Updated core competencies in pharmacoepidemiology to inform contemporary curricula and training for academia, government, and industry.

PURPOSE: The first paper to specify the core content of pharmacoepidemiology as a profession was published by an ISPE (International Society for Pharmacoepidemiology) workgroup in 2012 (Jones JK et al. PDS 2012; 21[7]:677-689). Due to the broader and evolving scope of pharmacoepidemiology, ISPE considers it important to proactively identify, update and expand the list of core competencies to inform curricula of education programs; thus, better positioning pharmacoepidemiologists across academic, government (including regulatory), and industry positions. The aim of this project was to update the list of core competencies in pharmacoepidemiology. METHODS: To ensure applicability of findings to multiple areas, a working group was established consisting of ISPE members with positions in academia, industry, government, and other settings. All competencies outlined by Jones et al. were extracted from the initial manuscript and presented to the working group for review. Expert-based judgments were collated and used to identify consensus. It was noted that some competencies could contribute to multiple groups and could be directly or indirectly related to a group. RESULTS: Five core domains were proposed: (1) Epidemiology, (2) Clinical Pharmacology, (3) Regulatory Science, (4) Statistics and data science, and (5) Communication and other professional skills. In total, 55 individual competencies were proposed, of which 25 were new competencies. No competencies from the original work were dropped but aggregation or amendments were made where considered necessary. CONCLUSIONS: While many core competencies in pharmacoepidemiology have remained the same over the past 10 years, there have also been several updates to reflect new and emerging concepts in the field.

Pharmacoepidemiology and Clinical Correlates of Lithium Treatment for Bipolar Disorder in Asia.

BACKGROUND: As clinical practices with lithium salts for patients diagnosed with bipolar disorder (BD) are poorly documented in Asia, we studied the prevalence and clinical correlates of lithium use there to support international comparisons. METHODS: We conducted a cross-sectional study of use and dosing of lithium salts for BD patients across 13 Asian sites and evaluated bivariate relationships of lithium treatment with clinical correlates followed by multivariate logistic regression modeling. RESULTS: In a total of 2139 BD participants (52.3% women) of mean age 42.4 years, lithium salts were prescribed in 27.3% of cases overall, varying among regions from 3.20% to 59.5%. Associated with lithium treatment were male sex, presence of euthymia or mild depression, and a history of seasonal mood change. Other mood stabilizers usually were given with lithium, often at relatively high doses. Lithium use was associated with newly emerging and dose-dependent risk of tremors as well as risk of hypothyroidism. We found no significant differences in rates of clinical remission or of suicidal behavior if treatment included lithium or not. CONCLUSIONS: Study findings clarify current prevalence, dosing, and clinical correlates of lithium treatment for BD in Asia. This information should support clinical decision-making regarding treatment of BD patients and international comparisons of therapeutic practices.

Prescription Sequence Symmetry Analysis (PSSA) to assess prescribing cascades: a step-by-step guide.

Prescribing cascades occur when patients are prescribed medication to treat the adverse drug reaction of previously prescribed medication. Prescription sequence symmetry analysis (PSSA) can be used to assess the association between two medications in prescription or dispensing databases and thus the potential occurrence of prescribing cascades. In this article, a step-by-step guide is presented for conducting PSSA to assess prescribing cascades. We describe considerations for medication data collection and setting time periods for relevant parameters, including washout window, exposure window, continued exposure interval and blackout period. With two examples, we illustrate the impact of changes in these parameters on the strengths of associations observed. Given the impact seen, we recommend that researchers clearly specify and explain all considerations regarding medication included and time windows set when studying prescribing cascades with PSSA, and conduct subgroup and sensitivity analyses.

Successful implementation of a stakeholder engagement program for pharmacoepidemiologic research.

PURPOSE: Rigorously conducted pharmacoepidemiologic research requires methodologically complex study designs and analysis yet evaluates problems of high importance to patients and clinicians. Despite this, participation in and mechanisms for stakeholder engagement in pharmacoepidemiologic research are not well-described. Here, we describe our approach and lessons learned from engaging stakeholders, of varying familiarity with research methods, in a rigorous multi-year pharmacoepidemiologic research program evaluating the comparative effectiveness of diabetes medications. METHODS: We recruited 5 patient and 4 clinician stakeholders; each was compensated for their time. Stakeholders received initial formal training in observational research and pharmacoepidemiologic methods sufficient to enable contribution to the research project. After onboarding, stakeholder engagement meetings were held virtually, in the evening, 2-3 times annually. Each was approximately 90 min and focused on 1-2 specific questions about the project, with preparatory materials sent in advance. RESULTS: Stakeholder meeting attendance was high (89%-100%), and all stakeholders engaged with the research project, both during and between meetings. Stakeholders reported positive experiences with meetings, satisfaction, and interest in the research project and its findings, and dedication to the success of the project's goals. They affirmed the value of receiving materials to review in advance and the effectiveness of a virtual platform. Their contributions included prioritizing and suggesting research questions, optimizing written evidence briefs for a lay audience, and guidance on broader topics such as research audience and methods of dissemination. CONCLUSIONS: Stakeholder engagement in pharmacoepidemiologic research using complex study designs and analysis is feasible, acceptable, and positively impacts the research project.

The State of Use and Utility of Negative Controls in Pharmacoepidemiologic Studies.

Uses of real-world data in drug safety and effectiveness studies are often challenged by various sources of bias. We undertook a systematic search of the published literature through September 2020 to evaluate the state of use and utility of negative controls to address bias in pharmacoepidemiologic studies. Two reviewers independently evaluated study eligibility and abstracted data. Our search identified 184 eligible studies for inclusion. Cohort studies (115, 63%) and administrative data (114, 62%) were, respectively, the most common study design and data type used. Most studies used negative control outcomes (91, 50%), and for most studies the target source of bias was unmeasured confounding (93, 51%). We identified 4 utility domains of negative controls: 1) bias detection (149, 81%), 2) bias correction (16, 9%), 3) P-value calibration (8, 4%), and 4) performance assessment of different methods used in drug safety studies (31, 17%). The most popular methodologies used were the 95% confidence interval and P-value calibration. In addition, we identified 2 reference sets with structured steps to check the causality assumption of the negative control. While negative controls are powerful tools in bias detection, we found many studies lacked checking the underlying assumptions. This article is part of a Special Collection on Pharmacoepidemiology.

Inventory of real-world data sources in Japan: Annual survey conducted by the Japanese Society for Pharmacoepidemiology Task Force.

PURPOSE: The Database Task Force of the Japan Society for Pharmacoepidemiology began its annual surveys of databases available for clinico and pharmacoepidemiological studies in 2010. In this report, we summarize the characteristics of the databases available in Japan based on the results of our 2021 survey to illustrate the recent developments in the infrastructure for database research in Japan. METHODS: We included 20 major databases from the academia, government, or industry that were accessible to third parties. We used a web-based questionnaire to ask the database providers about their characteristics, such as their organization, data source(s), numbers of individuals enrolled, age distribution, code(s) used, and average follow-up periods. RESULTS: We received responses from all 20 databases approached: eight hospital-based databases, six insurer-based databases, four pharmacy-based databases, and two in the "other" category. Among them, 17 contained information from medical claims, pharmacy claims, and/or Diagnosis Procedure Combination data. Most insurer databases contained health check-up data that could be attached to the claims component. Some hospital-based databases had data from electronic medical records. Most insurer-based databases collected data from the insurers of working-age employees and therefore had limited coverage of older people. Most databases coded their medication data using the Japanese reimbursement codes, and many provided Anatomical Therapeutic Chemical Classification codes. CONCLUSIONS: The number of databases available for clinico and pharmacoepidemiological research and the proportion of the population they cover are increasing in Japan. The differences in their characteristics mean that the appropriate database must be selected for a particular study purpose.

Overview of global real-world data sources for pediatric pharmacoepidemiologic research.

PURPOSE: Given limited information available on real-world data (RWD) sources with pediatric populations, this study describes features of globally available RWD sources for pediatric pharmacoepidemiologic research. METHODS: An online questionnaire about pediatric RWD sources and their attributes and capabilities was completed by members and affiliates of the International Society for Pharmacoepidemiology and representatives of nominated databases. All responses were verified by database representatives and summarized. RESULTS: Of 93 RWD sources identified, 55 unique pediatric RWD sources were verified, including data from Europe (47%), United States (38%), multiregion (7%), Asia-Pacific (5%), and South America (2%). Most databases had nationwide coverage (82%), contained electronic health/medical records (47%) and/or administrative claims data (42%) and were linkable to other databases (65%). Most (71%) had limited outside access (e.g., by approval or through local collaborators); only 10 (18%) databases were publicly available. Six databases (11%) reported having >20 million pediatric observations. Most (91%) included children of all ages (birth until 18th birthday) and contained outpatient medication data (93%), while half (49%) contained inpatient medication data. Many databases captured vaccine information for children (71%), and one-third had regularly updated data on pediatric height (31%) and weight (33%). Other pediatric data attributes captured include diagnoses and comorbidities (89%), lab results (58%), vital signs (55%), devices (55%), imaging results (42%), narrative patient histories (35%), and genetic/biomarker data (22%). CONCLUSIONS: This study provides an overview with key details about diverse databases that allow researchers to identify fit-for-purpose RWD sources suitable for pediatric pharmacoepidemiologic research.

Real-world treatment patterns of rheumatoid arthritis in Brazil: analysis of DATASUS national administrative claims data for pharmacoepidemiology studies (2010-2020).

Our study assessed DATASUS as a potential source for pharmacoepidemiologic studies in rheumatoid arthritis (RA) in the Brazilian population focusing on treatment patterns and determinants of initiating or switching to a novel therapy. This was a descriptive database study of RA patients with at least one claim of RA and ≥ 2 claims of disease-modifying anti-rheumatic drug (DMARD); conventional synthetic (cs), biologic (b) or targeted synthetic (ts) DMARD with more than 6 months of follow-up from 01-Jan-2010 to 31-Dec-2020. Analyses were stratified for SUS-exclusive and SUS+ private user cohorts. We identified 250,251 patients with RA in DATASUS: mean age of 58.4 years, majority female (83%) and white (58%). 62% were SUS-exclusive and 38% SUS+ private. Most common bDMARDs were adalimumab and etanercept. Age (adjusted odds ratio 1.78 [50+]; 95% CI 1.57-2.01), SUS exclusive status (0.53; 0.47-0.59), distance to clinic [160+ km] (0.57; 0.45-0.72), and pre-index csDMARD claims (1.23; 1.08-1.41) were independent predictors of initiating a novel oral tsDMARD. Switching from bDMARD to tsDMARD, associations were similar, except for the direction of associations for SUS exclusive status (adjusted hazard ratio 1.10; 1.03-1.18), distance to clinic (1.18; 1.03-1.35), and number of previous bDMARD (0.15; 0.14-0.16). DATASUS is a source suitable for treatment-related analyses in RA reflecting the public health system in Brazil.

Clinical pharmacology facing the real-world setting: Pharmacovigilance, pharmacoepidemiology and the economic evaluation of drugs.

Traditionally, clinical pharmacology has focused its activities on drug-organism interaction, from an individual or collective perspective. Drug efficacy assessment by performing randomized clinical trials and analysis of drug use in clinical practice by carrying out drug utilization studies have also been other areas of interest. From now on, Clinical pharmacology should move from the analysis of the drug-individual interaction to the analysis of the drug-individual-society interaction. It should also analyze the clinical and economic consequences of the use of drugs in the conditions of normal clinical practice, beyond clinical trials. The current exponential technological development that facilitates the analysis of real-life data offers us a golden opportunity to move to all these other areas of interest. This review describes the role that clinical pharmacology has played at the beginning and during the evolution of pharmacovigilance, pharmacoepidemiology and economic drug evaluations in Spain. In addition, the challenges that clinical pharmacology is going to face in the following years in these three areas are going to be outlined too.

Development and evaluation of an algorithm to link mothers and infants in two US commercial healthcare claims databases for pharmacoepidemiology research.

BACKGROUND: Administrative healthcare claims databases are used in drug safety research but are limited for investigating the impacts of prenatal exposures on neonatal and pediatric outcomes without mother-infant pair identification. Further, existing algorithms are not transportable across data sources. We developed a transportable mother-infant linkage algorithm and evaluated it in two, large US commercially insured populations. METHODS: We used two US commercial health insurance claims databases during the years 2000 to 2021. Mother-infant links were constructed where persons of female sex 12-55 years of age with a pregnancy episode ending in live birth were associated with a person who was 0 years of age at database entry, who shared a common insurance plan ID, had overlapping insurance coverage time, and whose date of birth was within ± 60-days of the mother's pregnancy episode live birth date. We compared the characteristics of linked vs. non-linked mothers and infants to assess similarity. RESULTS: The algorithm linked 3,477,960 mothers to 4,160,284 infants in the two databases. Linked mothers and linked infants comprised 73.6% of all mothers and 49.1% of all infants, respectively. 94.9% of linked infants' dates of birth were within ± 30-days of the associated mother's pregnancy episode end dates. Characteristics were largely similar in linked vs. non-linked mothers and infants. Differences included that linked mothers were older, had longer pregnancy episodes, and had greater post-pregnancy observation time than mothers with live births who were not linked. Linked infants had less observation time and greater healthcare utilization than non-linked infants. CONCLUSIONS: We developed a mother-infant linkage algorithm and applied it to two US commercial healthcare claims databases that achieved a high linkage proportion and demonstrated that linked and non-linked mother and infant cohorts were similar. Transparent, reusable algorithms applied to large databases enable large-scale research on exposures during pregnancy and pediatric outcomes with relevance to drug safety. These features suggest studies using this algorithm can produce valid and generalizable evidence to inform clinical, policy, and regulatory decisions.

Acontecimientos adversos en embarazadas con la vacuna tetravalente contra la gripe obtenida de cultivos celulares / Adverse events in pregnant women with the tetravalent influenza vaccine obtained from cell cultures

La vacunación de la gripe en embarazadas muestra una clara relación beneficio/riesgo. En la actualidad se están desarrollando vacunas contra la gripe utilizando nuevas plataformas. Es imprescindible analizar la seguridad de estas nuevas vacunas en este grupo poblacional, infrarrepresentado en los ensayos clínicos. En la temporada 2019-2020 se aconsejó una vacuna obtenida en cultivo celular a las embarazadas en 2comunidades autónomas. Se recogió información de los centros de vacunación y de farmacovigilancia de ambas comunidades. La tasa de notificación de casos de acontecimientos adversos tras la vacunación en embarazadas fue de 4,02/100.000 dosis administradas y, en mujeres de 18 a 64 años no embarazadas, de 5,9/100.000 dosis administradas. La tasa de acontecimientos adversos notificados fue de 8,04 y 17,74, respectivamente. No se notificaron abortos espontáneos, prematuridad ni malformaciones fetales. Este análisis señala la seguridad en embarazadas de la vacuna de la gripe obtenida de cultivos celulares.(AU)

Influenza vaccination in pregnant women shows a clear benefit/risk ratio. Influenza vaccines are currently being developed using new platforms. It is essential to analyze the safety of these new vaccines in this population group, underrepresented in clinical trials. In the 2019-2020 season, a vaccine obtained in cell culture was recommended to pregnant women in 2autonomous communities. Information is collected from the vaccination and pharmacovigilance centers of both communities. The reporting rate of adverse events after vaccination in pregnant women was 4.02/100,000 doses administered, and in non-pregnant women aged 18-64 years it was 5.9/100,000 doses administered. The rate of adverse events reported was 8.04 and 17.74, respectively. No spontaneous abortions, prematurity or fetal malformations were reported. This analysis suggests the safety in pregnant women of the influenza vaccine obtained from cell cultures.(AU)

Improving data capture of race and ethnicity for the Food and Drug Administration Sentinel database: a narrative review.

PURPOSE: The U.S. Food and Drug Administration's Sentinel System is a national medical product safety surveillance system consisting of a large multisite distributed database of administrative claims supplemented by electronic health-care record data. The program seeks to improve data capture of race and ethnicity for pharmacoepidemiology studies. METHODS: We conducted a narrative literature review of published research on data augmentation and imputation methods to improve race and ethnicity capture in U.S. health-care systems databases. We focused on methods with limited (five-digit ZIP codes only) or full patient identifiers available to link to external sources of self-reported data. We organized the literature by themes: (1) variation in data capture of self-reported data, (2) data augmentation from external sources of self-reported data, and (3) imputation methods, including Bayesian analysis and multiple regression. RESULTS: Researchers reduced data missingness with high validity for Asian, Black, White, and Pacific Islander racial groups and Hispanic ethnicity. Native American and multiracial groups were difficult to validate due to relatively small sample sizes. CONCLUSIONS: Limitations on accessible self-reported data for validation will dictate methods to improve race and ethnicity data capture. We recommend methods leveraging multiple sources that account for variations in geography, age, and sex.

Prognostic Factors of COVID-19: An Umbrella Review Endorsed by the International Society for Pharmacoepidemiology.

During the coronavirus disease 2019 (COVID-19) pandemic, the urgency for updated evidence to inform public health and clinical care placed systematic literature reviews (SLRs) at the cornerstone of research. We aimed to summarize evidence on prognostic factors for COVID-19 outcomes through published SLRs and to critically assess quality elements in the findings' interpretation. An umbrella review was conducted via electronic databases from January 2020 to April 2022. All SLRs (and meta-analyses) in English were considered. Data screening and extraction were conducted by two independent reviewers. AMSTAR 2 tool was used to assess SLR quality. The study was registered with PROSPERO (CRD4202232576). Out of 4,564 publications, 171 SLRs were included of which 3 were umbrella reviews. Our primary analysis included 35 SLRs published in 2022, which incorporated studies since the beginning of the pandemic. Consistent findings showed that, for adults, older age, obesity, heart disease, diabetes, and cancer were more strongly predictive of risk of hospitalization, intensive care unit admission, and mortality due to COVID-19. Male sex was associated with higher risk of short-term adverse outcomes, but female sex was associated with higher risk of long COVID. For children, socioeconomic determinants that may unravel COVID-19 disparities were rarely reported. This review highlights key prognostic factors of COVID-19, which can help clinicians and health officers identify high-risk groups for optimal care. Findings can also help optimize confounding adjustment and patient phenotyping in comparative effectiveness research. A living SLR approach may facilitate dissemination of new findings. This paper is endorsed by the International Society for Pharmacoepidemiology.

Análisis de las prescripciones y dispensaciones de psicofármacos en una oficina de farmacia de la provincia de Mendoza, Argentina / Prescriptions and dispensations analysis of psychotropic drugs in a pharmacy office of Mendoza province, Argentina

El Uso Racional de Medicamentos refiere a prácticas adecuadas en cada componente de la cadena de utilización. En este trabajo, nuestro objetivo radicó en determinar el perfil de las prescripciones de psicofármacos recibidas y dispensadas en una oficina de farmacia de la provincia de Mendoza (Argentina), evaluar posibles errores, medir la magnitud del consumo e identificar los psicofármacos de primera elección. Se efectuó un análisis observacional, transversal y retrospectivo de prescripciones dispensadas entre el 1 de enero y el 30 de junio de 2020. Los datos se obtuvieron directamente desde las prescripciones. Los fármacos se codificaron según el sistema de clasificación ATC y los diagnósticos según la Clasificación Internacional de Enfermedades, ambos propuestos por la OMS. La prueba del Chi-cuadrado se utilizó para comparar las variables. Una probabilidad de p<0,05 fue considerada estadísticamente significativa. Se registraron 7.836 prescripciones en 7.041 recetas (media por paciente = 1,11±0,32). Hubo mayor prescripción de psicofármacos a pacientes femeninos (χ2 p<0,001). Las especialidades médicas que más prescribieron los psicofármacos dispensados fueron Clínica, Medicina Familiar y Psiquiatría. Los fármacos psicolépticos fueron los mayormente prescritos, seguido de los antiepilépticos, psicoanalépticos y analgésicos. El 43,76% del total correspondió a benzodiacepinas, principalmente clonazepam, alprazolam y bromazepam. Clonazepam fue el fármaco más prescrito en el período analizado (21,75%), principalmente para diagnósticos de trastornos de ansiedad, hipertensión arterial y depresión. Los registros obtenidos muestran un elevado consumo de ciertos psicofármacos, resultando coincidente con estudios semejantes, hallándose idéntica relación con los fármacos más prescritos, sexo y especialidad del profesional prescriptor. (AU)

The Rational Use of Medicines it refers to adequate practices in each component of the utilization chain. In this work, our objective was to determinate profile of psychotropic drugs prescriptions received and dispensed in a pharmacy office of Mendoza province (Argentina), with evaluation of possible errors, determination of the magnitude consumption and identification of first-choice psychotropic drugs. It was performed an observational, cross-sectional, and retrospective analysis of the prescriptions dispensed between January 1 and June 30, 2020. Data were obtained directly from prescriptions. Drugs were coded according to the ATC classification system and diagnoses according to the International Classification of Diseases, both proposed by the WHO. The Chi-square test was used to compare the variables. A probability of p<0.05 was considered significant statistically. It was registered 7,836 prescriptions in 7,041 prescriptions (mean per patient = 1.11±0.32). There was a greater prescription of psychotropic drugs to female patients (χ2 p<0.001). The clinical medical did result the professional that more prescribed the psychotropic drugs dispensed followed by Family Medicine and Psychiatry specialties. Psycholeptic drugs were the most prescribed, followed by antiepileptic, psychoanaleptic and analgesic drugs. 43.76% of the total corresponded to benzodiazepines, mainly clonazepam, alprazolam and bromazepam. Clonazepam was the most prescribed drug in the analyzed period (21.75%), mainly for diagnosing anxiety disorders, arterial hypertension, and depression. The records obtained show a high consumption of certain psychotropic drugs groups, which coincides with similar studies, finding an identical relationship with the most prescribed drugs, sex, and specialty of the prescribing professional. (AU)

The application of lag times in cancer pharmacoepidemiology: a narrative review.

PURPOSE: With the increasing utilization of medications worldwide, coupled with the increasing availability of long-term data, there is a growing opportunity and need for robust studies evaluating drug-cancer associations. One methodology of importance in such studies is the application of lag times. METHODS: In this narrative review, we discuss the main reasons for using lag times. RESULTS: Namely, we discuss the typically long latency period of cancer concerning both tumor promoter and initiator effects and outline why cancer latency is a key consideration when choosing a lag time. We also discuss how the use of lag times can help reduce protopathic and detection bias. Finally, we present practical advice for implementing lag periods. CONCLUSIONS: In general, we recommend that researchers consider the information that generated the hypothesis as well as clinical and biological knowledge to inform lag period selection. In addition, given that latency periods are usually unknown, we also advocate that researchers examine multiple lag periods in sensitivity analyses as well as duration analyses and flexible modeling approaches.

[Millennials looking for their place in epidemiology.] / I millennials alla ricerca del proprio posto nell'epidemiologia.

The "millennial" epidemiologists, born between the beginning of the 80s and the end of the 90s, are the generation that most of all, today, lives between the present and the future of this discipline. This issue of Recenti Progressi in Medicina aims to talk about what young (and no longer young) epidemiologists and public health researchers are dealing with and to reflect on the most relevant topics in our field, with an eye to the future. Starting from the profile of the "millennial" epidemiologists in Italy and the topics on which they work, the issue develops through three parts dealing with relevant topics for the present and the future of Public health. The first part deals with the important issue of finding a balance between the protection of personal data and the protection of health through a dialogue between researchers, jurists and citizens. The second part aims to clarify the issue of big data and its implications for producing health. The third part touches on four relevant topics for the perspectives of epidemiology through reflections and application examples of machine learning, integration between pharmacoepidemiology and environmental epidemiology, health prevention and promotion involving citizens and other stakeholders, and epidemiology of mental health. In a constantly changing world, challenges for those who work to produce health are not lacking, as is the determination to face them. With this issue, we hope to contribute to the awareness of who we are and our potential, to help millennials (but not only) find their place in epidemiology, today and tomorrow.