Clinical research methodology I: introduction to randomized trials.
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ABSTRACT:
SUBMITTER: Kao LS
PROVIDER: S-EPMC2366892 | biostudies-literature | 2008 Feb
REPOSITORIES: biostudies-literature
Publications
Clinical research methodology I: introduction to randomized trials.
Kao Lillian S LS Tyson Jon E JE Blakely Martin L ML Lally Kevin P KP
Journal of the American College of Surgeons 20080201 2
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Project description:A randomized clinical trial is widely regarded as the most rigorous study design to determine the efficacy of intervention because spurious causality and bias associated with other experimental designs can be avoided. The purpose of this article is to provide clinicians and clinical researchers the types of randomized clinical trials used in stroke studies and to discuss the advantages and the limitations for each type of randomized stroke clinical trials.
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Project description:Randomized clinical trials are considered the milestones of clinical research in oncology, and guided the development and approval of new compounds so far. In the last few years, however, molecular and genomic profiling led to a change of paradigm in therapeutic algorithms of many cancer types, with the spread of different biomarker-driven therapies (or targeted therapies). This scenario of "personalized medicine" revolutionized therapeutic strategies and the methodology of the supporting clinical research. New clinical trial designs are emerging to answer to the unmet clinical needs related to the development of these targeted therapies, overcoming the "classical" structure of randomized studies. Innovative trial designs able to evaluate more than one treatment in the same group of patients or many groups of patients with the same treatment (or both) are emerging as a possible future standard in clinical trial methodology. These are identified as "master protocols", and include umbrella, basket and platform trials. In this review, we described the main characteristics of these new trial designs, focusing on the opportunities and limitations of their use in the era of personalized medicine.
| S-EPMC8618758 | biostudies-literature
Project description:ImportanceThe results of numerous large randomized clinical trials (RCTs) have changed clinical practice in gastric cancer (GC). However, research waste (ie, unpublished data, inadequate reporting, or avoidable design limitations) is still a major challenge for evidence-based medicine.ObjectivesTo determine the characteristics of GC RCTs in the past 20 years and the presence of research waste and to explore potential targets for improvement.Design, setting, and participantsIn this cross-sectional study of GC RCTs, ClinicalTrials.gov was searched for phase 3 or 4 RCTs registered from January 2000 to December 2019 using the keyword gastric cancer. Independent investigators undertook assessments and resolved discrepancies via consensus. Data were analyzed from August through December 2020.Main outcomes and measuresThe primary outcomes were descriptions of the characteristics of GC RCTs and the proportion of studies with signs of research waste. Research waste was defined as unpublished data, inadequate reporting, or avoidable design limitations. Publication status was determined by searching PubMed and Scopus databases. The adequacy of reporting was evaluated using the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline checklist. Avoidable design limitations were determined based on existing bias or lack of cited systematic literature reviews. In the analyses of research waste, 125 RCTs that ended after June 2016 without publication were excluded.ResultsA total of 262 GC RCTs were included. The number of RCTs increased from 25 trials in 2000 to 2004 to 97 trials in 2015 to 2019, with a greater increase among RCTs of targeted therapy or immunotherapy, which increased from 0 trials in 2000 to 2004 to 36 trials in 2015 to 2019. The proportion of RCTs that were multicenter was higher in non-Asian regions than in Asian regions (50 of 71 RCTs [70.4%] vs 96 of 191 RCTs [50.3%]; P = .004). The analysis of research waste included 137 RCTs, of which 81 (59.1%) were published. Among published RCTs, 65 (80.2%) were judged to be adequately reported and 63 (77.8%) had avoidable design defects. Additionally, 119 RCTs (86.9%) had 1 or more features of research waste. Study settings that included blinding (odds ratio [OR], 0.56; 95% CI, 0.33-0.93; P = .03), a greater number of participants (ie, ≥200 participants; OR, 0.07; 95% CI, 0.01-0.51; P = .01), and external funding support (OR, 0.22; 95% CI, 0.08-0.60; P = .004) were associated with lower odds of research waste. Additionally, 35 RCTs (49.3%) were referenced in guidelines, and 18 RCTs (22.2%) had their prospective data reused.Conclusions and relevanceTo our knowledge, this study is the first to describe the characteristics of GC RCTs in the past 20 years, and it found a research waste burden, which may provide evidence for the development of rational RCTs and reduction of waste in the future.
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Project description:BackgroundThere have been many changes in clinical trials methodology since the introduction of lithium and the beginning of the modern era of psychopharmacology in 1949. The nature and importance of these changes have not been fully addressed to date. As methodological flaws in trials can lead to false-negative or false-positive results, the objective of our study was to evaluate the impact of methodological changes in psychopharmacology clinical research over the past 60 years.Methodology/principal findingsWe performed a systematic review from 1949 to 2009 on MEDLINE and Web of Science electronic databases, and a hand search of high impact journals on studies of seven major drugs (chlorpromazine, clozapine, risperidone, lithium, fluoxetine and lamotrigine). All controlled studies published 100 months after the first trial were included. Ninety-one studies met our inclusion criteria. We analyzed the major changes in abstract reporting, study design, participants' assessment and enrollment, methodology and statistical analysis. Our results showed that the methodology of psychiatric clinical trials changed substantially, with quality gains in abstract reporting, results reporting, and statistical methodology. Recent trials use more informed consent, periods of washout, intention-to-treat approach and parametric tests. Placebo use remains high and unchanged over time.Conclusions/significanceClinical trial quality of psychopharmacological studies has changed significantly in most of the aspects we analyzed. There was significant improvement in quality reporting and internal validity. These changes have increased study efficiency; however, there is room for improvement in some aspects such as rating scales, diagnostic criteria and better trial reporting. Therefore, despite the advancements observed, there are still several areas that can be improved in psychopharmacology clinical trials.
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Project description:Big data and (deep) machine learning have been ambitious tools in digital medicine, but these tools focus mainly on association. Intervention in medicine is about the causal effects. The average treatment effect has long been studied as a measure of causal effect, assuming that all populations have the same effect size. However, no "one-size-fits-all" treatment seems to work in some complex diseases. Treatment effects may vary by patient. Estimating heterogeneous treatment effects (HTE) may have a high impact on developing personalized treatment. Lots of advanced machine learning models for estimating HTE have emerged in recent years, but there has been limited translational research into the real-world healthcare domain. To fill the gap, we reviewed and compared eleven recent HTE estimation methodologies, including meta-learner, representation learning models, and tree-based models. We performed a comprehensive benchmark experiment based on nationwide healthcare claim data with application to Alzheimer's disease drug repurposing. We provided some challenges and opportunities in HTE estimation analysis in the healthcare domain to close the gap between innovative HTE models and deployment to real-world healthcare problems.
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Project description:ImportanceIncentivizing research participation is controversial and variably regulated because of uncertainty regarding whether financial incentives serve as undue inducements by diminishing peoples' sensitivity to research risks or unjust inducements by preferentially increasing enrollment among underserved individuals.ObjectiveTo determine whether incentives improve enrollment in real randomized clinical trials (RCTs) or serve as undue or unjust inducements.Design, setting, and participantsTwo RCTs of incentives that were embedded in 2 parent RCTs, 1 comparing smoking cessation interventions (conducted at smoking cessation clinics in 2 health systems) and 1 evaluating an ambulation intervention (conducted across wards of the Hospital of the University of Pennsylvania) included all persons eligible for the parent trials who did not have prior knowledge of the incentives trials. Recruitment occurred from September 2017 to August 2019 for the smoking trial and January 2018 through May 2019 for the ambulation trial; data were analyzed from January 2020 to July 2020.InterventionsPatients were randomly assigned to incentives of $0, $200, or $500 for participating in the smoking cessation trial and $0, $100, or $300 for the ambulation trial.Main outcomes and measuresThe primary outcome of each incentive trial was the proportion of people assigned to each recruitment strategy that consented to participate. Each trial was powered to test the hypotheses that incentives served neither as undue inducements (based on the interaction between incentive size and perceived research risk, as measured using a 10-point scale, on the primary outcome), nor unjust inducements (based on the interaction between incentive size and participants' self-reported income). Noninferiority methods were used to test whether the data were compatible with these 2 effects of incentives and superiority methods to compare the primary and other secondary outcomes.ResultsThere were a total of 654 participants (327 women [50.0%]; mean [SD] age, 50.6 [12.1] years; 394 Black/African American [60.2%], 214 White [32.7%], and 24 multiracial individuals [3.7%]) in the smoking trial, and 642 participants (364 women [56.7%]; mean [SD] age, 46.7 [15.6] years; 224 Black/African American [34.9%], 335 White [52.2%], and 5 multiracial individuals [0.8%]) in the ambulation trial. Incentives significantly increased consent rates among those in the smoking trial in 47 of 216 (21.8%), 78 of 217 (35.9%), and 104 of 221 (47.1%) in the $0, $200, and $500 groups, respectively (adjusted odds ratio [aOR] for each increase in incentive, 1.70; 95% CI, 1.34-2.17; P < .001). Incentives did not increase consent among those in the ambulation trial: 98 of 216 (45.4%), 102 of 212 (48.1%), and 92 of 214 (43.0%) in the $0, $100, and $300 groups, respectively (aOR, 0.88; 95% CI, 0.64-1.22; P = .45). In neither trial was there evidence of undue or unjust inducement (upper confidence limits of ORs for undue inducement, 1.15 and 0.99; P < .001 showing noninferiority; upper confidence limits of ORs for unjust inducement, 1.21 and 1.26; P = .01 and P < .001, respectively). There were no significant effects of incentive size on the secondary outcomes in either trial, including time spent reviewing the risk sections of consent forms, perceived research risks, trial understanding, perceived coercion, or therapeutic misconceptions.Conclusions and relevanceIn these 2 randomized clinical trials, financial incentives increased trial enrollment in 1 of 2 trials and did not produce undue or unjust inducement or other unintended consequences in either trial.Trial registrationClinicalTrials.gov Identifier: NCT02697799.
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Project description:The objectives of the 1st EFORT European Consensus on 'Medical and Scientific Research Requirements for the Clinical Introduction of Artificial Joint Arthroplasty Devices' were foremost to focus on patient safety by establishing performance requirements for medical devices. The 1st EFORT European Consensus applied an a priori-defined, modified Delphi methodology to produce unbiased, high-quality recommendation statements, confirmed by consensus voting of a European expert panel. Intended key outcomes are practical guidelines justified by the current stage of knowledge and based on a broad European Expert Consensus, to maintain innovation and optimisation of orthopaedic devices within the boundaries of MDR 2017/745. Twenty-one main research areas of relevance were defined relying on input from the EFORT IPSI WG1 'Introduction of Innovation' recommendations and a related survey. A modified Delphi approach with a preparatory literature review and work in small groups were used to prepare answers to the research questions in the form of 32 draft Consensus statements. A Consensus Conference in a hybrid format, on-site in the Carl Gustav Carus University of Dresden was organised to further refine the draft statements and define consensus within the complete group of participants by final voting, intended to further quantify expert opinion knowledge. The modified Delphi approach provides practical guidelines for hands-on orientation for orthopaedic surgeons, research institutes and laboratories, orthopaedic device manufacturers, patient representatives, Notified Bodies, National Institutes and authorities. For the first time, initiated by the EFORT IPSI (WG1 'Introduction of Innovation'), knowledge of all related stakeholders was combined in the 1st EFORT European Consensus to develop guidelines and result in a comprehensive set of recommendations.
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Project description:ObjectivesTo describe randomized controlled trial (RCT) methodology reporting over time.Study design and settingWe used a deep learning-based sentence classification model based on the Consolidated Standards of Reporting Trials (CONSORT) statement, considered minimum requirements for reporting RCTs. We included 176,469 RCT reports published between 1966 and 2018. We analyzed the reporting trends over 5-year time periods, grouping trials from 1966 to 1990 in a single stratum. We also explored the effect of journal impact factor (JIF) and medical discipline.ResultsPopulation, Intervention, Comparator, Outcome (PICO) items were commonly reported during each period, and reporting increased over time (e.g., interventions: 79.1% during 1966-1990 to 87.5% during 2010-2018). Reporting of some methods information has increased, although there is room for improvement (e.g., sequence generation: 10.8-41.8%). Some items are reported infrequently (e.g., allocation concealment: 5.1-19.3%). The number of items reported and JIF are weakly correlated (Pearson's r (162,702) = 0.16, P < 0.001). The differences in the proportion of items reported between disciplines are small (<10%).ConclusionOur analysis provides large-scale quantitative support for the hypothesis that RCT methodology reporting has improved over time. Extending these models to all CONSORT items could facilitate compliance checking during manuscript authoring and peer review, and support metaresearch.
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Project description:The Clinical Research Networks of the National Institute of Health Research have transformed clinical research in the UK, leading to a doubling in the number of patients involved in clinical research studies over the past 3 years. This has been achieved by streamlining the trials approvals process, by providing local infrastructure such as research nurse support for clinical trials recruitment and through recognition of the time and funding necessary for clinicians to contribute to clinical research. Here, we describe the structure and roles of the Comprehensive Clinical Research Networks in gastrointestinal disease and hepatology, particularly in England. We will explain how the networks have already accelerated clinical research in gastrointestinal and liver disease, as well as provide a simple guide about how individual clinicians can contribute to ongoing studies via the networks.
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Project description:As electronic medical records enable increasingly ambitious studies of treatment outcomes, ethical issues previously important only to limited clinical trials become relevant to unlimited whole populations. For randomized clinical trials, adaptive assignment strategies are known to expose substantially fewer patients to avoidable treatment failures than strategies with fixed assignments (e.g., equal sample sizes). An idealized adaptive case--the two-armed Bernoulli bandit problem--can be exactly optimized for a variety of ethically motivated cost functions that embody principles of duty-to-patient, but the solutions have been thought computationally infeasible when the numbers of patients in the study (the "horizon") is large. We report numerical experiments that yield a heuristic approximation that applies even to very large horizons, and we propose a near-optimal strategy that remains valid even when the horizon is unknown or unbounded, thus applicable to comparative effectiveness studies on large populations or to standard-of-care recommendations. For the case in which the economic cost of treatment is a parameter, we give a heuristic, near-optimal strategy for determining the superior treatment (whether more or less costly) while minimizing resources wasted on any inferior, more expensive, treatment. Key features of our heuristics can be generalized to more complicated protocols.
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