Analysis of reported adverse liver reactions associated with drugs used to treat patients with coronavirus disease 2019

Abstract Hepatic injury has been documented in patients with coronavirus disease 2019 (COVID-19). However, pharmacotherapy can frequently impact liver alterations, given the known hepatotoxic potential of drugs not effective to treat COVID-19. The objective of the present study was to evaluate reports of suspected liver reactions to drugs used for treating COVID-19, compare their use for other indications among patients with COVID-19, and assess possible interactions between them. We obtained reports on drugs used to treat COVID-19 (tocilizumab, remdesivir, hydroxychloroquine, and/or lopinavir/ritonavir), registered on June 30, 2020, from the Food and Drug Administration Adverse Event Reporting System (FAERS) Public Dashboard. We then analyzed the risk of developing liver events with these drugs by calculating the reported odds ratios (ROR). We identified 662, 744, and 1381 reports related to tocilizumab, lopinavir/ ritonavir, and hydroxychloroquine use, respectively. The RORs (95% confidence intervals) were 6.32 (5.28-7.56), 6.12 (5.22-7.17), and 9.07 (8.00-10.29), respectively, demonstrating an increased risk of liver events among patients with COVID-19 when compared with uninfected patients. The elevated risk of reporting adverse liver events in patients with COVID-19 who receive these drugs, alone or in combination, highlights the need for careful drug selection and efforts to reduce drug combinations without notable benefits. Similar to any other condition, the use of drugs without established efficacy should be avoided.

Recommendations for the development of Clinical Practice Guidelines / Recomendações para o desenvolvimento de Diretrizes de Prática Clínica

Clinical practice guidelines are statements that include recommendations intended to optimize patient care, are informed by a systematic review of evidence and an assessment of the benefits and harms of alternative care options, and ensure that the best available clinical knowledge is used to provide effective and quality care. They can reduce inappropriate care and variability in clinical practice and can support the translation of new research knowledge into clinical practice. Recommendations from clinical practice guidelines can support health professionals by facilitating the decision-making process, empowering them to make more informed health care choices, clarifying which interventions should be priorities based on a favorable tradeoff, and discouraging the use of those that have proven ineffective, dangerous, or wasteful. This review aims to summarize the key components of high-quality and trustworthy guidelines. Articles were retrieved from various libraries, databases, and search engines using free-text term searches adapted for different databases, and selected according to author discretion. Clinical practice guidelines in geriatrics can have a major impact on prevention, diagnosis, treatment, rehabilitation, health care, and the management of diseases and conditions, but they should only be implemented when they have high-quality, rigorous, and unbiased methodologies that consider older adult priorities and provide valid recommendations.

As diretrizes de prática clínica são declarações que incluem recomendações destinadas a otimizar o atendimento ao paciente, informadas por uma revisão sistemática de evidências e uma avaliação dos benefícios e malefícios de opções alternativas de atendimento, garantindo que o melhor conhecimento clínico disponível seja usado para fornecer atendimento eficaz e de qualidade. Elas contribuem reduzindo os cuidados inadequados e a variabilidade na prática clínica e podem apoiar a tradução de novos conhecimentos de pesquisa. As recomendações dessas diretrizes podem apoiar os profissionais de saúde, facilitando o processo de tomada de decisão, capacitando-os a fazer escolhas de cuidados de saúde mais informadas, esclarecendo quais intervenções devem ser prioritárias com base em um trade-off favorável e desencorajando o uso daquelas comprovadamente ineficazes, perigosas ou que consistam em desperdício. Esta revisão visa resumir os principais componentes de diretrizes confiáveis e de alta qualidade. Os artigos foram recuperados de várias bibliotecas, bancos de dados e mecanismos de busca por meio de buscas de termos de texto livre adaptados para diferentes bancos de dados e selecionados de acordo com o critério do autor. As diretrizes de prática clínica em geriatria podem ter grande impacto na prevenção, diagnóstico, tratamento, reabilitação, assistência à saúde e manejo de doenças e condições, mas só devem ser implementadas quando tiverem metodologias de alta qualidade, rigorosas e imparciais, que considerem as prioridades da pessoa idosa e forneçam recomendações válidas.

Potential kidney damage associated with the use of remdesivir for COVID-19: analysis of a pharmacovigilance database.

The U.S. Food and Drug Administration (FDA) has stated that the prescription of remdesivir should be cautious for patients with estimated glomerular filtration rate (eGFR) < 30 and some studies reported risk of adverse renal events. The available information on the renal safety profile for remdesivir is limited, thus we analyzed the renal and urinary adverse reactions attributed to remdesivir reported in a large open pharmacovigilance database. We obtained reports of remdesivir and other drugs used to treat COVID-19 (tocilizumab, hydroxychloroquine, lopinavir/ritonavir) registered by September 30 2020, from the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS). We analyzed the reporting odds ratios (RORs) for reports of adverse renal and urinary events for remdesivir and other drugs. We found 2,922 reports with remdesivir registered in FAERS for COVID-19. Among these, 493 renal and urinary adverse effects (16.9%) were reported. The most frequent events were acute kidney injury (338; 11.6%), renal impairment (86; 2.9%), and renal failure (53; 1.8%). Versus hydroxychloroquine, lopinavir/ritonavir, or tocilizumab, the use of remdesivir was associated with an increased chance of reporting renal and urinary disorders regardless of gender and age of patients (2.53; 95%CI: 2.10-3.06). The ROR remained significant when we restricted the analysis to hydroxychloroquine (4.31; 95%CI: 3.25-5.71) or tocilizumab (3.92; 95%CI: 2.51-6.12). Our results reinforce this already reported signal, emphasizing that it could be extremely useful for health professionals who prescribe this new antiviral to treat COVID-19, mainly knowing its low efficacy.

Pharmacogenetic testing in psychiatry and neurology: an overview of reviews.

Pharmacogenetic testing is available to healthcare professionals to guide drug selection and prevent adverse events. However, its implementation in the clinical practice of psychiatry/neurology still has barriers, mainly due to a lack of evidence. We conducted a literature search on Cochrane Library, Embase and Pubmed, from their inception to 18 June 2020. We included 16 published systematic reviews. The most studied drug categories were anticonvulsants and selective serotonin reuptake inhibitors associated with human leukocyte antigen and cytochrome P450 genes (HLA-A, HLA-B, CYP2C9, CYP2D6, CYP2C19), classified as critically low quality/low quality. There is a need for more robust studies with adequate design to assess the potential benefits of adopting pharmacogenetics in health systems and services.

Evaluation of the initial response in clinical trial efforts for COVID-19 in Brazil. / Avaliação da resposta inicial de desenvolvimento de ensaios clínicos para COVID-19 no Brasil.

OBJECTIVE: To describe the methodological characteristics and good research practices of COVID-19 interventional studies developed in Brazil in the first months of the pandemic. METHODS: We reviewed the bulletin of the National Research Ethics Committee - Coronavirus Special Edition (Comissão Nacional de Ética em Pesquisa - CONEP-COVID) (May 28, 2020) and the databases of the International Clinical Trials Registry Platform (ICTRP), ClinicalTrials.gov, and Brazilian Clinical Trials Registry (Registro Brasileiro de Ensaios Clínicos - ReBEC) to identify interventional studies registered in Brazil that assessed drug type, biological therapy, or vaccines. We described their methodological characteristics and calculated their power for different effect magnitudes. RESULTS: A total of 62 studies were included, 55 retrieved from the CONEP website, and 7 from registry databases. The most tested pharmacological interventions in these studies were: chloroquine/hydroxychloroquine, azithromycin, convalescent plasma, tocilizumab, sarilumab, eculizumab, vaccine, corticosteroids, anticoagulants, n-acetylcysteine, nitazoxanide, ivermectin, and lopinavir/ritonavir. Out of 22 protocols published on registry databases until May 2020, 18 (82%) were randomized clinical trials, and 13 (59%) had an appropriate control group. However, 9 (41%) of them were masked, and only 5 (24%) included patients diagnosed with a specific laboratory test (for example, reverse transcription polymerase chain reaction - RT-PCR). Most of these studies had power > 80% only to identify large effect sizes. In the prospective follow-up, 60% of the studies available at CONEP until May 2020 had not been published on any registry platform (ICTRP/ReBEC/ClinicalTrials) by July 21, 2020. CONCLUSION: The interventions evaluated during the Brazilian research response reflect those of international initiatives, but with a different distribution and a large number of studies assessing hydroxychloroquine/chloroquine. Limitations in methodological design and sample planning represent challenges that could affect the research outreach.

OBJETIVO: Descrever as características metodológicas e de boas práticas em pesquisa dos estudos de intervenção para COVID-19 desenvolvidos no Brasil nos primeiros meses da pandemia. MÉTODOS: Revisamos o boletim da Comissão Nacional de Ética em Pesquisa - edição especial Coronavírus (CONEP-COVID) (28 de maio de 2020) e as bases International Clinical Trials Registry Platform (ICTRP), ClinicalTrials.gov e Registro Brasileiro de Ensaios Clínicos (ReBEC) para identificar estudos registrados no Brasil que avaliassem intervenções de tipo de medicamento, terapia biológica ou vacinas. Descrevemos as características metodológicas e calculamos o poder para diferentes magnitudes de efeito. RESULTADOS: Foram incluídos 62 estudos, 55 identificados no site da CONEP e mais sete nas bases de registro. As intervenções medicamentosas mais frequentemente testadas nesses estudos foram: cloroquina/hidroxicloroquina, azitromicina, plasma convalescente, tocilizumabe, sarilumabe, eculizumabe, vacina, corticoides, anticoagulantes, n-acetilcisteína, nitazoxanida, ivermectina e lopinavir/ritonavir. De 22 protocolos publicados até maio de 2020 nas bases de registro, 18 (82%) eram ensaios clínicos randomizados e 13 (59%) tinham grupo controle adequado. Entretanto, nove (41%) eram mascarados e somente cinco (24%) incluíam pacientes diagnosticados com teste de laboratório específico (por exemplo, transcrição reversa seguida de reação em cadeia da polimerase - RT-PCR). A maioria desses trabalhos teria poder > 80% apenas para identificar grandes tamanhos de efeito. Em seguimento prospectivo, observamos que 60% dos estudos disponíveis na CONEP até maio de 2020 não estavam em nenhuma das plataformas de registro (ICTRP/ReBEC/ClinicalTrials) até o dia 21 de julho de 2020. CONCLUSÃO: As intervenções avaliadas durante a resposta brasileira em pesquisa refletem iniciativas internacionais, porém com distribuição diferente, tendo número elevado de estudos que avaliam hidroxicloroquina/cloroquina. Limitações no delineamento metodológico e planejamento amostral representam desafios que podem afetar o alcance dos trabalhos.

Potential kidney damage associated with the use of remdesivir for COVID-19: analysis of a pharmacovigilance database / Potencial nefropatia associada ao uso do remdesivir para COVID-19: análise de uma base de dados de farmacovigilância / Potenciales lesiones renales asociadas con el uso de remdesivir para la COVID-19: análisis de una base de datos de farmacovigilancia

Abstract: The U.S. Food and Drug Administration (FDA) has stated that the prescription of remdesivir should be cautious for patients with estimated glomerular filtration rate (eGFR) < 30 and some studies reported risk of adverse renal events. The available information on the renal safety profile for remdesivir is limited, thus we analyzed the renal and urinary adverse reactions attributed to remdesivir reported in a large open pharmacovigilance database. We obtained reports of remdesivir and other drugs used to treat COVID-19 (tocilizumab, hydroxychloroquine, lopinavir/ritonavir) registered by September 30 2020, from the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS). We analyzed the reporting odds ratios (RORs) for reports of adverse renal and urinary events for remdesivir and other drugs. We found 2,922 reports with remdesivir registered in FAERS for COVID-19. Among these, 493 renal and urinary adverse effects (16.9%) were reported. The most frequent events were acute kidney injury (338; 11.6%), renal impairment (86; 2.9%), and renal failure (53; 1.8%). Versus hydroxychloroquine, lopinavir/ritonavir, or tocilizumab, the use of remdesivir was associated with an increased chance of reporting renal and urinary disorders regardless of gender and age of patients (2.53; 95%CI: 2.10-3.06). The ROR remained significant when we restricted the analysis to hydroxychloroquine (4.31; 95%CI: 3.25-5.71) or tocilizumab (3.92; 95%CI: 2.51-6.12). Our results reinforce this already reported signal, emphasizing that it could be extremely useful for health professionals who prescribe this new antiviral to treat COVID-19, mainly knowing its low efficacy.

Resumo: De acordo com a Agência de Controle de Alimentos e Medicamentos dos Estados Unidos (FDA), a prescrição do remdesivir deve ser feita com cautela em pacientes com taxa de filtração glomerular estimada (TFGe) < 30, sendo que diversos estudos relatam risco de eventos adversos renais. São limitados os dados disponíveis sobre o perfil de segurança renal do remdesivir. Assim, analisamos as reações adversas renais e urinárias atribuídas ao remdesivir e notificadas em um grande base de dados abertos de farmacovigilância. Obtivemos notificações sobre remdesivir e outros medicamentos usados para tratar a COVID-19 (tocilizumabe, hidroxicloroquina, lopinavir/ritonavir) registradas até 30 de setembro de 2020 do Sistema de Notificação de Eventos Adversos da FDA (FAERS). Analisamos as razões de chances de notificação (RORs) para notificações de eventos adversos renais e urinários referentes ao remdesivir e outros medicamentos. Encontramos 2.922 notificações sobre remdesivir registradas no FAERS para COVID-19. Entre esses casos, foram notificados 493 efeitos adversos renais e urinários (16,9%). Os eventos mais frequentes foram lesão renal aguda (338; 11,6%), comprometimento renal (86; 2,9%) e insuficiência renal (53; 1,8%). Comparado com a hidroxicloroquina, lopinavir/ritonavir ou tocilizumabe, o uso do remdesivir esteve associado com um aumento das chances de notificação de transtornos renais e urinários, independentemente do sexo e idade dos pacientes (2,53; IC95%: 2,10-3,06). A ROR permaneceu significativo quando limitamos a análise à hidroxicloroquina (4,31; IC95%: 3,25-5,71) ou ao tocilizumabe (3,92; IC95%: 2,51-6,12). Nossos resultados corroboram outros estudos e destacam a utilidade para profissionais da saúde que usam esse novo antiviral para tratar a COVID-19, sobretudo em função de sua baixa eficácia.

Resumen: La Agencia Americana de Control de Alimentos y Medicamentos (FDA) ha destacado que la prescripción de remdesivir debe ser prudente con pacientes con tasa de filtración glomerular estimada (TGFe) < 30; además, algunos estudios informaron del riesgo de reacciones adversas renales. La información disponible sobre el perfil de seguridad renal, en el caso del remdesivir, es limitada. Por ello, analizamos las reacciones adversas renales y urinarias atribuidas al remdesivir e notificadas en una extensa base de datos abierta de farmacovigilancia. Obtuvimos las notificaciones de remdesivir y otros medicamentos usados para tratar la COVID-19 (tocilizumab, hidroxicloroquina, lopinavir/ritonavir) registrados el 30 de septiembre de 2020 por el Sistema de Notificación de Eventos Adversos de la FDA (FAERS). Analizamos las odds ratios informadas (RORs) en el caso de informes de eventos adversos renales y urinarios adversos relacionados con el remdesivir y otros medicamentos. En el FAERS, encontramos 2.922 notificaciones de remdesivir registradas como medicament sospechoso usado en COVID-19. De estos, habían 493 con efectos renales y urinarios adversos (16,9%). Los efectos adversos más frecuentes fueron lesiones renales agudas (338; 11,6%), insuficiencia renal (86; 2,9%), y fallo renal (53; 1,8%). Frente a hidroxicloroquina, lopinavir/ritonavir, o tocilizumab, el uso de remdesivir se asoció con un riesgo mayor de notificar alteraciones renales y urinarios, independientemente del género y edad de los pacientes (2,53; IC95%: 2,10-3,06). La ROR permaneció significativo al restringir el análisis a la hidroxicloroquina (4,31; IC95%: 3,25-5,71) o tocilizumab (3,92; IC95%: 2,51-6,12). Nuestros resultados corroboran datos previos, algo que podría ser extremadamente útil para los profesionales de la salud que decidan usar este nuevo antiviral para tratar la COVID-19, sobre todo conociendo su baja eficacia.

Critical appraisal and comparison of recommendations of clinical practice guidelines for treatment of schizophrenia in children and adolescents: a methodological survey protocol.

INTRODUCTION: The number of clinical practice guidelines (CPGs) have increased substantially mainly in the paediatric area of mental health. However, little is known about the quality or how recommendations for the treatment of disorders such as schizophrenia in children and adolescents have changed over time. The aim of this study will be to assess the quality of the development of CPGs for the treatment and management of schizophrenia in children and adolescents over time using the Appraisal of Guidelines for Research and Evaluation II (AGREE II) tool and to compare the recommendations and interventions described in these documents. METHODS AND ANALYSIS: CPGs will be identified using a prospective protocol through a systematic search of multiple databases (Medline, Embase, Health Systems Evidence, Epistemonikos, Lilacs, etc) and guideline websites from 2004 to December 2020. The quality of the guidelines will be assessed by three reviewers, independently using the AGREE II. CPGs will be considered of high-quality if they scored ≥60% in four or more domains of the AGREE II instrument. Non-parametric tests will be used to test for the change of quality over time. We will summarise the different evidence grading systems and compare the recommendations. ETHICS AND DISSEMINATION: Ethical approval is not required since it is a literature-based study. Future results of the research can be submitted for publication in scientific journals of high impact, peer reviewed and also published in national and international conferences. The results derived from this study will contribute to the improvement of health institutions and policies, informing about existing recommendation guidelines and about deficiencies and qualities found in those. This study may also identify key areas for future research. This study may guide the search and choice for high quality CPGs by health policy makers and health professionals and subsidise future adaptations. PROTOCOL REGISTRATION NUMBER: CRD42020164899.

Even High-Quality CPGs Seldom Include Implementation Strategies.

Background: Implementation is a key step in ensuring that high-quality clinical practice guideline (CPG) recommendations are followed and have a positive impact. This step must be planned during CPG development. This study aims to inform professionals tasked with developing and implementing CPGs regarding implementation strategies and tools reported in high-quality CPGs for chronic non-communicable diseases (NCDs). Methods: NCD guidelines were selected based on Appraisal of Guideline Research and Evaluation (AGREE) II assessment. CPGs with a score of ≥60% in AGREE II domains 3 (rigor of development), 5 (applicability), and 6 (editorial independence), were considered high quality. The content related to implementation was extracted from CPG full texts and complementary materials. Implementation strategies and tools were assessed and classified using Mazza taxonomy. Results: Twenty high-quality CPGs were selected, most of which were developed by government institutions (16; 80%) with public funding (16; 80%); almost half (9; 45%) addressed the treatment of cardiovascular diseases. The countries with the most high-quality CPGs were the UK (6; 30%) and Colombia (5; 25%). These countries also had the highest average number of strategies, Colombia with 28 (SD = 1) distributed in all levels, and the UK with 15 (SD = 7), concentrating on professional and organizational levels. Although the content of the Colombian CPGs was similar regardless the disease, the CPGs from the UK were specific and contained data-based feedback reports and information on CPG compliance. Implementation strategies most frequently identified were at the professional level, such as distributing reference material (18; 80%) and educating groups of healthcare professionals (18; 80%). At the organizational level, the most frequent strategies involve changes in structure (15; 75%) and service delivery method (13; 65%). Conclusion: Countries with established CPG programs, such as the UK and Colombia, where identified as having the highest number of high-quality CPGs, although CPG implementation content had significant differences. Among high-quality CPGs, the most common implementation strategies were at the professional and organizational levels. There is still room for improvement regarding the implementation strategies report, even among high-quality CPGs, especially concerning monitoring of implementation outcomes and selection of strategies based on relevant implementation barriers.

Conhecimento inadequado sobre medicamentos prescritos e seus preditores em pacientes muito idosos e seus cuidadores / Inadequate knowledge of prescription drugs and their predictors in very old patients and their caregivers

Resumo Objetivo Identificar preditores do conhecimento inadequado sobre medicamentos prescritos a pacientes ambulatoriais muito idosos e seus cuidadores. Método O conhecimento sobre os medicamentos prescritos para 80 pacientes com 80 anos ou mais de idade foi avaliado por meio de um questionário validado, em uma entrevista realizada com os pacientes ou seus cuidadores (quando os pacientes apresentavam dificuldades de comunicação, demência ou qualquer necessidade de assistência para ajudá-los a usar medicamentos). Dois modelos de regressão logística hierárquica avaliaram a associação entre conhecimento inadequado sobre medicamentos e variáveis ​​sociodemográficas e medicamentosas. Resultados Trinta e nove (48,8%) entrevistados eram cuidadores. Conhecimento inadequado foi encontrado em 81,5% (404/496) dos medicamentos prescritos. Forma de administração, Dose, Frequência e Duração do Tratamento foram os aspectos de maior conhecimento, enquanto Reações Adversas, Precauções, Interações e Contraindicações, os de menor. No primeiro modelo, o conhecimento inadequado foi associado à escolaridade do ensino fundamental completo ao médio incompleto (Razão de Chances (RC):0,12; p=0,018), do médio ao superior incompleto (RC:0,12; p<0,001), superior completo (RC:0,13; p<0,001), agentes que atuam no sistema renina-angiotensina (SRA) (RC:0,30; p=0,001), diuréticos (RC:0,31; p=0,013) e antitrombóticos (RC:12,59; p=0,027). No segundo modelo, os preditores foram cuidadores (RC:0,17; p<0,001), agentes que atuam no SRA (RC:0,33; p=0,002), diuréticos (RC:0,35; p=0,024) e antitrombóticos (RC:12,57; p=0,026). Conclusão A maioria dos medicamentos prescritos para pessoas muito idosas é pouco conhecida. Além disso, o aconselhamento acerca de informações sobre medicamentos deve ser mais intensivo para os pacientes do que para seus cuidadores, com foco em informações de segurança e ser direcionado a antitrombóticos.

Abstract Objective Identify predictors of inadequate knowledge about the medication prescribed to very old outpatients and their caregivers. Method The knowledge on the medication prescribed for 80 patients aged 80 years and over was assessed using a validated questionnaire to interview patients or their caregivers (when patients had communication difficulties, dementia, or any need for care to help them take the medication). Two hierarchical logistic regression models assessed the association between inadequate knowledge of the medication and sociodemographic and drug variables. Results Thirty-nine (48.8%) respondents were caregivers. Inadequate knowledge was found in 81.5% (404/496) of medication prescribed. Route of Administration, Dose, Frequency, and Duration of Treatment were the aspects of greatest knowledge, whereas Adverse Effects, Precautions, Interactions, and Contraindications were the least known ones. In the first model, inadequate knowledge was associated to the level of education from complete elementary school to incomplete high school (Odds Ratio (OR): 0.12; p=0.018), from high school to incomplete higher education (OR: 0.12; p<0.001), complete higher education (OR: 0.13; p<0.001), agents acting on the renin-angiotensin system (RAS) (OR: 0.30; p=0.001), diuretics (OR: 0.31; p=0.013) and antithrombotic (OR: 12.59; p=0.027). In the second model, the predictors were caregivers (OR: 0.17; p<0.001), agents working in the RAS (OR: 0.33; p=0.002), diuretics (OR: 0.35; p=0.024) and antithrombotic (OR: 12.57; p=0.026). Conclusion Most of the medication prescribed for very old people is not very well known. Also, advice on drug information should be more intensive to patients than to their caregivers, with a focus on safety information and targeted at antithrombotics.

Registro de medicamentos com indicação agnóstica já é realidade no Brasil: o que significa para a judicialização? / Drug approval with agnostic indication is already a reality in Brazil: what does it mean for judicialization? / El registro de medicamentos con indicación agnóstica ya es una realidad en Brasil: ¿qué significa para la judicialización?

Objetivo: descrever os aspectos regulatórios do larotrectinibe, o primeiro medicamento aprovado com indicação de tumor-agnóstico no Brasil, e seus prováveis impactos na judicialização no país. Métodos: trata-se de um estudo exploratório descritivo. Resultados e discussão: o larotrectinibe foi aprovado no Brasil cerca de 225 dias após a aprovação pelo FDA. Sua aprovação traz novos elementos para a discussão da judicialização em saúde, pois poucos são os pacientes que se beneficiarão dessa terapia. É sabido que a prevalência de fusão do gene do receptor da NTRK (mutação alvo do larotrectinibe) é 0,31% dos tumores de adultos e 0,34% dos tumores de pacientes pediátricos. Além disso, é necessário a realização de exames farmacogenéticos para confirmação dessa mutação. Conclusão: com o registro de medicamentos com indicação tumor-agnóstica tornando-se uma realidade no Brasil, a necessidade por apresentação e interpretação de testes farmacogenéticos é crescente. Entretanto, essa não é uma realidade no Sistema Único de Saúde e, por isso, esses medicamentos tendem a beneficiar apenas aqueles que tenham acesso a testes farmacogenéticos e apresentem a mutação específica para o tratamento, promovendo, assim, demandas judiciais e restringindo o acesso à grande maioria da população.

Objective: to describe the regulatory aspects of larotrectinib, the first approved drug with indication for tumor-agnosis in Brazil, and its likely impacts on judicialization in the country. Methods: this is a descriptive exploratory study. Results and discussion: larotrectinib was approved in Brazil about 225 days after FDA approval. Its approval brings new elements to the discussion of judicialization in health, since few patients will benefit from this therapy. The prevalence of fusion of the NTRK receptor (larotrectinib target mutation) gene is known to be 0.31% of adult tumors and 0.34% of pediatric patient tumors. In addition, pharmacogenetic tests are required to confirm this mutation. Conclusion: with the registration of drugs with tumor-agnostic indication becoming a reality in Brazil, the need for presentation and interpretation of pharmacogenetic tests is increasing. However, this is not a reality in the Unified Health System and, therefore, these drugs tend to benefit only those who have access to pharmacogenetic tests, have the specific mutation for treatment, thus promoting legal demands and thus restricting their access to large majority of the population. Keywords: Health's Judicialization. Pharmaceutical Services. Access to Essential Medicines and Health Technologies. Brazilian Health Surveillance Agency.

Objetivo: describir los aspectos regulatorios de larotrectinib, el primer fármaco aprobado con indicación de diagnóstico de tumor en Brasil, y sus probables impactos en la judicialización en el país. Métodos: este es un estudio exploratorio descriptivo. Resultados y discusión: larotrectinib fue aprobado en Brasil unos 225 días después de la aprobación de lo FDA. Su aprobación aporta nuevos elementos a la discusión de la judicialización en salud, ya que pocos pacientes se beneficiarán de esta terapia. Se sabe que la prevalencia de fusión del gen del receptor NTRK (mutación objetivo de larotrectinib) es del 0,31% de los tumores adultos y del 0,34% de los tumores de pacientes pediátricos. Además, se requieren pruebas farmacogenéticas para confirmar esta mutación. Conclusión: con el registro de medicamentos con indicación agnóstica tumoral que se hace realidad en Brasil, la necesidad de presentación e interpretación de pruebas farmacogenéticas está aumentando. Sin embargo, esto no es una realidad en el Sistema Único de Salud y, por lo tanto, estos medicamentos tienden a beneficiar solo a aquellos que tienen acceso a pruebas farmacogenéticas, tienen la mutación específica para el tratamiento, promoviendo así demandas legales y restringiendo así su acceso a Gran mayoría de la población.

Comparison of the methodological quality and transparency of Brazilian practice guidelines.

This study aims to compare the differences between clinical practice guidelines (CPGs) of the Ministry of Health (MoH) and those of other Brazilian health institutions. A systematic review of Brazilian CPGs was carried out. CPGs with recommendations for the pharmacological treatment of non-communicable disease (NCDs) were included. CPG methodological quality and transparency was independently assessed by 2 reviewers using the AGREE II. CPGs were rated as high, moderate, and low quality (ranging from A to C). Twenty-six CPGs were assessed for quality. MoH CPGs were published more recently, and were of better quality than the others: 6/6 (100%) were rated as Moderate-A. Although CPGs presented a wide range of methodological quality and transparency, MoH CPGs presented better consistency in the preparation method. To avoid confusion and to improve the quality of care within finite resources in Brazil, and to avoid potential bias, conflicts of interest, national CPGs used within SUS should be developed by Conitec with partners who have no conflict of interest.

Comparison of the methodological quality and transparency of Brazilian practice guidelines / Comparação da qualidade metodológica e transparência das guias de prática clínica brasileiras

Abstract This study aims to compare the differences between clinical practice guidelines (CPGs) of the Ministry of Health (MoH) and those of other Brazilian health institutions. A systematic review of Brazilian CPGs was carried out. CPGs with recommendations for the pharmacological treatment of non-communicable disease (NCDs) were included. CPG methodological quality and transparency was independently assessed by 2 reviewers using the AGREE II. CPGs were rated as high, moderate, and low quality (ranging from A to C). Twenty-six CPGs were assessed for quality. MoH CPGs were published more recently, and were of better quality than the others: 6/6 (100%) were rated as Moderate-A. Although CPGs presented a wide range of methodological quality and transparency, MoH CPGs presented better consistency in the preparation method. To avoid confusion and to improve the quality of care within finite resources in Brazil, and to avoid potential bias, conflicts of interest, national CPGs used within SUS should be developed by Conitec with partners who have no conflict of interest.

Resumo O objetivo deste estudo é comparar as diferenças entre as guias de prática clínica (GPCs) do Ministério da Saúde (MS) e as de outras instituições de saúde brasileiras. Foi realizada uma revisão sistemática das GPCs brasileiras. Foram incluídas GPCs com recomendações para o tratamento farmacológico de doenças crônicas não transmissíveis elencadas (DCNTs). A qualidade metodológica e a transparência das GPCs foram avaliadas de forma independente por 2 revisores utilizando o AGREE II. As GPCs foram classificadas como alta, moderada e baixa qualidade (variando de A a C). Vinte e seis GPCs foram avaliadas quanto à qualidade. As GPCs do MS foram publicadas mais recentemente, e apresentaram melhor qualidade do que as outras: 6/6 (100%) foram classificadas como Moderada-A. Embora as GPCs tenham apresentado uma ampla gama de qualidade metodológica e transparência, as GPCs do MS apresentaram melhor consistência no desenvolvimento. Para evitar confusão e melhorar a qualidade do cuidado com os recursos limitados no Brasil e, para evitar viés, conflitos de interesse, GPCs nacionais usadas no SUS devem ser desenvolvidas, sobretudo, pela Conitec e parceiros sem conflitos de interesse.

[Validation of the "Conocimiento del Paciente sobre sus Medicamentos" (CPM-ES-ES) questionnaire]. / Validação do questionário "Conocimiento del Paciente sobre sus Medicamentos" (CPM-ES-ES).

This work cross-culturally adapted the Spanish questionnaire `Patients' knowledge about their medications ("Conocimiento del Paciente sobre sus Medicamentos" - CPM-ES-ES) for use in Brazil. It measures the level of medication knowledge by means of 11 questions. Eighty patients ≥ 80 years were investigated and in 39 cases the caregivers were interviewed. The evaluation of conceptual and item equivalences considered the concept of knowledge and the questions that assess it as pertinent. Semantic equivalence was obtained by the correspondence in the denotative and connotative meaning of items. The study of measurement equivalence included factorial analysis and the calculation of validity and reliability estimates. As with the original questionnaire, principal component analysis identified 4 components, however, in 2 of them there were differences regarding included items. One question was removed from this analysis due to its sample inadequacy. Medication knowledge was correlated with medication regimen complexity r = -.22, p = .046. Medication knowledge of antihypertensives was correlated with their adherence r = .70, p < .001, and blood pressure control rb = .46, p = .029. The adapted version revealed functional equivalence, therefore it can be used in the Brazilian context.

Este trabalho adaptou transculturalmente o questionário espanhol "Conocimiento del Paciente sobre sus Medicamentos" (CPM-ES-ES) para uso no Brasil. Ele mede o grau de conhecimento sobre medicamentos por meio de 11 perguntas. Oitenta pacientes ≥ 80 anos foram investigados e com 39 também foi entrevistado o cuidador. A avaliação das equivalências conceitual e de item considerou o conceito de conhecimento e as perguntas que o medem como pertinentes. A equivalência semântica foi obtida pela correspondência de significado denotativo e conotativo dos itens. O estudo da equivalência de mensuração incluiu análise fatorial e o cálculo de estimativas de validade e confiabilidade. Semelhante ao questionário original, a análise de componentes principais identificou 4 componentes, porém, em 2 deles houve diferenças nos itens incluídos. Uma pergunta foi removida desta análise devido à sua inadequação amostral. O conhecimento sobre medicamentos esteve correlacionado à complexidade da prescrição r = -0,22, p = 0,046. O conhecimento sobre anti-hipertensivos esteve correlacionado à sua adesão r = 0,70, p < 0,001, e ao controle da pressão arterial rb = 0,46, p = 0,029. A versão adaptada apresentou equivalência funcional de modo que pode ser usada no contexto brasileiro.

A judicialização de medicamentos imunoterápicos sem registro na Anvisa: o caso do Estado de São Paulo / The judicialization of immunotherapy drugs without registration with Anvisa: the case of the State of São Paulo, Brazil

Objetivos: o registro sanitário garante minimamente a segurança nas indicações de bula. Com o julgamento do Recurso Extraordinário (RE) nº 657.718/2019, essa questão não está pacificada. O objetivo desse estudo é comparar as indicações aprovadas nas agências sanitárias americana, europeia e brasileira e analisar dados referentes à indicação de medicamentos imunoterápicos para o tratamento de câncer, em demandas judiciais contra a Secretaria de Estado da Saúde de São Paulo (SES/SP). Métodos: foi realizada uma pesquisa documental nas bulas de seis medicamentos imunoterápicos, disponíveis em julho de 2019 nos websites das agências sanitárias elegidas para o estudo, e comparada a indicação desses medicamentos em demandas judiciais no Estado de São Paulo, utilizando os dados de relatórios ou documentos escaneados disponíveis no sistema S-Codes. Resultados: todos os medicamentos têm registro sanitário para, ao menos, uma indicação em bula nas três agências sanitárias, porém, com diferenças nas indicações aprovadas, muitas delas sendo aprovações aceleradas (fast track). O tempo médio entre a aprovação na Food and Drug Administration (FDA) e na Agência de Vigilância Sanitária (Anvisa) foi de 464,5 ± 170,8 dias; e 278 (98%) das demandas judiciais ocorreram pós-registro na Anvisa. Há pouca informação disponível nos documentos escaneados, mas foi possível identificar situações envolvendo indicações de medicamentos, além de resultados de testes genéticos. Discussão e conclusão: a análise mostra que a FDA tende a ser menos rigorosa na aprovação de novas indicações, e que a maioria das demandas não se enquadraria nos critérios do RE nº 657.718/2019. Apesar do avanço, faz-se necessária a discussão do uso off-label desses medicamentos e sua especificidade. (AU).

Objectives: The drug approval minimally guarantees the safety in the label directions. With the judgment of Extraordinary Appeal No. 67718, this issue is not pacified. The aim of this study is to compare the indications approved by the American (FDA), European (EMA) and Brazilian (Anvisa) health agencies and to analyze data regarding the indication of immunotherapeutic drugs for cancer treatment, in lawsuits against the Secretary of State of Health of São Paulo (SES/SP). Methods: Documentary research was performed on the package leaflets of six immunotherapeutic drugs available in July 2019 on the websites of the health agencies eligible for the study, and comparing the indication of these drugs in lawsuits in the state of São Paulo, using data from reports. or scanned documents available on the S-Codes system. Results: All drugs are registered for at least one indication in the 3 health agencies, but with differences in the approved indications, many of them being conditional approvals (fast track). The average time between FDA and Anvisa approval was 464.5 ± 170.8 days, and 278 (98%) of the demands occurred post-registration with Anvisa. There is little information available in the scanned documents, but it was possible to identify situations involving indications as well as genetic test results. Discussion and Conclusion: analysis shows that the FDA tends to be less rigorous in approving new indications, and that most demands would not meet the criteria of RE 657718/2019. Despite the progress in discussions involving the judicialization of health, it is necessary to discuss the off-label use of these drugs and their specificity. (AU).

Objetivos: el registro sanitario garantiza mínimamente la seguridad de las instrucciones de etiquetado. Con la sentencia de Apelación Extraordinaria (RE) No. 657,718 / 2019, este asunto no se pacifica. El objetivo de este estudio es comparar las indicaciones aprobadas por las agencias de salud estadounidenses, europeas y brasileñas y analizar datos sobre la indicación de medicamentos de inmunoterapia para el tratamiento del cáncer, en demandas contra el Departamento de Salud del Estado de São Paulo (SES / SP). Métodos: se realizó una investigación documental en los prospectos de seis medicamentos inmunoterapéuticos, disponibles en julio de 2019, en los sitios web de las agencias de salud elegibles para el estudio. documentos escaneados disponibles en el sistema S-Codes. Resultados: todos los medicamentos tienen un historial médico para al menos una indicación de etiqueta en las tres agencias de salud, pero con diferencias en las indicaciones aprobadas, muchas de ellas son aprobaciones aceleradas. El tiempo promedio entre la aprobación de la Food and Drug Administration (FDA) y la Agencia de Vigilancia de la Salud (Anvisa) fue de 464.5 ± 170.8 días; y 278 (98%) de las demandas ocurrieron después de registrarse con Anvisa. Hay poca información disponible en los documentos escaneados, pero fue posible identificar situaciones que implican indicaciones de drogas, así como resultados de pruebas genéticas. Discusión y conclusión: el análisis muestra que la FDA tiende a ser menos rigurosa en la aprobación de nuevas indicaciones, y que la mayoría de las demandas no se ajustan a los criterios de RE 657.718/2019. A pesar del progreso, es necesario discutir el uso fuera de etiqueta de estos medicamentos y su especificidad. (AU).

Impacto econômico das ações judiciais para o fornecimento de medicamentos no Estado de São Paulo / Economic impact of lawsuits for drug supply in the State of São Paulo

Objetivos: compreender a participação das despesas com medicamentos judicializados nas despesas totais liquidadas com medicamentos (DTLM) no Estado de São Paulo (SP). SP. Métodos: realizou-se análise exploratória de dados do Sistema de Informações Gerenciais da Execução Orçamentária (Sigeo) e do Sistema de Informação de Orçamento Público em Saúde (Siops), de 2010 a 2018. Resultados: no período estudado, as DTLM em SP superaram 11 bilhões de reais, apresentando tendência decrescente em valores globais e na participação percentual em relação à despesa total com saúde (de 11,32% em 2010 para 8,95% em 2018). De 2016 a 2018, 17% das DTLM foram destinadas às ações judiciais (R$ 679.935.967,31), sendo a tendência crescente. Discussão: a representatividade dos medicamentos judicializados na DTLM alerta para questões de custo, mas também para a segurança do paciente e sustentabilidade das políticas públicas de saúde, pois o rol também contempla medicamentos novos, para os quais a superioridade em efetividade e segurança ainda não foram comprovadas comparando-se às alternativas disponíveis, e/ou com uso off-label. Conclusões: as demandas judiciais por medicamentos não têm levado ao aumento da destinação de recursos para sua aquisição, mas à concorrência por recursos originalmente destinados à política de assistência farmacêutica, com redução da participação percentual dos medicamentos das listas oficiais do Sistema Único de Saúde (SUS) a cada ano.

Objective: to understand the participation of expenses with judicialized medicines in total expenditure on drugs (DTLM) in São Paulo State (SP). Methods: it was conducted an exploratory analysis of data from Sistema de Informações Gerenciais da Execução Orçamentária (Sigeo) and Sistema de Informação de Orçamento Público em Saúde (Siops) from 2010 to 2018. Results: in this period, DTLM in SP exceeded 11 billion of reais, showing a downward trend in global values and percentage share in relation to total health expenditure (from 11.32% in 2010 to 8.95% in 2018). From 2016 to 2018, 17% of DTLM were destined to lawsuits (R$ 679,935,967.31), with a growing trend. Discussion: the representativeness of judicialized drugs in DTLM warns of cost issues, but also for patient safety and sustainability of public health policies, because this list also includes new drugs, which have not been proved superior in effectiveness and safety yet, comparing to available alternatives, and/or off label use. Conclusions: the legal demands for medicines have not led to an increase in the allocation of funds for their purchase, but to competition for resources originally destinated for the pharmaceutical services policy, with a reduction in the percentage participation of medicines from SUS official lists each year.

Objetivos: comprender la participación de los gastos con drogas judicializadas en los gastos totales con drogas (DTLM) en el Estado de São Paulo (SP). Métodos: se realizó un análisis exploratorio de datos del Sistema de Informações Gerenciais da Execução Orçamentária (Sigeo) y el Sistema de Informação de Orçamento Público em Saúde (Siops) de 2010 a 2018. Resultados: en este período, DTLM en SP superó los 11 mil millones de reales, mostrando una tendencia a la baja en los valores globales y la participación porcentual en relación con el gasto total en salud (del 11.32% en 2010 al 8.95% en 2018). De 2016 a 2018, el 17% de DTLM se destinó a estas demandas (R$ 679,935,967.31), con una tendencia creciente. Discusión: la representatividad de los medicamentos judicializados en DTLM advierte sobre los costos, pero también sobre la seguridad del paciente y la sostenibilidad de las políticas de salud pública, porque esta lista también incluye nuevos medicamentos, que aún no han demostrado ser superiores en comparación de efectividad y seguridade a alternativas disponibles, y/o uso off-label. Conclusiones: los pleitos de medicamentos no han llevado a un aumento en la asignación de fondos para su compra, sino a la competencia por los recursos originalmente destinados a la política de asistencia farmacéutica, con una reducción en el porcentaje de participación de medicamentos de las listas oficiales del SUS cada año.

Validação do questionário "Conocimiento del Paciente sobre sus Medicamentos" (CPM-ES-ES) / Validation of the "Conocimiento del Paciente sobre sus Medicamentos" (CPM-ES-ES) questionnaire

Resumo Este trabalho adaptou transculturalmente o questionário espanhol "Conocimiento del Paciente sobre sus Medicamentos" (CPM-ES-ES) para uso no Brasil. Ele mede o grau de conhecimento sobre medicamentos por meio de 11 perguntas. Oitenta pacientes ≥ 80 anos foram investigados e com 39 também foi entrevistado o cuidador. A avaliação das equivalências conceitual e de item considerou o conceito de conhecimento e as perguntas que o medem como pertinentes. A equivalência semântica foi obtida pela correspondência de significado denotativo e conotativo dos itens. O estudo da equivalência de mensuração incluiu análise fatorial e o cálculo de estimativas de validade e confiabilidade. Semelhante ao questionário original, a análise de componentes principais identificou 4 componentes, porém, em 2 deles houve diferenças nos itens incluídos. Uma pergunta foi removida desta análise devido à sua inadequação amostral. O conhecimento sobre medicamentos esteve correlacionado à complexidade da prescrição r = -0,22, p = 0,046. O conhecimento sobre anti-hipertensivos esteve correlacionado à sua adesão r = 0,70, p < 0,001, e ao controle da pressão arterial rb = 0,46, p = 0,029. A versão adaptada apresentou equivalência funcional de modo que pode ser usada no contexto brasileiro.

Abstract This work cross-culturally adapted the Spanish questionnaire `Patients' knowledge about their medications ("Conocimiento del Paciente sobre sus Medicamentos" - CPM-ES-ES) for use in Brazil. It measures the level of medication knowledge by means of 11 questions. Eighty patients ≥ 80 years were investigated and in 39 cases the caregivers were interviewed. The evaluation of conceptual and item equivalences considered the concept of knowledge and the questions that assess it as pertinent. Semantic equivalence was obtained by the correspondence in the denotative and connotative meaning of items. The study of measurement equivalence included factorial analysis and the calculation of validity and reliability estimates. As with the original questionnaire, principal component analysis identified 4 components, however, in 2 of them there were differences regarding included items. One question was removed from this analysis due to its sample inadequacy. Medication knowledge was correlated with medication regimen complexity r = -.22, p = .046. Medication knowledge of antihypertensives was correlated with their adherence r = .70, p < .001, and blood pressure control rb = .46, p = .029. The adapted version revealed functional equivalence, therefore it can be used in the Brazilian context.

Factors Associated With High-Quality Guidelines for the Pharmacologic Management of Chronic Diseases in Primary Care: A Systematic Review.

Importance: As the rate of publication of new and sometimes conflicting medical research increases, clinicians rely heavily on clinical practice guidelines (CPGs) to inform practice. However, CPGs are of widely variable quality, and there are no existing objective measures to rate the quality of CPGs. Objective: To systematically assess 421 CPGs for the management of common noncommunicable diseases in primary care using the validated Appraisal of Guidelines for Research and Evaluation Instrument, version II (AGREE-II) tool and elucidate the factors associated with quality of CPGs. Evidence Review: MEDLINE, Embase, the Cochrane Library, and 12 websites for CPGs were searched for CPGs for the management of common noncommunicable diseases in primary care published between January 1, 2011, and August 30, 2017. The assessment of the quality of CPGs was performed by 3 appraisers using the 6 domains of the AGREE-II instrument. A multiple logistic regression was performed to identify factors associated with quality of CPGs. Findings: Of the 421 CPGs reviewed, 23.5% (99) were classified as high quality. Among included guidelines, clarity of presentation (70%) and scope and purpose (61%) had the highest median AGREE-II scores. The domains with the lowest median scores were applicability (22%) and rigor of development (33%). Factors associated with high-quality CPGs included having more than 20 authors (odds ratio, 9.08; 95% CI, 3.35-24.62), development at governmental institutions (odds ratio, 10.38; 95% CI, 2.72-39.60), and reporting funding (odds ratio, 10.34; 95% CI, 4.77-22.39). Year of publication, region, guideline version, and scope were not associated with quality among included CPGs. Conclusions and Relevance: Primary care professionals and policymakers should be aware that CPGs in primary care are of widely variable quality, with less than 25% of included CPGs rated as high quality. High-quality CPGs were associated with a higher number of authors, governmental institutions, and the report of funding. Region of origin was not associated with quality of CPGs, which suggests that the improvement of the quality of CPGs should be an international concern.

The appropriate use of human albumin in a Brazilian University Hospital: therapeutic indication and dosage regimen

The objective of the study was to evaluate the use of human albumin in a Brazilian university hospital, in compliance with the institutional protocol and other clinical guidelines, taking into account the therapeutic indications and the dosage regimens. Data was obtained from the pharmacy dispensing records of human albumin, the requests for use it and, when available, the patient's records between January and October 2017. After evaluation the therapeutic indications and the dosage regimens were classified as "appropriate" and "inappropriate". The analysis of 98 requests showed that, when compared to the institutional protocol, 54 (55.1%) requests had an inappropriate therapeutic indication. However, when a comparison was made between 25 medical records (54 requests) and other clinical guidelines, it was observed that the therapeutic indication had none classified as inappropriate. In addition, 16 (29.7%) requests were considered inappropriate in relation to dosage regimens. From these results, it was possible to conclude that although the use of human albumin in the hospital was associated to a clinical protocol, it was outdated. Thus, it is possible to affirm that not only the adoption of a clinical protocol, but its periodical updating is an important strategy to promote the rational use of drugs.