Cochrane Collaboration

About: Cochrane Collaboration is a nonprofit organization based out in Oxford, United Kingdom. It is known for research contribution in the topics: Systematic review & Randomized controlled trial. The organization has 1995 authors who have published 3928 publications receiving 382695 citations.

Meta-analysis of individual patient data from randomized trials: a review of methods used in practice.

Abstract: Background Meta-analyses based on individual patient data (IPD) are regarded as the gold standard for systematic reviews. However, the methods used for analysing and presenting results from IPD met...

Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children

Abstract: Planning for outbreaks of influenza is a high priority public health issue for national governments. Neuraminidase inhibitors (NIs) are thought to help reduce the symptoms of influenza with several possible mechanisms proposed. NIs have been stockpiled with a view to their widespread use in the event of a pandemic. However, the evidence base for this class of agents remains a source of debate. In a previous review we have documented substantial risks of publication bias of trials of NIs for influenza (60% of patient data from phase III treatment trials of oseltamivir have never been published) and reporting bias in the published trials. Our confidence in the conclusions of previous versions of this review has been subsequently undermined. Since we have become aware of a large number of unpublished trials of NIs in the management of influenza, this review updates and merges existing reviews in this area. To review clinical study reports of placebo-controlled randomised trials, regulatory comments and reviews ('regulatory information') of the effects of the NIs oseltamivir and zanamivir for influenza in all age groups and appraise trial programmes, rather than single studies.Clinical study reports are very detailed, unpublished clinical trial data containing in-depth descriptions of protocol rationale, methods analysis plans, trial results and organisational documents (such as contracts). A series of clinical studies designed and conducted by one sponsor represents a trial programme of a drug indication (for example treatment of influenza). We searched trial registries, cross-referencing published and unpublished sources and corresponded with manufacturers and regulators. We searched the archives of the US Food and Drug Administration (FDA) and European and Japanese regulators. The evidence in this review reflects searches to obtain relevant information up to 12 April 2011. We included regulatory information based on assessments of randomised controlled trials (RCTs) conducted in people of any age who had either confirmed or suspected influenza, or who had been exposed to influenza in the local community or place of residence. We included information which had been made available by our deadline. We indexed regulatory information in two purpose-built instruments and reconstructed trials using CONSORT statement-based templates. To progress to Stage 2 (full analysis) we sought manufacturer explanations of discrepancies in the data. GlaxoSmithKline (GSK) offered us individual patient data and responded to our queries, but Roche did not provide us with complete clinical study reports. In Stage 2 we intended to analyse trials with validated data (i.e. assuming our validation questions aimed at clarifying omissions and discrepancies were resolved). No studies progressed to Stage 2. We carried out analyses of the effects of oseltamivir on time to first alleviation of symptoms and hospitalisations using the intention-to-treat (ITT) population and tested five hypotheses generated post-protocol publication. We included and analysed data from 25 studies (15 oseltamivir and 10 zanamivir studies). We could not use data from a further 42 studies due to insufficient information or unresolved discrepancies in their data. The included trials were predominantly conducted in adults during influenza seasons in both hemispheres. A small number of studies were conducted in older people residing in care homes and in people with underlying respiratory diseases. The studies had adequate randomisation and blinding procedures, but imbalances in the analysis populations available (ITT influenza-infected) left many of the studies at risk of attrition bias. All the studies were sponsored by manufacturers of NIs. Time to first alleviation of symptoms in people with influenza-like illness symptoms (i.e. ITT population) was a median of 160 hours (range 125 to 192 hours) in the placebo groups and oseltamivir shortened this by around 21 hours (95% confidence interval (CI) -29.5 to -12.9 hours, P < 0.001; five studies) but there was no evidence of effect on hospitalisations based on seven studies with a median placebo group event rate of 0.84% (range 0% to 11%): odds ratio (OR) 0.95; 95% CI 0.57 to 1.61, P = 0.86). These results are based on the comprehensive ITT population data and are unlikely to be biased. A post-protocol analysis showed that participants randomised to oseltamivir in treatment trials had a reduced odds being diagnosed with influenza (OR 0.83; 95% CI 0.73 to 0.94, P = 0.003; eight studies), probably due to an altered antibody response. Zanamivir trials showed no evidence of this. Due to limitations in the design, conduct and reporting of the trial programme, the data available to us lacked sufficient detail to credibly assess a possible effect of oseltamivir on complications and viral transmission. We postponed analysis of zanamivir evidence because of the offer of individual patient data (IPD) from its manufacturer. The authors have been unable to obtain the full set of clinical study reports or obtain verification of data from the manufacturer of oseltamivir (Roche) despite five requests between June 2010 and February 2011. No substantial comments were made by Roche on the protocol of our Cochrane Review which has been publicly available since December 2010. We found a high risk of publication and reporting biases in the trial programme of oseltamivir. Sub-population analyses of the influenza infected population in the oseltamivir trial programme are not possible because the two arms are non-comparable due to oseltamivir's apparent interference with antibody production. The evidence supports a direct oseltamivir mechanism of action on symptoms but we are unable to draw conclusions about its effect on complications or transmission. We expect full clinical study reports containing study protocol, reporting analysis plan, statistical analysis plan and individual patient data to clarify outstanding issues. These full clinical study reports are at present unavailable to us.

Placebo interventions for all clinical conditions.

Abstract: Background Placebo interventions are often claimed to substantially improve patient-reported and observer-reported outcomes in many clinical conditions, but most reports on effects of placebos are based on studies that have not randomised patients to placebo or no treatment Two previous versions of this review from 2001 and 2004 found that placebo interventions in general did not have clinically important effects, but that there were possible beneficial effects on patient-reported outcomes, especially pain Since then several relevant trials have been published Objectives Our primary aims were to assess the effect of placebo interventions in general across all clinical conditions, and to investigate the effects of placebo interventions on specific clinical conditions Our secondary aims were to assess whether the effect of placebo treatments differed for patient-reported and observer-reported outcomes, and to explore other reasons for variations in effect Search methods We searched the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library Issue 4, 2007), MEDLINE (1966 to March 2008), EMBASE (1980 to March 2008), PsycINFO (1887 to March 2008) and Biological Abstracts (1986 to March 2008) We contacted experts on placebo research, and read references in the included trials Selection criteria We included randomised placebo trials with a no-treatment control group investigating any health problem Data collection and analysis Two authors independently assessed trial quality and extracted data We contacted study authors for additional information Trials with binary data were summarised using relative risk (a value of less than 1 indicates a beneficial effect of placebo), and trials with continuous outcomes were summarised using standardised mean difference (a negative value indicates a beneficial effect of placebo) Main results Outcome data were available in 202 out of 234 included trials, investigating 60 clinical conditions We regarded the risk of bias as low in only 16 trials (8%), five of which had binary outcomes In 44 studies with binary outcomes (6041 patients), there was moderate heterogeneity (P < 0001; I2 45%) but no clear difference in effects between small and large trials (symmetrical funnel plot) The overall pooled effect of placebo was a relative risk of 093 (95% confidence interval (CI) 088 to 099) The pooled relative risk for patient-reported outcomes was 093 (95% CI 086 to 100) and for observer-reported outcomes 093 (95% CI 085 to 102) We found no statistically significant effect of placebo interventions in four clinical conditions that had been investigated in three trials or more: pain, nausea, smoking, and depression, but confidence intervals were wide The effect on pain varied considerably, even among trials with low risk of bias In 158 trials with continuous outcomes (10,525 patients), there was moderate heterogeneity (P < 0001; I2 42%), and considerable variation in effects between small and large trials (asymmetrical funnel plot) It is therefore a questionable procedure to pool all the trials, and we did so mainly as a basis for exploring causes for heterogeneity We found an overall effect of placebo treatments, standardised mean difference (SMD) -023 (95% CI -028 to -017) The SMD for patient-reported outcomes was -026 (95% CI -032 to -019), and for observer-reported outcomes, SMD -013 (95% CI -024 to -002) We found an effect on pain, SMD -028 (95% CI -036 to -019)); nausea, SMD -025 (-046 to -004)), asthma (-035 (-070 to -001)), and phobia (SMD -063 (95% CI -117 to -008)) The effect on pain was very variable, also among trials with low risk of bias Four similarly-designed acupuncture trials conducted by an overlapping group of authors reported large effects (SMD -068 (-085 to -050)) whereas three other pain trials reported low or no effect (SMD -013 (-028 to 003)) The pooled effect on nausea was small, but consistent The effects on phobia and asthma were very uncertain due to high risk of bias There was no statistically significant effect of placebo interventions in the seven other clinical conditions investigated in three trials or more: smoking, dementia, depression, obesity, hypertension, insomnia and anxiety, but confidence intervals were wide Meta-regression analyses showed that larger effects of placebo interventions were associated with physical placebo interventions (eg sham acupuncture), patient-involved outcomes (patient-reported outcomes and observer-reported outcomes involving patient cooperation), small trials, and trials with the explicit purpose of studying placebo Larger effects of placebo were also found in trials that did not inform patients about the possible placebo intervention Authors' conclusions We did not find that placebo interventions have important clinical effects in general However, in certain settings placebo interventions can influence patient-reported outcomes, especially pain and nausea, though it is difficult to distinguish patient-reported effects of placebo from biased reporting The effect on pain varied, even among trials with low risk of bias, from negligible to clinically important Variations in the effect of placebo were partly explained by variations in how trials were conducted and how patients were informed

Philadelphia Panel Evidence-Based Clinical Practice Guidelines on Selected Rehabilitation Interventions for Low Back Pain

Abstract: Introduction. A structured and rigorous methodology was developed for the formulation of evidence-based clinical practice guidelines (EBCPGs), then was used to develop EBCPGs for selected rehabilitation interventions for the management of low back pain. Methods. Evidence from randomized controlled trials (RCTs) and observational studies was identified and synthesized using methods defined by the Cochrane Collaboration that minimize bias by using a systematic approach to literature search, study selection, data extraction, and data synthesis. Meta-analysis was conducted where possible. The strength of evidence was graded as level I for RCTs or level II for nonrandomized studies. Developing Recommendations. An expert panel was formed by inviting stakeholder professional organizations to nominate a representative. This panel developed a set of criteria for grading the strength of both the evidence and the recommendation. The panel decided that evidence of clinically important benefit (defined as 15% greater relative to a control based on panel expertise and empiric results) in patient-important outcomes was required for a recommendation. Statistical significance was also required, but was insufficient alone. Patient-important outcomes were decided by consensus as being pain, function, patient global assessment, quality of life, and return to work, providing that these outcomes were assessed with a scale for which measurement reliability and validity have been established. Validating the Recommendations. A feedback survey questionnaire was sent to 324 practitioners from 6 professional organizations. The response rate was 51%. Results. Four positive recommendations of clinical benefit were developed. Therapeutic exercises were found to be beneficial for chronic, subacute, and postsurgery low back pain. Continuation of normal activities was the only intervention with beneficial effects for acute low back pain. These recommendations were mainly in agreement with previous EBCPGs, although some were not covered by other EBCPGs. There was wide agreement with these recommendations from practitioners (greater than 85%). For several interventions and indications (eg, thermotherapy, therapeutic ultrasound, massage, electrical stimulation), there was a lack of evidence regarding efficacy. Conclusions. This methodology of developing EBCPGs provides a structured approach to assessing the literature and developing guidelines that incorporates clinicians' feedback and is widely acceptable to practicing clinicians. Further well-designed RCTs are warranted regarding the use of several interventions for patients with low back pain where evidence was insufficient to make recommendations.