Number of citations 1 year after publication of trial results and their relation to medicines regulatory approval.
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ABSTRACT:
SUBMITTER: Dal-Re R
PROVIDER: S-EPMC4799912 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BACKGROUND: At the time of approval of a new medicine, there are few long-term data on the medicine's benefit-risk balance. Clinical trials are designed to demonstrate efficacy, but have major limitations with regard to safety in terms of patient exposure and length of follow-up. This study of the number of patients who had been administered medicines at the time of medicine approval by the European Medicines Agency aimed to determine the total number of patients studied, as well as the number of patients studied long term for chronic medication use, compared with the International Conference on Harmonisation's E1 guideline recommendations. METHODS AND FINDINGS: All medicines containing new molecular entities approved between 2000 and 2010 were included in the study, including orphan medicines as a separate category. The total number of patients studied before approval was extracted (main outcome). In addition, the number of patients with long-term use (6 or 12 mo) was determined for chronic medication. 200 unique new medicines were identified: 161 standard and 39 orphan medicines. The median total number of patients studied before approval was 1,708 (interquartile range [IQR] 968-3,195) for standard medicines and 438 (IQR 132-915) for orphan medicines. On average, chronic medication was studied in a larger number of patients (median 2,338, IQR 1,462-4,135) than medication for intermediate (878, IQR 513-1,559) or short-term use (1,315, IQR 609-2,420). Safety and efficacy of chronic use was studied in fewer than 1,000 patients for at least 6 and 12 mo in 46.4% and 58.3% of new medicines, respectively. Among the 84 medicines intended for chronic use, 68 (82.1%) met the guideline recommendations for 6-mo use (at least 300 participants studied for 6 mo and at least 1,000 participants studied for any length of time), whereas 67 (79.8%) of the medicines met the criteria for 12-mo patient exposure (at least 100 participants studied for 12 mo). CONCLUSIONS: For medicines intended for chronic use, the number of patients studied before marketing is insufficient to evaluate safety and long-term efficacy. Both safety and efficacy require continued study after approval. New epidemiologic tools and legislative actions necessitate a review of the requirements for the number of patients studied prior to approval, particularly for chronic use, and adequate use of post-marketing studies. Please see later in the article for the Editors' Summary.
| S-EPMC3601954 | biostudies-literature
Project description:The assessment of scientific publications is an integral part of the scientific process. Here we investigate three methods of assessing the merit of a scientific paper: subjective post-publication peer review, the number of citations gained by a paper, and the impact factor of the journal in which the article was published. We investigate these methods using two datasets in which subjective post-publication assessments of scientific publications have been made by experts. We find that there are moderate, but statistically significant, correlations between assessor scores, when two assessors have rated the same paper, and between assessor score and the number of citations a paper accrues. However, we show that assessor score depends strongly on the journal in which the paper is published, and that assessors tend to over-rate papers published in journals with high impact factors. If we control for this bias, we find that the correlation between assessor scores and between assessor score and the number of citations is weak, suggesting that scientists have little ability to judge either the intrinsic merit of a paper or its likely impact. We also show that the number of citations a paper receives is an extremely error-prone measure of scientific merit. Finally, we argue that the impact factor is likely to be a poor measure of merit, since it depends on subjective assessment. We conclude that the three measures of scientific merit considered here are poor; in particular subjective assessments are an error-prone, biased, and expensive method by which to assess merit. We argue that the impact factor may be the most satisfactory of the methods we have considered, since it is a form of pre-publication review. However, we emphasise that it is likely to be a very error-prone measure of merit that is qualitative, not quantitative.
| S-EPMC3792863 | biostudies-literature
Project description:Drug development in oncology is resource intensive and has a high failure rate. In this exploratory analysis, we aimed to identify the characteristics and outcomes of published Phase I studies associated with future Food and Drug Administration (FDA) approval.Phase I studies of approved and non-approved anticancer agents between 2000 and 2013 were retrospectively examined. Fisher's exact and chi-squared tests were used to compare the potential predictive measures.Phase I studies of 88 anticancer agents (54 approved and 34 non-approved by the FDA), treating a total of 4,423 subjects, were examined. The median number of patients in Phase I trials of approved and non-approved agents was 44.5 and 32, respectively. A total of 423 subjects (86 reporting studies) had a complete responses, and 342 subjects (80 reporting studies) had a partial responses (PR). A higher number of PR (P < 0.001), PR rate (P = 0.003) and longer PR duration (P = 0.001) were predictive of regulatory success.These preliminary findings indicate that objective responses in Phase I trials may have predictive value for later regulatory approval.
| S-EPMC4489154 | biostudies-literature
Project description:Since 2005, more than 40 new medicines for the treatment of type 2 diabetes have been introduced on the market. These consist of 15 new active substances establishing three new classes of non-insulin products, and several new or modified insulin products and combinations. The approval of these products in Europe is regulated via the centralized procedure at the European Medicines Agency. Demonstration of benefit with regard to improved glucose control remains the principal outcome required from confirmatory studies to demonstrate efficacy. For the majority of these new medicines approved since 2005, cardiovascular outcome trials have now been completed, and have invariably supported the cardiovascular safety of these products. In some of these trials additional important benefits have been observed, for instance, a reduction in major adverse cardiovascular events and improvement of renal outcome. The existing regulatory framework and the continuous adaption of regulatory requirements to emerging developments will continue to guide the approval of new products in the future.
| S-EPMC6667915 | biostudies-literature
Project description:BACKGROUND:Long-term data following endovascular aneurysm repair (EVAR) exist but are limited to endografts that are no longer in use. The aim of the ENGAGE Post Approval Study is to describe the long-term safety and effectiveness data following EVAR using the Endurant stent graft system. METHODS:From August 2011 to June 2012, 178 patients were enrolled and treated with the Endurant stent graft system. Clinical and radiologic data were prospectively collected and analyzed. The primary end point was abdominal aortic aneurysm (AAA)-related mortality, and secondary end points were overall mortality, endoleak, secondary interventions, and device-related complications. Kaplan-Meier estimates were used for late outcomes. RESULTS:A total of 178 patients underwent EVAR with the Endurant stent graft across 24 centers (82% men; median age 71, interquartile range [IQR] 66-79). Median aortic diameter was 55 mm (IQR 51-58 mm). There was a 98.9% technical success rate. Three-year clinical and radiographic follow-up data were available for 87% and 74% of patients, respectively. Median follow-up was 37 months (IQR 30-38 months). Three-year aneurysm-related mortality rate was 1.1%, with 2 deceased patients in the perioperative period. All-cause mortality rate at 3 years was 13%. No patients suffered from aneurysm rupture or underwent conversion to open repair through 3 years of follow-up. Only 11 patients (6.2%) had undergone reintervention at 3 years. Younger age was associated with reintervention (HR 3.3 per younger decade, 95% confidence interval 1.3-7.6, P < 0.01), but neck diameter, length, and angulation were not significantly associated with reintervention. CONCLUSIONS:The Endurant stent graft system provides a safe, durable approach to treating infrarenal AAA. No patients experienced late rupture or aneurysm-related mortality, and only 1 in 16 patients underwent reintervention by 3 years. The rate of reintervention with the Endurant graft appears to be lower than other contemporary grafts, despite more liberal "Instructions For Use" parameters, but further research including direct graft comparisons will be necessary to guide appropriate graft selection.
| S-EPMC6014884 | biostudies-literature
Project description:BackgroundMandatory trial registration, and later results reporting, were proposed to mitigate selective clinical trial publication and outcome reporting. The Food and Drug Administration (FDA) Amendments Act (FDAAA) was enacted by Congress on September 27, 2007, requiring the registration of all non-phase I clinical trials involving FDA-regulated medical interventions and results reporting for approved drugs. The association between FDAAA enactment and the registration, results reporting, and publication bias of neuropsychiatric trials has not been studied.MethodsWe conducted a retrospective cohort study of all efficacy trials supporting FDA new drug approvals between 2005 to 2014 for neuropsychiatric indications. Trials were categorized as pre- or post-FDAAA based on initiation and/or completion dates. The main outcomes were the proportions of trials registered and reporting results in ClinicalTrials.gov, and the degree of publication bias, estimated using the relative risks pre- and post-FDAAA of both the publication of positive vs non-positive trials, as well as of publication of positive vs non-positive trials without misleading interpretations. Registration and results reporting proportions were compared pre- and post-FDAAA using the two-tailed Fisher exact test, and the degrees of publication bias were compared by calculating the ratio of relative risks (RRR) for each period.ResultsThe FDA approved 37 new drugs for neuropsychiatric indications between 2005 and 2014 on the basis of 142 efficacy trials, of which 101 were pre-FDAAA and 41 post-FDAAA. Post-FDAAA trials were significantly more likely to be registered (100% vs 64%; p <?0.001) and report results (100% vs 10%; p <?0.001) than pre-FDAAA trials. Pre-FDAAA, positive trials were more likely to be published (relative risk [RR]?=?1.52; 95% confidence interval [CI]?=?1.17-1.99; p?=?0.002) and published without misleading interpretations (RR?=?2.47; CI?=?1.57-3.73; p?<?0.001) than those with non-positive results. In contrast, post-FDAAA positive trials were equally likely to have been published (RR?=?1; CI?=?1-1, p?=?NA) and published without misleading interpretations (RR?=?1.20; CI?=?0.84-1.72; p?=?0.30). The likelihood of publication bias pre-FDAAA vs post-FDAAA was greater for positive vs non-positive trials (RRR?=?1.52; CI?=?1.16-1.99; p?=?0.002) and for publication without misleading interpretations (RRR?=?2.06, CI?=?1.17-3.61, p?=?0.01).ConclusionsThe enactment of FDAAA was followed by significantly higher proportions of trials that were registered and reporting results on ClinicalTrials.gov and significantly lower degrees of publication bias among trials supporting recent FDA approval of drugs for neuropsychiatric indications.
| S-EPMC6199729 | biostudies-literature
Project description:BACKGROUND:Social media coverage is increasingly used to spread the message of scientific publications. Traditionally, the scientific impact of an article is measured by the number of citations. At a journal level, this conventionally matures over a 2-year period, and it is challenging to gauge impact around the time of publication. OBJECTIVE:We, therefore, aimed to assess whether Web-based attention is associated with citations and to develop a predictive model that assigns relative importance to different elements of social media coverage: the #SoME_Impact score. METHODS:We included all original articles published in 2015 in a selection of the highest impact journals: The New England Journal of Medicine, The Lancet, the Journal of the American Medical Association, Nature, Cell, and Science. We first characterized the change in Altmetric score over time by taking a single month's sample of recently published articles from the same journals and gathered Altmetric data daily from the time of publication to create a mixed effects spline model. We then obtained the overall weighted Altmetric score for all articles from 2015, the unweighted data for each Altmetric component, and the 2-year citation count from Scopus for each of these articles from 2016 to 2017. We created a stepwise multivariable linear regression model to develop a #SoME_Score that was predictive of 2-year citations. The score was validated using a dataset of articles from the same journals published in 2016. RESULTS:In our unselected sample of 145 recently published articles, social media coverage appeared to plateau approximately 14 days after publication. A total of 3150 articles with a median citation count of 16 (IQR 5-33) and Altmetric score of 72 (IQR 28-169) were included for analysis. On multivariable regression, compared with articles in the lowest quantile of #SoME_Score, articles in the second, third, and upper quantiles had 0.81, 15.20, and 87.67 more citations, respectively. On the validation dataset, #SoME_Score model outperformed the Altmetric score (adjusted R2 0.19 vs 0.09; P<.001). Articles in the upper quantile of #SoME_Score were more than 5 times more likely to be among the upper quantile of those cites (odds ratio 5.61, 95% CI 4.70-6.73). CONCLUSIONS:Social media attention predicts citations and could be used as an early surrogate measure of scientific impact. Owing to the cross-sectional study design, we cannot determine whether correlation relates to causation.
| S-EPMC7195668 | biostudies-literature
Project description:Background: Scopus is a leading bibliometric database. It contains a large part of the articles cited in peer-reviewed publications . The journals included in Scopus are periodically re-evaluated to ensure they meet indexing criteria and some journals might be discontinued for 'publication concerns'. Previously published articles may remain indexed and can be cited. Their metrics have yet to be studied. This study aimed to evaluate the main features and metrics of journals discontinued from Scopus for publication concerns, before and after their discontinuation, and to determine the extent of predatory journals among the discontinued journals. Methods: We surveyed the list of discontinued journals from Scopus (July 2019). Data regarding metrics, citations and indexing were extracted from Scopus or other scientific databases, for the journals discontinued for publication concerns. Results: A total of 317 journals were evaluated. Ninety-three percent of the journals (294/317) declared they published using an Open Access model. The subject areas with the greatest number of discontinued journals were Medicine (52/317; 16%), Agriculture and Biological Science (34/317; 11%), and Pharmacology, Toxicology and Pharmaceutics (31/317; 10%). The mean number of citations per year after discontinuation was significantly higher than before (median of difference 16.89 citations, p<0.0001), and so was the number of citations per document (median of difference 0.42 citations, p<0.0001). Twenty-two percent (72/317) were included in the Cabell's blacklist. The DOAJ currently included only 9 journals while 61 were previously included and discontinued, most for 'suspected editorial misconduct by the publisher'. Conclusions: Journals discontinued for 'publication concerns' continue to be cited despite discontinuation and predatory behaviour seemed common. These citations may influence scholars' metrics prompting artificial career advancements, bonus systems and promotion. Countermeasures should be taken urgently to ensure the reliability of Scopus metrics for the purpose of scientific assessment of scholarly publishing at both journal- and author-level.
| S-EPMC7512033 | biostudies-literature
Project description:Purpose: There is a need to develop hybrid trial methodology combining the best parts of traditional randomized controlled trials (RCTs) and observational study designs to produce real-world evidence (RWE) that provides adequate scientific evidence for regulatory decision-making.Methods: This review explores how hybrid study designs that include features of RCTs and studies with real-world data (RWD) can combine the advantages of both to generate RWE that is fit for regulatory purposes.Results: Some hybrid designs include randomization and use pragmatic outcomes; other designs use single-arm trial data supplemented with external comparators derived from RWD or leverage novel data collection approaches to capture long-term outcomes in a real-world setting. Some of these approaches have already been successfully used in regulatory decisions, raising the possibility that studies using RWD could increasingly be used to augment or replace traditional RCTs for the demonstration of drug effectiveness in certain contexts. These changes come against a background of long reliance on RCTs for regulatory decision-making, which are labor-intensive, costly, and produce data that can have limited applicability in real-world clinical practice.Conclusions: While RWE from observational studies is well accepted for satisfying postapproval safety monitoring requirements, it has not commonly been used to demonstrate drug effectiveness for regulatory purposes. However, this position is changing as regulatory opinions, guidance frameworks, and RWD methodologies are evolving, with growing recognition of the value of using RWE that is acceptable for regulatory decision-making.
| S-EPMC7687110 | biostudies-literature
Project description:The results of all clinical drug trials should be published promptly and nonselectively after trial completion. The publication of results appears as a central ethical rule in the Declaration of Helsinki of the World Medical Association. German university hospitals are increasingly being criticized for not meeting these requirements sufficiently.In this article, different forms of publication of clinical drug trial results are discussed (summary results on registries and journal articles) and the current performance of German university hospitals is analyzed. Three registries and databases for clinical studies were examined for publication of summary results: the European Union Clinical Trials Register (EUCTR), the US registry ClinicalTrials.gov and the exclusively German language portal PharmNet.Bund. Positions of different stakeholders are outlined and possible steps for improvement are proposed.German university hospitals do not sufficiently fulfil their regulatory and ethical obligations regarding the publication of clinical drug trial results. Two years after the study completion date, two thirds of the studies listed on ClinicalTrials.gov that were completed from 2010-2014 had not yet published results in scientific journals and only 4.7% had posted summary results in the registry. In the European trial registry, the publication rate in the form of summary results has been found to be less than 7%. Less than 15% of relevant entries in the PharmNet.Bund database have results available.In order to improve the reporting performance of German university hospitals, political will and commitment of the hospitals themselves are needed. The benefits of access to all clinical drug trial results for public health and science far outweigh the (marginal) additional investments that university hospitals have to make to ensure that all their trial results are made public in line with regulatory and ethical requirements.
| S-EPMC7686199 | biostudies-literature