Lindgren Silvana, Bass Alan S, Briscoe Richard, Bruse Kristy, Friedrichs Gregory S, Kallman Mary Jeanne, Markgraf Carrie, Patmore Leslie, Pugsley Michael K
Safety Pharmacology, Safety Assessment, AstraZeneca R&D, 15185 Södertälje, Sweden.
J Pharmacol Toxicol Methods. 2008 Sep-Oct;58(2):99-109. doi: 10.1016/j.vascn.2008.07.001. Epub 2008 Jul 19.
The objectives of this survey were to obtain a global information update regarding current industry perspectives that describe Safety Pharmacology programs as they relate to the ICH S7A and S7B regulatory guidelines but also to obtain a broader perspective of other practises practices in the field currently used by companies. Preliminary findings were presented at the 7th Annual Meeting of the Safety Pharmacology Society (SPS) (Edinburgh, Scotland, Sept 19-21, 2007).
The survey was distributed by the SPS to 125 pharmaceutical companies. Survey topics included (a) an update on ICH S7A and S7B practices, (b) frontloading Safety Pharmacology studies prior to selection of candidate drugs, (c) abuse and dependence-liability studies and (d) an extended evaluation of industry practises practices as assessed by Contract Research Organizations (CROs).
Respondents (>94%) include GLP core battery (CV, CNS and respiratory) studies in the drug package submitted to regulatory agencies, and approximately 40% also submit studies on gastrointestinal and renal function. Respondents to the ICH S7B aspects indicate approximately 98% include the hERG assay and QT interval (in vivo) data in submissions, 63% include APD in vitro data and another 23% APD in vivo and other cardiac channel data (26%). SP frontloading is performed by 78% of all responding companies. Respondents indicate that 39% of these non-GLP CV studies are conducted before lead optimization (LO) and 85% during LO and before candidate drug selection. The hERG, CNS selectivity binding screens and rodent behavioral studies are frontloaded by 100%, 90% and 74% of respondents. Responding CROs (26) were surveyed on the services offered including Irwin or Functional Observational Battery (FOB) tests (70%), respiratory studies (85%), in vivo telemeterized dogs (69%) and in vitro CV studies (50%). Only 38% of SP studies are combined with toxicology studies at the CROs.
The survey results indicate that ICH S7A core battery studies are implemented by most of the responding companies with a clear trend of an enhanced submission of renal and GI studies. The impact of ICH S7B is clear since, all respondents assess cardiac repolarization using cellular hERG (I(Kr)) and whole animal (QT interval) assays as a component of their safety assessment. Responses indicate a diversity of approaches for conducting abuse liability studies, which primarily use the methods of self-administration and drug discrimination. While early SP frontloading of studies seems to vary, the methods used appear to be generic to some extent and include in vitro 'off-target' evaluations and in vivo tests to determine the potential for CNS and cardiovascular issues.
本次调查的目的是获取有关当前行业观点的全球信息更新，这些观点描述了与国际人用药品注册技术协调会（ICH）S7A和S7B监管指南相关的安全药理学计划，同时也获取公司目前在该领域使用的其他做法的更广泛观点。初步调查结果在安全药理学会（SPS）第七届年会上公布（2007年9月19日至21日，苏格兰爱丁堡）。
SPS将调查问卷分发给125家制药公司。调查主题包括：（a）ICH S7A和S7B实践的更新情况；（b）在候选药物选择之前提前开展安全药理学研究；（c）滥用和成瘾性研究；（d）由合同研究组织（CRO）评估的行业实践的扩展评价。
超过94%的受访者在提交给监管机构的药物包中纳入了GLP核心组（心血管、中枢神经系统和呼吸系统）研究，约40%的受访者还提交了胃肠和肾功能研究。关于ICH S7B方面的受访者表示，约98%的提交材料中包含人ether-à-go-go相关基因（hERG）检测和QT间期（体内）数据，63%包含动作电位时程（APD）体外数据，另有23%包含APD体内数据和其他心脏通道数据（26%）。78%的所有回复公司进行了安全药理学提前加载。受访者表示，这些非GLP心血管研究中，39%在先导化合物优化（LO）之前进行，85%在LO期间和候选药物选择之前进行。100%、90%和74%的受访者对hERG、中枢神经系统选择性结合筛选和啮齿动物行为学研究进行了提前加载。对回复的CRO（26家）就所提供的服务进行了调查，包括欧文试验或功能观察组合（FOB）测试（70%）、呼吸研究（85%）、体内遥测犬研究（69%）和体外心血管研究（50%）。在CRO中，只有38%的安全药理学研究与毒理学研究相结合。
调查结果表明，大多数回复公司实施了ICH S7A核心组研究，并且有明显趋势显示肾脏和胃肠道研究的提交量有所增加。ICH S7B的影响很明显，因为所有受访者在其安全性评估中都使用细胞hERG（I(Kr)）和整体动物（QT间期）检测来评估心脏复极化。回复表明进行滥用可能性研究的方法多种多样，主要采用自我给药和药物辨别方法。虽然研究的早期安全药理学提前加载情况似乎各不相同，但所使用的方法在某种程度上似乎具有通用性，包括体外“脱靶”评估和体内测试，以确定中枢神经系统和心血管问题的可能性。
