Alpha-lipoic acid for diabetic peripheral neuropathy.

BACKGROUND: Diabetic peripheral neuropathy (DPN) is a frequent complication in people living with type 1 or type 2 diabetes. There is currently no effective treatment for DPN. Although alpha-lipoic acid (ALA, also known as thioctic acid) is widely used, there is no consensus about its benefits and harms. OBJECTIVES: To assess the effects of alpha-lipoic acid as a disease-modifying agent in people with diabetic peripheral neuropathy. SEARCH METHODS: On 11 September 2022, we searched the Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE, Embase, and two clinical trials registers. We also searched the reference lists of the included studies and relevant review articles for additional references not identified by the electronic searches. SELECTION CRITERIA: We included randomised clinical trials (RCTs) that compared ALA with placebo in adults (aged 18 years or older) and that applied the study interventions for at least six months. There were no language restrictions. DATA COLLECTION AND ANALYSIS: We used standard methods expected by Cochrane. The primary outcome was change in neuropathy symptoms expressed as changes in the Total Symptom Score (TSS) at six months after randomisation. Secondary outcomes were change in neuropathy symptoms at six to 12 months and at 12 to 24 months, change in impairment, change in any validated quality of life total score, complications of DPN, and adverse events. We assessed the certainty of the evidence using GRADE. MAIN RESULTS: Our analysis incorporated three trials involving 816 participants. Two studies included people with type 1 or type 2 diabetes, while one study included only people with type 2 diabetes. The duration of treatment was between six months and 48 months. We judged all studies at high risk of overall bias due to attrition. ALA compared with placebo probably has little or no effect on neuropathy symptoms measured by TSS (lower score is better) after six months (mean difference (MD) -0.16 points, 95% confidence interval (CI) -0.83 to 0.51; 1 study, 330 participants; moderate-certainty evidence). The CI of this effect estimate did not contain the minimal clinically important difference (MCID) of 0.97 points. ALA compared with placebo may have little or no effect on impairment measured by the Neuropathy Impairment Score-Lower Limbs (NIS-LL; lower score is better) after six months (MD -1.02 points, 95% CI -2.93 to 0.89; 1 study, 245 participants; low-certainty evidence). However, we cannot rule out a significant benefit, because the lower limit of the CI surpassed the MCID of 2 points. There is probably little or no difference between ALA and placebo in terms of adverse events leading to cessation of treatment within six months (risk ratio (RR) 1.48, 95% CI 0.50 to 4.35; 3 studies, 1090 participants; moderate-certainty evidence). No studies reported quality of life or complications associated with DPN. AUTHORS' CONCLUSIONS: Our analysis suggests that ALA probably has little or no effect on neuropathy symptoms or adverse events at six months, and may have little or no effect on impairment at six months. All the studies were at high risk of attrition bias. Therefore, future RCTs should ensure complete follow-up and transparent reporting of any participants missing from the analyses.

A scoping review establishes need for consensus guidance on reporting health equity in observational studies.

OBJECTIVES: To evaluate the support from the available guidance on reporting of health equity in research for our candidate items and to identify additional items for the Strengthening Reporting of Observational studies in Epidemiology-Equity extension. STUDY DESIGN AND SETTING: We conducted a scoping review by searching Embase, MEDLINE, CINAHL, Cochrane Methodology Register, LILACS, and Caribbean Center on Health Sciences Information up to January 2022. We also searched reference lists and gray literature for additional resources. We included guidance and assessments (hereafter termed "resources") related to conduct and/or reporting for any type of health research with or about people experiencing health inequity. RESULTS: We included 34 resources, which supported one or more candidate items or contributed to new items about health equity reporting in observational research. Each candidate item was supported by a median of six (range: 1-15) resources. In addition, 12 resources suggested 13 new items, such as "report the background of investigators". CONCLUSION: Existing resources for reporting health equity in observational studies aligned with our interim checklist of candidate items. We also identified additional items that will be considered in the development of a consensus-based and evidence-based guideline for reporting health equity in observational studies.

In Cochrane nutrition reviews assessment of dietary adherence varied considerably.

OBJECTIVES: Our aim was to investigate if and how Cochrane nutrition reviews assess dietary adherence to a specific dietary regimen. STUDY DESIGN AND SETTING: Cochrane nutrition reviews fulfilling the following criteria were included: systematic review of randomized controlled trials including adults and investigating the effect of caloric restriction, dietary pattern, foods, nutrients, supplements, or other nutrition-related-interventions. Extensive data extraction and descriptive statistics were conducted. RESULTS: Overall, 226 Cochrane reviews were included. Most reviews mentioned dietary adherence in the main text (n = 174), predominantly in the Methods and Results. Dietary adherence was assessed in 76 reviews and defined in 19. It was included in the risk of bias (RoB) assessment in 20 reviews with nine using a newly created RoB domain for dietary adherence, and considered as outcome in 37 reviews. Seventy-five reviews addressed degree of adherence and five treatment effects considering the degree of adherence. CONCLUSION: Dietary adherence was reported in a heterogeneous manner in Cochrane nutrition reviews. Due to its high importance, we suggest that systematic reviews report the assessment and degree of dietary adherence measured in primary studies. Dietary adherence can further be examined as outcome, evaluated within the RoB (deviations from intended interventions) and included in sensitivity analyses.

The RIPI-f (Reporting Integrity of Psychological Interventions delivered face-to-face) checklist was developed to guide reporting of treatment integrity in face-to-face psychological interventions.

OBJECTIVES: Intervention integrity is the degree to which the study intervention is delivered as intended. This article presents the RIPI-f checklist (Reporting Integrity of Psychological Interventions delivered face-to-face) and summarizes its development methods. RIPI-f proposes guidance for reporting intervention integrity in evaluative studies of face-to-face psychological interventions. STUDY DESIGN AND SETTING: We followed established procedures for developing reporting guidelines. We examined 56 documents (reporting guidelines, bias tools, and methodological guidance) for relevant aspects of face-to-face psychological intervention integrity. Eighty four items were identified and grouped as per the template for intervention description and replication (TIDieR) domains. Twenty nine experts from psychology and medicine and other scholars rated the relevance of each item in a single-round Delphi survey. A multidisciplinary panel of 11 experts discussed the survey results in three online consensus meetings and drafted the final version of the checklist. RESULTS: We propose RIPI-f, a checklist with 50 items. Our checklist enhances TIDieR with important extensions, such as therapeutic alliance, provider's allegiance, and the adherence of providers and participants. CONCLUSION: RIPI-f can improve the reporting of face-to-face psychological interventions. The tool can help authors, researchers, systematic reviewers, and guideline developers. We suggest using RIPI-f alongside other reporting guidelines.

Reporting quality of clinical trial protocols: a repeated cross-sectional study about the Adherence to SPIrit Recommendations in Switzerland, CAnada and GErmany (ASPIRE-SCAGE).

OBJECTIVES: Comprehensive protocols are key for the planning and conduct of randomised clinical trials (RCTs). Evidence of low reporting quality of RCT protocols led to the publication of the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) checklist in 2013. We aimed to examine the quality of reporting of RCT protocols from three countries before and after the publication of the SPIRIT checklist. DESIGN: Repeated cross sectional study. SETTING: Swiss, German and Canadian research ethics committees (RECs). PARTICIPANTS: RCT protocols approved by RECs in 2012 (n=257) and 2016 (n=292). PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcomes were the proportion of reported SPIRIT items per protocol and the proportion of trial protocols reporting individual SPIRIT items. We compared these outcomes in protocols approved in 2012 and 2016, and built regression models to explore factors associated with adherence to SPIRIT. For each protocol, we also extracted information on general trial characteristics and assessed whether individual SPIRIT items were reported RESULTS: The median proportion of reported SPIRIT items among RCT protocols showed a non-significant increase from 72% (IQR, 63%-79%) in 2012 to 77% (IQR, 68%-82%) in 2016. However, in a preplanned subgroup analysis, we detected a significant improvement in investigator-sponsored protocols: the median proportion increased from 64% (IQR, 55%-72%) in 2012 to 76% (IQR, 64%-83%) in 2016, while for industry-sponsored protocols median adherence was 77% (IQR 72%-80%) for both years. The following trial characteristics were independently associated with lower adherence to SPIRIT: single-centre trial, no support from a clinical trials unit or contract research organisation, and investigator-sponsorship. CONCLUSIONS: In 2012, industry-sponsored RCT protocols were reported more comprehensively than investigator-sponsored protocols. After publication of the SPIRIT checklist, investigator-sponsored protocols improved to the level of industry-sponsored protocols, which did not improve.

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

BACKGROUND: We 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 FINDINGS: We 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. CONCLUSIONS: We 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.

Investigators' sense of failure thwarted transparency in clinical trials discontinued for poor recruitment.

BACKGROUND AND OBJECTIVE: When a randomized clinical trial (RCT) prematurely discontinues, it is essential that stakeholders do the right thing to ensure that lessons can be learnt and trust in clinical research is maintained. There is, however, a lack of evidence exploring this issue. This study aimed to examine clinical trial stakeholders' practices following trial discontinuation due to poor participant recruitment and their views on implications of such discontinuation. METHODS: Individual semi-structured qualitative interviews were conducted with 49 clinical trial stakeholders from Switzerland (n = 39), Germany (n = 9) and Canada (n = 1) between August 2015 and November 2016. RESULTS: After interviews with 49 clinical trial stakeholders (75% male presenting), it was found that stakeholders were aware of the risks of premature trial discontinuation wasting limited resources, adversely impacting scientific evidence, and having negative personal and professional implications. However, barriers continue to undermine transparency regarding trial discontinuation in practice, with it being reported that most investigators of discontinued trials are failing to notify stakeholders or publishing their results. Investigators sense of failure and associated negative emotions were identified as a key reason why investigators are not more transparent following discontinuation. CONCLUSION: The decision to notify stakeholders and publish results of a discontinued clinical trial should not rest solely on individual investigators but come from a systemic approach. However, until health research proactively requires the dissemination of results of all clinical trials, much will rest on individual investigators being motivated to do the right thing. Support programs might be helpful for investigators involved in discontinued trials and promote transparency and learning lessons.

Exploring reasons for recruitment failure in clinical trials: a qualitative study with clinical trial stakeholders in Switzerland, Germany, and Canada.

BACKGROUND: Poor participant recruitment is the most frequent reason for premature discontinuation of randomized clinical trials (RCTs), particularly if they are investigator-initiated. The aims of this qualitative study were to investigate (1) the views of clinical trial stakeholders from three different countries regarding reasons for recruitment failure in RCTs and (2) how these compare and contrast with the causes identified in a previous systematic review of RCT publications. METHODS: From August 2015 to November 2016, we conducted 49 semi-structured interviews with a purposive sample of clinical trial stakeholders. This included investigators based in Germany (n = 9), Switzerland (n = 6) and Canada (n = 1) with personal experience of a discontinued RCT and 33 other stakeholders (e.g., representatives of ethics committees, clinical trial units, pharmaceutical industry) in Switzerland. Individual semi-structured qualitative interviews were conducted and analyzed using thematic analysis. RESULTS: Interviewees identified a total of 29 different reasons for recruitment failure. Overoptimistic recruitment estimates, too narrow eligibility criteria, lack of engagement of recruiters/trial team, lack of competence/training/experience of recruiters, insufficient initial funding, and high burden for trial participants were mentioned most frequently. The interview findings largely confirm the previous systematic review on published reasons for recruitment failure. However, eight new reasons for recruitment failure were identified in the interviews, which led to the checklist of reasons for recruitment failure being revised and a new category describing research environment-related factors being added. CONCLUSIONS: This study highlights the diversity of often interlinked reasons for recruitment failure in RCTs. Integrating the findings of this interview study with a previous systematic review of RCT publications led to a comprehensive, structured checklist of empirically-informed reasons for recruitment failure. The checklist may be useful to guide further research on interventions to improve participant recruitment in RCTs and helpful for trial investigators, research ethics committees, and funding agencies when assessing trial feasibility with respect to recruitment.

Expert guidance for COVID-19 vaccine deployment in Switzerland: a Delphi process.

BACKGROUND AND AIM: Vaccines providing protection against COVID-19 are a core tool for ending the pandemic. Though international organisations created guidance in 2020 for vaccine deployment, this had to be adapted for each country's situation and values. We aimed to assist public health decision makers by identifying areas of consensus among Swiss experts for the deployment of one or more novel COVID-19 vaccines. METHODS: An electronic, modified Delphi process between September and November 2020. We recruited a convenience sample of experts working in Switzerland from a variety of specialities, who completed two anonymous questionnaires. They voted on clarification questions and guidance statements from 0 (complete disagreement) to 10 (complete agreement). Responses for guidance statements with a median ≥8 and a lower inter-quartile range bound ≥7 were considered as reaching consensus. RESULTS: Sixty-five experts accepted (66% response rate), with 47 completing the first questionnaire (72%), and 48 the second (74%). Statements reaching consensus included: in the first phase we should vaccinate front-line healthcare professionals and people ≥65 years with risk factors; widespread vaccination of children and adolescents should not be an early priority; and vaccines should be provided free of charge in the setting of national or cantonal vaccination campaigns. Statements not reaching consensus included: early vaccination of people living with someone with risk factors who are not themselves at risk; vaccination of people with previous confirmed or suspected COVID-19; and whether vaccination should be mandatory for individuals with certain activities, such as front-line healthcare professionals. CONCLUSIONS: Experts reached consensus on several statements that were available for decision-makers when making key decisions for COVID-19 vaccine deployment in Switzerland. Statements without consensus highlighted areas requiring expert and public dialogue. The modified Delphi process allowed us to rapidly synthesise views from a broad panel of experts on sensitive topics, and could be considered for a broad range of issues during public health crises.

Reporting quality of trial protocols improved for non-regulated interventions but not regulated interventions: A repeated cross-sectional study.

OBJECTIVES: To investigate the adherence of randomised controlled trial (RCT) protocols evaluating non-regulated interventions (including dietary interventions, surgical procedures, behavioural and lifestyle interventions, and exercise programmes) in comparison with regulated interventions to the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) 2013 Statement. METHODS: We conducted a repeated cross-sectional investigation in a random sample of RCT protocols approved in 2012 (n = 257) or 2016 (n = 292) by research ethics committees in Switzerland, Germany, or Canada. We investigated the proportion of accurately reported SPIRIT checklist items in protocols of trials with non-regulated as compared to regulated interventions. RESULTS: Overall, 131 (24%) of trial protocols tested non-regulated interventions. In 2012, the median proportion of SPIRIT items reported in these protocols (59%, interquartile range [IQR], 53%-69%) was lower than in protocols with regulated interventions (median, 74%, IQR, 66%-80%). In 2016, the reporting quality of protocols with non-regulated interventions (median, 75%, IQR, 62%-83%) improved to the level of regulated intervention protocols, which had not changed on average. CONCLUSIONS: Reporting of RCT protocols evaluating non-regulated interventions improved between 2012 and 2016, although remained suboptimal. SPIRIT recommendations need to be further endorsed by researchers, ethics committees, funding agencies, and journals to optimize reporting of RCT protocols.

Open versus laparoscopic pyloromyotomy for pyloric stenosis.

BACKGROUND: Infantile hypertrophic pyloric stenosis (IHPS) is a disorder of young children (aged one year or less) and can be treated by laparoscopic (LP) or open (OP) longitudinal myotomy of the pylorus. Since the first description in 1990, LP is being performed more often worldwide. OBJECTIVES: To compare the efficacy and safety of open versus laparoscopic pyloromyotomy for IHPS. SEARCH METHODS: We conducted a literature search on 04 February 2021 to identify all randomised controlled trials (RCTs), without any language restrictions. We searched the following electronic databases: MEDLINE (1990 to February 2021), Embase (1990 to February 2021), and the Cochrane Central Register of Controlled Trials (CENTRAL). We also searched the Internet using the Google Search engine (www.google.com) and Google Scholar (scholar.google.com) to identify grey literature not indexed in databases. SELECTION CRITERIA: We included RCTs and quasi-randomised trials comparing LP with OP for hypertrophic pyloric stenosis. DATA COLLECTION AND ANALYSIS: Two review authors independently screened references and extracted data from trial reports. Where outcomes or study details were not reported, we requested missing data from the corresponding authors of the primary RCTs. We used a random-effects model to calculate risk ratios (RRs) for binary outcomes, and mean differences (MDs) for continuous outcomes. Two review authors independently assessed risks of bias. We used GRADE to assess the certainty of the evidence for all outcomes. MAIN RESULTS: The electronic database search resulted in a total of 434 records. After de-duplication, we screened 410 independent publications, and ultimately included seven RCTs (reported in 8 reports) in quantitative analysis. The seven included RCTs enrolled 720 participants (357 with open pyloromyotomy and 363 with laparoscopic pyloromyotomy). One study was a multi-country trial, three were carried out in the USA, and one study each was carried out in France, Japan, and Bangladesh. The evidence suggests that LP may result in a small increase in mucosal perforation compared with OP (RR 1.60, 95% CI 0.49 to 5.26; 7 studies, 720 participants; low-certainty evidence). LP may result in up to 5 extra instances of mucosal perforation per 1,000 participants; however, the confidence interval ranges from 4 fewer to 44 more per 1,000 participants. Four RCTs with 502 participants reported on incomplete pyloromyotomy. They indicate that LP may increase the risk of incomplete pyloromyotomy compared with OP, but the confidence interval crosses the line of no effect (RR 7.37, 95% CI 0.92 to 59.11; 4 studies, 502 participants; low-certainty evidence). In the LP groups, 6 cases of incomplete pyloromyotomy were reported in 247 participants while no cases of incomplete pyloromyotomy were reported in the OP groups (from 255 participants). All included studies (720 participants) reported on postoperative wound infections or abscess formations. The evidence is very uncertain about the effect of LP on postoperative wound infection or abscess formation compared with OP (RR 0.59, 95% CI 0.24 to 1.45; 7 studies, 720 participants; very low-certainty evidence). The evidence is also very uncertain about the effect of LP on postoperative incisional hernia compared with OP (RR 1.01, 95% CI 0.11 to 9.53; 4 studies, 382 participants; very low-certainty evidence). Length of hospital stay was assessed by five RCTs, including 562 participants. The evidence is very uncertain about the effect of LP compared to OP (mean difference -3.01 hours, 95% CI -8.39 to 2.37 hours; very low-certainty evidence). Time to full feeds was assessed by six studies, including 622 participants. The evidence is very uncertain about the effect of LP on time to full feeds compared with OP (mean difference -5.86 hours, 95% CI -15.95 to 4.24 hours; very low-certainty evidence). The evidence is also very uncertain about the effect of LP on operating time compared with OP (mean difference 0.53 minutes, 95% CI -3.53 to 4.59 minutes; 6 studies, 622 participants; very low-certainty evidence). AUTHORS' CONCLUSIONS: Laparoscopic pyloromyotomy may result in a small increase in mucosal perforation when compared with open pyloromyotomy for IHPS. There may be an increased risk of incomplete pyloromyotomy following LP compared with OP, but the effect estimate is imprecise and includes the possibility of no difference. We do not know about the effect of LP compared with OP on the need for re-operation, postoperative wound infections or abscess formation, postoperative haematoma or seroma formation, incisional hernia occurrence, length of postoperative stay, time to full feeds, or operating time because the certainty of the evidence was very low for these outcomes. We downgraded the certainty of the evidence for most outcomes due to limitations in the study design (most outcomes were susceptible to detection bias) and imprecision. There is limited evidence available comparing LP with OP for IHPS. The included studies did not provide sufficient information to determine the effect of training, experience, or surgeon preferences on the outcomes assessed.

Rationale and design of repeated cross-sectional studies to evaluate the reporting quality of trial protocols: the Adherence to SPIrit REcommendations (ASPIRE) study and associated projects.

BACKGROUND: Clearly structured and comprehensive protocols are an essential component to ensure safety of participants, data validity, successful conduct, and credibility of results of randomized clinical trials (RCTs). Funding agencies, research ethics committees (RECs), regulatory agencies, medical journals, systematic reviewers, and other stakeholders rely on protocols to appraise the conduct and reporting of RCTs. In response to evidence of poor protocol quality, the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guideline was published in 2013 to improve the accuracy and completeness of clinical trial protocols. The impact of these recommendations on protocol completeness and associations between protocol completeness and successful RCT conduct and publication remain uncertain. OBJECTIVES AND METHODS: Aims of the Adherence to SPIrit REcommendations (ASPIRE) study are to investigate adherence to SPIRIT checklist items of RCT protocols approved by RECs in the UK, Switzerland, Germany, and Canada before (2012) and after (2016) the publication of the SPIRIT guidelines; determine protocol features associated with non-adherence to SPIRIT checklist items; and assess potential differences in adherence across countries. We assembled an international cohort of RCTs based on 450 protocols approved in 2012 and 402 protocols approved in 2016 by RECs in Switzerland, the UK, Germany, and Canada. We will extract data on RCT characteristics and adherence to SPIRIT for all included protocols. We will use multivariable regression models to investigate temporal changes in SPIRIT adherence, differences across countries, and associations between SPIRIT adherence of protocols with RCT registration, completion, and publication of results. We plan substudies to examine the registration, premature discontinuation, and non-publication of RCTs; the use of patient-reported outcomes in RCT protocols; SPIRIT adherence of RCT protocols with non-regulated interventions; the planning of RCT subgroup analyses; and the use of routinely collected data for RCTs. DISCUSSION: The ASPIRE study and associated substudies will provide important information on the impact of measures to improve the reporting of RCT protocols and on multiple aspects of RCT design, trial registration, premature discontinuation, and non-publication of RCTs observing potential changes over time.

Prediction of RECRUITment In randomized clinical Trials (RECRUIT-IT)-rationale and design for an international collaborative study.

BACKGROUND: Poor recruitment of patients is the predominant reason for early termination of randomized clinical trials (RCTs). Systematic empirical investigations and validation studies of existing recruitment models, however, are lacking. We aim to provide evidence-based guidance on how to predict and monitor recruitment of patients into RCTs. Our specific objectives are the following: (1) to establish a large sample of RCTs (target n = 300) with individual patient recruitment data from a large variety of RCTs, (2) to investigate participant recruitment patterns and study site recruitment patterns and their association with the overall recruitment process, (3) to investigate the validity of a freely available recruitment model, and (4) to develop a user-friendly tool to assist trial investigators in the planning and monitoring of the recruitment process. METHODS: Eligible RCTs need to have completed the recruitment process, used a parallel group design, and investigated any healthcare intervention where participants had the free choice to participate. To establish the planned sample of RCTs, we will use our contacts to national and international RCT networks, clinical trial units, and individual trial investigators. From included RCTs, we will collect patient-level information (date of randomization), site-level information (date of trial site activation), and trial-level information (target sample size). We will examine recruitment patterns using recruitment trajectories and stratifications by RCT characteristics. We will investigate associations of early recruitment patterns with overall recruitment by correlation and multivariable regression. To examine the validity of a freely available Bayesian prediction model, we will compare model predictions to collected empirical data of included RCTs. Finally, we will user-test any promising tool using qualitative methods for further tool improvement. DISCUSSION: This research will contribute to a better understanding of participant recruitment to RCTs, which could enhance efficiency and reduce the waste of resources in clinical research with a comprehensive, concerted, international effort.

Uncertainties about the need for ethics approval in Switzerland: a mixed-methods study.

BACKGROUND: To ensure ethical oversight, researchers wanting to conduct “research” involving human beings are typically required to obtain prior approval from an independent ethics committee. However, it can sometimes be unclear if a project needs to be submitted for ethics approval. Swiss researchers can contact research ethics committees via a “jurisdictional inquiry” for clarification whether a project needs to be submitted for ethics approval. AIMS OF THE STUDY: (1) To examine the characteristics of Swiss jurisdictional inquiries, and (2) to identify possible uncertainties regarding the correct interpretation of existing legislation in Switzerland. METHODS: All jurisdictional inquiries submitted to Swiss research ethics committees between July and December 2017 were reviewed using qualitative content analysis. We then conducted an online survey between June 2018 and July 2018 with all researchers who had submitted a jurisdictional inquiry including a descriptive quantitative analysis. RESULTS: The review included 271 jurisdictional inquiries. Analysis identified three groups of jurisdictional inquiries: 80.4% (218/271) sought clarification whether the project had to be submitted for ethical approval; 18.5% (50/271) requested a “declaration of no objection”; and 1.1% (3/271) asked for a clarification about which of the two ordinances was applicable to the project. Analysis identified eight distinct legal issues that appeared to be the main cause for a number of jurisdictional inquiries, with the two most frequently identified issues being whether the project will produce generalisable knowledge, and whether the project uses fully anonymised data. Overall, research ethics committees decided that 78.6% (213/271) of the jurisdictional inquiries were outside their jurisdiction and did not require ethical approval, and that 15.6% required submission for ethical approval. The online survey achieved a 56.8% response rate. The majority of respondents (94/166; 56.6%) reported that all the questions they were asked during the submission of the jurisdictional inquiry were easy to understand. Respondents reported that 88% (147/166) of all projects were started or planned to start. The vast majority (154/166; 93%) of respondents also agreed with the decisions made by the research ethics committee. CONCLUSIONS: Jurisdictional inquiries are an important means for researchers to clarify whether their project requires ethical oversight. However, this mixed-methods study has identified some difficulties in the interpretation of legal terms, which often reflect persistent structural issues that many other countries also face. More detailed guidance may be helpful to reduce the researchers’ uncertainties and ethics committees’ workloads in relation to jurisdictional inquiries.

Trial Forge Guidance 2: how to decide if a further Study Within A Trial (SWAT) is needed.

The evidence base available to trialists to support trial process decisions-e.g. how best to recruit and retain participants, how to collect data or how to share the results with participants-is thin. One way to fill gaps in evidence is to run Studies Within A Trial, or SWATs. These are self-contained research studies embedded within a host trial that aim to evaluate or explore alternative ways of delivering or organising a particular trial process.SWATs are increasingly being supported by funders and considered by trialists, especially in the UK and Ireland. At some point, increasing SWAT evidence will lead funders and trialists to ask: given the current body of evidence for a SWAT, do we need a further evaluation in another host trial? A framework for answering such a question is needed to avoid SWATs themselves contributing to research waste.This paper presents criteria on when enough evidence is available for SWATs that use randomised allocation to compare different interventions.