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1.  Initiation and continuation of randomized trials after the publication of a trial stopped early for benefit asking the same study question: STOPIT-3 study design 
Trials  2013;14:335.
Background
Randomized control trials (RCTs) stopped early for benefit (truncated RCTs) are increasingly common and, on average, overestimate the relative magnitude of benefit by approximately 30%. Investigators stop trials early when they consider it is no longer ethical to enroll patients in a control group. The goal of this systematic review is to determine how investigators of ongoing or planned RCTs respond to the publication of a truncated RCT addressing a similar question.
Methods/design
We will conduct systematic reviews to update the searches of 210 truncated RCTs to identify similar trials ongoing at the time of publication, or started subsequently, to the truncated trials ('subsequent RCTs’). Reviewers will determine in duplicate the similarity between the truncated and subsequent trials. We will analyze the epidemiology, distribution, and predictors of subsequent RCTs. We will also contact authors of subsequent trials to determine reasons for beginning, continuing, or prematurely discontinuing their own trials, and the extent to which they rely on the estimates from truncated trials.
Discussion
To the extent that investigators begin or continue subsequent trials they implicitly disagree with the decision to stop the truncated RCT because of an ethical mandate to administer the experimental treatment. The results of this study will help guide future decisions about when to stop RCTs early for benefit.
doi:10.1186/1745-6215-14-335
PMCID: PMC3874848  PMID: 24131702
Randomized controlled trials stopped early for benefit; RCT; Systematic review; Protocol
2.  Opioids for chronic non-cancer pain: a protocol for a systematic review of randomized controlled trials 
Systematic Reviews  2013;2:66.
Background
Opioids are prescribed frequently and increasingly for the management of chronic non-cancer pain (CNCP). Current systematic reviews have a number of limitations, leaving uncertainty with regard to the benefits and harms associated with opioid therapy for CNCP. We propose to conduct a systematic review and meta-analysis to summarize the evidence for using opioids in the treatment of CNCP and the risk of associated adverse events.
Methods and design
Eligible trials will include those that randomly allocate patients with CNCP to treatment with any opioid or any non-opioid control group. We will use the guidelines published by the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) to inform the outcomes that we collect and present. We will use the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system to evaluate confidence in the evidence on an outcome-by-outcome basis. Teams of reviewers will independently and in duplicate assess trial eligibility, abstract data, and assess risk of bias among eligible trials. To ensure interpretability of our results, we will present risk differences and measures of relative effect for all outcomes reported and these will be based on anchor-based minimally important clinical differences, when available. We will conduct a priori defined subgroup analyses consistent with current best practices.
Discussion
Our review will evaluate both the effectiveness and the adverse events associated with opioid use for CNCP, evaluate confidence in the evidence using the GRADE approach, and prioritize patient-important outcomes with a focus on functional gains guided by IMMPACT recommendations. Our results will facilitate evidence-based management of patients with CNCP and identify key areas for future research.
Trial registration
Our protocol is registered on PROSPERO (CRD42012003023), http://www.crd.york.ac.uk/PROSPERO.
doi:10.1186/2046-4053-2-66
PMCID: PMC3765127  PMID: 23965223
Chronic pain; Opioid analgesics; Systematic review; Meta-analysis; Randomized controlled trials; Quality of life; Adverse effects
3.  Effects of Low-Level Laser Therapy, 660 nm, in Experimental Septic Arthritis 
ISRN Rheumatology  2013;2013:341832.
The effectiveness of low-level laser therapy (LLLT) in the presence of an infectious process has not been well elucidated. The aim of the study was to evaluate the effects of LLLT in an experimental model of septic arthritis. Methods. Twenty-one Wistar rats were divided as follows: control group, no bacteria; placebo group, bacteria were inoculated; Treated group, bacteria were injected and treatment with LLLTwas performed. To assess nociception, a von Frey digital analgesimeter was applied. Synovial fluid was streaked to analyze bacterial growth. The standard strain of S. aureus was inoculated in the right knee. LLLT was performed with 660 nm, 2 J/cm2, over 10 days. After treatment, the knees were fixed and processed for morphological analysis by light microscopy. Results. It was found that nociception increases in the right knee. There was a lack of results for the seeding of the synovial fluid. The morphological analysis showed slight recovery areas in the articular cartilage and synovia; however, there was the maintenance of the inflammatory infiltrate. Conclusion. The parameters used were not effective in the nociception reduction, even with the slight tissue recovery due to the maintenance of inflammatory infiltrate, but produced no change in the natural history of resolution of the infectious process.
doi:10.1155/2013/341832
PMCID: PMC3753738  PMID: 23997964
4.  Nociceptive and Histomorphometric Evaluation of Neural Mobilization in Experimental Injury of the Median Nerve 
The Scientific World Journal  2013;2013:476890.
The carpal tunnel syndrome is the most common peripheral neuropathy in the upper limb, but its treatment with conservative therapies such as neural mobilization (NM) is still controversial. The aim of this study was to investigate the efficacy of the NM as treatment in a model of median nerve compression. 18 Wistar rats were subjected to compression of the median nerve in the right elbow proximal region. Were randomly divided into G1 (untreated), G2 (NM for 1 minute), and G3 (NM for 3 minutes). For treatment, the animals were anesthetized and the right forelimb received mobilization adapted to humans, on alternated days, from the 3rd to the 13th day postoperatively (PO), totaling six days of therapy. Nociception was assessed by withdrawal threshold, and after euthanasia histomorphometric analysis of the median nerve was performed. The nociceptive evaluation showed in G2 and G3 delay in return to baseline. Histomorphometric analysis showed no significant differences in the variables analyzed. It is concluded that the NM was not effective in reducing nociceptive sensation and did not alter the course of nerve regeneration.
doi:10.1155/2013/476890
PMCID: PMC3725901  PMID: 23935419
5.  Return to Work Coordination Programmes for Work Disability: A Meta-Analysis of Randomised Controlled Trials 
PLoS ONE  2012;7(11):e49760.
Background
The dramatic rise in chronically ill patients on permanent disability benefits threatens the sustainability of social security in high-income countries. Social insurance organizations have started to invest in promising, but costly return to work (RTW) coordination programmes. The benefit, however, remains uncertain. We conducted a systematic review to determine the long-term effectiveness of RTW coordination compared to usual practice in patients at risk for long-term disability.
Methods and Findings
Eligible trials enrolled employees on work absence for at least 4 weeks and randomly assigned them to RTW coordination or to usual practice. We searched 5 databases (to April 2, 2012). Two investigators performed standardised eligibility assessment, study appraisal and data extraction independently and in duplicate. The GRADE framework guided our assessment of confidence in the meta-analytic estimates. We identified 9 trials from 7 countries, 8 focusing on musculoskeletal, and 1 on mental complaints. Most trials followed participants for 12 months or less. No trial assessed permanent disability. Moderate quality evidence suggests a benefit of RTW coordination on proportion at work at end of follow-up (risk ratio = 1.08, 95% CI = 1.03 to 1.13; absolute effect = 5 in 100 additional individuals returning to work, 95% CI = 2 to 8), overall function (mean difference [MD] on a 0 to 100 scale = 5.2, 95% CI = 2.4 to 8.0; minimal important difference [MID] = 10), physical function (MD = 5.3, 95% CI = 1.4 to 9.1; MID = 8.4), mental function (MD = 3.1, 95% CI = 0.7 to 5.6; MID = 7.3) and pain (MD = 6.1, 95% CI = 3.1 to 9.2; MID = 10).
Conclusions
Moderate quality evidence suggests that RTW coordination results in small relative, but likely important absolute benefits in the likelihood of disabled or sick-listed patients returning to work, and associated small improvements in function and pain. Future research should explore whether the limited effects persist, and whether the programmes are cost effective in the long term.
doi:10.1371/journal.pone.0049760
PMCID: PMC3501468  PMID: 23185429
6.  Evaluation of work disability and the international classification of functioning, disability and health: what to expect and what not 
BMC Public Health  2012;12:470.
Background
Individuals who are sick and unable to work may receive wage replacement benefits from an insurer. For these provisions, a disability evaluation is required. This disability evaluation is criticised for lack of standardisation and transparency. The International Classification of Functioning, Disability and Health (ICF) was developed to express the situation of people with disability. We discuss potential benefits of the ICF to structure and phrase disability evaluation in the field of social insurance. We describe core features of disability evaluation of the ICF across countries. We address how and to what extent the ICF may be applied in disability evaluation.
Discussion
The medical reports in disability evaluation contain the following core features: health condition, functional capacity, socio-medical history, feasibility of interventions and prognosis of work disability. Reports also address consistency, causal relations according to legal requirements, and ability to work. The ICF consists of a conceptual framework of functioning, disability and health, definitions referring to functioning, disability and health, and a hierarchical classification of these definitions. The ICF component ’activities and participation’ is suited to capture functional capacity. Interventions can be described as environmental factors but these would need an additional qualifier to indicate feasibility. The components ‘participation’ and ‘environmental factors’ are suited to capture work requirements. The socio-medical history, the prognosis, and legal requirements are problematic to capture with both the ICF framework and classification.
Summary
The ICF framework reflects modern thinking in disability evaluation. It allows for the medical expert to describe work disability as a bio-psycho-social concept, and what components are of importance in disability evaluation for the medical expert. The ICF definitions for body functions, structures, activity and participation, and environmental factors cover essential parts of disability evaluation. The ICF framework and definitions are however limited with respect to comprehensive descriptions of work disability.
doi:10.1186/1471-2458-12-470
PMCID: PMC3432619  PMID: 22720978
International Classification of Functioning; Disability and Health; Disability evaluation; Handicapped role
7.  Incorporating considerations of resources use into grading recommendations 
BMJ : British Medical Journal  2008;336(7654):1170-1173.
Guideline panellists have differing opinions on whether resource use should influence decisions on individual patients. As medical care costs rise, resource use considerations become more compelling, but panellists may find dealing with such considerations challenging
doi:10.1136/bmj.39504.506319.80
PMCID: PMC2394579  PMID: 18497416
8.  GRADE: Grading quality of evidence and strength of recommendations for diagnostic tests and strategies 
BMJ : British Medical Journal  2008;336(7653):1106-1110.
The GRADE system can be used to grade the quality of evidence and strength of recommendations for diagnostic tests or strategies. This article explains how patient-important outcomes are taken into account in this process
doi:10.1136/bmj.39500.677199.AE
PMCID: PMC2386626  PMID: 18483053
9.  Going from evidence to recommendations 
BMJ : British Medical Journal  2008;336(7652):1049-1051.
The GRADE system classifies recommendations made in guidelines as either strong or weak. This article explores the meaning of these descriptions and their implications for patients, clinicians, and policy makers
doi:10.1136/bmj.39493.646875.AE
PMCID: PMC2376019  PMID: 18467413
10.  What is “quality of evidence” and why is it important to clinicians? 
BMJ : British Medical Journal  2008;336(7651):995-998.
Guideline developers use a bewildering variety of systems to rate the quality of the evidence underlying their recommendations. Some are facile, some confused, and others sophisticated but complex
doi:10.1136/bmj.39490.551019.BE
PMCID: PMC2364804  PMID: 18456631
11.  GRADE: an emerging consensus on rating quality of evidence and strength of recommendations 
BMJ : British Medical Journal  2008;336(7650):924-926.
Guidelines are inconsistent in how they rate the quality of evidence and the strength of recommendations. This article explores the advantages of the GRADE system, which is increasingly being adopted by organisations worldwide
doi:10.1136/bmj.39489.470347.AD
PMCID: PMC2335261  PMID: 18436948
12.  How are "teaching the teachers" courses in evidence based medicine evaluated? A systematic review 
BMC Medical Education  2010;10:64.
Background
Teaching of evidence-based medicine (EBM) has become widespread in medical education. Teaching the teachers (TTT) courses address the increased teaching demand and the need to improve effectiveness of EBM teaching. We conducted a systematic review of assessment tools for EBM TTT courses. To summarise and appraise existing assessment methods for teaching the teachers courses in EBM by a systematic review.
Methods
We searched PubMed, BioMed, EmBase, Cochrane and Eric databases without language restrictions and included articles that assessed its participants. Study selection and data extraction were conducted independently by two reviewers.
Results
Of 1230 potentially relevant studies, five papers met the selection criteria. There were no specific assessment tools for evaluating effectiveness of EBM TTT courses. Some of the material available might be useful in initiating the development of such an assessment tool.
Conclusion
There is a need for the development of educationally sound assessment tools for teaching the teachers courses in EBM, without which it would be impossible to ascertain if such courses have the desired effect.
doi:10.1186/1472-6920-10-64
PMCID: PMC2958160  PMID: 20920240
13.  Effectiveness of an e-learning course in evidence-based medicine for foundation (internship) training 
Summary
Aim
To evaluate the educational effectiveness of a clinically integrated e-learning course for teaching basic evidence-based medicine (EBM) among postgraduate medical trainees compared to a traditional lecture-based course of equivalent content.
Methods
We conducted a cluster randomized controlled trial to compare a clinically integrated e-learning EBM course (intervention) to a lecture-based course (control) among postgraduate trainees at foundation or internship level in seven teaching hospitals in the UK West Midlands region. Knowledge gain among participants was measured with a validated instrument using multiple choice questions. Change in knowledge was compared between groups taking into account the cluster design and adjusted for covariates at baseline using generalized estimating equations (GEE) model.
Results
There were seven clusters involving teaching of 237 trainees (122 in the intervention and 115 in the control group). The total number of postgraduate trainees who completed the course was 88 in the intervention group and 72 in the control group. After adjusting for baseline knowledge, there was no difference in the amount of improvement in knowledge of EBM between the two groups. The adjusted post course difference between the intervention group and the control group was only 0.1 scoring points (95% CI −1.2–1.4).
Conclusion
An e-learning course in EBM was as effective in improving knowledge as a standard lecture-based course. The benefits of an e-learning approach need to be considered when planning EBM curricula as it allows standardization of teaching materials and is a potential cost-effective alternative to standard lecture-based teaching.
doi:10.1258/jrsm.2010.100036
PMCID: PMC2895523  PMID: 20522698
14.  Determinants of knowledge gain in evidence-based medicine short courses: an international assessment 
Open Medicine  2010;4(1):e3-e10.
Background
Health care professionals worldwide attend courses and workshops to learn evidence-based medicine (EBM), but evidence regarding the impact of these educational interventions is conflicting and of low methodologic quality and lacks generalizability. Furthermore, little is known about determinants of success. We sought to measure the effect of EBM short courses and workshops on knowledge and to identify course and learner characteristics associated with knowledge acquisition.
Methods
Health care professionals with varying expertise in EBM participated in an international, multicentre before–after study. The intervention consisted of short courses and workshops on EBM offered in diverse settings, formats and intensities. The primary outcome measure was the score on the Berlin Questionnaire, a validated instrument measuring EBM knowledge that the participants completed before and after the course.
Results
A total of 15 centres participated in the study and 420 learners from North America and Europe completed the study. The baseline score across courses was 7.49 points (range 3.97–10.42 points) out of a possible 15 points. The average increase in score was 1.40 points (95% confidence interval 0.48–2.31 points), which corresponded with an effect size of 0.44 standard deviation units. Greater improvement in scores was associated (in order of greatest to least magnitude) with active participation required of the learners, a separate statistics session, fewer topics, less teaching time, fewer learners per tutor, larger overall course size and smaller group size. Clinicians and learners involved in medical publishing improved their score more than other types of learners; administrators and public health professionals improved their score less. Learners who perceived themselves to have an advanced knowledge of EBM and had prior experience as an EBM tutor also showed greater improvement than those who did not.
Interpretation
EBM course organizers who wish to optimize knowledge gain should require learners to actively participate in the course and should consider focusing on a small number of topics, giving particular attention to statistical concepts.
PMCID: PMC3116678  PMID: 21686291
15.  Teaching trainers to incorporate evidence-based medicine (EBM) teaching in clinical practice: the EU-EBM project 
Background
Evidence based medicine (EBM) is considered an integral part of medical training, but integration of teaching various EBM steps in everyday clinical practice is uncommon. Currently EBM is predominantly taught through theoretical courses, workshops and e-learning. However, clinical teachers lack confidence in teaching EBM in workplace and are often unsure of the existing opportunities for teaching EBM in the clinical setting. There is a need for continuing professional development (CPD) courses that train clinical trainers to teach EBM through on-the-job training by demonstration of applied EBM real time in clinical practice. We developed such a course to encourage clinically relevant teaching of EBM in post-graduate education in various clinical environments.
Methods
We devised an e-learning course targeting trainers with EBM knowledge to impart educational methods needed to teach application of EBM teaching in commonly used clinical settings. The curriculum development group comprised experienced EBM teachers, clinical epidemiologists, clinicians and educationalists from institutions in seven European countries. The e-learning sessions were designed to allow participants (teachers) to undertake the course in the workplace during short breaks within clinical activities. An independent European steering committee provided input into the process.
Results
The curriculum defined specific learning objectives for teaching EBM by exploiting educational opportunities in six different clinical settings. The e-modules incorporated video clips that demonstrate practical and effective methods of EBM teaching in everyday clinical practice. The course encouraged focussed teaching activities embedded within a trainer's personal learning plan and documentation in a CPD portfolio for reflection.
Conclusion
This curriculum will help senior clinicians to identify and make the best use of available opportunities in everyday practice in clinical situations to teach various steps of EBM and demonstrate their applicability to clinical practice. Once fully implemented, the ultimate outcome of this pilot project will be a European qualification in teaching EBM, which will be used by doctors, hospitals, professional bodies responsible for postgraduate qualifications and continuing medical education.
doi:10.1186/1472-6920-9-59
PMCID: PMC2753626  PMID: 19744327
16.  Stopping randomized trials early for benefit: a protocol of the Study Of Trial Policy Of Interim Truncation-2 (STOPIT-2) 
Trials  2009;10:49.
Background
Randomized clinical trials (RCTs) stopped early for benefit often receive great attention and affect clinical practice, but pose interpretational challenges for clinicians, researchers, and policy makers. Because the decision to stop the trial may arise from catching the treatment effect at a random high, truncated RCTs (tRCTs) may overestimate the true treatment effect. The Study Of Trial Policy Of Interim Truncation (STOPIT-1), which systematically reviewed the epidemiology and reporting quality of tRCTs, found that such trials are becoming more common, but that reporting of stopping rules and decisions were often deficient. Most importantly, treatment effects were often implausibly large and inversely related to the number of the events accrued. The aim of STOPIT-2 is to determine the magnitude and determinants of possible bias introduced by stopping RCTs early for benefit.
Methods/Design
We will use sensitive strategies to search for systematic reviews addressing the same clinical question as each of the tRCTs identified in STOPIT-1 and in a subsequent literature search. We will check all RCTs included in each systematic review to determine their similarity to the index tRCT in terms of participants, interventions, and outcome definition, and conduct new meta-analyses addressing the outcome that led to early termination of the tRCT. For each pair of tRCT and systematic review of corresponding non-tRCTs we will estimate the ratio of relative risks, and hence estimate the degree of bias. We will use hierarchical multivariable regression to determine the factors associated with the magnitude of this ratio. Factors explored will include the presence and quality of a stopping rule, the methodological quality of the trials, and the number of total events that had occurred at the time of truncation.
Finally, we will evaluate whether Bayesian methods using conservative informative priors to "regress to the mean" overoptimistic tRCTs can correct observed biases.
Discussion
A better understanding of the extent to which tRCTs exaggerate treatment effects and of the factors associated with the magnitude of this bias can optimize trial design and data monitoring charters, and may aid in the interpretation of the results from trials stopped early for benefit.
doi:10.1186/1745-6215-10-49
PMCID: PMC2723099  PMID: 19580665
17.  The effectiveness of a clinically integrated e-learning course in evidence-based medicine: A cluster randomised controlled trial 
Background
To evaluate the educational effects of a clinically integrated e-learning course for teaching basic evidence-based medicine (EBM) among postgraduates compared to a traditional lecture-based course of equivalent content.
Methods
We conducted a cluster randomised controlled trial in the Netherlands and the UK involving postgraduate trainees in six obstetrics and gynaecology departments. Outcomes (knowledge gain and change in attitude towards EBM) were compared between the clinically integrated e-learning course (intervention) and the traditional lecture based course (control). We measured change from pre- to post-intervention scores using a validated questionnaire assessing knowledge (primary outcome) and attitudes (secondary outcome).
Results
There were six clusters involving teaching of 61 postgraduate trainees (28 in the intervention and 33 in the control group). The intervention group achieved slightly higher scores for knowledge gain compared to the control, but these results were not statistically significant (difference in knowledge gain: 3.5 points, 95% CI -2.7 to 9.8, p = 0.27). The attitudinal changes were similar for both groups.
Conclusion
A clinically integrated e-learning course was at least as effective as a traditional lecture based course and was well accepted. Being less costly than traditional teaching and allowing for more independent learning through materials that can be easily updated, there is a place for incorporating e-learning into postgraduate EBM curricula that offer on-the-job training for just-in-time learning.
Trial registration
Trial registration number: ACTRN12609000022268.
doi:10.1186/1472-6920-9-21
PMCID: PMC2688004  PMID: 19435520
18.  Harmonising Evidence-based medicine teaching: a study of the outcomes of e-learning in five European countries 
Background
We developed and evaluated the outcomes of an e-learning course for evidence based medicine (EBM) training in postgraduate medical education in different languages and settings across five European countries.
Methods
We measured changes in knowledge and attitudes with well-developed assessment tools before and after administration of the course. The course consisted of five e-learning modules covering acquisition (formulating a question and search of the literature), appraisal, application and implementation of findings from systematic reviews of therapeutic interventions, each with interactive audio-visual learning materials of 15 to 20 minutes duration. The modules were prepared in English, Spanish, German and Hungarian. The course was delivered to 101 students from different specialties in Germany (psychiatrists), Hungary (mixture of specialties), Spain (general medical practitioners), Switzerland (obstetricians-gynaecologists) and the UK (obstetricians-gynaecologists). We analysed changes in scores across modules and countries.
Results
On average across all countries, knowledge scores significantly improved from pre- to post-course for all five modules (p < 0.001). The improvements in scores were on average 1.87 points (14% of total score) for module 1, 1.81 points (26% of total score) for module 2, 1.9 points (11% of total score) for module 3, 1.9 points (12% of total score) for module 4 and 1.14 points (14% of total score) for module 5. In the country specific analysis, knowledge gain was not significant for module 4 in Spain, Switzerland and the UK, for module 3 in Spain and Switzerland and for module 2 in Spain. Compared to pre-course assessment, after completing the course participants felt more confident that they can assess research evidence and that the healthcare system in their country should have its own programme of research about clinical effectiveness.
Conclusion
E-learning in EBM can be harmonised for effective teaching and learning in different languages, educational settings and clinical specialties, paving the way for development of an international e-EBM course.
doi:10.1186/1472-6920-8-27
PMCID: PMC2386125  PMID: 18442424
19.  A clinically integrated curriculum in Evidence-based Medicine for just-in-time learning through on-the-job training: The EU-EBM project 
Background
Over the last years key stake holders in the healthcare sector have increasingly recognised evidence based medicine (EBM) as a means to improving the quality of healthcare. However, there is considerable uncertainty about the best way to disseminate basic knowledge of EBM. As a result, huge variation in EBM educational provision, setting, duration, intensity, content, and teaching methodology exists across Europe and worldwide. Most courses for health care professionals are delivered outside the work context ('stand alone') and lack adaptation to the specific needs for EBM at the learners' workplace. Courses with modern 'adaptive' EBM teaching that employ principles of effective continuing education might fill that gap. We aimed to develop a course for post-graduate education which is clinically integrated and allows maximum flexibility for teachers and learners.
Methods
A group of experienced EBM teachers, clinical epidemiologists, clinicians and educationalists from institutions from eight European countries participated. We used an established methodology of curriculum development to design a clinically integrated EBM course with substantial components of e-learning. An independent European steering committee provided input into the process.
Results
We defined explicit learning objectives about knowledge, skills, attitudes and behaviour for the five steps of EBM. A handbook guides facilitator and learner through five modules with clinical and e-learning components. Focussed activities and targeted assignments round off the learning process, after which each module is formally assessed.
Conclusion
The course is learner-centred, problem-based, integrated with activities in the workplace and flexible. When successfully implemented, the course is designed to provide just-in-time learning through on-the-job-training, with the potential for teaching and learning to directly impact on practice.
doi:10.1186/1472-6920-7-46
PMCID: PMC2228282  PMID: 18042271
21.  The unpredictability paradox: review of empirical comparisons of randomised and non-randomised clinical trials 
BMJ : British Medical Journal  1998;317(7167):1185-1190.
Objective To summarise comparisons of randomised clinical trials and non-randomised clinical trials, trials with adequately concealed random allocation versus inadequately concealed random allocation, and high quality trials versus low quality trials where the effect of randomisation could not be separated from the effects of other methodological manoeuvres.
Design Systematic review.
Selection criteria Cohorts or meta-analyses of clinical trials that included an empirical assessment of the relation between randomisation and estimates of effect.
Data sources Cochrane Review Methodology Database, Medline, SciSearch, bibliographies, hand searching of journals, personal communication with methodologists, and the reference lists of relevant articles.
Main outcome measures Relation between randomisation and estimates of effect.
Results Eleven studies that compared randomised controlled trials with non-randomised controlled trials (eight for evaluations of the same intervention and three across different interventions), two studies that compared trials with adequately concealed random allocation and inadequately concealed random allocation, and five studies that assessed the relation between quality scores and estimates of treatment effects, were identified. Failure to use random allocation and concealment of allocation were associated with relative increases in estimates of effects of 150% or more, relative decreases of up to 90%, inversion of the estimated effect and, in some cases, no difference. On average, failure to use randomisation or adequate concealment of allocation resulted in larger estimates of effect due to a poorer prognosis in non-randomly selected control groups compared with randomly selected control groups.
Conclusions Failure to use adequately concealed random allocation can distort the apparent effects of care in either direction, causing the effects to seem either larger or smaller than they really are. The size of these distortions can be as large as or larger than the size of the effects that are to be detected.
Key messagesEmpirical studies support using random allocation in clinical trials and ensuring that the allocation process is concealed—that is, that assignment is impervious to any influence by the people making the allocationThe effect of not using concealed random allocation can be as large or larger than the effects of worthwhile interventionsOn average, failure to use concealed random allocation results in overestimates of effect due to a poorer prognosis in non-randomly selected control groups compared with randomly selected control groups, but it can result in underestimates of effect, reverse the direction of effect, mask an effect, or give similar estimates of effectThe adequacy of allocation concealment may be a more sensitive measure of bias in clinical trials than scales used to assess the quality of clinical trialsIt is a paradox that the unpredictability of randomisation is the best protection against the unpredictability of the extent and direction of bias in clinical trials that are not properly randomised
PMCID: PMC28700  PMID: 9794851

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