Prevalence and predictors of data and code sharing in the medical and health sciences: systematic review with meta-analysis of individual participant data.

OBJECTIVES: To synthesise research investigating data and code sharing in medicine and health to establish an accurate representation of the prevalence of sharing, how this frequency has changed over time, and what factors influence availability. DESIGN: Systematic review with meta-analysis of individual participant data. DATA SOURCES: Ovid Medline, Ovid Embase, and the preprint servers medRxiv, bioRxiv, and MetaArXiv were searched from inception to 1 July 2021. Forward citation searches were also performed on 30 August 2022. REVIEW METHODS: Meta-research studies that investigated data or code sharing across a sample of scientific articles presenting original medical and health research were identified. Two authors screened records, assessed the risk of bias, and extracted summary data from study reports when individual participant data could not be retrieved. Key outcomes of interest were the prevalence of statements that declared that data or code were publicly or privately available (declared availability) and the success rates of retrieving these products (actual availability). The associations between data and code availability and several factors (eg, journal policy, type of data, trial design, and human participants) were also examined. A two stage approach to meta-analysis of individual participant data was performed, with proportions and risk ratios pooled with the Hartung-Knapp-Sidik-Jonkman method for random effects meta-analysis. RESULTS: The review included 105 meta-research studies examining 2 121 580 articles across 31 specialties. Eligible studies examined a median of 195 primary articles (interquartile range 113-475), with a median publication year of 2015 (interquartile range 2012-2018). Only eight studies (8%) were classified as having a low risk of bias. Meta-analyses showed a prevalence of declared and actual public data availability of 8% (95% confidence interval 5% to 11%) and 2% (1% to 3%), respectively, between 2016 and 2021. For public code sharing, both the prevalence of declared and actual availability were estimated to be <0.5% since 2016. Meta-regressions indicated that only declared public data sharing prevalence estimates have increased over time. Compliance with mandatory data sharing policies ranged from 0% to 100% across journals and varied by type of data. In contrast, success in privately obtaining data and code from authors historically ranged between 0% and 37% and 0% and 23%, respectively. CONCLUSIONS: The review found that public code sharing was persistently low across medical research. Declarations of data sharing were also low, increasing over time, but did not always correspond to actual sharing of data. The effectiveness of mandatory data sharing policies varied substantially by journal and type of data, a finding that might be informative for policy makers when designing policies and allocating resources to audit compliance. SYSTEMATIC REVIEW REGISTRATION: Open Science Framework doi:10.17605/OSF.IO/7SX8U.

Definition and rationale for placebo composition: Cross-sectional analysis of randomized trials and protocols published in high-impact medical journals.

BACKGROUND/AIMS: Inadequate description of trial interventions in publications has been repeatedly reported, a problem that extends to the description of placebo controls. Without describing placebo contents, it cannot be assumed that a placebo is inert. Pharmacologically active placebos complicate accurate estimation and interpretation of efficacy and safety data. In this study, we sought to assess whether placebo contents are described in study protocols and publications of trials published in high-impact medical journals. METHODS: We identified all placebo-controlled randomized clinical trials (RCTs) published in 2016 in Annals of Internal Medicine, The BMJ, the Journal of the American Medical Association (JAMA), The Lancet, and the New England Journal of Medicine (NEJM). We included all trials with publicly available study protocols. From journal publications and associated study protocols, we searched and recorded: description of placebo contents; the amount of each placebo ingredient; and investigators' stated rationale for selection of placebo ingredients. RESULTS: We included 113 placebo-controlled RCTs. Of the 113 trials, placebo content was described in 22 (19.5%) journal publications and 51 (45.1%) study protocols. The amount of each placebo ingredient was described in 15 (13.3%) journal publications and 47 (41.6%) study protocols. None of the journal publications explained the rationale for the choice of placebo ingredients, whereas a rationale was provided in 4 (3.5%) study protocols. The stated rationales were to ensure the placebo was visually indistinguishable from the experimental intervention (N = 3) and ensure comparability with a previous study (N = 1). CONCLUSION: There is no accessible record of the composition of placebos for approximately half of high-impact RCTs, even with access to study protocols. This impedes reproducibility and raises unanswerable questions about what effects-beneficial or harmful-the placebo may have had on trial participants, potentially confounding an accurate assessment of the experimental intervention's safety and efficacy. Considering that study protocols are unabridged, detailed documents describing the trial design and methodology, the fact that less than half of the study protocols described the placebo contents raises concerns about clinical trial transparency. To improve the reproducibility and potential of placebo-controlled RCTs to provide reliable evidence on the efficacy and safety profile of drugs and other experimental interventions, more detail regarding placebo contents must be included in trial documents.

Consistency between trials presented at conferences, their subsequent publications and press releases.

OBJECTIVE: This study examined the extent to which trials presented at major international medical conferences in 2016 consistently reported their study design, end points and results across conference abstracts, published article abstracts and press releases. DESIGN: Cross-sectional analysis of clinical trials presented at 12 major medical conferences in the USA in 2016. Conferences were identified from a list of the largest clinical research meetings aggregated by the Healthcare Convention and Exhibitors Association and were included if their abstracts were publicly available. From these conferences, all late-breaker clinical trials were included, as well as a random selection of all other clinical trials, such that the total sample included up to 25 trial abstracts per conference. MAIN OUTCOME MEASURES: First, it was determined if trials were registered and reported results in an International Committee of Medical Journal Editors-approved clinical trial registry. Second, it was determined if trial results were published in a peer-reviewed journal. Finally, information on trial media coverage and press releases was collected using LexisNexis. For all published trials, the consistency of reporting of the following characteristics was examined, through comparison of the trials' conference and publication abstracts: primary efficacy endpoint definition, safety endpoint identification, sample size, follow-up period, primary end point effect size and characterisation of trial results. For all published abstracts with press releases, the characterisation of trial results across conference abstracts, press releases and publications was compared. Authors determined consistency of reporting when identical information was presented across abstracts and press releases. Primary analyses were descriptive; secondary analyses included χ2 tests and multiple logistic regression. RESULTS: Among 240 clinical trials presented at 12 major medical conferences, 208 (86.7%) were registered, 95 (39.6%) reported summary results in a registry and 177 (73.8%) were published; 82 (34.2%) were covered by the media and 68 (28.3%) had press releases. Among the 177 published trials, 171 (96.6%) reported the definition of primary efficacy endpoints consistently across conference and publication abstracts, whereas 96/128 (75.0%) consistently identified safety endpoints. There were 107/172 (62.2%) trials with consistent sample sizes across conference and publication abstracts, 101/137 (73.7%) that reported their follow-up periods consistently, 92/175 (52.6%) that described their effect sizes consistently and 157/175 (89.7%) that characterised their results consistently. Among the trials that were published and had press releases, 32/32 (100%) characterised their results consistently across conference abstracts, press releases and publication abstracts. No trial characteristics were associated with reporting primary efficacy end points consistently. CONCLUSIONS: For clinical trials presented at major medical conferences, primary efficacy endpoint definitions were consistently reported and results were consistently characterised across conference abstracts, registry entries and publication abstracts; consistency rates were lower for sample sizes, follow-up periods, and effect size estimates. REGISTRATION: This study was registered at the Open Science Framework (https://doi.org/10.17605/OSF.IO/VGXZY).

Trends in antipsychotic use for youth with attention-deficit/hyperactivity disorder and disruptive behavior disorders.

PURPOSE: To examine trends in off-label antipsychotic use for youth with attention-deficit/hyperactivity disorder with and without a comorbid disruptive behavior disorder. METHOD: This cross-sectional study of annual trends from 2007 through 2015 used the IQVIA PharMetrics® Plus for Academics data. We identified 165 794 commercially-insured youth 3-18-year-old who had a diagnosis of attention-deficit/hyperactivity disorder and classified them into subgroups with and without disruptive behavior disorders comorbidities. Antipsychotic use, with or without a stimulant, was the primary dependent outcome. Logistic regression estimated the odds of antipsychotic use associated with comorbid attention-deficit/hyperactivity disorder and disruptive behavior disorders, adjusting for age, sex, study year, and other psychotropic use. RESULTS: Over 70% of the 165 794 youth with attention-deficit/hyperactivity disorder were 5-14-year-old and male, and 12% had disruptive behavior disorders. Antipsychotic prevalence, with or without a stimulant, was 4.4% in 2007 and 3.4% in 2015. Stimulants with antipsychotics increased significantly from 2007 to 2015 for females (19.5%-28.7%) and youth 15-18-year-old (25.9%-32.7%). Adjusting for age, sex, study year, and other psychotropic use, youth with a comorbid disruptive behavior had a 2.5 (95% CI: 2.3, 2.7) higher likelihood of receiving an antipsychotic than youth with attention-deficit/hyperactivity disorder and no comorbidities. CONCLUSIONS: Antipsychotic use was associated with comorbid disruptive behaviors in youth with attention-deficit/hyperactivity disorder. Off-label antipsychotic use has increased for females and older adolescents.

Rates and predictors of data and code sharing in the medical and health sciences: Protocol for a systematic review and individual participant data meta-analysis.

Numerous studies have demonstrated low but increasing rates of data and code sharing within medical and health research disciplines. However it remains unclear how commonly data and code are shared across all fields of medical and health research, as well as whether sharing rates are positively associated with implementation of progressive policies by publishers and funders, or growing expectations from the medical and health research community at large. Therefore this systematic review aims to synthesise the findings of medical and health science studies that have empirically investigated the prevalence of data or code sharing, or both. Objectives include the investigation of: (i) the prevalence of public sharing of research data and code alongside published articles (including preprints), (ii) the prevalence of private sharing of research data and code in response to reasonable requests, and (iii) factors associated with the sharing of either research output (e.g., the year published, the publisher's policy on sharing, the presence of a data or code availability statement). It is hoped that the results will provide some insight into how often research data and code are shared publicly and privately, how this has changed over time, and how effective some measures such as the institution of data sharing policies and data availability statements have been in motivating researchers to share their underlying data and code.

Patient-reported outcomes in breast cancer FDA drug labels and review documents.

BACKGROUND: Patient-reported outcomes (PROs) can provide valuable information about drug benefit-risk tradeoffs from the patient perspective and are particularly important to patients with breast cancer due to its symptoms and adverse events from breast cancer treatments. The United States Food and Drug Administration (U.S. FDA) has acknowledged PROs as important approval endpoints used in clinical trials of cancer drugs. However, previous studies found that PROs are rarely mentioned in cancer drug labels, a widely used and trusted source of information about drugs. Our objectives were to compare PRO data reported in FDA labeling versus FDA medical review documents for breast cancer drugs approved in the U.S. between 2000 and 2019 to identify possible causes for PRO-data labeling exclusions. METHODS: We included new molecular entities (NMEs) and biologic license applications (BLAs) initially approved for breast cancer treatment by the FDA between 1/1/2000 and 12/31/2019. Product labeling and FDA medical review documents were collected from the FDA-Approved Drugs database (Drugs@FDA). From these resources, details on PRO measures used in trials, design of trials using PRO measures, PRO-endpoint status, analytical methods, and FDA reviewer comments regarding PRO measurement were extracted. RESULTS: Of 633 FDA-approved drugs, 13 were indicated for breast cancer treatment; none of their prescribing information contained information about PROs. However, 11 of 13 (85%) included PRO measures and endpoint information in FDA medical review documents. PRO measures were used in 14 different clinical trials, and FDA reviewers' comments regarding PRO measurement were related to lack of meaningfulness and clinical significance, lack of content validity, and inadequate analytical methods. CONCLUSIONS: Despite the importance of PROs to patients with breast cancer, PRO measures were only described in FDA medical review documents of breast cancer drugs, but not in drug product labeling. Therefore, it appears that PRO data are often collected in breast cancer trials, but have not been methodologically acceptable to FDA reviewers. Collaborative efforts between the FDA and industry are warranted to increase the number of breast cancer drug applications with appropriate use of PRO measures and endpoints.

Evaluation of Switch-to-Brand Rates as a Potential Signal for Therapeutic Equivalency of Generic Antidepressants: A Real-World Retrospective Cohort Study.

Negative clinical outcomes after switching from brand to generic antidepressants have raised concerns regarding therapeutic equivalency. This research aims to estimate the prevalence of switching and to identify predictors for generic to brand switching for various antidepressants. This retrospective cohort study utilized data from a 10% random sample of enrollees in the IQVIA PharMetrics Plus claims database from 2007-2015. The base cohort consisted of commercially insured patients who were prescribed escitalopram, duloxetine, or venlafaxine extended release (ER) anytime from the year prior to the generic launch through December 2014. The primary outcome was defined as a switch from generic to a brand within 14 days of sustained generic use in a 1-year follow-up period. Adjusted logistic regression and generalized estimating equations for repeated measures estimated the drug specific and overall odds of switch-to-brand among brand initiators relative to generic initiators, respectively. A total of 102,831 unique patients across 3 drug products contributed to the final analytic sample. The overall prevalence of switch from generic to brand was 0.74%. Across all three antidepressants, brands initiators were more likely to experience a switch-to-brand: escitalopram (odds ratio (OR): 14.41, 95% confidence interval (CI): 11.14-18.64), duloxetine (OR: 8.08, 95% CI: 4.85-13.41) and venlafaxine ER (OR: 16.46, 95% CI: 11.56-23.46). The pooled odds of a switch-to-brand in brand vs. generic initiators was 13.77 (95% CI: 11.35-16.71). This study suggests a low overall switch-to-brand prevalence and may support therapeutic equivalence between brand and generic antidepressants. Initiating with a brand product was the strongest predictor for switching back to brand and suggests that patient experience may play a role in drug utilization.

Adjuvant-containing control arms in pivotal quadrivalent human papillomavirus vaccine trials: restoration of previously unpublished methodology.

PURPOSE: Trustworthy reporting of quadrivalent human papillomavirus (HPV) vaccine trials is the foundation for assessing the vaccine's risks and benefits. However, several pivotal trial publications incompletely reported important methodological details and inaccurately described the formulation that the control arms received. Under the Restoring Invisible and Abandoned Trials initiative (RIAT), we aim to restore the public record regarding the content and rationale of the controls used in the trials. METHODS: We assembled a cohort (five randomised controlled trials) described as placebo-controlled using clinical study reports (CSRs) obtained from the European Medicines Agency. We extracted the content and rationale for the choice of control used in each trial across six data sources: trial publications, register records, CSR synopses, CSR main bodies, protocols and informed consent forms. RESULTS: Across data sources, the control was inconsistently reported as 'placebo'-containing aluminium adjuvant (sometimes with dose information). Amorphous aluminium hydroxyphosphate sulfate (AAHS) was not mentioned in any trial registry entry, but was mentioned in all publications and CSRs. In three of five trials, consent forms described the control as an 'inactive' substance. No rationale for the selection of the control was reported in any trial publication, register, consent form, CSR synopsis or protocol. Three trials reported the rationale for choice of control in CSRs: to preserve blinding and assess the safety of HPV virus-like particles as the 'safety profile of (AAHS) is well characterised'. CONCLUSIONS: The stated rationale of using AAHS control-to characterise the safety of the HPV virus-like particles-lacks clinical relevance. A non-placebo control may have obscured an accurate assessment of safety and the participant consent process of some trials raises ethical concerns. TRIAL REGISTRATION NUMBERS: NCT00092482, NCT00092521, NCT00092534, NCT00090220, NCT00090285.

Availability of study protocols for randomized trials published in high-impact medical journals: A cross-sectional analysis.

BACKGROUND: To improve reporting transparency and research integrity, some journals have begun publishing study protocols and statistical analysis plans alongside trial publications. We sought to assess the overall availability and characteristics of protocols and statistical analysis plans of randomized clinical trials published in the top five (by impact factor) general medicine journals. METHODS: All randomized clinical trials published in Annals of Internal Medicine, BMJ, JAMA, Lancet, and NEJM in 2016 were identified. For each randomized clinical trial, we searched for protocols and statistical analysis plans on journal websites (including supplementary material) and in the article, for example, a referenced publication or link to trial or institutional website. Characteristics of randomized clinical trials were extracted from the publication and clinical trial registry. A detailed assessment of protocols and statistical analysis plans was conducted in a 20% random sample of randomized clinical trials. RESULTS: Protocols were available for 299 (82%) trials, ranging from 50% in BMJ to >95% in NEJM and JAMA. Statistical analysis plans were available for 182 (50%) trials and varied from <10% for Annals of Internal Medicine, BMJ, and Lancet to 92% for NEJM. Of the 76 randomized clinical trials in the 20% random sample, 63 (83%) had a protocol but less than half (31; 44%) included an a priori (dated prior to patient enrollment) version of the protocol. Statistical analysis plans were available for 35 (46%) trials, and only 5 (7%) included an a priori version. CONCLUSION: Protocols and statistical analysis plans are publicly available for the majority of trials. However, the a priori versions of these documents are only available for a minority of trials. More attention must be paid to ensuring the public availability of a priori versions.

Medication errors in community pharmacies: The need for commitment, transparency, and research.

Medication errors place a serious medical and economic burden on the United States (U.S.) healthcare system. Since 1975, government health agencies and non-profit organizations in the U.S., such as the Agency for Healthcare Research and Quality (AHRQ), the Institute of Medicine (IOM), and the Joint Commission, have undertaken initiatives intended to reduce medication errors, and there has been noteworthy progress in inpatient settings. However, there have been fewer advances in settings outside the hospital such as community pharmacies, where 4 billion prescriptions were dispensed to patients in 2017. There are limited information and research on community pharmacies' involvement in reducing and preventing medication errors. Most published studies on medication errors in community pharmacy settings are cross-sectional in design and often limited by geography, such that each study describes a single geographic region, i.e., one or a few practices in a single city or state within the U.S. An attempt to gain additional insight on how medication errors are managed was met with the inability of many pharmacy corporations to provide meaningful information. In order to reduce medication errors, improvement strategies such as transparency and bi-directional communication between pharmacists and patients are needed. Pharmacists are required by law to counsel patients, and research has shown that counseling can assist with detecting medication errors. Community pharmacies play a significant role in the U.S. healthcare system, but their efforts to reduce medication errors are not well known. By improving transparency in quality assurance processes and promoting patient engagement to improve patient safety, community pharmacies have the potential to play a more active role in reducing medication errors and safeguarding patients from harm.