Prospective Trial Registration Research Articles

Trials that turn from retrospectively registered to prospectively registered: a cohort study of “retroactively prospective” clinical trial registration using history data

BackgroundProspective registration of clinical trials is mandated by various regulations. However, clinical trial registries like ClinicalTrials.gov allow registry entries to be updated at any time, and key study elements, including the start date, may change before the first patient is enrolled. If a trial changes its start date after recruiting began, however, it may indicate a reason for concern. This study aimed to measure the rate of “retroactively prospective” trials. This refers to trials that are originally registered retrospectively, with the start date before the registration date, but that retroactively change their start date to be after the registration date, making them appear as if they were prospectively registered.MethodsWe retrieved clinical trial history data for all clinical trials registered on ClinicalTrials.gov with a first registration date in the year 2015 (N = 11,908). Using automated analyses, we determined the timepoints of registration in relation to the start date of the trial over time. For retroactively prospective trials and a set of control trials, we manually checked the accompanying publications to determine which start date they report and whether they report changes to the start date.ResultsWe found 235 clinical trials to be retroactively prospective, comprising 2.0% of all clinical trials in our sample of 11,908 trials. Among the 113 retroactively prospective clinical trials with an accompanying publication, 12 (10.6%) explicitly stated in the publication that they had been prospectively registered.ConclusionsRetroactively prospective trial registration happens in one in 50 trials. While these changes to the start date could be mistakes or legitimate edits based on the most up-to-date information, they could also indicate a retrospectively registered trial that has been made to appear as a prospectively registered trial, which would lead to biases unapparent to reviewers. Our results point to the need for more transparent reporting of changes to a trial’s details and have implications for the review and conduct of clinical trials, with our fully automated and freely available tools allowing reviewers or editors to detect these changes.Trial registrationThe preregistered protocol of our study is available via https://osf.io/rvq53. The most recent version of the protocol lists all deviations from the original study plan, including the rationale behind the changes, and additional analyses that were conducted.

Is there 'trustworthy' evidence for using manual therapy to treat patients with shoulder dysfunction?: A systematic review.

The primary objective of this review was to create a 'trustworthy,' living systematic review and meta-analysis for the application of manual therapy interventions in treating patients with shoulder dysfunction. Included studies were English-language randomized controlled trials published between 1/1/2010 and 8/3/2023, with searches performed in: PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), CINHAL, ProQuest Nursing & Allied Health, EBSCO Medline, and PEDro. The population of focus included adults 18 years and older with musculoskeletal impairments related to shoulder dysfunction. Our primary outcomes included pain and region-specific outcome measures. We excluded trials, including participants having shoulder dysfunction resulting from surgery, radicular pain, instability/dislocation, fracture, lymphedema, and radiation. Our screening methodology was based upon a previously published 'trustworthy' systematic review protocol. This included the application of our PICOTS criteria in addition to screening for prospective clinical trial registration and following of prospective intent, as well as assessment of PEDro scores, risk-of-bias ratings, GRADE scoring, and examination of confidence in estimated effects. Twenty-six randomized controlled trials met our PICOTS criteria; however, only 15 of these were registered. Only three were registered prospectively. Two of these did not have discussions and conclusions that aligned with their primary outcome. The remaining single study was found to have a high risk-of-bias, meaning the remainder of the protocol could not be employed and that no randomized controlled trials could undergo further assessment or meta-analysis. The results of this systematic review indicate there are no 'trustworthy' randomized controlled trials examining the effectiveness of manual therapy interventions for the treatment of patients with shoulder dysfunction, as defined by the prospectively established methodology. Therefore, these findings signal that creating a 'trustworthy,' living systematic review on this clinically relevant topic is not yet possible due to a lack of 'trustworthy' randomized controlled trials.

The efficacy of ultrasound-guided erector spinae plane block (ESPB) versus freehand ESPB in postoperative pain management after lumbar spinal fusion surgery: a randomized, non-inferiority trial.

Spine surgeries have experienced exponential growth over the past 2 decades. These surgeries are often accompanied by long and severe perioperative pain, presenting a significant management challenge. This study aims to assess and compare the efficacy of two techniques for postoperative pain (POP) management in lumbar spine surgeries: ultrasound-guided erector spinae plane block (ESPB) and intraoperative freehand ESPB. In this prospective randomized non-inferiority trial (Registration Number: IRCT20221107056427N1), adult patients who were candidates for lumbar spinal fusion surgery were randomly divided into two groups: ultrasound-guided ESPB (n = 29) and freehand ESPB (n = 29). The primary outcomes were the total amount of morphine consumed during the first 24h following the surgery and the numerical rating scale (NRS) pain score at various time points within the first 24h following the surgery. The secondary outcome was the fentanyl used during surgery. Participants in the intraoperative freehand approach had considerably higher total morphine consumption in the first postoperative 24h. The trend of NRS changes in both the ultrasound-guided ESPB group and the freehand ESPB group during the first 24h after surgery showed a significant decrease. Still, there was no significant difference between the two groups. However, the first analgesic demand time was significantly shorter in the intraoperative freehand ESPB group compared to the ultrasound-guided approach. According to our results, the ultrasound-guided approach of ESPB is more effective in POP management and opioid sparing in lumbar spinal fusion surgeries compared to the freehand approach. However, the data from this study are not sufficient to draw robust conclusions, and further randomized controlled trials with larger sample sizes are required to validate our results.

The Rising Quality of Randomized Controlled Trials in The Journal of Bone & Joint Surgery: An Updated Analysis from 2014 to 2022.

Previous reports found that 40% of randomized controlled trials (RCTs) published in The Journal of Bone & Joint Surgery (JBJS) from 1988 to 2000 and 47% of those published from 2001 to 2013 were of high quality. The purpose of this study was to assess the quality of RCTs published from 2014 to 2022 in JBJS and to compare these findings with those of prior analyses in order to identify trends over time and areas for continued improvement. PubMed was searched for the term "randomized controlled trial" to identify studies published in JBJS from 2014 to 2022. Each included RCT was evaluated with use of the Detsky score and a risk-of-bias assessment modified from the Cochrane tool. These evaluations were then compared with previous evaluations of RCTs from the 1988 to 2000 and 2001 to 2013 periods with use of independent-sample t tests. A transformed Detsky score of >75% and a modified risk-of-bias score of ≥8 were defined as being indicative of high quality. A total of 218 RCTs were published in JBJS from 2014 to 2022. An a priori sample size was calculated in 183 studies (83.9%). A total of 152 (83.1%) of the 183 studies enrolled the calculated number of patients, of which 126 (82.9%) maintained an adequate number at the time of final follow-up. Most RCTs were conducted at a single center (146 of 218; 67%), evaluated a surgical intervention (162 of 218; 74%), and reported positive results (142 of 218; 65%). The mean transformed Detsky score was 85% ± 10% (95% confidence interval, 83.7% to 86.3%), with 82% of trials (179 of 218) scored as high quality. The mean transformed Detsky score from 2014 to 2022 was higher than that from 1988 to 2000 and that from 2001 to 2013 (85% versus 76% and 68%, respectively; p < 0.001). The mean modified risk-of-bias score was 7 ± 1, with 42% of trials (92 of 218) scored as high quality. RCTs published from 2014 to 2022 had a higher mean modified risk-of-bias score than those published from 2001 to 2013 (7 ± 1 versus 6 ± 1; p < 0.001). Compared with the 2001 to 2013 and 2014 to 2022 periods, the 1988 to 2000 period had a greater proportion of trials that reported positive results (51% and 65% versus 82%, respectively; p < 0.001) and that included data from multiple centers (31% and 33% versus 67%; p < 0.001). The quality of RCTs published in JBJS from 2014 to 2022 has improved from that reported previously, as demonstrated by the increases in the modified risk-of-bias score and transformed Detsky score from prior periods. This may be the result of journal policies such as the requirements of CONSORT adherence and prospective trial registration. Investigators should focus on improving the clarity of reporting, limiting attrition bias, and making efforts to blind support staff in order to increase the quality of future RCTs. Improving the quality of RCTs is crucial given their potential to influence current clinical practice.

The safety and efficacy of ultrasound-guided erector spinae plane block in postoperative analgesic of PCNL: A systematic review and meta-analysis.

The patients received percutaneous nephrolithotomy (PCNL) with severe postoperative pain and discomfort. The erector spinae plane block (ESPB), as a new anesthesia method of plane block, has a positive effect on postoperative analgesia. But evidence of ESPB in PCNL is still lacking. The objective of this study was to systematically analyze the postoperative analgesic effect of ESPB in patients receiving PCNL. The literature searching was conducted in PubMed, EMBASE, Cochrane Library and Clinical Trial Database (clinicaltrials.gov). Two independent researchers screened the included studies and extracted data. Meta-analysis was conducted by using the random-effect model with 95% confidence intervals. Chi-squared test with a significance level of 0.1 was utilized to evaluate the heterogeneity of included studies. The subgroup analysis and meta-regression analysis were conducted in studies with high heterogeneity. The publication bias was assessed based on whether there were discrepancies between prospective trial registration and reported protocols. There were 8 studies involving 456 patients assessing the efficacy of ESPB in reducing postoperative pain score of PCNL compared with no block or other blocks, such as subcutaneous infiltration, general anesthesia or TPVB intrathecal morphine. ESPB was a significantly effective and safe anesthesia method, which not only improved postoperative pain response (MD -1.76; 95% CI -2.57 to -0.94; I 2 = 85%; p<0.01), but also reduced analgesic consumption (MD -16.92; 95% CI -26.25 to -7.59; I 2 = 92.2%; p<0.01) and prolonged the time of first request for postoperative analgesia (MD 93.27; 95% CI 35.79 to 150.75; I 2 = 85.3%; p = 0.001) in patients receiving PCNL without significant postoperative complications (MD 0.80; 95% CI 0.31 to 2.03; I 2 = 0%; p = 0.404). Compared with no block or other blocks, the ESPB was a safe and effective anesthesia for patients receiving PCNL.

Standard quality criteria in retracted vs nonretracted obstetrical randomized controlled trials

The number of retracted articles in peer-reviewed journals is increasing within the field of obstetrics. The most common reason for article retraction is scientific misconduct. Unfortunately, article retraction often occurs years after publication, allowing inaccurate data to be widely distributed to readers. There exists a great need for validated screening criteria for obstetric journals to use when reviewing randomized controlled trials for scientific misconduct. This study aimed to compare retracted obstetric randomized controlled trials with nonretracted randomized controlled trials with regard to their inclusion of 7 quality metrics: prospective trial registration, trial registration number, ethics approval statement, name of the approving committee, statement of informed consent, adherence to the Consolidated Standards of Reporting Trials guidelines, and a data sharing statement. Obstetric randomized controlled trials retracted between 1995 and 2021 identified through Retraction Watch were compared with nonretracted randomized controlled trials published between 2018 and 2020 with regard to inclusion of the 7 quality metrics. The main outcome was the difference in prospective trial registration. Secondary outcomes were the percentage of individual criteria met and the screening performance of quality criteria in predicting article retraction. A total of 150 randomized controlled trials were identified, of which 14 (9.3%) were retracted and 136 (90.7%) nonretracted. Retracted randomized controlled trials were less likely than nonretracted randomized controlled trials to be prospectively registered (14.3% vs 80.1%; P<.001). The median number of quality criteria met was lower for retracted randomized controlled trials (3 vs 6; P<.01). Using a cutoff of ≤4 criteria was associated with 85.7% (95% confidence interval, 57.2-98.2) sensitivity and 92.0% (95% confidence interval, 86.2-96.0) specificity in distinguishing the retracted randomized controlled trials from nonretracted studies. Retracted obstetric randomized controlled trials were less likely to include the 7 quality metrics required on submission by most top obstetrics and gynecology journals.

Publication bias in trials registered in the Australian New Zealand Clinical Trials Registry: Is it a problem? A cross-sectional study.

Timely publication of clinical trials is critical to ensure the dissemination and implementation of high-quality healthcare evidence. This study investigates the publication rate and time to publication of randomized controlled trials (RCTs) registered in the Australian New Zealand Clinical Trials Registry (ANZCTR). We conducted a cross-sectional study of RCTs registered with the ANZCTR in 2007, 2009, and 2011. Multiple bibliographic databases were searched until October 2021 to identify trial publications. We then calculated publication rates, proportions, and the time to publish calculated from the date of first participation enrolment to publication date. Of 1,970 trial registrations, 541 (27%) remained unpublished 10 to 14 years later, and the proportion of trials published decreased by 7% from 2007 to 2011. The average time to publish was 4.63 years. The prospective trial registration rate for 2007, 2009 and 2011 was 48% (952 trials) and over this time there was an increase of 19% (280 prospective trials). Trials funded by non-Industry organizations were more likely to be published (74%, 1204/1625 trials) than the industry-funded trials (61%, 224/345 trials). Larger trials with at least 1000 participants were published at a rate of 88% (85/97 trials) and on average took 5.4 years to be published. Smaller trials with less than 100 participants were published at a lower rate with 67% (687/1024 trials) published and these trials took 4.31 years on average to publish. Just over a quarter of all trials on the ANZCTR for 2007, 2009, and 2011 remain unpublished over a decade later. The average time to publication of nearly five years may reflect the larger trials which will have taken longer to recruit participants. Over half of study sample trials were retrospectively registered, but prospective registration improved over time, highlighting the role of mandating trial registration.

CTRI requirement of prospective trial registration: Not always consistent.

In a clinical trial registry, one determines whether a trial is registered prospectively or retrospectively by comparing the date of registration with the date on which enrollment started. However, in Clinical Trials Registry - India (CTRI), in addition, the top of each record is labelled with the phrase "Trial Registered Prospectively" or "Trial Registered Retrospectively". In examining CTRI records, we have found that (a) although retrospective registration has been disallowed from April 1, 2018, some trials were registered retrospectively; (b) in some cases, enrollment started after registration, even though they were labelled "Trial Registered Retrospectively", which is misleading; and (c) in some cases, the date of first enrollment was modified, changing a retrospective registration to a prospective one, although the label "Trial Registered Retrospectively" persisted. This, too, is misleading. The CTRI administration should take suitable steps to prevent late registration and mislabelling of trials regarding their registration status.

Identifying and managing problematic trials: A research integrity assessment tool for randomized controlled trials in evidence synthesis.

Evidence synthesis findings depend on the assumption that the included studies follow good clinical practice and results are not fabricated or false. Studies which are problematic due to scientific misconduct, poor research practice, or honest error may distort evidence synthesis findings. Authors of evidence synthesis need transparent mechanisms to identify and manage problematic studies to avoid misleading findings. As evidence synthesis authors of the Cochrane COVID-19 review on ivermectin, we identified many problematic studies in terms of research integrity and regulatory compliance. Through iterative discussion, we developed a research integrity assessment (RIA) tool for randomized controlled trials for the update of this Cochrane review. In this paper, we explain the rationale and application of the RIA tool in this case study. RIA assesses six study criteria: study retraction, prospective trial registration, adequate ethics approval, author group, plausibility of methods (e.g., randomization), and plausibility of study results. RIA was used in the Cochrane review as part of the eligibility check during screening of potentially eligible studies. Problematic studies were excluded and studies with open questions were held in awaiting classification until clarified. RIA decisions were made independently by two authors and reported transparently. Using the RIA tool resulted in the exclusion of >40% of studies in the first update of the review. RIA is a complementary tool prior to assessing "Risk of Bias" aiming to establish the integrity and authenticity of studies. RIA provides a platform for urgent development of a standard approach to identifying and managing problematic studies.

Adoption of World Health Organization Best Practices in Clinical Trial Transparency Among European Medical Research Funder Policies

Research funders can reduce research waste and publication bias by requiring their grantees to register and report clinical trials. To determine the extent to which 21 major European research funders' efforts to reduce research waste and publication bias in clinical trials meet World Health Organization (WHO) best practice benchmarks and to investigate areas for improvement. This cross-sectional study was based on 2 to 3 independent assessments of each funder's publicly available documentation and validation of results with funders during 2021. Included funders were the 21 largest nonmultilateral public and philanthropic medical research funders in Europe, with a combined budget of more than US $22 billion. Scoring of funders using an 11-item assessment tool based on WHO best practice benchmarks, grouped into 4 broad categories: trial registries, academic publication, monitoring, and sanctions. Funder references to reporting standards were captured. The primary outcome was funder adoption or nonadoption of 11 policy and monitoring measures to reduce research waste and publication bias as set out by WHO best practices. The secondary outcomes were whether and how funder policies referred to reporting standards. Outcomes were preregistered after a pilot phase that used the same outcome measures. Among 21 of the largest nonmultilateral public and philanthropic funders in Europe, some best practices were more widely adopted than others, with 14 funders (66.7%) mandating prospective trial registration and 6 funders (28.6%) requiring that trial results be made public on trial registries within 12 months of trial completion. Less than half of funders actively monitored whether trials were registered (9 funders [42.9%]) or whether results were made public (8 funders [38.1%]). Funders implemented a mean of 4 of 11 best practices in clinical trial transparency (36.4%) set out by WHO. The extent to which funders adopted WHO best practice items varied widely, ranging from 0 practices for the French Centre National de la Recherche Scientifique and the ministries of health of Germany and Italy to 10 practices (90.9%) for the UK National Institute of Health Research. Overall, 9 funders referred to reporting standards in their policies. This study found that many European medical research funder policy and monitoring measures fell short of WHO best practices. These findings suggest that funders worldwide may need to identify and address gaps in policies and processes.

Supporting parenting among Syrian refugees in Lebanon: a randomized controlled trial of the caregiver support intervention.

Parenting interventions in humanitarian settings have prioritized the acquisition of parenting knowledge and skills, while overlooking the adverse effects of stress and distress on parenting-a key mediator of refugee children's mental health. We evaluated the effectiveness of the Caregiver Support Intervention (CSI), which emphasizes caregiver wellbeing together with training in positive parenting. We conducted a two-arm randomized controlled trial of the CSI with Syrian refugees in Lebanon, with an intent-to-treat design, from September 2019-December 2020. A total of 480 caregivers from 240 families were randomized to the CSI or a waitlist control group (1:1). Retention from baseline to endline was 93%. Data on parenting and caregiver psychological wellbeing were collected at baseline, endline, and three-month follow-up. Prospective trial registration: ISRCTN22321773. We did not find a significant change on overall parenting skills at endline (primary outcome endpoint) (d = .11, p = .126) or at follow-up (Cohen's d = .15, p = .054). We did find a significant effect on overall parenting skills among participants receiving the full intervention-the sub-sample not interrupted by (COVID-19) (d = 0.25, p < .05). The CSI showed beneficial effects in the full sample at endline and follow-up on harsh parenting (d = -.17, p < .05; d = .19, p < .05), parenting knowledge (d = .63, p < .001; d = .50, p < .001), and caregiver distress (d = -.33, p < .001; d = .23, p < .01). We found no effects on parental warmth and responsiveness, psychosocial wellbeing, stress, or stress management. Changes in caregiver wellbeing partially mediated the impact of the CSI on harsh parenting, accounting for 37% of the reduction in harsh parenting. The CSI reduced harsh parenting and caregiver distress, and demonstrated the value of addressing caregiver wellbeing as a pathway to strengthening parenting in adversity. These effects were achieved despite a pandemic-related lockdown that impacted implementation, a severe economic crisis, and widespread social unrest. Replication under less extreme conditions may more accurately demonstrate the intervention's full potential.

Trial registration of abstracts from the American Society of Anesthesiologists Meetings 2010-2016: A review of prospective trial registration and selective outcome reporting.

Mandatory prospective trial registration was introduced in 2005 to reduce publication bias and selective outcome reporting. In this study, we measured the proportion of prospective trial registration in randomized controlled trials in the anesthesia literature after this introduction, discrepancies between these trial protocols and subsequent publications, the association between being prospectively registered and reporting positive or negative results, and between being prospectively registered and achieving publication. We reviewed all abstracts from the American Society of Anesthesiologists annual meetings between 2010–2016 and included randomized controlled trials in humans. The abstract conclusions were scored as positive or negative according to predetermined definitions. We conducted a systematic search for trial registration and subsequent publication. Of the 9789 abstracts reviewed, 1070 abstracts were included. 222 (21%) of these abstracts had undergone prospective trial registration. 168/222 (76%) had a corresponding journal publication. 81(48%) had a major discrepancy between registration and publication. 149 (67%) of the abstracts with registration had positive outcomes compared with 616 (73%) of those without (Odds Ratio 0.77; 95% CI: 0.56 to 1.06; P = 0.105). s that had been registered were more likely to proceed to publication than those that had not (Odds Ratio 3.82; 95% CI 2.73 to 5.35; P < 0.001). The proportion of randomized controlled trials being prospectively registered in anesthesia remains low. Discrepancies between registry entries and corresponding journal publications are common. There was no association between prospective trial registration and subsequent positive outcomes. There was a strong association between prospective trial registration and the likelihood of progression to journal publication.

Study of effect of nimodipine and acetaminophen on postictal symptoms in depressed patients after electroconvulsive therapy (SYNAPSE)

BackgroundPostictal phenomena as delirium, headache, nausea, myalgia, and anterograde and retrograde amnesia are common manifestations after seizures induced by electroconvulsive therapy (ECT). Comparable postictal phenomena also contribute to the burden of patients with epilepsy. The pathophysiology of postictal phenomena is poorly understood and effective treatments are not available. Recently, seizure-induced cyclooxygenase (COX)-mediated postictal vasoconstriction, accompanied by cerebral hypoperfusion and hypoxia, has been identified as a candidate mechanism in experimentally induced seizures in rats. Vasodilatory treatment with acetaminophen or calcium antagonists reduced postictal hypoxia and postictal symptoms. The aim of this clinical trial is to study the effects of acetaminophen and nimodipine on postictal phenomena after ECT-induced seizures in patients suffering major depressive disorder. We hypothesize that (1) acetaminophen and nimodipine will reduce postictal electroencephalographic (EEG) phenomena, (2) acetaminophen and nimodipine will reduce magnetic resonance imaging (MRI) measures of postictal cerebral hypoperfusion, (3) acetaminophen and nimodipine will reduce clinical postictal phenomena, and (4) postictal phenomena will correlate with measures of postictal hypoperfusion.MethodsWe propose a prospective, three-condition cross-over design trial with randomized condition allocation, open-label treatment, and blinded end-point evaluation (PROBE design). Thirty-three patients (age > 17 years) suffering from a depressive episode treated with ECT will be included. Randomly and alternately, single doses of nimodipine (60 mg), acetaminophen (1000 mg), or water will be given two hours prior to each ECT session with a maximum of twelve sessions per patient. The primary outcome measure is ‘postictal EEG recovery time’, expressed and quantified as an adapted version of the temporal brain symmetry index, yielding a time constant for the duration of the postictal state on EEG. Secondary outcome measures include postictal cerebral perfusion, measured by arterial spin labelling MRI, and the postictal clinical ‘time to orientation’.DiscussionWith this clinical trial, we will systematically study postictal EEG, MRI and clinical phenomena after ECT-induced seizures and will test the effects of vasodilatory treatment intending to reduce postictal symptoms. If an effect is established, this will provide a novel treatment of postictal symptoms in ECT patients. Ultimately, these findings may be generalized to patients with epilepsy.Trial registrationInclusion in SYNAPSE started in December 2019. Prospective trial registration number is NCT04028596 on the international clinical trial register on July 22, 2019.

Methodological Quality and Risk of Bias Assessment of Cardiovascular Disease Research: Analysis of Randomized Controlled Trials Published in 2017.

BackgroundAll randomized-controlled trials (RCTs) are required to follow high methodological standards. In this study, we aimed to assess the methodological quality of published cardiovascular clinical research trials in a representative sample of RCTs published in 2017.MethodsCochrane Central Register of Controlled Trials was used to identify cardiovascular clinical research trials with adult participants published in 2017. Overall, 250 (10%) RCTs were randomly selected from a total of 2,419 studies. Data on general trial characteristics were extracted and the risk of bias (RoB) was determined.ResultsOverall, 86% of RCTs have reported at least one statistically significant result, with the primary outcome significant in 69%, treatment favored in 55%, and adverse events reported in 68%. Less than one-third (29%) of trials were overall low RoB, while the other two-thirds were rated unclear (40%) or with high RoB (31%). Sequence generation, allocation concealment, and selective reporting were the domains most often rated with high RoB. Drug trials were more likely to have low RoB than non-drug trials. Significant differences were found in RoB for the allocation concealment and blinding of participants and personnel between industry-funded and non-industry-funded trials, with industry-funded trials more often rated at low RoB.ConclusionAlmost two-thirds of RCTs in the field of cardiovascular disease (CVD) research, were at high or unclear RoB, indicating a need for more rigorous trial planning and conduct. Prospective trial registration is a factor predicting a lower risk of bias.

Clinical trial registration was associated with lower risk of bias compared with non-registered trials among trials included in systematic reviews

ObjectiveTo examine the association between clinical trial registration and risk of bias in clinical trials that have been included in systematic reviews. As a secondary objective, we evaluated the risk of bias among trials registered prospectively vs. retrospectively. MethodClinical trials published in 2005 or after included in a sample of 100 Cochrane systematic reviews published from 2014-2019. ResultsOf 1,177 clinical trials identified, we verified 368 (31%) had been registered, of which 135 (36.7%) were registered prospectively (i.e., before or up to 1 month after enrollment of the first participant). Across the bias domains (one bias assessment for each domain per trial), the percentage of trials at low risk ranged from 29% to 58%; unclear risk ranged from to 26% to 61% and high risk ranged from 2% to 38%. Trials that had been registered had less high or unclear risk of bias in five domains: random sequence generation (univariate risk ratio [RR] 0.69, 95% confidence interval [95% CI] 0.58-0.81), allocation concealment (RR 0.64, 95% CI 0.57-0.72), performance bias (RR 0.65, 95% CI 0.58-0.72), detection bias (RR 0.70, 95% CI 0.62-0.78), and reporting bias (RR 0.62, 95% CI 0.53-0.73). An association between clinical trial registration and high or unclear risk of attrition bias could not be demonstrated nor refuted (RR 1.02, 95% CI 0.89-1.17). It also was observed in terms of overall risk of bias, that registered trials had less high or unclear overall risk of bias than trials that had not been registered (univariate RR 0.29, 95% CI 0.19-0.46). Prospective clinical trial registration was associated with low risks of selection bias due to inadequate allocation concealment, performance bias, and detection bias compared with retrospective clinical trial registration. ConclusionIn a large sample of clinical trials included in recently published systematic reviews of interventions, clinical trial registration was associated with low risk of bias for five of the six domains examined.

Prospective trial registration and publication rates of randomized clinical trials in digital health: A cross-sectional analysis of global trial registries

Objectives We sought to examine the prevalence of prospective registration and publication rates in digital health trials. Materials and Methods We included 417 trials that enrolled participants in 2012 and were registered in any of the 17 WHO data provider registries. The evaluation of the prospective trial registration was based on the actual difference between the registration and enrollment dates. We identified existing publications through an automated PubMed search by every trial registration number as well as a pragmatic search in PubMed and Google based on extracted metadata from the trial registries. Results The prospective registration and publication rates were at (38.4%) and (65.5%), respectively. We identified a statistically significant ( p &lt; 0.001) “Selective Registration Bias” with 95.7% of trials published within a year after registration, were registered retrospectively. We reported a statistically significant relationship ( p = 0.003) between prospective registration and funding sources, with industry-funded trials having the lowest compliance with prospective registration at (14.3%). The lowest non-publication rates were in the Middle East (26.7%) and Europe (28%), and the highest were in Asia (56.5%) and the U.S. (42.5%). We found statistically significant differences ( p &lt; 0.001) between trial location and funding sources with the highest percentage of industry-funded trials in Asia (17.4%) and the U.S. (3.3%). Conclusion The adherence of investigators to the best practices of trial registration and result dissemination is still evolving in digital health trials. Further research is required to identify contributing factors and mitigation strategies to low compliance rate with trial publication and prospective registration in digital health trials.

Practices and trends in clinical trial registration in the Pan African Clinical Trials Registry (PACTR): a descriptive analysis of registration data

BackgroundThe Pan African Clinical Trials Registry (PACTR) is a WHO International Clinical Trials Registry Platform primary register, which caters for clinical trials conducted in Africa. PACTR is the first and,...

The Unknown Prevalence of Postrandomization Bias in 15 Physical Therapy Journals: A Methods Review.

To determine the prevalence of prospective clinical trial registration and postrandomization bias in published musculoskeletal physical therapy randomized clinical trials (RCTs). A methods review. Articles indexed in MEDLINE and published between January 2016 and July 2020 were included. Two independent blinded reviewers identified the RCTs using Covidence. We included RCTs related to musculoskeletal interventions that were published in International Society of Physiotherapy Journal Editors member journals. Data were extracted independently for the variables of interest from the identified RCTs by 2 blinded reviewers. The data were presented descriptively or in frequency tables. One hundred thirty-eight RCTs were identified. One third of RCTs were consistent with their prospectively registered intent (49/138); consistency with prospectively registered intent could not be determined for two thirds (89/138) of the RCTs. Four RCTs (8%)reported inconsistent results with the primary aims and 7 (14%) with the outcomes from the prospective clinical trial registry, despite high methodological quality (Physiotherapy Evidence Database [PEDro] scale score). Differences between prospectively registered and non-prospectively registered RCTs for PEDro scale scores had a medium effect size (r = 0.30). Two of 15 journals followed their clinical trial registration policy 100% of the time; in 1 journal, the published RCTs were consistent with the clinical trial registration. Postrandomization bias in musculoskeletal physical therapy RCTs could not be ruled out, due to the lack of prospective clinical trial registration and detailed data analysis plans. J Orthop Sports Phys Ther 2021;51(11):542-550. Epub 21 Sep 2021. doi:10.2519/jospt.2021.10491.

Is mandatory prospective trial registration working? An update on the adherence to the International Committee of Medical Journal Editors guidelines across five psychiatry journals: 2015-2020.

Previous research indicated that the International Committee of Medical Journal Editors guidelines of prospective trial registration with clearly identified primary and secondary outcome measures are only adhered to in 14.4% of studies published in the top five psychiatry journals between 1 January 2009 and 31 July 2013. This study examined if adherence has improved. The registration information, article information, primary outcome measures (POMs), participant numbers and funding source were extracted from studies published in the same five psychiatry journals between 1 January 2015 and 31 December 2019. Discrepancies between POMs in the articles and registry were tracked. Of the 7268 publications, 268studies required registration. Three (1.1%) were unregistered, 107 (39.9%) were retrospectively registered, and 158 (58.9%) were prospectively registered. Of the 158 prospectively registered studies, 16 (10.1%) had unclear POMs in the article or registration, 22 (13.9%) had discrepancies between registered and published POMs, and 33 (20.9%) had no POM discrepancies but had retrospectively updated POMs in the registry. Of the 22studies with discrepancies, nine (40.9%) were determined to favour statistically significant results. Overall, 87 (32.5%) of the 268studies were prospectively registered with no discrepancies between registered and published POMs and no changes to registered POMs or timeframes. Although this rate of one third of published articles fully adhering to the guidelines is an improvement compared to previous research, further efforts still need to be made by both authors and journals to ensure full transparency in the reporting of studies in psychiatry.

How prospective trial registration can prevent selective outcome reporting and salami slicing?

BackgroundPre-registration of a clinical trial before the first participant is recruited can help to prevent selective outcome reporting and salami-slicing that can distort the evidence base for an intervention and result in people being offered care or treatment that is not effective. Rates of clinical trial registration in nursing and midwifery are low. AimTo use a hypothetical example from midwifery practice to illustrate how selective outcome reporting and salami-slicing can distort the evidence base. FindingsA trial of immersion in water during labour and birth is used to consider issues in outcome selection and how researchers may be drawn to switch primary outcomes or report different outcomes across multiple papers. DiscussionIn nursing and midwifery science, selective outcome and salami reporting are seemingly common. Prospective trial registration is intended to prevent these practices, enhancing the quality and integrity of the work. ConclusionClinical trials are a robust form of primary research evidence and directly impact clinical practice. Researchers must ensure their trials are correctly registered and editors need to reconcile submitted papers and registration entries as part of the review process.