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A Path Forward for Regenerative Medicine

Navigating Regulatory Challenges: Summary of Findings From the Cardiac Safety Research Consortium/Texas Heart Institute International Symposium on Cardiovascular Regenerative Medicine
Originally published Research. 2018;123:495–505


    Although clinical trials of cell-based approaches to cardiovascular disease have yielded some promising results, no cell-based therapy has achieved regulatory approval for a cardiovascular indication. To broadly assess the challenges to regulatory approval and identify strategies to facilitate this goal, the Cardiac Safety Research Consortium sponsored a session during the Texas Heart Institute International Symposium on Cardiovascular Regenerative Medicine in September 2017. This session convened leaders in cardiovascular regenerative medicine, including participants from academia, the pharmaceutical industry, the US Food and Drug Administration, and the Cardiac Safety Research Consortium, with particular focus on treatments closest to regulatory approval. A goal of the session was to identify barriers to regulatory approval and potential pathways to overcome them. Barriers identified include manufacturing and therapeutic complexity, difficulties identifying an optimal comparator group, limited industry capacity for funding pivotal clinical trials, and challenges to demonstrating efficacy on clinical end points required for regulatory decisions. Strategies to overcome these barriers include precompetitive development of a cell therapy registry network to enable dual-purposing of clinical data as part of pragmatic clinical trial design, development of standardized terminology for product activity and end points to facilitate this registry, use of innovative statistical methods and quality of life or functional end points to supplement outcomes such as death or heart failure hospitalization and reduce sample size, involvement of patients in determining the research agenda, and use of the Food and Drug Administration’s new Regenerative Medicine Advanced Therapy designation to facilitate early discussion with regulatory authorities when planning development pathways.

    Overview of Cell Therapy for Cardiovascular Disease

    Significant regenerative capacity is present in many animals. Although the human ability to regenerate tissue, especially cardiac tissue, is more limited, there are considerable data that some regenerative capacity is present. The major goals of regenerative medicine are to better understand this capacity and translate such knowledge to the treatment of human disease via either exogenous regeneration of tissues (where the administered product is expected to replace damaged native tissue) or stimulation of endogenous repair mechanisms.1 In cardiovascular regenerative medicine, these efforts have largely focused on repairing diseased myocardium in patients post–myocardial infarction (MI) or in chronic heart failure (HF) with reduced ejection fraction (HFrEF) and increasing vascular capacity in patients with advanced coronary and peripheral arterial disease and refractory angina pectoris.2

    Despite some initial successes, cell therapy faces several challenges, and the pathway to regulatory approval is uncertain. The cases of refractory angina and chronic HF each illustrate some of these barriers. In refractory angina, despite a well-established mechanism and consistently favorable clinical results, a relatively limited population discourages initial participation of the pharmaceutical and medical device industries. In chronic HF, cell therapy’s uncertain mechanism of action raises challenges in identifying appropriate surrogate outcomes, and there are numerous effective therapies, including transplantation and mechanical circulatory support, with which newer therapies have to contend. In both cases, cell therapy’s complexity, with multiple clinical indicators and dozens of different cell products that can be delivered to the myocardium in several different ways, represents a barrier to regulatory approval. Furthermore, therapies are expensive to produce and deliver, and the smaller companies and academic groups developing these therapies are not well-equipped to conduct the pivotal trials necessary for regulatory approval. The US Food and Drug Administration (FDA) has recognized these challenges and created the Regenerative Medicine Advanced Therapy (RMAT) designation to facilitate the expedited development and review of regenerative medicine therapies.3,4 Myocardial injection of allogeneic mesenchymal stem cells (MSCs) for use in patients with chronic HF who have a left ventricular (LV) assist device is the first cardiovascular therapy to earn this designation.5

    The Texas Heart Institute International Symposium on Cardiovascular Regenerative Medicine provided a broad view of the current state of cardiovascular regenerative medicine. A segment of the symposium, co-organized and coordinated by the Cardiac Safety Research Consortium, was devoted to discussing barriers to regulatory approval and strategies to advance the field closer to clinical application. The Cardiac Safety Research Consortium is a partnership of academia, industry, and regulatory authorities with a mission of advancing scientific knowledge about medical products by fostering an environment of collaboration. The goal of this session was to define barriers to approval of regenerative cardiovascular therapies, postulate solutions, and begin dialogue among these interested parties to find workable solutions.

    Discussions at the meeting identified several barriers to regulatory approval and action items for overcoming these barriers. This article represents the consensus of selected thought leaders in the field of regenerative medicine, including European and US members of the Transnational Alliance for Cell-based Regeneration Therapies in Cardiovascular Syndromes group, regulatory authorities, and industry sponsors. Herein, we (1) briefly review key clinical trial data from programs closest to regulatory approval, notably treatment of refractory angina and chronic HF; (2) discuss challenges in achieving regulatory approval; and (3) delineate key ways to move the field forward toward regulatory approval.

    Current State of the Field

    Chronic HF

    Chronic HF afflicts ≈6 million people in the United States, with exponential growth in this population in recent years.6 Despite several advances, 5-year mortality remains ≈50%.7 Moreover, existing medical or device-based HF therapies (aside from transplantation) do not directly address the myocardial dysfunction that characterizes chronic HFrEF, and cell therapy represents a potential alternative and complement to traditional HF therapies.

    In the area of myocardial regeneration or preservation, regenerative approaches were first targeted at replacement of the loss of myocardial contractile tissue that characterizes acute infarction or chronic systolic dysfunction. Initial preclinical studies and case reports described the intraoperative myocardial injection of skeletal muscle-derived myoblast cells in patients undergoing coronary artery bypass grafting in the early 2000s.8 In preclinical models, these cells directly led to engraftment and the development of new contractile tissue.9

    The first randomized controlled trials of cell therapy in cardiovascular disease involved intracoronary infusion of autologous unselected bone marrow cells (BMCs) in patients with prior MI and LV systolic dysfunction.1012 Results from individual studies were variable, but meta-analyses of these trials demonstrated modest improvements in LV ejection fraction, albeit with inconsistency between trials. Effects on major adverse cardiovascular events were likewise variable although in general favorable.13

    These promising findings spurred interest from patients and investigators in further development of this approach for chronic HFrEF, but the limited commercial potential of unselected BMCs hampered development of larger clinical trials needed to advance the field to the point that phase III trials were appropriate. In part to address this unmet need for phase I and II studies, the National Institutes of Health created the Cardiovascular Cell Therapy Research Network (CCTRN) to facilitate the cooperation of investigators.14 Building on the FOCUS-HF (First Bone Marrow Mononuclear Cell United States Study in Heart Failure) trial, which evaluated endomyocardial injection of unselected BMCs in patients with ischemic heart disease and chronic HFrEF, the CCTRN performed the phase II FOCUS-CCTRN (First Mononuclear Cells injected in the United States conducted by the CCTRN) trial.1517 FOCUS-CCTRN, conducted at 5 US network sites, randomized 92 patients with New York Heart Association II to IV HF, LV ejection fraction ≤45%, evidence of a perfusion abnormality, and coronary artery disease not amenable to further revascularization, to endomyocardial injection of unselected BMCs or placebo.17 The double-blinded trial completed enrollment in <2 years, demonstrating the potential efficacy of investigator cooperatives in trials of cell therapy, but demonstrated no differences between treatments in the trial’s coprimary outcomes: change in LV end-systolic volume index, maximal oxygen uptake (Vo2), or reversibility of ischemia on single-photon emission computed tomography imaging.17 The group treated with BMCs did have a significant increase in LV ejection fraction, and subsets of patients with greater numbers of CD34+ cells and younger age had greater improvement in LV ejection fraction.17 This finding highlights one of the principal limitations of transplanting autologous unselected BMCs: There is inherent patient-to-patient variability in cell quality, and some patients’ cells may have impaired regenerative capacity, especially patients with HF.1822

    The inconsistent results led to considerable debate within the field, with investigators hypothesizing that unmodified autologous BMCs may have insufficient regenerative capacity in patients with existing heart disease and that intracoronary administration of these cells may not deliver adequate numbers of cells to the target myocardium in patients with abnormal coronary perfusion. In addition, in contrast to myoblasts that survive and lead to formation of contractile tissue, the mechanism whereby other bone marrow or other autologous cells might improve heart function remained unclear, with paracrine cell signaling cited most frequently as a likely mechanism.23,24

    These hypotheses, together with concerns about the commercial viability of autologous BMCs, have subsequently led to the development of alternative cell preparations and methods of delivery. First-generation cell therapies, like those used in the original cell therapy trials in post-MI patients, involve autologous BMCs that are extracted and reintroduced without modification (Table 1). Second-generation cell therapies involve selection and expansion of cell lineages from autologous cells before reintroduction or introduction of selected and expanded allogeneic cells, extracted from young healthy donors. Alternatively, second-generation cell therapies may reprogram cells from autologous or allogeneic sources into stem cells particular to cardiovascular application (eg, cardiopoietic stem cells). These second-generation cells have largely been delivered via direct endomyocardial injection using specialized catheters.

    Table 1. Stem Cell Products Tested in Major HF and Refractory Angina Clinical Trials

    ProductDescriptionExample Trial
    First-generation stem cellsUnselected BMCsFOCUS-CCTRN
    Second-generation stem cellsSelected BMCs
     Autologous CD34+ cellsACT34-CMI
     Allogeneic mesenchymal stem cellsDREAM-HF
    Reprogrammed BMCs
     Autologous BMCs expanded in cardiac conditioning mediumCHART-1

    ACT34-CMI indicates A Double-blind, Prospective, Randomized, Placebo-controlled Study to Determine the Tolerability, Efficacy, Safety, and Dose Range of Intramyocardial Injections of G-CSF Mobilized Auto-CD34+ Cells for Reduction of Angina Episodes in Patients With Refractory Chronic Myocardial Ischemia; BMC, bone marrow cell; CHART, Safety and Efficacy of Autologous Cardiopoietic Cells for Treatment of Ischemic Heart Failure; DREAM-HF, Double-blind, Randomized, Sham-procedure-controlled, Parallel-Group Efficacy and Safety Study of Allogeneic Mesenchymal Precursor Cells in Chronic Heart Failure Due to LV dysfunction; FOCUS-CCTRN, First Mononuclear Cells injected in the United States conducted by the Cardiovascular Cell Therapy Research Network; and HF, heart failure.

    The first approaches to the use of second-generation stem cells in the treatment of HF were stem cells derived from autologous peripheral muscle; however, the largest studies evaluating this approach either showed no effect on the surrogate outcome of ejection fraction or were stopped prematurely for financial reasons or slow enrollment.25,26 Other programs have evaluated adipose-derived stromal vascular fraction and cardiac stem cells isolated from surgical or endomyocardial biopsy.2729 These programs have evolved into subsequent trials, the most significant of which is the CONCERT-HF (Combination of Mesenchymal and C-kit+ Cardiac Stem Cells as Regenerative Therapy for Heart Failure) trial currently being conducted by the CCTRN.30

    Allogeneic MSCs are attractive for patients with chronic HF because they are capable of multilineage differentiation into both myocytes and supporting structures in the heart and release angiogenic and antiapoptotic paracrine factors.31,32 Moreover, as an allogeneic product, they are available off-the-shelf, which enhances their commercial viability and avoids patient-to patient-variability in cell quality. In a phase II, dose-escalation study, endomyocardial injection of stromal precursor antigen-3+ allogeneic MSCs in patients with ischemic or nonischemic cardiomyopathy led to a significant reduction in LV volumes and a reduction in HF-related major adverse cardiovascular events with the highest dose compared with placebo.33 In a 65-patient study of patients with ischemic cardiomyopathy, allogeneic MSCs resulted in greater improvements in infarct size and 6-minute walk distance than unselected autologous bone marrow mononuclear cells.34 Finally, in a small (n=22), placebo-controlled, crossover study, intravenous injection of allogeneic MSCs in patients with nonischemic cardiomyopathy improved 6-minute walk distance and Kansas City Cardiomyopathy Questionnaire clinical summary score, but had no effect on LV geometry.35 These efforts have culminated in the ongoing DREAM-HF (Double-blind, Randomized, Sham-procedure-controlled, Parallel-Group Efficacy and Safety Study of Allogeneic Mesenchymal Precursor Cells in Chronic Heart Failure Due to LV dysfunction), which will randomize 600 patients with New York Heart Association class II or III HFrEF of ischemic or nonischemic pathogenesis to endomyocardial injection of allogeneic MSCs or a sham procedure. The trial’s primary end point is cardiac death and hospitalizations for HF, and when completed, DREAM-HF will be the first phase III cardiac cell therapy trial powered for a clinical outcome (death or HF hospitalization).

    Newer generation approaches, including modified stem cells and truly pluripotent (induced pluripotent, genetically modified, and embryonic stem cell) cellular approaches, are being rapidly developed for this disease. Reprogramming autologous BMCs or MSCs using cardiopoietic medium attempts to address the impairment in stem cell function in patients with advanced HFrEF. A phase III, randomized, double-blind clinical trial comparing endomyocardial injection of reprogrammed autologous MSCs with a sham procedure found no difference in outcomes between the 2 groups on a hierarchical composite clinical end point at 1 year, but there were subgroups of patients that did benefit from cell therapy, as well as signals of reverse remodeling in the stem cell group.36,37 Another processed bone marrow–derived product, ixmyelocel-T, demonstrated significant reduction in total cardiac events in patients with dilated cardiomyopathy in a phase II trial.38 Finally, intracoronary injection of selected CD34+ BMCs improved mortality, as well as a variety of markers of HF, including BNP (brain natriuretic peptide) and remodeling parameters as assessed using imaging.39 Rather remarkably, this was demonstrated in a population of patients with nonischemic cardiomyopathy, suggesting that regenerative approaches may be beneficial in HF secondary to a variety of insults.

    Other approaches, using truly pluripotent stem cells, remain in preclinical stages at this time but are attempting to achieve the initial goal of cell therapy: true cell-based myocardial regeneration. That this goal remains elusive also reflects our current relative lack of understanding of the mechanisms of current therapies, which impacts selection of end points in both early and late phase trials, as well as how best to tailor therapy to this disease.

    Refractory Angina

    Advances in the management of coronary artery disease have prolonged survival but have led to the growth of a population of patients with significant angina burden because of unrevascularizable coronary disease. There are an estimated 600 000 refractory angina patients in the United States, including up to 15% of patients undergoing coronary angiography.4042 These patients are characterized by severe, debilitating angina symptoms, leading to recurrent hospitalizations, impaired quality of life, and lost workforce productivity, but relatively low mortality.4245 Importantly, these patients characteristically have normal or near normal heart function; thus, the goals of therapy are different from regenerative approaches to HF. Experimental therapies have, therefore, focused on reducing angina burden and improving quality of life. Randomized clinical trials conducted in the United States and Europe have demonstrated the ability of stem or progenitor cell therapies, both first- and second-generation, to improve quality of life in this cohort of patients, and 1 European center has developed a cell therapy protocol for use in clinical practice. In contrast to post-MI systolic dysfunction and chronic HFrEF, regenerative approaches to advanced ischemic heart disease build on preclinical data demonstrating improvement in perfusion as a mechanistic underpinning for the use of angiogenic approaches for treatment of refractory angina.46

    In 2007, investigators at Leiden University in the Netherlands published their initial experience with cell therapy in patients with refractory angina.47 In this study, 50 patients with refractory angina and evidence of ischemia on noninvasive imaging underwent bone marrow aspiration and direct endomyocardial injection of either unselected BMCs or saline/albumin solution. Compared with the control group, the group treated with BMCs had significantly greater improvements in myocardial perfusion as assessed by Tc-99m tetrofosmin single-photon emission computed tomography at 3 months’ follow-up, as well as in angina severity and quality of life at 6 months’ follow-up. On the strength of this evidence, as well as a series of follow-up studies demonstrating that (1) long-term mortality is low in cell therapy–treated patients, (2) the benefits persist with some attenuation out to 5 years’ follow-up, and (3) BMC reinjection can improve symptoms in patients whose symptoms have recurred after a first injection,48,49 the Leiden University investigators have developed a European Medicines Agency–approved program to treat patients with refractory angina using endomyocardial injections of unselected BMCs. There is a compelling evidence base supporting the use of unselected BMCs for patients with refractory angina, who have few other treatment options, but the commercial viability of such a strategy is limited, and there is little momentum for moving this strategy forward in the United States.

    In the United States, building on preclinical work showing that CD34+ endothelial progenitor cells are capable of effecting revascularization in multiple models of ischemia, a phase I tolerability/safety study,50 a phase II dose-finding randomized clinical trial,51 and a phase III planned pivotal randomized clinical trial evaluated endomyocardial delivery of autologous bone marrow–derived CD34+ cells in patients with refractory angina.52,53 In these trials, CD34+ cells were mobilized from patients’ bone marrow by granulocyte-colony stimulating factor injection, collected by apheresis, and injected into electromechanically defined areas of myocardial ischemia. The phase II ACT34-CMI (A Double-blind, Prospective, Randomized, Placebo-controlled Study to Determine the Tolerability, Efficacy, Safety, and Dose Range of Intramyocardial Injections of G-CSF Mobilized Auto-CD34+ Cells for Reduction of Angina Episodes in Patients With Refractory Chronic Myocardial Ischemia) clinical trial randomized 167 refractory angina patients to moderate or high doses of mobilized autologous CD34+ cells versus placebo.51 Compared with placebo, patients treated with CD34+ cells reported fewer weekly angina episodes and had a greater improvement in exercise tolerance at 6 and 12 months, with similar efficacy in the moderate- and high-dose arms.

    The results of this phase II trial led to a phase III randomized clinical trial designed to definitively assess the safety and efficacy of this treatment. The RENEW (Efficacy and Safety of Targeted Intramyocardial Delivery of Auto CD34(+) Stem Cells for Improving Exercise Capacity in Subjects With Refractory Angina) trial was designed with regulatory input on necessary safety data. RENEW included 2 control arms: (1) a blinded arm similar to the control arm in ACT34-CMI, in which patients underwent CD34+ cell mobilization and apheresis with placebo endomyocardial injection; and (2) an open-label standard-of-care arm, included to assess the safety of the cell mobilization and injection procedure.52 RENEW was unfortunately terminated for business reasons after enrollment of 112 of a planned 444 patients, making it impossible to reach a valid scientific conclusion.53 Among the factors that may have contributed to early termination of RENEW was a 34-month delay between the completion of ACT34-CMI and the start of RENEW, the inclusion of the standard-of-care control arm, which may have slowed enrollment, and the FDA’s requirement (at the time) for a second, confirmatory trial before regulatory approval even if RENEW had met its primary end point.53

    Two meta-analyses of trials enrolling patients with refractory ischemia, neither of which included RENEW, showed that cell therapy reduced angina frequency by 7.8 episodes/week (95% confidence interval, 0.4–15.3; P=0.04) and increased exercise time by 61 (95% confidence interval, 18–104) seconds (P=0.005) compared with placebo.54,55 These results compare favorably with enhanced extracorporeal counterpulsation, the only therapy approved by the FDA for use in patients with refractory angina, which increased exercise time by 16 seconds in the pivotal clinical trial leading to FDA approval.56 Importantly, cell therapy for refractory angina seems to be safe; in fact, patients treated with cell therapy in the trials had a decreased risk of MI, arrhythmias, and major adverse cardiac events compared with those treated with placebo.54,55 More recently, an analysis of combined patient-level data from the CD34+ cell program, incorporating data from phase I, ACT34-CMI, and RENEW, showed statistically significant improvements in exercise time, angina frequency, and mortality in patients treated with cell therapy compared with placebo.57 Results were consistent in both intention-to-treat and as-treated analyses, as well as in an analysis of patients treated with the dose of cells (1×105 cells/kg) taken forward for evaluation in RENEW. These results suggest that had RENEW been completed, this regenerative medicine approach to the treatment of patients with refractory angina may have met criteria for regulatory approval.

    Challenges to Development of Regenerative Therapies

    Despite their promising findings, clinical trials of cell therapy in refractory angina and chronic HF highlight many of the major challenges in achieving regulatory approval for cell therapy to treat these disease processes (Table 2).

    Table 2. Major Challenges to Regulatory Approval for Cell Therapy and Strategies to Overcome Them

    Highly complex product with countless potential variations involving cell extraction, processing, and reintroductionStandardized definitions of therapeutic classes and product activity
    Active discussion with regulatory authorities on which aspects of therapy are novel and require regulatory approval
    Regulatory consideration of treating all first- and second-generation stem cell products as a class for safety reasons
    Difficulty in defining a proper comparator groupActive discussion with regulatory authorities
    Regulatory consideration of study designs that can adequately demonstrate safety of the study procedures (eg, cell extraction and injection) without necessarily requiring a concurrent standard-of-care control group for a given study
    Regulatory approval sought by small companies or nonindustry collaboratives with limited fundingDual purposing of clinical data for research purposes precompetitive build-out of a registry and site network that can be used as a platform for pragmatic clinical trials
    Active discussion with regulatory authorities on data quality needs for pragmatic clinical trials intended to support regulatory approval
    Use of innovative statistical methods and quality of life or functional end points rather than clinical end points like death or myocardial infarction to reduce sample size
    Regulatory consideration of approving first- or second-generation stem cell therapies with a single well-run clinical trial with aggressive postmarketing monitoring
    Uncertain mechanism of action makes biomarker and surrogate end point determination difficultInvolve patients to determine which outcomes are important to them, especially patients with severe symptomatic disease with limited treatment options, like chronic HF and refractory angina
    Consider focus on patient-reported outcomes, functional outcomes, and quality of life
    Active discussion with regulatory authorities, involving patient representatives, to ensure outcomes is adequate for regulatory approval
    Development of truly regenerative therapiesActive discussion with regulatory authorities to highlight how the differences between these therapies and first- and second-generation stem cell therapies may have implications on the design of individual clinical studies and regulatory considerations for the clinical development program

    HF indicates heart failure.

    In refractory angina, a principal challenge is the relatively small number of patients who qualify for clinical trials, which require strict designs given their end points of exercise duration or angina frequency. The limited number of patients affects the commercial viability of any therapy, which in turn limits the interest of commercial entities in developing new therapies and shepherding them through the regulatory approval process. This challenge is made more acute by the scientific complexity of cell therapy, which leads to difficulty with clinical trial design and commercial development in several ways.

    Cell therapy is a multistep treatment paradigm, potentially involving (1) cell acquisition by tissue or bone marrow harvest, endomyocardial biopsy, or apheresis; (2) cell storage, isolation, culture, and processing; and (3) cell delivery. Depending on the therapy, this multistep paradigm, with attendant technical complexity, increases resource utilization and costs of the therapeutic approach, which has implications in the clinical trial phase and, ultimately, for scalability after regulatory approval. It also creates challenges in defining a comparator group in clinical trials. For example, in RENEW, the sponsor was ultimately required to include a standard-of-care control group to demonstrate the safety of their cell extraction and injection processes and a placebo injection double-blind control group to demonstrate the efficacy of CD34+ cells in improving symptoms of refractory angina.53 The need for multiple control groups increased the cost, complexity, and duration of the study and likely contributed to its early termination. Second, autologous cell products have inherent variability that may affect their regenerative ability, contributing to the inconsistent results in trials using first-generation stem cell products.5860 Second-generation autologous and allogeneic products have overcome some of the concerns related to variability by selecting and expanding certain cell populations and performing extensive phenotyping of cells before injection.61 However, these processes often add complexity and increase the cost of goods. Electromechanical mapping and specialized endomyocardial injection catheters used to deliver modern stem cell therapies are also expensive. The high costs and complexities of delivering these therapies have resulted in trials that enroll slowly,62,63 have long gaps between phases II and III,51,53 are underpowered to detect clinically relevant end points, and that use complex hierarchical end points that reduce sample size but may also reduce interpretability of the primary efficacy outcomes.36 In the most extreme cases, promising cell therapy products may be abandoned entirely. Although ixmyelocel-T reduced all-cause death and cardiovascular admissions by 37% (P=0.03) in patients with HFrEF in the randomized, double-blind, placebo-controlled phase II ixCELL DCM (An Efficacy, Safety and Tolerability Study of Ixmyelocel-T Administered Via Transendocardial Catheter-based Injections to Subjects With Heart Failure Due to Ischemic Dilated Cardiomyopathy) trial,38 published in 2016, a phase III trial has not been initiated.

    These challenges are accentuated by the fact that clinical trials in regenerative medicine have been conducted almost exclusively by smaller companies or nonindustry collaboratives. Because emerging therapies like cell therapy are often explored by universities and small companies, a regulatory paradigm that requires drugs and biological therapies to demonstrate effectiveness in at least 2 adequate and well-controlled studies, each convincing on its own, per FDA regulations, may inhibit development of complex novel therapies.64 FDA guidance does allow for biological products like cell therapy to be considered for approval based on the results of a single adequate and well-conducted trial; this may be a viable option for certain cell therapy products but not for others.

    In chronic HF, a global epidemic, the number of patients with the condition is attractive; however, the presence of multiple treatment options, including improving durable mechanical circulatory support technology, together with an uncertain mechanism of action, represents major barriers. In contrast to other areas of cardiovascular medicine, in which the biology, physiology, and mechanism of action of key therapeutics are well understood, cell therapy’s mechanism of action in patients with HF is understood only in broad terms. Although there is no requirement that a therapy’s mechanism of action is well elucidated before its obtaining regulatory approval, understanding this aspect is important for efficient trial design, particularly when choosing biomarkers and surrogate end points. Allogeneic MSCs, for example, seem to improve quality of life and functional capacity without any effect on ejection fraction,33 and prior trials of autologous cell therapies focusing on ejection fraction may have been focusing on the wrong end point.17

    In addition, regenerative therapies are unique among cardiovascular treatments in that they are aimed at the underlying condition, not symptoms, and are designed to be long lasting. The next generation of regenerative therapies, including scaffolding to facilitate tissue regeneration, induced pluripotent stem cells, and embryonic stem cells, are designed to have truly regenerative/tissue replacement capabilities. Regulatory authorities and institutional review boards have limited experience with therapies designed to regenerate diseased tissue rather than treat or palliate the underlying disease, and it is likely that these products will raise numerous unforeseen questions.

    Legislators and the FDA have recognized the major challenges facing the development of regenerative therapies, and regenerative medicine was highlighted in the 21st Century Cares Act. Under the FDA’s draft guidance describing the new RMAT designation, regenerative medicine therapies intended to treat or cure a serious condition, with preliminary clinical evidence that the therapy has the potential to address unmet needs with that condition, are eligible for FDA assistance in drug development.3 The RMAT designation is particularly notable because a therapy only has to demonstrate preliminary evidence of efficacy, not evidence of a substantial effect beyond that of available therapies.4 This assistance may include intensive guidance from senior FDA leadership, including early interaction to discuss surrogate or intermediate end points, as well as consideration of accelerated approval on the basis of these end points with a commitment to generate postapproval evidence of efficacy and safety.4 Depending on the therapy, postapproval commitments may range from traditional clinical trials to observational real-world evidence from registries. Future pivotal trials of regenerative medicine therapies may, therefore, be able to take advantage of these pathways and earn regulatory approval by showing a benefit on a surrogate measure, such as, for example, physical activity measured by a wearable device, and fulfill postapproval commitments with a pragmatic clinical trial to demonstrate the therapy’s safety. More broadly, FDA leadership has publicly recognized that the dynamic and innovative nature of cell-based regenerative medicine may be ill-served by a traditional approach to regulation and has encouraged dialogue with investigators and companies seeking regulatory approval for these therapies.4

    A Path Forward

    Although the RMAT pathway reduces burdens to regulatory approval, substantial challenges remain. Although the nature of the challenges are different in refractory angina and chronic HF, in both cases, these challenges result in difficulty conducting the large and free-standing phase III clinical trials that traditionally support regulatory approval. In the case of refractory angina, the start-up industry sponsors and academic consortia conducting pivotal trials have limited funding. Although chronic HF has attracted more interest from the pharmaceutical and device industry, the companies participating in cell therapy trials remain relatively small: Mesoblast, which is developing the allogeneic MSCs used in DREAM-HF, has a market capitalization of ≈$650 million and has not successfully brought a product to market in the United States. Vericel, which developed ixmyelocel-T, has a market capitalization of ≈$400 million. By comparison, Novartis, manufacturer of sacubitril-valsartan, a recently FDA-approved chronic HF medication, has a market capitalization of ≈$200 billion. Furthermore, an uncertain mechanism of action for cell therapy in patients with chronic HF and the presence of numerous other viable therapies make clinical trial enrollment challenging. In both cases, the development of creative and innovative approaches to clinical evaluation of these therapies will be critical.

    In the early 2000s, when it became clear that the funding environment was inadequate for conducting completely independent phase II trials of the size and quality necessary to evaluate the efficacy and safety of unselected BMCs in patients with MI and HF, the National Institutes of Health and key investigators formed the CCTRN, which conducted the FOCUS-CCTRN, TIME (Timing In Myocardial infarction Evaluation), and LATE-TIME (Late-Timing in Myocardial infarction Evaluation) clinical trials. Although none showed a clinical benefit, these remain 3 of the largest stem cell clinical trials conducted in the United States.17,65,66 Importantly, each trial was rigorously conducted, completed, presented, and published in an expeditious manner. Similarly, European investigators, leveraging immense interest in cell therapy in Europe, obtained funding for a clinical trial powered to detect a difference in all-cause mortality between patients treated with unselected BMCs or placebo after acute MI (BAMI [Bone Marrow in Acute Myocardial Infarction]).67 Unfortunately, due largely to logistical and enrollment concerns, recruitment into the trial did not reach its 3000-patient goal. Nonetheless, with ≈400 patients randomized, BAMI will still be the largest cell therapy trial in acute MI, and its results will add to our understanding of unselected BMC therapy for this condition.

    In the current environment, novel cooperation will again be critical to surmount the challenge of achieving regulatory approval. Proposed solutions to the major challenges in achieving regulatory approval for cell therapy center on 3 themes: (1) improved cooperation and collaboration between the pharmaceutical industry, academia, regulatory agencies, and patients; (2) forming consensus on key definitions; and (3) innovative clinical trial designs that take advantage of this cooperation and consensus (Figure).


    Figure. The path forward to regulatory approval. The central axis portrays a general outline of a path to regulatory approval for regenerative medicine therapies, with individual factors aligned to approximate steps where they are most likely to play a role. Early engagement with regulatory authorities, using the Regenerative Medicine Advanced Therapy process in the United States, will delineate how nontraditional methodologies can best be used to support regulatory approval for individual therapies. Engagement of patients and the development of consensus definitions will aid in the design of pragmatic clinical trials, which may incorporate novel statistical approaches focused on patient-centered outcomes. Regulatory approval may be aided by safety assessment in pooled data across similar approaches. Consensus definitions would also aid in the development of coordinated registry networks to allow postapproval assessments needed for full approval.

    Precompetitive collaboration between pharmaceutical companies involved in regenerative medicine, academia, and regulatory authorities provides a paradigm that could enable the development of pragmatic clinical trials that are more informative and less expensive than the traditional, fragmented clinical studies approach. Cardiac catheterization laboratories, where cell therapies are usually delivered, are required to record baseline patient and procedure data for clinical documentation purposes. Traditional clinical research requires dual entry of data—once for clinical purposes and a second time for research purposes.68 Pragmatic clinical trial designs, like the TASTE (Thrombus Aspiration in ST-Elevation Myocardial Infarction in Scandinavia) trial in Sweden and the SAFE STEMI for Seniors (Study of Access Site for Enhancing PCI in STEMI for Seniors) study in the United States, leverage cardiac catheterization laboratory clinical documentation for research purposes, reducing research-related site-based workload and costs substantially.69,70 To optimally leverage clinical documentation for research purposes, the development and implementation of standardized key data fields, definitions, and outcome measures are required. A common vocabulary surrounding cell doses, descriptors, and procedural techniques would facilitate the use of clinical documentation as a platform for clinical research. Data from sites using the common vocabulary could naturally be linked, forming a national (or international) multicenter registry. The quality of such a registry (completeness of data, etc) could be monitored to ensure that it would be suitable to provide evidence for regulatory decisions. Participation in this registry would produce a ready-made, experienced group of sites for multicenter clinical trials and could even be used to capture baseline and procedural data from trial participants. In addition, by linking standardized clinical procedure documentation with claims data and electronic health records to form coordinated registry networks, outcomes like death, HF hospitalization, MI, and recurrent revascularization can potentially be ascertained from administrative data, as in the ongoing ADAPTABLE (Aspirin Dosing: A Patient-Centric Trial Assessing Benefits and Long-term Effectiveness) clinical trial.71 Although claims data are imperfect and no study using data of this nature has been used to support a regulatory application in biologics,72 application of quality-by-design principles to clinical research suggests that claims data need not be perfect but only good enough to achieve the goals of the study.73

    Standardization of definitions and adjudication processes would allow for pooling of data across trials. To the extent that there is commonality among regenerative approaches—including (1) assessment of cell potency, purity, and content; (2) similarity in trial design and comparator groups (controls); (3) anticipated mechanism of action; (4) method of delivery; and (5) cell class (allogenic versus autologous, purified/selected versus modified)—it may be possible to pool data from trials assessing similar strategies, supporting accrual of knowledge over multiple studies over time. Meta-analysis of data from trials using standardized processes could then be used for safety assessment if similar regenerative strategies (eg, cellular approaches with common or similar underlying cell types) could be assessed as classes of therapies.

    However, even leveraging pragmatic methods, individual studies powered to detect a difference in cardiovascular outcomes like death, MI, or HF hospitalization may be prohibitively large for this type of therapy. For this reason, it may be useful to consider focusing pivotal cell therapy clinical trials on patient-centered outcomes, a strategy that has proven effective in other areas of cardiovascular medicine. Therapies for pulmonary hypertension have been approved on the basis of improvements in 6-minute walk distance,74 and enhanced external counterpulsation was approved for treatment of angina based on changes in time to ST segment depression on an exercise test.56 The FDA’s requirement that end points be validated in the population of interest does introduce a barrier; however, validation of these outcomes can be done cooperatively and precompetitively. For example, accelerometer data from wearable fitness devices could be used to measure changes in functional status in patients with HF or refractory angina, avoiding the need and expense of return visits for 6-minute walk testing or exercise treadmill testing. Funding the necessary research to validate this end point may not make sense for a company seeking to develop one product, but for a consortium of companies seeking to develop multiple products, funding a portion of the research may be practical, especially if regulatory authorities indicate that such novel end points could be the basis for regulatory approval.

    Many of the patients with refractory angina and chronic HF that would potentially benefit from cell therapy have limited therapeutic options, and many would accept improved quality of life without documentation of increased longevity.75,76 Engagement of these patients in the clinical research process may help investigators, the pharmaceutical industry, and regulatory authorities better incorporate the patient perspective and may build support for use of patient-centered outcomes in regulatory decision making.

    Finally, novel statistical approaches could help reduce sample size and drive down clinical trial costs. Hierarchical composite end points, like the Finkelstein-Schoenfeld composite or the global ranking end point, combine multiple end points into a single test, increasing power to detect a difference between treatments.77,78 For example, in CHART-1 (Safety and Efficacy of Autologous Cardiopoietic Cells for Treatment of Ischemic Heart Failure), the hierarchical composite end point was comprised all-cause mortality, number of worsening HF events, the Minnesota Living with Heart Failure Questionnaire score, 6-minute walk distance, LV end-systolic volume, and change in LV ejection fraction.36 These types of composite end points require careful interpretation and robust statistical handling as a treatment that increases the risk of death (eg) while improving other components may be found superior to one that does improves mortality while minimally impacting other components.77 An alternative approach uses Bayesian methods to integrate the total body of evidence generated by a study79 or group of studies.80 In this latter case, use of a consistent data structure and definitions will enhance the exchangeability of data and facilitate accrual of knowledge across multiple studies.


    First- and second-generation cell therapies have now been used in thousands of patients without evidence of major safety concerns and generally suggest signs of efficacy, especially in refractory angina and chronic HF55,81; however, regulatory approval has not yet been achieved.

    The FDA’s draft guidance describing the RMAT designation helps delineate the path to regulatory approval, but challenges remain. Cell therapies are complex and expensive to manufacture and deliver, have inherent variability, may affect outcomes via complex and only partially understood mechanisms of action, may be aimed at treating the underlying condition rather than symptoms, are designed to be long lasting, and have largely been developed by start-up companies and academic consortia unable to finance the large and free-standing phase III clinical trials that traditionally support regulatory approval. To move the field forward and bring these novel biological therapeutics to the bedsides of patients with cardiovascular disease such as refractory angina and chronic HF, these barriers need to be addressed pragmatically and with attention to the limited resources of start-up industry.

    This Cardiac Safety Research Consortium/Texas Heart Institute symposium is a model for the type of precompetitive collaborative dialogue among industry, academia, and regulatory authorities that may help overcome these barriers. Key themes identified at this meeting which might lead to progress toward approval include standardization of key elements and definitions in regenerative clinical trials, building registry-based networks, dual-purposing clinical data for research applications, incorporation of patient voices and patient-centered outcomes, and engaging further with regulatory authorities to determine whether and how pragmatic design and novel statistical approaches can be used. Given the well-documented safety profile of these therapies, a key outcome from the symposium for future discussion was the development of common definitions and processes for cell-processing methods, potency assessments, controls, and trial end points. Such standardization may allow for regulatory authorities to make safety assessments of similar classes of regenerative therapies based on common elements among cell therapies and trial designs, allowing pooling of data across programs.

    Nonstandard Abbreviations and Acronyms


    bone marrow cell


    Cardiovascular Cell Therapy Research Network


    Food and Drug Administration


    heart failure


    heart failure with reduced ejection fraction


    left ventricular


    myocardial infarction


    mesenchymal stem cell


    Efficacy and Safety of Targeted Intramyocardial Delivery of Auto CD34(+) Stem Cells for Improving Exercise Capacity in Subjects With Refractory Angina


    Regenerative Medicine Advanced Therapy


    Correspondence to Thomas J. Povsic, MD, PhD, Division of Cardiology, Duke University School of Medicine, 2400 Pratt St, Durham, NC 27707. Email


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