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.

HARmonized Protocol Template to Enhance Reproducibility of hypothesis evaluating real-world evidence studies on treatment effects: A good practices report of a joint ISPE/ISPOR task force.

PROBLEM: Ambiguity in communication of key study parameters limits the utility of real-world evidence (RWE) studies in healthcare decision-making. Clear communication about data provenance, design, analysis, and implementation is needed. This would facilitate reproducibility, replication in independent data, and assessment of potential sources of bias. WHAT WE DID: The International Society for Pharmacoepidemiology (ISPE) and ISPOR-The Professional Society for Health Economics and Outcomes Research (ISPOR) convened a joint task force, including representation from key international stakeholders, to create a harmonized protocol template for RWE studies that evaluate a treatment effect and are intended to inform decision-making. The template builds on existing efforts to improve transparency and incorporates recent insights regarding the level of detail needed to enable RWE study reproducibility. The overarching principle was to reach for sufficient clarity regarding data, design, analysis, and implementation to achieve 3 main goals. One, to help investigators thoroughly consider, then document their choices and rationale for key study parameters that define the causal question (e.g., target estimand), two, to facilitate decision-making by enabling reviewers to readily assess potential for biases related to these choices, and three, to facilitate reproducibility. STRATEGIES TO DISSEMINATE AND FACILITATE USE: Recognizing that the impact of this harmonized template relies on uptake, we have outlined a plan to introduce and pilot the template with key international stakeholders over the next 2 years. CONCLUSION: The HARmonized Protocol Template to Enhance Reproducibility (HARPER) helps to create a shared understanding of intended scientific decisions through a common text, tabular and visual structure. The template provides a set of core recommendations for clear and reproducible RWE study protocols and is intended to be used as a backbone throughout the research process from developing a valid study protocol, to registration, through implementation and reporting on those implementation decisions.

The Aetion Coalition to Advance Real-World Evidence through Randomized Controlled Trial Emulation Initiative: Oncology.

Legislative and technological advancements over the past decade have given rise to the proliferation of healthcare data generated from routine clinical practice, often referred to as real-world data (RWD). These data have piqued the interest of healthcare stakeholders due to their potential utility in generating evidence to support clinical and regulatory decision making. In the oncology setting, studies leveraging RWD offer distinct advantages that are complementary to randomized controlled trials (RCTs). They also permit the conduct of investigations that may not be possible through prospective designs due to ethics or feasibility. Despite its promise, the use of RWD for the generation of clinical evidence remains controversial due to concerns of unmeasured confounding and other sources of bias that must be carefully addressed in the study design and analysis. To facilitate a better understanding of when RWD can provide reliable conclusions on drug effectiveness, we seek to conduct 10 RWD-based studies that emulate RCTs in oncology using a systematic, protocol-driven approach described herein. Results of this investigation will help inform clinical, scientific, and regulatory stakeholders on the applications of RWD in the context of product labeling expansion, drug safety, and comparative effectiveness in oncology.

HARmonized Protocol Template to Enhance Reproducibility of Hypothesis Evaluating Real-World Evidence Studies on Treatment Effects: A Good Practices Report of a Joint ISPE/ISPOR Task Force.

OBJECTIVES: Ambiguity in communication of key study parameters limits the utility of real-world evidence (RWE) studies in healthcare decision-making. Clear communication about data provenance, design, analysis, and implementation is needed. This would facilitate reproducibility, replication in independent data, and assessment of potential sources of bias. METHODS: The International Society for Pharmacoepidemiology (ISPE) and ISPOR-The Professional Society for Health Economics and Outcomes Research (ISPOR) convened a joint task force, including representation from key international stakeholders, to create a harmonized protocol template for RWE studies that evaluate a treatment effect and are intended to inform decision-making. The template builds on existing efforts to improve transparency and incorporates recent insights regarding the level of detail needed to enable RWE study reproducibility. The over-arching principle was to reach for sufficient clarity regarding data, design, analysis, and implementation to achieve 3 main goals. One, to help investigators thoroughly consider, then document their choices and rationale for key study parameters that define the causal question (e.g., target estimand), two, to facilitate decision-making by enabling reviewers to readily assess potential for biases related to these choices, and three, to facilitate reproducibility. STRATEGIES TO DISSEMINATE AND FACILITATE USE: Recognizing that the impact of this harmonized template relies on uptake, we have outlined a plan to introduce and pilot the template with key international stakeholders over the next 2 years. CONCLUSION: The HARmonized Protocol Template to Enhance Reproducibility (HARPER) helps to create a shared understanding of intended scientific decisions through a common text, tabular and visual structure. The template provides a set of core recommendations for clear and reproducible RWE study protocols and is intended to be used as a backbone throughout the research process from developing a valid study protocol, to registration, through implementation and reporting on those implementation decisions.

Os 75 Anos da RBC e o Desafio da Ciência Aberta / The 75 Years of RBC and the Challenge of Open Science / Los 75 Años de RBC y el Desafío de la Ciencia Abierta

A Revista Brasileira de Cancerologia (RBC) representa um marco na editoração científica nas áreas do controle do câncer no Brasil. Sua história teve início em 1941, quando o Decreto-Lei n.º 3.643, de 23 de setembro de 19411, instituiu, no então Departamento Nacional de Saúde do Ministério da Educação e Saúde, o Serviço Nacional de Câncer e criou uma revista científica de cancerologia. No entanto, somente em setembro de 1947, foi publicado o seu primeiro número na intenção de divulgar, à comunidade acadêmica, conhecimentos no campo da cancerologia. Nas publicações da época, a RBC apresentava não somente artigos científicos e relatos de casos clínicos, mas também notícias relacionadas ao tema, material de divulgação de congressos e seminários, sessão de "perguntas e respostas", discursos completos do ministro da Saúde em eventos da área de câncer e saúde pública, além de anúncios de auxílios financeiros em pesquisa. Com o tempo, a RBC teve a sua importância e manutenção ainda mais valorizadas, e, em agosto de 1968, foi criado o Corpo Editorial, visando ao direcionamento e à indicação de pautas das futuras publicações. Até então, a revista trabalhava somente com redatores permanentes. Em 1982, buscando mais visibilidade, a revista foi indexada na base de dados denominada Literatura Latino-Americana e do Caribe em Ciências da Saúde (LILACS). Apesar do aperfeiçoamento do seu projeto editorial, e de ter se tornado um grande veículo de comunicação científica na área da cancerologia no país, poucos avanços aconteceram em busca de uma maior internacionalização e indexação em outras bases de dados, até 2017

The Revista Brasileira de Cancerologia (RBC) is a milestone in scientific editing in the area of cancer control in Brazil. Its history started in 1941 after the issue of Decree-Law number 3,643, dated September 23, 19411 , which created the National Cancer Service and a cancerology scientific journal at the former National Department of Health of the Ministry of Education and Health. Nevertheless, only in 1947 the first edition came to light with the purpose of divulging knowledge in cancerology to the scholar community. Of the journals published at that time, RBC issued not only scientific articles and case reports but also theme-related news, press material for congresses and seminaries, Q&A (questions and answers) sections, complete addresses of the Ministry of Health in events on cancer and public health, further to notices about financial funding of researches2 . As time went by, RBC grew in importance and worth and the Editorial Board was created in August 1968 to put together guidelines and agenda of the upcoming editions. Until then, the journal counted only with permanent writers. In 1982, for more visibility, the journal was indexed at the database Latin American and Caribbean in Health Sciences (LILACS). Notwithstanding its editorial betterment and having stepped up to be a great vehicle of scientific communication in cancerology in the country, few advances in attempting a wider internationalization and indexation occurred at other databases until 2017

A systematic review of validated suicide outcome classification in observational studies.

BACKGROUND: Suicidal outcomes, including ideation, attempt, and completed suicide, are an important drug safety issue, though few epidemiological studies address the accuracy of suicidal outcome ascertainment. Our primary objective was to evaluate validated methods for suicidal outcome classification in electronic health care database studies. METHODS: We performed a systematic review of PubMed and EMBASE to identify studies that validated methods for suicidal outcome classification published 1 January 1990 to 15 March 2016. Abstracts and full texts were screened by two reviewers using prespecified criteria. Sensitivity, specificity, and predictive value for suicidal outcomes were extracted by two reviewers. Methods followed PRISMA-P guidelines, PROSPERO Protocol: 2016: CRD42016042794. RESULTS: We identified 2202 citations, of which 34 validated the accuracy of measuring suicidal outcomes using International Classification of Diseases (ICD) codes or algorithms, chart review or vital records. ICD E-codes (E950-9) for suicide attempt had 2-19% sensitivity, and 83-100% positive predictive value (PPV). ICD algorithms that included events with 'uncertain' intent had 4-70% PPV. The three best-performing algorithms had 74-92% PPV, with improved sensitivity compared with E-codes. Read code algorithms had 14-68% sensitivity and 0-56% PPV. Studies estimated 19-80% sensitivity for chart review, and 41-97% sensitivity and 100% PPV for vital records. CONCLUSIONS: Pharmacoepidemiological studies measuring suicidal outcomes often use methodologies with poor sensitivity or predictive value or both, which may result in underestimation of associations between drugs and suicidal behaviour. Studies should validate outcomes or use a previously validated algorithm with high PPV and acceptable sensitivity in an appropriate population and data source.

The Effect of FDA Drug Safety Communications on Patterns of Tiotropium Dispensing: A U.S. Health Plan Claims Database Study.

BACKGROUND: The FDA issued 2 main drug safety communications (DSCs) on the cardiovascular safety of tiotropium in March 2008 (warning of a potential increased stroke risk) and January 2010 (informing of an absence of a significant increased stroke risk or cardiovascular events based on findings from a large trial). OBJECTIVE: To describe the effect of the FDA DSCs on medication dispensing of tiotropium in a large U.S. claims database. METHODS: Initiation of tiotropium products among patients with chronic obstructive pulmonary disease (COPD) aged 40 years and older was determined monthly from 2006-2012 using medication dispensing from the IMS Lifelink Health Plan Claims Database. Similarly, monthly initiation of products containing long-acting beta-agonists (LABAs) was calculated to explore product switching. The effect of the 2008 and 2010 FDA DSCs was measured using interrupted time-series analysis. Subgroups of patients with greater cardiovascular risk were also examined. RESULTS: A decreasing trend in initiation of tiotropium-containing products was present before the initial 2008 DSC. The decline in tiotropium initiation continued until January 2010, accompanied by an increased initiation of LABA-containing products in patients with COPD. In the presence of the existing decreasing trend, the initial DSC was followed by an immediate 2.8% (P = 0.02) further reduction in tiotropium initiation. Tiotropium initiation increased 2.5% (P = 0.03) immediately after the 2010 DSC, reducing the overall decline in rate and stabilizing (flattening) the trend. No significant changes in dispensing level or trend were observed among COPD patients with cardiovascular comorbidity. CONCLUSIONS: Cardiovascular safety concerns may have affected tiotropium initiation as indicated by the decrease in tiotropium dispensing shown immediately following the initial DSC. The effect was alleviated as concerns lessened following the most recent DSC. DISCLOSURES: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. The authors are employed by the FDA and have no conflict of interest relevant to the content of this study. The views expressed herein do not necessarily represent the views of the FDA.

Entacapone and prostate cancer in Parkinson's disease patients: A large Veterans Affairs healthcare system study.

BACKGROUND: An increased incidence of prostate cancer was observed in Parkinson's disease (PD) patients treated with entacapone during a pre-approval randomized clinical trial; the relation has not been robustly investigated in the U.S. ambulatory setting. OBJECTIVE: To investigate whether entacapone is associated with prostate cancer and to assess whether the associations are correlated with advanced disease at the time of cancer diagnosis. METHODS: Using data from the Department of Veterans Affairs healthcare system, new-user cohorts were created of PD patients treated with add-on entacapone or add-on dopamine agonist/monoamine oxidase B inhibitors between January 2000 and December 2014. Patients were followed on-treatment for occurrence of prostate cancer, identified via linkage to the VA cancer registry. RESULTS: Mean follow-up time was 3.1 and 4.0 years in the entacapone and control cohort, respectively. There were 17,666 subjects meeting study criteria (mean age, 74 (SD 8.6) years); the entacapone-treated group comprised 5,257 subjects. Twenty-three prostate cancer cases occurred in the entacapone cohort and ninety-seven in the control cohort. The overall incidence of prostate cancer was 1.8 per 1,000 person-years of risk. There was no difference in risk of prostate cancer between the cohorts for increased duration of entacapone intake (adjusted HR: 1.08; 95% confidence interval: 0.46-2.51 for cumulative exposure of ≥2 years). Time since starting drug therapy and cumulative dose (mg) also do not suggest a difference in prostate cancer risk between cohorts. CONCLUSIONS: Prolonged therapy with entacapone was not associated with increased prostate cancer incidence; however, findings suggest a higher severity of prostate cancer.

Research Directions in Genetic Predispositions to Stevens-Johnson Syndrome / Toxic Epidermal Necrolysis.

Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) is one of the most devastating of adverse drug reactions (ADRs) and was, until recently, essentially unpredictable. With the discovery of several risk alleles for drug-induced SJS/TEN and the demonstration of effectiveness of screening in reducing incidence, the stage is set for implementation of preventive strategies in populations at risk. Yet much remains to be learned about this potentially fatal complication of commonly used drugs.

A Synthesis of Current Surveillance Planning Methods for the Sequential Monitoring of Drug and Vaccine Adverse Effects Using Electronic Health Care Data.

INTRODUCTION: The large-scale assembly of electronic health care data combined with the use of sequential monitoring has made proactive postmarket drug- and vaccine-safety surveillance possible. Although sequential designs have been used extensively in randomized trials, less attention has been given to methods for applying them in observational electronic health care database settings. EXISTING METHODS: We review current sequential-surveillance planning methods from randomized trials, and the Vaccine Safety Datalink (VSD) and Mini-Sentinel Pilot projects-two national observational electronic health care database safety monitoring programs. FUTURE SURVEILLANCE PLANNING: Based on this examination, we suggest three steps for future surveillance planning in health care databases: (1) prespecify the sequential design and analysis plan, using available feasibility data to reduce assumptions and minimize later changes to initial plans; (2) assess existing drug or vaccine uptake, to determine if there is adequate information to proceed with surveillance, before conducting more resource-intensive planning; and (3) statistically evaluate and clearly communicate the sequential design with all those designing and interpreting the safety-surveillance results prior to implementation. Plans should also be flexible enough to accommodate dynamic and often unpredictable changes to the database information made by the health plans for administrative purposes. CONCLUSIONS: This paper is intended to encourage dialogue about establishing a more systematic, scalable, and transparent sequential design-planning process for medical-product safety-surveillance systems utilizing observational electronic health care databases. Creating such a framework could yield improvements over existing practices, such as designs with increased power to assess serious adverse events.

Challenges in evaluating cancer as a clinical outcome in postapproval studies of drug safety.

Pharmaceuticals approved in the United States are largely not known human carcinogens. However, cancer signals associated with pharmaceuticals may be hypothesized or arise after product approval. There are many study designs that can be used to evaluate cancer as an outcome in the postapproval setting. Because prospective systematic collection of cancer outcomes from a large number of individuals may be lengthy, expensive, and challenging, leveraging data from large existing databases are an integral approach. Such studies have the capability to evaluate the clinical experience of a large number of individuals, yet there are unique methodological challenges involved in their use to evaluate cancer outcomes. To discuss methodological challenges and potential solutions, the Food and Drug Administration and the National Cancer Institute convened a two-day public meeting in 2014. This commentary summarizes the most salient issues discussed at the meeting.

Design and analysis choices for safety surveillance evaluations need to be tuned to the specifics of the hypothesized drug-outcome association.

BACKGROUND: We reviewed the results of the Observational Medical Outcomes Research Partnership (OMOP) 2010 Experiment in hopes of finding examples where apparently well-designed drug studies repeatedly produce anomalous findings. OMOP had applied thousands of designs and design parameters to 53 drug-outcome pairs across 10 electronic data resources. Our intent was to use this repository to elucidate some sources of error in observational studies. METHOD: From the 2010 OMOP Experiment, we sought drug-outcome-method combinations (DOMCs) that met consensus design criteria, yet repeatedly produced results contrary to expectation. We set aside DOMCs for which we could not agree on the suitability of the designs, then selected for an in-depth scrutiny one drug-outcome pair analyzed by a seemingly plausible methodological approach, whose results consistently disagreed with the a priori expectation. RESULTS: The OMOP "all-by-all" assessment of possible DOMCs yielded many combinations that would not be chosen by researchers as actual study options. Among those that passed a first level of scrutiny, two of seven drug-outcome pairs for which there were plausible research designs had anomalous results. The use of benzodiazepines was unexpectedly associated with acute renal failure and upper gastrointestinal bleeding. We chose the latter as an example for in-depth study. The factitious appearance of a bleeding risk may have been partly driven by an excess of procedures on the first day of treatment. A risk window definition that excluded the first day largely removed the spurious association. CONCLUSION: One cause of reproducible "error" may be repeated failure to tie design choices closely enough to the research question at hand. Copyright © 2016 John Wiley & Sons, Ltd.

Use of Prescription Drug Samples in the USA: A Descriptive Study with Considerations for Pharmacoepidemiology.

INTRODUCTION: Free prescription drug samples provided in physician offices can lead to exposure misclassification in pharmacoepidemiologic studies that rely on pharmacy claims data. METHODS: We quantified drug-specific sample provision rates based on nationally projected data from a survey of over 3200 US office-based physicians for 1993-2013. RESULTS: Between 2009 and 2013, a total of 44.7 % of newly initiated brand-only sitagliptin but only 3.6 % of generically available metformin therapy was provided as samples. We observed similar discrepancies between newly initiated rosuvastatin and simvastatin, dabigatran and warfarin, atomoxetine and methylphenidate, and between oral antibiotic drugs. During continued therapy, sample use was still present though to a lesser extent (sitagliptin 17.0 %, rosuvastatin 23.9 %), and remained high for some oral contraceptives (norethindrone 55.8 %). Oral contraceptives had the longest average days of sample supply (levonorgestrel, continued use 85.1 days). The average days of supply for all other chronically used study drugs ranged from 13.4 (dabigatran, new use) to 25.3 (exenatide, continued use) per sample provided. From 1993 to 2013, we found pronounced drops in sample provisions over time coinciding with more recent generic approval dates. CONCLUSIONS: We observed markedly differential exposure to medication samples between branded and generic drugs. This can introduce bias in pharmacoepidemiologic studies, especially when adverse events that occur soon after drug initiation are of interest.

Identification of Stevens-Johnson syndrome and toxic epidermal necrolysis in electronic health record databases.

BACKGROUND: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) carry a high mortality risk. While identifying clinical and genetic risk factors for these conditions has been hindered by their rarity, large electronic health databases hold promise for identifying large numbers of cases for study, especially with the introduction in 2008 of ICD-9 codes more specific for these conditions. OBJECTIVE: The objective of this study is to estimate the validity of ICD-9 codes for ascertaining SJS/TEN in 12 collaborating research units in the USA, covering almost 60 million lives. METHODS: From the electronic databases at each site, we ascertained potential cases of SJS/TEN using ICD-9 codes. At five sites, a subset of medical records was abstracted and standardized criteria applied by board-certified dermatologists to adjudicate diagnoses. Multivariate logistic regression was used to identify factors independently associated with validated SJS/TEN cases. RESULTS: A total of 56 591 potential cases of SJS/TEN were identified. A subset of 276 charts was selected for adjudication and 39 (of the 276) were confirmed as SJS/TEN. Patients with the ICD-9 codes introduced after 2008 were more likely to be confirmed as cases (OR 3.32; 95%CI 0.82, 13.47) than those identified in earlier years. Likelihood of case status increased with length of hospitalization. Applying the probability of case status to the 56 591 potential cases, we estimated 475-875 to be valid SJS/TEN cases. CONCLUSION: Newer ICD-9 codes, along with length of hospitalization, identified patients with a high likelihood of SJS/TEN. This is important for identification of subjects for future pharmacogenomics studies.

Evaluating the validity of clinical codes to identify cataract and glaucoma in the UK Clinical Practice Research Datalink.

PURPOSE: The aim of this study is to determine (i) the positive predictive value (PPV) of an algorithm using clinical codes to identify incident glaucoma and cataract events in the Clinical Practice Research Datalink (CPRD) and (ii) the ability to capture the correct timing of these clinical events. METHODS: A total of 21,339 and 5349 potential cataract and glaucoma cases, respectively, were identified in CPRD between 1 January 1990 and 31 December 2010. Questionnaires were sent to the general practitioners (GP) of 1169 (5.5%) cataract and 1163 (21.7%) glaucoma cases for validation. GPs were asked to verify the diagnosis and the timing of the diagnosis and to provide other supporting information. RESULTS: A total of 986 (84.3%) valid cataract questionnaires and 863 (74.2%) glaucoma questionnaires were completed. 92.1% and 92.4% of these used information beyond EMR to verify the diagnosis. Cataract and glaucoma diagnoses were confirmed in the large majority of the cases. The PPV (95% CI) of the cataract and glaucoma Read code algorithm were 92.0% (90.3-93.7%) and 84.1% (81.7-86.6%), respectively. However, timing of diagnosis was incorrect for a substantial proportion of the cases (20.3% and 32.8% of the cataract and glaucoma cases, respectively) among whom 30.4% and 49.2% had discrepancies in diagnosis timing greater than 1 year. CONCLUSIONS: High PPV suggests that the algorithms based on the clinical Read codes are sufficient to identify the cataract and glaucoma cases in CPRD. However, these codes alone may not be able to accurately identify the timing of the diagnosis of these eye disorders. Ltd.