Reacciones adversas en ensayos clínicos con nuevos fármacos conducidos en Brasil: años 2000 y 2012 / Adverse reactions in clinical trials carried out in Brazil with new drugs, years 2000-2012

Introducción: los ensayos clínicos constituyen un diseño de tipo experimental utilizado para evaluar cualquier actuación diagnóstica y terapéutica aplicada a humanos.Objetivo: evaluar los relatos de reacciones adversas a medicamentos, en cuanto a causalidad, gravedad, edad y grupos vulnerables en protocolos de ensayos clínicos con nuevos fármacos analizados en el Comité de Ética de la Investigación de la Secretaria de Salud de Brasilia. Distrito Federal, Brasil.Método: estudio observacional, descriptivo y transversal, en la modalidad de estudio de caso, se consideró como universo de trabajo los proyectos evaluados por el Comité de Ética en Investigación-CEI/SES/DF en el período comprendido entre los años 2000 y 2012. Resultados: el 59 por ciento de las investigaciones se correspondieron con estudios nacionales y el 41 por ciento con estudios internacionales. La industria farmacéutica fue la fuente financiadora en el 65 por ciento de los casos y en el 41 por ciento de ellos existió participación extranjera. De los medicamentos estudiados el 19 por ciento no poseían registro en la Agencia Nacional de Vigilancia Sanitaria-ANVISA y solo en el 9,5 por ciento de los ensayos se utilizó grupo control. Las reacciones adversas fueron consideradas como relacionadas a los medicamentos, posibles o improbables en el 15,7 por ciento, 19,8 por ciento y 63,6 por ciento, respectivamente.Conclusiones: la mayor parte de las investigaciones en las que se evaluaron nuevos medicamentos fueron conducidas por instituciones brasileñas y en la mayoría se recibió financiación internacional. La falta de registro de algunos de los nuevos productos en la agencia nacional reguladora y la no existencia de grupo control, en diferentes ensayos clínicos, fueron limitaciones identificadas en el proceso de evaluación. Se identificó la no existencia de modelos únicos legalmente validados para la evaluación de los eventos adversos a los medicamentos(AU)

Background: clinical trials are an experimental kind design used to assess any diagnostic and therapeutic performance applied to human beings.Aim: to assess the reports of adverse reactions to drugs, according to causality, seriousness, age and vulnerable groups in protocols of new drugs clinical trials analyzed in the Research Ethic Committee of Brasilia Health Secretariat, Federal District, Brazil. Method: cross-sectional, descriptive, observational study of case study kind. As universe of work, we took into account the projects assessed by the Research Ethic Committee of Brasilia Health Secretariat, Federal District (CEI/SES/DF in Portuguese) in the period from 2000 to 2012.Outcomes: 59 percent of the research corresponded to national studies and 41 percent to international ones. The pharmaceutical industry was the financeable source in 65 percent of the cases and there it was foreign participation in 41 percent of them. 19 percent of the studied drugs were not registered in the National Agency of Sanitary Surveillance (ANVISA in Portuguese) and control group was used in only 9,5 percent of the trials. The adverse reactions were considered as related to drugs, possible or improbable in 15,7 percent, 19,8 percent and 63,6 percent, respectively.Conclusions: most of the research where new drugs were assessed was carried out by Brazilian institutions and most of them received international financial support. The lack of registration of several new products in the national regulatory agency and not using control groups were limitations identified during the assessing process in several clinical trials. We identified the inexistence of unique models legally validated for the evaluation of adverse events to drugs(AU)

[Efficacy of TAS-102].

Of late, there has been rapid development of chemotherapeutic agents for treating metastatic colorectal cancers. However, the so-called "druglag" is a long-standingproblem; it refers to the drugapproval delays in Japan that occur after drugs have been developed and approved in Europe and the USA. Clinical trials for the drugTAS -102 were stopped in the USA, but the drugwas evaluated in phase I and II clinical trials in Japan. The Phase II trial for TAS-102 in Japan provided positive results, and it received approval in Japan first, ahead of the world. Data from the global phase III RECOURSE trial were presented in the ESMO-GI 2014, where the efficacy of TAS-102 was proved again. Herein, we present data about the efficacy and side effects of TAS-102 from each clinical trial.

Evaluating the risks of clinical research: direct comparative analysis.

OBJECTIVES: Many guidelines and regulations allow children and adolescents to be enrolled in research without the prospect of clinical benefit when it poses minimal risk. However, few systematic methods exist to determine when research risks are minimal. This situation has led to significant variation in minimal risk judgments, raising concern that some children are not being adequately protected. To address this concern, we describe a new method for implementing the widely endorsed "risks of daily life" standard for minimal risk. This standard defines research risks as minimal when they do not exceed the risks posed by daily life activities or routine examinations. METHODS: This study employed a conceptual and normative analysis, and use of an illustrative example. RESULTS: Different risks are composed of the same basic elements: Type, likelihood, and magnitude of harm. Hence, one can compare the risks of research and the risks of daily life by comparing the respective basic elements with each other. We use this insight to develop a systematic method, direct comparative analysis, for implementing the "risks of daily life" standard for minimal risk. The method offers a way of evaluating research procedures that pose the same types of risk as daily life activities, such as the risk of experiencing anxiety, stress, or other psychological harm. We thus illustrate how direct comparative analysis can be applied in practice by using it to evaluate whether the anxiety induced by a respiratory CO2 challenge poses minimal or greater than minimal risks in children and adolescents. CONCLUSIONS: Direct comparative analysis is a systematic method for applying the "risks of daily life" standard for minimal risk to research procedures that pose the same types of risk as daily life activities. It thereby offers a method to protect children and adolescents in research, while ensuring that important studies are not blocked because of unwarranted concerns about research risks.

A multivariate approach linking reported side effects of clinical antidepressant and antipsychotic trials to in vitro binding affinities.

The vast majority of approved antidepressants and antipsychotics exhibit a complex pharmacology. The mechanistic understanding of how these psychotropic medications are related to adverse drug reactions (ADRs) is crucial for the development of novel drug candidates and patient adherence. This study aims to associate in vitro assessed binding affinity profiles (39 compounds, 24 molecular drug targets) and ADRs (n=22) reported in clinical trials of antidepressants and antipsychotics (n>59.000 patients) by the use of robust multivariate statistics. Orthogonal projection to latent structures (O-PLS) regression models with reasonable predictability were found for several frequent ADRs such as nausea, diarrhea, hypotension, dizziness, headache, insomnia, sedation, sleepiness, increased sweating, and weight gain. Results of the present study support many well-known pharmacological principles such as the association of hypotension and dizziness with α1-receptor or sedation with H1-receptor antagonism. Moreover, the analyses revealed novel or hardly investigated mechanisms for common ADRs including the potential involvement of 5-HT6-antagonism in weight gain, muscarinic receptor antagonism in dizziness, or 5-HT7-antagonism in sedation. To summarize, the presented study underlines the feasibility and value of a multivariate data mining approach in psychopharmacological development of antidepressants and antipsychotics.

Crecimiento bacteriano en la úlcera del pie diabético previo al uso de Heberprot-P / Bacterial growth in diabetic foot ulcer prior to Heberprot-P

Objetivo: determinar el comportamiento del crecimiento microbiológico en las úlceras de pie diabético, previo al uso del Heberprot-P. Métodos: estudio descriptivo mediante la revisión de las historias clínicas de 52 pacientes, incluidos en los ensayos clínicos fase I y II del Heberprot-P en la úlcera de pie diabético. Se tomaron 63 muestras y se consideró el estudio microbiológico realizado en cualquier momento de su evolución, en el período de estudio.Resultados: cuatro muestras resultaron negativas y 29 positivas a Staphylococcus aureus meticillin resistente, que fue el germen más frecuentemente cultivado, por lo que un tercio de los pacientes requirió tratamiento antimicrobiano. Conclusiones: se recomienda realizar estudio microbiológico a todos los pacientes con úlcera de pie diabético, previo al uso de Heberprot-P aun cuando no existan evidencias clínicas de infección local.(AU)

Objective: to determine the microbiological growth behavior in diabetic foot ulcers, pre Heberprot-P. Methods: descriptive study was conducted by reviewing the medical records of 52 patients enrolled in Heberprot-P clinical trials phase I and II of diabetic foot ulcer. 63 samples were taken and microbiological study was considered at any point in its evolution in the study period. Results: four samples were negative and 29 positive to Staphylococcus aureus meticillin resistant, which was the most frequently cultivated germ, so that one third of the patients required antibiotic treatment. Conclusions: microbiological study is recommended to all patients with diabetic foot ulcer, prior to the use of Heberprot-P even when there is no clinical evidence of local infection(AU)