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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., (© 2024. The Author(s).)

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/., (© 2022. The Author(s).)

Background: Duloxetine is an antidepressant that benefits from a wide range of approval in the elderly population, while its safety for use compared to non-elderly is not clearly assessed. This protocol outlines a systematic review and individual participant data meta-analysis comparing the tolerability of duloxetine between elderly and non-elderly., Methods: Searches will be conducted in PubMed, ClinicalTrials.gov , Clinicaltrialsregister.eu, data sharing platforms, FDA drug approval packages, European public assessment reports and withdrawn applications from the EMA website. The review will be performed on studies available in electronic databases from their date of inception to the 31 March 2022. Only randomized controlled clinical trials, comparing duloxetine to placebo, will be included in this meta-analysis. The studies will be selected if they comprise both elderly and non-elderly adults, in conditions of use of duloxetine approved by the European Medical Agency (EMA) and the Food and Drug Administration (FDA). The primary outcome will be the rate ratio of serious adverse events under duloxetine compared to placebo, between participants at least 65 years old and non-elderly. Second, the number of any adverse events, clinical efficacy and quality of life will be compared between elderly and non-elderly under both interventions. The quality of evidence in the tolerability of duloxetine will be assessed using the GRADE system. A one or two-stage individual participant data random effect meta-analysis will be conducted depending on the availability of the data., Discussion: This meta-analysis will investigate the tolerability safety of duloxetine in the elderly population across all conditions approved by European and American regulatory authorities. The results from this meta-analysis are intended to help prescribers to provide better care for the elderly population., Systematic Review Registration: The protocol has been registered at the International Prospective Register of Systematic Reviews (PROSPERO; registration number: CRD42019130488 )., (© 2022. The Author(s).)

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., (© 2022. The Author(s).)

Background: Data-sharing policies in randomized clinical trials (RCTs) should have an evaluation component. The main objective of this case-control study was to assess the impact of published re-uses of RCT data in terms of media attention (Altmetric) and citation rates., Methods: Re-uses of RCT data published up to December 2019 (cases) were searched for by two reviewers on 3 repositories (CSDR, YODA project, and Vivli) and matched to control papers published in the same journal. The Altmetric Attention Score (primary outcome), components of this score (e.g. mention of policy sources, media attention) and the total number of citations were compared between these two groups., Results: 89 re-uses were identified: 48 (53.9%) secondary analyses, 34 (38.2%) meta-analyses, 4 (4.5%) methodological analyses and 3 (3.4%) re-analyses. The median (interquartile range) Altmetric Attention Scores were 5.9 (1.3-22.2) for re-use and 2.8 (0.3-12.3) for controls (p = 0.14). No statistical difference was found on any of the components of in the Altmetric Attention Score. The median (interquartile range) numbers of citations were 3 (1-8) for reuses and 4 (1 - 11.5) for controls (p = 0.30). Only 6/89 re-uses (6.7%) were cited in a policy source., Conclusions: Using all available re-uses of RCT data to date from major data repositories, we were not able to demonstrate that re-uses attracted more attention than a matched sample of studies published in the same journals. Small average differences are still possible, as the sample size was limited. However matching choices have some limitations so results should be interpreted very cautiously. Also, citations by policy sources for re-uses were rare., Trial Registration: Registration: osf.io/fp62e.

Objective: To describe surgical journals' position statements on data-sharing policies (primary objective) and to describe key features of their research transparency promotion., Methods: Only "SURGICAL" journals with an impact factor higher than 2 (Web of Science) were eligible for the study. They were included, if there were explicit instructions for clinical trial publication in the official instructions for authors (OIA) or if they had published randomised controlled trial (RCT) between 1 January 2016 and 31 December 2018. The primary outcome was the existence of a data-sharing policy included in the instructions for authors. Data-sharing policies were grouped into 3 categories, inclusion of data-sharing policy mandatory, optional, or not available. Details on research transparency promotion were also collected, namely the existence of a "prospective registration of clinical trials requirement policy", a conflict of interests (COIs) disclosure requirement, and a specific reference to reporting guidelines, such as CONSORT for RCT., Results: Among the 87 surgical journals identified, 82 were included in the study: 67 (82%) had explicit instructions for RCT and the remaining 15 (18%) had published at least one RCT. The median impact factor was 2.98 [IQR = 2.48-3.77], and in 2016 and 2017, the journals published a median of 11.5 RCT [IQR = 5-20.75]. The OIA of four journals (5%) stated that the inclusion of a data-sharing statement was mandatory, optional in 45% (n = 37), and not included in 50% (n = 41). No association was found between journal characteristics and the existence of data-sharing policies (mandatory or optional). A "prospective registration of clinical trials requirement" was associated with International Committee of Medical Journal Editors (ICMJE) allusion or affiliation and higher impact factors. Journals with specific RCT instructions in their OIA and journals referenced on the ICMJE website more frequently mandated the use of CONSORT guidelines., Conclusion: Research transparency promotion is still limited in surgical journals. Standardisation of journal requirements according to ICMJE guidelines could be a first step forward for research transparency promotion in surgery.

Background: Different methodological choices such as inclusion/exclusion criteria and analytical models can yield different results and inferences when meta-analyses are performed. We explored the range of such differences, using several methodological choices for indirect comparison meta-analyses to compare nalmefene and naltrexone in the reduction of alcohol consumption as a case study., Methods: All double-blind randomized controlled trials (RCTs) comparing nalmefene to naltrexone or one of these compounds to a placebo in the treatment of alcohol dependence or alcohol use disorders were considered. Two reviewers searched for published and unpublished studies in MEDLINE (August 2017), the Cochrane Library, Embase, and ClinicalTrials.gov and contacted pharmaceutical companies, the European Medicines Agency, and the Food and Drug Administration. The indirect comparison meta-analyses were performed according to different inclusion/exclusion criteria (based on medical condition, abstinence of patients before inclusion, gender, somatic and psychiatric comorbidity, psychological support, treatment administered and dose, treatment duration, outcome reported, publication status, and risk of bias) and different analytical models (fixed and random effects). The primary outcome was the vibration of effects (VoE), i.e. the range of different results of the indirect comparison between nalmefene and naltrexone. The presence of a "Janus effect" was investigated, i.e. whether the 1st and 99th percentiles in the distribution of effect sizes were in opposite directions., Results: Nine nalmefene and 51 naltrexone RCTs were included. No study provided a direct comparison between the drugs. We performed 9216 meta-analyses for the indirect comparison with a median of 16 RCTs (interquartile range = 12-21) included in each meta-analysis. The standardized effect size was negative at the 1st percentile (- 0.29, favouring nalmefene) and positive at the 99th percentile (0.29, favouring naltrexone). A total of 7.1% (425/5961) of the meta-analyses with a negative effect size and 18.9% (616/3255) of those with a positive effect size were statistically significant (p < 0.05)., Conclusions: The choice of inclusion/exclusion criteria and analytical models for meta-analysis can result in entirely opposite results. VoE evaluations could be performed when overlapping meta-analyses on the same topic yield contradictory result., Trial Registration: This study was registered on October 19, 2016, in the Open Science Framework (OSF, protocol available at https://osf.io/7bq4y/ ).

Background: The available evidence on the benefits and harms of novel drugs and therapeutic biologics at the time of approval is reported in publicly available documents provided by the US Food and Drug Administration (FDA). We aimed to create a comprehensive database providing the relevant information required to systematically analyze and assess this early evidence in meta-epidemiological research., Methods: We designed a modular and flexible database of systematically collected data. We identified all novel cancer drugs and therapeutic biologics approved by the FDA between 2000 and 2016, recorded regulatory characteristics, acquired the corresponding FDA approval documents, identified all clinical trials reported therein, and extracted trial design characteristics and treatment effects. Herein, we describe the rationale and design of the data collection process, particularly the organization of the data capture, the identification and eligibility assessment of clinical trials, and the data extraction activities., Discussion: We established a comprehensive database on the comparative effects of drugs and therapeutic biologics approved by the FDA over a time period of 17 years for the treatment of cancer (solid tumors and hematological malignancies). The database provides information on the clinical trial evidence available at the time of approval of novel cancer treatments. The modular nature and structure of the database and the data collection processes allow updates, expansions, and adaption for a continuous meta-epidemiological analysis of novel drugs. The database allows us to systematically evaluate benefits and harms of novel drugs and therapeutic biologics. It provides a useful basis for meta-epidemiological research on the comparative effects of innovative cancer treatments and continuous evaluations of regulatory developments.

Background: Psychic transparency is described as a psychic crisis occurring during pregnancy. The objective was to test if it was clinically detectable., Methods: Seven primiparous and seven nulliparous subjects were recorded during 5 min of spontaneous speech about their dreams. 25 raters from five groups (psychoanalysts, psychiatrists, general practitioners, pregnant women and medical students) listened to the audiotapes. They were asked to rate the probability of the women being pregnant or not. Their ability to discriminate the primiparous women was tested. The probability of being identified correctly or not was calculated for each woman. A qualitative analysis of the speech samples was performed., Results: No group of rater was able to correctly classify pregnant and non-pregnant women. However, the raters' choices were not completely random. The wish to be pregnant or to have a baby could be linked to a primiparous classification whereas job priorities could be linked to a nulliparous classification., Conclusions: It was not possible to detect Psychic transparency in this study. The wish for a child might be easier to identify. In addition, the raters' choices seemed to be connected to social representations of motherhood.

In a meta-analysis published in BMC Medicine, we explored whether evidence-based medicine can actually be sure that 'sucrose = sucrose' in the treatment of depression. This paper, based upon a reductio ad absurdum, addressed an epistemological question using a 'scientific' approach, and could be disconcerting as suggested by Cipriani and Geddes' commentary. However, most papers are based upon a mixture of observations and discussions about sense and meaning. Ultimately, there is nothing more than a story, told with words or numbers. Randomised controlled trials provide information about average patients that do not exist. These results ignores an entire segment of therapeutics that plays a crucial role, namely care. This information is usually set out using a 'grammar' that is ambiguous, since statistical tests of hypothesis have raised epistemological questions that are not as yet solved. Moreover, many of these stories remain untold, and unpublished. For these reasons evidence-based medicine is a vehicle for many paradoxes and controversies. Reductio ad absurdum can be useful in precisely this case, to underline how and why the medical literature can sometimes give an impression of absurdity of this sort. Even if the data analysis in our paper was rather rhetorical, we agree that it should comply with the classic standards of reporting and we provide the important extra data that Cipriani and Geddes have requested.

Background: Antidepressants are often considered to be mere placebos despite the fact that meta-analyses are able to rank them. It follows that it should also be possible to rank different placebos, which are all made of sucrose. To explore this issue, which is rather more epistemological than clinical, we designed an unusual meta-analysis to investigate whether the effects of placebo in one situation are different from the effects of placebo in another situation., Methods: Published and unpublished studies were searched for by three reviewers on Medline, the Cochrane Library, Embase, clinicaltrials.gov, Current Controlled Trial, in bibliographies, and by mailing key organizations. The following studies in first-line treatment for major depressive disorder were considered to construct an "evidence network": 1) randomized controlled trials (RCTs) versus placebo on fluoxetine, venlafaxine and 2) fluoxetine versus venlafaxine head-to-head RCTs.Two network meta-analyses were run to indirectly compare response and remission rates among three different placebos: 1) fluoxetine placebo, 2) venlafaxine placebo, and 3) venlafaxine/fluoxetine placebo (that is, placebo compared to both venlafaxine and fluoxetine). Publication biases were assessed using funnel plots and statistically tested., Results: The three placebos were not significantly different in terms of response or remission. The antidepressant agents were significantly more efficacious than the placebos, and venlafaxine was more efficacious than fluoxetine. The funnel plots, however, showed a major publication bias., Conclusion: The presence of significant levels of publication bias indicates that we cannot even be certain of the conclusion that sucrose equals sucrose in trials of major depressive disorder. This result should remind clinicians to step back to take a more objective view when interpreting a scientific result. It is of crucial importance for their practice, far more so than ranking antidepressant efficacy.

Objective: This review aimed to investigate the therapeutic potential of Deep Brain Stimulation (DBS) for treating resistant Major Depressive Disorder (MDD). We explored the role of Nucleus accumbens (Nac) as a target for treatment., Method: We made a systematic review of all studies examining the mechanisms of action of high frequency brain stimulation and the pathophysiology of MDD. We also reported all the studies exploring the therapeutic potential of DBS in MDD., Results: As a central relay-structure, the Nac seems to play a central role in MDD symptomatology. We investigated its role as a primary target for DBS in depressed patients. Anatomically the Nac is at the centre of the interactions between dopaminergic, serotoninergic and glutamatergic systems. Functionally, the Nac is involved in both normal and abnormal reward processes and in anhedonia and loss of motivation. Due to its central location between the emotional system, the cognitive system and motor control system, the Nac seems to have a central role in mood and feeling regulation., Conclusion: According to encouraging recent studies, DBS seems to be a promising technique in resistant MDD treatment.