Safety driven regulatory actions from 2010 to 2015: a comparative study between EU and US

Tese de mestrado, Regulação e Avaliação do Medicamento e Produtos de Saúde, Universidade de Lisboa, Faculdade de Farmácia, 2018O incompleto perfil de segurança dos novos medicamentos e o insuficiente conhecimento da relação benefício-risco no momento uma autorização de introdução no mercado (AIM) é concedida são premisas estabelecidas em farmacovigilânica. Na verdade, elas mesmas justificam a contínua monitorização do perfil de segurança dos medicamentos com AIM aprovada e identificação de riscos associados à sua utilização – actividades essenciais à manutenção da própria AIM. Ora, a deteção e avaliação de reacções adversas aos medicamentos, seguida do estabelecimento de medidas de prevenção e minimização de risco, não só fazem parte da missão da farmacovigilância, como também integram os objectivos e responsabilidades das agências reguladoras e da indústria farmacêutica. Algumas publicações científicas procuraram, ao longo dos anos, versar sobre estas mesmas medidas de prevenção e minimização de risco, mediante o estudo do conjunto de acções regulamentares face a questões de segurança. Na sua maioria, a análise foi efectuada em contextos singulares, como o caso de produtos biológicos, medicamentos órfãos, medicamentos com AIM concedida em circunstâncias excecionais, ou considerando as acções regulamentares no contexto de um determinado país ou pequeno grupo de países, como é o caso de exemplos publicados no Reino Unido, Espanha, Estados Unidos da América e Holanda. Os resultados obtidos sugerem que tais acções regulamentares foram desencadeadas pelas autoridades reguladoras em cerca de 9 a 25% dos medicamentos com AIM aprovada em análise. Dois outros estudos denotam que, entre 1975 e 1999, pelo menos uma acção regulamentar foi tomada em função de problemas de segurança para 10% dos medicamentos com AIM aprovada nos Estados Unidos da América. Mais recentemente, um conjunto de productos biológicos foi associado a uma probabilidade de 14% de necessitar de uma primeira acção regulamentar derivada de questões de segurança nos primeiros 3 anos após a aprovação da AIM. Sendo que, para a mesma classe de medicamentos, os produtos biológicos com a primeira aprovação de AIM possuiam um risco acrescido de requerer tais acções de segurança. No entanto, e apesar das várias agências reguladoras dos medicamentos e productos de saúde possuírem, objectivos e responsabilidades semelhantes no que tangue à necessidade de garantir a qualidade, eficácia e segurança dos medicamentos nos mercados em que actuam, nem sempre partilham da mesma interpretação e tomada de decisão face a um determinado conjunto de informações de segurança e eficácia para um mesmo medicamento. As diferenças nos enquadramentos regulamentares, nas estruturas organizacionais e no modo de funcionamento das agências dos Estados Unidos da América (FDA) e da União Europeia (EMA) encontram-se descritas em detalhe na literatura publicada, tendo sido extensamente analizadas e comparadas. Ao longo das últimas decadas, estas desemelhanças têm conduzindo a avaliações e recommendações divergentes. No âmbito da aprovação de medicamentos e produtos de saúde, a literatura analisada denota que, entre 1995 e 2008, 20% dos medicamentos oncológicos em estudo possuiam uma AIM aprovada pela FDA ou pela EMA, mas não por ambas. De igual modo, o conteúdo do resumo das caracteristicas possuía importantes diferenças em 28% do conjunto de medicamentos com AIM aprovada nos dois territórios. Finalmente, existem vários exemplos de decisões distintas no que se refere a acções regulamentares derivadas de questões de segurança num contexto pós-AIM, alguns dos quais particulamente mediáticos, como é o caso da rosiglitazona. Por outro lado, importantes desenvolvimentos regulamentares tiveram lugar no contexto da farmacovigilância, quer no território dos Estados Unidos da América, em 2007, quer na União Europeia, em 2012. Estas alterações legislativas pretendiam, entre outros objectivos, dotar as referidas agências de mais recursos e de um maior poder de decisão, implementando, ao mesmo tempo, um conjunto mais rigoroso de requerimentos e obrigações para a indústria farmacêutica/para os detentores de AIM. Perante este cenário de alterações legislativas e na ausência de uma recente análise das acções regulamentares derivadas de questões de segurança para um conjunto mais abrangente de medicamentos, este estudo foi proposto. A elaboração desta tese possui como objectivo o estudo, análise e discussão das acções regulamentares derivadas de questões de segurança entre 2010 e 2015, nos Estados Unidos da América e na União Europeia. Paralelamente, propõe-se a considerar a frequência, o timing após a AIM ter sido concedida e a natureza destas mesmas acções regulamentares, bem como a analisar quais as áreas/classes terapêuticas com maior número de acções regulamentares derivadas de questões de segurança. As actividades regulamentares da EMA e da FDA, bem como as decisões em estudo, serão comparadas e analisadas, visando reflectir-se sobre a aparente reduzida harmonização na avaliação de medicamentos e produtos de saúde entre estas duas autoridades. Por fim, de modo a ilustrar as diferenças descritas, é apresentado um caso de estudo de um medicamento associado a uma recente discussão de segurança, e do conjunto de acções regulamentares tomadas em ambos os territórios. Um estudo/descrição abrangente da história, estrutura organizacional, processos e missão das autoridades reguladoras em questão foi efectuado. As diferenças substânciais entre a FDA e a EMA no que se refere às atividades de farmacovigilância e acções regulamentares em função de questões de segurança foram igualmente analisadas. Simultaneamente, procurou-se estabelecer pontos de convergência no que respeita às responsabilidades e objectivos propostos, e ilustrar as múltiplas iniciativas de importante colaboração entre as agências destas duas regiões. Para a análise das acções regulamentares foram consideradas (i) as comunicações dirigidas aos profissionais de saúde (Direct Heathcare Professional Communication - DHPC) publicadas em Portugal, no Reino Unido e as Dear Health Care Professional (DHCP) Letter nos Estados Unidos da América e (ii) as revogações de AIM em medicamentos comercializados na União Europeia em associação aos medicamentos retirados do mercado nos Estados Unidos da América por questões de segurança. Os resultados obtidos indicam um maior recurso às comunicações dirigidas aos profissionais de saúde nos países da União Europeia que nos Estados Unidos da América, no período entre 2010 e 2015. A disseminação dos riscos de segurança associados aos produtos comercializados nos Estados Unidos da América decorre, de acordo com dos dados disponíveis, através de outras ferramentas de informação comunicação de risco, actualmente disponíveis para a FDA. Dentro da globalidade dos dados analisadas, as pequenas moléculas apresentaram quer um maior número de comunicações de segurança, quer uma maior frequência de revogação/suspensão de AIM por razões de segurança. Por outro lado, os eventos adversos relacionados com os distúrbios cardíacos surgem como um dos principais impulsionadores das acções de segurança para as pequenas moléculas. Os dados obtidos demonstram ainda uma necessidade crescente de enfoque no que concerne a questões de segurança devido a erros de medicação. Resultados estes suportados pelas conclusões presentes na literatura actualmente publicada. De igual modo, as notificações espontâneas de reacções adversas a medicamentos continuam a representar a maior fonte de informação de segurança desencadeadora de de comunicações dirigidas aos profissionais de saúde como acção regulamentar em todos os países analisados. Todavia, verifica-se uma crescente utilização de dados de ensaios clínicos e estudos epidemiológicos tanto na identificação, como na avaliação de problemas de segurança, o que sugere um real incremento da importância dos mesmos no universo da farmacovigilância. Finalmente, no que diz respeito ao timing das acções regulamentares, 66,6% das revogações de AIM por questões de segurança tiveram lugar até 5 anos após a aprovação da AIM, enquanto que 50,4% das comunicações dirigidas aos profissionais de saúde foram emitidas até 6 anos após a aprovação da AIM. O caso de estudo escolhido versou sobre as recentes discussões de segurança relativamente ao ácido valpróico (e derivados) e sua utilização em crianças, mulheres de idade fértil e grávidas, nomeadamente face aos riscos de malformações congénitas, alterações estruturais graves e importantes efeitos neurológicos adversos nestas subpopulações. O contexto da utlização destes medicamentos foi descrito e as recomendações/acções regulamentares da FDA e EMA, bem como de algumas autoridades nacionais de estados membros da União Europeia, apresentadas. Os diferentes mecanismos e estruturas nos processos de farmacovigilância implementados e os instrumentos/medidas de minimização de risco disponíveis para cada uma das entidades reguladoras parecem justificar as diferentes recomendações e decisões observadas. Por outro lado, observam-se importantes dissemelhanças na estrutura e no conteúdo do resumo das características do medicaments/folheto informativo nestas duas regiões. Pela observação dos aspectos em estudo conclui-se que a análise e contextualização do quadro legislativo e do conjunto de processos e procedimentos actualmente disponíveis para a FDA e para a EMA é fundamentar no entendimento das decisões regulamentares e nas recomendações face a questões de segurança de medicamentos. A familiardidade com estes conceitos poderá promover uma maior sensibilização e entendimento, não só dos profissionais de saúde, mas também dos doentes e da população em geral, quer no que tange às avalições de medicamentos aquando do pedido de AIM, quer no que se refere às análise de dados de eficácia, qualidade ou segurança, que suportam a gestão de sinais, as alterações no conteúdo do resumo das característica do medicamento/folheto informativo, a implementação de medidas adicionais de minimização de risco e as decisões de revogação/suspensão de uma AIM. Verificou-se ainda que a natureza dinâmica dos processos regulamentares no âmbito da farmacovigilância permanece bastante atual, pelo que a necessidade de colaboração permanente entre os múltiplos intervenientes é fundamental na redução da duplicação de esforços e no suporte dos processos de avaliação, concessão e manutenção das AIM, em benefício dos reguladores, indústria farmacêutica e particularmente dos doentes.The natural history of approved drugs comprehends the discovery of new and important safety information in the post-marketing setting. In fact, studies show that for 9 to 25% of the drugs analysed, national or regional regulatory authorities required a safety-related regulatory action after their approval. Over the years, these publications have analysed safety-related regulatory actions, mostly on specific settings, such as for particular drug groups (e.g. biologicals, orphan medicines and exceptional circumstances/ conditional (accelerated) approval procedures) or individual countries. On the other hand, although current FDA and EMA guidance are driven by similar objectives regarding the identification, monitoring and minimization of risks, commonly leading to generation of similar data needs, there are cases where the two regulatory agencies have recommended distinct regulatory actions in response to the same safety issues identified. Substantial differences have also been identified with regards to risk communication and in monitoring implementation of risk minimization measures. Therefore, this study proposes to discuss and characterize the regulatory framework of pharmacovigilance activities within the European Union region and the United States of America, and analyse and compare the safety-driven regulatory actions for medicinal products, both small molecules and biologics, between the years of 2010 and 2015, following updates in applicable regulations in 2007 (for the US) and in 2012 (for the EU). The frequency, timing and nature of such regulatory actions evaluated, as well as the most impacted therapeutic groups. The direct communications to healthcare providers disseminated in Portugal, United Kingdom and US and the requests of withdrawal of medicinal products in the EU and the US territories were considered when analysing safety-related regulatory actions. Such recommendations provided by the EMA and the FDA were used to discuss the apparent lack of consistency in the assessment of medicinal products by these regulatory bodies. Finally, a case-study of a drug whose safety profile has been recently under evaluation in both territories is presented, and the recommendations/safety-related regulatory actions taken described. The results suggest that direct communications to healthcare providers are more frequently distributed in the EU than the US, with the majority of the safety risks associated to marketed products in the US territory having been announced to HCP and the general public by other risk communication tools currently available to the FDA. Both safety driven direct communications to healthcare providers and withdrawals were more frequent for small molecule medicinal products. Additionally, the data retrieved supports previous findings on differences having been shown to exist in the nature of the safetyrelated regulatory actions for biologicals compared with small molecules. Cardiac disorders related AE appear as a leading trigger for safety-driven regulatory actions for small molecules. Evidence also suggests more efforts still need to be allocated for tackling medication error-related adverse events. Spontaneous reports continue to account for the majority of the source data for triggering safety driven direct communications to healthcare providers in all regions, but relevant findings originating from clinical trials and epidemiological studies were observed, supporting the increasing importance of these sources in identifying and evaluating safety issues. With regards to timing of regulatory action, 66.6% of the safety-related withdrawals were issued within 5 years after approval, while 50.4% of the safety driven direct communications to healthcare providers were issued within 6 years after approval. The use of valproic acid in children, women of childbearing potential and during pregnancy given the associated risks of congenital malformations, major structural abnormalities and serious neurodevelopmental effects was chosen as case study. The distinct set of regulatory actions taken might be justified by the structurally different pharmacovigilance implemented mechanisms and instruments available to regulators in each territory but also given the inconsistencies in both structure and content of the labelling information between EU and US territories and to some extent within in EU territories. Given the study performed, it is possible to conclude that the analysis and contextualization of the on legislative framework and processes of the FDA and the EMA is essential to understand the agencies regulatory decisions and recommendations. Dissemination of these may help improve overall awareness and allow for a better insight and understanding on matters of divergent drug approvals and post-marketing safety recommendations, either it being signal management activities, label updates, additional risk minimization measures and withdrawals/suspensions. The dynamic nature of regulatory processes for pharmaceuticals risk management is still present on today’s exciting pharmacovigilance landscape and future regulatory standardization and increased collaboration is necessary to further help in reducing redundancy and support the review/assessment processes for the benefit of regulators, pharmaceutical industries and the patients

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

Translating Clinical Findings into Knowledge in Drug Safety Evaluation - Drug Induced Liver Injury Prediction System (DILIps)

Drug-induced liver injury (DILI) is a significant concern in drug development due to the poor concordance between preclinical and clinical findings of liver toxicity. We hypothesized that the DILI types (hepatotoxic side effects) seen in the clinic can be translated into the development of predictive in silico models for use in the drug discovery phase. We identified 13 hepatotoxic side effects with high accuracy for classifying marketed drugs for their DILI potential. We then developed in silico predictive models for each of these 13 side effects, which were further combined to construct a DILI prediction system (DILIps). The DILIps yielded 60–70% prediction accuracy for three independent validation sets. To enhance the confidence for identification of drugs that cause severe DILI in humans, the “Rule of Three” was developed in DILIps by using a consensus strategy based on 13 models. This gave high positive predictive value (91%) when applied to an external dataset containing 206 drugs from three independent literature datasets. Using the DILIps, we screened all the drugs in DrugBank and investigated their DILI potential in terms of protein targets and therapeutic categories through network modeling. We demonstrated that two therapeutic categories, anti-infectives for systemic use and musculoskeletal system drugs, were enriched for DILI, which is consistent with current knowledge. We also identified protein targets and pathways that are related to drugs that cause DILI by using pathway analysis and co-occurrence text mining. While marketed drugs were the focus of this study, the DILIps has a potential as an evaluation tool to screen and prioritize new drug candidates or chemicals, such as environmental chemicals, to avoid those that might cause liver toxicity. We expect that the methodology can be also applied to other drug safety endpoints, such as renal or cardiovascular toxicity

Digital Pharmacovigilance: the medwatcher system for monitoring adverse events through automated processing of internet social media and crowdsourcing

Thesis (Ph.D.)--Boston UniversityHalf of Americans take a prescription drug, medical devices are in broad use, and population coverage for many vaccines is over 90%. Nearly all medical products carry risk of adverse events (AEs), sometimes severe. However, pre- approval trials use small populations and exclude participants by specific criteria, making them insufficient to determine the risks of a product as used in the population. Existing post-marketing reporting systems are critical, but suffer from underreporting. Meanwhile, recent years have seen an explosion in adoption of Internet services and smartphones. MedWatcher is a new system that harnesses emerging technologies for pharmacovigilance in the general population. MedWatcher consists of two components, a text-processing module, MedWatcher Social, and a crowdsourcing module, MedWatcher Personal. With the natural language processing component, we acquire public data from the Internet, apply classification algorithms, and extract AE signals. With the crowdsourcing application, we provide software allowing consumers to submit AE reports directly. Our MedWatcher Social algorithm for identifying symptoms performs with 77% precision and 88% recall on a sample of Twitter posts. Our machine learning algorithm for identifying AE-related posts performs with 68% precision and 89% recall on a labeled Twitter corpus. For zolpidem tartrate, certolizumab pegol, and dimethyl fumarate, we compared AE profiles from Twitter with reports from the FDA spontaneous reporting system. We find some concordance (Spearman's rho= 0.85, 0.77, 0.82, respectively, for symptoms at MedDRA System Organ Class level). Where the sources differ, milder effects are overrepresented in Twitter. We also compared post-marketing profiles with trial results and found little concordance. MedWatcher Personal saw substantial user adoption, receiving 550 AE reports in a one-year period, including over 400 for one device, Essure. We categorized 400 Essure reports by symptom, compared them to 129 reports from the FDA spontaneous reporting system, and found high concordance (rho = 0.65) using MedDRA Preferred Term granularity. We also compared Essure Twitter posts with MedWatcher and FDA reports, and found rho= 0.25 and 0.31 respectively. MedWatcher represents a novel pharmacoepidemiology surveillance informatics system; our analysis is the first to compare AEs across social media, direct reporting, FDA spontaneous reports, and pre-approval trials

Pharmacoepidemiologic Exploration of Increased Eating Drives Associated with Antidiabetic Medications

학위논문(박사) -- 서울대학교대학원 : 의과대학 임상의과학과, 2021.8. 최형진.임상 개발 과정에서 대부분의 안전성 탐지, 분석 노력은 동물 독성 연구에서 얻은 중요한 결과 또는 1 차 및 2 차 약력학적 효과에 기반한 가설을 사람에서 유심히 관찰하는 것에 집중되어 있다. 약물이 시장에 출시된 후 약물 역학적 연구는 주로 사망률, 심각한 이환율 또는 객관적으로 정량화 할 수 있는 결과들 (예: 검사 수치, 영상 바이오마커)의 분석에 결과에 집중되어 있다. 현존하는 약물 안전의 제도는 임상 현장에서 혹은 실생활에서 환자의 주관적인 약물 경험을 조사하는 데 큰 관심을 보이지 않았다. 이 논문은 기존 약물 감시 데이터베이스 중 미국 FDA의 약물 부작용 보고 시스템 (FAERS)의 빅데이터가 환자의 주관적 약물 경험을 탐색할 수 있는지를 보고자 했다. 환자의 주관적 경험 중 배고픔, 식욕, 음식에 대한 갈망 등 식이 행동의 동기와 연관된 지각들이 약물 부작용으로 경험되고 보고되는지를 탐색했다. 탐색에는 미국 FDA의 시판 후 약물 부작용 데이터베이스에 보고된 당뇨약과 연관된 식사 동기를 증가시키는 부작용이 사용되었다. 미국의 약물 처방 자료를 참고하여 미국에서 많이 쓰이는 6개의 약물군에 속한 15개의 당뇨약과 식욕 증가와 관련된 부작용 용어가 조합된 보고를 추출했다. 부작용 용어로 배고픔 (hunger), 음식에 대한 갈망 (food craving), 식욕 증가 (increased appetite)가 사용되었다. 이 부작용 들은 개별적 신호 탐색에도 쓰였고 세 부작용 용어의 보고 빈도의 합으로도 탐색 되었다. 미 FDA 데이터베이스에서 1968년부터 2020년 12월 30일까지 전체 데이터에서 약물-부작용 조합을 추출하였다. 부작용 신호 탐색에 흔히 쓰는 기법 중 reporting odds ratio (ROR)을 사용하였다. 이는 다른 모든 약과 비교해서 특정 약물의 특정 부작용 보고 비율의 비교의 균형을 보는 불균형 계산 (disproportionality) 방법 중 하나로 이 값의 95% 신뢰 구간의 하부경계값이 1을 넘으면 부작용 신호로 해석했다. 모든 계열의 당뇨약이 식사 동기 증가 부작용과 2.00 [1.74, 2.31]에서 12.38 [11.81, 12.98] 범위의 ROR [95 % CI] 값의 유의한 연관을 보였다. 개별 당뇨약의 식사 동기 증가 부작용의 ROR [95 % CI]은 다음과 같았다: 메트포르민은 2.00 [1.74, 2.31], 리나글립틴은 2.29 [1.46, 3.59], 삭 사글립틴 1.85 [0.96, 3.55], 시타글립틴 3.20 [2.64, 3.89], 둘라글루타이드 4.69 [4.06, 5.42], 엑세나타이드 16.22 [15.31, 17.18], 리라글루타이드 12.55 [11.42, 13.78], 세마글루타이드 9.63 [7.50, 12.37], 카나글리플로진 2.98 [2.39, 3.73], 다파글리플로진 6.93 [5.17, 9.29], 엠파글리플로진 2.49 [1.84, 3.37], 글리메피리드 3.07 [2.12, 4.45], 글리피지드 5.03 [3.90, 6.48], 글리부라이드 3.31 [2.39, 4.57], 피오글리타존 3.06 [2.42, 3.87]. FAERS에는 상당한 수의 주관적인 환자 경험 ADR이 포함되었다. 20,000 개가 넘는 부작용 용어 중 세 개의 식사 동기 증가 용어가 전체 부작용 보고 사례의 0.1 %를 차지했다. 약물 주관적 경험은 의료인보다 소비자가 더 자주 보고하는 것으로 보인다. 식사 동기 증가 부작용의 보고자 중 69.33 %는 소비자, 23.94 %는 의료인이었다. 모든 계열의 당뇨약에서 의료인 (9.89-35.48 %)보다 소비자 (33.82-89.70 %)가 더 많은 보고를 하였고, 남성 (25.64-34.36 %)보다 여성 (57.26-72.45 %)에서 더 많은 식사 동기 증가가 보고되었다. FAERS는 환자의 주관적 경험에 대한 초기 신호 탐색 및 가설 생성을 위한 유용한 도구로 보여진다. 심각한 부작용이 더 선택적으로 보고되는 것으로 보여지나 환자의 주관적 불편함도 충분한 사례가 보고되어 있다. 환자의 주관적인 약물 경험은 의료인보다는 환자가 보고하는 경우가 많았는데 이것이 환자와 의사가 생각하는 치료의 목표와 그 과정에서 중요하게 생각하는 점의 불일치에서 기인하는지를 이해하는 것은 치료의 관계 및 약물 순응도에 중요할 것으로 보여진다. 약물감시체계가 이런 주관적인 환자 경험을 탐색할 수 있는 유용한 도구가 되기 위해서는 약물과 부작용 관리 시스템에 대한 환자의 지식과 이해를 필요로 한다. 미국 FDA 데이터베이스는 의미 있는 정보원이 될 수 있을 것으로 보인다.During clinical development, much of the safety detection and analysis effort is centered on assessing the human equivalent of significant findings from animal toxicology studies. Moreover, toxicities hypothesized from primary and secondary pharmacologic effects profiling are also used for safety analysis. After a drug launches in the market, postmarketing safety surveillance systems focus mainly on hard outcomes of mortality, serious morbidity, or objectively quantifiable outcomes (e.g., laboratory data, imaging biomarkers). Institutions using these pillars of drug safety have not had much interest in examining “soft signs” or subjective patient drug experiences. This study explores whether an existing pharmacovigilance database, namely the U.S. Food and Drug Administration’s Adverse Events Reporting System (FAERS), can be used to examine soft signals of subjective patient experiences, especially those related to motivational aspects of eating. Antidiabetic drugs were used to examine whether subjective patient drug experiences of increased eating drives could be detected using the FAERS. Referencing U.S. prescription data, 15 non-insulin, single agent antidiabetic drugs (ADDs) most frequently prescribed in the United States from 6 ADD classes were used. Event terms used to extract adverse drug reactions (ADRs) of increased eating drives were hunger, food craving, and increased appetite. An aggregate search was also performed combining the 3 event terms. Drug-event pairs were extracted for periods of FAERS existence from 1968 to December 31, 2020. The reporting odds ratio (ROR) was used for a disproportionality calculation in which a ROR with a lower margin of the 95% CI >1 was defined as a positive ADR signal. All ADD classes yielded positive safety signals of increased eating drives: ROR [95% CI] calculations ranging from 2.00 [1.74, 2.31] to 12.38 [11.81, 12.98]. For the individual ADDs, the RORs [95% CI] for increased eating drives were: 2.00 [1.74, 2.31] for metformin, 2.29 [1.46, 3.59] for linagliptin, 1.85 [0.96, 3.55] for saxagliptin, 3.20 [2.64, 3.89] for sitagliptin, 4.69 [4.06, 5.42] for dulaglutide, 16.22 [15.31, 17.18] for exenatide, 12.55 [11.42, 13.78] for liraglutide, 9.63 [7.50, 12.37] for semaglutide, 2.98 [2.39, 3.73] for canagliflozin, 6.93 [5.17, 9.29] for dapagliflozin, 2.49 [1.84, 3.37] for empagliflozin, 3.07 [2.12, 4.45] for glimepiride, 5.03 [3.90, 6.48] for glipizide, 3.31 [2.39, 4.57] for glyburide, and 3.06 [2.42, 3.87] for pioglitazone. The FAERS contained substantial numbers of subjective patient experience ADRs. Out of over 20,000 event terms, the three event terms for increased eating drives totaled 0.1% of all case reports in the FAERS. Soft signals seem to be more frequently reported by consumers than by healthcare providers. 69.33% of the reports of increased eating drives for all drugs were from consumers and 23.94% from healthcare providers. For all ADD classes, more reports of increased eating drives were received from consumers (33.82-89.70%) than healthcare providers (9.89-35.48%) and from women (57.26-72.45%) than men (25.64-34.36%). Patients may offer information about previously unknown ADRs that physicians cannot observe or quantify. Educated consumers can be valuable partner in the post-marketing surveillance of drug safety. Patient distressful drug experiences can affect treatment adherence and therapeutic. FAERS and other patient reporting systems might be useful tools in detecting adverse patient drug experiences.1. INTRODUCTION 1 1.1. Pharmacovigilance systems 1 1.1.1. Rationale for legislation: protection of public health 1 1.1.2. Definitions 2 1.1.3. Sources of report 2 1.1.4. Valid report 3 1.1.5. Coding of AEs: MedDRA 4 1.1.6. Causality 9 1.1.7. Non-clinical safety 11 1.1.8. Clinical trial safety data 12 1.1.9. Continuous characterization of safety in the post-market authorization 15 1.2. Spontaneous reporting systems 17 1.2.1. Limitations of spontaneous reports 18 1.2.2. Strengths of SRS 21 1.2.3. Databases 22 1.3. Signal detection 24 1.3.1. Disproportionality Analyses 26 1.4. Relatively benign soft ADRs 30 1.4.1. ABCDE Classification 30 1.4.2. Where do subjective patient experience ADRs fit in the ABCDE scheme? 31 1.4.3. Patient drug experience and adherence 31 1.4.4. Examples of soft signals detected from SRS 34 1.5. Increased eating drive as an ADR 35 1.5.1. Hunger, appetite, craving—wanting, liking, needing 36 1.6. Diabetes, antidiabetic drugs and the drive to eat 40 1.6.1. Glucostatic theory 41 1.6.2. Food addiction and diabetes 42 1.6.3. Biologically driven to eat more 45 1.7. Research question: antidiabetic drug—increased eating drives explored with FAERS data 45 2. METHODS 47 2.1. Source of spontaneous report database 47 2.1.1. FAERS 47 2.1.2. Characteristics of individual case safety reports in FAERS 47 2.2. Reaction terms examined 55 2.2.1. ADD-increased eating drives 55 2.3. Drug names 59 2.3.1. ADD-increased eating drives 59 2.4. Disproportionality analyses 62 2.5. Ethical statements 62 3. RESULTS 63 3.1. All cases for all drugs in the FAERS 63 3.2. ICSR characteristics of ADD classes 64 3.3. Disproportionality analyses 67 4. DISCUSSION 80 4.1. Summary of key findings 80 4.1.1. Appearance of a reporting bias of serious and lethal cases in FAERS 80 4.1.2. Numerous spontaneous ADR reports of increased eating drives were in FAERS 81 4.1.3. Three-fold more reports of increased eating drives are received from consumers (especially women) than healthcare professionals 81 4.1.4. Increased eating drives was a positive ADR signal for all ADD classes; strongest signal was observed with GLP1RAs 82 4.1.5. Increased drive to eat, behavioral output, and associated physical exam were not trending together in the FAERS 83 4.2. Interpretations 83 4.2.1. Bias toward reporting ADRs with serious outcomes 83 4.2.2. Patients, especially women, were more likely to report increased eating drives than physicians 84 4.2.3. What was unexpected—associations of GLP1RA and increased eating drives 86 4.2.4. Discordance in signal directions of eating drives, eating behavior, and weight increase 98 4.3. Limitations 104 4.3.1. Cannot assess comparative risk based on strength of the signal 104 4.3.2. The magnitude of the problem cannot be estimated 105 4.3.3. Association is not causation 107 4.4. Implications 108 4.4.1. FAERS can be used to detect signals of subjective patient experience ADRs 108 4.4.2. Consumer reports may be more sensitive to detect soft signals of subjective patient experiences 108 4.4.3. Informed consumers may be key to successful PV activities for signals that matter to patients 110 4.4.4. Increased eating drives associated with ADDs requires further evaluation 113 4.5. Recommendations for signal evaluation of increased eating drives associated with ADDs 114 4.5.1. For characterization 114 4.5.2. Susceptibility factors 114 5. CONCLUSION 115 REFERENCES 116 국문 초록 137박

J Biomed Inform

Targeted anticancer drugs such as imatinib, trastuzumab and erlotinib dramatically improved treatment outcomes in cancer patients, however, these innovative agents are often associated with unexpected side effects. The pathophysiological mechanisms underlying these side effects are not well understood. The availability of a comprehensive knowledge base of side effects associated with targeted anticancer drugs has the potential to illuminate complex pathways underlying toxicities induced by these innovative drugs. While side effect association knowledge for targeted drugs exists in multiple heterogeneous data sources, published full-text oncological articles represent an important source of pivotal, investigational, and even failed trials in a variety of patient populations. In this study, we present an automatic process to extract targeted anticancer drug-associated side effects (drug-SE pairs) from a large number of high profile full-text oncological articles. We downloaded 13,855 full-text articles from the Journal of Oncology (JCO) published between 1983 and 2013. We developed text classification, relationship extraction, signaling filtering, and signal prioritization algorithms to extract drug-SE pairs from downloaded articles. We extracted a total of 26,264 drug-SE pairs with an average precision of 0.405, a recall of 0.899, and an F1 score of 0.465. We show that side effect knowledge from JCO articles is largely complementary to that from the US Food and Drug Administration (FDA) drug labels. Through integrative correlation analysis, we show that targeted drug-associated side effects positively correlate with their gene targets and disease indications. In conclusion, this unique database that we built from a large number of high-profile oncological articles could facilitate the development of computational models to understand toxic effects associated with targeted anticancer drugs.DP2 HD084068/HD/NICHD NIH HHS/United StatesDP2HD084068/DP/NCCDPHP CDC HHS/United StatesR25 CA094186/CA/NCI NIH HHS/United StatesR25CA094186-06/CA/NCI NIH HHS/United StatesUL1 RR024989/RR/NCRR NIH HHS/United StatesUL1 TR000439/TR/NCATS NIH HHS/United States2016-06-01T00:00:00Z25817969PMC458266

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

Pharmacovigilance of pregnancy exposures to medicinal products focusing on the risk of orofacial clefts

Background: It is important to obtain robust scientific information on possible safety concerns related to the use of drugs during pregnancy in post-approval settings. Since pregnant women are actively excluded from trials in the clinical development of most products, at the time of the drug entry in the market meaningful human data on the effects of that drug during pregnancy are rarely available. There are approximately 5 million pregnancies in the EU each year, and about 1 in every 10 women of childbearing age is pregnant each year. Insufficient information for management of maternal disease during pregnancy can have teratogenic impact on fetus. Aim and objectives: This reach comprises three studies, in the first study; the goal was to evaluate the maternal use of medicines and the associated risks of cleft lip and/or palate in fetus and to link this to the accuracy and currency of safety information available in prescribing information. The second area of research was aimed at identifying and exploring social and digital media to understand patients’ experiences regarding medicine use during pregnancy. Last, but not least, I contributed to the development of an enhanced pharmacovigilance programme for analysing drug exposure during pregnancy and outcomes in neonate. Method: Firstly, I identified medication-induced risk factors for oral clefts with safety signal detection and safety signal evaluation techniques. Then I assessed the completeness of the safety information for pregnancy exposures in the Summary of Product Characteristics and the Patient Information in the UK and the US. In second study, the content of posts concerning pregnancy and use of medicines in online pregnancy forums was analysed using artificial intelligence in the form of natural language processing and machine learning algorithms. Third, the PRIM (PRegnancy outcomes Intensive Monitoring) system was developed as an enhanced pharmacovigilance data collection method. This was used to improve the quality and content of prospective case reports using sets of targeted checklists, structured follow-up, a rigorous process of data entry and data quality control, and programmed aggregate analysis. Results: For 12 antiepileptic drugs studied there was a statistical disproportionality in individual case safety reports indicative of an increased risk of cleft lip and/or palate. There are inconsistencies between the UK and US safety labels, despite the same evidence being available for assessment. The second study showed that in social media forums many pregnant women with MS shared profound uncertainties and specific concerns about taking medicines during the reproductive period. There was evidence of concealment of information with health care professionals; however, the same evidence was shared with a peer group. The PRIM method of enhanced pharmacovigilance has yielded substantially more information on the safety of fingolimod exposure during pregnancy than has been achieved via the regulatory authority-mandated pregnancy registry. Conclusion: Use of medicines during pregnancy is an important topic for public health. There is a significant need to provide inclusive, unbiased, up to- date information to prescribers and women of childbearing age concerning the use of medicines in pregnancy and postpartum during breastfeeding. Information must be provided in a timely manner by a trusted source and patients should have access to health care professionals with the relevant expertise and knowledge. It is important that the full anonymised data set, along with evidence-based conclusions are made publicly available to inform decision-making