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Drug Safety
Journal Prestige (SJR): 1.447
Citation Impact (citeScore): 3
Number of Followers: 155  
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ISSN (Print) 0114-5916 - ISSN (Online) 1179-1942
Published by Adis Homepage  [21 journals]
  • The Impact of Litigation-Associated Reports on Signal Identification in
           the US FDA’s Adverse Event Reporting System
    • PubDate: 2019-10-01
  • 19th ISoP Annual Meeting “New Opportunities for New Generations”
           Bogotá, Colombia, 26–29 October, 2019
    • PubDate: 2019-10-01
  • Intravenous Infusion Administration: A Comparative Study of Practices and
           Errors Between the United States and England and Their Implications for
           Patient Safety
    • Abstract: Introduction Intravenous medication administration is widely reported to be error prone. Technologies such as smart pumps have been introduced with a view to reducing these errors. An international comparison could provide evidence of their effectiveness, including consideration of contextual factors such as regulatory systems and local cultures. Objectives The aim of this study was to investigate similarities and differences in practices and error types involving intravenous medication administration in the United States and England, and summarise methodological differences necessary to perform these parallel studies. Methods We drew on findings of separate point prevalence studies conducted across hospitals in each country. In these, we compared what was being administered at the time of observation with the prescription and relevant policies, errors were classified by type and severity, and proportions of infusions featuring each error type were calculated. We also reviewed what adaptations to the US protocol were needed for England.
      Authors independently reviewed findings from both studies and proposed themes for comparison. In online meetings, each country’s research team clarified assumptions and explained their findings. Results Key themes included commonalities and contrasts in methods, findings, practices and policies. Although US sites made greater use of smart infusion devices, and had more precisely defined requirements around infusion device use, patterns of errors were similar. Differences among clinical contexts within each country were as marked as differences across countries. Regulatory and quality control systems shape practices, but causal relationships are complex. Conclusion Infusion administration is a complex adaptive system with multiple interacting agents (professionals, patients, software systems, etc.) that respond in rich ways to their environments; safety depends on complex, interrelated factors.
      PubDate: 2019-10-01
  • Evaluating Renal Stress Using Pharmacokinetic Urinary Biomarker Data in
           Critically Ill Patients Receiving Vancomycin and/or
           Piperacillin–Tazobactam: A Secondary Analysis of the Multicenter
           Sapphire Study
    • Abstract: Introduction A drug combination that has gained recent attention for an additive risk of nephrotoxicity is vancomycin plus piperacillin–tazobactam. Clinicians need to better understand whether tubular cell stress occurs with piperacillin–tazobactam administration to establish whether renal injury associated with this combination is a valid clinical concern. Objective An evaluation of the pharmacokinetics of urinary tissue inhibitor of metalloproteinase-2 (TIMP-2) and insulin-like growth factor binding-protein 7 (IGFBP7) for patients receiving vancomycin alone, piperacillin–tazobactam alone, and vancomycin plus piperacillin–tazobactam in combination was conducted to understand the impact on acute kidney cell stress and compare the rates of dialysis or death at 9 months among these three drug exposure types. Methods A secondary analysis of the prospective, multicenter Sapphire study ( identifier NCT01209169) including 35 intensive care units (ICUs) in North America and Europe was performed. Critically ill adult patients at risk for acute kidney injury (AKI) were included. Urinary [TIMP-2]∙[IGFBP7] was measured serially. Patients who received vancomycin alone, piperacillin–tazobactam alone, or vancomycin plus piperacillin–tazobactam were grouped according to their maximum AKI stage within 3 days of the first drug dose. Results Of 723 critically ill adults admitted to the ICU, 46% received either piperacillin–tazobactam (n = 110), vancomycin (n = 156), or both (n = 67). The urinary [TIMP-2]∙[IGFBP7] was highest on day 1 for the combination group. AKI stage 2/3 occurred more frequently in patients receiving the drug combination than in those receiving piperacillin–tazobactam alone (p = 0.03) but not vancomycin alone (p = 0.29). Risk of death or dialysis at 9 months was greatest for vancomycin plus piperacillin–tazobactam (48%) and similar for patients receiving vancomycin alone (29%) or piperacillin–tazobactam alone (35%) (p = 0.03 for unadjusted and p = 0.048 after adjusting for covariates). Conclusion After exposure to piperacillin–tazobactam and vancomycin in combination, there was a greater release of AKI biomarkers in patients who develop AKI than with piperacillin–tazobactam or vancomycin monotherapy and the combination is associated with possible increased long-term adverse outcomes.
      PubDate: 2019-10-01
  • Cardiovascular Safety of Prucalopride in Patients with Chronic
           Constipation: A Multinational Population-Based Cohort Study
    • Abstract: Introduction The serotonin 5-HT4 receptor agonist prucalopride is approved in the European Union for the treatment of chronic constipation. This offered the unique opportunity to include real-world observational data on cardiovascular safety in the new drug application for approval of prucalopride in the USA. Methods This observational population-based cohort study (EUPAS9200) conducted in five data sources (three in the UK, one in Sweden, and one in Germany [which was subsequently excluded from the pooled analyses]) aimed to estimate the pooled adjusted incidence rate ratio for major adverse cardiovascular events (defined as hospitalization for non-fatal acute myocardial infarction or stroke, and in-hospital cardiovascular death) in adult initiators of prucalopride compared with initiators of polyethylene glycol 3350 (PEG) following a common protocol. Standardized incidence rates and incidence rate ratios of major adverse cardiovascular events were derived using propensity score stratification. Sensitivity analyses explored the impact of exposure definition, outcome categories, interim cancer, and unmeasured confounding. Results The pooled analyses included 5715 initiators of prucalopride and 29,372 initiators of PEG. Average duration of use was 175 days for prucalopride and 82 days for PEG. The pooled standardized incidence rate per 1000 person-years (95% confidence interval) of major adverse cardiovascular events was 6.57 (3.90–10.39) for patients initiating prucalopride and 10.24 (6.97–14.13) for PEG. The pooled adjusted incidence rate ratio for major adverse cardiovascular events was 0.64 (95% confidence interval 0.36–1.14). Results remained consistent in various sensitivity analyses. Conclusions The pooled incidence rate ratio estimate was consistent with no indication of an increased risk above the pre-specified safety threshold of 3.00 for major adverse cardiovascular events in patients with chronic constipation using prucalopride as compared with PEG.
      PubDate: 2019-10-01
  • Comparative Effectiveness and Safety of Direct Oral Anticoagulants in
           Patients with Atrial Fibrillation: A Systematic Review and Meta-Analysis
           of Observational Studies
    • Abstract: Background There are no head-to-head randomized controlled trials comparing different direct oral anticoagulants (DOACs). Thus, we systematically reviewed and meta-analyzed observational studies assessing the comparative effectiveness and safety of DOACs for stroke prevention in patients with atrial fibrillation (AF). Methods We systematically searched MEDLINE and EMBASE up to February 2019 for observational studies comparing different DOACs head-to-head in patients with AF. Two independent reviewers identified studies, extracted data, and assessed the risk of bias using the Risk Of Bias In Non-randomized Studies of Interventions (ROBINS-I) tool. Random-effects models were used to meta-analyze data across higher-quality studies. Results We identified 25 cohort studies including 1,079,565 patients with AF treated with DOACs. Meta-analysis of the 19 studies at moderate risk of bias yielded a similar risk of ischemic stroke for rivaroxaban versus dabigatran (six studies; hazard ratio [HR] 0.93; 95% confidence interval [CI] 0.83–1.04; I2: 0%), apixaban versus dabigatran (five studies; HR 0.94; 95% CI 0.82–1.09; I2: 0%), and apixaban versus rivaroxaban (four studies; HR 1.07; 95% CI 0.93–1.23; I2: 0%). Regarding major bleeding, there was an increased risk for rivaroxaban versus dabigatran (six studies; HR 1.33; 95% CI 1.20–1.47; I2: 22%) and decreased risks for apixaban versus either dabigatran (eight studies; HR 0.71; 95% CI 0.64–0.78; I2: 0%) or rivaroxaban (eight studies; HR 0.56; 95% CI 0.48–0.65; I2: 69%). Conclusions As head-to-head trials comparing different DOACs do not exist, available evidence derives exclusively from observational studies. These data suggest that while dabigatran, rivaroxaban, and apixaban have a similar effect on the risk of ischemic stroke, apixaban may be associated with a decreased risk of major bleeding compared with either dabigatran or rivaroxaban.
      PubDate: 2019-10-01
  • Pharmacovigilance as Scientific Discovery: An Argument for
    • Abstract: Pharmacovigilance currently faces several unsolved challenges. Of particular importance are issues concerning how to ascertain, collect, confirm, and communicate the best evidence to assist the clinical choice for individual patients. Here, we propose that these practical challenges partially stem from deeper fundamental issues concerning the epistemology of pharmacovigilance. After reviewing some of the persistent challenges, recent measures, and suggestions in the current pharmacovigilance literature, we support the argument that the detection of potential adverse drug reactions ought to be seen as a serendipitous scientific discovery. We further take up recent innovations from the multidisciplinary field of serendipity research about the importance of networks, diversity of expertise, and plurality of methodological perspectives for cultivating serendipitous discovery. Following this discussion, we explore how pharmacovigilance could be systematized in a way that optimizes serendipitous discoveries of untargeted drug effects, emerging from the clinical application. Specifically, we argue for the promotion of a trans-disciplinary responsive network of scientists and stakeholders. Trans-disciplinarity includes extending the involvement of stakeholders beyond the regulatory community, integrating diverse methods and sources of evidence, and enhancing the ability of diverse groups to raise signals of harms that ought to be followed up by the network. Consequently, promoting a trans-disciplinary approach to pharmacovigilance is a long-term effort that requires structural changes in medical education, research, and enterprise. We suggest a number of such changes, discuss to what extent they are already in process, and indicate the advantages from both epistemological and ethical perspectives.
      PubDate: 2019-10-01
  • Unintended Effects of Communicating About Drug Safety Issues: A Critical
           Review of the Literature
    • Abstract: Communications about the safety and effectiveness of human drugs can influence patients’ and prescribers’ perceptions and behaviors, which in turn can affect the public’s health more broadly. We conducted a critical review of the literature on the unintended effects from communicating information to the public about safety issues with prescription and over-the-counter drugs. We searched PubMed for peer-reviewed studies published from 1990 to 2017 where study authors reported probable unintended effects of communicating drug safety. The types of communications included in these studies were news reports, direct-to-consumer advertisements, and those released by government agencies. Among the 26 studies identified, the most commonly reported unintended effects were decreased drug use or discontinuation. Other unintended effects included spillover to populations not targeted by the communications (e.g., discontinuation of antidepressants among adults following communications concerning use among youth), shifts in clinical diagnoses (e.g., fewer diagnoses of depression), increased use of alternative therapies, and other undesirable behaviors (e.g., possible increased suicide attempts because antidepressants were discontinued). Limitations to the literature include the inability to establish causation or to isolate the effects of multiple communication sources and messages. Further, because the intended effect of many communications was not known, our study was limited by challenges in defining some effects as unintended. Most studies used health insurer claims data to identify unintended effects of communications, which provide an incomplete picture; few used self-reported or other methodologies that could help illuminate the reasons underlying the effects observed in the claims data. Best practices for communicating about the potential benefits and harms of drugs in a manner that minimizes negative unintended effects are needed to protect and improve public health.
      PubDate: 2019-10-01
  • Pooling Different Safety Data Sources: Impact of Combining Solicited and
           Spontaneous Reports on Signal Detection In Pharmacovigilance
    • Abstract: Introduction The volume of adverse events (AEs) collected, analysed, and reported has been increasing at a rapid rate for over the past 10 years, largely due to the growth of solicited programmes. The proportion of various forms of solicited case data has evolved over time, with the main relative volume increase coming from Patient Support Programmes. In this study, we sought to examine the impact of the pooling of AE report data from solicited sources with data from spontaneous sources to safety signal detection using disproportionality analysis methods. Methods Two conditions were explored in which disproportionality scores from hypothetical drugs were evaluated in a simulated safety database. The first condition held occurrence of events constant and varied solicited case volume, while the second condition varied both proportion of occurrence of events and solicited case volume. Results In the first setting, where all AE terms have the same probability to occur with any drug, increasing volumes of solicited cases while keeping occurrence of events constant leads to reduced variability in disproportionality scores, consequently reducing or eliminating identified signals of disproportionate reporting. In the second setting, varying both case volume and reporting rates can mask true safety signals and falsely identify signals where there are none. Conclusions This analysis of simulated data suggests that pooling AE data from solicited sources with spontaneous case data may impact the results of disproportionality analyses, masking true safety signals and identifying false positives. Therefore, increased volumes of safety data do not necessarily correlate with improved safety signal detection.
      PubDate: 2019-10-01
  • Study Design and Cohort Comparability in a Study of Major Cardiovascular
           Events in New Users of Prucalopride Versus Polyethylene Glycol 3350
    • Abstract: Introduction Given prior safety experience with other 5-HT4 agonists for chronic constipation, an observational, population-based cohort study in five data sources from Germany, Sweden, and the UK was conducted to evaluate the cardiovascular safety of prucalopride. Objectives Our objective is to describe the methods and resulting comparability of cohorts in a multi-database, multinational study of prucalopride initiators and polyethylene glycol 3350 (PEG) initiators following a harmonized protocol. Methods Prucalopride initiators were matched on age, sex, and index date to PEG initiators (1:5 ratio). Study exposures, cardiovascular risk factors, and other covariates were identified from healthcare utilization codes harmonized across databases. Cardiovascular outcomes were identified using database-specific algorithms based on diagnosis codes. The propensity score (PS) in each database was estimated using logistic regression, with prucalopride versus PEG as the outcome and including clinically relevant variables associated with major adverse cardiovascular events. Results In total, 12,030 prucalopride initiators and 59,985 PEG initiators were identified. After matching and trimming, cohorts from the UK and Sweden were well-balanced for cardiovascular risk factors and cancer. However, in Germany, PEG initiators remained older and sicker than prucalopride initiators. The prevalence of these characteristics also differed from those in the UK and Sweden. The pooled analyses included only data from the UK and Sweden. Conclusions Matching, trimming, and PS stratification yielded comparable cohorts in four of five data sources. Use of these methods could not achieve balance for key covariates within the German cohort, likely due to reimbursement differences in Germany.
      PubDate: 2019-10-01
  • Correction to: Patient Registries: An Underused Resource for Medicines
    • Abstract: The fourth sentence under the heading “1.1 Use of Patient Registries for Supporting Regulatory Assessments” in “1 Introduction” section should read as below.
      PubDate: 2019-09-05
  • Randomized Placebo-Controlled Trial Evaluating the Ophthalmic Safety of
           Single-Dose Tafenoquine in Healthy Volunteers
    • Abstract: Introduction Tafenoquine has been recently registered for the prevention of relapse in Plasmodium vivax malaria. Objective This study assessed the pharmacodynamic effects of 300-mg single-dose tafenoquine on the retina. Methods This phase I, prospective, multicenter, randomized, single-masked, placebo-controlled, parallel-group study was conducted between 2 February 2016 and 14 September 2017 at three US study centers. Adult healthy volunteers were randomized (2:1) to receive either a single 300-mg oral dose of tafenoquine or matched placebo on day 1. Ophthalmic assessments, including spectral domain optical coherence tomography (SD-OCT) and fundus autofluorescence (FAF), were conducted at baseline and day 90 and evaluated for pre-determined endpoints by an independent, masked reading center. Results One subject in each group met the composite primary endpoint for retinal changes identified with SD-OCT or FAF, i.e., one out of 306 (0.3%) with tafenoquine, one out of 161 (0.6%) with placebo. Both cases had unilateral focal ellipsoid zone disruption at day 90 with no effect on best-corrected visual acuity. The tafenoquine-treated subject had this abnormality at baseline, and was enrolled in error. There was no difference in ophthalmic safety between tafenoquine and placebo. Conclusion There was no evidence of any pharmacodynamic effect of 300-mg single-dose tafenoquine on the retina or any short-term clinically relevant effects on ophthalmic safety. This clinical trial is registered with (identifier: NCT02658435).
      PubDate: 2019-09-01
  • Antidepressants and the Risk of Hemorrhagic Stroke in the Elderly: a
           Nested Case–Control Study
    • Abstract: Background and Purpose Selective serotonin reuptake inhibitors (SSRIs) are frequently prescribed in the elderly due to a more favorable risk profile than other antidepressants (ADs). However, SSRIs are associated with an increased risk of gastrointestinal bleeding, while evidence on the risk of hemorrhagic stroke (HS) is limited. Therefore, we compared the risk of HS associated with the use of ADs in the elderly. Methods Based on data from the German Pharmacoepidemiological Research Database (GePaRD), a case–control study matched on age, sex, and health insurance provider, nested in a cohort of incident users of ADs ≥ 65 years of age was performed. Cases were identified from hospital discharge diagnoses, and exposure was identified from outpatient prescriptions. Multivariable conditional logistic regression was used to estimate adjusted odds ratios (ORs) with 95% confidence intervals (CIs). Results Based on 4059 cases and 40,590 controls, an increased risk of HS was found in current use of SSRIs (OR 1.39, 95% CI 1.22–1.58), selective serotonin and noradrenaline reuptake inhibitors (1.69, 1.35–2.11), noradrenergic and specific serotonergic ADs (1.44, 1.22–1.69), and noradrenaline reuptake inhibitors (3.81, 1.54–9.43) compared with tri- and tetracyclic antidepressants. An increased risk of HS was seen in patients with a high baseline risk of bleeding and in patients with depression. The risk of HS varied between individual ADs. Conclusion Our study shows that the use of medications inhibiting serotonin and/or noradrenaline reuptake increases the risk of HS in patients aged 65 years and older and that the risk varies across individual ADs.
      PubDate: 2019-09-01
  • Prevalence, Safety and Long-Term Retention Rates of Biologics in Hong Kong
           from 2001 to 2015
    • Abstract: Background Biologic agents were initially introduced as treatment for rheumatoid arthritis (RA) but have since been used for other medical conditions. As new biologics become increasingly widespread in treatment regimens, it is important to understand their safety and utilization in the post-marketing context. Purpose The aim of this study was to investigate long-term prescribing patterns and the safety of biologics in real clinical settings in Hong Kong. Methods This was a population-based drug utilization study in Hong Kong using a territory-wide electronic medical database Clinical Data Analysis and Reporting System (CDARS). Patients who received biologic treatments from 2001 to 2015 were identified and their corresponding demographic and clinical details retrieved from CDARS. The annual prevalence of biologic prescriptions, the long-term retention rates and incidence rates of infections associated with biologic treatments were evaluated. Results A total of 30,298 patients (male: 44%) prescribed biologic treatments were identified from CDARS from 2001 to 2015. The annual prevalence of biologic prescriptions increased from 0.1 to 16.1 per 100 persons for both sexes. Infliximab had the highest first-year retention rate of 95.6% among all biologics and continuously attained the highest retention rate from second to fifth year. The overall incidence rate of serious infections was less than five per 100 person-years. Specifically, the incidence rates of tuberculosis, upper and lower respiratory infections and herpes zoster were 0.52, 3.24, 4.99 and 1.01 per 100 person-years, respectively. Conclusion This population-based study revealed an increasing prevalence of biologic prescribing. Results from the study described the long-term retention rates and incidence rates of serious infections of biologic treatments for all indications, and confirmed the safety of biologic treatments. Since this study provides an overview of all biologic utilization, further studies on cost effectiveness, safety and compliance of treatment in different patient groups are still warranted.
      PubDate: 2019-09-01
  • Fluoroquinolone Use and the Risk of Collagen-Associated Adverse Events: A
           Systematic Review and Meta-Analysis
    • Abstract: Introduction It has been suggested that fluoroquinolone antibiotics increase the risk of developing collagen-associated adverse events such as aortic dissection and aortic aneurysm. These are life-threatening emergencies that need to be prevented. Objectives We performed this systematic review to clarify the association between fluoroquinolones and three collagen-associated adverse events: aortic aneurysm or aortic dissection, retinal detachment, and tendon disorders. Methods We searched PubMed, Embase, and Scopus for observational studies up to January 2019. Cohort and case–control studies were included if they reported data on the risk of collagen-related adverse events associated with fluoroquinolone exposure versus no exposure. We assessed the quality of the included studies using the Newcastle–Ottawa Scale. Effect statistics were pooled using random-effects models. Sensitivity and subgroup analyses were performed to identify any source of heterogeneity. Results After screening 2729 citations, we included 22 observational studies (12 cohort studies and ten case–control studies) with 19,207,552 participants. Current use of fluoroquinolones was significantly associated with aortic aneurysm and aortic dissection (odds ratio [OR] 2.20; 95% confidence interval [CI] 1.92–2.52), tendon disorders (OR 1.89; 95% CI 1.53–2.33), and retinal detachment (sensitivity analysis, OR 1.25; 95% CI 1.01–1.53). Past fluoroquinolone use (> 30 and ≤ 365 days) was associated with retinal detachment (OR 1.27; 95% CI 1.09–1.47). Conclusions Fluoroquinolone use incurs a risk of developing three collagen-associated diseases (aortic aneurysm or aortic dissection, retinal detachment, and tendon disorders). Patients at an increased risk of collagen-associated diseases should not use fluoroquinolones unless no other options are available.
      PubDate: 2019-09-01
  • Auto-Generated Physiological Chain Data for an Ontological Framework for
           Pharmacology and Mechanism of Action to Determine Suspected Drugs in Cases
           of Dysuria
    • Abstract: Introduction Patients often take several different medications for multiple conditions concurrently. Therefore, when adverse drug events (ADEs) occur, it is necessary to consider the mechanisms responsible. Few approaches consider the mechanisms of ADEs, such as changes in physiological states. We proposed that the ontological framework for pharmacology and mechanism of action (pharmacodynamics) we developed could be used for this approach. However, the existing knowledge base contains little data on physiological chains (PCs). Objective We aimed to investigate a method for automatically generating missing PC from the viewpoint of anatomical structures. This study was conducted to determine dysuria-related adverse events more likely to occur during multidrug administration. Methods We adopted a systematic approach to determine drugs suspected to cause adverse events and incorporated existing data and data generated in our newly developed method into our ontological framework. The performance of automated data generation was evaluated using this newly developed system. Suspected drugs determined by the system were compared with those derived from adverse events databases. Results Of the 242 drugs involving suspected drug-induced urinary retention or dysuria, 26 suspected drugs were determined. Of these, five were drugs with side effects not listed in drug package inserts. The system derived potential mechanisms of action, PCs, and suspected drugs. Conclusion Our method is novel in that it generates PC data from anatomical structural properties and could serve as a knowledge base for determining suspected drugs by potential mechanisms of action.
      PubDate: 2019-09-01
  • Evaluation of Use of Technologies to Facilitate Medical Chart Review
    • Abstract: Introduction While medical chart review remains the gold standard to validate health conditions or events identified in administrative claims and electronic health record databases, it is time consuming, expensive and can involve subjective decisions. Aim The aim of this study was to describe the landscape of technology-enhanced approaches that could be used to facilitate medical chart review within and across distributed data networks. Method We conducted a semi-structured survey regarding processes for medical chart review with organizations that either routinely do medical chart review or use technologies that could facilitate chart review. Results Fifteen out of 17 interviewed organizations used optical character recognition (OCR) or natural language processing (NLP) in their chart review process. None used handwriting recognition software. While these organizations found OCR and NLP to be useful for expediting extraction of useful information from medical charts, they also mentioned several challenges. Quality of medical scans can be variable, interfering with the accuracy of OCR. Additionally, linguistic complexity in medical notes and heterogeneity in reporting templates used by different healthcare systems can reduce the transportability of NLP-based algorithms to diverse healthcare settings. Conclusion New technologies including OCR and NLP are currently in use by various organizations involved in medical chart review. While technology-enhanced approaches could scale up capacity to validate key variables and make information about important clinical variables from medical records more generally available for research purposes, they often require considerable customization when employed in a distributed data environment with multiple, diverse healthcare settings.
      PubDate: 2019-09-01
  • Evaluation of Potential Drug–Drug Interactions in Adults in the
           Intensive Care Unit: A Systematic Review and Meta-Analysis
    • Abstract: Introduction There is an increased risk of potential drug–drug interactions (pDDIs) in critically ill patients based on the number of drugs received. The occurrence of pDDIs and clinical significance is not well described. Objective The aim was to provide insight into important clinical issues and offer guidance on drug–drug interaction (DDI) surveillance through the performance of a systematic review. Methods Five targeted objectives were developed, a priori, which guided study selection and data abstraction. Two independent reviewers extracted the definition, frequency, type, and clinical significance of pDDIs. A meta-analysis was performed to evaluate the proportion of patients exposed to a pDDI. Three data sources (PubMed, Embase, and Scopus) were utilized for the search to include studies that evaluated pDDIs in adult critically ill patients. Included studies in the systematic review and meta-analysis were required to be full text. Results A total of 39 studies met inclusion criteria. Definitions of pDDIs were diverse. Frequency of pDDIs varied by study, but was most commonly between one and five pDDIs per patient. Fifty-eight percent of patients were exposed to at least one pDDI during their intensive care unit admission. Types of pDDIs identified were numerous, with aspirin being the most common drug involved. As expected, not all pDDIs were clinically significant. Clinical significance was determined by varied definitions and sources. Conclusions Improving the understanding of clinically significant pDDIs and alerts that clinicians encounter may guide better development of surveillance through clinical decision support and decrease alert fatigue.
      PubDate: 2019-09-01
  • Enabling Data-Driven Clinical Quality Assurance: Predicting Adverse Event
           Reporting in Clinical Trials Using Machine Learning
    • Abstract: Introduction Adverse event (AE) under-reporting has been a recurrent issue raised during health authorities Good Clinical Practices (GCP) inspections and audits. Moreover, safety under-reporting poses a risk to patient safety and data integrity. The current clinical Quality Assurance (QA) practices used to detect AE under-reporting rely heavily on investigator site and study audits. Yet several sponsors and institutions have had repeated findings related to safety reporting, and this has led to delays in regulatory submissions. Recent developments in data management and IT systems allow data scientists to apply techniques such as machine learning to detect AE under-reporting in an automated fashion. Objective In this project, we developed a predictive model that enables Roche/Genentech Quality Program Leads oversight of AE reporting at the program, study, site, and patient level. This project was part of a broader effort at Roche/Genentech Product Development Quality to apply advanced analytics to augment and complement traditional clinical QA approaches. Method We used a curated data set from 104 completed Roche/Genentech sponsored clinical studies to train a machine learning model to predict the expected number of AEs. Our final model used 54 features built on patient (e.g., demographics, vitals) and study attributes (e.g., molecule class, disease area). Results In order to evaluate model performance, we tested how well it would detect simulated test cases based on data not used for model training. For relevant simulation scenarios of 25%, 50%, and 75% under-reporting on the site level, our model scored an area under the curve (AUC) of the receiver operating characteristic (ROC) curve of 0.62, 0.79, and 0.92, respectively. Conclusion The model has been deployed to evaluate safety reporting performance in a set of ongoing studies in the form of a QA/dashboard cockpit available to Roche Quality Program Leads. Applicability and production performance will be assessed over the next 12–24 months in which we will develop a validation strategy to fully integrate our model into Roche QA processes.
      PubDate: 2019-09-01
  • Transparent Reporting on Research Using Unstructured Electronic Health
           Record Data to Generate ‘Real World’ Evidence of Comparative
           Effectiveness and Safety
    • Abstract: Research that makes secondary use of administrative and clinical healthcare databases is increasingly influential for regulatory, reimbursement, and other healthcare decision-making. Consequently, there are numerous guidance documents on reporting for studies that use ‘real-world’ data captured in administrative claims and electronic health record (EHR) databases. These guidance documents are intended to improve transparency, reproducibility, and the ability to evaluate validity and relevance of design and analysis decisions. However, existing guidance does not differentiate between structured and unstructured information contained in EHRs, registries, or other healthcare data sources. While unstructured text is convenient and readily interpretable in clinical practice, it can be difficult to use for investigation of causal questions, e.g., comparative effectiveness and safety, until data have been cleaned and algorithms applied to extract relevant information to structured fields for analysis. The goal of this paper is to increase transparency for healthcare decision makers and causal inference researchers by providing general recommendations for reporting on steps taken to make unstructured text-based data usable for comparative effectiveness and safety research. These recommendations are designed to be used as an adjunct for existing reporting guidance. They are intended to provide sufficient context and supporting information for causal inference studies involving use of natural language processing- or machine learning-derived data fields, so that researchers, reviewers, and decision makers can be confident in their ability to evaluate the validity and relevance of derived measures for exposures, inclusion/exclusion criteria, covariates, and outcomes for the causal question of interest.
      PubDate: 2019-08-26
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