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1,017 randomized clinical trials (RCTs) approved between 2000 and 2003 were discontinued prematurely, and 44% remained unpublished at a median of 12 years follow-up.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 One in 5 trials (21%; 70/326) remained unpublished at 10 years follow-up, and 21% of unpublished trials (15/70) were unregistered.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.     

Clear obstacles and hidden challenges: understanding recruiter perspectives in six pragmatic randomised controlled trials

Background

Recruitment of sufficient participants in an efficient manner is still widely acknowledged to be a major challenge to the mounting and completion of randomised controlled trials (RCTs). Few recruitment interventions have involved staff undertaking recruitment. This study aimed i) to understand the recruitment process from the perspective of recruiters actively recruiting RCT participants in six pragmatic RCTs, and ii) to identify opportunities for interventions to improve recruitment.

Methods

Interviews were undertaken with 72 individuals (32 doctors or RCT Chief investigators (CIs); 40 nurses/other health professionals) who were actively recruiting participants in six RCTs to explore their experiences of recruitment. The RCTs varied in scale, duration, and clinical contexts. Interviews were fully transcribed and analysed using qualitative content and thematic analytic methods derived from grounded theory. For this analysis, data were systematically extracted from each RCT and synthesised across all six RCTs to produce a detailed and nuanced understanding of the recruitment process from the perspectives of the recruiters.

Results

Recruiters readily identified organisational difficulties, fewer than expected eligible patients, and patients’ treatment preferences as the key barriers to recruitment. As they described their experiences of recruitment, several previously hidden issues related to their roles as researchers and clinicians emerged, imbued with discomfort and emotion. The synthesis across the RCTs showed that doctors were uncomfortable about aspects of patient eligibility and the effectiveness of interventions, whereas nurses were anxious about approaching potential RCT participants and conflicts between the research and their clinical responsibilities. Recruiters seemed unaware that their views contributed to recruitment difficulties. Their views were not known to RCT CIs. Training and support needs were identified for both groups of staff.

Conclusions

The synthesis showed that recruitment to these RCTs was a complex and fragile process. Clear obstacles were identified but hidden challenges related to recruiters’ roles undermined recruitment, unbeknown to RCT CIs. Qualitative research can elicit and identify the hidden challenges. Training and support are then needed for recruiters to become more comfortable with the design and principles of RCTs, so that they can engage more openly with potentially eligible participants and create a more resilient recruitment process.     

Assessment of the Quality of Reporting in Abstracts of Randomized Controlled Trials Published in Five Leading Chinese Medical Journals

Background

Clear, transparent and sufficiently detailed abstracts of randomized trials (RCTs), published in journal articles are important because readers will often base their initial assessment of a trial on such information. However, little is known about the quality of reporting in abstracts of RCTs published in medical journals in China.

Methods

We identified RCTs abstracts from 5 five leading Chinese medical journals published between 1998 and 2007 and indexed in MEDLINE. We assessed the quality of reporting of these abstracts based on the Consolidated Standards of Reporting Trials (CONSORT) abstract checklist. We also sought to identify whether any differences exist in reporting between the Chinese and English language version of the same abstract.

Results

We identified 332 RCT abstracts eligible for examination. Overall, the abstracts we examined reported 0–8 items as designated in the CONSORT checklist. On average, three items were reported per abstract. Details of the interventions (288/332; 87%), the number of participants randomized (216/332; 65%) and study objectives (109/332; 33%) were the top three items reported. Only two RCT abstracts reported details of trial registration, no abstracts reported the method of allocation concealment and only one mentioned specifically who was blinded. In terms of the proportion of RCT abstracts fulfilling a criterion, the absolute difference (percentage points) between the Chinese and English abstracts was 10% (ranging from 0 to 25%) on average, per item.

Conclusions

The quality of reporting in abstracts of RCTs published in Chinese medical journals needs to be improved. We hope that the introduction and endorsement of the CONSORT for Abstracts guidelines by journals reporting RCTs will lead to improvements in the quality of reporting.     

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.     

A Statistical Perspective on Prevention Trials: A View from the Women’s Health Initiative

Chronic disease prevention trials test strategies to reduce the risk of a specific health event in generally healthy people. These strategies are often thought to affect other health conditions and their use in the population requires a very favorable safety profile. A prevention trial assessing such a strategy is most valuable when designed to capture the overall public health impact and hence provide more comprehensive, reliable information for policy and practice. This broad agenda, and particularly the assessment of multiple outcomes, creates statistical challenges in the design, monitoring, and reporting of such a trial. In this article these issues are described in the context of the Women’s Health Initiative, a large randomized prevention trial testing three interventions in post-menopausal women: hormone therapy, a low-fat diet and calcium and vitamin D supplementation. Each intervention was hypothesized to influence multiple chronic disease rates including cardiovascular disease, stroke, cancers, and fractures. Here the design, monitoring, and reporting of the WHI trials is reviewed in the context of multiple outcomes and the approach to a global assessment of these interventions is described.     

Reduced patient restrictions following total hip arthroplasty: study protocol for a randomized controlled trial

Stepped wedge cluster randomised trials introduce interventions to groups of clusters in a random order and have been used to evaluate interventions for health and wellbeing. Standardised guidance for reporting stepped wedge trials is currently absent, and a range of potential analytic approaches have been described. We systematically identified and reviewed recently published (2010 to 2014) analyses of stepped wedge trials. We extracted data and described the range of reporting and analysis approaches taken across all studies. We critically appraised the strategy described by three trials chosen to reflect a range of design characteristics. Ten reports of completed analyses were identified. Reporting varied: seven of the studies included a CONSORT diagram, and only five also included a diagram of the intervention rollout. Seven assessed the balance achieved by randomisation, and there was considerable heterogeneity among the approaches used. Only six reported the trend in the outcome over time. All used both ‘horizontal’ and ‘vertical’ information to estimate the intervention effect: eight adjusted for time with a fixed effect, one used time as a condition using a Cox proportional hazards model, and one did not account for time trends. The majority used simple random effects to account for clustering and repeat measures, assuming a common intervention effect across clusters. Outcome data from before and after the rollout period were often included in the primary analysis. Potential lags in the outcome response to the intervention were rarely investigated. We use three case studies to illustrate different approaches to analysis and reporting. There is considerable heterogeneity in the reporting of stepped wedge cluster randomised trials. Correct specification of the time-trend underlies the validity of the analytical approaches. The possibility that intervention effects vary by cluster or over time should be considered. Further work should be done to standardise the reporting of the design, attrition, balance, and time-trends in stepped wedge trials.     

Treatment Trials for Neonatal Seizures: The Effect of Design on Sample Size

Neonatal seizures are common in the neonatal intensive care unit. Clinicians treat these seizures with several anti-epileptic drugs (AEDs) to reduce seizures in a neonate. Current AEDs exhibit sub-optimal efficacy and several randomized control trials (RCT) of novel AEDs are planned. The aim of this study was to measure the influence of trial design on the required sample size of a RCT. We used seizure time courses from 41 term neonates with hypoxic ischaemic encephalopathy to build seizure treatment trial simulations. We used five outcome measures, three AED protocols, eight treatment delays from seizure onset (T_d) and four levels of trial AED efficacy to simulate different RCTs. We performed power calculations for each RCT design and analysed the resultant sample size. We also assessed the rate of false positives, or placebo effect, in typical uncontrolled studies. We found that the false positive rate ranged from 5 to 85% of patients depending on RCT design. For controlled trials, the choice of outcome measure had the largest effect on sample size with median differences of 30.7 fold (IQR: 13.7–40.0) across a range of AED protocols, T_d and trial AED efficacy (p<0.001). RCTs that compared the trial AED with positive controls required sample sizes with a median fold increase of 3.2 (IQR: 1.9–11.9; p<0.001). Delays in AED administration from seizure onset also increased the required sample size 2.1 fold (IQR: 1.7–2.9; p<0.001). Subgroup analysis showed that RCTs in neonates treated with hypothermia required a median fold increase in sample size of 2.6 (IQR: 2.4–3.0) compared to trials in normothermic neonates (p<0.001). These results show that RCT design has a profound influence on the required sample size. Trials that use a control group, appropriate outcome measure, and control for differences in T_d between groups in analysis will be valid and minimise sample size.     

Study protocol of a mixed-methods evaluation of a cluster randomized trial to improve the safety of NSAID and antiplatelet prescribing: data-driven quality improvement in primary care

ABSTRACT: BACKGROUND: Trials of complex interventions are criticized for being 'black box', so the UK Medical Research Council recommends carrying out a process evaluation to explain the trial findings. We believe it is good practice to pre-specify and publish process evaluation protocols to set standards and minimize bias. Unlike protocols for trials, little guidance or standards exist for the reporting of process evaluations. This paper presents the mixed-method process evaluation protocol of a cluster randomized trial, drawing on a framework designed by the authors.Methods/designThis mixed-method evaluation is based on four research questions and maps data collection to a logic model of how the data-driven quality improvement in primary care (DQIP) intervention is expected to work. Data collection will be predominately by qualitative case studies in eight to ten of the trial practices, focus groups with patients affected by the intervention and quantitative analysis of routine practice data, trial outcome and questionnaire data and data from the DQIP intervention. DISCUSSION: We believe that pre-specifying the intentions of a process evaluation can help to minimize bias arising from potentially misleading post-hoc analysis. We recognize it is also important to retain flexibility to examine the unexpected and the unintended. From that perspective, a mixed-methods evaluation allows the combination of exploratory and flexible qualitative work, and more pre-specified quantitative analysis, with each method contributing to the design, implementation and interpretation of the other.As well as strengthening the study the authors hope to stimulate discussion among their academic colleagues about publishing protocols for evaluations of randomized trials of complex interventions.Data-driven quality improvement in primary care trial registrationClinicalTrials.gov: NCT01425502.     

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.     

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 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.     

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.     

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.     

Quality of Reporting of Randomised Controlled Trials of Herbal Interventions in ASEAN Plus Six Countries: A Systematic Review

Background

Many randomised controlled trials (RCTs) of herbal interventions have been conducted in the ASEAN Communities. Good quality reporting of RCTs is essential for assessing clinical significance. Given the importance ASEAN placed on herbal medicines, the reporting quality of RCTs of herbal interventions among the ASEAN Communities deserved a special attention.

Objectives

To systematically review the quality of reporting of RCTs of herbal interventions conducted in the ASEAN Plus Six Countries.

Methods

Searches were performed using PubMed, EMBASE, The Cochrane Library, and Allied and Complementary Medicine (AMED), from inception through October 2013. These were limited to studies specific to humans and RCTs. Herbal species search terms were based on those listed in the National List of Essential Medicines [NLEM (Thailand, 2011)]. Studies conducted in the ASEAN Plus Six Countries, published in English were included.

Results

Seventy-one articles were identified. Thirty (42.25%) RCTs were from ASEAN Countries, whereas 41 RCTs (57.75%) were from Plus Six Group. Adherence to the recommended CONSORT checklist items for reporting of RCTs of herbal interventions among ASEAN Plus Six Countries ranged from 0% to 97.18%. Less than a quarter of the RCTs (18.31%) reported information on standardisation of the herbal products. However, the scope of our interventions of interest was limited to those developed from 20 herbal species listed in the NLEM of Thailand.

Conclusions

The present study highlights the need to improve reporting quality of RCTs of herbal interventions across ASEAN Plus Six Communities.     

The randomized controlled trial in studies using biomarkers

The randomized controlled trial (RCT) is a scientific experiment during which observations on the effects of therapy or a preventive action are conducted by the researcher under rigorous control. The purpose of the experiment is to clear the uncertainties surrounding a clinical/research issue and involves isolating the 'treatment' and 'end result' variables from external influences. RCTs therefore make use of scientific method standards: measuring, which includes the possibility of reproducing observations; controlling factors unconnected to the cause-effect relationship of interest; and the external verification or 'falsification' of the cause-effect relationship. Many RCTs are now including biomarkers to answer scientific questions in a more accurate way. In the present methodological paper, the main aspects involved in the design and conduction of a trial are discussed, with special emphasis on the use of biomarkers. Aspects that are often overlooked by scientists involved in the design of trials include multiple comparisons, subgroup analysis, the duration of the observations, the use of surrogate endpoints, and ethical issues. This review summarizes the main issues that should be addressed in a protocol, and illustrates these with an example.     

The face of equipoise - delivering a structured education programme within a randomized controlled trial: qualitative study

Background

In trials of behavioural interventions, the individuals who deliver the intervention are in a position of key influence on the success of the trial. Their fidelity to the intervention is crucial. Yet little is understood about the experiences of this group of trial personnel. This study aimed to investigate the views and experiences of educators who delivered a structured education intervention to people with type 2 diabetes, which incorporated training in self-monitoring of either blood glucose (SMBG) or urine glucose (SMUG) as part of a randomized controlled trial (RCT).

Methods

Educators’ views were explored through focus groups before and after training (N?=?18) and approximately 1 year into the trial (N?=?14), and semi-structured telephone interviews at approximately 2 years (N?=?7). Analysis was based on the constant comparative method.

Results

Educators held preferences regarding the intervention variants; thus, they were not in individual equipoise. Training raised awareness of preferences and their potential to impact on delivery. Educators were confident in their unbiased delivery, but acknowledged the challenges involved. Concealing their preferences was helped by a sense of professionalism, the patient-centred nature of the intervention, and concessions in the trial protocol (enabling participants to swap monitoring methods if needed). Commitment to unbiased delivery was explained through a desire for evidence-based knowledge in the contentious area of SMBG.

Conclusions

The findings provide insight into a previously unexplored group of trial personnel - intervention deliverers in trials of behavioural interventions - which will be useful to those designing and running similar trials. Rather than individual equipoise, it is intervention deliverers’ awareness of personal preferences and their potential impact on the trial outcome that facilitates unbiased delivery. Further, awareness of community equipoise, the need for evidence, and relevance to the individual enhance commitment to the RCT.

Trial registration

ISRCTN95696668