Correction: A survey of biomedical journals to detect editorial bias and nepotistic behavior.

[This corrects the article DOI: 10.1371/journal.pbio.3001133.].

A novel framework to assess haematology and oncology registration trials: The THEOREMM project.

BACKGROUND: Methodological limitations affect a significant number of oncology and haematology trials, raising concerns about the applicability of their results. For example, a suboptimal control arm or limited access to best care upon progression may skew the trial results toward a benefit in the experimental arm. Beyond the fact that such limitations do not prevent drugs reaching the market, other assessment tools, such as those developed by professional societies-ESMO-MCBS and ASCO Value Framework-do not integrate these important shortcomings. METHODS: We propose creating a novel framework with the scope of assessing registration cancer clinical trials in haematology and oncology (randomized or single arm)-that is trials leading to a marketing authorization. The main steps of the methods are (1) assembling a scientific board; (2) defining the scope, goal and methods through pre-specified, pre-registered and protocolized methodology; (3) preregistration of the protocol; (4) conducting a scoping review of limitations and biases affecting oncology trials and assessing existing scores or methods; (5) developing a list of features to be included and assessed within the framework; (6) assessing each feature through a questionnaire sent to highly cited haematologists and oncologists involved in clinical trials; and (7) finalizing the first version of framework. RESULTS: Not applicable. CONCLUSIONS: Our proposal emerged in response to the lack of consideration for key limitations in current trial assessments. The goal is to create a framework specifically designed to assess single trials leading to marketing authorization in the field of oncology and haematogy.

A survey of biomedical journals to detect editorial bias and nepotistic behavior.

Alongside the growing concerns regarding predatory journal growth, other questionable editorial practices have gained visibility recently. Among them, we explored the usefulness of the Percentage of Papers by the Most Prolific author (PPMP) and the Gini index (level of inequality in the distribution of authorship among authors) as tools to identify journals that may show favoritism in accepting articles by specific authors. We examined whether the PPMP, complemented by the Gini index, could be useful for identifying cases of potential editorial bias, using all articles in a sample of 5,468 biomedical journals indexed in the National Library of Medicine. For articles published between 2015 and 2019, the median PPMP was 2.9%, and 5% of journal exhibited a PPMP of 10.6% or more. Among the journals with the highest PPMP or Gini index values, where a few authors were responsible for a disproportionate number of publications, a random sample was manually examined, revealing that the most prolific author was part of the editorial board in 60 cases (61%). The papers by the most prolific authors were more likely to be accepted for publication within 3 weeks of their submission. Results of analysis on a subset of articles, excluding nonresearch articles, were consistent with those of the principal analysis. In most journals, publications are distributed across a large number of authors. Our results reveal a subset of journals where a few authors, often members of the editorial board, were responsible for a disproportionate number of publications. To enhance trust in their practices, journals need to be transparent about their editorial and peer review practices.

Ten (not so) simple rules for clinical trial data-sharing.

Clinical trial data-sharing is seen as an imperative for research integrity and is becoming increasingly encouraged or even required by funders, journals, and other stakeholders. However, early experiences with data-sharing have been disappointing because they are not always conducted properly. Health data is indeed sensitive and not always easy to share in a responsible way. We propose 10 rules for researchers wishing to share their data. These rules cover the majority of elements to be considered in order to start the commendable process of clinical trial data-sharing: Rule 1: Abide by local legal and regulatory data protection requirementsRule 2: Anticipate the possibility of clinical trial data-sharing before obtaining fundingRule 3: Declare your intent to share data in the registration stepRule 4: Involve research participantsRule 5: Determine the method of data accessRule 6: Remember there are several other elements to shareRule 7: Do not proceed aloneRule 8: Deploy optimal data management to ensure that the data shared is usefulRule 9: Minimize risksRule 10: Strive for excellence.

Reporting of interventional clinical trial results in an academic center: a survey of completed studies.

BACKGROUND: The dissemination of clinical trial results is an important scientific and ethical endeavour. This survey of completed interventional studies in a French academic center describes their reporting status. METHODS: We explored all interventional studies sponsored by Rennes University Hospital identified on the French Open Science Monitor which tracks trials registered on EUCTR or clinicaltrials.gov, and provides an automatic assessment of the reporting of results. For each study, we ascertained the actual reporting of results using systematic searches on the hospital internal database, bibliographic databases (Google Scholar, PubMed), and by contacting all principal investigators (PIs). We describe several features (including total budget and numbers of trial participants) of the studies that did not report any results. RESULTS: The French Open Science Monitor identified 93 interventional studies, among which 10 (11%) reported results. In contrast, our survey identified 36 studies (39%) reporting primary analysis results and an additional 18 (19%) reporting results for secondary analyses (without results for their primary analysis). The overall budget for studies that did not report any results was estimated to be €5,051,253 for a total of 6,735 trial participants. The most frequent reasons for the absence of results reported by PIs were lack of time for 18 (42%), and logistic difficulties (e.g. delay in obtaining results or another blocking factor) for 12 (28%). An association was found between non-publication and negative results (adjusted Odds Ratio = 4.70, 95% Confidence Interval [1.67;14.11]). CONCLUSIONS: Even allowing for the fact that automatic searches underestimate the number of studies with published results, the level of reporting was disappointingly low. This amounts to a waste of trial participants' implication and money. Corrective actions are needed. TRIAL REGISTRATION: https://osf.io/q5hcs.

Data-sharing and re-analysis for main studies assessed by the European Medicines Agency-a cross-sectional study on European Public Assessment Reports.

BACKGROUND: Transparency and reproducibility are expected to be normative practices in clinical trials used for decision-making on marketing authorisations for new medicines. This registered report introduces a cross-sectional study aiming to assess inferential reproducibility for main trials assessed by the European Medicines Agency. METHODS: Two researchers independently identified all studies on new medicines, biosimilars and orphan medicines given approval by the European Commission between January 2017 and December 2019, categorised as 'main studies' in the European Public Assessment Reports (EPARs). Sixty-two of these studies were randomly sampled. One researcher retrieved the individual patient data (IPD) for these studies and prepared a dossier for each study, containing the IPD, the protocol and information on the conduct of the study. A second researcher who had no access to study reports used the dossier to run an independent re-analysis of each trial. All results of these re-analyses were reported in terms of each study's conclusions, p-values, effect sizes and changes from the initial protocol. A team of two researchers not involved in the re-analysis compared results of the re-analyses with published results of the trial. RESULTS: Two hundred ninety-two main studies in 173 EPARs were identified. Among the 62 studies randomly sampled, we received IPD for 10 trials. The median number of days between data request and data receipt was 253 [interquartile range 182-469]. For these ten trials, we identified 23 distinct primary outcomes for which the conclusions were reproduced in all re-analyses. Therefore, 10/62 trials (16% [95% confidence interval 8% to 28%]) were reproduced, as the 52 studies without available data were considered non-reproducible. There was no change from the original study protocol regarding the primary outcome in any of these ten studies. Spin was observed in the report of one study. CONCLUSIONS: Despite their results supporting decisions that affect millions of people's health across the European Union, most main studies used in EPARs lack transparency and their results are not reproducible for external researchers. Re-analyses of the few trials with available data showed very good inferential reproducibility. TRIAL REGISTRATION: https://osf.io/mcw3t/.

Tivozanib in renal cell carcinoma: a systematic review of the evidence and its dissemination in the scientific literature.

BACKGROUND: Tivozanib (Fotivda) is an anti-angiogenic tyrosine kinase inhibitor that was denied access to the US market by the Food and Drug Administration (FDA). In contrast, it was granted approval by the European Medicines Agency (EMA) for the treatment of Renal Cell Carcinoma in adults. Given the conflicting decisions from these regulatory agencies, the objectives of the following study are (i) to critically review the evidence supporting the approval of tivozanib; (ii) to analyse the dissemination of this evidence in the literature by way of a citation analysis. METHODS: Pivotal trials were searched by two independent reviewers using Medline, Cochrane Library, ClinicalTrials.gov and the European Public Assessment Report. The risk of bias for each trial was then inductively assessed. Articles citing any of these trials were identified using Web of Sciences. Finally, the quality of the citations was evaluated by two independent reviewers according to standard data extraction methods. RESULTS: The search for primary evidence identified two pivotal studies: TIVO-1 upon which the FDA and the EMA decisions were based, and TIVO-3 which was conducted after the agencies' decisions had been issued. The TIVO-1 trial presented several limitations that compromised causal inference, in relation to (i) design (absence of blinding, inappropriate comparator, and one-way crossover), (ii) poor internal consistency in the results for the primary endpoint, (iii) a discrepancy between a benefit observed for progression-free survival (HR: 0.80, 95% CI [0.64-0.99]) and the absence of difference for overall survival (HR: 1.25, 95% CI [0.95 - 1.62]). Our citation search protocol identified 229 articles that cited TIVO-1 in the 7 years following its publication, among which 151 (65.9%) citing articles discussing efficacy. Presence of spin was identified in 64 (42.4%) of these 151 citing articles, and 39 (25.8%) additional articles citing results without providing enough elements to interpret the TIVO-1 results. CONCLUSION: EMA's approval was based on a single pivotal trial presenting critical limitations, rendering the results from the trial potentially inconclusive. The broad dissemination of TIVO-1 results in the scientific literature may have been affected by spin or results were presented in an inadequate critical manner.

Overlapping network meta-analyses on psoriasis systemic treatments, an overview: quantity does not make quality.

BACKGROUND: Network meta-analyses (NMAs) have become successful in addressing gaps in the comparative effectiveness of systemic treatments in moderate-to-severe psoriasis. However, their increasing number carries both a risk of overlap and reproducibility issues that can hamper clinical decision-making. OBJECTIVES: In this overview, we aimed to assess redundancy across these NMAs and to describe their characteristics. MATERIALS AND METHODS: We considered all systematic reviews with NMAs of randomized controlled trials that included adult patients with moderate-to-severe psoriasis and that evaluated the efficacy and/or safety of systemic treatments compared with placebo or with an active comparator. PubMed/MEDLINE, Epistemonikos, PROSPERO and the Evidence update of the Centre of Evidence-Based Dermatology of the University of Nottingham were searched up to 25 February 2021. Our main outcome was the number per year of redundant NMAs and the extent of their overlap. We also described their features, especially, the confidence in the results of the reviews, the funding of the studies and the presence of spin (a description that overstates efficacy and/or understates harm), reporting issues and methodological characteristics. RESULTS: In total, 47 redundant NMAs were included. Only two of 47 (4%) included all available treatments. Both efficacy and safety were evaluated in 14 of 47 (30%) NMAs and both short- and long-term evaluations were assessed in five of 47 (11%). Confidence in the results was critically low for 39 of 47 (83%) NMAs and only 10 of 47 (21·3%) registered a protocol. Twenty-six of 47 NMAs (55%) received pharmaceutical funding. Contract research organizations were involved in 19 of 47 (40%) NMAs. Reporting was poor across most of the NMA abstracts and spin was present in all of the abstracts. Almost half of the NMAs failed to consider important limitations such as heterogeneity (considered in 32%) or consistency (considered in 66%). CONCLUSIONS: In addition to a duplication of efforts, our overview showed heterogeneous methods and poor confidence in the results in a majority of the included NMAs, further distorted by reporting issues and spin. Clinicians need to interpret NMAs with caution when looking for the most reliable and comprehensive evidence.

How do they add up? The interaction between the placebo and treatment effect: A systematic review.

AIM: The placebo effect and the specific effect are often thought to add up (additive model). Whether additivity holds can dramatically influence the external validity of a trial. This assumption of additivity was tested by Kleijnen et al in 1994 but the data produced since then have not been synthetized. In this review, we aimed to systematically review the literature to determine whether additivity held. METHODS: We searched Medline and PsychInfo up to 10 January 2019. Studies using the balanced placebo design (BPD), testing two different strengths of placebos, were included. The presence of interaction was evaluated by comparing each group in the BPD with analysis of variance or covariance. RESULTS: Thirty studies were included and the overall risk of bias was high: four found evidence of additivity and 16 studies found evidence of interaction (seven had evidence of positive additivity). CONCLUSION: Evidence of additivity between placebo and specific features of treatments was rare in included studies. We suggest interventions for placebo-sensitive ailments should be tested in trials designed to take interactions seriously once an exploratory RCTs has proven their efficacy with sufficient internal validity.

An open science pathway for drug marketing authorization-Registered drug approval.

Florian Naudet and co-authors propose a pathway involving registered criteria for evaluation and approval of new drugs.

Medical journal requirements for clinical trial data sharing: Ripe for improvement.

Florian Naudet and co-authors discuss strengthening requirements for sharing clinical trial data.

Clinical trials during pandemics and beyond: time for a more efficient pharmacological strategy.

During the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, clinical trials on antiviral or symptomatic drugs have been conducted very rapidly even for drugs with a poor pharmacological rationale for efficacy on SARS-CoV-2. Despite lacking basic pharmacological information, most of these clinical trials were also extremely redundant. Applying simple rules, (such as identifying a mechanistic rationale, confirming the ability to reach exposure targets at therapeutic dosage and ensuring tests show drug efficacy in appropriate in vitro and animal models before entering clinical trials) might have saved considerable amounts of time and money, and might have avoided useless research. Moreover, combining these simple rules with the implementation of a relevant policy at both an international and a national level, by limiting studies with a poor methodological/scientific approach and aggregating studies with similar design into single clinical trials, is potentially a far more-efficient strategy.

Assessing scientists for hiring, promotion, and tenure.

Assessment of researchers is necessary for decisions of hiring, promotion, and tenure. A burgeoning number of scientific leaders believe the current system of faculty incentives and rewards is misaligned with the needs of society and disconnected from the evidence about the causes of the reproducibility crisis and suboptimal quality of the scientific publication record. To address this issue, particularly for the clinical and life sciences, we convened a 22-member expert panel workshop in Washington, DC, in January 2017. Twenty-two academic leaders, funders, and scientists participated in the meeting. As background for the meeting, we completed a selective literature review of 22 key documents critiquing the current incentive system. From each document, we extracted how the authors perceived the problems of assessing science and scientists, the unintended consequences of maintaining the status quo for assessing scientists, and details of their proposed solutions. The resulting table was used as a seed for participant discussion. This resulted in six principles for assessing scientists and associated research and policy implications. We hope the content of this paper will serve as a basis for establishing best practices and redesigning the current approaches to assessing scientists by the many players involved in that process.

Characteristics of available studies and dissemination of research using major clinical data sharing platforms.

BACKGROUND/AIMS: Over the past decade, numerous data sharing platforms have been launched, providing access to de-identified individual patient-level data and supporting documentation. We evaluated the characteristics of prominent clinical data sharing platforms, including types of studies listed as available for request, data requests received, and rates of dissemination of research findings from data requests. METHODS: We reviewed publicly available information listed on the websites of six prominent clinical data sharing platforms: Biological Specimen and Data Repository Information Coordinating Center, ClinicalStudyDataRequest.com, Project Data Sphere, Supporting Open Access to Researchers-Bristol Myers Squibb, Vivli, and the Yale Open Data Access Project. We recorded key platform characteristics, including listed studies and available supporting documentation, information on the number and status of data requests, and rates of dissemination of research findings from data requests (i.e. publications in a peer-reviewed journals, preprints, conference abstracts, or results reported on the platform's website). RESULTS: The number of clinical studies listed as available for request varied among five data sharing platforms: Biological Specimen and Data Repository Information Coordinating Center (n = 219), ClinicalStudyDataRequest.com (n = 2,897), Project Data Sphere (n = 154), Vivli (n = 5426), and the Yale Open Data Access Project (n = 395); Supporting Open Access to Researchers did not provide a list of Bristol Myers Squibb studies available for request. Individual patient-level data were nearly always reported as being available for request, as opposed to only Clinical Study Reports (Biological Specimen and Data Repository Information Coordinating Center = 211/219 (96.3%); ClinicalStudyDataRequest.com = 2884/2897 (99.6%); Project Data Sphere = 154/154 (100.0%); and the Yale Open Data Access Project = 355/395 (89.9%)); Vivli did not provide downloadable study metadata. Of 1201 data requests listed on ClinicalStudyDataRequest.com, Supporting Open Access to Researchers-Bristol Myers Squibb, Vivli, and the Yale Open Data Access Project platforms, 586 requests (48.8%) were approved (i.e. data access granted). The majority were for secondary analyses and/or developing/validating methods (ClinicalStudyDataRequest.com = 262/313 (83.7%); Supporting Open Access to Researchers-Bristol Myers Squibb = 22/30 (73.3%); Vivli = 63/84 (75.0%); the Yale Open Data Access Project = 111/159 (69.8%)); four were for re-analyses or corroborations of previous research findings (ClinicalStudyDataRequest.com = 3/313 (1.0%) and the Yale Open Data Access Project = 1/159 (0.6%)). Ninety-five (16.1%) approved data requests had results disseminated via peer-reviewed publications (ClinicalStudyDataRequest.com = 61/313 (19.5%); Supporting Open Access to Researchers-Bristol Myers Squibb = 3/30 (10.0%); Vivli = 4/84 (4.8%); the Yale Open Data Access Project = 27/159 (17.0%)). Forty-two (6.8%) additional requests reported results through preprints, conference abstracts, or on the platform's website (ClinicalStudyDataRequest.com = 12/313 (3.8%); Supporting Open Access to Researchers-Bristol Myers Squibb = 3/30 (10.0%); Vivli = 2/84 (2.4%); Yale Open Data Access Project = 25/159 (15.7%)). CONCLUSION: Across six prominent clinical data sharing platforms, information on studies and request metrics varied in availability and format. Most data requests focused on secondary analyses and approximately one-quarter of all approved requests publicly disseminated their results. To further promote the use of shared clinical data, platforms should increase transparency, consistently clarify the availability of the listed studies and supporting documentation, and ensure that research findings from data requests are disseminated.

French Validation of the Alcohol Urge Questionnaire: Psychometric Properties and Relationship with Alcohol Dependence and Drinking Behavior.

AIM: To validate a French translation of the Alcohol Urge Questionnaire (AUQ) that measures craving in patients with alcohol dependence. METHOD: All patients aged > 18 years who were hospitalized for alcohol detoxification from February to May 2019 in the alcohol unit of the Rennes university hospital were eligible. A back-translated version of the AUQ was completed at admission. Patients were interviewed at the end of the 7-day detoxification program by a trained addiction psychiatrist (MS), using tablet computed-based questionnaires assessing state craving (visual analog scale), alcohol dependence severity, drinking behavior, psychological distress and physical/mental health. The same investigator assessed relapse 1 month after discharge. RESULTS: A total of 80 inpatients were recruited and completed questionnaires. The single factor structure of the French version of the AUQ was similar to the original questionnaire, and was supported by strong internal reliability and item-scale validity. The AUQ score correlated highly acute craving measure, but moderately scales assessing the severity of alcohol dependence, drinking behavior and mental health. Relapse 1 month after discharge was significantly related to AUQ score assessed either at baseline, or with better estimate at the end of the 7-day detoxification period. CONCLUSION: The French version of the AUQ provides a reliable measure of phasic craving, which is best described as a context-dependent single-factor variable, related to but distinct from tonic craving, dependence severity and drinking behavior. The ease of administration makes the AUQ a useful tool for French-speaking patients with alcohol dependence.

Clinical application of mesenchymal stem cells in periodontal regeneration: A systematic review and meta-analysis.

OBJECTIVE: To evaluate the potential efficacy of mesenchymal stem cells (MSCs) in periodontal regeneration in humans on the following main outcomes: clinical attachment level (CAL), probing depth (PD), and gingival recession (GR). BACKGROUND: The clinical application of stem cells in periodontal regeneration has begun in recent years, but clinical practices are not yet standardized and no recommendations are available at this time. METHODS: Electronic database searches and hand searches were conducted. All types of studies, case series, and case reports were qualitatively described. Double-blind randomized controlled trials (RCTs) evaluating MSCs in periodontal regeneration were included in a meta-analysis if they compared administration of MSCs vs application of stem cell-free therapy in the control group, in healthy patients with periodontal defects, with a minimum of three mo of follow-up. RESULTS: Fifteen reports were included in qualitative analysis, involving 123 patients and 158 periodontal defects. Only two small RCTs at high risk of bias, with a total of 59 patients and 70 periodontal defects, were included in the meta-analysis. A small but significant difference between test and control groups was found for CAL at three mo (-0.90 mm, 95% CI [-1.51; -0.29]), but not for PD and GR. CONCLUSION: Low-quality evidence suggests that MSC-based therapy may have a small impact on periodontal regeneration. However, due to the monocentric character, the small sample size, and potential heterogeneity across the two included RCTs, these results must not be considered as definitive. High-quality RCTs are needed before any clinical use of MSCs in periodontal regeneration.