An evaluation of confidence intervals for a cumulative proportion to enable decisions at interim reviews of single-arm trials.

BACKGROUND: Clinical trials often include interim analyses of the proportion of participants experiencing an event by a fixed time-point. A pre-specified proportion excluded from a corresponding confidence interval (CI) may lead an independent monitoring committee to recommend stopping the trial. Frequently this cumulative proportion is estimated by the Kaplan-Meier estimator with a Wald approximate CI, which may have coverage issues with small samples. METHODS: We reviewed four alternative CI methods for cumulative proportions (Beta Product Confidence Procedure (BPCP), BPCP Mid P, Rothman-Wilson, Thomas-Grunkemeier) and two CI methods for simple proportions (Clopper-Pearson, Wilson). We conducted a simulation study comparing CI methods across true event proportions for 12 scenarios differentiated by sample sizes and censoring patterns. We re-analyzed interim data from A5340, a HIV cure trial considering the proportion of participants experiencing virologic failure. RESULTS: Our simulation study highlights the lower and upper tail error probabilities for each CI method. Across scenarios, we found differences in the performance of lower versus upper bounds. No single method is always preferred. The upper bound of a Wald approximate CI performed reasonably with some error inflation, whereas the lower bound of the BPCP Mid P method performed well. For a trial design similar to A5340, we recommend BPCP Mid P. CONCLUSIONS: The design of future single-arm interim analyses of event proportions should consider the most appropriate CI method based on the relevant bound, anticipated sample size and event proportion. Our paper summarizes available methods, demonstrates performance in a simulation study, and includes code for implementation.

Data monitoring committees in pediatric randomized controlled trials registered in ClinicalTrials.gov.

BACKGROUND: Data monitoring committees advise on clinical trial conduct through appraisal of emerging data to ensure participant safety and scientific integrity. While consideration of their use is recommended for trials performed with vulnerable populations, previous research has shown that data monitoring committees are reported infrequently in publications of pediatric randomized controlled trials. We aimed to assess the frequency of reported data monitoring committee adoption in ClinicalTrials.gov registry records and to examine the influence of key trial characteristics. METHODS: We conducted a cross-sectional data analysis of all randomized controlled trials performed exclusively in a pediatric population and registered in ClinicalTrials.gov between 2008 and 2021. We used the Access to Aggregate Content of ClinicalTrials.gov database to retrieve publicly available information on trial characteristics and data on safety results. Abstracted data included reported trial design and conduct parameters, population and intervention characteristics, reasons for prematurely halting, serious adverse events, and mortality outcomes. We performed descriptive analyses on the collected data and explored the influence of clinical, methodological, and operational trial characteristics on the reported adoption of data monitoring committees. RESULTS: We identified 13,928 pediatric randomized controlled trial records, of which 39.7% reported adopting a data monitoring committee, 49.0% reported not adopting a data monitoring committee, and 11.3% did not answer on this item. While the number of registered pediatric trials has been increasing since 2008, we found no clear time trend in the reported adoption of data monitoring committees. Data monitoring committees were more common in multicenter trials (50.6% vs 36.9% for single-center), multinational trials (60.2% vs 38.7% for single-country), National Institutes of Health-funded (60.3% vs 40.1% for industry-funded or 37.5% for other funders), and placebo-controlled (47.6% vs 37.5% for other types of control groups). Data monitoring committees were also more common among trials enrolling younger participants, trials employing blinding techniques, and larger trials. Data monitoring committees were more common in trials with at least one serious adverse event (52.6% vs 38.4% for those without) as well as for trials with reported deaths (70.3% vs 38.9% for trials without reported deaths). In all, 4.9% were listed as halted prematurely, most often due to low accrual rates. Trials with a data monitoring committee were more often halted for reasons related to scientific data than trials without a data monitoring committee (15.7% vs 7.3%). CONCLUSION: According to registry records, the use of data monitoring committees in pediatric randomized controlled trials was more frequent than previously reported in reviews of published trial reports. The use of data monitoring committees varied across key clinical and trial characteristics based on which their use is recommended. Data monitoring committees may still be underutilized in pediatric trials, and reporting of this item could be improved.

Comitês de monitoramento para a proteção de participantes de pesquisa / Monitoring committees for research participant protection / Comités de seguimiento para la protección de los participantes en investigación

Resumo O tema segurança tem sido intensamente discutido, mostrando-se cada vez mais relevante na saúde pública e em projetos de pesquisa envolvendo seres humanos. Participantes de estudos clínicos estão sujeitos a riscos, físicos ou não, que impactam em sua integridade, direitos ou autonomia. Este trabalho apresenta e discute a atuação do Comitê de Monitoramento de Dados e de Segurança para a proteção do participante de pesquisa e minimização de riscos em pesquisa clínica. A metodologia consiste em revisão integrativa da literatura, realizada com o propósito de identificar as funções dos comitês e seu papel na proteção dos participantes. Identificou-se que grande parte das publicações analisadas confirmam que os comitês de monitoramento têm como responsabilidade principal a proteção do participante de pesquisa, além da garantia de integridade e credibilidade da pesquisa.

Abstract Of increasingly relevance in public health and research projects involving human beings, the topic of safety has been intensely discussed. Participants in clinical trials are subject to risks, physical or otherwise, that impact their integrity, rights, or autonomy. This study outlines and discusses the performance of the Data and Safety Monitoring Committee for research participant protection and risk minimization in clinical research. An integrative literature review was conducted to identify the committees' duties and role in protecting participants. Most of the analyzed articles confirm that the monitoring committees are mainly responsible for protecting research participants, as well as ensuring research integrity and credibility.

Resumen La seguridad ha sido un tema muy discutido, por lo que muestra su relevancia para la salud pública y los proyectos de investigación que involucran a seres humanos. Los participantes en estudios clínicos están sujetos a riesgos físicos o de otro tipo, que impactarán su integridad, derechos o autonomía. Este texto realiza un debate sobre el desempeño del Comité de Seguimiento de Datos y Seguridad destinado a la protección de los participantes de investigación y la mitigación de los riesgos en investigación clínica. Se realizó una revisión integradora de la literatura, con el propósito de identificar las funciones de los comités y su rol en la protección de los participantes. La mayoría de las publicaciones analizadas confirman que los comités de seguimiento tienen como principal responsabilidad la protección del participante de la investigación, además de garantizar la integridad y credibilidad de la investigación.

The Essential Role of Data and Safety Monitoring Boards (DSMBs) in Ensuring the Ethics of Global Vaccine Trials to Address Coronavirus Disease 2019 (COVID-19O).

Coronavirus disease 2019 (COVID-19) vaccines are being developed and implemented with unprecedented speed. Accordingly, trials considered ethical at their inception may quickly become concerning. We provide recommendations for Data and Safety Monitoring Boards (DSMBs) on monitoring the ethical acceptability of COVID-19 vaccine trials, focusing on placebo-controlled trials in low- and middle-income countries.

Adverse events following immunization against SARS-CoV-2 (covid-19) in the state of Minas Gerais / Eventos adversos pós-vacinação contra o SARS-CoV-2 (covid-19) no estado de Minas Gerais

ABSTRACT OBJECTIVE To analyze adverse events following immunization (AEFI) against SARS-CoV-2 (covid-19) in the state of Minas Gerais (MG), Brazil. METHODS Epidemiological, descriptive study, with data from e-SUS Notifica (e-SUS Notification) in the state of Minas Gerais from January 20 to March 5, 2021. All suspected cases of AEFI of the covid-19 vaccine in the state were analyzed, totaling 7,305 cases. In this study, we verified the possible correlation between AEFI and the possible immunobiological administered causalities. The variables analyzed for AEFI cases were the immunobiological agent administered (AstraZeneca or Coronavac), the type of event, the evolution of the case, and the time in days since the administration of the immunobiological agent and the onset of symptoms and causality. The incidence rate (IT) was calculated for 100,000 doses applied. RESULTS The occurrence of AEFI as a result of the covid-19 vaccine was frequent (TI: 777.12) in the state. However, only 3% were classified as a severe AEFI, with a 20.85 IT, and 4.71% of them evolved to deaths (8.19 deaths per 100,000 doses applied). Among the deaths analyzed, 84.4% were classified as preexisting conditions caused by factors other than vaccines. Regarding non-serious AEFI, 1.11% occurred by immunization errors (TI: 8.62 EI for every 100 thousand doses applied). CONCLUSION This work encourages the discussion about the importance of recording AEFI related to covid-19 vaccines, demonstrating its safety for the population.

RESUMO OBJETIVO Analisar os eventos adversos pós-vacinação (EAPV) contra o SARS-CoV-2 (covid-19) no estado de Minas Gerais (MG). MÉTODOS Estudo epidemiológico, descritivo, com dados do e-SUS Notifica no estado de Minas Gerais durante o período de 20 de janeiro a 5 de março de 2021. Foram analisados todos os casos suspeitos de EAPV da vacina contra covid-19 no estado, totalizando 7.305 casos. Para este estudo, verificou-se a possível correlação entre os EAPV e a causalidade com o imunobiológico administrado no período estabelecido. As variáveis analisadas para os casos de EAPV foram o imunobiológico administrado (AstraZeneca ou Coronavac), o tipo de evento, a evolução do caso e o tempo em dias da administração do imunobiológico e o início dos sintomas e causalidade. Calculou-se a taxa de incidência (TI) para 100 mil doses aplicadas. RESULTADOS A ocorrência dos EAPV em decorrência da vacina contra covid-19 foi frequente (TI: 777,12) no estado. Entretanto, somente 3% foram classificados como EAPV grave, com TI de 20,85, sendo que 4,71% deles evoluíram para óbitos com TI (8,19 óbitos a cada 100 mil doses aplicadas). Dentre os óbitos analisados, 84,4% foram classificados como condições preexistentes causadas por outros fatores e não por vacinas. Em relação aos EAPV não graves, 1,11% foram em decorrência de erros de imunização (TI: 8,62 EI a cada 100 mil doses aplicadas). CONCLUSÃO Esse trabalho fomenta, portanto, a discussão sobre a importância dos registros dos EAPV decorrentes das vacinas contra covid-19, demonstrando sua segurança para a população.

Exemptions and Limited Institutional Review Board Review: A Practical Look at the 2018 Common Rule Requirements for Exempt Research.

Background: The revised Common Rule sought to modernize an outdated regulatory framework, provide clarity to the research community about the application of regulations, and reduce regulatory burden. From the advance notice of proposed rulemaking in 2011 to the implementation of the Final Rule, a significant amount of commentary and opinion was generated about the rules that govern most federally funded human subjects research. Methods: This article provides insight into the changes to the regulatory framework for low-risk research, clarifies when exemptions can be applied, and explains the use of limited institutional review board (IRB) review. Results: In attempting to fulfill the objectives of reducing regulatory burden, freeing IRB administrative resources, and protecting human subjects, the new regulations acknowledge low-risk research and privacy concerns, as well as the increased use of biospecimens. In the Final Rule, the Office for Human Research Protections updated the definition of human subject and expanded the exemption framework. The definition of human subject in the Final Rule includes biospecimens, and the new exemption framework includes expanded definitions, modifications to existing exemption categories, the creation of new categories, and the creation of a new concept called limited IRB review. The expanded exemption framework was designed to help alleviate the regulatory burdens of low-risk research. Conclusion: Whether the revised regulations will meet the needs of the research community and human subject participants is unknown. While the revised Common Rule includes some welcome modifications and additions, the changes have also introduced new concepts that are not fully elucidated and have therefore introduced new ambiguities.

Problemas éticos en las publicaciones científicas / Ethical problems in scientific publications

Ethical problems have always been present in scientific publications. Since the founding of medical journals, in the XIX Century, until today they are a source of concern because one main purpose of medical scientific publications is to add new, reliable information that could guide or modify medical decisions and public health policies. Since 1997, Revista Médica de Chile has published several articles clarifying this situation and emphasizing the need to avoid ethical misbehavior. The present review reminds that the main sources of information dealing with publication ethics appear in the web sites of ICMJE, COPE and WAME. Misconduct have been detected in Revista Médica de Chile in a few cases of redundant publications, plagiarism, lack of recognition of conflicts of interest mainly with pharmaceutical companies, and one attempt of forging the publication of an article that had been previously rejected. In handling situations identified as ethical misbehavior, the editors of this journal have successfully followed rules established by COPE. This article reviews and reinforces recommendations to avoid ethical misbehavior in biomedical research and in manuscripts submitted for publication.

Análisis interino en ensayos clínicos: un estudio meta-epidemiológico / Interim analysis in clinical trials: A meta-epidemiological study / Análise interino em ensaios clínicos: um estudo meta-epidemiológico

Objetivo: la responsabilidad ética del investigador obliga al monitoreo de la seguridad de los participantes a través del estudio y, por ende, se requiere de un comité de monitoreo de datos, cuya tarea principal es el análisis interino que se refiere a la supervisión de variables como beneficios dramáticos, efectos adversos, mortalidad y futilidad, que lleven a la terminación temprana del estudio. El objetivo de esta investigación es determinar los métodos estadísticos más utilizados en el análisis interino en los ensayos clínicos aleatorizados y publicados en 2016 en una revista médica general de alto factor de impacto. Metodología: se realizó un estudio meta-epidemiológico descriptivo, constituido por ensayos clínicos aleatorizados publicados en el The New England Journal of Medicine, desde el 7 de enero hasta el 10 de noviembre de 2016. Resultados: se analizaron 104 artículos con una muestra promedio de 5 531 ± 762 pacientes y un tiempo de seguimiento promedio de 31 ± 45 meses. De los estudios evaluados se encontró que 88 (84.61%) realizaron análisis interino y 16 (15.38%) no lo realizaron. Los métodos estadísticos utilizados en los artículos fueron O'Brien-Fleming en 30 (34.09%), Haybittle-Peto en 13 (14.77%); otros métodos en dos (2.27%) y no especificado en 43 (48.86%) de ellos. Conclusiones: la mayoría de los ensayos clínicos aleatorizados realizó análisis interino y lo describen en su protocolo. Aproximadamente la mitad de los estudios no especificó el método estadístico; sin embargo, el método descrito más utilizado fue O'Brien-Fleming y, en segundo lugar, Haybittle-Peto y en ningún estudio se especificó el método de Pocock.

Objective: The ethical responsibility of the researcher requires that the safety of participants be monitored throughout the study. Thus, a data monitoring committee is required, whose main function is the interim analysis, which monitors variables such as dramatic benefits, adverse effects, mortality and futility that lead to the early termination of a study. The objective of this study is to determine the most frequently used statistical methods in interim analysis in randomized clinical trials published during 2016 in a high impact factor medical journal. Methodology: Meta-epidemiological descriptive study, consisting of randomized clinical trials published in The New England Journal of Medicine from January 7 to November 10 of 2016. Results: 104 articles were analyzed, where the mean sample was 5,531 ± 762 patients and and average follow-up time was 31 ± 45 months. Of the studies evaluated, 88 (84.61%) performed interim analysis, while 16 (15.38%) did not. Regarding statistical methods used, O'Brien-Fleming was used in 30 (34.09%) studies, Haybittle-Peto in 13 (14.77%), other methods in two (2.27%), and the method was not specified in 43 (48.86%). Conclusions: most of the randomized clinical trials reviewed had interim analysis and described it in their protocol. Approximately half of the studies did not specify the statistical method; however, the most commonly described method was O'Brien-Fleming, followed by Haybittle-Peto; no study used the Pocock method.

Objetivo: a responsabilidade ética do investigador obriga à monitoração da segurança dos participantes através do estudo e, por consequência, se requere de um comitê de monitoração de dados, cuja a tarefa principal é a análise interino que se refere à supervisão de variáveis como benefícios dramáticos, efeitos adversos, mortalidade e futilidade, que levem à terminação precoce do estudo. O objetivo desta investigação é determinar os métodos estatísticos mais utilizados na análise interino nos ensaios clínicos aleatorizados e publicados em 2016 em uma revista médica geral de alto fator de impacto. Metodologia: se realizou um estudo meta-epidemiológico descritivo, constituído por ensaios clínicos aleatorizados publicados no The New England Journal of Medicine, desde o dia 7 de Janeiro até o dia 10 de novembro de 2016. Resultados: se analisaram 104 artigos com uma amostra média de 5 531 ± 762 pacientes e um tempo de seguimento médio de 31 ± 45 meses. Dos estudos avaliados se encontrou que 88 (84.61%) realizaram análise interino e 16 (15.38%) não o realizaram. Os métodos estatísticos utilizados nos artigos foram O'Brien-Fleming em 30 (34.09%), Haybittle-Peto em 13 (14.77%); outros métodos em dois (2.27%) e não especificado em 43 (48.86%) deles. Conclusões: a maioria dos ensaios clínicos aleatorizados realizou análise interino e o descrevem no seu protocolo. Aproximadamente a metade dos estudos não especificou o método estatístico; mas, o método descrito mais utilizado foi O'Brien-Fleming e, em segundo lugar, Haybittle-Peto e em nenhum estudo se especificou o método de Pocock.

Declaración de la Academia Chilena de Medicina sobre el Título V de la Ley 20. 850 (Ley Ricarte Soto) y su proyecto de reglamento "De los ensayos clínicos de productos farmacéuticos y elementos de uso médico" / Declaration of the Chilean Academy of Medicine of Law 20. 850 "On clinical trials of pharmaceutical products and medical devices" and of the bylaw that will regulate its application

In Chile, high cost treatments required by selected medical conditions are financed by the State, according to Law 20.850. A bylaw under discussion by the Senate regulates clinical trials, posing complex issues that will endanger local interest in front-line research: 1) The exclusive and mandatory control bestowed to the Institute of Public Health during all stages of the trials and also the surveillance of institutions performing clinical trials, overriding their Clinical Research Review Boards; 2) The 10 year period during which any adverse event is assumed to have been caused by the medication or devise evaluated by the trial, unless the contrary is proven in a judicial process; 3) Individuals submitted to the trials are entitled to free post trial access to the treatment received during the study, financed by the trial supporting entities and as long as the drug or devise is considered to be useful. While agreeing with the need to have a National Registry of Clinical Trials, we predict that the mentioned critical issues in the bylaw will lead to difficulties and unnecessary judicial processes, thus limiting clinicians’ interest in performing research. We propose to modify the bylaw, excluding responsibilities on events associated with the natural evolution of the medical condition, with patients’ ageing or with comorbidities and clinical events considered unpredictable when the protocol was accepted. We recommend that the free post trial access should be a joint decision involving the patient and the attending physician, taking in consideration that the volunteer has been exposed to risks and burdens, or when discontinuation of treatment entails a vital risk until the treatment under study has been approved and becomes available in the national market.

En Chile los tratamientos de alto costo requeridos por seleccionadas condiciones médicas son financiados por el Estado, de acuerdo a la Ley 20.85, que se hizo efectiva en noviembre de 2015. Un reglamento de esta ley -actualmente en discusión por el Senado- incluye la regulación de los ensayos clínicos y plantea importantes aspectos que van a poner en riesgo la realización de investigaciones clínicas avanzadas: 1) El control exclusivo y mandatorio otorgado al Instituto de Salud Pública durante todas las etapas de los ensayos y la vigilancia de las instituciones que los realizan, que sobrepasa las atribuciones de los Comités de Ética Científica Institucionales; 2) El período de hasta 10 años después de la aparición de cualquier efecto adverso, durante el cual se asume causado por el medicamento o dispositivo evaluado en el ensayo, mientras no se demuestre lo contrario en un proceso judicial; 3) Los participantes de los estudios tienen derecho a continuar con el tratamiento recibido durante el estudio una vez terminado este, financiado por las entidades que patrocinan los estudios y mientras el fármaco o dispositivo se consideren útil. Estamos de acuerdo con la necesidad de contar con un Registro Nacional de Ensayos Clínicos. Sin embargo, predecimos que los aspectos críticos del reglamento causarán dificultades y procesos judiciales innecesarios, lo que limitará el interés de los clínicos en realizar investigación. Proponemos que el reglamento debe modificarse a fin de excluir responsabilidades sobre eventos asociados con la evolución natural de la condición clínica, el envejecimiento del paciente, comorbilidades y eventos clínicos no predecibles cuando se aceptó el estudio. Recomendamos que el acceso gratuito posterior al estudio debe constituir una decisión conjunta del paciente y su médico tratante, considerando los riesgos y la carga a que se expuso el paciente, o al riesgo vital secundario a la suspensión del tratamiento del estudio mientras no esté disponible en el mercado nacional.

Declaración de la Academia Chilena de Medicina sobre el Título V de la Ley 20. 850 (Ley Ricarte Soto) y su proyecto de reglamento “De los ensayos clínicos de productos farmacéuticos y elementos de uso médico” / Declaration of the Chilean Academy of Medicine of Law 20. 850 On clinical trials of pharmaceutical products and medical devices” and of the bylaw that will regulate its application

In Chile, high cost treatments required by selected medical conditions are financed by the State, according to Law 20.850. A bylaw under discussion by the Senate regulates clinical trials, posing complex issues that will endanger local interest in front-line research: 1. The exclusive and mandatory control bestowed to the Institute of Public Health during all stages of the trials and also the surveillance of institutions performing clinical trials, overriding their Clinical Research Review Boards; 2.The 10 year period during which any adverse event is assumed to have been caused by the medication or devise evaluated by the trial, unless the contrary is proven in a judicial process; 3. Individuals submitted to the trials are entitled to free post trial access to the treatment received during the study, financed by the trial supporting entities and as long as the drug or devise is considered to be useful. While agreeing with the need to have a National Registry of Clinical Trials, we predict that the mentioned critical issues in the bylaw will lead to difficulties and unnecessary judicial processes, thus limiting clinicians’ interest in performing research. We propose to modify the bylaw, excluding responsibilities on events associated with the natural evolution of the medical condition, with patients’ ageing or with comorbidities and clinical events considered unpredictable when the protocol was accepted. We recommend that the free post trial access should be a joint decision involving the patient and the attending physician, taking in consideration that the volunteer has been exposed to risks and burdens, or when discontinuation of treatment entails a vital risk until the treatment under study has been approved and becomes available in the national market.