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To compare the results of meta-analysis of nonrandomized comparative studies (NRCSs) of a surgical procedure with that of randomized controlled trials (RCTs), and to assess the effect of design and conduct issues in NRCSs on measured outcomes. Two meta-analyses of RCTs and NRCSs (2,512 and 6,438 procedures, respectively) of laparoscopic resection for colorectal cancer were performed according to accepted protocols, and 13 outcomes common between them were compared. Odds ratios (ORs) and 95% confidence intervals (CI) for dichotomous outcomes were assessed for the degree of overlap. Continuous outcomes were compared using cumulative weighted ratios (CWRs) and percentages for which a mean and standard deviation (SD) were calculated. The effects of design and conduct issues in the meta-analysis of NRCSs on measured morbidity rates were assessed using subgroup analysis. The ORs of the three dichotomous outcomes overlapped widely. For the 10 continuous variables, the mean difference (SD) in the results of the two meta-analyses was only 5.6% (4.9%). Fulfillment of certain quality and conduct issues in the NRCSs determined the statistical homogeneity of the results of meta-analysis and their comparability with the “gold standard.” Meta-analysis of well-designed NRCSs of surgical procedures is probably as accurate as that of RCTs.

Background. End points used to detect influenza in vaccine efficacy trials have varied. Both the inactivated and live attenuated influenza vaccines are efficacious; however, failure to protect occurs. Methods. We compared characteristics of influenza A (H3N2) and B cases from 3 years of a comparative placebo-controlled trial of inactivated and live attenuated vaccines, and we evaluated the laboratory end points used to determine efficacy. Results. Although illness duration and reported symptoms did not differ by intervention, subjects with influenza in the inactivated vaccine group were less likely than those in the placebo group to report medically attended illnesses. All influenza type A (H3N2) and B cases isolated in cell culture were also identified by real-time polymerase chain reaction (rtPCR). However, only 69% of type A (H3N2) cases identified by rtPCR also were isolated in cell culture. Isolation frequency was lowest among live attenuated vaccine failures, a reflection of lower specimen viral loads. Among cases of rtPCR identified influenza A (H3N2), 90% of placebo and 87% of live attenuated vaccine recipients but only 23% of inactivated vaccine recipients demonstrated serologic confirmation of infection. Conclusions. In influenza vaccine efficacy studies, virus identification using rtPCR is the ideal end point. Isolation in cell culture will miss cases, and a serologic end point alone will overestimate inactivated vaccine efficacy.

Lack of standardization of outcome measures limits the usefulness of clinical trial evidence to inform health care decisions. This can be addressed by agreeing on a minimum core set of outcome measures per health condition, containing measures relevant to patients and decision makers. Since 1992, the Outcome Measures in Rheumatology (OMERACT) consensus initiative has successfully developed core sets for many rheumatologic conditions, actively involving patients since 2002. Its expanding scope required an explicit formulation of its underlying conceptual framework and process. Literature searches and iterative consensus process (surveys and group meetings) of stakeholders including patients, health professionals, and methodologists within and outside rheumatology. To comprehensively sample patient-centered and intervention-specific outcomes, a framework emerged that comprises three core “Areas,” namely Death, Life Impact, and Pathophysiological Manifestations; and one strongly recommended Resource Use. Through literature review and consensus process, core set development for any specific health condition starts by identifying at least one core “Domain” within each of the Areas to formulate the “Core Domain Set.” Next, at least one applicable measurement instrument for each core Domain is identified to formulate a “Core Outcome Measurement Set.” Each instrument must prove to be truthful (valid), discriminative, and feasible. In 2012, 96% of the voting participants (n=125) at the OMERACT 11 consensus conference endorsed this model and process. The OMERACT Filter 2.0 explicitly describes a comprehensive conceptual framework and a recommended process to develop core outcome measurement sets for rheumatology likely to be useful as a template in other areas of health care.

Background:Findings of substantial remaining morbidity in treated major depressive disorder (MDD) led us to review controlled trials of treatments aimed at preventing early relapses or later recurrences in adults diagnosed with MDD to summarize available data and to guide further research.Methods:Reports (n = 97) were identified through systematic, computerized literature searching up to February 2015. Treatment versus control outcomes were summarized by random-effects meta-analyses.Results:In 45 reports of 72 trials (n = 14 450 subjects) lasting 33.4 weeks, antidepressants were more effective than placebos in preventing relapses (response rates [RR] = 1.90, confidence interval [CI]: 1.73–2.08; NNT = 4.4; p < 0.0001). In 35 reports of 37 trials (n = 7253) lasting 27.0 months, antidepressants were effective in preventing recurrences (RR = 2.03, CI 1.80–2.28; NNT = 3.8; p < 0.0001), with minor differences among drug types. In 17 reports of 22 trials (n = 1 969) lasting 23.7 months, psychosocial interventions yielded inconsistent or inconclusive results.Conclusions:Despite evidence of the efficacy of drug treatment compared to placebos or other controls, the findings further underscore the substantial, unresolved morbidity in treated MDD patients and strongly encourage further evaluations of specific, improved individual and combination therapies (pharmacological and psychological) conducted over longer times, as well as identifying clinical predictors of positive or unfavorable responses and of intolerability of long-term treatments in MDD.

Most controlled trials of acupuncture have used minimal, superficial, sham, or ‘placebo’ acupuncture. It has recently been demonstrated that light touch of the skin stimulates mechanoreceptors coupled to slow conducting unmyelinated (C) afferents resulting in activity in the insular region, but not in the somatosensory cortex. Activity in these C tactile afferents has been suggested to induce a ‘limbic touch’ response resulting in emotional and hormonal reactions. It is likely that, in many acupuncture studies, control procedures that are meant to be inert are in fact activating these C tactile afferents and consequently result in the alleviation of the affective component of pain. This could explain why control interventions are equally effective as acupuncture in alleviating pain conditions that are predominantly associated with affective components such as migraine or low back pain, but not those with a more pronounced sensory component, such as osteoarthritis of the knee or lateral epicondylalgia.

While research on chronic ankle instability (CAI) and awareness of its impact on society and health care systems has grown substantially in the last 2 decades, the inconsistency in participant or patient selection criteria across studies presents a potential obstacle to addressing the problem properly. This major gap within the literature limits the ability to generalize this evidence to the target patient population. Therefore, there is a need to provide standards for patient or participant selection criteria in research focused on CAI with justifications using the best available evidence. The International Ankle Consortium provides this position paper to present and discuss an endorsed set of selection criteria for patients with CAI based on the best available evidence to be used in future research and study designs. These recommendations will enhance the validity of research conducted in this clinical population with the end goal of bringing the research evidence to the clinician and patient.

While clinical deprescribing trials are increasingly being performed, there is no guidance on the optimum conduction of such studies. The aim of this survey was to explore the perspectives, attitudes, interests, barriers, and enablers of conducting clinical deprescribing trials among health professionals and researchers. An anonymous survey was developed, reviewed, and piloted by all investigators and informed by consultation with experts, as well as current deprescribing guidelines. The questions were formulated around current clinical trial frameworks and incorporated identified enablers and barriers of performing deprescribing studies. The survey was sent to members of Australian and international deprescribing, pharmacological, and pharmacy organizations, and other researchers published in deprescribing. A total of 96 respondents completed the survey (92.3% completion rate). Respondents indicated the main deprescribing trial rationale is to generate evidence to optimize patient‐centered outcomes (79.2%). Common barriers identified included the time and effort required (18.2%), and apprehension of health professionals involved in trials (17.1%). Studies are enabled by positive attitudes toward deprescribing of treating prescribers (24.4%) and patients (20.9%). Classical randomized controlled trials (RCTs) were deemed the most appropriate methodology (93.2%). Sixty percent of participants indicated a good clinical practice framework is required to guide the conduct of deprescribing trials. There were no significant differences in responses based on previous experience in conducting clinical deprescribing trials. In conclusion, clinical deprescribing trials should be conducted to investigate whether deprescribing medications improves patient care. A future deprescribing trial framework should use classical RCTs as a model, ensure participant safety, and target patient‐centered outcomes.

Background There is an increasing number of meta-analyses including data from non-randomized studies for therapeutic evaluation. We aimed to systematically assess the methods used in meta-analyses including non-randomized studies evaluating therapeutic interventions. Methods For this methodological review, we searched MEDLINE via PubMed, from January 1, 2013 to December 31, 2013 for meta-analyses including at least one non-randomized study evaluating therapeutic interventions. Etiological assessments and meta-analyses with no comparison group were excluded. Two reviewers independently assessed the general characteristics and key methodological components of the systematic review process and meta-analysis methods. Results One hundred eighty eight meta-analyses were selected: 119 included both randomized controlled trials (RCTs) and non-randomized studies of interventions (NRSI) and 69 only NRSI. Half of the meta-analyses ( n  = 92, 49 %) evaluated non-pharmacological interventions. “Grey literature” was searched for 72 meta-analyses (38 %). An assessment of methodological quality or risk of bias was reported in 135 meta-analyses (72 %) but this assessment considered the risk of confounding bias in only 33 meta-analyses (18 %). In 130 meta-analyses (69 %), the design of each NRSI was not clearly specified. In 131 (70 %), whether crude or adjusted estimates of treatment effect for NRSI were combined was unclear or not reported. Heterogeneity across studies was assessed in 182 meta-analyses (97 %) and further explored in 157 (84 %). Reporting bias was assessed in 127 (68 %). Conclusions Some key methodological components of the systematic review process—search for grey literature, description of the type of NRSI included, assessment of risk of confounding bias and reporting of whether crude or adjusted estimates were combined—are not adequately carried out or reported in meta-analyses including NRSI.

Background While there is some consensus on methods for investigating statistical and methodological heterogeneity, little attention has been paid to clinical aspects of heterogeneity. The objective of this study is to summarize and collate suggested methods for investigating clinical heterogeneity in systematic reviews. Methods We searched databases (Medline, EMBASE, CINAHL, Cochrane Library, and CONSORT, to December 2010) and reference lists and contacted experts to identify resources providing suggestions for investigating clinical heterogeneity between controlled clinical trials included in systematic reviews. We extracted recommendations, assessed resources for risk of bias, and collated the recommendations. Results One hundred and one resources were collected, including narrative reviews, methodological reviews, statistical methods papers, and textbooks. These resources generally had a low risk of bias, but there was minimal consensus among them. Resources suggested that planned investigations of clinical heterogeneity should be made explicit in the protocol of the review; clinical experts should be included on the review team; a set of clinical covariates should be chosen considering variables from the participant level, intervention level, outcome level, research setting, or others unique to the research question; covariates should have a clear scientific rationale; there should be a sufficient number of trials per covariate; and results of any such investigations should be interpreted with caution. Conclusions Though the consensus was minimal, there were many recommendations in the literature for investigating clinical heterogeneity in systematic reviews. Formal recommendations for investigating clinical heterogeneity in systematic reviews of controlled trials are required.

Background Multi-arm trials enable the evaluation of multiple treatments within a single trial. They provide a way of substantially increasing the efficiency of the clinical development process. However, since multi-arm trials test multiple hypotheses, some regulators require that a statistical correction be made to control the chance of making a type-1 error (false-positive). Several conflicting viewpoints are expressed in the literature regarding the circumstances in which a multiple-testing correction should be used. In this article we discuss these conflicting viewpoints and review the frequency with which correction methods are currently used in practice. Methods We identified all multi-arm clinical trials published in 2012 by four major medical journals. Summary data on several aspects of the trial design were extracted, including whether the trial was exploratory or confirmatory, whether a multiple-testing correction was applied and, if one was used, what type it was. Results We found that almost half (49%) of published multi-arm trials report using a multiple-testing correction. The percentage that corrected was higher for trials in which the experimental arms included multiple doses or regimens of the same treatments (67%). The percentage that corrected was higher in exploratory than confirmatory trials, although this is explained by a greater proportion of exploratory trials testing multiple doses and regimens of the same treatment. Conclusions A sizeable proportion of published multi-arm trials do not correct for multiple-testing. Clearer guidance about whether multiple-testing correction is needed for multi-arm trials that test separate treatments against a common control group is required.