RESUMO
This publication describes uniform definitions for cardiovascular and stroke outcomes developed by the Standardized Data Collection for Cardiovascular Trials Initiative and the US Food and Drug Administration (FDA). The FDA established the Standardized Data Collection for Cardiovascular Trials Initiative in 2009 to simplify the design and conduct of clinical trials intended to support marketing applications. The writing committee recognizes that these definitions may be used in other types of clinical trials and clinical care processes where appropriate. Use of these definitions at the FDA has enhanced the ability to aggregate data within and across medical product development programs, conduct meta-analyses to evaluate cardiovascular safety, integrate data from multiple trials, and compare effectiveness of drugs and devices. Further study is needed to determine whether prospective data collection using these common definitions improves the design, conduct, and interpretability of the results of clinical trials.
Assuntos
Doenças Cardiovasculares/diagnóstico , Coleta de Dados/normas , Determinação de Ponto Final/normas , Acidente Vascular Cerebral/diagnóstico , Ensaios Clínicos como Assunto , Humanos , Estados Unidos , United States Food and Drug AdministrationAssuntos
Cardiomiopatia Dilatada/etiologia , Distrofia Muscular de Duchenne/complicações , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Animais , Arritmias Cardíacas/tratamento farmacológico , Arritmias Cardíacas/etiologia , Bancos de Espécimes Biológicos/organização & administração , Cardiomiopatia Dilatada/tratamento farmacológico , Cardiomiopatia Dilatada/terapia , Ensaios Clínicos como Assunto , Terapia Combinada , Técnicas de Diagnóstico Cardiovascular , Modelos Animais de Doenças , Genótipo , Glucocorticoides/uso terapêutico , Coração Auxiliar , Humanos , Masculino , Distrofia Muscular de Duchenne/genética , Fenótipo , Sistema de Registros , Transtornos Respiratórios/etiologia , Transtornos Respiratórios/terapia , Respiração Artificial , Disfunção Ventricular Esquerda/tratamento farmacológico , Disfunção Ventricular Esquerda/etiologia , Disfunção Ventricular Esquerda/terapiaRESUMO
Drug-induced cardiac toxicity is a recognized challenge in development and implementation of pharmacotherapy. Appropriate biomarkers are needed to detect these abnormalities early in development and to manage the risk of potentially cardiotoxic drugs or biologic agents. Circulating cardiac troponin (cTn) is the most widely used biomarker for detection of myocardial injury. Although most commonly used to detect myonecrosis in the setting of ischemia, cTns are also elevated with other acute and chronic disease processes, including heart failure, renal failure, sepsis, pulmonary embolic disease, and many others. High-sensitivity assays for both cTnI and cTnT are now available that achieve acceptable imprecision (coefficient of variation <10%) at the 99th percentile of a normal reference population. Even more sensitive assays are being developed that detect cTn in ranges that are near the level of normal cellular turnover (apoptosis). These properties of cTn and the continuing evolution of highly sensitive assays position cTn as a potentially uniquely informative marker for early detection of cardiac toxicity. This article summarizes collaborative discussions among key stakeholders in the Cardiac Safety Research Consortium about the use of cTn monitoring in drug development.
Assuntos
Pesquisa Biomédica , Fármacos Cardiovasculares/efeitos adversos , Avaliação de Medicamentos , Cardiopatias/sangue , Coração/efeitos dos fármacos , Troponina/sangue , United States Food and Drug Administration , Animais , Fármacos Cardiovasculares/uso terapêutico , Educação Médica Continuada , Cardiopatias/tratamento farmacológico , Humanos , Estados UnidosRESUMO
OBJECTIVE: It was the aim of this study to document the risks of symptomatic patients with angina in placebo-controlled, anti-anginal drug development trials in which symptom-limited exercise testing was used as the primary endpoint. PATIENTS AND METHODS: The original case report forms submitted to the United States Food and Drug Administration in support of approval of new or supplemental new drug applications between 1973 and 2001 were identified and subjected to a by-patient meta-analysis, utilizing both a maximum likelihood analysis and classical Mantel-Haenszel methods. RESULTS: There were 63 placebo-controlled, clinical trials that randomized 10,865 patients, with 1,047 patient-years of observation time. The trials involved 21 different chemical entities from 4 different drug classes. The relative risk (RR) for withdrawal (placebo compared to drug-treated patients) was not increased [RR = 0.92, 95% confidence interval (CI) 0.78-1.08; p = 0.28]. Of interest, a RR of 0.54 (95% CI 0.26-1.04; p < 0.068) for irreversible harm (a combination of cerebrovascular accidents, myocardial infarction and death) and a RR of 0.89 (95% CI 0.61-1.30; p = 0.56) for serious cardiovascular events (myocardial infarction, congestive heart failure, cerebrovascular accidents) both non-statistically significantly favored being randomized to placebo. CONCLUSIONS: For the development of current or future drugs for the treatment of angina, there is no obvious contraindication to the use of placebo controls and exercise tolerance testing.
Assuntos
Angina Pectoris/tratamento farmacológico , Segurança do Paciente , Placebos/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto/efeitos adversos , Acetanilidas/uso terapêutico , Antagonistas Adrenérgicos beta/uso terapêutico , Angina Instável/tratamento farmacológico , Bloqueadores dos Canais de Cálcio/uso terapêutico , Doenças Cardiovasculares/induzido quimicamente , Aprovação de Drogas , Inibidores Enzimáticos/uso terapêutico , Feminino , Hospitalização/estatística & dados numéricos , Humanos , Masculino , Prontuários Médicos/estatística & dados numéricos , Pessoa de Meia-Idade , Nitratos/uso terapêutico , Variações Dependentes do Observador , Pacientes Desistentes do Tratamento/estatística & dados numéricos , Piperazinas/uso terapêutico , Ranolazina , Medição de Risco/métodos , Fatores de Risco , Falha de TratamentoRESUMO
This white paper, prepared by members of the Cardiac Safety Research Consortium, discusses several important issues regarding the evaluation of ventricular arrhythmias in early clinical pharmacology trials and their potential consequences for later clinical drug development. Ventricular arrhythmias are infrequent but potentially important medical events whose occurrence in early clinical pharmacology trials can dramatically increase safety concerns. Given the increasing concern with all potential safety signals and the resultant more extensive electrocardiographic monitoring of subjects participating in early phase trials, an important question must be addressed: Are relatively more frequent observations of ventricular arrhythmias related simply to more extensive monitoring, or are they genuinely related to the drug under development? The discussions in this paper provide current thinking and suggestions for addressing this question.
Assuntos
Arritmias Cardíacas/induzido quimicamente , Ensaios Clínicos Fase I como Assunto , Arritmias Cardíacas/epidemiologia , Arritmias Cardíacas/fisiopatologia , Ensaios Clínicos Fase I como Assunto/normas , Análise Custo-Benefício , Descoberta de Drogas , Eletrocardiografia , Humanos , Monitorização Fisiológica , Seleção de Pacientes , Prevalência , Medição de Risco , TelemetriaRESUMO
Electrocardiographic monitoring is an integral component of the clinical assessment of cardiac safety of all compounds in development. The International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use E14 guideline recommends a dedicated study to evaluate drug-induced effects on cardiac repolarization ("thorough QT/QTc study"). There has been limited published information on QT interval changes secondary to therapeutic proteins; however, in theory, biologic therapies may affect cardiac electrical activity either directly or indirectly. This article summarizes scientific discussions of members of the Cardiac Safety Research Consortium and includes possible approaches to consider for the clinical evaluation of drug-induced QT prolongation in development programs of therapeutic proteins.
Assuntos
Arritmias Cardíacas , Pesquisa Biomédica/métodos , Eletrocardiografia/métodos , Guias de Prática Clínica como Assunto/normas , Proteínas/uso terapêutico , Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/fisiopatologia , Arritmias Cardíacas/terapia , HumanosRESUMO
Duchenne muscular dystrophy (DMD) is one of the most commonly recognized dystrophinopathies. There are no approved therapeutic options available for this disease but recent discoveries have led to hope that effective therapies might be forthcoming. With funding from patient advocacy groups, private investors, and governmental bodies such as the Food and Drug Administration Office of Orphan Product Development (FDA/OOPD), gene modification and other molecular therapies are being actively investigated. However, since DMD patients are few in number and disease manifestations vary considerably in early and late stages of disease, obtaining the data needed for full evaluation of putative therapies may prove challenging. Should ambulation remain the focus of Phase 2/3 studies or should consideration be given to the primary causes of late-stage morbidity and mortality, e.g., cardiac and respiratory dysfunction related to reduced or absent dystrophin production? It seems reasonable to argue that clinical trials planned for DMD should consider the entire population.
Assuntos
Tratamento Farmacológico/normas , Tratamento Farmacológico/tendências , Distrofia Muscular de Duchenne/tratamento farmacológico , Androgênios/uso terapêutico , Animais , Ensaios Clínicos como Assunto/métodos , Ensaios Clínicos como Assunto/normas , Gentamicinas/uso terapêutico , Humanos , Legislação de Medicamentos/normas , Legislação de Medicamentos/tendências , Distrofia Muscular de Duchenne/genética , Oxandrolona/uso terapêutico , Fenótipo , Doenças Raras/tratamento farmacológico , Pesquisa/normas , Esteroides/uso terapêutico , Estados Unidos , United States Food and Drug AdministrationAssuntos
Cardiologia/normas , Doenças Cardiovasculares/terapia , Ensaios Clínicos como Assunto/normas , Determinação de Ponto Final/normas , American Heart Association , Cardiologia/legislação & jurisprudência , Doenças Cardiovasculares/diagnóstico , Elementos de Dados Comuns , Confidencialidade , Bases de Dados Factuais , Health Insurance Portability and Accountability Act , Humanos , Garantia da Qualidade dos Cuidados de Saúde , Qualidade da Assistência à Saúde , Reprodutibilidade dos Testes , Projetos de Pesquisa , Sociedades Médicas , Terminologia como Assunto , Pesquisa Translacional Biomédica , Resultado do Tratamento , Estados UnidosRESUMO
Assessing the potential for a new drug to cause life-threatening arrhythmias is now an integral component of premarketing safety assessment. International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use Guideline (ICH) E14 recommends the "Thorough QT Study" (TQT) to assess clinical QT risk. Such a study calls for careful evaluation of drug effects on the electrocardiographic QT interval at multiples of therapeutic exposure and with a positive control to confirm assay sensitivity. Yet for some drugs and diseases, elements of the TQT Study may be impractical or unethical. In these instances, alternative approaches to QT risk assessment must be considered. This article presents points to consider for evaluation of QT risk when alternative approaches are needed.
Assuntos
Drogas em Investigação/efeitos adversos , Síndrome do QT Longo/induzido quimicamente , Animais , Ensaios Clínicos Controlados como Assunto/métodos , Aprovação de Drogas/organização & administração , Avaliação Pré-Clínica de Medicamentos/métodos , Eletrocardiografia/efeitos dos fármacos , Humanos , Cooperação Internacional , Síndrome do QT Longo/fisiopatologiaRESUMO
Several risk factors for development of a potentially fatal ventricular arrhythmia, torsade de pointes, have been observed, including female gender. However, in most investigations, only few torsade events were included and/or rarely were postdose heart rate corrected QT (QTc) measurements included, as a surrogate of drug exposure. We developed a multivariate logistic regression model using data from 22,214 patients (33% women) with 84 torsade events (56% women) to evaluate the relationship between risk factors for torsade using data from four anti-arrhythmic drug development programs. Before model development, we evaluated different QT/QTc postdose metrics (average, maximum, etc.) to determine which QT metric should be included into the model. The developed multivariate model showed that, after accounting for known risk factors for torsade and postdose QTc, that female gender remained a significant risk factor for torsade.
Assuntos
Antiarrítmicos/efeitos adversos , Desenvolvimento de Medicamentos/métodos , Descoberta de Drogas/métodos , Sistema de Condução Cardíaco/efeitos dos fármacos , Torsades de Pointes/induzido quimicamente , Potenciais de Ação/efeitos dos fármacos , Idoso , Mineração de Dados/métodos , Bases de Dados Factuais , Medicina Baseada em Evidências/métodos , Feminino , Sistema de Condução Cardíaco/fisiopatologia , Frequência Cardíaca/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Teóricos , Segurança do Paciente , Medição de Risco , Fatores de Risco , Fatores Sexuais , Torsades de Pointes/diagnóstico , Torsades de Pointes/fisiopatologiaRESUMO
This publication describes uniform definitions for cardiovascular and stroke outcomes developed by the Standardized Data Collection for Cardiovascular Trials Initiative and the U.S. Food and Drug Administration (FDA). The FDA established the Standardized Data Collection for Cardiovascular Trials Initiative in 2009 to simplify the design and conduct of clinical trials intended to support marketing applications. The writing committee recognizes that these definitions may be used in other types of clinical trials and clinical care processes where appropriate. Use of these definitions at the FDA has enhanced the ability to aggregate data within and across medical product development programs, conduct meta-analyses to evaluate cardiovascular safety, integrate data from multiple trials, and compare effectiveness of drugs and devices. Further study is needed to determine whether prospective data collection using these common definitions improves the design, conduct, and interpretability of the results of clinical trials.