Opportunities and Challenges for Decentralized Clinical Trial Approaches: European Health Technology Assessment Perspective.

OBJECTIVES: Decentralized clinical trial (DCT) approaches are clinical trials in which some or all trial activities take place closer to participants' proximities instead of a traditional investigative site. Data from DCTs may be used for clinical and economic evaluations by health technology assessment (HTA) bodies to support reimbursement decision making. This study aimed to explore the opportunities and challenges for DCT approaches from an HTA perspective by interviewing representatives from European HTA bodies. METHODS: We conducted semistructured interviews with 25 European HTA representatives between September 2022 and February 2023, and transcripts were analyzed after thematic analysis. RESULTS: Two main themes were identified from the data relating to (1) DCT approaches in HTA and (2) trial-level acceptance and relevance. Experience with assessing DCTs was limited and a variety of knowledge about DCTs was observed. The respondents recognized the opportunity of DCTs to reduce recall bias when participant-reported outcome data can be collected more frequently and conveniently from home. Concerns were expressed about the data quality when participants become responsible for data collection. Despite this challenge, the respondents recognized the potential of DCTs to increase the generalizability of results because data can be collected in a setting reflective of the everyday situation potentially from a more diverse participant group. CONCLUSIONS: DCTs could generate relevant results for HTA decision making when data are collected in a real-world setting from a diverse participant group. Increased awareness of the opportunities and challenges could help HTA assessors in their appraisal of DCT approaches.

Describing diversity of real world data sources in pharmacoepidemiologic studies: The DIVERSE scoping review.

PURPOSE: Real-world evidence (RWE) is increasingly used for medical regulatory decisions, yet concerns persist regarding its reproducibility and hence validity. This study addresses reproducibility challenges associated with diversity across real-world data sources (RWDS) repurposed for secondary use in pharmacoepidemiologic studies. Our aims were to identify, describe and characterize practices, recommendations and tools for collecting and reporting diversity across RWDSs, and explore how leveraging diversity could improve the quality of evidence. METHODS: In a preliminary phase, keywords for a literature search and selection tool were designed using a set of documents considered to be key by the coauthors. Next, a systematic search was conducted up to December 2021. The resulting documents were screened based on titles and abstracts, then based on full texts using the selection tool. Selected documents were reviewed to extract information on topics related to collecting and reporting RWDS diversity. A content analysis of the topics identified explicit and latent themes. RESULTS: Across the 91 selected documents, 12 topics were identified: 9 dimensions used to describe RWDS (organization accessing the data source, data originator, prompt, inclusion of population, content, data dictionary, time span, healthcare system and culture, and data quality), tools to summarize such dimensions, challenges, and opportunities arising from diversity. Thirty-six themes were identified within the dimensions. Opportunities arising from data diversity included multiple imputation and standardization. CONCLUSIONS: The dimensions identified across a large number of publications lay the foundation for formal guidance on reporting diversity of data sources to facilitate interpretation and enhance replicability and validity of RWE.

Which Benefits Can Justify Risks in Research?

Research ethics committees (RECs) evaluate whether the risk-benefit ratio of a study is acceptable. Decentralized clinical trials (DCTs) are a novel approach for conducting clinical trials that potentially bring important benefits for research, including several collateral benefits. The position of collateral benefits in risk-benefit assessments is currently unclear. DCTs raise therefore questions about how these benefits should be assessed. This paper aims to reconsider the different types of research benefits, and their position in risk-benefit assessments. We first propose a categorization of research benefits, based on the types of benefits that can be distinguished from the literature and ethical guidelines. Secondly, we will reconsider the position of collateral benefits. We argue that these benefits are not fundamentally different from other benefits of research and can therefore be included in risk-benefit assessments of DCTs.

Suspected adverse reactions reported for blood, blood components, and blood products in VigiBase.

INTRODUCTION: Since being designated as medicines by World Health Organization (WHO), blood components are subject to pharmacovigilance reporting. Using VigiBase, the WHO global database of individual case safety reports (ICSRs), we characterized reports of adverse reactions for all blood products. STUDY DESIGN AND METHODS: ICSRs involving blood products as the suspected medicine in VigiBase between 1968 and 2021 were extracted. MedDRA preferred terms and the International Society of Blood Transfusion haemovigilance definitions were used to stratify adverse reactions. Descriptive statistics were used to characterize ICSR demographics. RESULTS: A total of 111,033 ICSRs containing 577,577 suspected adverse reactions with 6152 MedDRA preferred terms were reported for 34 blood products. There were 12,153 (10.9%) reports for blood components, 98,135 (88.4%) reports for plasma-derived medicines, and 745 (0.7%) reports for recombinant products. The majority of reports (21.0% and 19.7%, respectively) were from patients aged 45-64 and over 65 years. The Americas contributed the most ICSRs (49.7%). Top reported suspected adverse reactions were for the following MedDRA preferred terms: headache (3.5%), pyrexia (2.8%), chills (2.8%), dyspnoea (1.8%), and nausea (1.8%). CONCLUSION: VigiBase already has a large number of reports on blood products. When compared to other existing haemovigilance databases, our study found reports from a broader range of countries and reporters. This may provide us with new perspectives, but for VigiBase to reach its full potential in haemovigilance some alterations in what is captured in reports are required.

Unintended impact of pharmacovigilance regulatory interventions: A systematic review.

AIMS: Studies assessing the impact of pharmacovigilance regulatory interventions often focus on the expected (or intended) outcomes, while any possible unintended impact may be overlooked. The update of the Good Pharmacovigilance Practice guideline in 2017 elaborated on impact assessment, emphasizing the need also to assess possible unintended impact. This systematic literature review investigated how often the unintended impact of regulatory interventions was considered in publications of studies investigating pharmacovigilance regulatory interventions in Europe. METHODS: We conducted a systematic review of the literature on MEDLINE and EMBASE from 1 January 2012 to 28 February 2022 to identify publications that investigated the impact of regulatory interventions in Europe. The primary outcome of the study was the number of publications reporting assessments of unintended impact. In addition, we studied the characteristics of these publications, including the type of outcomes assessed, the analytical methods applied and the type of data used. RESULTS: In total, 96 publications were included in the analysis. The unintended impact of pharmacovigilance regulatory interventions was investigated in 23 of 96 publications (24%). The drug classes most frequently studied in the publications assessing unintended impact of regulatory interventions were oral glucose-lowering drugs (n = 6, 26%), opioids (n = 4, 17%), antidepressants (n = 4, 17%) and antipsychotics (n = 3, 13%). The reported methods to assess the unintended impact were interrupted time series (n = 10, 43%) and descriptive statistics with or without significance testing (n = 2 [9%] and n = 9 [39%], respectively). The outcomes selected for unintended impact assessments included the use of other drugs (n = 16, 70%), health outcomes (n = 8, 35%) and behavioural changes (n = 4, 17%). Most of the publications reported on the use of electronic health record databases (n = 13, 57%) or claims databases (n = 13, 57%), while registries were used in 4 publications (17%). CONCLUSION: The unintended impact of pharmacovigilance regulatory interventions was reported in only a quarter of identified publications. There was no apparent increase in attention to unintended impact assessments after the update of the Good Pharmacovigilance Practice guidelines.

Primary nonadherence to drugs prescribed by general practitioners: A Dutch database study.

AIM: Primary nonadherence (PNA) is defined as not filling the first prescription for a drug treatment. PNA can lead not only to poor patient outcomes but also to exposure misclassification in written prescription databases. This study aims to estimate PNA in primary care in the Netherlands and to investigate associated factors. METHODS: Patients from the Nivel Primary Care Database (Nivel-PCD) who received a new prescription (>1 year not prescribed) from a general practitioner in 2012 were linked to pharmacy dispensing information of consenting pharmacies based on sex, year of birth, four-digit postal code and at least 50% matching Anatomical Therapeutic Classification codes. PNA was defined as not having a prescription dispensed within 30 days from the prescribing date. PNA was assessed overall and per drug class. The associations between PNA and several patient- and prescription-related characteristics were assessed using mixed-effects logistic regression models. RESULTS: After matching 86 361 of 396 251 subjects (21.8%) in the Nivel-PCD records to the pharmacy records, this study included 65 877 subjects who received 181 939 new drug prescriptions. Overall, PNA was 11.5%. PNA was lowest for thyroid hormones (5.5%) and highest for proton pump inhibitors (12.8%). Several factors were associated with PNA, such as having comorbidities (odds ratio [OR] 1.46, 95% confidence interval [CI] 1.37-1.56 for >3 active diagnoses, compared to no active diagnoses) or reimbursement status (OR 2.78, 95% CI 2.65-2.92 for not reimbursed drugs compared to fully reimbursed drugs). CONCLUSIONS: A total of 11.5% of newly prescribed drugs were not dispensed. This can lead to overestimation of the actual drug exposure status when using written prescription databases.

Direct-to-participant investigational medicinal product supply in clinical trials in Europe: Exploring the experiences of sponsors, site staff and couriers.

AIMS: Insights into the current practice of direct-to-participant (DtP) supply of investigational medicinal product (IMP) in the context of clinical trials conducted in Europe are needed, as regulations are unharmonized. This study is set out to explore how DtP IMP supply has been employed in Europe and what the advantages and disadvantages and barriers and facilitators of its implementation are. METHODS: We conducted semi-structured interviews with representatives from sponsor companies, courier services and site study staff involved in the IMP dispensing and delivery process in Europe. Interviews were conducted between May and November 2021, and data were analysed following thematic analysis. RESULTS: Sixteen respondents participated in one of the 12 interviews. Respondents had experience with different models of DtP IMP supply including shipment from the investigative site, a central pharmacy (a depot under the control of a pharmacist) and a local pharmacy-aiming to reduce trial participation burden. The respondents indicated that investigative site-to-participant shipment is not affected by regulatory barriers, but could burden site staff. Shipment from central locations was considered most efficient, but possible regulatory barriers related to maintaining participants' privacy and investigator oversight were identified. The respondents indicated that the involvement of local pharmacies to dispense IMP can be considered when the IMP is authorized. CONCLUSIONS: Several DtP IMP supply models are implemented in clinical trials conducted in Europe. In this study, three main DtP IMP models were identified, which can be referenced when describing these approaches for regulatory approval.

Prescribing of low-dose rivaroxaban in patients with atherosclerotic cardiovascular disease in the United Kingdom and the Netherlands.

AIMS: Low-dose rivaroxaban has been indicated for the management of atherosclerotic cardiovascular disease (ASCVD) after recent (2019-2020) updates to European guidelines. We aimed to describe prescription trends of low-dose rivaroxaban in ASCVD patients over the period 2015-2022 in two European countries, to compare the trends before and after guideline changes, and to determine the characteristics of users. METHODS: In a cross-sectional interrupted time series analysis, utilization of low-dose rivaroxaban (2.5 mg, twice daily) was measured in Clinical Practice Research Datalink Aurum (United Kingdom [UK]) and the PHARMO Database Network (the Netherlands) from 1 January 2015 to 28 February 2022 in patients with an ASCVD diagnosis. Incidence rates (IRs) and incidence rate ratios (IRRs) of new use (within 182 days) compared to the reference period, 2015-2018, were calculated. Age, sex and comorbidities of users were compared to those of nonusers. RESULTS: In the UK, from 721 271 eligible subjects the IR of new use of low-dose rivaroxaban in the period 2015-2018, before guideline changes, was 12.4 per 100 000 person-years and after guideline changes in 2020-2022 was 124.0 (IRR 10.0, 95% confidence interval [CI] 8.5, 11.8). In the Netherlands from 394 851 subjects, the IR in 2015-2018 was 2.4 per 100 000 person-years and in 2020 was 16.3 (IRR 6.7, 95% CI 4.0, 11.4). Users were younger (UK mean difference [MD] -6.1 years, Netherlands -2.4 years; P < .05) and more likely to be male (UK difference 11.5%, Netherlands 13.4%; P < .001) than nonusers. CONCLUSIONS: There was a statistically significant increase in the use of low-dose rivaroxaban for the management of ASCVD after guideline changes in the UK and the Netherlands. There were international differences, but low-dose rivaroxaban has not been put into widespread practice.

Tell me what you want, what you really really want: Estimands in observational pharmacoepidemiologic comparative effectiveness and safety studies.

PURPOSE: Ideally, the objectives of a pharmacoepidemiologic comparative effectiveness or safety study should dictate its design and data analysis. This paper discusses how defining an estimand is instrumental to this process. METHODS: We applied the ICH-E9 (Statistical Principles for Clinical Trials) R1 addendum on estimands - which originally focused on randomized trials - to three examples of observational pharmacoepidemiologic comparative effectiveness and safety studies. Five key elements specify the estimand: the population, contrasted treatments, endpoint, intercurrent events, and population-level summary measure. RESULTS: Different estimands were defined for case studies representing three types of pharmacological treatments: (1) single-dose treatments using a case study about the effect of influenza vaccination versus no vaccination on mortality risk in an adult population of ≥60 years of age; (2) sustained-treatments using a case study about the effect of dipeptidyl peptidase 4 inhibitor versus glucagon-like peptide-1 agonist on hypoglycemia risk in treatment of uncontrolled diabetes; and (3) as needed treatments using a case study on the effect of nitroglycerin spray as-needed versus no nitroglycerin on syncope risk in treatment of stabile angina pectoris. CONCLUSIONS: The case studies illustrated that a seemingly clear research question can still be open to multiple interpretations. Defining an estimand ensures that the study targets a treatment effect that aligns with the treatment decision the study aims to inform. Estimand definitions further help to inform choices regarding study design and data-analysis and clarify how to interpret study findings.

Bias in observational studies on the effectiveness of in hospital use of hydroxychloroquine in COVID-19.

PURPOSE: During the first waves of the coronavirus pandemic, evidence on potential effective treatments was urgently needed. Results from observational studies on the effectiveness of hydroxychloroquine (HCQ) were conflicting, potentially due to biases. We aimed to assess the quality of observational studies on HCQ and its relation to effect sizes. METHODS: PubMed was searched on 15 March 2021 for observational studies on the effectiveness of in-hospital use of HCQ in COVID-19 patients, published between 01/01/2020 and 01/03/2021 on. Study quality was assessed using the ROBINS-I tool. Association between study quality and study characteristics (journal ranking, publication date, and time between submission and publication) and differences between effects sizes found in observational studies compared to those found in RCTs, were assessed using Spearman's correlation. RESULTS: Eighteen of the 33 (55%) included observational studies were scored as critical risk of bias, eleven (33%) as serious risk and only four (12%) as moderate risk of bias. Biases were most often scored as critical in the domains related to selection of participants (n = 13, 39%) and bias due to confounding (n = 8, 24%). There were no significant associations found between the study quality and the characteristics nor between the study quality and the effect estimates. DISCUSSION: Overall, the quality of observational HCQ studies was heterogeneous. Synthesis of evidence of effectiveness of HCQ in COVID-19 should focus on RCTs and carefully consider the added value and quality of observational evidence.

The association between patient satisfaction with information and adherence to oral anticancer agents.

INTRODUCTION: Adherence to anticancer agents is a critical factor in achieving adequate clinical response, and became a major challenge for patients and caregivers since the increased substitution of parenteral cytostatic by oral drugs. One of the factors that influences adherence is how well informed patients are about their therapy. This study assesses the association between patient satisfaction with information about oral anticancer agents and adherence. MATERIALS AND METHODS: This study was conducted among patients (≥18 years) who began oral anticancer therapy. Patients satisfaction with information and adherence were assessed using validated questionnaires. Adherence was also assessed using refill data. Logistic regression was applied to assess the association between overall patient satisfaction with information and both self-reported adherence and adherence based on an MPR value of above 80%. RESULTS: In total, 124 patients were included in the study. The median (IQR) satisfaction with information was 15.0(4) on a scale of 0-17. Eighty-two percent of participants reported adherence, while the refill data demonstrated that 64.5% of patients had an adherence rate of 80% or higher. Overall satisfaction with information was not significantly associated with self-reported adherence (OR adj 0.98 [95% CI 0.85-1.15]) or refill-based adherence (OR adj 1.11 [95% CI 0.99-1.24]). CONCLUSION: The findings indicate no significant relationship between patient satisfaction with information and adherence. The population was highly satisfied with information about the oral anticancer agents, which indicates a high level of satisfaction with usual care. However, the refill data reveals that 35.5% of patients were not adherent.

Impact of regulatory interventions to restrict the combined use of renin-angiotensin system blockers: A Danish nationwide drug utilisation study.

This study aimed to evaluate the impact of the risk minimisation measures issued by the European Medicines Agency in 2014 to restrict the combined use of renin-angiotensin system (RAS) blocking agents in Denmark. Data from the Danish National Prescription Registry covering all medications dispensed during January 2008-December 2018 was used. The outcome was monthly prevalence of patients codispensed RAS blockers. Autoregressive integrated moving average interrupted time series regression was used to evaluate dispensing trends. The prevalence of patients codispensed RAS blockers decreased from 0.01 to 0.0003%. Preintervention trend was declining and further decreased with an additional -0.45 (95% confidence interval -0.66, -0.25) codispensing per million population after the intervention. Overall, the intervention had minimal impact on the combined use of RAS blockers. However, as the combined use of RAS blockers is low, further interventions to restrict the combined use of RAS blockers may not be required in Denmark at this point.

Long-term survival of Icelandic women following acute myocardial infarction.

Objective. To evaluate the impact of sex on treatment and survival after acute myocardial infarction (AMI) in Iceland. Methods. A retrospective, nationwide cohort study of patients with STEMI (2008-2018) and NSTEMI (2013-2018) and obstructive coronary artery disease. Patient and procedural information were obtained from a registry and electronic health records. Survival was estimated with Kaplan-Meier method and Cox regression analysis used to identify risk factors for long-term mortality. Excess mortality from the AMI episode was estimated by comparing the survival with age- and sex-matched population in Iceland at 30-day interval. Results. A total of 1345 STEMI-patients (24% women) and 1249 NSTEMI-patients (24% women) were evaluated. Women with STEMI (mean age: 71 ± 11 vs. 67 ± 12) and NSTEMI (mean age: 69 ± 13 vs. 62 ± 12) were older and less likely to have previous cardiovascular disease. There was neither sex difference in the extent of coronary artery disease nor treatment. Although crude one-year post-STEMI survival was lower for women (88.7% vs. 93.4%, p = .006), female sex was not an independent risk factor after adjusting for age and co-morbidities after STEMI and was protective for NSTEMI (HR 0.67, 95% CI: 0.46-0.97). There was excess 30-day mortality in both STEMI and NSTEMI for women compared with sex-, age- and inclusion year-matched Icelandic population, but thereafter the mortality rate was similar. Conclusion. Women and men with AMI in Iceland receive comparable treatment including revascularization and long-term survival appears similar. Prognosis after NSTEMI is better in women, whereas higher early mortality after STEMI may be caused by delays in presentation and diagnosis.

Impact of anticoagulant exposure misclassification on the bleeding risk of direct oral anticoagulants.

AIMS: Drug exposure status based on routinely collected data might be misclassified when the database contains only prescriptions from 1 type of prescriber (e.g. general practitioner and not specialist). This study aims to quantify the impact of such exposure misclassification on the risk of major bleeding and stroke/transient ischaemic attack (TIA)associated with direct oral anticoagulants (DOACs) vs. vitamin K antagonists (VKAs). METHODS: Incident anticoagulant users (>12 mo free of anticoagulation use) in the Dutch PHARMO Database Network between 2008 and 2017 were included. Drug exposure was assessed using pharmacy dispensing information. The risks of hospital admission of major bleeding for DOAC vs. VKA users was assessed with Cox regression analysis, where exposure was based on all dispensings, on general practitioner (GP)-prescribed dispensings only or on specialist-prescribed dispensings only. Hazard ratios (HRs) were estimated also for hospitalization for gastrointestinal bleeding, intracranial bleeding and stroke/TIA. RESULTS: We included 99 182 VKA-initiators and 21 795 DOAC-initiators. Use of DOAC was associated with a lower risk of major bleeding compared to VKA use; HR 0.79 (95% confidence interval 0.70-0.90), 0.78 (0.68-0.91) and 0.62 (0.50-0.76), for exposure based on complete dispensing information, only GP- and only specialist-prescribed dispensings, respectively. Similar results were found for the other bleeding outcomes. For stroke/TIA the HRs were 0.96 (0.84-1.09), 1.00 (0.84-1.18) and 0.72 (0.58-0.90), respectively. CONCLUSION: Including only GP-prescribed anticoagulant dispensings in this case did not materially impact the effect estimates compared to including all anticoagulant dispensings. Including only specialist-prescribed dispensings, however, strengthened the effect estimates.

Comparing risk of major bleeding between users of different oral anticoagulants in patients with nonvalvular atrial fibrillation.

AIMS: The introduction of direct oral anticoagulants (DOACs) has broadened the treatment arsenal for nonvalvular atrial fibrillation, but observational studies on the benefit-risk balance of DOACs compared to vitamin K antagonists (VKAs) are needed. The aim of this study was to characterize the risk of major bleeding in DOAC users using longitudinal data collected from electronic health care databases from 4 different EU-countries analysed with a common study protocol. METHODS: A cohort study was conducted among new users (≥18 years) of DOACs or VKAs with nonvalvular atrial fibrillation using data from the UK, Spain, Germany and Denmark. The incidence of major bleeding events (overall and by bleeding site) was compared between current use of DOACs and VKAs. Cox regression analysis was used to calculate hazard ratios and 95% confidence intervals (CI) and adjust for confounders. RESULTS/CONCLUSION: Overall, 251 719 patients were included across the 4 study cohorts (mean age ~75 years, % females between 41.3 and 54.3%), with overall hazard ratios of major bleeding risk for DOACs vs VKAs ranging between 0.84 (95% CI: 0.79-0.90) in Denmark and 1.13 (95% CI 1.02-1.25) in the UK. When stratifying according to the bleeding site, risk of gastrointestinal bleeding was increased by 48-67% in dabigatran users and 30-50% for rivaroxaban users compared to VKA users in all data sources except Denmark. Compared to VKAs, apixaban was not associated with an increased risk of gastrointestinal bleeding in all data sources and seemed to be associated with the lowest risk of major bleeding events compared to dabigatran and rivaroxaban.

Drug exposure misclassification in pharmacoepidemiology: Sources and relative impact.

BACKGROUND: Drug exposure assessment based on dispensing data can be misclassified when patients do not adhere to their therapy or when information about over-the-counter drugs is not captured in the study database. Previous research has considered hypothetical sensitivity and specificity values, whereas this study aims to assess the impact of literature-based real values of exposure misclassification. METHODS: A synthetic cohort study was constructed based on the proportion of exposure theoretically captured in a database (range 0.5-1.0) and the level of adherence (0.5-1.0). Three scenarios were explored: nondifferential misclassification, differential misclassification (misclassifications dependent on an unmeasured risk factor doubling the outcome risk), and nondifferential misclassification in a comparative effectiveness study (RRA and RRB both 2.0 compared to nonuse, RRA-B 1.0). RESULTS: For the scenarios with nondifferential misclassification, 25% nonadherence or 25% uncaptured exposure changed the RR from 2.0 to 1.75, and 1.95, respectively. Applying different proportions of nonadherence or uncaptured use (20% vs. 40%) for subgroups with and without the risk factor, an RR of 0.95 was observed in the absence of a true effect (i.e., true RR = 1). In the comparative effectiveness study, no effect on RR was seen for different proportions of uncaptured exposure; however, different levels of nonadherence for the drugs (20% vs. 40%) led to an underestimation of RRA-B (0.89). DISCUSSION: All scenarios led to biased estimates, but the magnitude of the bias differed across scenarios. When testing the robustness of findings of pharmacoepidemiologic studies, we recommend using realistic values of nonadherence and uncaptured exposure based on real-world data.

A systematic review of how missing data are handled and reported in multi-database pharmacoepidemiologic studies.

PURPOSE: Pharmacoepidemiologic multi-database studies (MDBS) provide opportunities to better evaluate the safety and effectiveness of medicines. However, the issue of missing data is often exacerbated in MDBS, potentially resulting in bias and precision loss. We sought to measure how missing data are being recorded and addressed in pharmacoepidemiologic MDBS. METHODS: We conducted a systematic literature search in PubMed for pharmacoepidemiologic MDBS published between 1st January 2018 and 31st December 2019. Included studies were those that used ≥2 distinct databases to assess the same safety/effectiveness outcome associated with a drug exposure. Outcome variables extracted from the studies included strategies to execute a MDBS, reporting of missing data (type, bias evaluation) and the methods used to account for missing data. RESULTS: Two thousand seven hundred and twenty-six articles were identified, and 62 studies were included: using data from either North America (56%), Europe (31%), multiple regions (11%) or East-Asia (2%). Thirty-five (56%) articles reported missing data: 11 of these studies reported that this could have introduced bias and 19 studies reported a method to address missing data. Thirteen (68%) carried out a complete case analysis, 2 (11%) applied multiple imputation, 2 (11%) used both methods, 1 (5%) used mean imputation and 1 (5%) substituted information from a similar variable. CONCLUSIONS: Just over half of the recent pharmacoepidemiologic MDBS reported missing data and two-thirds of these studies reported how they accounted for it. We should increase our vigilance for database completeness in MDBS by reporting and addressing the missing data that could introduce bias.

New-user and prevalent-user designs and the definition of study time origin in pharmacoepidemiology: A review of reporting practices.

BACKGROUND: Guidance reports for observational comparative effectiveness and drug safety research recommend implementing a new-user design whenever possible, since it reduces the risk of selection bias in exposure effect estimation compared to a prevalent-user design. The uptake of this guidance has not been studied extensively. METHODS: We reviewed 89 observational effectiveness and safety cohort studies published in six pharmacoepidemiological journals in 2018 and 2019. We developed an extraction tool to assess how frequently new-user and prevalent-user designs were reported to be implemented. For studies that implemented a new-user design in both treatment arms, we extracted information about the extent to which the moment of meeting eligibility criteria, treatment initiation, and start of follow-up were reported to be aligned. RESULTS: Of the 89 studies included, 40% reported implementing a new-user design for both the study exposure arm and the comparator arm, while 13% reported implementing a prevalent-user design in both arms. The moment of meeting eligibility criteria, treatment initiation, and start of follow-up were reported to be aligned in both treatment arms in 53% of studies that reported implementing a new-user design. We provided examples of studies that minimized the risk of introducing bias due to unclear definition of time origin in unexposed participants, immortal time, or a time lag. CONCLUSIONS: Almost half of the included studies reported implementing a new-user design. Implications of misalignment of study design origin were difficult to assess because it would require explicit reporting of the target estimand in original studies. We recommend that the choice for a particular study time origin is explicitly motivated to enable assessment of validity of the study.

Major bleeding in users of direct oral anticoagulants in atrial fibrillation: A pooled analysis of results from multiple population-based cohort studies.

OBJECTIVE: To establish the risk of major bleeding in direct oral anticoagulant (DOAC) users (overall and by class) versus vitamin K antagonist (VKA) users, using health care databases from four European countries and six provinces in Canada. METHODS: A retrospective cohort study was performed according to a similar protocol. First-users of VKAs or DOACs with a diagnosis of non-valvular atrial fibrillation (NVAF) were included. The main outcome of interest was major bleeding and secondary outcomes included gastrointestinal (GI) bleeding and intracranial haemorrhage (ICH). Incidence rates of events per 1000 person years were calculated. Hazard ratios (HRs) and 95% confidence intervals (95% CI) were estimated using a Cox proportional hazard regression model. Exposure and confounders were measured and analysed in a time-dependant way. Risk estimates were pooled using a random effect model. RESULTS: 421 523 patients were included. The risk of major bleeding for the group of DOACs compared to VKAs showed a pooled HR of 0.94 (95% CI: 0.87-1.02). Rivaroxaban showed a modestly increased risk (HR 1.11, 95% CI: 1.06-1.16). Apixaban and dabigatran showed a decreased risk of respectively HR 0.76 (95% CI: 0.69-0.84) and HR 0.85 (95% CI: 0.75-0.96). CONCLUSIONS: This study confirms that the risk of major bleeding of DOACs compared to VKAs is not increased when combining all DOACs. However, we observed a modest higher risk of major bleeding for rivaroxaban, whereas for apixaban and dabigatran lower risks of major bleeding were observed compared to VKAs.

Comparison of consistency and complementarity of reporting biosimilar quality attributes between regulatory and scientific communities: An adalimumab case study.

Biosimilar approval relies on the comparability of quality attributes (QAs), for which information can be derived from regulatory or scientific communities. Limited information is known about whether these sources are consistent with or complementary to each other. The consistency and complementarity of QA reporting in biosimilarity assessments for adalimumab biosimilars approved by the European Medicines Agency in European public assessment reports (EPARs) and scientific publications was assessed. A classification of 77 different QAs (53 structural and 24 functional attributes) was used to assess the types of and information on QAs reported. Six adalimumab biosimilars were analyzed, for which the number of QAs reported in EPARs and publications varied (range = 47 [61%]-60 [78%]). The proportion of QAs consistently reported in both sources varied (range = 28%-75%) among biosimilars; functional QAs (mean = 21 QAs [88%]; range = 19-23) were more consistently reported than structural QAs (mean = 33 QAs [62%]; range = 27-34). The EPARs frequently reported biosimilarity interpretation without providing test results (9-57 QAs in EPARs versus 0-8 QAs in publications), whereas publications frequently reported both test results and interpretations (13-40 QAs in publications versus 0-3 QAs in EPARs). Both sources provided information on the biosimilarity of QAs in a complementary manner and the same biosimilarity interpretation of test results for reported QAs (mean = 90%; range = 78%-100%), with a small discrepancy in biosimilarity interpretations of a few clinically relevant QAs related to post-translation modifications and biological activity. Comprehensive reporting of QAs can contribute to an improved understanding of the role of structural and functional attributes in establishing biosimilarity and the mechanism of action of biological substances in general.