key: cord-0922715-g8m0h55l authors: Thébaud, Bernard; Lalu, Manoj; Renesme, Laurent; van Katwyk, Sasha; Presseau, Justin; Thavorn, Kednapa; Cobey, Kelly D.; Hutton, Brian; Moher, David; Soll, Roger F.; Fergusson, Dean title: Benefits and obstacles to cell therapy in neonates: The INCuBAToR (Innovative Neonatal Cellular Therapy for Bronchopulmonary Dysplasia: Accelerating Translation of Research) date: 2021-02-11 journal: Stem Cells Transl Med DOI: 10.1002/sctm.20-0508 sha: b24d71b9f3aec85702dc2f6c307e131de2640c4b doc_id: 922715 cord_uid: g8m0h55l Cell‐based therapies hold promise to substantially curb complications from extreme preterm birth, the main cause of death in children below the age of 5 years. Exciting preclinical studies in experimental neonatal lung injury have provided the impetus for the initiation of early phase clinical trials in extreme preterm infants at risk of developing bronchopulmonary dysplasia. Clinical translation of promising therapies, however, is slow and often fails. In the adult population, results of clinical trials so far have not matched the enticing preclinical data. The neonatal field has experienced many hard‐earned lessons with the implementation of oxygen therapy or postnatal steroids. Here we briefly summarize the preclinical data that have permitted the initiation of early phase clinical trials of cell‐based therapies in extreme preterm infants and describe the INCuBAToR concept (Innovative Neonatal Cellular Therapy for Bronchopulmonary Dysplasia: Accelerating Translation of Research), an evidence‐based approach to mitigate the risk of translating advanced therapies into this vulnerable patient population. The INCuBAToR addresses several of the shortcomings at the preclinical and the clinical stage that usually contribute to the failure of clinical translation through (a) systematic reviews of preclinical and clinical studies, (b) integrated knowledge transfer through engaging important stakeholders early on, (c) early economic evaluation to determine if a novel therapy is viable, and (d) retrospective and prospective studies to define and test ideal eligibility criteria to optimize clinical trial design. The INCuBAToR concept can be applied to any novel therapy in order to enhance the likelihood of success of clinical translation in a timely, transparent, rigorous, and evidence‐based fashion. BPD is a multifactorial disease in which inflammation, oxidative stress, and mechanical stretch disrupt the normal sequence of lung growth. 2 As a consequence, the prevention of lung injury has become increasingly more challenging with no progress over the past decade. 4 Preclinical proof-of-concept 5 Systematic reviews and meta-analyses (SRMAs) provide the most robust and evidence-based overview of the evidence on a topic and can point out knowledge gaps and thus guide future studies. Yet, their application to first-in-human trials has been limited and preclinical SRMAs for neonatal interventions were until recently nonexistent. We undertook two systematic reviews (SRs) to justify and inform our clinical trial: (a) a preclinical SR of studies testing MSCs in experimental models of neonatal lung injury and (b) a clinical SR to examine evidence for MSCs in BPD. 30 We used the standard search strategy of the Cochrane Neonatal review group (https://neonatal.cochrane.org/resources-review-authors). We also searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles for randomized controlled trials and quasirandomized trials. As of 2017, there was one published phase I trial using highly expanded MSCs from cord blood (Pneumostem; MEDIPOST Co., Ltd., Seongnam, South-Korea) from a commercial entity. 9 This first trial was a phase I dose-escalation trial in preterm When compared with historical controls, BPD severity was lower in MSC recipients, and rates of other adverse outcomes did not differ between the comparison group and MSC recipients. Since publication of this clinical SR, the 2-year follow-up study of these nine preterm infants reported no adverse effects on growth, respiratory, and neurodevelopmental outcomes. 31 A second phase I dose-escalation trial using the same cord blood-derived MSC product (Pneumostem) and a similar trial design was published in 2019, confirming feasibility and absence of serious adverse events in 12 preterm infants. 11 These studies indicate feasibility and absence of short-term toxicity in a small number of patients. As of 18 November 2020, there were 18 registered trials in ClinicalTrials.gov under the terms "bronchopulmonary dysplasia" and "mesenchymal stem cells" at various stages of development with one completed phase II trial (NCT01828957). F I G U R E 1 The INCuBAToR (Innovative Neonatal Cellular Therapy for BPD: Accelerating Translation of Research) for the successful clinical translation of cell-based therapies in neonates. The classical pathway to clinical translation includes the preclinical stage of discovery, exploratory, and confirmatory studies that provide the biological plausibility for the use of a novel therapy for a given disease and the rationale for initiating clinical trials. Numerous clinical trials fail because of shortcomings in the preclinical stages and/or lack of integration of critical information into clinical trial design. The INCuBAToR is designed to mitigate the risk of translating cell therapies into the clinic by providing an evidence-based approach through the following. A, Preclinical and clinical systematic reviews and meta-analyses to evaluate, synthesize, and quantitatively assess the best available evidence and identify knowledge gaps. B, Integrated knowledge translation to engage pertinent stakeholders, including patients, parents, physicians, nurses, and regulatory agencies, to identify opportunities and barriers in clinical trial implementation. C, Early economic evaluation to establish a "headroom analysis" for early determination of the potential value of the cell therapy. D, Retrospective cohort studies to estimate sample size, adverse events, and understanding of current patterns of care; this information can then be further refined by prospective observational cohort studies to provide "real world, real time" evidence to ensure feasibility and ultimately success of the clinical translation Failure to enroll patients is a major concern to trial feasibility. 18 Understanding underlying beliefs, concerns, and perspectives are crucial to directly improve processes surrounding consent, refine eligibility criteria and trial outcomes to optimize the experience of deciding to enroll their child in a trial (parents) and optimize recruitment, retention, and trial delivery practices (clinicians). 35 In a novel application of the theoretical domain framework 36 and first systematic evaluation of stakeholder beliefs prior to embarking on any cellular therapy study, semistructured interviews were used with directed content analysis to identify barriers and enablers that may influence parents' and neonatologists' participation in clinical trials of MSC for BPD. 37 One-on-one interviews with parents of extremely preterm infants (n = 18) and neonatologists (n = 16) revealed key barriers for parents, including lack of knowledge about clinical trials and stem cells, concerns about their risks and side effects, and preferences for who should help them make the decision. Physicians reported competing priorities, time commitment, costs, and lack of institutional support as significant barriers to their ability to recruit patients. Using this methodological approach-which is typically used to inform later phase trials-helped to identify barriers that were unanticipated and may not have otherwise been flagged. The approach allowed us to systematically identify how to better support parents and clinicians by con- Early engagement of parents and clinicians directly informs trial design, improves informed consent documents and process, and identifies feasibility issues associated with clinical adoption of MSC therapy. Early economic evaluation is now recognized as a tool to support product investment decision making. 39 Such evaluation is novel in neonatology, yet crucial to ensure that MSC therapy for BPD will be economically viable. Given the lack of available data in the literature and the difficulty of obtaining reliable information from routinely collected databases, we developed a new, flexible tool to reliably forecast short-and long-term costs and health outcomes of BPD. The tool used an individual sample Markov model with seven health states in preterm infants born at 23-28 weeks. According to this tool, we have shown that BPD patients will incur over CAD$700 000 in lifetime health systems costs associated with BPD and resulting complications. 40 This new model will now enable the "headroom" and the "value of information (VOI)" analyses. The headroom analysis presents the "cost-effectiveness gap" or maximum cost for which the MSC therapy can be brought to market and still be considered cost effective from the perspective of health care payers. 41 The VOI analysis identifies parameters that have large impact on the cost-effectiveness profile of MSC therapy for BPD and estimates optimal sample size and follow-up period in future randomized controlled trials. The VOI analysis will also identify research areas that will have the highest impact on reimbursement decisions. 42 we will use an early economic evaluation to estimate the potential price of MSCs at which the therapy is still considered cost effective for BPD. This estimated price will be based on early evidence on the potential impact of MSCs on health outcomes of infants with BPD. Defining and "testing" optimal eligibility criteria are of particular importance in first-in-human trials as they enhance safety by excluding patients with an unacceptably high risk of treatment-related toxicity (relative to benefit) and/or insufficient expectation of efficacy. Too restrictive eligibility criteria can significantly reduce trial feasibility, as they limit patient accrual, and results may not be generalizable. Trials can also experience significant delays related to recruitment. As many as 86% of clinical trials do not reach recruitment targets within their specified time periods. 43 This is of particular concern in cell therapy trials, as failure to enroll patients within anticipated periods has been a major threat to trial feasibility. 44 Such an approach, paired with the abovementioned early economic evaluation, may have averted the shelving of a promising ventilation strategy for preterm infants. 45 To provide estimates of the number of eligible patients expected during the study period, as well as the expected event rates for these patients, retrospective cohort studies are useful and increasingly facilitated by national or international repositories (eg, Canadian Neonatal Network, Vermont Oxford Network, German Neonatal Network, etc.) that gather data on antenatal characteristics, risk stratification, resource utilization, and outcomes from neonatal intensive care unit patients. Using eligibility criteria and outcomes refined and justified by the retrospective cohort study, a prospective observational cohort study provides "real world, real time" evidence to further refine proposed criteria to ensure feasibility while balancing concerns of safety. This is a novel approach to highly refine and evidence-inform a trial protocol prior to conducting a high-stakes, resource-intensive, interventional study. Given the acuity and expected high incidence of adverse events in extreme premature infants, data from a prospective cohort of patients are needed for appropriate comparative assessment of safety in phase I/II trials. This is of particular use for investigators, data safety monitor- interventional study. This observational cohort strategy is timely as the current pandemic seems to indicate a reduction in extreme preterm birth 46 and may lead to revaluated timelines. In summary, the INCuBAToR provides a rational, evidence-based approach to ensure safe and successful translation of MSC therapy in a vulnerable patient population. As with any disruptive innovation, the INCuBAToR will go through several iterations to improve over time. Indeed, although it enabled the rapid launch of a phase I trial, it also uncovered-but did not address-some major obstacles to progress of MSC therapy. The SRMAs revealed important disparities in MSC characterization, indication, and administration strategies. [32] [33] [34] This has also been the experience of the Food and Drug Administration, which reported important differences in cell characterization, product bioactivity assessment, and tissue sourcing and product manufacturing in initial filings of 66 investigational new drug submissions for MSC-based therapies. 47 These inconsistencies and the stark contrast between promising results in the lab vs mitigated success in the clinic have led to major criticism regarding MSC therapy. 48 Current shortcomings, including an incomplete definition 49 and the lack of (a) potency assays to predict in vivo response, (b) standardized methods for manufacturing and use at bedside, 50 found only one published reporting guideline for studies evaluating biologics in orthopedics (platelet-rich plasma and MSCs). 57 We propose a method to establish a consensus definition of MSC and to establish relevant reporting guidelines. Our approach will directly address the pitfalls and criticisms of previous attempts to generate consensus in the MSC field by using the Delphi method, a highly studied and well-established social science approach to reach group consensus on highly contentious issues (eg, biomedical editors core competencies, defining predatory journals). 58, 59 The Delphi method allows for broader input beyond a small panel of experts, encourages independent reflection, and limits negative aspects of group decision making such as peer pressure, limited time to express point of view and reach agreement, lack of formal feedback, and nonstructured interactions and aggregation of opinion. Importantly, we will take an integrated knowledge translation approach where diverse stakeholders are part of the program from its inception, 60 which will help ensure that the definition and related reporting guidelines created are relevant to the community and ultimately are effectively adopted to improve quality, transparency, and reproducibility in basic and translational MSC research. Nuances in the manufacturing processes can significantly influence bioactivity and functional outcomes of the MSC preparations. The challenge here may lie in the fact that specific manufacturing processes may be proprietary and thus not disclosed particularly by commercial entities. This caveat will need to be addressed as the field matures further. 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