ABSTRACT
Los ensayos clínicos en Fase I se realzan con la participación de voluntarios sanos de prueban la seguridad y tolerabilidad de los productos farmacéuticos en investigación. En ellos, los participantes están expuestos a riesgos de medicamentos del estudio sin la posibilidad de un beneficio médico directo y, por lo general, deben pasar días o semanas en un centro de investigación. Los incentivos, como pagos monetarios se utilizan para incentivar la inscripción y compensar a los participantes por su tiempo. Estas características de los ensayos voluntarios sanos de fase I crean un contexto de investigación que difiere notablemente de la mayoría de las otras investigaciones clínicas, pues la mayoría de ellos son personas vulnerables económicamente. Este artículo presenta el objetivo de analizar factores bioéticos que inciden en el otorgamiento de incentivos a participantes voluntarios sanos en investigaciones Fase I.
Phase I Clinical Trials are conducted with the participation of healthy volunteers to test the safety and tolerability of pharmaceutical products. In them, participants are exposed to study drug risks without the possibility of direct medical benefit and usually must spend days or weeks at a research site. Incentives such as monetary payments are used to encourage enrollment and compensate participants for their time. These characteristics of Phase I healthy volunteer trials create a research context that differs markedly from most other clinical research, as most of them are financially vulnerable individuals. This paper aims to analyze bioethical factors that influence the granting of incentives to healthy volunteer participants in Phase I research.
ABSTRACT
To point out the importance of risk management for biological agents in phase I clinical trials, taking a healthy subject for an example who suffered from agranulocytosis after the application of Tozumab. In order to ensure the safety of the subjects and smooth progress of clinical trials, risk management should be implemented in several aspects such as: informing, screening, administration, subject training, and adverse event management and so on.
ABSTRACT
AIM: To introduce a novel and flexible model-assisted design for Phase I clinical trials: Bayesian optimal interval (BOIN) design, including the process of implementation, practical implementation, and evaluation of its performance. METHODS: BOIN design decides dose escalation/de-escalation by comparing the observed toxicity rate at the current dose with an escalation boundary and a de-escalation boundary that are optimized to minimize the probability of making incorrect decision of dose assignment. The application of the BOIN design is illustrated using a trial example. RESULTS: BOIN combines the advantages of the algorithm-based methods and model-based methods. It enjoys desirable statistical properties -it is optimal, safe, robust and easy to implement. Simulation study shows that the BOIN substantially outperforms the existing designs with higher accuracy to identify the maximum tolerated dose (MTD). CONCLUSION: BOIN design possesses the similar statistical performance to the much more complicated model-based designs. It is simple to implement, and easy to calibrate to meet the safety requirement mandated by regulatory agents. The BOIN design has been widely used in different types of cancers. It is a novel design that holds great potential to substantially improve phase I trials in China.
ABSTRACT
PURPOSE: When integrating molecularly targeted compounds in radiotherapy, synergistic effects of the systemic agent and radiation may extend the limits of patient tolerance, increasing the demand for understanding the pathophysiological mechanisms of treatment toxicity. In this Pelvic Radiation and Vorinostat (PRAVO) study, we investigated mechanisms of adverse effects in response to the histone deacetylase (HDAC) inhibitor vorinostat (suberoylanilide hydroxamic acid, SAHA) when administered as a potential radiosensitiser. MATERIALS AND METHODS: This phase I study for advanced gastrointestinal carcinoma was conducted in sequential patient cohorts exposed to escalating doses of vorinostat combined with standard-fractionated palliative radiotherapy to pelvic target volumes. Gene expression microarray analysis of the study patient peripheral blood mononuclear cells (PBMC) was followed by functional validation in cultured cell lines and mice treated with SAHA. RESULTS: PBMC transcriptional responses to vorinostat, including induction of apoptosis, were confined to the patient cohort reporting dose-limiting intestinal toxicities. At relevant SAHA concentrations, apoptotic features (annexin V staining and caspase 3/7 activation, but not poly-(ADP-ribose)-polymerase cleavage) were observed in cultured intestinal epithelial cells. Moreover, SAHA-treated mice displayed significant weight loss. CONCLUSION: The PRAVO study design implemented a strategy to explore treatment toxicity caused by an HDAC inhibitor when combined with radiotherapy and enabled the identification of apoptosis as a potential mechanism responsible for the dose-limiting effects of vorinostat. To the best of our knowledge, this is the first report deciphering mechanisms of normal tissue adverse effects in response to an HDAC inhibitor within a combined-modality treatment regimen.
Subject(s)
Animals , Humans , Mice , Apoptosis , Cells, Cultured , Clinical Trials, Phase I as Topic , Cohort Studies , Drug-Related Side Effects and Adverse Reactions , Epithelial Cells , Gene Expression , Histone Deacetylase Inhibitors , Histone Deacetylases , Histones , Hydroxamic Acids , Microarray Analysis , Radiotherapy , Weight LossABSTRACT
Subject recruitment is an important part of clinical researches. It should follow the ethical principles of fairness and representativeness. The recruitment process should pay attention to protecting the privacy of sub-jects. Various recruitment materials must be approved by the ethics committee before use. Whether could recruit el-igible subjects during Phase I clinical trials will have a significant impact on the results, which should attract the relevant persons′attention including the ethics committee, researchers, clinical research associate and the sponsor.