Assessing the magnitude of changes from protocol to publication-a survey on Cochrane and non-Cochrane Systematic Reviews.

Objective: To explore differences between published reviews and their respective protocols in a sample of 97 non-Cochrane Systematic Reviews (non-CSRs) and 97 Cochrane Systematic Reviews (CSRs) in terms of PICOS (Patients/Population, Intervention, Comparison/Control, Outcome, Study type) elements and the extent to which they were reported. Study Design and Setting: We searched PubMed and Cochrane databases to identify non-CSRs and CSRs that were published in 2018. We then searched for their corresponding Cochrane or PROSPERO protocols. The published reviews were compared to their protocols. The primary outcome was changes from protocol to review in terms of PICOS elements. Results: We identified a total of 227 changes from protocol to review in PICOS elements, 1.11 (Standard Deviation (SD), 1.22) changes per review for CSRs and 1.23 (SD, 1.12) for non-CSRs per review. More than half of each sub-sample (54.6% of CSRs and 67.0% of non-CSRs) (Absolute Risk Reduction (ARR) 12.4% [-1.3%; 26.0%]) had changes in PICOS elements. For both subsamples, approximately a third of all changes corresponded to changes related to primary outcomes. Marked differences were found between the sub-samples for the reporting of changes. 95.8% of the changes in PICOS items were not reported in the non-CSRs compared to 42.6% in the CSRs (ARR 53.2% [43.2%; 63.2%]). Conclusion: CSRs showed better results than non-CSRs in terms of the reporting of changes. Reporting of changes from protocol needs to be promoted and requires general improvement. The limitations of this study lie in its observational design. Registration: https://osf.io/6j8gd/.

The evidence base of US Food and Drug Administration approvals of novel cancer therapies from 2000 to 2020.

Concerns have been raised that regulatory programs to accelerate approval of cancer drugs in cancer may increase uncertainty about benefits and harms for survival and quality of life (QoL). We analyzed all pivotal clinical trials and all non-pivotal randomized controlled trials (RCTs) for all cancer drugs approved for the first time by the FDA between 2000 and 2020. We report regulatory and trial characteristics. Effects on overall survival (OS), progression-free survival and tumor response were summarized in meta-analyses. Effects on QoL were qualitatively summarized. Between 2000 and 2020, the FDA approved 145 novel cancer drugs for 156 indications based on 190 clinical trials. Half of indications (49%) were approved without RCT evidence; 82% had a single clinical trial only. OS was primary endpoint in 14% of trials and QoL data were available from 25%. The median OS benefit was 2.55 months (IQR, 1.33-4.28) with a mean hazard ratio for OS of 0.75 (95%CI, 0.72-0.79, I2  = 42). Improvement for QoL was reported for 7 (4%) of 156 indications. Over time, priority review was used increasingly and the mean number of trials per indication decreased from 1.45 to 1.12. More trials reported results on QoL (19% in 2000-2005; 41% in 2016-2020). For 21 years, novel cancer drugs have typically been approved based on one single, often uncontrolled, clinical trial, measuring surrogate endpoints. This leaves cancer patients without solid evidence that novel drugs improve their survival or QoL and there is no indication towards improvement.

Meta-research studies should improve and evaluate their own data sharing practices.

Data sharing is gradually becoming a requirement across all fields of science, owing to its key benefits in verifying the reproducibility of findings and reusing existent data for new purposes. Although metaresearch studies are complex, time-consuming, and hinge on the availability of data produced and curated by others, there has been little focus on how they make their own data available. This is in stark contrast to the heightened attention data sharing has received in clinical research. Yet, as secondary data users par excellence, metaresearchers are ethically bound to both improving and evaluating data sharing practices and correctly sharing their own data. We contrast particularities of data sharing in metaresearch and clinical research, such as benefits, barriers, and inadequate and potentially pervasive sharing practices. We conclude with an array of concrete and tailored recommendations for improvement.

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.

Pharmacology and pharmacovigilance of protein kinase inhibitors.

Protein kinase inhibitors experienced their advent in the 2000s. Their market introduction made it possible to constitute a class of targeted therapies administered orally. This name was chosen to mark a break with conventional chemotherapy drugs, but it is important to stress that these are multi-target drugs with complex affinity profiles. Adverse effects can be explained by direct interactions with their targets of interest, chosen for their indications (on-target) but also interactions with other targets (off-target). The adverse effect profiles of these drugs are therefore varied and it is possible to identify common profiles related to inhibitions of common targets. Identification of these targets has improved the global understanding of the pathophysiological mechanisms underlying the onset of adverse drug reactions as well as of the related diseases, and makes it possible to predict the adverse effect profile of new protein kinase inhibitors based on their affinities. In this review, we describe the main adverse drug reactions associated with protein kinase inhibitors, their frequency and their plausible mechanisms of action.

Intent to share Annals of Internal Medicine's trial data was not associated with data re-use.

OBJECTIVE: To explore the impact of the Annals of Internal Medicine (AIM) data-sharing policy for randomized controlled trials (RCTs) in terms of output from data-sharing (i.e. publications re-using the data). STUDY DESIGN AND SETTING: Retrospective study. RCTs published in the AIM between 2007 and 2017 were retrieved on PubMed. Publications where the data had been re-used were identified on Web of Science. Searches were performed by two independent reviewers. The primary outcome was any published re-use of the data (re-analysis, secondary analysis, or meta-analysis of individual participant data [MIPD]), where the first, last and corresponding authors were not among the authors of the RCT. Analyses used Cox (primary analysis) models adjusting for RCTs characteristics (registration: https://osf.io/8pj5e/). RESULTS: 185 RCTs were identified. 106 (57%) mentioned willingness to share data and 79 (43%) did not. 208 secondary analyses, 67 MIPD and no re-analyses were identified. No significant association was found between intent to share and re-use where the first, last and corresponding authors were not among the authors of the primary RCT (adjusted hazard ratio = 1.04 [0.47-2.30]). CONCLUSION: Over ten years, RCTs published in AIM expressing an intention to share data were not associated with more extensive re-use of the data.

Data-sharing recommendations in biomedical journals and randomised controlled trials: an audit of journals following the ICMJE recommendations.

OBJECTIVE: To explore the implementation of the International Committee of Medical Journal Editors (ICMJE) data-sharing policy which came into force on 1 July 2018 by ICMJE-member journals and by ICMJE-affiliated journals declaring they follow the ICMJE recommendations. DESIGN: A cross-sectional survey of data-sharing policies in 2018 on journal websites and in data-sharing statements in randomised controlled trials (RCTs). SETTING: ICMJE website; PubMed/Medline. ELIGIBILITY CRITERIA: ICMJE-member journals and 489 ICMJE-affiliated journals that published an RCT in 2018, had an accessible online website and were not considered as predatory journals according to Beall's list. One hundred RCTs for member journals and 100 RCTs for affiliated journals with a data-sharing policy, submitted after 1 July 2018. MAIN OUTCOME MEASURES: The primary outcome for the policies was the existence of a data-sharing policy (explicit data-sharing policy, no data-sharing policy, policy merely referring to ICMJE recommendations) as reported on the journal website, especially in the instructions for authors. For RCTs, our primary outcome was the intention to share individual participant data set out in the data-sharing statement. RESULTS: Eight (out of 14; 57%) member journals had an explicit data-sharing policy on their website (three were more stringent than the ICMJE requirements, one was less demanding and four were compliant), five (35%) additional journals stated that they followed the ICMJE requirements, and one (8%) had no policy online. In RCTs published in these journals, there were data-sharing statements in 98 out of 100, with expressed intention to share individual patient data reaching 77 out of 100 (77%; 95% CI 67% to 85%). One hundred and forty-five (out of 489) ICMJE-affiliated journals (30%; 26% to 34%) had an explicit data-sharing policy on their website (11 were more stringent than the ICMJE requirements, 85 were less demanding and 49 were compliant) and 276 (56%; 52% to 61%) merely referred to the ICMJE requirements. In RCTs published in affiliated journals with an explicit data-sharing policy, data-sharing statements were rare (25%), and expressed intentions to share data were found in 22% (15% to 32%). CONCLUSION: The implementation of ICMJE data-sharing requirements in online journal policies was suboptimal for ICMJE-member journals and poor for ICMJE-affiliated journals. The implementation of the policy was good in member journals and of concern for affiliated journals. We suggest the conduct of continuous audits of medical journal data-sharing policies in the future. REGISTRATION: The protocol was registered before the start of the research on the Open Science Framework (https://osf.io/n6whd/).