El panorama de los ensayos clínicos sobre COVID-19 en América Latina y el Caribe: evaluación y desafíos / The landscape of COVID-19 clinical trials in Latin America and the Caribbean: assessment and challenges

RESUMEN Se está llevando a cabo un número considerable de ensayos clínicos en todo el mundo en respuesta a la pandemia de COVID-19, incluso en países de ingresos bajos y medios como los de América Latina y el Caribe. Sin embargo, la abundancia de estudios no necesariamente acorta el camino para encontrar intervenciones seguras y eficaces frente a la COVID-19. Se analizaron los ensayos para el tratamiento y la prevención de la COVID-19 de los países de América Latina y el Caribe que están registrados en la Plataforma de Registros Internacionales de Ensayos Clínicos de la Organización Mundial de la Salud, y se identificó una tendencia hacia la realización de estudios pequeños, repetitivos y no rigurosos que duplican los esfuerzos y merman recursos limitados sin producir conclusiones significativas sobre la seguridad y la eficacia de las intervenciones evaluadas. Se evaluaron asimismo los desafíos que plantea la realización de investigaciones científicamente sólidas y socialmente valiosas en América Latina y el Caribe a fin de brindar recomendaciones que alienten la realización de ensayos clínicos que tengan más probabilidades de producir evidencia sólida durante la pandemia.

ABSTRACT A considerable number of clinical trials is being conducted globally in response to the COVID-19 pandemic, including in low- and middle-income countries such as those in the Latin America and Caribbean region (LAC). Yet, an abundance of studies does not necessarily shorten the path to find safe and efficacious interventions for COVID-19. We analyze the trials for COVID-19 treatment and prevention that are registered from LAC countries in the International Clinical Trials Registry Platform, and identify a trend towards small repetitive non-rigorous studies that duplicate efforts and drain limited resources without producing meaningful conclusions on the safety and efficacy of the interventions being tested. We further assess the challenges to conducting scientifically sound and socially valuable research in the LAC region in order to inform recommendations to encourage clinical trials that are most likely to produce robust evidence during the pandemic.

El panorama de los ensayos clínicos sobre COVID-19 en América Latina y el Caribe: evaluación y desafíos / The landscape of COVID-19 clinical trials in Latin America and the Caribbean: assessment and challenges

RESUMEN Se está llevando a cabo un número considerable de ensayos clínicos en todo el mundo en respuesta a la pandemia de COVID-19, incluso en países de ingresos bajos y medios como los de América Latina y el Caribe. Sin embargo, la abundancia de estudios no necesariamente acorta el camino para encontrar intervenciones seguras y eficaces frente a la COVID-19. Se analizaron los ensayos para el tratamiento y la prevención de la COVID-19 de los países de América Latina y el Caribe que están registrados en la Plataforma de Registros Internacionales de Ensayos Clínicos de la Organización Mundial de la Salud, y se identificó una tendencia hacia la realización de estudios pequeños, repetitivos y no rigurosos que duplican los esfuerzos y merman recursos limitados sin producir conclusiones significativas sobre la seguridad y la eficacia de las intervenciones evaluadas. Se evaluaron asimismo los desafíos que plantea la realización de investigaciones científicamente sólidas y socialmente valiosas en América Latina y el Caribe a fin de brindar recomendaciones que alienten la realización de ensayos clínicos que tengan más probabilidades de producir evidencia sólida durante la pandemia.

ABSTRACT A considerable number of clinical trials is being conducted globally in response to the COVID-19 pandemic, including in low- and middle-income countries such as those in the Latin America and Caribbean region (LAC). Yet, an abundance of studies does not necessarily shorten the path to find safe and efficacious interventions for COVID-19. We analyze the trials for COVID-19 treatment and prevention that are registered from LAC countries in the International Clinical Trials Registry Platform, and identify a trend towards small repetitive non-rigorous studies that duplicate efforts and drain limited resources without producing meaningful conclusions on the safety and efficacy of the interventions being tested. We further assess the challenges to conducting scientifically sound and socially valuable research in the LAC region in order to inform recommendations to encourage clinical trials that are most likely to produce robust evidence during the pandemic.

Identificación y análisis de los ensayos clínicos intervencionales planificados y registrados sobre COVID-19 / Identification and analysis of ongoing registered clinical intervention trials on COVID-19

Introducción La infección por SARS CoV-2 fue declarada pandemia el 11 de marzo de 2020. Desde entonces, se han propuesto e iniciado numerosos estudios, cuyo propósito incluye prevención, diagnóstico, manejo y tratamiento de esta nueva enfermedad. Objetivo Identificar y categorizar los estudios intervencionales hasta mayo de 20202 relacionados con la infección por SARS-CoV-2, de acuerdo con población y ubicación geográfica (con énfasis en Latinoamérica) y comprobar si existe correlación según el propósito, fase y estado de reclutamiento de los mismos. Metodología Se seleccionaron 1672 de los 1705 estudios disponibles en la plataforma de ensayos clínicos de la Organización Mundial de la Salud (OMS) relacionados con COVID-19. Se utilizaron las herramientas Jupyter y Python para el procesamiento y depuración de datos. Resultados Se encontraron 1672 estudios de tipo intervencional relacionados con la infección por SARS-CoV-2. China, Estados Unidos, Irán, Francia y España son los países que participan en mayor cantidad de estudios, mientras que solamente 4,1% proviene de América Latina (mayoritaria-mente brasileños). Las investigaciones que se centran únicamente en adultos mayores son 28, y solamente 10 estudios se basan exclusivamente en población menor de 19 años. Conclusión El interés mundial por esta nueva enfermedad se ve reflejado en la cantidad creciente de estudios intervencionales que se han realizado hasta la fecha. Sin embargo, los estudios analizados no abarcan proporcionalmente los grupos etarios más vulnerables, y no cuentan con una participa-ción equitativa de los países del orbe. En el caso de América Latina se agudiza esta problemática debido a las limitaciones sociales, económicas y políticas de la región. Debido a que es una enfermedad emergente, aún no existe suficiente información para poder establecer correlaciones contundentes entre las variables estudiadas. La estandarización definitiva de protocolos resulta prematura, ya que la mayoría de los estudios se encuentran en curso.

Introduction The World Health Organization declared the disease caused by the novel coronavirus (SARS-CoV-2), a pandemic on March 11, 2020. Several studies have been proposed and started since then, mainly covering prevention, diagnosis, management, and treatment. Objective To identify and categorize all intervention studies up to the end of May related to SARS-CoV-2 infection, according to population and geo-graphical location (emphasis in Latin America) and to verify if there is any correlation according to purpose, phase, and recruitment status. Methods One thousand six hundred seventy-two trials were selected from 1705 until May 24 on the World Health Organization clinical trials platform related to COVID-19. Jupyter and Python tools were used for data processing and cleaning. Results One thousand six hundred seventy-two intervention studies related to SARS-CoV-2 infection were found. China, The United States, Iran, France, and Spain are the countries participating in the largest number of studies, while only 4,1% are from Latin America (mostly Brazilian). 28 studies are focusing only on older adults, and ten studies are based exclusively on populations under 19 years of age. Conclusion The worldwide interest in this new disease is reflected in the increasing number of intervention studies that are being carried out to date. How-ever, the studies analyzed do not cover the most vulnerable age groups proportionally and do not have equitable participation of all the coun-tries. In Latin America, this problem is exacerbated by the region's social, economic, and political limitations. Because it is an emerging disease, there is still not enough information to establish strong correlations between the analyzed variables, and the standardization of protocols is not yet definite because most of the studies are in progress.

Federal university hospitals: heterogeneity in the coordination of clinical trials authorized by the National Health Surveillance Agency

Introduction: This study aimed to describe clinical trials approved by the Brazilian Health Surveillance Agency (ANVISA) and coordinated by federal university hospitals (FUHs), as well as to investigate the relationship between the number of clinical trials and the assistance provided by these FUHs. Methods: This is a cross-sectional study based on data obtained from the ANVISA clinical trial consultation system. The National Register of Health Care Facilities and the Ambulatory Care Information System of the Unified Health System (SUS) were used as sources of information on the assistance provided by FUHs, such as the mean number of specialized medical consultations and the number of beds. Scatter plot and Spearman's correlation coefficient analyses were used to verify the association between these aspects of FUHs and the number of clinical trials. Results: Between 2012 and 2013, ANVISA authorized 209 trials to be coordinated by 23 FUHs; 75% of the trials were coordinated by 7 FUHs, 69.8% were phase III trials, and 94% were multicenter studies. The number of clinical trials presented positive and statistically significant associations with the mean number of specialized medical consultations and the number of beds (Spearman's correlation coefficients r = +0.70 and r = +0.64, respectively). Conclusion: FUHs have a leadership role in the conduction of clinical trials in Brazil, but showed heterogeneity regarding their assistance capacities and the number of clinical trials. A predominance of phase III trials may be interpreted as a low use of the scientific potentiality of these facilities. (AU)

Búsqueda manual y electrónica de ensayos clínicos en revistas médicas cubanas: análisis de la terminología utilizada en su descripción / Manual and electronic search of clinical trials in Cuban medical journals: analysis of terminology

INTRODUCCIÓN Los ensayos clínicos se consideran la regla de oro para evaluar la eficacia y seguridad de las intervenciones. De manera independiente, pueden no ser suficientes para generalizar resultados, pero constituyen la base de revisiones sistemáticas que sintetizan sus resultados y suelen aportar evidencias de mayor calidad. Pero una vez publicados, la pobre descripción del método científico y el uso insuficiente de palabras clave, dificultan su recuperación por búsqueda electrónica y se requiere de la búsqueda manual. OBJETIVOS Comparar la capacidad de recuperación entre la búsqueda manual y estrategias múltiples de búsqueda electrónica para localizar ensayos clínicos en revistas médicas cubanas, y determinar la terminología utilizada para describir el ensayo clínico. Métodos Se combinó la búsqueda electrónica en la biblioteca virtual Scientific Electronic Library Online de Cuba (SciELO Cuba), y la base de datos de bibliografía médica cubana Cumed con la búsqueda manual utilizando la guía de búsqueda de Cochrane, para localizar los ensayos en tres revistas cubanas en el período 2000 a 2012. Se identificaron los términos significativos incluidos en título, resumen, palabras clave y métodos de cada artículo según la guía Cochrane, CONSORT y el tesauro de ciencias de la salud. RESULTADOS Se identificaron 50 ensayos en la búsqueda manual, de ellos cuatro coincidieron en la búsqueda electrónica; todos a través de SciELO Cuba (8%) y ninguno en Cumed. Las secciones menos descriptivas fueron el título y las palabras clave. Se utilizaron más palabras clave que descriptores autorizados; los únicos conceptos empleados en más de la mitad de los estudios fueron: "controlado" (60%) y "grupos de estudio" (52%); "aleatorizado" fue usado en el 50% de los artículos. Aunque son más específicos, no fueron muy usados los términos "ensayo clínico", "fase" y "código del ensayo". CONCLUSIONES La búsqueda electrónica es insuficiente para la identificación de ensayos clínicos respecto de la búsqueda manual. Por lo tanto, se precisa la combinación de ambos métodos para lograr un mayor índice de recobrado. La terminología usada para describir los ensayos clínicos en las revistas seleccionadas fue deficiente, debido a la subutilización del tesauro de ciencias de la salud.

INTRODUCTION Clinical trials are the gold standard for testing the efficacy and safety of interventions. On their own they may not be enough to reach definitive conclusions, but they are the basis for systematic reviews that synthesize the results of several studies. However, once clinical trials have been published, a poor description of the study design and lack of specific key words and descriptors make it difficult to retrieve them by electronic searches, thus requiring hand searching. OBJECTIVES To compare the retrieving capacity between hand search and the multiple strategies of electronic searches for identifying clinical trials in Cuban medical journals, and to determine the terminology used for describing these studies. METHODS We combined electronic searches in the Scientific Electronic Library Online of Cuba (SciELO Cuba) and Cuban database Cumed with hand search using the Cochrane guide to locate trials in three Cuban journals in the period 2000-2012. We identified the significant terms included in the title, summary, keywords and methods of each article according to Cochrane, CONSORT, and the health sciences thesaurus. RESULTS We identified 50 trials by hand search; four of them were retrieved by electronic search through SciELO Cuba (8%) while none was found through Cumed. The less descriptive sections were the title and the keywords. More keywords than authorized descriptors were used; the only specific concepts used in over half of the retrieved trials were "controlled" (60%), and "study groups" (52%); "randomized" was used in 50% of the retrieved documents. While more specific, the terms "clinical trial", "phase", and "clinical trial registration" were not used. CONCLUSIONS Compared to hand searching, electronic searches are insufficient to identify clinical trials. Therefore, the combination of the two meth-ods is necessary to reach higher retrieval rates. The terminology used to describe clinical trials in the selected journals was deficient due to underutilization of the health sciences thesaurus.

Adherence to clinical trial registration in countries of Latin America and the Caribbean, 2015 / Cumplimiento del registro de ensayos clínicos en los países de América Latina y el Caribe, 2015 / Adesão ao registro de ensaios clínicos em países da América Latina e Caribe, 2015

ABSTRACT Objective To determine the prevalence of clinical trial registration in the International Clinical Trial Registry Platform (ICTRP) for studies from Latin America and the Caribbean (LAC) and to identify the key characteristics that lead to prospective and retrospective registration. Methods A cross-sectional study identified published, clinical trial studies through a search of PubMed, LILACS (Latin American and Caribbean Center on Health Sciences Information), and the Cochrane Central Register of Controlled Trials. Studies were included if published on 1 January - 31 December 2015, at least one author was affiliated with at least one LAC country, the clinical trial was conducted in at least one LAC site, and the full text of the article was available. A manual search of reference lists was also conducted. ICTRP registration information and key trial characteristics were compared. Results Of 1 502 CT references that met inclusion criteria, 297 were randomly-selected, 90.9% of which were published in English, 65% from Brazil, and 76.8% had a LAC author as the first author. The proportion of CT registered in the ICTRP was 59.9 %, of which 51.7% were registered prospectively. Clinicaltrials.gov was most frequently used registry (84.8%), followed by the Registro Brasileiro de Ensaios Clínicos and the Registro Público Cubano de Ensayos Clínicos. Key characteristics that favored registration were being in study phase 3 or 4 or being a multi-center study. Data was compared to a similar study from 2013 that reported a registration rate of only 19.8%. Conclusions Registration adherence and prospective registration have increased in LAC in recent years, but the proportion of unregistered CT remains high. While there are still many challenges to overcome, the adherence strategies implemented in recent years have proven effective.

RESUMEN Objetivo Determinar la prevalencia del registro de ensayos clínicos de América Latina y el Caribe en la Plataforma de Registros Internacionales de Ensayos Clínicos (ICTRP, por su sigla en inglés) y definir los elementos clave que fomentan el registro prospectivo y retrospectivo de estudios. Métodos Se realizó un estudio transversal para encontrar los ensayos clínicos publicados mediante una búsqueda en PubMed, LILACS (Centro Latinoamericano y del Caribe para Información en Ciencias de la Salud) y el Registro Central Cochrane de Ensayos Clínicos Controlados. Se incluyeron los estudios que habían sido publicados entre el 1 de enero y el 31 de diciembre del 2015, que tenían cuando menos un autor afiliado a uno o más países de América Latina y el Caribe, que se habían realizado al menos en un centro de América Latina y el Caribe, y que tenían el texto completo del artículo disponible. También se llevó a cabo una búsqueda manual en listas de referencia. Se comparó la información sobre registros de la ICTRP y las características clave de los ensayos clínicos. Resultados De las 1 502 referencias que cumplieron los criterios de inclusión, se seleccionaron 297 aleatoriamente. De estas, 90,9% se habían publicado en inglés, 65% eran de Brasil y 76,8% tenían como primer autor un investigador de América Latina y el Caribe. La proporción de ensayos clínicos registrados en la ICTRP fue de 59,9%, de los cuales 51,7% se habían registrado prospectivamente. Clinicaltrials.gov fue el registro usado con mayor frecuencia (84,8%), seguido por el Registro Brasileiro de Ensaios Clínicos y el Registro Público Cubano de Ensayos Clínicos. Se determinó que las características clave que favorecían el registro eran que fuese un estudio de fase 3 o 4 o un estudio multicéntrico. Se compararon los datos con un estudio similar del 2013 en el que se había informado que la tasa de registro era de apenas 19,8%. Conclusiones En América Latina y el Caribe se ha observado en los últimos años un aumento en el cumplimiento del registro y del registro prospectivo de ensayos clínicos, pero la proporción de estudios sin registrar sigue siendo alta. Sin embargo, aunque persisten muchos retos que se deben superar, las estrategias adoptadas en los últimos años para que se cumpla este requisito han sido eficaces.

RESUMO Objetivo Determinar a prevalência do registro de estudos clínicos na Plataforma Internacional de Registro de Ensaios Clínicos (ICTRP) para estudos realizados na América Latina e Caribe (ALC) e identificar as principais características que conduzem ao registro prospectivo e retrospectivo. Métodos Em um estudo transversal, foram identificados os estudos clínicos publicados através de uma busca nas bases de dados PubMed, LILACS (Centro Latino-Americano e do Caribe de Informação em Ciências da Saúde) e Cochrane Central Register of Controlled Trials (CENTRAL). Foram incluídos estudos publicados de 1o. de janeiro a 31 de dezembro de 2015, em que pelo menos um dos autores provinha de um país da ALC, realizados em um ou mais centros na ALC e que apresentavam o texto completo disponível. Foi também feita uma busca manual das listas de referências. Foram comparados os dados sobre o registro na ICTRP e as principais características dos estudos. Resultados Das 1.502 referências de estudos clínicos que atenderam os critérios de inclusão, 297 foram selecionadas aleatoriamente. Verificou-se que 90,9% dos estudos foram publicados em inglês, 65% eram provenientes do Brasil e 76,8% tinham como primeiro autor um pesquisador da ALC. O percentual de registro dos estudos clínicos na ICTRP foi de 59,9%, sendo 51,7% registrado de forma prospectiva. Clinicaltrials.gov foi o registro mais usado (84,8%), seguido do Registro Brasileiro de Ensaios Clínicos e do Registro Público Cubano de Ensayos Clínicos. As principais características que contribuíram para o registro foram ser estudo de fase 3 ou 4 ou multicêntrico. Os dados foram comparados com um estudo semelhante realizado em 2013 que verificou uma taxa de registro de apenas 19,8%. Conclusões Houve um aumento na adesão ao registro e no registro prospectivo na ALC nos últimos anos, porém o percentual de estudos clínicos não registrados continua alto. Embora ainda existam muitos desafios a serem vencidos, as estratégias de adesão implementadas nos últimos anos têm sido eficazes.

Reports of uncontrolled clinical trials for directly placed restorations in vital teeth

Abstract Uncontrolled trials are criticized as unreliable. This study aimed to establish how the number of published reports from uncontrolled clinical trials compares to that of controlled trials for directly placed restorations in vital teeth and whether their annual number is increasing, stable or decreasing. PubMed was searched and suitable citations of uncontrolled and controlled trial reports published between 1990-2016 were included. Reference check and hand searching were conducted. The median annual report number with 25 and 75% percentile was calculated for both types of trials. 695 reports were found. The median number of reports per year was 4 (3-7) and 22 (15-26) from uncontrolled and controlled trials, respectively. A statistically significant decreasing ratio of uncontrolled to controlled trial reports was observed (p = 0.01) by linear regression analysis. The number of reports of uncontrolled clinical trials listed in PubMed over the last 27 years appears at least five times smaller than that of controlled clinical trials and its number in relation to that of controlled trials seems to decrease over time.

Sponsored multicentric clinical research conducted in Brazil in the respiratory area - losses and gains / Pesquisas clínicas multicêntricas patrocinadas realizadas na área respiratória no Brasil - Perdas e ganhos

Summary Objective: To evaluate the sponsored centers for clinical trial in the respiratory care setting in Brazil: profile; logistics and structure. Methods: Principal investigators (29) and subinvestigators (30) of 39 research centers completed the questionnaires that addressed personal identification and training of researchers, the centers' facilities and advantages and/or disadvantages of performing sponsored trials. Results: 75.6% of the centers were located in southern and southeastern Brazil. Most principal investigators were men with a mean age of 53.4 years. The clinical trials in the respiratory care setting focus on asthma and chronic obstructive pulmonar disease (COPD). 80% of the researchers cited delay of the Conep and Anvisa as a barrier to performing research. The advantages of participating in clinical trials were updating knowledge of the researcher and the team, and additional income for the team. The main disadvantages mentioned by the researchers included low financial compensation for the performed workload, and time availability. The median number of professionals per research center was six people, predominantly physicians. Conclusion: The number of research centers in the respiratory care setting in Brazil is still relatively small. The teams have good training for performing the clinical trials. Asthma and COPD are the most studied diseases in sponsored clinical trials. The main barrier is delay by the Conep and Anvisa. The factors that lead investigators to participate range from being updated along with the team, to site and staff financial issues; the main disadvantage is the low compensation for the required workload demand.

Resumo Objetivo: avaliar nos centros de pesquisas clínicas patrocinadas na área respiratória no Brasil o perfil, a logística e a estrutura. Método: questionários foram respondidos por pesquisadores principais (29) e subinvestigadores (30) de 39 centros de pesquisa relativos a identificação e formação dos pesquisadores, instalações dos centros e vantagens e desvantagens quanto à participação nas pesquisas patrocinadas. Resultados: setenta e cinco por cento (75,6%) dos centros se localizavam nas regiões Sul e Sudeste do Brasil. A maioria dos investigadores principais eram homens com média de idade de 53,4 anos. As pesquisas na área respiratória se concentravam no estudo da asma e da doença pulmonar obstrutiva crônica (DPOC). Oitenta por cento dos pesquisadores citaram a demora na Comissão Nacional de Ética em Pesquisa (Conep) e na Agência Nacional de Vigilância Sanitária (Anvisa) como fator de entrave para a realização das pesquisas. As vantagens em participar das pesquisas clínicas foram a atualização própria ou da equipe envolvida, com rendimento adicional para a equipe. A principal desvantagem apontada pelos pesquisadores foi a baixa compensação financeira em relação ao volume de trabalho e disponibilidade de tempo. A mediana de profissionais por centro de pesquisa foi de seis pessoas, com predominância de médicos. Conclusão: o número de centros na área respiratória no Brasil ainda é relativamente pequeno. As equipes apresentam boa formação para a realização das pesquisas. Asma e DPOC são as doenças mais estudadas pelas pesquisas clínicas patrocinadas. O principal entrave é a demora da Conep e da Anvisa. Os fatores que levam os investigadores a participarem variam desde atualização própria/equipe até questões financeiras para a equipe e o centro; a principal desvantagem relatada é a baixa remuneração diante da demanda de trabalho exigida.

A snapshot of cancer in Chile: analytical frameworks for developing a cancer policy

INTRODUCTION: The South American country Chile now boasts a life expectancy of over 80 years. As a consequence, Chile now faces the increasing social and economic burden of cancer and must implement political policy to deliver equitable cancer care. Hindering the development of a national cancer policy is the lack of comprehensive analysis of cancer infrastructure and economic impact. OBJECTIVES: Evaluate existing cancer policy, the extent of national investigation and the socio-economic impact of cancer to deliver guidelines for the framing of an equitable national cancer policy. METHODS: Burden, research and care-policy systems were assessed by triangulating objective system metrics -epidemiological, economic, etc. - with political and policy analysis. Analysis of the literature and governmental databases was performed. The oncology community was interviewed and surveyed. RESULTS: Chile utilizes 1% of its gross domestic product on cancer care and treatment. We estimate that the economic impact as measured in Disability Adjusted Life Years to be US$ 3.5 billion. Persistent inequalities still occur in cancer distribution and treatment. A high quality cancer research community is expanding, however, insufficient funding is directed towards disproportionally prevalent stomach, lung and gallbladder cancers. CONCLUSIONS: Chile has a rapidly ageing population wherein 40% smoke, 67% are overweight and 18% abuse alcohol, and thus the corresponding burden of cancer will have a negative impact on an affordable health care system. We conclude that the Chilean government must develop a national cancer strategy, which the authors outline herein and believe is essential to permit equitable cancer care for the country.

How sample size influences research outcomes

Sample size calculation is part of the early stages of conducting an epidemiological, clinical or lab study. In preparing a scientific paper, there are ethical and methodological indications for its use. Two investigations conducted with the same methodology and achieving equivalent results, but different only in terms of sample size, may point the researcher in different directions when it comes to making clinical decisions. Therefore, ideally, samples should not be small and, contrary to what one might think, should not be excessive. The aim of this paper is to discuss in clinical language the main implications of the sample size when interpreting a study.

O cálculo amostral faz parte dos estágios iniciais de realização de um estudo epidemiológico, clínico ou laboratorial. Há indicações éticas e metodológicas para o seu emprego na elaboração de um trabalho científico. Duas pesquisas, realizadas com a mesma metodologia obtendo resultados equivalentes, e que diferem apenas no tamanho da amostra, podem apontar para diferentes direções no processo de tomada de decisão clínica. Portanto, as amostras estudadas idealmente não devem ser pequenas e, ao contrário do que pode-se pensar, não devem ser excessivas. O objetivo desse artigo é discutir, numa linguagem clínica, as principais implicações do tamanho das amostras na interpretação de um estudo.

Análisis del número y diseño de ensayos clínicos y de la prescripción de medicamentos para indicaciones no incluidas en su ficha técnica en pacientes hospitalizados pediátricos / Analysis of clinical trials and off-label drug use in hospitalized pediatric patients

Introducción. La falta de ensayos clínicos en pediatría (ECP) conduce a la prescripción off-label de medicamentos en niños (POMN). Nuestro objetivo fue analizar el número y diseño de ECP y de POMN en los últimos años. Población, material y métodos. Estudio observacional, retrospectivo de ECP y POMN desde 2007 hasta 2012 realizados en un hospital infantil con 252 camas. Se analizó el número y diseño de ECP y de POMN por año y sus características. Resultados. Se evaluaron 87 ECP y 449 principios activos correspondientes a 1049 medicamentos prescritos a niños hospitalizados. De ellos, 117 (26%) se utilizaron fuera de prospecto. Los ECP fueron en aumento desde 2008 hasta 2011. Ese año, el 52,2% de los ECP fueron no aleatorizados ni controlados y solo 39,1% fueron aleatorizados controlados. Un 77% de los fármacos investigados eran prescritos fuera de prospecto. La POMN se mantuvo estable durante el estudio. Conclusiones. En nuestro hospital, ha aumentado la investigación en pediatría en los últimos años; los estudios no aleatorizados ni controlados fueron los más frecuentes. La POMN no se ha modificado.

Introduction. The lack of pediatric clinical trials (PCTs) leads to an off-label drug use (OLDU) in children. Our objective was to analyze the number and design of PCTs and OLDU in children in the past years. Population, material and methods. Observational and retrospective study on PCTs and OLDU in children, conducted from 2007 to 2012 in a 252-bed children's hospital. The number and design of PCTs and OLDU in children were analyzed by year and by characteristics. Results. Eighty-seven PCTs and 449 active ingredients corresponding to 1049 drugs prescribed to hospitalized children were evaluated.Of these, 117 (26%) were used off-label. The number of PCTs increased from 2008 to 2011. In 2011, 52.2% of PCTs were non-randomized and uncontrolled studies, and only 39.1% were randomized, controlled trials. Of all studied drugs, 77% corresponded to off-label use. OLDU in children remained steady throughout the study period. Conclusions. In our hospital, the number of pediatric research studies has increased in the past years, being non-randomized and uncontrolled studies the most frequent. OLDU in children has not changed

Bibliometric analysis of scientific articles published in Brazilian and international orthodontic journals over a 10-year period

Objective: This study aimed at describing the profiles of Brazilian and international studies published in orthodontic journals. Methods: The sample comprised 635 articles selected from two scientific journals, i.e., Dental Press Journal of Orthodontics and American Journal of Orthodontics and Dentofacial Orthopedics, which were analyzed at three different intervals over a 10-year period (1999 - 2004 - 2009). Articles were described in terms of knowledge domain, study design, and country of origin (or state of origin for Brazilian papers). Results: The most frequent study designs adopted in international studies were cohort (23.9%) and cross-sectional (21.7%) designs. Among Brazilian papers, cross-sectional studies (28.9%) and literature reviews (24.6%) showed greater frequency. The topics most often investigated were dental materials (17%) and treatment devices (12.4%) in international articles, with the latter topic being addressed by 16% of the Brazilian publications, followed by malocclusion, with 12.6%. In all cases, the most frequent countries of origin coincided with the countries of origin of each journal. Conclusions: The majority of the studies analyzed featured a low level of scientific evidence. Moreover, the findings showed that journals tend to publish studies produced in their own country of origin, and that there are marked discrepancies in the number of papers published by different Brazilian states. .

Objetivo: determinar o perfil das publicações nacionais e internacionais nos periódicos de Ortodontia. Métodos: foram avaliados 635 artigos da Revista Dental Press de Ortodontia e Ortopedia Facial e American Journal of Orthodontics and Dentofacial Orthopedics, em três tempos distintos, dentro de um intervalo de 10 anos (1999, 2004 e 2009), caracterizando as áreas de conhecimento, os delineamentos utilizados e identificando países e estados brasileiros com maior produção científica. Resultados: os delineamentos dos estudos internacionais mais utilizados foram estudos de coorte (23,9%) e transversal (21,7%). Em estudos nacionais, destacam-se os delineamentos transversais (28,9%) e revisão de literatura (24,6%). Nas publicações internacionais, as categorias temáticas mais pesquisadas foram materiais dentários (17%), além de dispositivos de tratamento (12,4%); essa mesma categoria esteve presente em 16% das publicações nacionais, e a má oclusão dentária em 12,6%. A nacionalidade das publicações mais observada foi a do próprio país de origem do periódico. Conclusões : a maioria dos artigos publicados refere-se a estudos de menor potencial para estabelecer evidências científicas. Além disso, a situação detectada ilustra a propensão das revistas publicarem os artigos produzidos dentro de seu país de origem, bem como as disparidades entre os estados do Brasil quanto ao número de publicações. .

La investigación científica en las instituciones de salud del Gobierno de la Ciudad de Buenos Aires / Scientific research in public health institutions of the City of Buenos Aires

Los hospitales con mayor actividad académica brindan mejor atención a sus pacientes. El Gobierno de la Ciudad de Buenos Aires (GCBA) posee una extensa red de establecimientos de salud, pero existe poca información sobre su producción científica. Nuestro objetivo fue estimar la proporción de artículos científicos en MEDLINE originados en hospitales del GCBA, evaluar la contribución de cada hospital, comparar el desempeño en relación al país y describir algunas características de los artículos. Es un estudio transversal por búsqueda en MEDLINE, incorporando el nombre de cada uno de los 33 hospitales del GCBA en el campo "affiliation". Sobre más de 22 millones de citas, 1781 correspondían a hospitales del GCBA (4.4% de las citas argentinas), 66.5% se encontraban en inglés, 83.7% se referían a humanos, 30.1% eran de los últimos 5 años, 8.3% correspondía a investigaciones con alto nivel de evidencia científica (ensayos clínicos y meta-análisis) y 31.1% a investigaciones que incluían niños. En comparación con el resto de la producción nacional, las citas del GCBA incluyen menos trabajos en inglés (66.5% vs. 90.0%; OR: 0.22; p < 0.0001), menos trabajos recientes (30.1% vs. 34.6%; OR: 0.81; p < 0.0001), más investigaciones en humanos (83.7% vs. 37.3%; OR: 8.65; p < 0.0001), más ensayos clínicos (8.0% vs. 2.8%; OR: 2.9; p < 0.0001) y más investigación en niños (31.1% vs. 9.2%; OR: 4.44; p < 0.0001). Los hospitales del GCBA aportaron 4.4% del total de citas atribuidas a la Argentina en MEDLINE. Las referencias de instituciones del GCBA incluyen más ensayos clínicos e investigación en niños, y son menos recientes.

Hospitals with academic activities offer better services to their patients. The Government of Buenos Aires City (GBAC) has an important network of health facilities, but there is little information regarding their academic activities. Our aim was to estimate the proportion of articles included in MEDLINE originated in GBAC hospitals, to evaluate their contribution regarding the whole country (Argentina), and to describe some characteristics of these papers. It is a cross-sectional study based on a MEDLINE search, using the name of each of the 33 GBAC hospitals in the "affiliation" field. Among 22 million references, 1781 belonged to GBAC hospitals (4.4% of all references from Argentina); 66.5% were in English, 83.7% were related to humans, 30.1% were from the last 5 years, 8.3% included high level scientific evidence research (meta-analysis or randomized controlled trials), and 31.1% included research in children. Regarding the rest of the references from Argentina, those from GBAC hospitals included less papers in English (66.5% vs. 90.0%; OR: 0.22; p < 0.0001), less recent papers (30.1% vs. 34.6%; OR: 0.81; p < 0.0001), more research in humans (83.7% vs. 37.3%; OR: 8.65; p < 0.0001), more randomized controlled trials (8.0% vs. 2.8%; OR: 2,9; p < 0.0001), and more research in children (31.1% vs. 9.2%; OR: 4.44; p < 0.0001). GBAC hospitals contributed with 4.4% of references attributed to Argentina in MEDLINE. References from GBAC hospitals were less recent, and included more randomized controlled trials and research in children.

Clinical trials in Brazilian journals of ophthalmology: where we are / Ensaios clínicos em periódicos brasileiros de oftalmologia: onde estamos

PURPOSE: To compare clinical trials published in Brazilian journals of ophthalmology and in foreign journals of ophthalmology with respect to the number of citations and the quality of reporting [by applying the Consolidated Standards for Reporting Trials (CONSORT) statement writing standards]. METHODS: The sample of this systematic review comprised the two Brazilian journals of ophthalmology indexed at Science Citation Index Expanded and six of the foreign journals of ophthalmology with highest Impact Factor® according ISI. All clinical trials (CTs) published from January 2009 to December 2010 at the Brazilians journals and a 1:1 randomized sample of the foreign journals were included. The primary outcome was the number of citations through the end of 2011. Subgroup analysis included language. The secondary outcome included likelihood of citation (cited at least once versus no citation), and presence or absence of CONSORT statement indicators. RESULTS: The citation counts were statistically significantly higher (P<0.001) in the Foreign Group (10.50) compared with the Brazilian Group (0.45). The likelihood citation was statistically significantly higher (P<0.001) in the Foreign Group (20/20 - 100%) compared with the Brazilian Group (8/20 - 40%). The subgroup analysis of the language influence in Brazilian articles showed that the citation counts were statistically significantly higher in the papers published in English (P<0.04). Of 37 possible CONSORT items, the mean for the Foreign Group was 20.55 and for the Brazilian Group was 13.65 (P<0.003). CONCLUSION: The number of citations and the quality of reporting of clinical trials in Brazilian journals of ophthalmology still are low when compared with the foreign journals of ophthalmology with highest Impact Factor®.

OBJETIVO: Comparar ensaios clínicos publicados em periódicos brasileiros de oftalmologia e em periódicos estrangeiros de oftalmologia em relação ao número de citações e à qualidade da informação [através da aplicação do Consolidated Standards for Reporting Trials (CONSORT) statement]. MÉTODOS: A amostra desta revisão sistemática abrangeu os dois periódicos brasileiras de oftalmologia indexaoas no Science Citation Index Expanded (Grupo Brasileiro) e seis dos periódicos estrangeiros de oftalmologia com maior fator de impacto de acordo com o ISI (Grupo Estrangeiro). Todos os ensaios clínicos, publicados entre janeiro de 2009 a dezembro de 2010, nos dois periódicos brasileiros e numa amostra aleatória 1:1 dos periódicos estrangeiros foram incluídos. O desfecho primário foi o número de citações até o final de 2011. A análise de subgrupos incluiu o idioma. O desfecho secundário incluiu a probabilidade de citação (citado ao menos uma vez versus não citado), e a presença ou ausência de indicadores da declaração CONSORT. RESULTADOS: O número de citações foi significativamente maior (P<0,001) no Grupo Estrangeiro (10,50) em comparação com o Grupo Brasileiro (0,45). A probabilidade de citação foi estatisticamente superior (P<0,001) no Grupo Estrangeiro (20/20-100%) comparado com o Grupo Brasileiro (8/20-41%). A análise de subgrupo sobre a influência da língua em artigos Brasileiros mostrou que o número de citações foi significativamente maior nos artigos publicados em Inglês (P<0,04). Dos 37 itens do CONSORT possíveis, a média para o Grupo Estrangeiro foi de 20,55 e para o Grupo Brasileiro foi 13,65 (P<0,003). CONCLUSÃO: O número de citações e a qualidade da redação dos ensaios clínicos em periódicos Brasileiros de oftalmologia ainda são baixos quando comparados com os periódicos estrangeiros de oftalmologia com mais alto fator de impacto.

Características de los ensayos clínicos autorizados en el Perú, 1995-2012 / Characteristics of clinical trials authorized in Peru: 1995-2012

Objetivos. Describir las principales características de los ensayos clínicos (EC) autorizados en el Perú desde 1995 a agosto de 2012. Materiales y métodos. Se realizó un estudio transversal, en el que se revisaron todos los expedientes de protocolos de EC presentados para su evaluación y posible aprobación al INS, cuyos datos forman parte del Registro Peruano de EC. Se realizó el análisis descriptivo de los estados de aprobación de los EC, fase de estudio, especialidad, y otras características afines a ellos. Resultados. Se encontraron 1475 EC, de los cuales 1255 (85,1%) fueron autorizados. De un EC registrado el año 1995 se incrementó a 176 ensayos presentados en el 2008, disminuyendo en el 2011 a 128 ensayos. Entre los EC aprobados, el 64,1% corresponden a EC en fase III. Oncología (22,4%), Infectología (15,5%) y Endocrinología (12,7%) fueron las especialidades más estudiadas y solo el 1.19%, corresponde a enfermedades tropicales desatendidas. Los hipoglicemiantes orales, antivirales de uso sistémico y antineoplásico fueron los medicamentos más estudiados. La industria farmacéutica transnacional fue el principal patrocinador (87,1%) y ejecutor de ensayos clínicos (62,3%) los cuales se realizan mayormente en Lima. Conclusiones. Los ensayos clínicos que se realizan en el país son principalmente en enfermedades no transmisibles y son estudios en fase III. La industria farmacéutica constituye el principal patrocinador. Solo el 1.2%, corresponde a enfermedades tropicales desatendidas, lo cual muestra la poca atención a los problemas de salud de poblaciones en situaciones de vulnerabilidad.

Objective. To identify main characteristics of clinical trials (CT) authorized by the National Institute of Health (INS) of Peru from 1995 to August 2012. Material and methods. Cross-sectional study, which reviewed all records of CT submitted for review and possible approval by INS, whose data are part of the Peruvian Registry of Clinical Trials. We performed a descriptive analysis of the states of the CT approval and other characteristics. Results. 1475 clinical trials were assessed, of which 1255 (85.1%) were authorized. From 1 clinical trial officially registered in 1995, its quantity increased to 176 trials submitted in 2008, and then, declined to 128 in 2011. Among the approved CT, 64.1% was in Phase III. Oncology (22.4%), infectious diseases (15.5%) and endocrinology (12.7%) were the most studied specialties and a only 1.2% were for neglected tropical diseases. The oral hypoglycemic drugs, systemic antiviral and antineoplastic agents were the most studied investigational products. The transnational pharmaceutical industry was the main sponsor (87.1%) and executors (62.3%) of clinical trials were mostly in Lima. Conclusions. Clinical trials in Peru mainly focus on noncommunicable diseases and phase III studies. The pharmaceutical industry is the main sponsor. A very small number of authorized clinical trials in Peru were for neglected tropical diseases that shows little attention to the health problems in vulnerable populations.

El número necesario a tratar como medida de efecto en el tratamiento de la trombocitopenia inmune primaria / The number needed to treat as a measure of effect in the treatment of primary immune thrombocytopenia

En estudios aleatorios placebo controlados o comparativos cuyos resultados son de tipo binario, el efecto de un determinado tratamiento puede ser reportado usando la reducción absoluta del riesgo (RAR) y el número necesario a tratar (NNT), el cual es el inverso de la RAR (1/RAR=NNT). El objetivo del presente estudio fue realizar una revisión de diferentes tipos de tratamiento en Trombocitopenia Inmune Primaria (PTI), calculando como medidas de efecto la RAR y el NNT con sus respectivos intervalos de confianza (IC 95%). El número necesario para dañar (NNH, del inglés Harm) se calcula de la misma forma que el NNT y señala el nivel de seguridad del medicamento, solo que en este caso se toma en cuenta los eventos adversos (escala CTCAE) del tratamiento en relación con el grupo control. Los resultados mostraron que el NNT en estudios aleatorios controlados fue mejor que en estudios de inferior diseño, Los resultados del NNH señalaron un nivel de seguridad aceptable para la mayoría de los tratamientos. Se pudo observar que la edad (menor a 40 años) y la condición no esplenectomizados influyen en algunas ocasiones en el reporte de NNT favorable. Se concluye que dadas las ventajas de la RAR y el NNT el cual engloba tanto la significación estadística como la clínica, deberían ser reportadas conjuntamente con otras medidas de efecto en cualquier trabajo observacional sobre tratamiento de PTI con resultados binarios o dicotómicos, porque orientan sustancialmente hacia la toma de decisiones clínicas apropiadas.

In randomized or comparative studies, when the outcomes are binary or dichotomous, the effect of a specific treatment can be reported using the absolute risk reduction (ARR) and the number needed to treat (NNT), which is the reciprocal of the ARR (1/ARR=NNT). The objective of the present study was to realize a review of the different modalities of treatment of primary immune thrombocytopenia (ITP), using as effect measurement the calculation of the ARR and NNT and their confidence intervals (CI95%). The number needed to harm (NNH) can be calculated with the same formula of NNT, taking in account only the adverse events (CTCAE scale) of the treatment in relation with those in the control group. The results showed the effect of different types of treatment of ITP. The NNT was better in randomized studies than those of inferior design. The NNH calculation showed the safe level of the intervention. It can be observed that age (youth) and no splenectomy condition exhibited some influence in the favorable NNT report. In conclusion, given the advantages of the ARR and the NNT for clinical decision making, it can be suggested that these measurements of effect should also be reported, in addition to other statistical measurements for ITP treatment or any observational study with dichotomous or binary outcomes.

Función de la estadística en el contexto de los ensayos clínicos / Role of statistics in the clinical trials

La complejidad y los elevados costos que se asocian al desarrollo de medicamentos han impuesto la búsqueda de estrategias más eficientes que combinen reducción de tiempo con calidad de investigación. La metodología estadística tiene una función fundamental en este proceso. En el presente trabajo se realiza una revisión bibliográfica de la función de la estadística en las investigaciones terapéuticas, cuyos objetivos consisten en describir cómo interviene la estadística en los ensayos clínicos y exponer algunos avances y retos que enfrenta el bioestadístico en el contexto actual del desarrollo de estos estudios. Se describe el proceso estadístico dentro del ensayo clínico desde un punto de vista práctico, exigencias regulatorias y disposición documental. Se exponen algunos temas metodológicos específicos y técnicas estadísticas desarrolladas con aplicaciones en estos estudios. En conclusión, la metodología estadística en los ensayos clínicos ha experimentado un desarrollo creciente en los últimos años. Las investigaciones proponen el uso de diseños flexibles que dinamizan los estudios y métodos de análisis más sensibles. Las entidades regulatorias establecen guías en estos temas que orientan para la presentación armonizada de ensayos clínicos ante diversas situaciones. La aplicación de técnicas estadísticas más sensibles y el uso de la tecnología que sustenta estos avances es un tema en desarrollo y con creciente presencia en la literatura de ensayos clínicos

The complexity and high costs associated to the development of drugs have brought about the search for more efficient strategies combining time saving and research quality. The statistical methodology plays a fundamental role in this process. The present paper made a literature review of the role of statistics in therapeutic research. The objectives were to describe how statistics participate in the clinical trials and to present some advances attained as well as the challenges met by the biostatician in the present context of development of these studies. The statistical process was described in the clinical trial from the practical viewpoint, including regulatory demands and documentary availability. Some specific methodological topics as well as application-developed statistical techniques were presented. It was concluded that the statistical methodology in clinical trials has experienced growing development in the last few years. The research suggested the use of flexible designs that would speed up the most sensitive studies and methods of analysis. The regulatory bodies set guidelines that give instructions for the harmonized presentation of clinical trials under various circumstances. The application of more sensitive statistical techniques and the use of technologies supporting these advances is a subject that is increasingly dealt with by the scientific literature on clinical trials