RESUMEN
The review of requests for a positive opinion of the ethics committees (application procedure) as a requirement to start a clinical trial in Germany has been completely redesigned with the transposition of EU Directive 2001/20/EC in the 12(th) Amendment of the German Medicines Act in August 2004. The experience of applicants (sponsors, legal representatives of sponsors in the EU and persons or organizations authorized by the sponsors to make the application, respectively) in terms of interactions with the ethics committees in Germany has been positive overall, especially with respect to ethics committee adherence to the statutory timelines applicable for review of requests. However, inconsistencies between ethics committees exist in terms of the form and content of the requirements for application documents and their evaluation. With the objective of further improving both the quality of applications and the evaluation of those applications by ethics committees, a survey among members of the German Association of Research-Based Pharmaceutical Companies (VFA) was conducted from January to April 2008. Based on reasoned opinions issued by the respective ethics committee in charge of the coordinating principal investigator (coordinating ethics committee), the type and frequency of formal and content-related objections to applications according to section sign 7 of the German Good Clinical Practice (GCP) Regulation were systematically documented, and qualitative and quantitative analyses performed. 21 out of 44 members of the VFA participated in the survey. 288 applications for Phase I-IV studies submitted between January and December 2007 to 40 ethics committees were evaluated. This survey shows that about one in six applications is incomplete and has formal and/or content objections, respectively, especially those that pertain to documents demonstrating the qualification of the investigator and/or suitability of the facilities. These objections are attributable to some extent to the differing and/or unclear requirements of the individual ethics committees on the content and comprehension of the submission documents. However, applicants also need to pay more attention to the completeness and validity of the submission documents. The majority of content-related objections apply to the patient information and consent documents and study protocols submitted. Applicants on average acted upon only 3 out of 4 objections, for various reasons: the relevant information was already given in the submitted documents, but had not been taken into consideration by the ethics committees; objections were not applicable; objections lacked a legal basis. In such cases the applicants made reference to the specific information already submitted or gave reasons for not acting on the objection. This course of action was accepted by the ethics committees, with few exceptions. The survey sheds light on the existing inconsistencies in the evaluations of applications by the various ethics committees and suggests ways in which the existing constructive dialogue between applicants and ethics committees may provide a basis to further harmonize both the requirements regarding form and content of application documents, and the criteria for evaluation of applications by ethics committees within the legal framework.
Asunto(s)
Comités de Monitoreo de Datos de Ensayos Clínicos/ética , Ensayos Clínicos como Asunto/ética , Evaluación de Medicamentos/legislación & jurisprudencia , Comités de Ética en Investigación/legislación & jurisprudencia , Ética Médica , Preparaciones Farmacéuticas/normas , Alemania , Regulación Gubernamental , Humanos , Estudios RetrospectivosRESUMEN
AIMS: To characterize the pharmacokinetics of terbogrel, a new combined thromboxane A2 (TxA2) receptor and synthase inhibitor, in healthy human subjects after single or multiple oral administration. METHODS: Forty-eight healthy male subjects received a single oral dose (10, 25, 50, 100, 150 or 200 mg) of terbogrel or placebo and 32 different subjects received one of the following treatments twice daily for 7 days: 50, 100 or 150 mg terbogrel, placebo, or once-a-day 330 mg acetylsalicylic acid. RESULTS: Terbogrel was well tolerated without obvious adverse effects following either a single oral dose or administration over 7 days. Plasma drug concentrations were dose-linear and there was no accumulation over 7 days. There was a dose-dependent blockade of TxA2 receptors and of inhibition of thromboxane synthase activity with values for IC50 of 12 ng ml(-1) and 6.7 ng ml(-1), respectively. At the highest dose tested (150 mg) there was almost complete inhibition of thomboxane synthase and thromboxane receptor occupancy. Even at trough concentrations, receptor occupancy remained above 80% and thromboxane synthase was still completely inhibited. These two activities were associated with a dose-dependent inhibition of platelet aggregation (>80% at the 150 mg dose of terbogrel) and enhanced prostacyclin production. CONCLUSIONS: Terbogrel is a potent agent having two distinct, complimentary pharmacodynamic actions, namely inhibition of thromboxane synthase and antagonism of the TxA2 receptor. The antithrombotic effect of terbogrel was dose-dependent and was associated with enhanced prostacyclin production. Terbogrel is an attractive candidate for long-term antithrombotic therapy.
Asunto(s)
Piridinas/farmacocinética , Tromboxano A2/antagonistas & inhibidores , Tromboxano-A Sintasa/antagonistas & inhibidores , 6-Cetoprostaglandina F1 alfa/metabolismo , Adulto , Aspirina/administración & dosificación , Tiempo de Sangría , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Humanos , Masculino , Agregación Plaquetaria/efectos de los fármacos , Piridinas/farmacologíaRESUMEN
BACKGROUND: Circulating mediators, including thromboxane A2, the vasoconstrictor, platelet aggregant, and smooth muscle mitogen, may contribute to the progression of vascular narrowing in primary pulmonary hypertension (PPH). METHODS: To further understand the contribution of thromboxane and to provide novel therapy for PPH, we administered the potent orally active thromboxane synthetase inhibitor and thromboxane receptor antagonist terbogrel for 12 weeks to patients with New York Heart Association functional classification II and III PPH. The study had a multicenter randomized placebo-controlled design. The primary endpoint was a change in the distance walked during 6 minutes. The pharmacologic effects of terbogrel on thromboxane and prostacyclin metabolism also were studied. RESULTS: Although the planned enrollment was 135 patients, the study was halted after only 71 patients had been randomized because of the unforeseen side effect of leg pain, which occurred almost exclusively in patients with terbogrel treatment. Only 52 patients completed the 12-week study, and only 22 patients (31%) were fully compliant with the study medication. The leg pain confounded the primary endpoint of walking distance. On an intention-to-treat analysis, no improvements in 6-minute walk distance or in hemodynamics in patients with terbogrel treatment were seen. However, terbogrel was effective from a pharmacologic standpoint, reducing thromboxane metabolites by as much as 98% (P <.0001), with a modest but statistically insignificant (39%) rise in prostacyclin metabolites. CONCLUSION: Inhibition of thromboxane with an orally active agent is feasible in PPH, but the incidence of severe leg pain with terbogrel precludes its use in this disorder. Similar therapeutic efforts, with other thromboxane inhibitors, should be considered.