ANÁLISIS DE LOS ESTUDIOS DE FARMACOLOGÍA CLÍNICA DE ONCOLOGÍA AUTORIZADOS POR LA AGENCIA REGULATORIA NACIONAL EN ARGENTINA ENTRE 2018 Y 2022 / Analysis of oncology clinical pharmacology studies authorized by the national regulatory agency of Argentina between 2018 and 2022

El paradigma tradicional de la investigación clínica farmacológica comprende la realización de estudios de fase 1, 2 y 3. Sin embargo, el reciente avance de lo que se ha dado en llamar "medicina de precisión" ha impulsado el surgimiento de innovaciones en el diseño de ensayos clínicos, en especial en el área de la oncología. Este artículo tiene como propósito describir y caracterizar los estudios de farmacología clínica de oncología autorizados por la Administración Nacional de Medicamentos, Alimentos y Tecnología Médica (ANMAT) durante el período comprendido entre agosto de 2018 y julio de 2022; analizar el estado de situación de los diseños de los ensayos clínicos en oncología, las fases de investigación, los productos en investigación y el sitio de localización tumoral en relación con el avance de la medicina de precisión y los diseños innovadores.

The traditional paradigm of pharmacological clinical research involves carrying out phase 1, 2, and 3 studies. However, the recent advance of what has been called "precision medicine" has promoted the emergence of innovations in the design of clinical trials, especially in the area of oncology. The purpose of this article is to describe and characterize oncology clinical pharmacology studies authorized by the National Administration of Drugs, Food and Medical Devices (ANMAT) during the period from August 2018 to July 2022, and analyze the status of the clinical trial designs, research phases, investigational products and tumor site locations concerning the advancement of precision medicine and innovative designs

Protocolos maestros: Enfoque regulatorio de nuevos diseños en ensayos de farmacología clínica / Master Protocols: Regulatory approach about new clinical trial designs

El avance de la ciencia y tecnología en los últimos años dio lugar a la necesidad de dar respuesta a una mayor cantidad de preguntas en investigación de forma más eficiente. Esto ha provocado la generación de nuevos diseños en investigación, dando origen a los "protocolos maestros". A diferencia de los diseños tradicionales en los que en cada ensayo clínico se prueba habitualmente un solo fármaco, en una única población, con una patología determinada, los protocolos maestros utilizan una estructura con un diseño de ensayo clínico y un protocolo para evaluar simultáneamente múltiples fármacos y/o enfermedades, en múltiples sub-estudios. Entre estos novedosos diseños se pueden mencionar tres tipos: canasta (basket), paraguas (umbrella) y plataforma (platform) los cuales serán analizados en este artículo. Debido a su complejidad, el abordaje de estos nuevos modelos de ensayo clínico requiere la revisión y actualización permanente de los estándares vigentes y una constante discusión por parte de las diferentes agencias regulatorias a nivel mundial. Estos diseños no deben considerarse a priori como medios para reducir la rigurosidad de la planificación de los ensayos clínicos ni disminuir los estándares regulatorios, sino como herramientas para gestionar situaciones experimentales complejas. Desde el punto de vista regulatorio, para poder analizar y dar respuesta a estos desafíos, ANMAT cuenta, actualmente, con espacios de intercambio que permiten crear el ámbito apropiado de discusión científica-regulatoria que aliente el desarrollo de nuevos medicamentos, pero manteniendo estrictos estándares de calidad éticos y científicos. En esta revisión se plantea la necesidad de conocer en detalle estos nuevos diseños analizando sus potenciales beneficios y limitaciones

The need to answer a greater number of questions more efficiently has led to the generation of new designs in research, giving rise to the "master protocols". This term refers to a clinical trial design created to evaluate multiple hypotheses through substudies that are developed simultaneously and that may contain an adaptive design. Among these novel designs, three types can be mentioned: basket, umbrella and platform which will be analyzed in this article. Due to their complexity, the approach of these new clinical trial designs requires the continuing revision and updating of the current standards and a constant discussion by the different regulatory agencies worldwide. From the regulatory point of view, in order to analyze and satisfy these challenges, ANMAT currently has exchange spaces that allow the creation of the appropriate field of scientific-regulatory discussions that encourage the development of new medicines, while maintaining strict standards of ethical and scientific quality. This revision raises the need to know in detail these new designs analyzing their potential benefits and limitations.

Universal determination of microsatellite instability using BAT26 as a single marker in an Argentine colorectal cancer cohort.

Microsatellite instability (MSI) is a hallmark tool for Lynch syndrome (LS) screening and a prognostic marker for sporadic colorectal cancer (CRC). In regions with limited resources and scarce CRC molecular characterization as South America, the implementation of universal MSI screening is under debate for both its purposes. We sought to estimate the frequency of BAT26 in colorectal adenocarcinomas and to determine associated clinical and histological features. Consecutive patients from a CRC registry were included. BAT26 determination was performed in all cases; if instability was found, immunohistochemistry (IHC) and BRAF mutation analyses were done, as appropriate. Differences were assessed by chi-squared or Fisher's exact test, or by T test or Mann-Whitney. Multiple logistic regression was used to identify factors independently associated with BAT26-unstable tumors. We included 155 patients; mean age was 65.6 (SD 14.4) and 56.1% were male. The frequency of BAT26-unstable tumors was 22% (95% CI 15.7-29.3). Factors independently associated with BAT26-unstable tumors were right colon localization (OR 3.4, 95% CI 1.3-8.7), histological MSI features (OR 5.1, 95% CI 1.9-13.6) and Amsterdam criteria (OR 23.2, 95% CI 1.9-286.7). IHC was altered in 85.3% BAT26-unstable tumors and 70.6% lacked MLH1 expression; 47.8% of these harbored BRAF V600E mutation. We provide evidence to link the frequency of BAT26 to an increased diagnostic yield (up to 1.4-folds) of suspected LS cases in comparison to the revised Bethesda guidelines alone. In regions with limited resources, clinical and histological features associated with BAT26-unstable status could be useful to direct MSI screening in sporadic CRCs and may help guide clinical care and future research.

Síntomas gripales asociados a la vacunación antigripal en personal de salud / Flu-like symptoms associated with influenza vaccination in health personnel

Introducción: En el Hospital Italiano de Buenos Aires se realizó una campaña de vacunación masiva destinada al personalde la institución durante mayo de 2009.Objetivo: Medir síntomas gripales asociados a la vacunación en personal de salud. Métodos: Estudio de cohorte. Se compararon, mediante riesgo relativo, las incidencias de los síntomas gripales informados para la semana epidemiológica 20, por 400 vacunados durante dicha semana y 400 no vacunados, apareados por edad, sexo y profesión. Los síntomas comunicados dentro de las 48 horas posteriores a la vacunación se consideraron secundarios a ella. Resultados: Fueron encuestados 583 (72.5%) de los cuales 281 vacunados y 302 no vacunados: edad media 36 (DS 11) vs. 35.2 (DS 10.5); mujeres 54% vs. 57% y médicos 21% vs. 18%. En la semana de vacunación presentaron fiebre 12.46% vs. 6.95% (RR 1.79, IC95% 1.07-3), coriza 24.2% vs. 17.22% (RR 1.41 IC95%1.02-1.94), odinofagia 11.74% vs. 0.33%(RR 35.47 IC 95% 4.88-257), dolor corporal 18.86% vs. 14.57% (RR 1.29 IC 95% 0.9-1.87) vacunados y no vacunados, respectivamente. Se atribuyen a la vacuna: dolor corporal 9.25% (IC95% 6.3-13.6), coriza 8.19% (IC95% 5.4-12.31); fiebre 6.78% (IC95% 4.31-10.6) y odinofagia 4.27% (IC 95% 2.42-7.5). Y dolor de brazo 65%. Los médicos no informaronmayor frecuencia de síntomas gripales.Discusión: En la literatura, la odinofagia y la coriza no están asociadas a la vacunación, la frecuencia de los otros síntomas a las 48 horas fue similar a la informada. Conclusión: El síndrome gripal fue descripto con mayor frecuencia entre los vacunados y puede ser resultado de un sesgo de reporte.

Introduction: In May 2009, prior to the beginning of winter in the Southern hemisphere, a massive vaccination campaign for the personnel was performed at the Hospital Italiano de Buenos Aires. Objective: To assess symptoms associated with influenza vaccination in health personnel. Methods: In a cohort study, the impact of flu symptoms reported for the epidemiological week number 20 were compared using the relative risk between 400 vaccinated vs. 400 unvaccinated individuals matched for age, sex and occupation. Symptoms reported within 48 hours after vaccination were considered secondary this event. Results: 583 people were respondents (72.5%) of whom 281 were vaccinated vs. 302 who were unvaccinated (mean age, 36 yr (SD 11 yr) vs. 35.2 yr (SD 10.5 yr); women, 54% vs. 57%; doctors 21% vs. 18%, respectively). During the vaccination week, 12.46% vaccinated vs. 6.95% unvaccinated individuals presented fever (RR 1.79, CI95% 1.07-3); a cold, 24.2% vs. 17.2% (RR 1.41, CI95% 1.02-1.94); sore throat, 11.74% vs. 0.33% (RR 35.47, CI 95% 4.88-257); body pain, 18.86% vs. 14.57% (RR 1.29, CI 95% 0.9-1.87), respectively. Symptoms attributed to the vaccine were: body pain, 9.25% (CI95% 6.3-13.6); cold, 8.19% (CI95% 5.4-12.31); fever, 6.78% (CI95% 4.31-10.6); sore throat, 4.27% (CI 95% 2.42-7.5); and arm pain, 65%. Doctors did not report a higher frequency of flu symptoms.Discussion: Sore throat and cold are not symptoms commonly reported in association with vaccination. The frequency of other symptoms following the first 48 hours of vaccination was similar to previous reports. Conclusion: The flu syndrome was reported more frequently in vaccinated people as compared with those unvaccinated.However, these results might be due to a reporting bias.

Síntomas gripales asociados a la vacunación antigripal en personal de salud / Flu-like symptoms associated with influenza vaccination in health personnel

Introducción: En el Hospital Italiano de Buenos Aires se realizó una campaña de vacunación masiva destinada al personalde la institución durante mayo de 2009.Objetivo: Medir síntomas gripales asociados a la vacunación en personal de salud. Métodos: Estudio de cohorte. Se compararon, mediante riesgo relativo, las incidencias de los síntomas gripales informados para la semana epidemiológica 20, por 400 vacunados durante dicha semana y 400 no vacunados, apareados por edad, sexo y profesión. Los síntomas comunicados dentro de las 48 horas posteriores a la vacunación se consideraron secundarios a ella. Resultados: Fueron encuestados 583 (72.5%) de los cuales 281 vacunados y 302 no vacunados: edad media 36 (DS 11) vs. 35.2 (DS 10.5); mujeres 54% vs. 57% y médicos 21% vs. 18%. En la semana de vacunación presentaron fiebre 12.46% vs. 6.95% (RR 1.79, IC95% 1.07-3), coriza 24.2% vs. 17.22% (RR 1.41 IC95%1.02-1.94), odinofagia 11.74% vs. 0.33%(RR 35.47 IC 95% 4.88-257), dolor corporal 18.86% vs. 14.57% (RR 1.29 IC 95% 0.9-1.87) vacunados y no vacunados, respectivamente. Se atribuyen a la vacuna: dolor corporal 9.25% (IC95% 6.3-13.6), coriza 8.19% (IC95% 5.4-12.31); fiebre 6.78% (IC95% 4.31-10.6) y odinofagia 4.27% (IC 95% 2.42-7.5). Y dolor de brazo 65%. Los médicos no informaronmayor frecuencia de síntomas gripales.Discusión: En la literatura, la odinofagia y la coriza no están asociadas a la vacunación, la frecuencia de los otros síntomas a las 48 horas fue similar a la informada. Conclusión: El síndrome gripal fue descripto con mayor frecuencia entre los vacunados y puede ser resultado de un sesgo de reporte.(AU)

Introduction: In May 2009, prior to the beginning of winter in the Southern hemisphere, a massive vaccination campaign for the personnel was performed at the Hospital Italiano de Buenos Aires. Objective: To assess symptoms associated with influenza vaccination in health personnel. Methods: In a cohort study, the impact of flu symptoms reported for the epidemiological week number 20 were compared using the relative risk between 400 vaccinated vs. 400 unvaccinated individuals matched for age, sex and occupation. Symptoms reported within 48 hours after vaccination were considered secondary this event. Results: 583 people were respondents (72.5%) of whom 281 were vaccinated vs. 302 who were unvaccinated (mean age, 36 yr (SD 11 yr) vs. 35.2 yr (SD 10.5 yr); women, 54% vs. 57%; doctors 21% vs. 18%, respectively). During the vaccination week, 12.46% vaccinated vs. 6.95% unvaccinated individuals presented fever (RR 1.79, CI95% 1.07-3); a cold, 24.2% vs. 17.2% (RR 1.41, CI95% 1.02-1.94); sore throat, 11.74% vs. 0.33% (RR 35.47, CI 95% 4.88-257); body pain, 18.86% vs. 14.57% (RR 1.29, CI 95% 0.9-1.87), respectively. Symptoms attributed to the vaccine were: body pain, 9.25% (CI95% 6.3-13.6); cold, 8.19% (CI95% 5.4-12.31); fever, 6.78% (CI95% 4.31-10.6); sore throat, 4.27% (CI 95% 2.42-7.5); and arm pain, 65%. Doctors did not report a higher frequency of flu symptoms.Discussion: Sore throat and cold are not symptoms commonly reported in association with vaccination. The frequency of other symptoms following the first 48 hours of vaccination was similar to previous reports. Conclusion: The flu syndrome was reported more frequently in vaccinated people as compared with those unvaccinated.However, these results might be due to a reporting bias.(AU)