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致命试验一年之后……
来源:中国科学报      作者:晋楠      时间:2017-01-10 17:09      关键词:药物学家,谴责,葡萄牙一制药公司,不当操作
摘要:药物学家谴责葡萄牙一制药公司不当操作

 

2016年1月,临床试验参与者被送到这家法国雷恩医院进行治疗。 图片来源:Stephanie Mahe/Reuters

一家药物公司的灾难性临床试验导致1名参试者死亡,4人患上长期神经病症,并招致广泛批评。事实上,该公司在未使用特定数据的情况下,就决定提高被证明存在致命风险的药物剂量,这导致批评声音愈加汹涌。

2016年12月15日,葡萄牙的这家名为比亚尔公司的一名科学家在一次会议上做了报告,结果显示在决定增加剂量之前,该公司并未使用叫作药效(PD)数据的资料,即药物BIA 10-2474在接受低剂量的参试者中会如何反应。

“我们认为这件事出乎意料。”英国药理学会(BPS)理事长David Webb说,他主持了这场在英国伦敦举行的会议。这项试验在法国雷恩进行,在2016年1月产生了灾难性的结果。

比亚尔公司药物安全监督和药品安全办公室主任Helena Gama在BPS会议上为该公司辩护。在被问及为什么该公司做剂量递增决定没考虑PD数据时,她表示:开始增加新药之前的评估基于安全评估和药物代谢动力学数据,即药物如何被机体吸收、分散、代谢及排出体外。“我们没有排除进一步增加药物剂量选择的任何数据”。

比亚尔并未在法律上被要求使用PD数据,但其试验方案已经被法国医疗管理机构——国家药品和医疗产品安全局(ANSM)终止。

但药物研发和临床试验设计领域的专家称,该公司应该包含这些数据。“如果没有PD数据,他们会盲目前进。这正是偶然事故出现之时。”Webb说,“我认为这是疏忽。”

此前在ANSM科学顾问委员会工作的生物统计学家Catherine Hill也对比亚尔公司未采用PD数据感到吃惊。“这似乎难以置信。”她说,“用盲目前进描述它恰如其分。”

尽管并非每一项试验都会使用PD数据,但最好这样做,英国利物浦大学分子和临床药理学家Munir Pirmohamed说。

比亚尔公司的临床试验是在人体首次验证BIA 10-2474。该药物的设计目标是了解这种在小鼠、狗、猴子和大鼠身上已经安全的药物,用于人体时是否同样安全。

Webb表示,由于BIA 10-2474相对来说是非选择性的,这意味着它在体内除了针对需要靶向的目标之外还可能产生其他效应,因此收集PD数据尤其重要。

这种药物会结合一种酶——脂肪酰胺水解酶(FAAH),使其有效地治疗焦虑、与阿尔茨海默氏症关联的运动性障碍以及与癌症等疾病关联的慢性疼痛。PD数据能够揭示大脑中这种酶的副本接近饱和的时间,在这个节点上如果增加药物剂量可能会导致自由流动的药物水平陡然增高,从而可能导致对其他酶产生“脱靶”效应。BPS会议上的批评专家认为,由于该公司在决定增加剂量时未考虑PD数据,因此它没有意识到FAAH已经饱和。

但比亚尔公司并不接受这一结论。“这项试验的所有官方报告都是非决定性的,所有报告都认为此次事件是不可预测的,无论如何,包括先期试验在内,并没有迹象显示会出现这种结果。”该公司一名发言人说。

在悲剧发生后,法国官方和位于伦敦的欧洲药品管理局均对此次首例人体临床试验公布了更新指导。ANSM所作的一份独立报告对改善未来临床试验行为提出了6点建议。

Gama还公布了4名试验参与幸存者的新数据。她表示他们尚未从神经紊乱症状中恢复,包括失忆、头痛、运动障碍以及震颤等。对于服用低剂量该药物的志愿者,她还列举了神经系统负作用的10个例子,包括头晕、视觉模糊等,不过她表示这些症状比较轻微和短暂。

对于受影响更加严重的志愿者的长期健康效应此前并不明确,但事实上,他们仍在经历的症状表明,该药物的致命反应并非一次性的,Webb说。“这是我们首次知道他们反应很激烈,他们现在仍在遭受伤害”。

临床试验之后,比亚尔公司就处于科学界的强烈压力之下,并被要求公布临床和前期试验的所有数据。BPS报告揭示了一些相关数据,但透明化的呼声愈加强烈。

“是不是已经到了正式公布所有数据的时候?这样以来我们就可以讨论它。”荷兰莱顿大学临床药理学家、《英国临床药理学杂志》总编Adam Cohen说。他表示,该公司尤其应该公开其“研究人员手册”、药物前期临床试验档案以及该临床试验自身的所有人体数据。

Cohen和Webb质问为何在致命临床试验发生11个月后,该公司仍然未能公开相关数据,Gama拒绝对公开数据作出具体评述。但她补充说:“如果要向科学界公开相关数据,我们不存在任何问题。”(晋楠编译)


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