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Stem cell trials for cardiovascular medicine: ethical rationale.

ABSTRACT: Stem cell-based interventions provide new treatment prospects for many disease conditions, including cardiovascular disorders. Clinical trials are necessary to collect adequate evidence on (long-term) safety and efficacy of novel interventions such as stem cells, but the design and launch of clinical trials, from first-in-human studies to larger randomized controlled trials (RCTs), is scientifically and ethically challenging. Stem cells are different from traditional pharmaceuticals, surgical procedures, and medical devices in the following ways: the novelty and complexity of stem cells, the invasiveness of the procedures, and the novel aim of regeneration. These specifics, combined with the characteristics of the study population, will have an impact on the design and ethics of RCTs. The recently closed JUVENTAS trial will serve as an example to identify the (interwoven) scientific and ethical challenges in the design and launch of stem cell RCTs. The JUVENTAS trial has investigated the efficacy of autologous bone marrow cells in end-stage vascular patients, in a double-blind sham-controlled design. We first describe the choices, considerations, and experiences of the JUVENTAS team. Subsequently, we identify the main ethical and scientific challenges and discuss what is important to consider in the design of future stem cell RCTs: assessment of risks and benefits, the choice for outcome measures, the choice for the comparator, the appropriate selection of participants, and adequate informed consent. Additionally, the stem cell field is highly in the spotlight due to the (commercial) interests and expectations. This warrants a cautious pace of translation and scrupulous set up of clinical trials, as failures could put the field in a negative light. At the same time, knowledge from clinical trials is necessary for the field to progress. We conclude that in the scientifically and ethically challenging field of stem cell RCTs, researchers and clinicians have to maneuver between the Skylla of hyper accelerated translation without rigorously conducted RCTs and the Charybdis of the missed opportunity of valuable knowledge.

SUBMITTER: Niemansburg SL

PROVIDER: S-EPMC4195508 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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Stem cell trials for cardiovascular medicine: ethical rationale.

Niemansburg Sophie L SL Teraa Martin M Hesam Husna H van Delden Johannes J M JJ Verhaar Marianne C MC Bredenoord Annelien L AL

Tissue engineering. Part A 20131211 19-20

Stem cell-based interventions provide new treatment prospects for many disease conditions, including cardiovascular disorders. Clinical trials are necessary to collect adequate evidence on (long-term) safety and efficacy of novel interventions such as stem cells, but the design and launch of clinical trials, from first-in-human studies to larger randomized controlled trials (RCTs), is scientifically and ethically challenging. Stem cells are different from traditional pharmaceuticals, surgical pr ...[more]

PMID: 24164351

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Project description:BackgroundNoninferiority trials are increasingly common in cardiovascular medicine, but their reporting and interpretation are challenging, particularly when an absolute risk difference is used as noninferiority margin.ObjectivesThis study aimed to investigate the effect of using absolute rather than relative noninferiority margins in cardiovascular trials.MethodsWe reviewed noninferiority trials presented at major cardiovascular conferences from 2015 to 2022 and published within the same period. Based on the actual versus anticipated event rates in the control group, we recalculated the absolute noninferiority margin and re-assessed the trial results. The primary outcome of interest was the proportion of trials with a different interpretation after recalculation. Additionally, we analyzed the conclusion statements of these trials to determine if cautionary notes for the interpretation of study results were included.ResultsWe analyzed a total of 768 trials, of which 88 had a noninferiority design and 66 used an absolute noninferiority margin. Of 48 comparisons from 45 trials qualifying for the analysis, 11 (22.9%) had divergent results after recalculation of the absolute noninferiority margin based on the observed rather than anticipated event rate. Ten trials originally claiming noninferiority, did not meet it after the margin recalculation. All of them did not include statements suggesting cautionary interpretation of the study results in the conclusion section. Compared with the other trials, these displayed a larger median difference between anticipated and recalculated noninferiority margins (44.7% [IQR: 38.6%-56.7%] vs 15.3% [IQR: -1.5% to 28.9%]; P < 0.001).ConclusionsRecalculating noninferiority margins based on actual event rates, rather than anticipated ones, led to different outcomes in approximately 1 out of 4 cardiovascular trials, with most divergent trials lacking cautionary interpretation. These findings emphasize the importance of using or supplementing the relative noninferiority margin, particularly in studies with significant deviations between observed and expected event rates. This underscores the critical need for enhanced methodological and reporting standards in noninferiority trials, especially those employing absolute margins.

Project description:UnlabelledWe aim to provide an innovative, comprehensive way of mapping the profusion of stem cell-based clinical trials registered at ClinicalTrials.gov to explore the diversity of the fields of application and the temporal complexity of the domain. We used a chord diagram and phylogenetic-like tree visualizations to assist in data mining and knowledge discovery. The search strategy used the following terms: "stromal OR stem OR mesenchymal OR progenitor." The Medical Subject Headings (MeSH) thesaurus was used to more finely classify diseases treated by stem cells, from large fields of application to specific diseases. Of the 5,788 trials screened, 939 were included, 51.1% of which were related to mesenchymal stem cells (MSCs). No real specificity emerged as to the therapeutic uses of the different types of stem cells. More than half the MSC studies concerned allogeneic MSCs and received more support from industry than autologous MSC studies (p < .001). Over time, the uses of cultured cells have increased greatly, particularly since 2009. Cells derived from adipose tissue are also increasingly used in trials compared with bone marrow cells. The use of adipose-derived stromal cells was predominantly autologous (p < .001), restricted to European countries (p < .01), and supported by industry (p = .02) compared with other MSCs. Details about MeSH keywords are available at http://multireview.perso.sfr.fr/. In conclusion, mapping may reveal a lack of global strategy despite the regulations and the related costs associated with good manufacturing practices. A systematic approach to preclinical data, intended to objectively and robustly reveal the most appropriate fields with the most efficient cells, is needed. Repeated exchanges between the bench and the bedside are necessary.SignificanceExcept for a few trials concerning specific tissue stem cells used in their corresponding tissues, this global analysis revealed no real specificity of stem cell uses (including mesenchymal stromal cells). This raised the question of the physiopathological rationale for these uses and the lack of a global strategy despite the regulations and the related costs associated with good manufacturing practices. This original method, leading to the development of new concepts from already available data, would help policymakers to optimize resources and investments in terms of public health priorities. Such an approach should draw parallels between in vitro, in vivo, and human data. Exchanges in both directions between preclinical and clinical research could optimize the parameters of clinical trials step by step.

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Stem cell trials for cardiovascular medicine: ethical rationale.

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Stem cell trials for cardiovascular medicine: ethical rationale.

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