A prediction model-based algorithm for computer-assisted database screening of adverse drug reactions in the Netherlands

PURPOSE: The statistical screening of pharmacovigilance databases containing spontaneously reported adverse drug reactions (ADRs) is mainly based on disproportionality analysis. The aim of this study was to improve the efficiency of full database screening using a prediction model-based approach. METHODS: A logistic regression-based prediction model containing 5 candidate predictors was developed and internally validated using the Summary of Product Characteristics as the gold standard for the outcome. All drug-ADR associations, with the exception of those related to vaccines, with a minimum of 3 reports formed the training data for the model. Performance was based on the area under the receiver operating characteristic curve (AUC). Results were compared with the current method of database screening based on the number of previously analyzed associations. RESULTS: A total of 25 026 unique drug-ADR associations formed the training data for the model. The final model contained all 5 candidate predictors (number of reports, disproportionality, reports from healthcare professionals, reports from marketing authorization holders, Naranjo score). The AUC for the full model was 0.740 (95% CI; 0.734-0.747). The internal validity was good based on the calibration curve and bootstrapping analysis (AUC after bootstrapping = 0.739). Compared with the old method, the AUC increased from 0.649 to 0.740, and the proportion of potential signals increased by approximately 50% (from 12.3% to 19.4%). CONCLUSIONS: A prediction model-based approach can be a useful tool to create priority-based listings for signal detection in databases consisting of spontaneous ADRs. KEY POINTS Current methods for full database screening of ADRs are mainly based on disproportionality, which has its limits due to its sensitivity for several types of selection bias. We developed a prediction model-based approach to generate a priority list of drug-ADR associations to be analyzed. The performance of the model and the comparison with the current method showed that the prediction model-based approach is to be preferred over the current method

Adverse Drug Reactions of Intranasal Corticosteroids in the Netherlands:An Analysis from the Netherlands Pharmacovigilance Center

BACKGROUND: Intranasal corticosteroids are one of the cornerstone treatment options for allergic rhinitis and chronic sinusitis complaints. Safety information in the summary of product characteristics may not be representative for observations in daily clinical practice. The Netherlands Pharmacovigilance Center (Lareb) collects post-marketing safety information, using spontaneous reporting systems. OBJECTIVE: Our objective was to analyse reports of adverse drug reactions associated with intranasal corticosteroids reported in the Dutch spontaneous reporting database of the Netherlands Pharmacovigilance Center Lareb to obtain insight into real-world safety data. METHODS: We retrospectively examined all adverse drug reactions of intranasal corticosteroids reported to the Netherlands Pharmacovigilance Center Lareb, entered into the database from 1991 until 1 July, 2020. RESULTS: In total, 2263 adverse drug reactions after intranasal corticosteroid use were reported in 1258 individuals. Headache (n = 143), epistaxis (n = 124) and anosmia (n = 57) were reported most frequently. Nasal septum perforation (reporting odds ratio 463.2; 95% confidence interval: 186.7-1149.7) had the highest reporting odds ratio, followed by nasal mucosal disorder (reporting odds ratio 104.5; 95% confidence interval 36.3-301.3) and hyposmia (reporting odds ratio 90.8; 95% confidence interval 45.1-182.7). Moreover, 101 (4.5%) reports were classified as serious by Lareb, including reports of Cushing's syndrome, adrenal cortical hypofunction and growth retardation. CONCLUSIONS: Many side effects are consistent with the safety information in the summary of product characteristics of intranasal corticosteroids. Several serious (systemic) side effects are reported and it is important to realise that intranasal corticosteroids may contribute to the development. Healthcare providers and patients should be aware of the potential (individual) adverse drug reactions of intranasal corticosteroids. This information could help in discussing treatment options

Medicine is not science

ABSTRACT: Abstract Most modern knowledge is not science. The physical sciences have successfully validated theories to infer they can be used universally to predict in previously unexperienced circumstances. According to the conventional conception of science such inferences are falsified by a single irregular outcome. And verification is by the scientific method which requires strict regularity of outcome and establishes cause and effect. Medicine, medical research and many “soft” sciences are concerned with individual people in complex heterogeneous populations. These populations cannot be tested to demonstrate strict regularity of outcome in every individual. Neither randomised controlled trials nor observational studies in medicine are science in the conventional conception. Establishing and using medical and other “soft science” theories cannot be scientific. It requires conceptually different means: requiring expert judgement applying all available evidence in the relevant available factual matrix. The practice of medicine is observational. Prediction of outcomes for the individual requires professional expertise applying available medical knowledge and evidence. Expertise in any profession can only be acquired through experience. Prior cases are the fundament of knowledge and expertise in medicine. Case histories, studies and series can provide knowledge of extremely high reliability applicable to establishing reliable general theories and falsifying others. Their collation, study and analysis should be a priority in medicine. Their devaluation as evidence, the failure to apply their lessons, the devaluation of expert professional judgement and the attempt to emulate the scientific method are all historic errors in the theory and practice of modern medicine

Associating adverse drug effects with protein targets by integrating adverse event, in vitro bioactivity, and pharmacokinetic data

Adverse drug effects are unintended and undesirable effects of medicines, causing attrition of molecules in drug development and harm to patients. To anticipate potential adverse effects early, drug candidates are commonly screened for pharmacological activity against a panel of protein targets. However, there is a lack of large-scale, quantitative information on the links between routinely screened proteins and the reporting of adverse events (AEs). This work describes a systematic analysis of associations between AEs observed in humans and bioactivities of drugs while taking into account drug plasma concentrations. In the first chapter, post-marketing drug-AE associations are derived from the United States Food and Drug Administration Adverse Event Reporting System using disproportionality methods, while applying Propensity Score Matching to reduce confounding factors. The resulting drug-AE associations are compared to those from the Side Effect Resource, which are primarily derived from clinical trials. The analysis reveals that the datasets generally share less than 10% of reported AEs for the same drug and have different distributions of AEs across System Organ Classes (SOCs). Using the drugs from the two AE datasets described in the first chapter, the second chapter integrates corresponding bioactivities, i.e. measured potencies and affinities from the ChEMBL database and ligand-based target predictions obtained with the tool PIDGIN, with drug plasma concentrations compiled from literature, such as Cmax. Compared to a constant bioactivity cut-off of 1 uM, using the ratio of the unbound drug plasma concentration over the drug potency, i.e. Cmax/XC50, results in different binary activity calls for protein targets. Whether deriving activity calls in this way results in the selection of targets with greater relevance to human AEs is investigated in the third chapter, which computes relationships between targets and AEs using different measures of statistical association. Using the Cmax/XC50 ratio results in higher Likelihood Ratios and Positive Predictive Values (PPVs) for target-AE associations that were previously reported in the context of secondary pharmacology screening, at the cost of a lower recall, possibly due to the smaller size of the dataset with available plasma concentrations. Furthermore, a large-scale quantitative assessment of bioactivities as indicators of AEs reveals a trade-off between the PPV and how many AE-associated drugs can potentially be detected from in vitro screening, although using combinations of targets can improve the detection rate in ~40% of cases at limited cost to the PPV. The work highlights AEs most strongly related to bioactivities and their SOC distribution. Overall, this thesis contributes to knowledge of the relationships between in vitro bioactivities and empirical evidence of AEs in humans. The results can inform the selection of proteins for secondary pharmacology screening and the development of computational models to predict AEs.Lhasa Limite

Data Mining Techniques in Pharmacovigilance: Analysis of the Publicly Accessible FDA Adverse Event Reporting System (AERS)

Pharmacovigilance is a clinically oriented discipline, which may guide appropriate drug use through a balanced assessment of drug safety. Although much has been done in recent years, efforts are needed to expand the border of pharmacovigilance. We have provided insight into the FDA_Adverse Events Reporting Systems (FDA_AERS), a worldwide publicly available pharmacovigilance archive, to exemplify how to address major methodological issues. We believe that fostering discussion among researchers will increase transparency and facilitate definition of the most reliable approaches. By virtue of its large population coverage and free availability, the FDA_AERS has the potential to pave the way to a new way of looking to signal detection in PhV. Our key messages are: (1) before applying statistical tools (i.e., Data Mining Approaches - DMAs) to pharmacovigilance database for signal detection, all aspects related to data quality should be considered (e.g., drug mapping, missing data and duplicates); (2) at present, the choice of a given DMA mostly relies on local habits, expertise and attitude and there is room for improvement in this area; (3) DMA performance may be highly situation dependent; (4) over-reliance on these methods may have deleterious consequences, especially with the so-called "designated medical events", for which a case-by-case analysis is mandatory and complements disproportionality; and (5) the most appropriate selection of pharmacovigilance tools needs to be tailored to each situation, being mindful of the numerous biases and confounders that may influence performance and incremental utility of DMAs

Safety Assessment of Medications in Elderly: Contribution of the Pharmacovigilance System

As a result of the industrialisation and technological and scientific advances in healthcare, there has been a substantial increase in aging of the population worldwide, and Portugal is no exception. In fact, in Portugal, the average life expectancy is increasing and therefore the number of elderly people. Additionally, the proportion of elderly patients with multiple comorbidities is rising, which in turn leads to an increase in medication use and in the risk of adverse drug reactions (ADRs). In fact, ADRs in elderly can be considered a public health problem, having high costs and being a relevant cause of hospitalization and mortality. Pharmacovigilance is the science concerned with the detection, analysis, evaluation, understanding, and prevention of ADRs. It is a fundamental area for the continuous monitoring of the safety of medicines, particularly relevant in the initial periods of the widespread marketing of new drugs, due to relative scarcity of drug safety information available at the time of marketing authorization, which arises, at this stage, essentially based on pre-marketing clinical trials. Pharmacovigilance allows the identification of problems related to the use of drugs, which are often detected in the post-marketing phase. This is essential to prevent and minimize potential iatrogenic risks to the health of patients. Therefore, monitoring the iatrogenicity of medication that particularly affects elderly patients is fundamental to maximize the safety information of medicines in this special population. Additionally, there is an increasing prevalence of elderly patients with diabetes mellitus and musculoskeletal diseases, whereby is important the knowledge generated from real-world pharmacovigilance data to minimize the risk of harm that may occur with drugs used for the treatment of these conditions. The central aim of this work was to characterize the ADRs profile in elderly patients spontaneously reported to the Portuguese Pharmacovigilance System (PPS). Additionally, this work also intended to characterize the ADRs in elderly diabetic patients and to evaluate the safety of non-steroidal anti-inflammatory drugs (NSAIDs) in this age group. For this propose, firstly, all spontaneous ADRs reported to the PPS from 2013 to 2017 were examined. However, considering the aim of this study, ADRs referring to patients aged 65 and over were analysed in higher detail and compared with those reported in non-elderly adults. Secondly, a retrospective analysis of suspected ADRs reports from PPS between 2008 to 2018 was performed, involving patients aged ≥65 years with diabetes mellitus. Finally, it was carried out a comprehensive literature review of NSAIDs safety in elderly patients and, in parallel, considering the same period of time (i.e., 2008-2018), the suspected ADRs related to these drugs reported to a database of pharmacovigilance, for people aged ≥65, were analysed. Reports were analysed in terms of gender of the involved patients, seriousness and type of ADRs, according to the “System Organ Class” from the Medical Dictionary for Regulatory Activities terminology. In the reports with fatal outcome a deeper analysis in terms of “Preferred Term” for each report was performed. In the general analysis of spontaneous reports in the elderly, the most frequent suspected ADRs fall within the categories of general disorders and administration site conditions, and skin and subcutaneous tissue complaints. Regarding the therapeutic agents involved, the antineoplastic drugs were the most commonly implicated. In addition, the antineoplastic and antithrombotic drugs were the most represented pharmacotherapeutic groups of suspected drugs involved in patient’s death. In the analyses of ADRs in elderly diabetic patients, the most frequent were hypoglycaemia and lactic acidosis, and the drugs specifically indicated for glycaemic control were the most frequently involved. Finally, in the literature review performed on NSAIDs safety in elderly patients, most studies concluded that the risk of a gastrointestinal adverse event with the use of cyclooxygenase-2 (COX-2)-selective NSAIDs seems to be lower when compared with conventional NSAIDs. In addition, celecoxib was considered the safest of all other NSAIDs. However, the risk of gastrointestinal events in patients aged ≥75 years taking selective COX-2 inhibitors was higher when compared with younger patients. Additionally, diclofenac was associated with relevant renal adverse events in patients aged 75 years or older as well as in those with some renal impairment. Regarding cardiovascular events the incidence was lower with coxibs than with conventional NSAIDs and celecoxib led to a lower incidence of these events when compared with etoricoxib. In the analysis performed in PPS data most of suspected ADRs had diclofenac as suspected drug. The suspected ADRs most frequently reported fall within the categories of skin and subcutaneous tissue disorders. Serious gastrointestinal ADRs occurred mostly in patients taking more than one NSAID and/or another concomitant drug that increases the incidence of these events, in the absence of gastroprotection. The majority of serious ADRs related to renal and cardiac disorders occurred in patients with history of renal disorders or diabetes mellitus and hypertension, respectively. All the studies performed with the data belonging to PPS concluded that the majority of ADRs were serious, occurred predominantly in female and were expected. Hence, an accurate identification of ADRs, especially the detection of preventable ADRs, is an important starting point to improve drug safety in elderly. Therefore, studies targeting elderly patients are needed to improve the safety information of these drugs in this special population, considering their multiple medical conditions, thus highlighting the importance of active pharmacovigilance. In this context, it is important to emphasize that pharmacovigilance databases are important tools to evaluate issues related to the safety of drugs in older people, enabling to improve the knowledge on the safety profile of medicines in these patients.Com a industrialização e os avanços tecnológicos e científicos na área da saúde, tem-se assistido a um aumento substancial do envelhecimento da população a nível mundial, e Portugal não é exceção. De facto, em Portugal, a esperança média de vida está a aumentar e, consequentemente, o número de idosos. Além disso, a proporção de doentes idosos com múltiplas comorbilidades está a aumentar, o que, por sua vez, leva a um aumento no uso de medicamentos e a um acréscimo do risco de reações adversas a medicamentos (RAMs). Na verdade, as RAMs em idosos podem ser consideradas um problema de saúde pública, com custos elevados, pois são uma causa relevante de hospitalização e mortalidade. A farmacovigilância é a ciência que se centra na deteção, análise, avaliação, compreensão e prevenção de RAMs. É uma área fundamental para a monitorização contínua da segurança dos medicamentos, especialmente relevante nos períodos iniciais da comercialização alargada de novos fármacos, devido à escassez relativa de informação de segurança disponível no momento da autorização de introdução no mercado, a qual advém, nesta fase, essencialmente dos ensaios clínicos conduzidos durante a fase de pré-comercialização. A farmacovigilância permite a identificação de problemas relacionados com o uso de medicamentos, frequentemente detetados apenas na fase de pós-comercialização. Isso é essencial para prevenir e minimizar os riscos iatrogénicos potenciais para a saúde dos doentes. Portanto, monitorizar a iatrogenicidade dos medicamentos, a qual afeta de uma forma mais marcada os doentes idosos, é fundamental para maximizar a informação de segurança dos mesmos nesta população especial. Além disso, há uma prevalência crescente de doentes idosos com quadros clínicos de multipatologia, incluindo a presença de diabetes mellitus e doenças músculo-esqueléticas, sendo importante o conhecimento gerado a partir dos dados de farmacovigilância obtidos em contexto de vida real para minimizar os riscos decorrentes do uso de medicamentos nestas condições. O objetivo central deste trabalho consistiu na caraterização do perfil de RAMs em doentes idosos, em Portugal, notificadas espontaneamente ao Sistema Nacional de Farmacovigilância (SNF). Adicionalmente, esta tese contemplou também a caracterização das RAMs em doentes idosos diabéticos e a avaliação da segurança dos fármacos anti-inflamatórios não esteroides (AINEs) nesta faixa etária. Para tal, em primeiro lugar, foram avaliadas todas as RAMs comunicadas ao SNF de 2013 a 2017. No entanto, considerando o objetivo deste estudo, as RAMs referentes a doentes com 65 ou mais anos foram analisadas detalhadamente e comparadas com as que foram notificadas em adultos não idosos. Em segundo lugar, foi realizada uma análise retrospetiva das notificações de suspeitas de RAMs submetidas ao SNF entre 2008 e 2018, envolvendo doentes com idade ≥65 anos com diabetes mellitus. Por fim, foi realizada uma revisão compreensiva da literatura sobre a segurança dos AINEs em doentes idosos e, em paralelo, considerando o mesmo período de tempo (i.e., 2008-2018) foram analisadas as suspeitas de RAMs relacionadas com este tipo de medicamentos, manifestadas em indivíduos com 65 ou mais anos e notificadas para o SNF. As notificações foram analisadas relativamente ao género dos doentes envolvidos, gravidade e tipo de RAMs, de acordo com a terminologia “Classe de Sistemas e Órgãos” do dicionário médico para a atividade regulamentar. Nos casos com desfecho fatal, foi realizada uma análise mais aprofundada em termos do “Termo Preferencial” para cada caso. Na análise geral das notificações espontâneas em idosos, as RAMs mais frequentes enquadraram-se nas categorias de distúrbios gerais e perturbações no local de administração e afeções da pele e do tecido subcutâneo. Em relação aos grupos terapêuticos envolvidos, os medicamentos antineoplásicos foram os mais comumente implicados. Além disso, os medicamentos antineoplásicos e antitrombóticos foram os grupos farmacoterapêuticos mais representados entre os medicamentos suspeitos envolvidos na morte de doentes. Mediante análise das RAMs em doentes idosos diabéticos, as mais frequentes foram a hipoglicémia e a acidose láctica, sendo os medicamentos especificamente indicados para o controlo glicémia os mais frequentemente envolvidos. Finalmente, tendo em conta a revisão da literatura realizada referente à segurança de AINEs em doentes idosos, a maioria dos estudos concluiu que o risco de um evento adverso gastrointestinal é inferior com o uso de AINEs seletivos para a isoenzima cicloxigenase-2 (COX-2) do que com o uso de AINEs convencionais. Mais especificamente, entre os AINEs, o celecoxib foi considerado o fármaco mais seguro. No entanto, o risco de eventos gastrointestinais em doentes com idade ≥75 anos a tomar AINEs seletivos para COX-2 foi maior que o observado em doentes mais jovens. Além disso, o diclofenac foi associado a eventos adversos renais relevantes em doentes com 75 ou mais anos, bem como naqueles com algum grau de insuficiência renal. Em relação aos eventos adversos cardiovasculares, a sua incidência foi menor com os coxibes do que com os AINEs convencionais, e o celecoxib levou a uma incidência menor desses eventos quando comparado ao etoricoxib. Em resultado da análise realizada aos dados do SNF, foi possível constatar que a maioria das suspeitas de RAMs envolveu o diclofenac. As suspeitas de RAMs mais frequentemente relatadas enquadraram-se nas categorias de afeções da pele e do tecido subcutâneo. As RAMs gastrointestinais graves ocorreram principalmente em doentes a tomar mais que um AINE e/ou outro medicamento concomitante, o que aumenta a incidência desses eventos, na ausência de gastroproteção. A maioria das RAMs graves relacionadas com distúrbios renais ou distúrbios cardíacos ocorreram em doentes com história clínica de distúrbios renais ou diabetes mellitus e de hipertensão arterial, respetivamente. Todos os estudos realizados com os dados do SNF que suportam esta tese concluíram que a maioria das RAMs eram graves, ocorreram predominantemente em mulheres e eram expetáveis. A identificação exata de RAMs, especialmente a deteção de RAMs evitáveis, é um ponto de partida importante para melhorar a segurança dos medicamentos em idosos. Portanto, estudos direcionados para a população geriátrica são necessários para melhorar a informação de segurança desses medicamentos nesta população especial, considerando as suas múltiplas condições médicas, destacando-se assim a importância da farmacovigilância ativa. Nesse contexto, é importante enfatizar que as bases de dados de farmacovigilância são ferramentas importantes para avaliar questões relacionadas com a segurança dos medicamentos em idosos, possibilitando aprimorar o conhecimento sobre o perfil de segurança de medicamentos nestes doentes

Challenges and opportunities for mining adverse drug reactions: perspectives from pharma, regulatory agencies, healthcare providers and consumers

Monitoring drug safety is a central concern throughout the drug life cycle. Information about toxicity and adverse events is generated at every stage of this life cycle, and stakeholders have a strong interest in applying text mining and artificial intelligence (AI) methods to manage the ever-increasing volume of this information. Recognizing the importance of these applications and the role of challenge evaluations to drive progress in text mining, the organizers of BioCreative VII (Critical Assessment of Information Extraction in Biology) convened a panel of experts to explore ‘Challenges in Mining Drug Adverse Reactions’. This article is an outgrowth of the panel; each panelist has highlighted specific text mining application(s), based on their research and their experiences in organizing text mining challenge evaluations. While these highlighted applications only sample the complexity of this problem space, they reveal both opportunities and challenges for text mining to aid in the complex process of drug discovery, testing, marketing and post-market surveillance. Stakeholders are eager to embrace natural language processing and AI tools to help in this process, provided that these tools can be demonstrated to add value to stakeholder workflows. This creates an opportunity for the BioCreative community to work in partnership with regulatory agencies, pharma and the text mining community to identify next steps for future challenge evaluations.M.K.: This work was supported in part through the collaboration between the Spanish Plan for the Advancement of Language Technology (Plan TL) and the Barcelona Supercomputing Center; we also acknowledge the 2020 Proyectos de I+D+i - RTI Tipo A (PID2020-119266RA-I00) for support. Ö.U.: This study was supported in part by the National Library of Medicine under Award Number R15LM013209 and R13LM013127.Peer ReviewedPostprint (published version