Nonregistration,discontinuation, and nonpublication of randomized trials: A repeated metaresearch analysis

BackgroundWe previously found that 25% of 1,017 randomized clinical trials (RCTs) approved between 2000 and 2003 were discontinued prematurely, and 44% remained unpublished at a median of 12 years follow-up. We aimed to assess a decade later (1) whether rates of completion and publication have increased; (2) the extent to which nonpublished RCTs can be identified in trial registries; and (3) the association between reporting quality of protocols and premature discontinuation or nonpublication of RCTs.Methods and findingsWe included 326 RCT protocols approved in 2012 by research ethics committees in Switzerland, the United Kingdom, Germany, and Canada in this metaresearch study. Pilot, feasibility, and phase 1 studies were excluded. We extracted trial characteristics from each study protocol and systematically searched for corresponding trial registration (if not reported in the protocol) and full text publications until February 2022. For trial registrations, we searched the (i) World Health Organization: International Clinical Trial Registry Platform (ICTRP); (ii) US National Library of Medicine (ClinicalTrials.gov); (iii) European Union Drug Regulating Authorities Clinical Trials Database (EUCTR); (iv) ISRCTN registry; and (v) Google. For full text publications, we searched PubMed, Google Scholar, and Scopus. We recorded whether RCTs were registered, discontinued (including reason for discontinuation), and published. The reporting quality of RCT protocols was assessed with the 33-item SPIRIT checklist. We used multivariable logistic regression to examine the association between the independent variables protocol reporting quality, planned sample size, type of control (placebo versus other), reporting of any recruitment projection, single-center versus multicenter trials, and industry versus investigator sponsoring, with the 2 dependent variables: (1) publication of RCT results; and (2) trial discontinuation due to poor recruitment.Of the 326 included trials, 19 (6%) were unregistered. Ninety-eight trials (30%) were discontinued prematurely, most often due to poor recruitment (37%; 36/98). One in 5 trials (21%; 70/326) remained unpublished at 10 years follow-up, and 21% of unpublished trials (15/70) were unregistered. Twenty-three of 147 investigator-sponsored trials (16%) reported their results in a trial registry in contrast to 150 of 179 industry-sponsored trials (84%).The median proportion of reported SPIRIT items in included RCT protocols was 69% (interquartile range 61% to 77%). We found no variables associated with trial discontinuation; however, lower reporting quality of trial protocols was associated with nonpublication (odds ratio, 0.71 for each 10% increment in the proportion of SPIRIT items met; 95% confidence interval, 0.55 to 0.92; p = 0.009). Study limitations include that the moderate sample size may have limited the ability of our regression models to identify significant associations.ConclusionsWe have observed that rates of premature trial discontinuation have not changed in the past decade. Nonpublication of RCTs has declined but remains common; 21% of unpublished trials could not be identified in registries. Only 16% of investigator-sponsored trials reported results in a trial registry. Higher reporting quality of RCT protocols was associated with publication of results. Further efforts from all stakeholders are needed to improve efficiency and transparency of clinical research.

Benjamin Speich and colleagues investigate whether rates of trial completion and publication have increased over the past decade, the extent to which non-published trials can be identified in registries, and the association between reporting quality of protocols and premature discontinuation or non-publication of trials.     

Transparency of Outcome Reporting and Trial Registration of Randomized Controlled Trials Published in the Journal of Consulting and Clinical Psychology

Background

Confidence that randomized controlled trial (RCT) results accurately reflect intervention effectiveness depends on proper trial conduct and the accuracy and completeness of published trial reports. The Journal of Consulting and Clinical Psychology (JCCP) is the primary trials journal amongst American Psychological Association (APA) journals. The objectives of this study were to review RCTs recently published in JCCP to evaluate (1) adequacy of primary outcome analysis definitions; (2) registration status; and, (3) among registered trials, adequacy of outcome registrations. Additionally, we compared results from JCCP to findings from a recent study of top psychosomatic and behavioral medicine journals.

Methods

Eligible RCTs were published in JCCP in 2013–2014. For each RCT, two investigators independently extracted data on (1) adequacy of outcome analysis definitions in the published report, (2) whether the RCT was registered prior to enrolling patients, and (3) adequacy of outcome registration.

Results

Of 70 RCTs reviewed, 12 (17.1%) adequately defined primary or secondary outcome analyses, whereas 58 (82.3%) had multiple primary outcome analyses without statistical adjustment or undefined outcome analyses. There were 39 (55.7%) registered trials. Only two trials registered prior to patient enrollment with a single primary outcome variable and time point of assessment. However, in one of the two trials, registered and published outcomes were discrepant. No studies were adequately registered as per Standard Protocol Items: Recommendation for Interventional Trials guidelines. Compared to psychosomatic and behavioral medicine journals, the proportion of published trials with adequate outcome analysis declarations was significantly lower in JCCP (17.1% versus 32.9%; p = 0.029). The proportion of registered trials in JCCP (55.7%) was comparable to behavioral medicine journals (52.6%; p = 0.709).

Conclusions

The quality of published outcome analysis definitions and trial registrations in JCCP is suboptimal. Greater attention to proper trial registration and outcome analysis definition in published reports is needed.     

Intervention description is not enough: evidence from an in-depth multiple case study on the untold role and impact of context in randomised controlled trials of seven complex interventions

ABSTRACT: BACKGROUND: A number of single case reports have suggested that the context within which intervention studies take place may challenge the assumptions that underpin RCTs. However, the diverse ways in which context may challenge the central tenets of the RCT, and the degree to which this information is known to researchers and/or subsequently reported, has received much less attention. In this paper we explore these issues by focussing on 7 RCTs of interventions ranging in type and degree of complexity, and across diverse contexts. METHODS: This in-depth multiple case study using interviews, focus groups and documentary analysis was conducted in two phases. In phase one, a RCT of a nurse-led intervention provided a single exploratory case and informed the design, sampling and data collection within the main study. Phase two consisted of a multiple explanatory case study covering a range of trials of different types of complex intervention. A total of 84 data sources across the 7 trials were accessed. RESULTS: We present consistent empirical evidence across all trials to indicate that four key elements of context (personal, organisational, trial and problem context) are crucial to understanding how a complex intervention works and to enable both assessments of internal validity and likely generalizability to other settings. The ways in which context challenged trial operation was often complex, idiosyncratic, and subtle; often falling outside of current trial reporting formats. However, information on such issues appeared to be available via first hand "insider accounts" of each trial suggesting that improved reporting on the role of context is possible. CONCLUSIONS: Sufficient detail about context needs to be understood and reported in RCTs of complex interventions, in order for the transferability of complex interventions to be assessed. Improved reporting formats that require and encourage the clarification of both general and project-specific threats to the likely internal and external validity need to be developed. In addition a cultural change is required in which the open and honest reporting of such issues is seen as an indicator of study strength and researcher integrity, rather than a symbol of a poor quality study or investigator ability.     

Can We Depend on Investigators to Identify and Register Randomized Controlled Trials?

Purpose

To reduce publication bias, systematic reviewers are advised to search conference abstracts to identify randomized controlled trials (RCTs) conducted in humans and not published in full. We assessed the information provided by authors to aid identification of RCTs for reviews.

Methods

We handsearched the Association for Research in Vision and Ophthalmology (ARVO) meeting abstracts for 2004 to 2009 to identify reports of RCTs. We compared our classification with that of authors (requested by ARVO 2004–2006), and authors’ report of trial registration (required by ARVO 2007–2009).

Results

Authors identified their study as a clinical trial for 169/191 (88%; 95% CI, 84–93) RCTs we identified for 2004, 174/212 (82%; 95% CI, 77–87) for 2005 and 162/215 (75%; 95% CI, 70–81) for 2006. Authors provided registration information for 107/172 (62%; 95% CI, 55–69) RCTs for 2007, 103/153 (67%; 95% CI, 60–75) for 2008, and 126/171 (74%; 95% CI, 67–80) for 2009. Most RCT authors providing a trial register name specified ClinicalTrials.gov (276/312; 88%; 95% CI, 85–92) and provided a valid ClinicalTrials.gov registration number (261/276; 95%; 95% CI, 92–97). Based on information provided by authors, trial registration information would be accessible for 48% (83/172) (95% CI, 41–56) of all ARVO abstracts describing RCTs in 2007, 63% (96/153) (95% CI, 55–70) in 2008, and 70% in 2009 (118/171) (95% CI, 62–76).

Conclusions

Authors of abstracts describing RCTs frequently did not classify them as clinical trials nor comply with reporting trial registration information, as required by the conference organizers. Systematic reviewers cannot rely on authors to identify relevant unpublished trials or report trial registration, if present.     

Trial Registration Numbers Are Underreported in Biomedical Publications

Context

Since September 2005, the International Committee of Medical Journal Editors (ICMJE) has required that randomised controlled trials (RCTs) are prospectively registered in a publicly accessible database. After registration, a trial registration number (TRN) is assigned to each RCT, which should make it easier to identify future publications and cross-check published results with associated registry entries, as long as the unique identification number is reported in the article.

Objective

Our primary objective was to evaluate the reporting of trial registration numbers in biomedical publications. Secondary objectives were to evaluate how many published RCTs had been registered and how many registered RCTs had resulted in a publication, using a sample of trials from the Netherlands Trials Register (NTR).

Design, Setting

Two different samples of RCTs were examined: 1) RCTs published in November 2010 in core clinical journals identified in MEDLINE; 2) RCTs registered in the NTR with a latest expected end date of 31 August 2008.

Results

Fifty-five percent (166/302) of the reports of RCTs found in MEDLINE and 60% (186/312) of the published reports of RCTs from the NTR cohort contained a TRN. In both samples, reporting of a TRN was more likely in RCTs published in ICMJE member journals as compared to non-ICMJE member journals (MEDLINE 58% vs. 45%; NTR: 70% vs. 49%). Thirty-nine percent of published RCTs in the MEDLINE sample appear not to have been registered, and 48% of RCTs registered in the NTR seemed not to have been published at least two years after the expected date for study completion.

Conclusion

Our results show that further promotion and implementation of trial registration and accurate reporting of TRN is still needed. This might be helped by inclusion of the TRN as an item on the CONSORT checklist.     

The Effectiveness of Cognitive Behavioural Treatment for Non-Specific Low Back Pain: A Systematic Review and Meta-Analysis

Objectives

To assess whether cognitive behavioural (CB) approaches improve disability, pain, quality of life and/or work disability for patients with low back pain (LBP) of any duration and of any age.

Methods

Nine databases were searched for randomised controlled trials (RCTs) from inception to November 2014. Two independent reviewers rated trial quality and extracted trial data. Standardised mean differences (SMD) and 95% confidence intervals were calculated for individual trials. Pooled effect sizes were calculated using a random-effects model for two contrasts: CB versus no treatment (including wait-list and usual care (WL/UC)), and CB versus other guideline-based active treatment (GAT).

Results

The review included 23 studies with a total of 3359 participants. Of these, the majority studied patients with persistent LBP (>6 weeks; n=20). At long term follow-up, the pooled SMD for the WL/UC comparison was -0.19 (-0.38, 0.01) for disability, and -0.23 (-0.43, -0.04) for pain, in favour of CB. For the GAT comparison, at long term the pooled SMD was -0.83 (-1.46, -0.19) for disability and -0.48 (-0.93, -0.04) for pain, in favour of CB. While trials varied considerably in methodological quality, and in intervention factors such as provider, mode of delivery, dose, duration, and pragmatism, there were several examples of lower intensity, low cost interventions that were effective.

Conclusion

CB interventions yield long-term improvements in pain, disability and quality of life in comparison to no treatment and other guideline-based active treatments for patients with LBP of any duration and of any age.

Systematic Review Registration

PROSPERO protocol registration number: CRD42014010536.     

Registration Quality Assessment of Acupuncture Clinical Trials

Background

Registration can help with transparency of acupuncture clinical trials (ACTs) by making protocol information and results available to the public. Recently, the number of registered ACTs has increased greatly, but only a few researchers have focused on the quality of ACTs registration. This review provides the first assessment of the registration quality of ACTs and the baseline information for future development.

Methods

All records of ACTs registered in the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) were collected. Data was extracted and input to Excel spreadsheets. The current 20 items of the WHO Trial Registration Data Set (TRDS) and the special prepared items for acupuncture intervention details were used to assess the registration quality of ACTs.

Results

A total of 740 records, found in 11 registries, were examined. The number of registered ACTs increased rapidly and involved a number of different diseases. The completeness of 20 items was not too poor due to 16 of them had a higher reported percentage (>85%). The completeness of the 20 items was different among registries. For example, the average registration percentage of 20 items in Clinicaltrials.gov, ChiCTR, ISRCTN and ANZCTR were 89.6%, 92.2%, 82.4% and 91.6% respectively. Detailed information regarding acupuncture intervention was seriously insufficient. Among the 740 registration records, 89.2% lacked information on the style of acupuncture, 80.8% did not contain details regarding the needles used, 53.5% lacked information on the treatment regimen and 76.2% did not give details of other interventions administered with acupuncture.

Conclusions

The overall registration quality of ACTs is not high enough due to the serious lack of information on the specifics of acupuncture intervention. It is vital that a number of special items be set regarding acupuncture in order to develop a suitable system for the registration of ACTs.     

Patient-level interventions to reduce alcohol-related harms in low- and middle-income countries: A systematic review and meta-summary

BackgroundDisease and disability from alcohol use disproportionately impact people in low- and middle-income countries (LMICs). While varied interventions have been shown to reduce alcohol use in high-income countries, their efficacy in LMICs has not been assessed. This systematic review describes current published literature on patient-level alcohol interventions in LMICs and specifically describes clinical trials evaluating interventions to reduce alcohol use in LMICs.Methods and findingsIn accordance with PRISMA, we performed a systematic review using an electronic search strategy from January 1, 1995 to December 1, 2020. Title, abstract, as well as full-text screening and extraction were performed in duplicate. A meta-summary was performed on randomized controlled trials (RCTs) that evaluated alcohol-related outcomes. We searched the following electronic databases: PubMed, EMBASE, Scopus, Web of Science, Cochrane, WHO Global Health Library, and PsycINFO. Articles that evaluated patient-level interventions targeting alcohol use and alcohol-related harm in LMICs were eligible for inclusion. No studies were excluded based on language.After screening 5,036 articles, 117 articles fit our inclusion criteria, 75 of which were RCTs. Of these RCTs, 93% were performed in 13 middle-income countries, while 7% were from 2 low-income countries. These RCTs evaluated brief interventions (24, defined as any intervention ranging from advice to counseling, lasting less than 1 hour per session up to 4 sessions), psychotherapy or counseling (15, defined as an interaction with a counselor longer than a brief intervention or that included a psychotherapeutic component), health promotion and education (20, defined as an intervention encouraged individuals’ agency of taking care of their health), or biologic treatments (19, defined as interventions where the biological function of alcohol use disorder (AUD) as the main nexus of intervention) with 3 mixing categories of intervention types. Due to high heterogeneity of intervention types, outcome measures, and follow-up times, we did not conduct meta-analysis to compare and contrast studies, but created a meta-summary of all 75 RCT studies. The most commonly evaluated intervention with the most consistent positive effect was a brief intervention; similarly, motivational interviewing (MI) techniques were most commonly utilized among the diverse array of interventions evaluated.ConclusionsOur review demonstrated numerous patient-level interventions that have the potential to be effective in LMICs, but further research to standardize interventions, populations, and outcome measures is necessary to accurately assess their effectiveness. Brief interventions and MI techniques were the most commonly evaluated and had the most consistent positive effect on alcohol-related outcomes.Trial registrationProtocol Registry: PROSPERO CRD42017055549

Catherine Staton and co-workers report on evidence about interventions against harmful alcohol use in low- and middle-income countries.     

Consideration Of Chronic Pain In Trials To Promote Physical Activity For Diabetes: A Systematic Review Of Randomized Controlled Trials

Background

Chronic pain has been estimated to affect 60% of patients with diabetes and is strongly associated with reduced activity tolerance. We systematically reviewed randomized controlled trials (RCTs) that explored interventions to improve physical activity among patients with diabetes to establish whether co-morbid chronic pain was captured at baseline or explored as an effect modifier and if trials reported a component designed to target chronic pain.

Methodology/principal Findings

We searched CINAHL, Cochrane Central Registry of Controlled Trials, EMBASE, ERIC, MEDLINE, SPORTDiscus and PsycInfo from inception of each database to March 2012 for RCTs that enrolled patients with diabetes and randomly assigned them to an intervention designed to promote physical activity. Two reviewers independently selected trials and abstracted data. We identified 136 trials meeting our inclusion criteria, only one of which that reported capturing chronic pain measures at baseline. No trial reported on specific interventions to address chronic pain as a competing demand, or as an effect modifier.

Conclusion/significance

Only 1 trial identified that aimed to promote physical activity among patients with diabetes reported that co-morbid chronic pain was captured at baseline. No trials reported exploring chronic pain as an effect modifier or targeting it as part of its intervention.     

Outcomes in registered, ongoing randomized controlled trials of patient education

Background

With the increasing prevalence of chronic noncommunicable diseases, patient education is becoming important to strengthen disease prevention and control. We aimed to systematically determine the extent to which registered, ongoing randomized controlled trials (RCTs) evaluated an educational intervention focus on patient-important outcomes (i.e., outcomes measuring patient health status and quality of life).

Methods

On May 6, 2009, we searched for all ongoing RCTs registered in the World Health Organization International Clinical Trials Registry platform. We used a standardized data extraction form to collect data and determined whether the outcomes assessed were 1) patient-important outcomes such as clinical events, functional status, pain, or quality of life or 2) surrogate outcomes, such as biological outcome, treatment adherence, or patient knowledge.

Principal Findings

We selected 268 of the 642 potentially eligible studies and assessed a random sample of 150. Patient-important outcomes represented 54% (178 of 333) of all primary outcomes and 46% (286 of 623) of all secondary outcomes. Overall, 69% of trials (104 of 150) used at least one patient-important outcome as a primary outcome and 66% (99 of 150) as a secondary outcome. Finally, for 31% of trials (46 of 150), primary outcomes were only surrogate outcomes. The results varied by medical area. In neuropsychiatric disorders, patient important outcomes represented 84% (51 of 61) of primary outcomes, as compared with 54% (32 of 59) in malignant neoplasm and 18% (4 of 22) in diabetes mellitus trials.In addition, only 35% assessed the long-term impact of interventions (i.e., >6 months).

Conclusions

There is a need to improve the relevance of outcomes and to assess the long term impact of educational interventions in RCTs.     

Multifactorial day hospital intervention to reduce falls in high risk older people in primary care: a multi-centre randomised controlled trial [ISRCTN46584556]

Background

There are many barriers to patient participation in randomised controlled trials of cancer treatments. To increase participation in trials, strategies need to be identified to overcome these barriers. Our aim was to assess the effectiveness of interventions to overcome barriers to patient participation in randomised controlled trials (RCTs) of cancer treatments.

Methods

A systematic review was conducted. Published and unpublished studies in any language were searched for in fifteen electronic databases, including MEDLINE, EMBASE, CINAHL and PsycINFO, from inception to the end of 2004. Studies of any interventions to improve cancer patient participation in RCTs, which reported the change in recruitment rates, were eligible for inclusion. RCTs and non-randomised controlled trials as well as before and after studies reporting baseline rates specific to the population being investigated were included. Data were extracted by one reviewer into structured summary tables and checked for accuracy by a second reviewer. Each included study was assessed against a checklist for methodological quality by one reviewer and checked by a second reviewer. A narrative synthesis was conducted.

Results

Eight studies were identified that met the inclusion criteria: three RCTs, two non-randomised controlled trials and three observational studies. Six of the studies had an intervention that had some relevance to the UK. There was no robust evidence that any of the interventions investigated led to an increase in cancer patient participation in RCTs, though one good quality RCT found that urologists and nurses were equally effective at recruiting participants to a treatment trial for prostate cancer. Although there was no evidence of an effect in any of the studies, the evidence was not of sufficient quality to be able to conclude that these interventions therefore do not work.

Conclusion

There is not a strong evidence-base for interventions that increase cancer patient participation in randomised trials. Further research is required to evaluate the effectiveness of strategies to increase participation in cancer treatment trials.     

Sexual Risk Reduction for HIV-Infected Persons: A Meta-Analytic Review of “Positive Prevention” Randomized Clinical Trials

Background

Prevention intervention trials have been conducted to reduce risk of sexual transmission among people living with HIV/AIDS (PLWHA), but the findings were inconsistent. We performed a systematic review and meta-analysis to evaluate overall efficacy of prevention interventions on unprotected vaginal or anal intercourse (UVAI) among PLWHA from randomized clinical trials (RCTs).

Methods

RCTs of prevention interventions among PLWHA published as of February 2012 were identified by systematically searching thirteen electronic databases. The primary outcome was UVAI. The difference of standardized mean difference (SMD) of UVAI between study arms, defined as effect size (ES), was calculated for each study and then pooled across studies using standard meta-analysis with a random effects model.

Results

Lower likelihood of UVAI was observed in the intervention arms compared with the control arms either with any sexual partners (mean ES: −0.22; 95% confidence interval [CI]: −0.32, −0.11) or with HIV-negative or unknown-status sexual partners (mean ES and 95% CI: −0.13 [−0.22, −0.04]). Short-term efficacy of interventions with ≤10 months of follow up was significant in reducing UVAI (1–5 months: −0.27 [−0.45, −0.10]; 6–10 months: −0.18 [−0.30, −0.07]), while long-term efficacy of interventions was weaker and might have been due to chance (11–15 months: −0.13 [−0.34, 0.08]; >15 months: −0.05 [−0.43, 0.32]).

Conclusions

Our meta-analyses confirmed the short-term impact of prevention interventions on reducing self-reported UVAI among PLWHA irrespective of the type of sexual partner, but did not support a definite conclusion on long-term effect. It is suggested that booster intervention sessions are needed to maintain a sustainable reduction of unprotected sex among PLWHA in future risk reduction programs.     

Characteristics of Randomized Trials Published in Latin America and the Caribbean According to Funding Source

Introduction

Few studies have assessed the nature and quality of randomized controlled trials (RCTs) in Latin America and the Caribbean (LAC).

Methods and Findings

The aims of this systematic review are to evaluate the characteristics (including the risk of bias assessment) of RCT conducted in LAC according to funding source. A review of RCTs published in 2010 in which the author''s affiliation was from LAC was performed in PubMed and LILACS. Two reviewers independently extracted data and assessed the risk of bias. The primary outcomes were risk of bias assessment and funding source. A total of 1,695 references were found in PubMed and LILACS databases, of which 526 were RCTs (N = 73.513 participants). English was the dominant publication language (93%) and most of the RCTs were published in non-LAC journals (84.2%). Only five of the 19 identified countries accounted for nearly 95% of all RCTs conducted in the region (Brazil 70.9%, Mexico 10.1%, Argentina 5.9%, Colombia 3.8%, and Chile 3.4%). Few RCTs covered priority areas related with Millennium Development Goals like maternal health (6.7%) or high priority infectious diseases (3.8%). Regarding children, 3.6% and 0.4% RCT evaluated nutrition and diarrhea interventions respectively but none pneumonia. As a comparison, aesthetic and sport related interventions account for 4.6% of all trials. A random sample of RCTs (n = 358) was assessed for funding source: exclusively public (33.8%); private (e.g. pharmaceutical company) (15.3%); other (e.g. mixed, NGO) (15.1%); no funding (35.8%). Overall assessments for risk of bias showed no statistically significant differences between RCTs and type of funding source. Statistically significant differences favoring private and others type of funding was found when assessing trial registration and conflict of interest reporting.

Conclusion

Findings of this study could be used to provide more direction for future research to facilitate innovation, improve health outcomes or address priority health problems.     

Geographical representativeness of published and ongoing randomized controlled trials. The example of: Tobacco consumption and HIV infection

Background

The challenge for evidence-based healthcare is to reduce mortality and the burden of diseases. This study aimed to compare where research is conducted to where research is needed for 2 public health priorities: tobacco consumption and HIV infection.

Methods

We identified randomized controlled trials (RCTs) included in Cochrane systematic reviews published between 1997 and 2007 and registered ongoing RCTs identified in January 2009 through the World Health Organization''s International Clinical Trials Registry Platform (WHO-ICTRP) evaluating interventions aimed at reducing or stopping tobacco use and treating or preventing HIV infection. We used the WHO and World Bank reports to classify the countries by income level, as well as map the global burden of disease and mortality attributable to tobacco use and HIV infection to the countries where the trials performed.

Results

We evaluated 740 RCTs included in systematic reviews and 346 ongoing RCTs. For tobacco use, 4% of RCTs included in systematic reviews and 2% of ongoing trials were performed in low- and middle-income countries, even though these countries represented 70% of the mortality related to tobacco use. For HIV infection, 31% of RCTs included in systematic reviews and 33% of ongoing trials were performed in low- and middle-income countries, even though these countries represented 99% of the mortality related to HIV infection.

Conclusions

Our results highlight an important underrepresentation of low- and middle-income countries in currently available evidence (RCTs included in systematic reviews) and awaiting evidence (registered ongoing RCTs) for reducing or stopping tobacco use and treating or preventing HIV infection.     

Nonadherence to treatment protocol in published randomised controlled trials: a review

ABSTRACT: This review aimed to ascertain the extent to which nonadherence to treatment protocol is reported and addressed in a cohort of published analyses of randomised controlled trials (RCTs). One hundred publications of RCTs, randomly selected from those published in BMJ, New England Journal of Medicine, the Journal of the American Medical Association and The Lancet during 2008, were reviewed to determine the extent and nature of reported nonadherence to treatment protocol, and whether statistical methods were used to examine the effect of such nonadherence on both benefit and harms analyses. We also assessed the quality of trial reporting of treatment protocol nonadherence and the quality of reporting of the statistical analysis methods used to investigate such nonadherence. Nonadherence to treatment protocol was reported in 98 of the 100 trials, but reporting on such nonadherence was often vague or incomplete. Forty-two publications did not state how many participants started their randomised treatment. Reporting of treatment initiation and completeness was judged to be inadequate in 64% of trials with short-term interventions and 89% of trials with long-term interventions. More than half (51) of the 98 trials with treatment protocol nonadherence implemented some statistical method to address this issue, most commonly based on per protocol analysis (46) but often labelled as intention to treat (ITT) or modified ITT (23 analyses in 22 trials). The composition of analysis sets for their benefit outcomes were not explained in 57% of trials, and 62% of trials that presented harms analyses did not define harms analysis populations. The majority of defined harms analysis populations (18 out of 26 trials, 69%) were based on actual treatment received, while the majority of trials with undefined harms analysis populations (31 out of 43 trials, 72%) appeared to analyse harms using the ITT approach. Adherence to randomised intervention is poorly considered in the reporting and analysis of published RCTs. The majority of trials are subject to various forms of nonadherence to treatment protocol, and though trialists deal with this nonadherence using a variety of statistical methods and analysis populations, they rarely consider the potential for bias introduced. There is a need for increased awareness of more appropriate causal methods to adjust for departures from treatment protocol, as well as guidance on the appropriate analysis population to use for harms outcomes in the presence of such nonadherence.     

The methodological quality of 176,620 randomized controlled trials published between 1966 and 2018 reveals a positive trend but also an urgent need for improvement

Many randomized controlled trials (RCTs) are biased and difficult to reproduce due to methodological flaws and poor reporting. There is increasing attention for responsible research practices and implementation of reporting guidelines, but whether these efforts have improved the methodological quality of RCTs (e.g., lower risk of bias) is unknown. We, therefore, mapped risk-of-bias trends over time in RCT publications in relation to journal and author characteristics. Meta-information of 176,620 RCTs published between 1966 and 2018 was extracted. The risk-of-bias probability (random sequence generation, allocation concealment, blinding of patients/personnel, and blinding of outcome assessment) was assessed using a risk-of-bias machine learning tool. This tool was simultaneously validated using 63,327 human risk-of-bias assessments obtained from 17,394 RCTs evaluated in the Cochrane Database of Systematic Reviews (CDSR). Moreover, RCT registration and CONSORT Statement reporting were assessed using automated searches. Publication characteristics included the number of authors, journal impact factor (JIF), and medical discipline. The annual number of published RCTs substantially increased over 4 decades, accompanied by increases in authors (5.2 to 7.8) and institutions (2.9 to 4.8). The risk of bias remained present in most RCTs but decreased over time for allocation concealment (63% to 51%), random sequence generation (57% to 36%), and blinding of outcome assessment (58% to 52%). Trial registration (37% to 47%) and the use of the CONSORT Statement (1% to 20%) also rapidly increased. In journals with a higher impact factor (>10), the risk of bias was consistently lower with higher levels of RCT registration and the use of the CONSORT Statement. Automated risk-of-bias predictions had accuracies above 70% for allocation concealment (70.7%), random sequence generation (72.1%), and blinding of patients/personnel (79.8%), but not for blinding of outcome assessment (62.7%). In conclusion, the likelihood of bias in RCTs has generally decreased over the last decades. This optimistic trend may be driven by increased knowledge augmented by mandatory trial registration and more stringent reporting guidelines and journal requirements. Nevertheless, relatively high probabilities of bias remain, particularly in journals with lower impact factors. This emphasizes that further improvement of RCT registration, conduct, and reporting is still urgently needed.

Many randomized controlled trials (RCTs) are biased and difficult to reproduce due to methodological flaws and poor reporting. Analysis of 176,620 RCTs published between 1966 and 2018 reveals that the risk of bias in RCTs generally decreased. Nevertheless, relatively high probabilities of bias remain, showing that further improvement of RCT registration, conduct, and reporting is still urgently needed.