Improving the translational hit of experimental treatments in multiple sclerosis
H. M. VesterinenEmily S. SenaCharles ffrench‐ConstantAnna WilliamsSiddharthan ChandranMalcolm Macleod
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Background: In other neurological diseases, the failure to translate pre-clinical findings to effective clinical treatments has been partially attributed to bias introduced by shortcomings in the design of animal experiments. Objectives: Here we evaluate published studies of interventions in animal models of multiple sclerosis for methodological design and quality and to identify candidate interventions with the best evidence of efficacy. Methods: A systematic review of the literature describing experiments testing the effectiveness of interventions in animal models of multiple sclerosis was carried out. Data were extracted for reported study quality and design and for neurobehavioural outcome. Weighted mean difference meta-analysis was used to provide summary estimates of the efficacy for drugs where this was reported in five or more publications. Results: The use of a drug in a pre-clinical multiple sclerosis model was reported in 1152 publications, of which 1117 were experimental autoimmune encephalomyelitis (EAE). For 36 interventions analysed in greater detail, neurobehavioural score was improved by 39.6% (95% CI 34.9—44.2%, p < 0.001). However, few studies reported measures to reduce bias, and those reporting randomization or blinding found significantly smaller effect sizes. Conclusions: EAE has proven to be a valuable model in elucidating pathogenesis as well as identifying candidate therapies for multiple sclerosis. However, there is an inconsistent application of measures to limit bias that could be addressed by adopting methodological best practice in study design. Our analysis provides an estimate of sample size required for different levels of power in future studies and suggests a number of interventions for which there are substantial animal data supporting efficacy.Keywords:
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TCM clinical research covers different design types on basis of objective of the study. For exploratory research of TCM, cross-sectional study and descriptive research (e.g. case report and case analysis) is suitable. For hypothesis-testing research, RCT design is commonly adopted. RCT is most commonly used in activity or prevention therapy research, when using randomized cross-over design, the influence of sequence effects should be considered, and double-blind method is the best choice. Cohort study includes various intervention measures, as it doesn’t involve randomized allocation and blinding. Case-control study is widely applicable, but it may bring about bias. Cross-sectional study is much used in syndrome investigation of TCM clinical research. Descriptive research is available for summarization of TCM clinical experience and TCM exploratory research. Third party-central randomization system is recommended, as the randomization is not easy to be damaged. Randomization concealment should also be attached importance to. When blinding is impossible, blindness testing could reduce measurement bias, positive control should be supported high-level evidence. Placebo application could improve the level of evidence-based medicine.
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Background: In other neurological diseases, the failure to translate pre-clinical findings to effective clinical treatments has been partially attributed to bias introduced by shortcomings in the design of animal experiments. Objectives: Here we evaluate published studies of interventions in animal models of multiple sclerosis for methodological design and quality and to identify candidate interventions with the best evidence of efficacy. Methods: A systematic review of the literature describing experiments testing the effectiveness of interventions in animal models of multiple sclerosis was carried out. Data were extracted for reported study quality and design and for neurobehavioural outcome. Weighted mean difference meta-analysis was used to provide summary estimates of the efficacy for drugs where this was reported in five or more publications. Results: The use of a drug in a pre-clinical multiple sclerosis model was reported in 1152 publications, of which 1117 were experimental autoimmune encephalomyelitis (EAE). For 36 interventions analysed in greater detail, neurobehavioural score was improved by 39.6% (95% CI 34.9—44.2%, p < 0.001). However, few studies reported measures to reduce bias, and those reporting randomization or blinding found significantly smaller effect sizes. Conclusions: EAE has proven to be a valuable model in elucidating pathogenesis as well as identifying candidate therapies for multiple sclerosis. However, there is an inconsistent application of measures to limit bias that could be addressed by adopting methodological best practice in study design. Our analysis provides an estimate of sample size required for different levels of power in future studies and suggests a number of interventions for which there are substantial animal data supporting efficacy.
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At least part of the failure in the transition from experimental to clinical studies in stroke has been attributed to the imprecision introduced by problems in the design of experimental stroke studies. Using a metaepidemiologic approach, we addressed the effect of randomization, blinding, and use of comorbid animals on the estimate of how effectively therapeutic interventions reduce infarct size.Electronic and manual searches were performed to identify meta-analyses that described interventions in experimental stroke. For each meta-analysis thus identified, a reanalysis was conducted to estimate the impact of various quality items on the estimate of efficacy, and these estimates were combined in a meta-meta-analysis to obtain a summary measure of the impact of the various design characteristics.Thirteen meta-analyses that described outcomes in 15,635 animals were included. Studies that included unblinded induction of ischemia reported effect sizes 13.1% (95% CI, 26.4% to 0.2%) greater than studies that included blinding, and studies that included healthy animals instead of animals with comorbidities overstated the effect size by 11.5% (95% CI, 21.2% to 1.8%). No significant effect was found for randomization, blinded outcome assessment, or high aggregate CAMARADES quality score.We provide empirical evidence of bias in the design of studies, with studies that included unblinded induction of ischemia or healthy animals overestimating the effectiveness of the intervention. This bias could account for the failure in the transition from bench to bedside of stroke therapies.
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A paradigm shift has occurred in conducting the clinical trials.[1] Minimum accepted protocol for conducting the in vivo and clinical trials has been proposed, published by standard organizations. It is essential that these research protocols are followed in conducting and reporting the trials for wider acceptance. The clinical research starts with the research question alike any other study design and preferably it must be stated as a need for future research in recent systematic reviews. The title of the manuscript should identify it as clinical trial with a structured abstract. The study design should have an explanation on the rationale with more specific orientation toward the problem and the objective of the study. The participants must be recruited with a distinct inclusion and exclusion criteria. The merits and limitations of the study should be explained to patients before recruiting them and appropriate consent (ICMR guidelines) should be obtained. The trial design should have a clear description on the type of design, allocation ratio, and the alternations in the protocol with justifications. The studies should report with the identifiable clinical trial registration number, method, type, mechanism of randomization sequence source of funding, protocol assessment, and a detailed protocol is mandatory for reporting clinical trials. Majority of the studies lack the randomization, blinding, and standard analytical procedures. Not all randomization methods can be adapted for prosthodontic research. It is mandatory that suitable and applicable method is followed among the randomization. The blinding improves research impact. Conventionally, single or double blinding is followed. The maximum blinding of research protocol should be followed to avoid the bias in research. Utmost care is taken in avoiding the bias in the research design. The amount of care followed in avoiding the bias and blinding can provide better appreciable research design. The details of participant enrollment, individual performing the intervention, and evaluator should be provided. The interventions done on patients should allow replication and should have all the details of method of data collection. The information on settings and location of environment can provide more external validity. The most updated, acceptable, and standardized protocol can provide better validity for the research. Outdated methodology and impactless protocol should be avoided to reduce the research waste. The trials alike any study design should start with definitive primary and secondary outcomes. The outcome becomes evidence for future systematic reviews and the research develops into a considerable evidence for a problem. If there are deviations made from the initial protocol, the details of it should be clearly defined with justifications on the changes made. The clinical trial or in vivo studies are becoming the order of the day. They provide better research impact benefiting the patients, health-care providers, researchers, journals, and to the organizations. In comparison to earlier decades, more clinical research is being done in the past few years.[2] More likely, the significant research protocol makes it essential to follow the guidelines. Many standard guidelines are proposed to obtain a globally acceptable research. Consort guidelines were proposed to obtain the same. Any manuscript or research design has to follow these guidelines to be more acceptable for publication. The Consort provides a checklist of items that helps us to cross-check the factors that can help us to understand, improve in conducting the clinical trial or in vivo studies, and also aid in better appreciation.[3]
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Background: The purpose of this investigation was to examine the methodology of clinical trials used by the U.S. Food and Drug Administration (FDA) to determine the safety and effectiveness of high-risk orthopaedic devices approved between 2001 and 2015. Methods: Utilizing the FDA’s online public database, this systematic review audited study design and methodological variables intended to minimize bias and confounding. An additional analysis of blinding as well as the Checklist to Evaluate a Report of a Nonpharmacological Trial (CLEAR NPT) was applied to the randomized controlled trials (RCTs). Results: Of the 49 studies, 46 (94%) were prospective and 37 (76%) were randomized. Forty-seven (96%) of the studies were controlled in some form. Of 35 studies that reported it, blinding was utilized in 21 (60%), of which 8 (38%) were reported as single-blinded and 13 (62%) were reported as double-blinded. Of the 37 RCTs, outcome assessors were clearly blinded in 6 (16%), whereas 15 (41%) were deemed impossible to blind as implants could be readily discerned on imaging. When the CLEAR NPT was applied to the 37 RCTs, >70% of studies were deemed “unclear” in describing generation of allocation sequences, treatment allocation concealment, and adequate blinding of participants and outcome assessors. Conclusions: This study manifests the highly variable reporting and strength of clinical research methodology accepted by the FDA to approve high-risk orthopaedic devices.
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The purpose of this study was to examine possible trends in the research designs used in Ugeskrift for Laeger during 25 years. The scientific articles in 12 issues of the journal selected at random from each of the years 1959, 1964, 1969, 1974, 1979, and 1984 were reviewed. From each article, the following information was obtained: type of article (original paper, case report, or review), origin of the paper and number of authors. For the original papers, it was noted whether it was a longitudinal or a cross-sectional study, and whether it was a cohort or a trohoc study. Furthermore the number of subjects and the use of control group, randomization and blinding were registered. The number of articles and the number of authors per article increased during the period. Contrary to similar studies of some widely circulated English-language journals, we could not demonstrate any increase of the frequency of studies with weak research design. On the other hand, no striking improvement was observed either. Most studies had no control group and randomization and blinding were used in less than 10% of the original papers. The present study does not permit an evaluation of whether the research designs used i Ugeskrift for Laeger are satisfactory.
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Methodological sources of bias and suboptimal reporting contribute to irreproducibility in preclinical science and may negatively affect research translation. Randomization, blinding, sample size estimation, and considering sex as a biological variable are deemed crucial study design elements to maximize the quality and predictive value of preclinical experiments.To examine the prevalence and temporal patterns of recommended study design element implementation in preclinical cardiovascular research.All articles published over a 10-year period in 5 leading cardiovascular journals were reviewed. Reports of in vivo experiments in nonhuman mammals describing pathophysiology, genetics, or therapeutic interventions relevant to specific cardiovascular disorders were identified. Data on study design and animal model use were collected. Citations at 60 months were additionally examined as a surrogate measure of research impact in a prespecified subset of studies, stratified by individual and cumulative study design elements. Of 28 636 articles screened, 3396 met inclusion criteria. Randomization was reported in 21.8%, blinding in 32.7%, and sample size estimation in 2.3%. Temporal and disease-specific analyses show that the implementation of these study design elements has overall not appreciably increased over the past decade, except in preclinical stroke research, which has uniquely demonstrated significant improvements in methodological rigor. In a subset of 1681 preclinical studies, randomization, blinding, sample size estimation, and inclusion of both sexes were not associated with increased citations at 60 months.Methodological shortcomings are prevalent in preclinical cardiovascular research, have not substantially improved over the past 10 years, and may be overlooked when basing subsequent studies. Resultant risks of bias and threats to study validity have the potential to hinder progress in cardiovascular medicine as preclinical research often precedes and informs clinical trials. Stroke research quality has uniquely improved in recent years, warranting a closer examination for interventions to model in other cardiovascular fields.
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Limited translational success in critical care medicine is thought to be in part due to inadequate methodology, study design, and reporting in preclinical studies. The purpose of this study was to compare reporting of core features of experimental rigor: blinding, randomization, and power calculations in critical care medicine animal experimental research. We hypothesized that these study design characteristics were more frequently reported in 2015 versus 2005. We performed an observational bibliometric study to grade manuscripts on blinding, randomization, and power calculations. Chi-square tests and logistic regression were used for analysis. Inter-rater agreement was assessed using kappa and Gwet's AC1. A total of 825 articles from seven journals were included. In 2005, power estimations were reported in 2%, randomization in 35%, and blinding in 20% (n = 482). In 2015, these metrics were included in 9, 47, and 36% of articles (n = 343). The increase in proportion for the metrics tested was statistically significant (p < 0.001, p = 0.002, and p < 0.001). Only a minority of published manuscripts in critical care medicine journals reported on recommended study design steps to increase rigor. Routine justification for the presence or absence of blinding, randomization, and power calculations should be considered to better enable readers to assess potential sources of bias.
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