An ethics framework for the transition to an operational learning healthcare system

Introduction: While Learning Healthcare Systems (LHSs) have received increasing attention in health care and research, the amount of operational LHSs remains limited. Given the investment of resources in these projects, a moral responsibility to pursue the transition toward an LHS falls on projects and their participating stakeholders. This paper provides an ethics framework for projects that have taken steps toward building an LHS and are in the position to transition to an operational LHS. Method: To articulate relevant ethical requirements, we analyze established ethics frameworks in the fields of LHSs, data-intensive health research, and transitioning or innovating health systems. The overlapping content and shared values are used to articulate overarching ethical requirements. To provide necessary context, we apply the insights from the analysis to the Innovative Medicines Initiative ConcePTION project. This project is specifically designed to generate knowledge on the safety of medications used during pregnancy and lactation through the establishment of an LHS. Results: Upon analyzing the consulted frameworks, we identified four overlapping ethical requirements that are also of significant relevance within the scope of our ethics framework. These requirements are: (1) public benefit and favorable harm–benefit ratio; (2) equity and justice; (3) stakeholder engagement; and (4) sustainability. Additionally, we apply these ethical requirements to the context of an LHS for pregnant and lactating people. Conclusion: Although tailored to the context of pregnancy and lactation, our ethics framework can provide guidance for the transition to an operational LHS across diverse healthcare domains

CodeMapper: semiautomatic coding of case definitions. A contribution from the ADVANCE project

Abstract Background: Assessment of drug and vaccine effects by combining information from different healthcare databases in the European Union requires extensive efforts in the harmonization of codes as different vocabularies are being used across countries. In this paper, we present a web application called CodeMapper, which assists in the mapping of case definitions to codes from different vocabularies, while keeping a transparent record of the complete mapping process. Methods: CodeMapper builds upon coding vocabularies contained in the Metathesaurus of the Unified Medical Language System. The mapping approach consists of three phases. First, medical concepts are automatically identified in a free‐text case definition. Second, the user revises the set of medical concepts by adding or removing concepts, or expanding them to related concepts that are more general or more specific. Finally, the selected concepts are projected to codes from the targeted coding vocabularies. We evaluated the application by comparing codes that were automatically generated from case definitions by applying CodeMapper's concept identification and successive concept expansion, with reference codes that were manually created in a previous epidemiological study. Results: Automated concept identification alone had a sensitivity of 0.246 and positive predictive value (PPV) of 0.420 for reproducing the reference codes. Three successive steps of concept expansion increased sensitivity to 0.953 and PPV to 0.616. Conclusions: Automatic concept identification in the case definition alone was insufficient to reproduce the reference codes, but CodeMapper's operations for concept expansion provide an effective, efficient, and transparent way for reproducing the reference codes

Fatal outcomes following immunization errors as reported to the EudraVigilance: A case series

Background: Serious adverse reactions after immunization are rare but do occur. In very rare instances, cases with fatal outcome have been reported. These reports can have a huge impact and even more so when due to an immunization error. The aim of this study is to systematically review immunization errors with fatal outcomes in EudraVigilance. Methods: This was a case-series analysis of Individual Case Safety Reports (ICSRs) reporting immunization errors and a fatal outcome. To determine the level of certainty of a causal association between the immunization errors and fatal outcomes two independent reviewers assessed all ICSRs using the WHO tool “Causality assessment of an Adverse Event Following Immunization (AEFI)”. In accordance with the tool, the ICSRs were classified as consistent, indeterminate, inconsistent/coincidental, or unclassifiable. In addition, we estimated the contribution of reported errors to the fatal outcomes as large, moderate, small, none, or unclassifiable using a classification developed f

Prolonged QTc Interval and Risk of Sudden Cardiac Death in a Population of Older Adults

ObjectivesThis study sought to investigate whether prolongation of the heart rate-corrected QT (QTc) interval is a risk factor for sudden cardiac death in the general population.BackgroundIn developed countries, sudden cardiac death is a major cause of cardiovascular mortality. Prolongation of the QTc interval has been associated with ventricular arrhythmias, but in most population-based studies no consistent association was found between QTc prolongation and total or cardiovascular mortality. Only very few of these studies specifically addressed sudden cardiac death.MethodsThis study was conducted as part of the Rotterdam Study, a prospective population-based cohort study that comprises 3,105 men and 4,878 women aged 55 years and older. The QTc interval on the electrocardiogram was determined during the baseline visit (1990 to 1993) and the first follow-up examination (1993 to 1995). The association between a prolonged QTc interval and sudden cardiac death was estimated using Cox proportional hazards analysis.ResultsDuring an average follow-up period of 6.7 years (standard deviation, 2.3 years) 125 patients died of sudden cardiac death. An abnormally prolonged QTc interval (>450 ms in men, >470 ms in women) was associated with a three-fold increased risk of sudden cardiac death (hazard ratio, 2.5; 95% confidence interval, 1.3 to 4.7), after adjustment for age, gender, body mass index, hypertension, cholesterol/high-density lipoprotein ratio, diabetes mellitus, myocardial infarction, heart failure, and heart rate. In patients with an age below the median of 68 years, the corresponding relative risk was 8.0 (95% confidence interval 2.1 to 31.3).ConclusionsAbnormal QTc prolongation on the electrocardiogram should be viewed as an independent risk factor for sudden cardiac death

Guillain-Barré syndrome and adjuvanted pandemic influenza A (H1N1) 2009 vaccines: A multinational self-controlled case series in Europe

BACKGROUND: The risk of Guillain-Barré syndrome (GBS) following the United States' 1976 swine flu vaccination campaign in the USA led to enhanced active surveillance during the pandemic influenza (A(H1N1)pdm09) immunization campaign. This study aimed to estimate the risk of GBS following influenza A(H1N1)pdm09 vaccination. METHODS: A self-controlled case series (SCCS) analysis was performed in Denmark, Finland, France, Netherlands, Norway, Sweden, and the United Kingdom. Information was collected according to a common protocol and standardised procedures. Cases classified at levels 1-4a of the Brighton Collaboration case definition were included. The risk window was 42 days starting the day after vaccination. Conditional Poisson regression and pooled random effects models estimated adjusted relative incidences (RI). Pseudo likelihood and vaccinated-only methods addressed the potential contraindication for vaccination following GBS. RESULTS: Three hundred and three (303) GBS and Miller Fisher syndrome cases were included. Ninety-nine (99) were exposed to A(H1N1)pdm09 vaccination, which was most frequently adjuvanted (Pandemrix and Focetria). The unadjusted pooled RI for A(H1N1)pdm09 vaccination and GBS was 3.5 (95% Confidence Interval (CI): 2.2-5.5), based on all countries. This lowered to 2.0 (95% CI: 1.2-3.1) after adjustment for calendartime and to 1.9 (95% CI: 1.1-3.2) when we accounted for contra-indications. In a subset (Netherlands, Norway, and United Kingdom) we further adjusted for other confounders and there the RI decreased from 1.7 (adjusted for calendar month) to 1.4 (95% CI: 0.7-2.8), which is the main finding. CONCLUSION: This study illustrates the potential of conducting European collaborative vaccine safety studies. The main, fully adjusted analysis, showed that the RI of GBS was not significantly elevated after influenza A(H1N1)pdm09 vaccination (RI = 1.4 (95% CI: 0.7-2.8). Based on the upper limits of the pooled estimate we can rule out with 95% certainty that the number of excess GBS cases after influenza A(H1N1)pdm09 vaccination would be more than 3 per million vaccinated

Measuring the impact of the 2012 European pharmacovigilance legislation on additional risk minimization measures

Aims: Additional risk minimization measures (aRMMs) may be needed to ensure that the benefits continue to outweigh the risks for medicines associated with serious risks. Prior research showed an increasing trend in medicines with aRMMs. We assessed whether the European pharmacovigilance legislation may have impacted the number and type of aRMMs. Methods: We included new active substances approved between 1 January 2010 and 31 December 2015. Information extracted from the summary of the Risk Management Plan at the time of licensing included date and type of marketing authorization, presence and type of aRMMs. We tested for differences using Pearson’s Χ2 test and segmented Poisson regression. Results: We identified 231 medicines approved during the study period, of which 30% had aRMMs at the time of licensing. ARMMs were in place for 38% of medicines before July 2012 and for 28% after (p = 0.16). Segmented Poisson regression did not show changes in trend or level of medicines with aRMMs. Discussion and conclusion: During the study period, no significant differences in the proportion or trend of products with aRMMs at the time of licensing before and after the pharmacovigilance legislation were identified

Measuring the impact of the 2012 European pharmacovigilance legislation on additional risk minimization measures

Aims: Additional risk minimization measures (aRMMs) may be needed to ensure that the benefits continue to outweigh the risks for medicines associated with serious risks. Prior research showed an increasing trend in medicines with aRMMs. We assessed whether the European pharmacovigilance legislation may have impacted the number and type of aRMMs. Methods: We included new active substances approved between 1 January 2010 and 31 December 2015. Information extracted from the summary of the Risk Management Plan at the time of licensing included date and type of marketing authorization, presence and type of aRMMs. We tested for differences using Pearson’s Χ2 test and segmented Poisson regression. Results: We identified 231 medicines approved during the study period, of which 30% had aRMMs at the time of licensing. ARMMs were in place for 38% of medicines before July 2012 and for 28% after (p = 0.16). Segmented Poisson regression did not show changes in trend or level of medicines with aRMMs. Discussion and conclusion: During the study period, no significant differences in the proportion or trend of products with aRMMs at the time of licensing before and after the pharmacovigilance legislation were identified

Blockchain technology applications to postmarket surveillance of medical devices

Introduction: The amount of mandatory data that needs to be analyzed as part of a medical device postmarket surveillance (PMS) system has grown exponentially in recent times. This is a consequence of increasingly demanding and complex regulatory requirements from Health Authorities, aimed at a better understanding of the medical device safety evaluation. Proactive approaches to PMS processes are becoming more necessary as regulators increase the scrutiny of device safety. New technologies have been explored to address some of the challenges associated with this changing regulatory environment. Areas covered: This paper focuses on the different technical aspects of blockchain and how this new technology has the potential to support the ongoing efforts to improve the PMS system for medical devices. Expert opinion: To address these challenges, we suggest to generate a private PMS data permissioned blockchain with a proof-of-authority consensus mechanism, to which only a restricted number of designated and audited participants have authorization to validate transactions and add them to the PMS data blockchain ledger. Blockchain has the potential to support a more efficient approach, which could offer many advantages to the different stakeholders involved in the PMS process, such as supporting with new regulatory initiatives