BackgroundSystematic reviews within the field of animal research are becoming more common. However, in animal translational research, issues related to methodological quality and quality of reporting continue to arise, potentially leading to underestimation or overestimation of the effects of interventions or prevent studies from being replicated. The various tools and checklists available to ensure good-quality studies and proper reporting include both unique and/or overlapping items and/or simply lack necessary elements or are too situational to certain conditions or diseases. Currently, there is no tool available, which covers all aspects of animal models, from bench-top activities to animal facilities, hence a new tool is needed. This tool should be designed to be able to assess all kinds of animal studies such as old, new, low quality, high quality, interventional and noninterventional on. It should do this on multiple levels through items on quality of reporting, methodological (technical) quality, and risk of bias, for use in assessing the overall quality of studies involving animal research.MethodsDuring a systematic review of meningioma models in animals, we developed a novel unifying tool that can assess all types of animal studies from multiple perspectives. The tool was inspired by the Collaborative Approach to Meta Analysis and Review of Animal Data from Experimental Studies (CAMARADES) checklist, the ARRIVE 2.0 guidelines, and SYRCLE's risk of bias tool, while also incorporating unique items. We used the interrater agreement percentage and Cohen's kappa index to test the interrater agreement between two independent reviewers for the items in the tool.ResultsThere was high interrater agreement across all items (92.9%, 95% CI 91.0-94.8). Cohen's kappa index showed quality of reporting had the best mean index of 0.86 (95%-CI 0.78-0.94), methodological quality had a mean index of 0.83 (95%-CI 0.78-0.94) and finally the items from SYRCLE's risk of bias had a mean kappa index of 0.68 (95%-CI 0.57-0.79).ConclusionsThe Critical Appraisal of Methodological (technical) Quality, Quality of Reporting and Risk of Bias in Animal Research (CRIME-Q) tool unifies a broad spectrum of information (both unique items and items inspired by other methods) about the quality of reporting and methodological (technical) quality, and contains items from SYRCLE's risk of bias. The tool is intended for use in assessing overall study quality across multiple domains and items and is not, unlike other tools, restricted to any particular model or study design (whether interventional or noninterventional). It is also easy to apply when designing and conducting animal experiments to ensure proper reporting and design in terms of replicability, transparency, and validity.

Background Animal models are widely used to study pathological processes and drug (side) effects in a controlled environment. There is a wide variety of methods available for establishing animal models depending on the research question. Commonly used methods in tumor research include xenografting cells (established/commercially available or primary patient-derived) or whole tumor pieces either orthotopically or heterotopically and the more recent genetically engineered models—each type with their own advantages and disadvantages. The current systematic review aimed to investigate the meningioma model types used, perform a meta-analysis on tumor take rate (TTR), and perform critical appraisal of the included studies. The study also aimed to assess reproducibility, reliability, means of validation and verification of models, alongside pros and cons and uses of the model types. Methods We searched Medline, Embase, and Web of Science for all in vivo meningioma models. The primary outcome was tumor take rate. Meta-analysis was performed on tumor take rate followed by subgroup analyses on the number of cells and duration of incubation. The validity of the tumor models was assessed qualitatively. We performed critical appraisal of the methodological quality and quality of reporting for all included studies. Results We included 114 unique records (78 using established cell line models (ECLM), 21 using primary patient-derived tumor models (PTM), 10 using genetically engineered models (GEM), and 11 using uncategorized models). TTRs for ECLM were 94% (95% CI 92–96) for orthotopic and 95% (93–96) for heterotopic. PTM showed lower TTRs [orthotopic 53% (33–72) and heterotopic 82% (73–89)] and finally GEM revealed a TTR of 34% (26–43). Conclusion This systematic review shows high consistent TTRs in established cell line models and varying TTRs in primary patient-derived models and genetically engineered models. However, we identified several issues regarding the quality of reporting and the methodological approach that reduce the validity, transparency, and reproducibility of studies and suggest a high risk of publication bias. Finally, each tumor model type has specific roles in research based on their advantages (and disadvantages). Systematic review registration: PROSPERO-ID CRD42022308833.

BACKGROUND:An estimated 60% of pharmacological randomised trials use placebo control interventions to blind (i.e. mask) participants. However, standard placebos do not control for perceptible non-therapeutic effects (i.e. side effects) of the experimental drug, which may unblind participants. Trials rarely use active placebo controls, which contain pharmacological compounds designed to mimic the non-therapeutic experimental drug effects in order to reduce the risk of unblinding. A relevant improvement in the estimated effects of active placebo compared with standard placebo would imply that trials with standard placebo may overestimate experimental drug effects.OBJECTIVES:We aimed to estimate the difference in drug effects when an experimental drug is compared with an active placebo versus a standard placebo control intervention, and to explore causes for heterogeneity. In the context of a randomised trial, this difference in drug effects can be estimated by directly comparing the effect difference between the active placebo and standard placebo intervention.SEARCH METHODS:We searched PubMed, CENTRAL, Embase, two other databases, and two trial registries up to October 2020. We also searched reference lists and citations and contacted trial authors.SELECTION CRITERIA:We included randomised trials that compared an active placebo versus a standard placebo intervention. We considered trials both with and without a matching experimental drug arm.DATA COLLECTION AND ANALYSIS:We extracted data, assessed risk of bias, scored active placebos for adequacy and risk of unintended therapeutic effect, and categorised active placebos as unpleasant, neutral, or pleasant. We requested individual participant data from the authors of four cross-over trials published after 1990 and one unpublished trial registered after 1990. Our primary inverse-variance, random-effects meta-analysis used standardised mean differences (SMDs) of active versus standard placebo for participant-reported outcomes at earliest post-treatment assessment. A negative SMD favoured the active placebo. We stratified analyses by trial type (clinical or preclinical) and supplemented with sensitivity and subgroup analyses and meta-regression. In secondary analyses, we investigated observer-reported outcomes, harms, attrition, and co-intervention outcomes.MAIN RESULTS:We included 21 trials (1462 participants). We obtained individual participant data from four trials. Our primary analysis of participant-reported outcomes at earliest post-treatment assessment resulted in a pooled SMD of -0.08 (95% confidence interval (CI) -0.20 to 0.04; I2 = 31%; 14 trials), with no clear difference between clinical and preclinical trials. Individual participant data contributed 43% of the weight of this analysis. Two of seven sensitivity analyses found more pronounced and statistically significant differences; for example, in the five trials with low overall risk of bias, the pooled SMD was -0.24 (95% CI -0.34 to -0.13). The pooled SMD of observer-reported outcomes was similar to the primary analysis. The pooled odds ratio (OR) for harms was 3.08 (95% CI 1.56 to 6.07), and for attrition, 1.22 (95% CI 0.74 to 2.03). Co-intervention data were limited. Meta-regression found no statistically significant association with adequacy of the active placebo or risk of unintended therapeutic effect.AUTHORS' CONCLUSIONS:We did not find a statistically significant difference between active and standard placebo control interventions in our primary analysis, but the result was imprecise and the CI compatible with a difference ranging from important to irrelevant. Furthermore, the result was not robust, because two sensitivity analyses produced a more pronounced and statistically significant difference. We suggest that trialists and users of information from trials carefully consider the type of placebo control intervention in trials with high risk of unblinding, such as those with pronounced non-therapeutic effects and participant-reported outcomes.

BACKGROUND:Reporting bias poses a fundamental threat to the transparency and validity of interpretations of clinical trials, which may, in part, be mitigated through access Clinical Study Reports (CSRs). The European Medicines Agency (EMA), under their Policy 0070, prospectively publishes clinical data, including CSRs, submitted as part of marketing authorization applications or post-authorization procedures, although this practice is currently suspended for non-COVID-19 medicines, and have set out planned timelines for publication.METHODS:We conducted a cross-sectional study assessing the content and characteristics of all clinical data packages released by the EMA under Policy 0070 and the time to their publication. We extracted the number and characteristics of trials included in the clinical packages, assessed the delay to publication relative to the EMAs planned timeline and whether it differed between the EMAs various transparency measures and types of application procedures.RESULTS:We identified 148 clinical data packages that contained data on a total of 1,005 clinical trials, of which 261 (26%) were labelled as phase 3 trials. Full CSRs were available for 913 (90•8%) of the trials. The median time to publication was 511 (IQR 411 to 574) days. Only 2 (1•4%) of the clinical data packages were published within the EMA's planned timeline. The delay was shorter for clinical data packages released under the EMAs transparency measures for COVID.19 medicines compared with their standard transparency measure.CONCLUSION:The clinical data packages released by the EMA under Policy 0070 contained CSRs on many trials but were published with considerable delays relative to the timeline set forth by the EMA, reducing their potential impact on reporting bias.

Objectives This is a protocol for a Cochrane Review (intervention). The objectives are as follows: To assess the benefits and harms of ECT for preventing relapse and recurrence of depression in children, adolescents, adults, and older people with major depressive disorder.

BACKGROUND Attention deficit hyperactivity disorder (ADHD) is a psychiatric diagnosis increasingly used in adults. The recommended first-line pharmacological treatment is central nervous system (CNS) stimulants, such as methylphenidate, but uncertainty remains about its benefits and harms. OBJECTIVES To assess the beneficial and harmful effects of extended-release formulations of methylphenidate in adults diagnosed with ADHD. SEARCH METHODS We searched CENTRAL, MEDLINE, Embase, nine other databases and four clinical trial registries up to February 2021. We searched 12 drug regulatory databases for clinical trial data up to 13 May 2020. In addition, we cross-referenced all available trial identifiers, handsearched reference lists, searched pharmaceutical company databases, and contacted trial authors. SELECTION CRITERIA Randomised, double-blind, parallel-group trials comparing extended-release methylphenidate formulations at any dose versus placebo and other ADHD medications in adults diagnosed with ADHD. DATA COLLECTION AND ANALYSIS Two review authors independently extracted data. We assessed dichotomous outcomes as risk ratios (RRs), and rating scales and continuous outcomes as mean differences (MDs) or standardised mean differences (SMDs). We used the Cochrane risk of bias tool to assess risks of bias, and GRADE to assess the certainty of the evidence. We meta-analysed the data using a random-effects model. We assessed three design characteristics that may impair the trial results' 'generalisability'; exclusion of participants with psychiatric comorbidity; responder selection based on previous experience with CNS stimulants; and risk of withdrawal effects. Our prespecified primary outcomes were functional outcomes, self-rated ADHD symptoms, and serious adverse events. Our secondary outcomes included quality of life, ADHD symptoms rated by investigators and by peers such as family members, cardiovascular variables, severe psychiatric adverse events, and other adverse events. MAIN RESULTS We included 24 trials (5066 participants), of which 21 reported outcome data for this review. We also identified one ongoing study. We included documents from six drug regulatory agencies covering eight trials. Twenty-one trials had an outpatient setting and three were conducted in prisons. They were primarily conducted in North America and Europe. The median participant age was 36 years. Twelve trials (76% of participants) were industry-sponsored, four (14% of participants) were publicly funded with industry involvement, seven (10% of participants) were publicly funded, and one had unclear funding. The median trial duration was eight weeks. One trial was rated at overall unclear risk of bias and 20 trials were rated at overall high risk of bias, primarily due to unclear blinding of participants and investigators, attrition bias, and selective outcome reporting. All trials were impaired in at least one of the three design characteristics related to 'generalisability'; for example, they excluded participants with psychiatric comorbidity such as depression or anxiety, or included participants only with a previous positive response to methylphenidate, or similar drugs. This may limit the trials' usefulness for clinical practice, as they may overestimate the benefits and underestimate the harms. Extended-release methylphenidate versus placebo (up to 26 weeks) For the primary outcomes, we found very low-certainty evidence that methylphenidate had no effect on 'days missed at work' at 13-week follow-up (mean difference (MD) -0.15 days, 95% confidence interval (CI) -2.11 to 1.81; 1 trial, 409 participants) or serious adverse events (risk ratio (RR) 1.43, CI 95% CI 0.85 to 2.43; 14 trials, 4078 participants), whereas methylphenidate improved self-rated ADHD symptoms (small-to-moderate effect; SMD -0.37, 95% CI -0.43 to -0.30; 16 trials, 3799 participants). For secondary outcomes, we found very low-certainty evidence that methylphenidate improved self-rated quality of life (small effect; SMD -0.15, 95% CI -0.25 to -0.05; 6 trials, 1888 participants), investigator-rated ADHD symptoms (small-to-moderate effect; SMD -0.42, 95% CI -0.49 to -0.36; 18 trials, 4183 participants), ADHD symptoms rated by peers such as family members (small-to-moderate effect; SMD -0.31, 95% CI -0.48 to -0.14; 3 trials, 1005 participants), and increased the risk of experiencing any adverse event (RR 1.27, 95% CI 1.19 to 1.37; 14 trials, 4214 participants). We rated the certainty of the evidence as 'very low' for all outcomes, primarily due to high risk of bias and 'indirectness of the evidence'. One trial (419 participants) had follow-up at 52 weeks and two trials (314 participants) included active comparators, hence long-term and comparative evidence is limited. AUTHORS' CONCLUSIONS We found very low-certainty evidence that extended-release methylphenidate compared to placebo improved ADHD symptoms (small-to-moderate effects) measured on rating scales reported by participants, investigators, and peers such as family members. Methylphenidate had no effect on 'days missed at work' or serious adverse events, the effect on quality of life was small, and it increased the risk of several adverse effects. We rated the certainty of the evidence as 'very low' for all outcomes, due to high risk of bias, short trial durations, and limitations to the generalisability of the results. The benefits and harms of extended-release methylphenidate therefore remain uncertain.

ObjectivesThis is a protocol for a Cochrane Review (intervention).The objectives are as follows:To assess the benefits and harms of ECT for preventing relapse and recurrence of a ective episodes (depression, hypomania, mania or mixed state) in children, adolescents, adults, and older people diagnosed with bipolar disorder.Electroconvulsive therapy for preventing relapse and recurrence in bipolar disorder (Protocol)

Objectives This is a protocol for a Cochrane Review (intervention). The objectives are as follows: To assess the benefits and harms of electroconvulsive therapy for an acute depressive episode in children, adolescents, adults, and older people.

Background Effective drug treatments for Covid-19 are needed to decrease morbidity and mortality for the individual and to alleviate pressure on health care systems. Remdesivir showed promising results in early randomised trials but subsequently a large publicly funded trial has shown less favourable results and the evidence is interpreted differently in clinical guidelines. Systematic reviews of remdesivir have been published, but none have systematically searched for unpublished data, including regulatory documents, and assessed the risk of bias due to missing evidence. Methods We will conduct a systematic review of randomised trials comparing remdesivir to placebo or standard of care in any setting. We will include trials regardless of the severity of disease and we will include trials examining remdesivir for indications other than Covid-19 for harms analyses. We will search websites of regulatory agencies, trial registries, bibliographic databases, preprint servers and contact trial sponsors to obtain all available data, including unpublished clinical data, for all eligible trials. Our primary outcomes will be all-cause mortality and serious adverse events. Our secondary outcomes will be length of hospital stay, time to death, severe disease, and adverse events. We will assess the risk of bias using the Cochranes Risk of Bias 2 tool and the risk of bias due to missing evidence (e.g. publication bias, selective reporting bias) using the ROB-ME tool. Where appropriate we will synthesise study results by conducting random-effects meta-analysis. We will present our findings in a Summary of Findings table and rate the certainty of the evidence using the GRADE approach. Discussion By conducting a comprehensive systematic review including unpublished data (where available), we expect to be able to provide valuable information for patients and clinicians about the benefits and harms of remdesivir for the treatment of Covid-19. This will help to ensure optimal treatment for individual patients and optimal utilisation of health care resources. Systematic review registration CRD42021255915.

This is a protocol to an umbrella review entitled, ‘Considering the methodological limitations and external validity issues of pharmacological drug trials in adult ADHD: An umbrella review (Open Protocol)’.

Objectives This is a protocol for a Cochrane Review (intervention). The objectives are as follows: To assess the benefits and harms of electroconvulsive therapy for an acute affective episode (hypomania, mania, mixed state or depression) in children, adolescents, adults and older people with bipolar disorder.

BACKGROUND: Selective reporting of trial results is common. OBJECTIVE: To study selective reporting in clinical study reports, company trial registers and publications of quality of life in placebo-controlled trials of antidepressants. METHODS: We compared clinical study reports of four antidepressants (fluoxetine, duloxetine, paroxetine and sertraline) obtained from two European drug regulators, data from online company registers, and publications received or retrieved from Eli Lilly and GlaxoSmithKline. Pfizer was also contacted but did not provide any publications. RESULTS: We included 15 trials (19,015 pages) and 4717 patients. Six trials had used SF-36, seven EQ-5D and two both instruments. Nine of the 15 CSRs (60%) displayed selective reporting. In the companies' online registers, there was selective reporting for all 15 trials (100%). We received 20 publications from Eli Lilly and retrieved six from the GlaxoSmithKline register. There was selective reporting in 24 of the 26 publications (92%). Despite extensive selective reporting, we found only small differences between placebo and active drugs. CONCLUSIONS: Access to the full raw data from clinical trials and to case report forms for all patients are needed to evaluate the effect of antidepressants on quality of life. Regulatory agencies should refuse to approve drugs or new indications based on incomplete reporting.

To assess the adverse e ects of electroconvulsive therapy across indications in children, adolescents, adults and older people. Adverse e ects of electroconvulsive therapy (Protocol)

BACKGROUND:Handwashing is important to reduce the spread and transmission of infectious disease. Ash, the residue from stoves and fires, is a material used for cleaning hands in settings where soap is not widely available. OBJECTIVES:To assess the benefits and harms of hand cleaning with ash compared with hand cleaning using soap or other materials for reducing the spread of viral and bacterial infections. SEARCH METHODS:On 26 March 2020 we searched CENTRAL, MEDLINE, Embase, WHO Global Index Medicus, and the WHO International Clinical Trials Registry Platform. SELECTION CRITERIA:We included all types of studies, in any population, that examined hand cleaning with ash compared to hand cleaning with any other material. DATA COLLECTION AND ANALYSIS:Two review authors independently screened titles and full texts, and one review author extracted outcome data and assessed risk of bias, which another review author double-checked. We used the ROBINS-I tool for observational studies, we used RoB 2.0 for three interventional studies, and we used GRADE to assess the certainty of the evidence. We planned to synthesise data with random-effects meta-analyses. Our prespecified outcome measures were overall mortality, number of cases of infections (as defined in the individual studies), severity of infectious disease, harms (as reported in the individual studies), and adherence. MAIN RESULTS:We included 14 studies described in 19 records using eight different study designs, but only one randomised trial. The studies were primarily conducted in rural settings in low- and lower-middle-income countries. Six studies reported outcome data relevant to our review. A retrospective case-control study and a cohort study assessed diarrhoea in children under the age of five years and self-reported reproductive tract symptoms in women, respectively. It was very uncertain whether the rate of hospital contacts for moderate-to-severe diarrhoea in children differed between households that cleaned hands using ash compared with households cleaning hands using soap (RR 0.97, 95% CI 0.84 to 1.11; very low-certainty evidence). Similarly, it was very uncertain whether the rate of women experiencing symptoms of reproductive tract infection differed between women cleaning hands with ash compared with cleaning hands using soap (RR 0.48, 95% CI 0.12 to 1.86; very low-certainty evidence) or when compared with handwashing with water only or not washing hands (RR 0.50, 95% CI 0.13 to 1.96; very low-certainty evidence). Four studies reported on bacteriological counts after hand wash. We rated all four studies at high risk of bias, and we did not synthesise data due to methodological heterogeneity and unclear outcome reporting. AUTHORS' CONCLUSIONS:Based on the available evidence, the benefits and harms of hand cleaning with ash compared with soap or other materials for reducing the spread of viral or bacterial infections are uncertain.

ObjectivesThis is a protocol for a Cochrane Review (methodology).The objectives are as follows:To estimate di erences in e ects between pharmacological active placebo interventions and standard placebo interventions in randomised trials. Active placebo versus standard placebo control interventions in pharmacological randomised trials (Protocol)

This is a protocol for the project entitled: 'Are clinical trial participants informed about potential benefits and harms? A comparison of informed consent materials and trial protocols.'

ObjectivesTo investigate whether the conclusion of a recent systematic review and network meta-analysis (Cipriani et al) that antidepressants are more efficacious than placebo for adult depression was supported by the evidence.DesignReanalysis of a systematic review, with meta-analyses.Data sources522 trials (116 477 participants) as reported in the systematic review by Cipriani et al and clinical study reports for 19 of these trials.AnalysisWe used the Cochrane Handbook’s risk of bias tool and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to evaluate the risk of bias and the certainty of evidence, respectively. The impact of several study characteristics and publication status was estimated using pairwise subgroup meta-analyses.ResultsSeveral methodological limitations in the evidence base of antidepressants were either unrecognised or underestimated in the systematic review by Cipriani et al. The effect size for antidepressants versus placebo on investigator-rated depression symptom scales was higher in trials with a ‘placebo run-in’ study design compared with trials without a placebo run-in design (p=0.05). The effect size of antidepressants was higher in published trials compared with unpublished trials (p<0.0001). The outcome data reported by Cipriani et al differed from the clinical study reports in 12 (63%) of 19 trials. The certainty of the evidence for the placebo-controlled comparisons should be very low according to GRADE due to a high risk of bias, indirectness of the evidence and publication bias. The mean difference between antidepressants and placebo on the 17-item Hamilton depression rating scale (range 0–52 points) was 1.97 points (95% CI 1.74 to 2.21).ConclusionsThe evidence does not support definitive conclusions regarding the benefits of antidepressants for depression in adults. It is unclear whether antidepressants are more efficacious than placebo.

OBJECTIVE:To investigate to what extent evidence from previous similar trials or systematic reviews was considered before conducting new trials.DESIGN:Cohort study of contemporary protocols for trials with ethical approval.METHODS:All protocols for randomised trials approved by the five ethical committees in Denmark between January 2012 and March 2013 were screened for eligibility. Included protocols were read in full to determine whether a systematic search had been conducted and references were checked to evaluate whether trial rationale and design could be challenged for not adequately considering previous evidence. To investigate whether protocols cited relevant trials, we used simple search strategies that could easily be conducted by researchers without experience with literature searches.RESULTS:Sixty-seven protocols were included. Only two (3%) of the protocols explicitly stated to have conducted a literature search and only one (1%) provided information that allowed the search to be replicated. Eleven (16%) of the protocols described trials where we found the information insufficient to judge if the trial was ethically justified, either due to a comparator that was not supported by the presented evidence (six protocols), because they did not present a rationale for conducting the trial (two protocols), or for both reasons (three protocols). For eight (12%) of the protocols, our search identified trials that could have been relevant to cite as justification.CONCLUSIONS:While most protocols seem to adequately consider existing evidence, a substantial minority of trials might lack a sufficient evidence base. Very few trials seemed to have been based on a literature search which makes it impossible to know whether all relevant previous trials had been considered. Rules for ethical approval should include requirements for systematic literature searches to ensure that research participants are not exposed to sub-optimal treatments or unnecessary harms as well as to reduce research waste.

BACKGROUND:Run-in periods are occasionally used in randomized clinical trials to exclude patients after inclusion, but before randomization. In theory, run-in periods increase the probability of detecting a potential treatment effect, at the cost of possibly affecting external and internal validity. Adequate reporting of exclusions during the run-in period is a prerequisite for judging the risk of compromised validity. Our study aims were to assess the proportion of randomized clinical trials with run-in periods, to characterize such trials and the types of run-in periods and to assess their reporting.MATERIALS AND METHODS:This was an observational study of 470 PubMed-indexed randomized controlled trial publications from 2014. We compared trials with and without run-in periods, described the types of run-in periods and evaluated the completeness of their reporting by noting whether publications stated the number of excluded patients, reasons for exclusion and baseline characteristics of the excluded patients.RESULTS:Twenty-five trials reported a run-in period (5%). These were larger than other trials (median number of randomized patients 217 vs 90, P=0.01) and more commonly industry trials (11% vs 3%, P<0.01). The run-in procedures varied in design and purpose. In 23 out of 25 trials (88%), the run-in period was incompletely reported, mostly due to missing baseline characteristics.CONCLUSION:Approximately 1 in 20 trials used run-in periods, though much more frequently in industry trials. Reporting of the run-in period was often incomplete, precluding a meaningful assessment of the impact of the run-in period on the validity of trial results. We suggest that current trials with run-in periods are interpreted with caution and that updates of reporting guidelines for randomized trials address the issue.