is often prolonged, taking as long as 4 to 5 years in some markets, and in some markets reimbursement may be rejected entirely, preventing patient access to a product.126

If one of these reimbursement components is missing, a cell therapy is unlikely to be affordable to most patients, and providers may not administer the cell therapy given the risk of inadequate, if any, reimbursement for the cost of procuring or producing the cell therapy product and/or the cost of administering the cell therapy to the patient. Accordingly, a survey of private regenerative medicine investors indicated uncertainty about pricing and reimbursement as the greatest risk to future investment in the space.18 Excellent reviews of market-specific and global reimbursement coding and payment mechanisms for outpatient and inpatient treatments are available.27,119,127–132

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Reimbursement of Orthopedic Cell Therapy

Reimbursement Coding and Payment in the United States

Reimbursement codes correspond to treatments, services, medical equipment, and/or supplies used to care for the patient, and/or an episode of care within which payment for a variety of treatments, services, medical equipment, and/or supplies are provided. Since preparing and administering cell therapies often entails significantly more procedural complexity, effort, time, and clinical resources, reimbursement codes sometimes correspond with insufficient payment rates to accommodate provider use of cell therapy in either the outpatient or inpatient setting.

In the United States, Medicare is the federal government-funded health insurance plan for those 65 years of age or above and younger patients with specific disabilities and/or conditions making them eligible for Medicare benefits (eg, patients with end-stage renal disease), while Medicaid is the federally-funded health insurance that is administered by each state to provide coverage to low-income populations. Although commercial payers in the United States rarely publish payment rates or fee schedules, as they typically negotiate them in confidence individually with providers and health systems, CMS publishes a nationally-binding, maximum fee schedule every year for most reimbursement codes that apply to all local Medicare Administrative Contractors (MACs) for traditional Medicare beneficiaries. State Medicaid plans also typically publish fee schedules annually defining maximum payment rates that are generally applicable to all Medicaid beneficiaries residing in the state. As an example, see Table 7 for Current Procedural Terminology (CPT) codes (which are managed and copyrighted by the American Medical Association) and corresponding 2018 payment rates for orthopedic cell and tissue transplantation for the knee under Medicare, along with estimated time specialists spend with the patient before, during, and after the procedure. These specific CPT codes and payment rates are also meant to cover ancillary time spent with the patient beyond that (eg, speaking with family members/carers), anesthesia services if done by the same physician who conducts the orthopedic procedure, patient chart notes, and the cost of standard supplies and materials typically included as part of the procedure (eg, syringes, antiseptic, standard pain medication, gauze, sutures).

TABLE 7

TABLE 7

In the outpatient care setting, prescribed drug therapies and cell therapies are often (although not always) eligible for separate payment from the procedure used to administer them. This separate payment process for administered therapy versus therapy administration allows providers to use higher-cost therapies without the financial strain imposed by provider reimbursement under a prospectively bundled payment. One example of an orthopedic cell therapy in which the administered cells would be eligible for separate payment is autologous chondrocytes for knee implantation. The autologous chondrocyte implantation to the knee procedure, billed by the provider using CPT code 27412 and reimbursed by CPT code 27412 for maximum payment of $1721.50 under Medicare (see Table 7 above), would be billed as a separate line item and reimbursed as a separate payment from the autologous cultured chondrocytes the provider obtained to treat the patient. Provider-administered drugs, medical devices, supplies, and materials are typically described for billing purposes under what are referred to as Healthcare Common Procedure Coding System (HCPCS) codes (see Alliance for Regenerative Medicine, Reimbursement Portfolio127 for an excellent review). As an example, the corresponding HCPCS code for autologous cultured chondrocytes for implantation to the knee is J7330. Although this code is listed in the national Medicare fee schedule, CMS does not provide an assigned payment rate, given that its reimbursement is left to the discretion of local MACs. State Medicaid plans that do reimburse autologous chondrocyte implantation, however, have published maximum allowed payment rates for J7330, some of which are listed in Table 8.

TABLE 8

TABLE 8

In contrast to reimbursement in the outpatient setting, therapies administered during an inpatient hospital stay are generally reimbursed to the provider as part of a prospectively bundled episode of care, diagnosis-related group (DRG), or case rate-based payment. For some inpatient episodes of care, existing DRG code descriptions are often sufficiently broad that novel treatments, such as cell therapies, may require reimbursement within the existing DRG code that best matches the procedure or diagnosis described by the DRG. That is if a cell therapy, such as autologous cultured chondrocytes, is administered to an inpatient, the provider would be unable to receive payment other than that for the All Patient Refined DRG (APR-DRG); a bill for J7330 would not be paid for the inpatient procedure. This attribute of DRG code-based inpatient reimbursement creates a scenario whereby the cost of a high-value cell therapy must be covered by an already constrained episode-of-care reimbursement, which in many cases barely covers the cost of the procedures originally anticipated when the DRG was issued and payment rates set.

To highlight this point more concretely, most state Medicaid plans utilize the APR-DRG for coding and payment rates that apply to inpatient stays (vs. the Medicare Severity DRGs used for Medicare beneficiaries). Each APR-DRG includes severity of illness modifier that adjusts payment based on whether the severity is considered minor, moderate, major, or extreme. The APR-DRG that would potentially best apply to an inpatient stay in which autologous chondrocytes might hypothetically be administered would be APR-DRG 313, which describes an inpatient stay for a knee or lower leg procedure (except foot). Table 9 highlights maximum payment rates for APR-DRG 313 in 2 states. Given a hypothetical cost of $30,067.33 (Table 8) to procure autologous cultured chondrocytes for implantation in the knee in an inpatient setting under Medicaid in these 2 states, a provider could potentially sustain a significant financial loss on the patient (as computed with assumptions in Table 8). Although this disconnect between the cost of innovative therapies, such as cell therapy, and existing DRG-based payment rates is common, the options to seek higher payment to accommodate a new, more costly therapy are limited, difficult, time-intensive, and represent a temporary fix at best in most cases.

TABLE 9

TABLE 9

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Payer Coverage for Orthopedic Cell Therapy in the United States and Ex-United States Markets

Another key to cell therapy reimbursement and market access is payer coverage, which essentially constitutes a commitment from the payer that the therapy will be reimbursed for eligible patients under specific clinical scenarios outlined in published reimbursement policies. In the United States, these clinical scenarios are explained in detail in policies published by various health plans to help inform provider treatment decisions for patients covered under that health plan. In other western countries, there are national, regional, and/or local levels (or even hospital level) HTA agencies or committees that evaluate health care products and services on suitability for reimbursement and pricing, as well as where to place them in the patient care pathway. These HTA agencies are important stakeholders, decision-makers, and influencers guiding whether a therapy will be made available and reimbursed in the market, and for whom. For excellent reviews and comparisons of ex-US HTA processes and impacts on reimbursement, see Angelis et al,141 Akehurst et al,131 Panteli et al.142

Given the decentralized and highly-fragmented system of health care payers in the United States including both private and government payers, there is no formal national level HTA organization or process uniformly affecting reimbursement. Instead, in addition to payer pharmacy and therapeutic and medical technology assessment committees maintained within most payers, there are public and private HTA bodies with varying degrees of impact on payer coverage decisions. A small number of these HTA organizations have a broad, meaningful influence on payer coverage policies, some of which include the following:

  • Agency for Healthcare Research and Quality (AHRQ), a division of the US Department of Health and Human Services.
  • BlueCross BlueShield Association (BCBSA).
  • ECRI Institute.
  • Hayes Inc.
  • Institute for Clinical and Economic Review (ICER).
  • InterQual.
  • MCG Health.
  • Medicare Evidence Development and Coverage Advisory Committee (MEDCAC).

Global payers and HTA organizations evaluate specific criteria in determining whether a cell therapy product and/or procedure should be reimbursed and if so at what product price and/or provider payment rate. The main criteria evaluated focus on the evidence available to support the value of cell therapy for the specific orthopedic application, including:

  • Unmet need in the target patient population.
  • Degree of product/procedure quality and uniformity/standardization.
  • Comparative impact on outcomes in target patients (eg, efficacy/effectiveness, the magnitude of therapeutic effect, duration of therapeutic effect, safety).
  • Comparative impact on humanistic outcomes (eg, quality of life for the patient and caregivers/carers).
  • Comparative impact on health economic outcomes in target patients (eg, impact on health care resource utilization such as avoidance of costly surgeries, emergency room visits, hospital stays, budget impact, cost-effectiveness/value for money).

The weight placed on these criteria varies between health systems and payers/HTA organizations, with many ex-US payers/HTA agencies tending to focus more on health economic impacts, value for money, and equitable access for all eligible patients. US payers generally focus more on unmet needs and clinical impacts. A review of published ex-US payer HTAs elaborating on reimbursement recommendations for orthopedic cell and tissue-based therapies accordingly highlights key criteria scrutinized by HTA agencies and their rationale for recommending or rejecting reimbursement (Fig. 5). Select US payer coverage policies for regenerative orthopedic cell and tissue-based therapies are highlighted in Figure 6. Payer rationale for orthopedic regenerative therapy nonreimbursement/noncoverage across ex-United States and United States markets generally align around clinical and humanistic evidence requirements not being met to support their clinical and economic value.

FIGURE 5

FIGURE 5

FIGURE 6

FIGURE 6

Few of these orthopedic regenerative therapies are covered by US payers, and those that are covered apply only to repairing specific knee cartilage defects and are frequently restricted to patients aged 50 to 60 years or below. Negative coverage policies in the United States frequently cited insufficient study design (eg, lack of properly controlled and blinded randomized trials), poor description/characterization of included patients/exclusion of populations with greatest unmet need, irrelevant comparators, inconsistent results across multiple published studies, small sample size, suboptimal endpoints captured, limited long-term follow-up, uncertain standardization of preparation and administration procedures, lack of regulatory approval/clearance, insufficient improvement in outcomes relative to existing standard of care to justify, and insufficient evidence to inform appropriate patients and/or therapy timing, frequency or dosing. Both US and ex-US HTA/payer criticisms noted above and in Figure 5 highlight the importance of developers of novel orthopedic cell therapies to conduct rigorous studies that are informed by substantial upfront and early vetting of pivotal study designs with key decision-makers to ensure evidentiary needs are met.

The age-based coverage restrictions imposed by most payers reflected in Figure 6 is the result of the limited evidence available from clinical trials supporting these procedures, which largely excluded older patients,158,159 effectively precluding Medicare coverage in most cases, since the vast majority of beneficiaries (84%) are 65 years of age or above.160 Coverage for autologous chondrocyte transplant/implant of the knee and osteochondral autograft or allograft of the meniscus is left to the discretion of local MACs, which, similar to commercial health plans, tend to restrict coverage of these procedures to younger patients. Thus, utilization of these procedures in Medicare beneficiaries is very low as highlighted by large differences in utilization of CPT codes in Figure 7 for autologous chondrocyte implantation of the knee (27412) (Fig. 7A) and open knee osteochondral autograft (27416) (Fig. 7B), which do not have published MAC-specific coverage policies (called local coverage determinations or LCDs), and total knee arthroplasty (27447) (Fig. 7C) and knee joint replacement/revision (27486) (Fig. 7D), which are explicitly covered in published LCDs. This illustrates the potential value of evidence development strategies that account for key decision-making criteria of payers, in this case, the patient population required by CMS for covering a therapy in all eligible Medicare patients. Another regenerative/cell therapy with little or no favorable coverage for orthopedic applications in the United States, both across commercial and government payers, is PRP injections (Fig. 6), which have limited evidence supporting their efficacy or effectiveness as highlighted in a recent review.161 PRP injections, which are described by HCPCS reimbursement code 0232T, are noncovered by most MACs for orthopedic indications as elaborated in LCDs. Therefore, as shown in Figure 8, nearly 100% of Medicare Part B charges for 0232T have been denied over the past few years, and thus largely patient self-paid at rates up to $800 to $1390 per procedure.162

FIGURE 7

FIGURE 7

FIGURE 8

FIGURE 8

Although an in-depth review of current and evolving global reimbursement mechanisms for cell therapy in orthopedic applications are not included here, we refer readers to a few excellent reviews that cover the topic in depth.1,24–26,32,127,130–132,142,163,164

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CONCLUSIONS AND FUTURE DIRECTIONS

The approaching wave of potentially transformative orthopedic cell and other regenerative therapies is anticipated to substantially impact the way orthopedic medicine is practiced, improve patient outcomes, and challenge the financial models underlying current health care systems. The market expectation for orthopedic cell therapies and other transformative therapies with curative intent is that they will be priced based on the value provided. Therefore, cell therapies are expected to be commercialized at relatively high costs rivaling the cumulative cost of medical procedures and products averted by their use. In contrast to conventional drug therapies for chronic orthopedic conditions (eg, osteoarthritis) that are administered over prolonged periods, future high-value cell therapies will, in many cases, be provided as a single administration while providing a durable therapeutic benefit over that same prolonged period.

Such therapies challenge payers’ ability to use conventional payment approaches (eg, upfront payment at the time of treatment), and the challenge will only be amplified when dozens to hundreds of similar kinds of therapies enter the market. The current health care system and reimbursement environment are not amenable to accommodating high-cost, transformative therapies, especially those with curative intent provided for many patients over a very short period of time. Therefore, it is becoming increasingly important to adopt new, alternative payment models for potentially curative, high-cost orthopedic cell therapies as they are developed over the next few years.20,26,125,165–170

Various payment models, including standard and alternative, have been envisaged to support high-cost transformative therapies, and only a few have been used in practice for either transformative and conventional therapies. Most payment models are still in the early stages of evolution for therapies with transformative and curative intent, and their feasibility and relevance will vary by market. Although there are precedents for adopting some alternative payment models in the United States, Europe, and other markets with specific conventional and transformative therapies (eg, milestone-based payments), most alternative payment models have not been utilized to any meaningful extent.171–175 The evolution of new payment models is necessary to prepare for the high number of transformative therapies coming down the pike and to the future practice of medicine. However, in the near term high-cost transformative therapies are likely to face individualized challenges to acceptance and uptake. In the interim, transformative therapy developers and manufacturers must plan early and iterate often on evidence development, value demonstration, and access groundwork well in advance of launch. Without a solid commitment, concerted effort, and critical eye toward value demonstration, health care system landscape factors, reimbursement, and alternative payment model considerations, from all relevant stakeholders, many transformative orthopedic cell therapies coming to market may face limited success and suboptimal access.

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ACKNOWLEDGMENT

The authors thank Amara Tiebout from Evidera | PPD for editing and formatting support on the manuscript.

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REFERENCES

1. Ali F, Slocomb T, Werner M. Curative regenerative medicines: preparing health care systems for the coming wave. In Vivo. 2016. Available at: http://alliancerm.org/sites/default/files/IN_VIVO_ARM_WhitePaper_CurativeRegenMed.pdf.
2. United States Bone and Joint Initiative. The burden of musculoskeletal diseases in the United States (BMUS); 2014; Third Edition. Available at: www.boneandjointburden.org/docs/The%20Burden%20of%20Musculoskeletal%20Diseases%20in%20the%20United%20States%20%28BMUS%29%203rd%20Edition%20%28Dated%2012.31.16%29.pdf. Accessed March 1, 2019.
3. He W, Goodkind D, Kowal P. US Census Bureau. International Population Reports, P95/16-1, An Aging World: 2015. Washington, DC: US Government Publishing Office; 2016.
4. United Nations, Department of Economic and Social Affairs, Population Division. World population ageing; 2017. Available at: www.un.org/en/development/desa/population/publications/pdf/ageing/WPA2017_Highlights.pdf. Accessed April 10, 2019.
5. Guess AJ, Abzug JM, Otsuru S. Use of mesenchymal stem/stromal cells for pediatric orthopedic applications. Tech Orthop. 2018. Available at: https://journals.lww.com/techortho/Abstract/publishahead/Use_of_Mesenchymal_Stem_Stromal_Cells_for.99836.aspx.
6. Mautner K, Carr D, Whitley J, et al. Allogeneic versus autologous injectable mesenchymal stem cells for osteoarthritis: review and current status. Tech Orthop. 2019. Available at: https://journals.lww.com/techortho/Abstract/publishahead/Allogeneic_Versus_Autologous_Injectable.99829.aspx#print-article-link.
7. McGowan KB, Stiegman G. Regulatory challenges for cartilage repair technologies. Cartilage. 2013;4:4–11.
8. Negoro T, Takagaki Y, Okura H, et al. Trends in clinical trials for articular cartilage repair by cell therapy. NPJ Regen Med. 2018;3:17.
9. Petricciani J, Hayakawa T, Stacey G, et al. Scientific considerations for the regulatory evaluation of cell therapy products. Biologicals. 2017;50:20–26.
10. Squillaro T, Peluso G, Galderisi U. Clinical trials with mesenchymal stem cells: an update. Cell Transplant. 2016;25:829–848.
11. Alliance for Regenerative Medicine (ARM). Q3 2018 Data Report; 2018. Available at: https://alliancerm.org/publication/q3-2018-data-report/. Accessed January 10, 2019.
12. Alliance for Regenerative Medicine (ARM). Q3 2017 Quarterly Data Report; 2017. Available at: https://alliancerm.org/wp-content/uploads/2018/04/ARM_Q3_2017_Web.pdf. Accessed January 10, 2019.
13. Rose LF, Wolf EJ, Brindle T, et al. The convergence of regenerative medicine and rehabilitation: federal perspectives. NPJ Regen Med. 2018;3:19.
14. Niemansburg SL, van Delden JJ, Oner FC, et al. Ethical implications of regenerative medicine in orthopedics: an empirical study with surgeons and scientists in the field. Spine J. 2014;14:1029–1035.
15. Mihos M, Spinner D, Ringo M, et al. Leveraging real-world evidence for regenerative medicine and advanced therapy success beyond the regulator. Evidence Forum. 2017:20–29.
16. Faulkner E, Han D. Addressing Uncertainty in Regenerative Medicine Value Demonstration: What is Mission Critical vs. Mission Impossible? Paper presented at: Meeting on the Mesa, Alliance for Regenerative Medicine, October 2016; La Jolla, CA.
17. Faulkner E. What Value Do We Place in a Cure? Implications for Regenerative Medicine Technologies. Paper presented at: Phacilitate Cell and Gene Therapy Meeting, January 2015; Washington, DC.
18. Bertram TA, Tentoff E, Johnson PC, et al. Hurdles in tissue engineering/regenerative medicine product commercialization: a pilot survey of governmental funding agencies and the financial industry. Tissue Eng Part A. 2012;18:2187–2194.
19. Carter PH, Berndt ER, DiMasi JA, et al. Investigating investment in biopharmaceutical R&D. Nat Rev Drug Discov. 2016;15:673–674.
20. Driscoll D, Farnia S, Kefalas P, et al. Concise review: the high cost of high tech medicine: planning ahead for market access. Stem Cells Transl Med. 2017;6:1723–1729.
21. DiMasi JA, Grabowski HG, Hansen RW. Innovation in the pharmaceutical industry: new estimates of R&D costs. J Health Econ. 2016;47:20–33.
22. Morgan S, Grootendorst P, Lexchin J, et al. The cost of drug development: a systematic review. Health Policy. 2011;100:4–17.
23. Vernon JA, Golec JH, Dimasi JA. Drug development costs when financial risk is measured using the Fama-French three-factor model. Health Econ. 2010;19:1002–1005.
24. Banda G, Tait J, Mittra J. Evolution of business models in regenerative medicine: effects of a disruptive innovation on the innovation ecosystem. Clin Ther. 2018;40:1084–1094.
25. Cook F, Slocomb T, Werner M. Regenerative medicine is here: new payment models key to patient access. In Vivo; 2018.
26. Faulkner E, Werner M, Slocomb T, et al. Ensuring patient access to regenerative and advanced therapies in managed care: how do we get there? [ARM Monograph]. J Manag Care Med. 2018. Available at: https://alliancerm.org/wp-content/uploads/2018/05/JMCMArm.pdf.
27. Finocchiaro Castro M, Guccio C, Pignataro G, et al. The effects of reimbursement mechanisms on medical technology diffusion in the hospital sector in the Italian NHS. Health Policy. 2014;115:215–229.
28. Hernandez J, Machacz SF, Robinson JC. US hospital payment adjustments for innovative technology lag behind those in Germany, France, and Japan. Health Aff. 2015;34:261–270.
29. Jonsson B, Hampson G, Michaels J, et al. Advanced therapy medicinal products and health technology assessment principles and practices for value-based and sustainable healthcare. Eur J Health Econ. 2019;20:427.
30. Jorgensen J, Kefalas P. Annuity payments can increase patient access to innovative cell and gene therapies under England’s net budget impact test. J Mark Access Health Policy. 2017;5:1355203.
31. Scheller-Kreinsen D, Quentin W, Busse R. DRG-based hospital payment systems and technological innovation in 12 European countries. Value Health. 2011;14:1166–1172.
32. Slocomb T, Werner M, Haack T, et al. New payment and financing models for curative regenerative medicines. In Vivo; 2017.
33. Of stem cells and ethics. Nat Cell Biol. 2017;19:1381.
34. EuroStemCell. Embryonic stem cell research: an ethical dilemma; 2016. Available at: www.eurostemcell.org/sites/default/files/documents/did-you-know/Factsheet_EmbryonicResearch.pdf. Accessed December 10, 2018.
35. King NM, Perrin J. Ethical issues in stem cell research and therapy. Stem cell Res Ther. 2014;5:85.
36. Volarevic V, Markovic BS, Gazdic M, et al. Ethical and safety issues of stem cell-based therapy. Int J Med Sci. 2018;15:36–45.
37. Lysaght T, Kerridge IH, Sipp D, et al. Ethical and regulatory challenges with autologous adult stem cells: a comparative review of international regulations. J Bioeth Inq. 2017;14:261–273.
38. Lysaght T, Lipworth W, Hendl T, et al. The deadly business of an unregulated global stem cell industry. J Med Ethics. 2017;43:744–746.
39. Sipp D. Challenges in the regulation of autologous stem cell interventions in the United States. Perspect Biol Med. 2018;61:25–41.
40. Sipp D, Caulfield T, Kaye J, et al. Marketing of unproven stem cell-based interventions: a call to action. Sci Transl Med. 2017;9:397.
41. Gomez-Tatay L, Hernandez-Andreu JM, Aznar J. Mitochondrial modification techniques and ethical issues. J Clin Med. 2017;6:3.
42. Munsie M, Gyngell C. Ethical issues in genetic modification and why application matters. Curr Opin Genet Dev. 2018;52:7–12.
43. Rossant J. Gene editing in human development: ethical concerns and practical applications. Development. 2018;145:16.
44. Davies BM, Smith J, Rikabi S, et al. A quantitative, multi-national and multi-stakeholder assessment of barriers to the adoption of cell therapies. J Tissue Eng. 2017;8:2041731417724413.
45. de Windt TS, Niemansburg SL, Vonk LA, et al. Ethics in musculoskeletal regenerative medicine; guidance in choosing the appropriate comparator in clinical trials. Osteoarthritis Cartilage. 2019;27:34–40.
46. Akpancar S, Tatar O, Turgut H, et al. The current perspectives of stem cell therapy in orthopedic surgery. Arch Trauma Res. 2016;5:e37976.
47. Cotter EJ, Wang KC, Yanke AB, et al. Bone marrow aspirate concentrate for cartilage defects of the knee: from bench to bedside evidence. Cartilage. 2018;9:161–170.
48. Maniar HH, Tawari AA, Suk M, et al. The current role of stem cells in orthopaedic surgery. Malays Orthop J. 2015;9:1–7.
49. Saltzman BM, Kuhns BD, Weber AE, et al. Stem cells in orthopedics: a comprehensive guide for the general orthopedist. Am J Orthop. 2016;45:280–326.
50. Atukorale YN, Lambert RS, Cameron AL, et al. Stem cell treatments within surgical specialities: what is the evidence? ANZ J Surg. 2018;88:11–12.
51. GSK. GSK receives positive CHMP opinion in Europe for Strimvelis™, the first gene therapy to treat very rare disease, ADA-SCID [press release]. London, UK; 2016.
52. Novartis Pharmaceuticals. The ELIANA Clinical Trial Fact Sheet. The ELIANA Trial (NCT02435849); 2017. Available at: https://novartis.gcs-web.com/static-files/110bee95-5916-483f-a0c9-20128105005f. Accessed March 18, 2019.
53. Rawlins MD. Crossing the fourth hurdle. Br J Clin Pharmacol. 2012;73:855–860.
54. Taylor RS, Drummond MF, Salkeld G, et al. Inclusion of cost effectiveness in licensing requirements of new drugs: the fourth hurdle. BMJ. 2004;329:972–975.
55. Alliance for Regenerative Medicine (ARM). Available Products; 2018. Available at: https://alliancerm.org/available-products/. Accessed January 1, 2019.
    56. Alliance for Regenerative Medicine (ARM). Annual Data Report; 2017. Available at: https://alliancerm.org/wp-content/uploads/2018/05/ARM_Annual_Report_2017_FINAL.pdf. Accessed January 1, 2019.
      57. European Medicines Agency (EMA). EMA Homepage; 2019. Available at: www.ema.europa.eu/en. Accessed March 8, 2019.
        58. Canadian Agency for Drugs and Technologies in Health (CADTH). Gene therapy: an overview of approved and pipeline technologies; 2018. Available at: https://cadth.ca/dv/ieht/gene-therapy-overview-approved-and-pipeline-technologies. Accessed January 1, 2019.
          59. Canadian Agency for Drugs and Technologies in Health (CADTH). Gene Therapy: International Regulatory and Health Technology Assessment Activities and Reimbursement Status. Project number: ES025-000. Product Line: Environmental Scans. Result type: Report; 2018. Available at: www.cadth.ca/gene-therapy-international-regulatory-and-health-technology-assessment-activities-and-reimbursement. Accessed January 1, 2019.
            60. Haydock I. Japan approvals include world firsts for romosozumab, spinal injury cell therapy. Pink Sheet; 2019.
              61. Pereira Chilima TD, Moncaubeig F, Farid SS. Impact of allogeneic stem cell manufacturing decisions on cost of goods, process robustness and reimbursement. Biochem Eng J. 2018;137:132–151.
              62. Health Canada. Guidance Document for Cell, Tissue and Organ Establishments—Safety of Human Cells, Tissues and Organs for Transplantation; 2018. Available at: www.canada.ca/en/health-canada/services/drugs-health-products/biologics-radiopharmaceuticals-genetic-therapies/regulatory-initiatives/cells-tissues-organs/guidance-document-safety-human-cells-tissues-organs-transplantation/document.html. Accessed January 1, 2019.
                63. Health Canada. Appendix 1: Decision Tree for Help in the Classification of CTO. Guidance Document for Cell, Tissue and Organ Establishments—Safety of Human Cells, Tissues and Organs for Transplantation; 2018. Available at: www.canada.ca/en/health-canada/services/drugs-health-products/biologics-radiopharmaceuticals-genetic-therapies/regulatory-initiatives/cells-tissues-organs/guidance-document-safety-human-cells-tissues-organs-transplantation/document.html#a3.1. Accessed January 1, 2019.
                  64. Ridgway A, Agbanyo F, Wang J, et al. Regulatory oversight of cell and gene therapy products in Canada. Adv Exp Med Biol. 2015;871:49–71.
                  65. Ridgway AA. The regulation of cell therapy products in Canada. Biologicals. 2015;43:406–409.
                  66. European Medicines Agency (EMA). Guideline on the risk-based approach according to annex I, part IV of Directive 2001/83/EC applied to advanced therapy medicinal products; 2013. Available at: www.ema.europa.eu/en/documents/scientific-guideline/guideline-risk-based-approach-according-annex-i-part-iv-directive-2001/83/ec-applied-advanced-therapy-medicinal-products_en.pdf. Accessed December 5, 2018.
                    67. Official Journal of the European Union. Regulation (EC) No 1394/2007 of the European Parliament and of the Council of 13 November 2007 on advanced therapy medicinal products and amending directive 2001/83/EC and regulation (EC) No 726/2004; 2007. Available at: https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-1/reg_2007_1394/reg_2007_1394_en.pdf. Accessed December 5, 2018.
                      68. Kusakabe T. Regulatory perspectives of Japan. Biologicals. 2015;43:422–424.
                      69. Inoue S. Regulatory update from MHLW/PMDA. 5th Joint Conference of Taiwan and Japan on Medical Products Regulation; 2017. Available at: www.pmda.go.jp/files/000221880.pdf. Accessed January 1, 2019.
                        70. Ministry of Health Labour and Welfare (MHLW). Strategy of SAKIGAKE; 2014. Available at: www.mhlw.go.jp/english/policy/health-medical/pharmaceuticals/140729-01.html. Accessed January 20, 2019.
                          71. Han E, Shin W. Regulation of cell therapy products in Korea. ISBT Sci Series. 2015;10(suppl 1):129–133.
                            72. Joung J. Regulatory update on cell and gene therapy products in Korea; 2016. Available at: www.pmda.go.jp/files/000211334.pdf. Accessed January 1, 2019.
                              73. Dennett R, Messmer K. FDA Regenerative Medicine Policy Framework and Advanced Therapy Designation. Regulatory Affairs Professionals Society—Regulatory Focus; 2018. Available at: www.raps.org/. Accessed December 10, 2018.
                              74. Marks P, Gottlieb S. Balancing safety and innovation for cell-based regenerative medicine. N Engl J Med. 2018;378:954–959.
                              75. Messmer K, Cumming R. 21st Century Cures Act: innovation, breakthroughs, and research in under-represented populations. Evidence Forum. 2017:15–19.
                              76. Yano K, Speidel AT, Yamato M. Four Food and Drug Administration draft guidance documents and the REGROW Act: a litmus test for future changes in human cell- and tissue-based products regulatory policy in the United States? J Tissue Eng Regen Med. 2018;12:1579–1593.
                              77. Knoepfler PS, Turner LG. The FDA and the US direct-to-consumer marketplace for stem cell interventions: a temporal analysis. Regen Med. 2018;13:19–27.
                              78. Master Z, Fu W, Paciulli D, et al. Industry responsibilities in tackling direct-to-consumer marketing of unproven stem cell treatments. Clin Pharmacol Ther. 2017;102:177–179.
                              79. Royal Australasian College of Surgeons. Stem cell therapy in surgery; 2016; 62p. Available at: www.surgeons.org/media/25343513/rpt_2016-11-24_stem_cell_therapy_in_surgery.pdf.
                              80. Turner L. Direct-to-consumer marketing of stem cell interventions by Canadian businesses. Regen Med. 2018;13:643–658.
                              81. Bauer G, Abou-El-Enein M, Kent A, et al. The path to successful commercialization of cell and gene therapies: empowering patient advocates. Cytotherapy. 2017;19:293–298.
                              82. Horner C, Tenenbaum E, Sipp D, et al. Can civil lawsuits stem the tide of direct-to-consumer marketing of unproven stem cell interventions. NPJ Regen Med. 2018;3:5.
                              83. Kuriyan AE, Albini TA, Townsend JH, et al. Vision loss after intravitreal injection of autologous “stem cells” for AMD. N Engl J Med. 2017;376:1047–1053.
                              84. Australian Academy of Sciences. Submission to the Therapeutic Goods Administration Consultation on Regulation of Autologous Stem Cell Therapies; 2015. Available at: www.science.org.au/files/userfiles/support/submissions/2015/consultation-on-regulation-of-stem-cell-therapies.pdf. Accessed December 10, 2018.
                              85. Miller D. Tampa Lawmaker Proposes Crack Down On For-Profit Stem Cell Clinics. Health News Florida; 2018. Available at: http://health.wusf.usf.edu/post/tampa-lawmaker-proposes-crack-down-profit-stem-cell-clinics. Accessed December 10, 2018.
                              86. Royal Australasian College of Surgeons. Stem Cell Therapy Position Paper; 2018; 2 pp. Available at: www.surgeons.org/media/25701304/2018-06-27_pos_fes-pst-063_stem_cell_therapy.pdf.
                              87. Wingerter M. Oklahoma researcher says FDA crackdown could be good for stem cell treatment. The Oklahoman, NewsOKcom; 2017.
                              88. Food and Drug Administration (FDA). FDA warns about stem cell therapies; 2017. Available at: www.fda.gov/forconsumers/consumerupdates/ucm286155.htm.
                              89. Eglovitch JS. FDA ups pressure on stem cell therapy makers to follow product approval rules. Pink Sheet; 2019.
                              90. Food and Drug Administration (FDA). FDA seeks permanent injunctions against two stem cell clinics; 2018. Available at: www.fda.gov/newsevents/newsroom/pressannouncements/ucm607257.htm.
                              91. Korol S. FDA warns Genetech for manufacturing unapproved orthobiologic products that may have led to infection—9 insights. Becker’s Spine Review 2018.
                              92. Paavola A. FDA cracks down on stem cell clinics offering unapproved treatments. Becker’s Hospital Review; 2017.
                              93. Prosser I. Therapeutic Goods Administration presentation on changes to the regulation of autologous cells and tissues; 2018. Available at: www.tga.gov.au/sites/default/files/presentation-changes-to-the-regulation-of-autologous-cells-and-tissues.pdf. Accessed December 10, 2018.
                              94. Therapeutic Goods Administration (TGA). Regulation of autologous cell and tissue products; 2017. Available at: www.tga.gov.au/media-release/regulation-autologous-cell-and-tissue-products. Accessed December 10, 2018.
                              95. Therapeutic Goods Administration (TGA). Australian Regulatory Guidelines for Advertising Therapeutic Goods (ARGATG): Guidance for advertisers. Version 2; 2018. Available at: www.tga.gov.au/sites/default/files/australian-regulatory-guidelines-advertising-therapeutic-goods-argatg.pdf.
                              96. Therapeutic Goods Administration (TGA). Therapeutic Goods Order No. 88; 2013. Available at: www.legislation.gov.au/Details/F2013L00854. Accessed December 10, 2018.
                              97. Health Canada. Health Canada Policy Position Paper—Autologous Cell Therapy Products; 2019. Available at: www.canada.ca/en/health-canada/services/drugs-health-products/biologics-radiopharmaceuticals-genetic-therapies/applications-submissions/guidance-documents/cell-therapy-policy.html. Accessed May 15, 2019.
                              98. Food and Drug Administration (FDA). Guidance for Industry. Preparation of IDEs and INDs for products intended to repair or replace knee cartilage; 2011. Available at: www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/CellularandGeneTherapy/UCM288011.pdf. Accessed June 4, 2018.
                              99. Food and Drug Administration (FDA). Cellular & Gene Therapy Guidances; 2018. Available at: www.fda.gov/biologicsbloodvaccines/guidancecomplianceregulatoryinformation/guidances/cellularandgenetherapy/default.htm. Accessed December 10, 2018.
                              100. Food and Drug Administration (FDA). Framework for the Regulation of Regenerative Medicine Products; 2017. Available at: www.fda.gov/biologicsbloodvaccines/cellulargenetherapyproducts/ucm585218.htm. Accessed December 10, 2018.
                              101. Food and Drug Administration (FDA). Regulatory Considerations for Human Cells, Tissues, and Cellular and Tissue-Based Products: Minimal Manipulation and Homologous Use; 2017. Available at: www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/CellularandGeneTherapy/UCM585403.pdf. Accessed December 10, 2018.
                              102. Food and Drug Administration (FDA). Same Surgical Procedure Exception under 21 CFR 1271.15(b): Questions and Answers Regarding the Scope of the Exception. Guidance for Industry; 2017. Available at: www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Tissue/UCM419926.pdf. Accessed December 9, 2018.
                              103. American Academy of Orthopaedic Surgeons (AAOS). Platelet-Rich Plasma (PRP); 2011. Available at: https://orthoinfo.aaos.org/en/treatment/platelet-rich-plasma-prp/. Accessed December 10, 2018.
                              104. Regence BlueCross BlueShield. Orthopedic applications of stem cell therapy, including bone substitutes used with autologous bone marrow. Medicine Policy No. MED142; 2018. Available at: blue.regence.com/trgmedpol/medicine/med142.pdf. Accessed January 1, 2019.
                              105. Regence BlueCross BlueShield. Orthopedic applications of stem cell therapy, including bone substitutes used with autologous bone marrow. Medicare Advantage Medicine Policy No. M-MED142; 2018. Available at: blue.regence.com/medicare/med/m-med142.pdf. Accessed January 1, 2019.
                              106. Food and Drug Administration (FDA). Approved cellular and gene therapy products; 2018. Available at: www.fda.gov/biologicsbloodvaccines/cellulargenetherapyproducts/approvedproducts/default.htm. Accessed December 3, 2018.
                              107. United States Congress. 21st Century Cures Act Public Law 114-255; 2016. Available at: www.congress.gov/114/plaws/publ255/PLAW-114publ255.pdf. Accessed December 10, 2018.
                              108. Alliance for Regenerative Medicine (ARM). Presentation on RMAT Designation—Impact on Regenerative Medicine Sector & How it Compares with Other Accelerated Approval Programs; 2018. Available at: https://alliancerm.org/wp-content/uploads/2018/06/ARM-RMAT-Webinar-Slides-PDF.pdf.
                              109. United States Congress. One Hundred Twelfth Congress of the United States of America at the Second Session (S. 3187). Available at: www.govinfo.gov/content/pkg/BILLS-112s3187enr/pdf/BILLS-112s3187enr.pdf: Food and Drug Administration Safety and Innovation Act (FDASIA). Accessed October 19, 2019.
                              110. Food and Drug Administration (FDA). Expedited programs for regenerative medicine therapies for serious conditions. Draft Guidance for Industry; 2017. Available at: www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/CellularandGeneTherapy/UCM585414.pdf. Accessed January 1, 2019.
                              111. Welsing PM, Oude Rengerink K, Collier S, et al. Series: pragmatic trials and real world evidence: Paper 6. Outcome measures in the real world. J Clin Epidemiol. 2017;90:99–107.
                              112. Zuidgeest MGP, Goetz I, Groenwold RHH, et al. Series: pragmatic trials and real world evidence: Paper 1. Introduction. J Clin Epidemiol. 2017;88:7–13.
                              113. Bryan WW. Regenerative Medicine Advanced Therapy (RMAT) Designation. Paper presented at: American Society of Gene & Cell Therapy Liaison Meeting September 13, 2018; Silver Spring, MD.
                              114. Adis Insight, Springer. What’s new—drugs in development; 2018. Available at: https://adisinsight.springer.com/. Accessed January 1, 2019.
                              115. Lei J, Priddy LB, Lim JJ, et al. Dehydrated human amnion/chorion membrane (dHACM) allografts as a therapy for orthopedic tissue repair. Tech Orthop. 2017;32:149–157.
                              116. Food and Drug Administration (FDA). Labeling for human prescription drug and biological products approved under the Accelerated Approval Regulatory Pathway. Guidance for Industry; 2019. Available at: www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM390058.pdf. Accessed January 1, 2019.
                              117. Sutter S. Accelerated approval: US FDA labeling guidance calls out surrogate endpoints needing ‘additional context’. Pink Sheet; 2019.
                              118. Hettle R, Corbett M, Hinde S, et al. The assessment and appraisal of regenerative medicines and cell therapy products: an exploration of methods for review, economic evaluation and appraisal. Health Technol Assess (Rockv). 2017;21:1–204.
                              119. Jorgensen J, Kefalas P. Reimbursement of licensed cell and gene therapies across the major European healthcare markets. J Mark Access Health Policy. 2015. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27123175.
                              120. Mistry H, Connock M, Pink J, et al. Autologous chondrocyte implantation in the knee: systematic review and economic evaluation. Health Technol Assess (Rockv). 2017;21:1–294.
                              121. Haute Autorité de Santé (HAS). ChondroCelect 10,000 cells/microlitre, implantation suspension. Transparency Committee Opinion; 2010. Available at: www.has-sante.fr/portail/jcms/c_994267/en/chondrocelect. Accessed January 1, 2019.
                              122. Haute Autorité de Santé (HAS). ChondroCelect 10,000 cells/microlitre, implantation suspension. Transparency Committee Opinion; 2013. Available at: www.has-sante.fr/portail/jcms/c_1615035/en/chondrocelect-chondrocytes-autologues. Accessed January 1, 2019.
                              123. Medical Services Advisory Committee (MSAC). Application No. 1140—Matrix induced autologous chondrocyte implantation and autologous chondrocyte implantation. Public Summary Document; 2011. Available at: www.msac.gov.au/internet/msac/publishing.nsf/Content/1140-public. Accessed January 1, 2019.
                              124. National Institute for Health and Care Excellence (NICE). Darvadstrocel for treating complex perianal fistula in Crohn’s disease. Technology appraisal guidance [TA566]; 2019. Available at: www.nice.org.uk/guidance/ta556/resources/darvadstrocel-for-treating-complex-perianal-fistulas-in-crohns-disease-pdf-82607025232069. Accessed January 1, 2019.
                              125. Center for Medicare & Medicaid Services (CMS). CMS: innovative treatments call for innovative payment models and arrangements; 2017. Available at: www.cms.gov/Newsroom/MediaReleaseDatabase/Press-releases/2017-Press-releases-items/2017-08-30-2.html. Accessed January 20, 2019.
                              126. European Federation of Pharmaceutical Industries and Associations (EFPIA). EFPIA market access delays analysis. Presentation; 2018.
                              127. Alliance for Regenerative Medicine (ARM). Alliance for Regenerative Medicine Reimbursement Portfolio; 2013. Available at: www.cirm.ca.gov/sites/default/files/files/agenda/ARM_Reimbursement_Portfolio_Oct_2013_0.pdf.
                              128. International Society for Pharmacoeconomics and Outcomes Research (ISPOR). The ISPOR Global Health Care Systems Road Map; 2019. Available at: https://tools.ispor.org/htaroadmaps/.
                              129. Academy of Managed Care Pharmacy (AMCP). AMCP Guide to Pharmaceutical Payment Methods 2013. Executive Summary Version 3.0; 2013. Available at: www.amcp.org/WorkArea/DownloadAsset.aspx?id=16476. Accessed January 10, 2019.
                              130. Remuzat C, Toumi M, Jorgensen J, et al. Market access pathways for cell therapies in France. J Mark Access Health Policy. 2015. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27123176.
                              131. Akehurst RL, Abadie E, Renaudin N, et al. Variation in health technology assessment and reimbursement processes in Europe. Value Health. 2017;20:67–76.
                              132. Mahalatchimy A. Reimbursement of cell-based regenerative therapy in the UK and France. Med Law Rev. 2016;24:234–258.
                              133. CodeMap®. CodeMap® Home Page; 2019. Available at: www.codemap.com/. Accessed March 8, 2019.
                                134. EncoderPro. EncoderPro.com—Product Information; 2019. Available at: www.encoderpro.com/epro/. Accessed March 8, 2019.
                                  135. AR Medicaid. Provider Documents—Arkansas; 2019. Available at: https://medicaid.mmis.arkansas.gov/provider/docs/docs.aspx. Accessed March 8, 2019.
                                    136. MD Medicaid, Maryland Department of Health. Provider information; 2019. Available at: https://mmcp.health.maryland.gov/Pages/Provider-Information.aspx. Accessed March 8, 2019.
                                      137. Minnesota Department of Human Services. Minnesota Health Care Programs (MHCP) Fee Schedule; 2019. Available at: https://mn.gov/dhs/partners-and-providers/policies-procedures/minnesota-health-care-programs/provider/billing/fee-schedule/mhcp.jsp. Accessed March 8, 2019.
                                        138. New Mexico Human Services Department. Medicaid providers and fee schedules; 2019. Available at: www.hsd.state.nm.us/providers/fee-schedules.aspx. Accessed March 8, 2019.
                                          139. Ohio Department of Medicaid. Fee schedules and rates; 2019. Available at: https://medicaid.ohio.gov/Provider/FeeScheduleandRates/SchedulesandRates. Accessed March 8, 2019.
                                            140. West Virginia Bureau for Medical Services. WV Medicaid physician’s fee schedules; 2019. Available at: https://dhhr.wv.gov/bms/FEES/Pages/default.aspx. Accessed March 8, 2019.
                                              141. Angelis A, Lange A, Kanavos P. Using health technology assessment to assess the value of new medicines: results of a systematic review and expert consultation across eight European countries. Eur J Health Econ. 2018;19:123–152.
                                              142. Panteli D, Eckhardt H, Nolting A, et al. From market access to patient access: overview of evidence-based approaches for the reimbursement and pricing of pharmaceuticals in 36 European countries. Health Res Policy Syst. 2015;13:39.
                                              143. National Institute for Health and Care Excellence (NICE). Autologous chondrocyte implantation for treating symptomatic articular cartilage defects of the knee. Technology appraisal guidance [TA477]; 2017. Available at: www.nice.org.uk/guidance/TA477. Accessed January 1, 2019.
                                                144. National Institute for Health and Care Excellence (NICE). Autologous chondrocyte implantation using chondrosphere for treating symptomatic articular cartilage defects of the knee. Technology appraisal guidance [TA508]; 2018. Available at: www.nice.org.uk/guidance/ta508. Accessed January 1, 2019.
                                                  145. National Institute for Health and Care Excellence (NICE). Autologous blood injection for tendinopathy. Interventional procedures guidance [IPG438]; 2013. Available at: www.nice.org.uk/guidance/ipg438. Accessed January 1, 2019.
                                                    146. National Institute for Health and Care Excellence (NICE). Mosaicplasty for symptomatic articular cartilage defects of the knee. Interventional procedures guidance [IPG607]; 2018. Available at: www.nice.org.uk/guidance/ipg607. Accessed January 1, 2019.
                                                      147. National Institute for Health and Care Excellence (NICE). Platelet-rich plasma injections for osteoarthritis of the knee. Interventional procedures guidance [IPG491]; 2014. Available at: www.nice.org.uk/guidance/ipg491. Accessed January 1, 2019.
                                                        148. Aetna. Aetna.com Homepage; 2019. Available at: www.aetna.com/. Accessed March 8, 2019.
                                                          149. Anthem. Anthem.com Homepage; 2019. Available at: www.anthem.com/. Accessed March 8, 2019.
                                                            150. BlueCross BlueShield. BlueCross BlueShield Homepage; 2019. Available at: www.bcbs.com/. Accessed March 8, 2019.
                                                              151. Cigna. Cigna.com Homepage—Insurance Plans and Products; 2019. Available at: www.cigna.com/. Accessed March 8, 2019.
                                                                152. Humana. Humana.com Homepage; 2019. Available at: www.humana.com/. Accessed March 8, 2019.
                                                                  153. Priority Health. PriorityHealth.com Homepage; 2019. Available at: www.priorityhealth.com/. Accessed March 8, 2019.
                                                                    154. Regence. Shop 2019 Medicare plans; 2019. Available at: www.regence.com/web/regence_medicare. Accessed March 8, 2019.
                                                                      155. United Healthcare. UnitedHealthcare Homepage; 2019. Available at: www.uhc.com/. Accessed March 8, 2019.
                                                                        156. Washington State Healthcare Authority. Washington State Healthcare Authority Homepage; 2019. Available at: www.hca.wa.gov/. Accessed March 8, 2019.
                                                                          157. Medicare. Medicare Advantage Plans; 2019. Available at: www.medicare.gov/sign-up-change-plans/types-of-medicare-health-plans/medicare-advantage-plans. Accessed March 8, 2019.
                                                                            158. Krill M, Early N, Everhart JS, et al. Autologous chondrocyte implantation (ACI) for knee cartilage defects: a review of indications, technique, and outcomes. JBJS reviews. 2018;6:e5.
                                                                            159. Vasiliadis HS, Wasiak J. Autologous chondrocyte implantation for full thickness articular cartilage defects of the knee. Cochrane Database Syst Rev. 2010;10:CD003323.
                                                                            160. Medicare Payment Advisory Commission (MedPAC). Data Book, Section 2: Medicare beneficiary demographics; 2018. Available at: medpac.gov/-documents-/data-book. Accessed January 1, 2019.
                                                                            161. Bashir J, Panero AJ, Sherman AL. The emerging use of platelet-rich plasma in musculoskeletal medicine. J Am Osteopath Assoc. 2015;115:24–31.
                                                                            162. Piuzzi NS, Ng M, Kantor A, et al. What is the price and claimed efficacy of platelet-rich plasma injections for the treatment of knee osteoarthritis in the United States? J Knee Surg. 2018;32:879–885.
                                                                            163. Abou-El-Enein M, Elsanhoury A, Reinke P. Overcoming challenges facing advanced therapies in the EU Market. Cell Stem Cell. 2016;19:293–297.
                                                                            164. Bubela T, McCabe C, Archibald P, et al. Bringing regenerative medicines to the clinic: the future for regulation and reimbursement. Regen Med. 2015;10:897–911.
                                                                            165. [No authors listed]. AMCP partnership forum: advancing value-based contracting. J Manag Care Spec Pharm. 2017;23:1096–1102.
                                                                            166. Brown JD, Sheer R, Pasquale M, et al. Payer and pharmaceutical manufacturer considerations for outcomes-based agreements in the United States. Value Health. 2018;21:33–40.
                                                                            167. Keohane N, Petrie K. Social Market Foundation. Outcomes-based reimbursement of medicines; 2017. Available at: www.smf.co.uk/wp-content/uploads/2017/07/Data-for-Outcomes-final.pdf. Accessed January 10, 2019.
                                                                            168. Kleinke JD, McGee N. Breaking the Bank: three financing models for addressing the drug innovation cost crisis. Am Health Drug Benefits. 2015;8:118–126.
                                                                            169. Montazerhodjat V, Weinstock DM, Lo AW. Buying cures versus renting health: financing health care with consumer loans. Sci Transl Med. 2016;8:327ps326.
                                                                            170. Yeung K, Suh K, Basu A, et al. Paying for cures: how can we afford it? managed care pharmacy stakeholder perceptions of policy options to address affordability of prescription drugs. J Manag Care Spec Pharm. 2017;23:1084–1090.
                                                                            171. [No authors listed]. AMCP partnership forum: designing benefits and payment models for innovative high-investment medications. J Manag Care Spec Pharm. 2019;25:156–162.
                                                                            172. Duhig AM, Saha S, Smith S, et al. The current status of outcomes-based contracting for manufacturers and payers: an AMCP Membership Survey. J Manag Care Spec Pharm. 2018;24:410–415.
                                                                            173. Goble JA, Ung B, van Boemmel-Wegmann S, et al. Performance-based risk-sharing arrangements: US Payer Experience. J Manag Care Spec Pharm. 2017;23:1042–1052.
                                                                            174. Nazareth T, Ko JJ, Sasane R, et al. Outcomes-based contracting experience: research findings from US and European Stakeholders. J Manag Care Spec Pharm. 2017;23:1018–1026.
                                                                            175. Yu JS, Chin L, Oh J, et al. Performance-based risk-sharing arrangements for pharmaceutical products in the United States: a systematic review. J Manag Care Spec Pharm. 2017;23:1028–1040.
                                                                            Keywords:

                                                                            advanced therapy medicinal product; stem cell therapy; medicinal product; gene therapy; market access; regulation; reimbursement; orthopedics; 21st Century cures act; autologous chondrocyte implant; osteoarthritis

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