Who is a 'healthy subject'?-consensus results on pivotal eligibility criteria for clinical trials.
Who is a 'healthy subject'?-consensus results on pivotal eligibility criteria for clinical trials.
复制标题
DOI：
10.1007/s00228-016-2189-8
复制
发表时间：
2017-04
影响因子：
2.9
通讯作者：
Wensing G
中科院分区：
文献类型：
--
作者：
Breithaupt-Groegler K;Coch C;Coenen M;Donath F;Erb-Zohar K;Francke K;Goehler K;Iovino M;Kammerer KP;Mikus G;Rengelshausen J;Sourgens H;Schinzel R;Sudhop T;Wensing G
德国非营利性应用人类药理学协会(Agah e.V.)主办了一个论坛。严格审查健康受试者临床试验的关键资格标准和停止规则，招募来自制药业、合同研究组织、学术界、伦理委员会和主管当局的利益相关者。关键的合格标准被定义为使用新的研究药物(IMP)或临床已建立的IMP的试验。一般来说，建议首次人体试验(FIH)的脉搏频率在50到90次/分钟之间，而如果没有甲状腺功能障碍的迹象，更宽的范围似乎可以接受用于临床确定的IMPS的试验。在FIH试验中，肝脏实验室参数不得超过正常上限(ULN)，包括ALT(丙氨酸氨基转移酶)和AST(天冬氨酸氨基转移酶)，而轻微升高(高于ULN 10%)在临床确立的IMPS临床试验中似乎是可以接受的，但没有已知的肝脏毒性。任何健康受试者的临床试验都需要正常的肾功能。采用了一种适应风险的办法来终止规则。个别受试者的停药规则是一次严重强度的不良事件或一次严重不良事件。在发生严重不良事件的情况下，一些利益攸关方要求与IMP建立因果关系(即不良反应)。一个队列的停药规则是一个严重的不良反应或≥50%的受试者经历任何中等或严重的不良反应。这一共识的实施减少了主管当局发布的议定书缺陷。
A discussion forum was hosted by the German not-for-profit Association for Applied Human Pharmacology (AGAH e.V.) to critically review key eligibility criteria and stopping rules for clinical trials with healthy subjects, enrolling stakeholders from the pharmaceutical industry, contract research organisations, academia, ethics committees and competent authority. Pivotal eligibility criteria were defined for trials with new investigational medicinal products (IMPs) or with clinically established IMPs. In general, a pulse rate ranging between 50 and 90 beats/min is recommended for first-in-human (FIH) trials, while wider ranges seem acceptable for trials with clinically established IMPs, provided there are no indications of thyroid dysfunction. Hepatic laboratory parameters not to exceed the upper limit of normal (ULN) comprise ALT (alanine aminotransferase) and AST (aspartate aminotransferase) in FIH trials, whereas slight elevations (10% above ULN) seem acceptable in trials with clinically established IMPs without known hepatotoxicity. A normal renal function is required for any clinical trial in healthy subjects. A risk-adapted approach for stopping rules was adopted. Stopping rules for an individual subject are one adverse event of severe intensity or one serious adverse event. In case of a severe adverse event, some stakeholders demand a causal relationship with the IMP (i.e. an adverse reaction). Stopping rules for a cohort are one serious adverse reaction or ≥50% of subjects experiencing any adverse reaction of moderate or severe intensity. The application of this consensus resulted in a reduction in protocol deficiencies issued by the competent authority.