Asunto(s)
Planificación en Desastres , Fiebre Hemorrágica Ebola/tratamiento farmacológico , Fiebre Hemorrágica Ebola/prevención & control , Cooperación Internacional , África Occidental/epidemiología , Ensayos Clínicos Fase I como Asunto/tendencias , Brotes de Enfermedades/prevención & control , Vacunas contra el Virus del Ébola , Fiebre Hemorrágica Ebola/epidemiología , HumanosAsunto(s)
Tecnología Farmacéutica/tendencias , Vacunas de ADN/uso terapéutico , Animales , Ensayos Clínicos Fase I como Asunto/tendencias , Enfermedades Transmisibles/tratamiento farmacológico , Enfermedades Transmisibles/genética , Enfermedades Transmisibles/inmunología , Humanos , Vacunas de ADN/genéticaRESUMEN
BACKGROUND: Phase I trials have traditionally been designed to assess toxicity and establish phase II doses with dose-finding studies and expansion cohorts but are frequently exceeding the traditional sample size to further assess endpoints in specific patient subsets. The scientific objectives of phase I expansion cohorts and their evolving role in the current era of targeted therapies have yet to be systematically examined. METHODS: Adult therapeutic phase I trials opened within Dana-Farber/Harvard Cancer Center (DF/HCC) from 1988 to 2012 were identified for sample size details. Statistical designs and study objectives of those submitted in 2011 were reviewed for expansion cohort details. RESULTS: Five hundred twenty-two adult therapeutic phase I trials were identified during the 25 years. The average sample size of a phase I study has increased from 33.8 patients to 73.1 patients over that time. The proportion of trials with planned enrollment of 50 or fewer patients dropped from 93.0% during the time period 1988 to 1992 to 46.0% between 2008 and 2012; at the same time, the proportion of trials enrolling 51 to 100 patients and more than 100 patients increased from 5.3% and 1.8%, respectively, to 40.5% and 13.5% (χ(2) test, two-sided P < .001). Sixteen of the 60 trials (26.7%) in 2011 enrolled patients to three or more sub-cohorts in the expansion phase. Sixty percent of studies provided no statistical justification of the sample size, although 91.7% of trials stated response as an objective. CONCLUSIONS: Our data suggest that phase I studies have dramatically changed in size and scientific scope within the last decade. Additional studies addressing the implications of this trend on research processes, ethical concerns, and resource burden are needed.
Asunto(s)
Bioestadística/métodos , Instituciones Oncológicas , Ensayos Clínicos Fase I como Asunto/tendencias , Estudios de Cohortes , Interpretación Estadística de Datos , Tamaño de la Muestra , Centros Médicos Académicos , Boston , Industria Farmacéutica , HumanosAsunto(s)
Dopamina/metabolismo , Terapia Genética/métodos , Enfermedad de Parkinson/terapia , Putamen/metabolismo , Ensayos Clínicos Fase I como Asunto/tendencias , Ensayos Clínicos Fase II como Asunto/tendencias , Francia , Vectores Genéticos/administración & dosificación , Glutamato Descarboxilasa/administración & dosificación , Glutamato Descarboxilasa/genética , Humanos , Infusiones Intraventriculares , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/metabolismo , Proyectos Piloto , Putamen/patología , Reino UnidoAsunto(s)
Ensayos Clínicos Fase I como Asunto/tendencias , Ensayos Clínicos Fase II como Asunto/tendencias , Ensayos Clínicos Fase III como Asunto/tendencias , Proyectos de Investigación/tendencias , Accidente Cerebrovascular/terapia , Relación Dosis-Respuesta a Droga , Humanos , Inutilidad Médica , Accidente Cerebrovascular/tratamiento farmacológico , Resultado del TratamientoAsunto(s)
Antineoplásicos/farmacología , Indazoles/farmacología , Compuestos Organometálicos/farmacología , Rutenio/farmacología , Saccharomyces cerevisiae/efectos de los fármacos , Animales , Ensayos Clínicos Fase I como Asunto/tendencias , Humanos , Compuestos de Rutenio , Saccharomyces cerevisiae/metabolismoRESUMEN
Acute kidney injury (AKI) is a common clinical entity with high morbidity and mortality rates and ever increasing medical costs. A large number of patients who are hospitalized with morbidities such as diabetes, vascular disease, or chronic kidney disease are at high risk to develop AKI due to ischemic and nephrotoxic insults. The pathophysiology of ischemic and toxic forms of AKI is complex and includes tubular and vascular cell damage and inflammation. Given the seriousness of this essentially therapy-resistant complication, treatment beyond supportive measures and renal replacement therapy is urgently needed. Recent stem cell research has shown promising results, and cell therapy-based interventions are advancing into clinical trials. An example is our phase 1 clinical trial (NCT00733876) in which cardiac surgery patients at high risk of postoperative AKI were treated safely with allogeneic mesenchymal stem cells. Together with the introduction of biomarkers for an earlier and specific AKI diagnosis, currently tested stem cell-based therapies are expected to provide an entirely new class of diagnostic and therapeutic tools.
Asunto(s)
Lesión Renal Aguda/fisiopatología , Lesión Renal Aguda/terapia , Riñón/fisiología , Trasplante de Células Madre Mesenquimatosas/métodos , Regeneración/fisiología , Lesión Renal Aguda/diagnóstico , Anciano , Ensayos Clínicos Fase I como Asunto/tendencias , Humanos , Masculino , Diálisis Renal/métodosRESUMEN
Pediatric oncology is an unrivaled success story in the recent history of medicine. This success is mostly based on a persistent refinement of evidence based therapeutic concepts. With that regard physicians and their staff are highly experience in the conduct of prospective evidence based trials and are therefore competent partners for the pharmaceutical industry. In times of personalized medicine the individual target population is diminishing and the borders of indications are not more disease based. A situation that requires new concepts from the industry. Therefore children with cancer could benefit early from the current developments as well as the pharmaceutical industry could benefit from the legislative incentives through highly recruiting and well conducted prospective trials. Pivotal is a functional platform of communication in order to maintain a close dialogue between academia and pharmaceutical companies.
Asunto(s)
Antineoplásicos/uso terapéutico , Ensayos Clínicos Fase I como Asunto/tendencias , Ensayos Clínicos Fase II como Asunto/tendencias , Conducta Cooperativa , Industria Farmacéutica/tendencias , Drogas en Investigación/uso terapéutico , Comunicación Interdisciplinaria , Leucemia/tratamiento farmacológico , Neoplasias/tratamiento farmacológico , Medicina de Precisión/tendencias , Centros Médicos Académicos/economía , Centros Médicos Académicos/legislación & jurisprudencia , Antineoplásicos/efectos adversos , Niño , Ensayos Clínicos Fase I como Asunto/economía , Ensayos Clínicos Fase I como Asunto/legislación & jurisprudencia , Ensayos Clínicos Fase II como Asunto/economía , Ensayos Clínicos Fase II como Asunto/legislación & jurisprudencia , Análisis Costo-Beneficio/economía , Análisis Costo-Beneficio/legislación & jurisprudencia , Análisis Costo-Beneficio/tendencias , Industria Farmacéutica/economía , Industria Farmacéutica/legislación & jurisprudencia , Drogas en Investigación/efectos adversos , Drogas en Investigación/economía , Europa (Continente) , Predicción , Accesibilidad a los Servicios de Salud/economía , Accesibilidad a los Servicios de Salud/legislación & jurisprudencia , Accesibilidad a los Servicios de Salud/tendencias , Necesidades y Demandas de Servicios de Salud/economía , Necesidades y Demandas de Servicios de Salud/legislación & jurisprudencia , Necesidades y Demandas de Servicios de Salud/tendencias , Humanos , Terapia Molecular Dirigida/economía , Terapia Molecular Dirigida/tendencias , Programas Nacionales de Salud/economía , Programas Nacionales de Salud/legislación & jurisprudencia , Programas Nacionales de Salud/tendencias , Medicina de Precisión/economía , Estudios ProspectivosRESUMEN
Clinical trials increasingly occured in Asia during the past years as pharmaceutical industries embraced globalization in the clinical research fields. The trend is true with phase III clinical trials but not for early stage/phase I clinical trials in Asian countries is still under-represented. The conduct of phase I clinical trials is considered more sophisticated and difficult than the later stage clinical trials. There are continuing concerns from the pharmaceutical industries about the capacity of Asian countries in conducting this type of clinical trials. We highlighted several problems concerning the ethical and scientific issues, the implementation of ICH-GCP and local regulations, investigators and clinical trial subjects. The purpose of this paper is to give some perspectives addressing the problems in conducting phase I clinical trials. Improving collaboration and capacity building among the Asian countries is a solution that we proposed in order to increase the quality and quantity of phase I clinical trials in Asian countries.
Asunto(s)
Ensayos Clínicos Fase I como Asunto/tendencias , Asia , Ensayos Clínicos Fase I como Asunto/ética , Ensayos Clínicos Fase I como Asunto/legislación & jurisprudencia , Ensayos Clínicos Fase I como Asunto/normas , Industria Farmacéutica/ética , Industria Farmacéutica/legislación & jurisprudencia , Industria Farmacéutica/normas , Industria Farmacéutica/tendencias , Comités de Ética en Investigación , Regulación Gubernamental , Humanos , Internacionalidad , Selección de Paciente/ética , Guías de Práctica Clínica como AsuntoAsunto(s)
Insuficiencia Cardíaca/tratamiento farmacológico , Hidralazina/uso terapéutico , Dinitrato de Isosorbide/uso terapéutico , Negro o Afroamericano/genética , Animales , Ensayos Clínicos Fase I como Asunto/tendencias , Ensayos Clínicos Fase II como Asunto/tendencias , Tolerancia al Ejercicio/efectos de los fármacos , Tolerancia al Ejercicio/fisiología , Predicción , Insuficiencia Cardíaca/genética , Insuficiencia Cardíaca/fisiopatología , Humanos , Hidralazina/farmacología , Dinitrato de Isosorbide/farmacología , Volumen Sistólico/efectos de los fármacos , Volumen Sistólico/fisiologíaRESUMEN
Olfactory mucosa, the sense organ of smell, is an adult tissue that is regenerated and repaired throughout life to maintain the integrity of the sense of smell. When the sensory neurons of the olfactory epithelium die they are replaced by proliferation of stem cells and their axons grow from the nose to brain assisted by olfactory ensheathing cells located in the lamina propria beneath the sensory epithelium. When transplanted into the site of traumatic spinal cord injury in rat, olfactory lamina propria or purified olfactory ensheathing cells promote behavioural recovery and assist regrowth of some nerves in the spinal cord. A Phase I clinical trial demonstrated that autologous olfactory ensheathing cell transplantation is safe, with no adverse outcomes recorded for three years following transplantation. Autologous olfactory mucosa transplantation is also being investigated in traumatic spinal cord injury although this whole tissue contains many cells in addition to olfactory ensheathing cells, including stem cells. If olfactory ensheathing cells are proven therapeutic for human spinal cord injury there are several important practical issues that will need to be solved before they reach general clinical application. This article is part of a Special Issue entitled: Understanding olfactory ensheathing glia and their prospect for nervous system repair.
Asunto(s)
Bulbo Olfatorio/fisiología , Bulbo Olfatorio/trasplante , Mucosa Olfatoria/fisiología , Mucosa Olfatoria/trasplante , Traumatismos de la Médula Espinal/cirugía , Animales , Trasplante de Células/métodos , Trasplante de Células/tendencias , Ensayos Clínicos Fase I como Asunto/métodos , Ensayos Clínicos Fase I como Asunto/tendencias , Humanos , Bulbo Olfatorio/citología , Mucosa Olfatoria/citología , Traumatismos de la Médula Espinal/patologíaRESUMEN
Advances in our knowledge of the molecular mechanisms involved in cancer biology have contributed to an increase in novel target-specific oncology therapeutics. Unfortunately, clinical development of new drugs is an expensive and slow process, and the patient and financial resources needed to study the vast number of potential therapies are limited, requiring novel approaches to clinical trial design and patient recruitment. In addition, traditional efficacy endpoints may not be adequate to fully determine the therapeutic worth of the new classes of targeted agents. In this new era of drug development, it has become increasingly clear that new clinical trial design paradigms that examine nontraditional endpoints have become necessary to assist in prioritizing the development of the most promising agents. It is also vital that individual patient management be considered, and the subpopulations of patients most likely to derive benefit or experience harm from a new therapy be identified as early as possible. Phase I and II clinical trials allow investigators doing clinical research the opportunity to define these critical endpoints and subpopulations early on, before conducting large-scale randomized phase III clinical trials, which require an abundance of financial and patient resources.
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Oncología Médica/métodos , Oncología Médica/tendencias , Neoplasias/terapia , Práctica Profesional/tendencias , Terapias en Investigación , Ensayos Clínicos Fase I como Asunto/métodos , Ensayos Clínicos Fase I como Asunto/tendencias , Ensayos Clínicos Fase II como Asunto/métodos , Ensayos Clínicos Fase II como Asunto/tendencias , Drogas en Investigación/efectos adversos , Drogas en Investigación/economía , Drogas en Investigación/uso terapéutico , Eficiencia , Humanos , Terapias en Investigación/métodos , Terapias en Investigación/tendencias , Resultado del TratamientoAsunto(s)
Antineoplásicos/uso terapéutico , Ensayos Clínicos Fase I como Asunto/tendencias , Neoplasias/tratamiento farmacológico , Neoplasias/enzimología , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Pirazoles/uso terapéutico , Piridinas/uso terapéutico , Quinasa de Linfoma Anaplásico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/enzimología , Crizotinib , Humanos , Linfoma Anaplásico de Células Grandes/tratamiento farmacológico , Linfoma Anaplásico de Células Grandes/enzimología , Proteínas Tirosina Quinasas/genética , Proteínas Tirosina Quinasas ReceptorasRESUMEN
The concept of microdosing has been around for approximately 10 years. In this time there have been an increasing number of drugs reported in the literature where the pharmacokinetics at a microdose have been compared with those observed at a therapeutic dose. Currently, approximately 80% of the microdose pharmacokinetics available in the public domain have been shown to scale to those observed at a therapeutic dose, within a twofold difference. Microdosing is now being extended into areas of drug development other than purely pharmacokinetic prediction. Microdosing has been applied to the study of drug-drug interactions by giving human volunteers a microdose of the candidate drug before and after the administration of a drug known to inhibit or induce certain enzymes, such as the cytochrome P450s. Early data on the metabolism of a drug candidate can be obtained by administering a (14)C-drug to human volunteers and comparing the plasma concentration-time curves for total (14)C and unchanged parent compound. Full metabolic profiles can be generated as an early indication of the drug's metabolism in humans, prior to Phase 1 clinical studies. Microdosing is also being applied to situations where the concentration of a drug in cell or tissue types is key to its efficacy. The application of microdosing as a tool in drug development is therefore widening into new and previously unforeseen fields.
Asunto(s)
Ensayos Clínicos Fase I como Asunto/métodos , Ensayos Clínicos Fase I como Asunto/tendencias , Animales , Interacciones Farmacológicas , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Humanos , Preparaciones Farmacéuticas/metabolismo , FarmacocinéticaRESUMEN
Evaluation of: Fujii M, Tomita K, Nishijima W et al. Phase I/II study of S-1 plus cisplatin combination chemotherapy in patients with advanced/recurrent head and neck cancer. Jpn. J. Clin. Oncol. 40(3), 214-221 (2010). A combination of 5-fluorouracil (5-FU) and cisplatin is the most commonly used chemotherapy regimen in patients with advanced head and neck cancer (HNC). Japanese investigators replaced 5-FU with the oral fluoropyrimidine S-1 (40 mg/m(2) twice daily on days 1-14 every 4 weeks) to treat patients with locally advanced, recurrent, or metastatic HNC; and determined that the dose of cisplatin on day 8 should be 70 mg/m(2). The authors also studied the efficacy and safety of this regimen in a continuing Phase II trial. Treatment with S-1 plus cisplatin resulted in a confirmed response rate of 44.1% and a median overall survival duration of 16.7 months. The most common grade 3 or 4 adverse events included anorexia (26.5%), nausea (14.7%), and neutropenia/thrombocytopenia (11.8%). Despite inclusion of patients heterogeneous in disease status and incomplete response evaluation, this study demonstrated that S-1 in combination with cisplatin is feasible for treatment of advanced/recurrent HNC.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Animales , Antimetabolitos Antineoplásicos/administración & dosificación , Cisplatino/administración & dosificación , Ensayos Clínicos Fase I como Asunto/métodos , Ensayos Clínicos Fase I como Asunto/tendencias , Ensayos Clínicos Fase II como Asunto/métodos , Ensayos Clínicos Fase II como Asunto/tendencias , Combinación de Medicamentos , Neoplasias de Cabeza y Cuello/mortalidad , Humanos , Ácido Oxónico/administración & dosificación , Tasa de Supervivencia/tendencias , Tegafur/administración & dosificación , Resultado del TratamientoRESUMEN
Pancreatic cancer is sometimes called a "silent killer" because it is often not diagnosed until it is advanced. It remains the fourth leading cause of cancer-related death in the United States. Gemcitabine has been the front line therapy for advanced pancreatic cancer over the past 10 years. Over this time period, survival benefit has not been able to improve substantially from studies of gemcitabine-based combination therapy. A breakthrough to improve treatment options in this setting is needed. In the 2010 ASCO Gastrointestinal Cancers Symposium in Orlando, Florida, USA, several abstracts were presented to explore new agents or combinations as first-line therapy in locally advanced or metastatic settings. In this article, we review and summarize the findings from these studies.