Investigator brochures for phase I/II trials lack information on the robustness of preclinical safety studies
Investigator brochures for phase I/II trials lack information on the robustness of preclinical safety studies
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DOI：
10.1111/bcp.14615
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发表时间：
2020-11-20
影响因子：
3.4
通讯作者：
Strech, Daniel
中科院分区：
文献类型：
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作者：
Sievers, Soeren;Wieschowski, Susanne;Strech, Daniel
目的有意义的和伦理的I/II期试验只能进行支持性的前瞻性风险效益评估。这在很大程度上依赖于解决治疗安全性和有效性的临床前动物研究。这些研究在研究者手册（IB）中报告，以告知伦理审查委员会和监管机构。我们的研究调查的程度，报告质量和可及性的临床前安全性研究（PCSS）编译在IBs.Methods我们分析了46个IB的I/II期试验的样本批准在德国领先的大学医学中心从2010年至2016年。我们提取了所有的PCSS中提出的46个IB和评估他们的报告方法的措施，以减少有效性threats.Results的46个IB包括777个PCSS。不到1%的研究报告了设盲结局评估、随机化和样本量计算。只有5%的PCSS提供了已发表数据的参考。符合良好实验室规范（GLP）的指导报告的52%的PCSSs，但GLP文件本身不包括任何相关的方法要求，有效性threats.Conclusion减少报告在IB和非常有限的公开数据PCSSs使它几乎不可能为调查人员严格评估药物安全性的临床前证据的稳健性。结合最近关于IB临床前疗效研究的发现，我们得出结论，目前IB的报告模式严重限制了对早期人体试验证据支持的独立审查。监管机构和IRB应要求在IB中更好地报告。
Aim Meaningful and ethical phase I/II trials can only be conducted with supportive prospective risk-benefit assessment. This relies largely on preclinical animal studies addressing the safety and efficacy of treatments. These studies are reported in an Investigator's Brochure (IB) to inform ethics review boards and regulatory authorities. Our study investigated the extent, reporting quality and accessibility of preclinical safety studies (PCSSs) compiled in IBs.Methods We analysed a sample of 46 IBs for phase I/II trials approved at a leading German university medical centre from 2010 to 2016. We extracted all PCSSs presented in the 46 IBs and assessed them for reporting on methodological measures to reduce validity threats.Results The 46 IBs included 777 PCSSs. Blinded outcome assessment, randomization and sample size calculation were reported for fewer than 1% of studies. Only 5% of the PCSSs provided a reference to published data. Compliance with Good Laboratory Practice (GLP) guidance was reported for 52% of PCSSs, but the GLP document itself does not include any relevant methodological requirements for the reduction of validity threats.Conclusion Scarce reporting in IBs and the very limited publicly available data on PCSSs make it almost impossible for investigators to critically evaluate the robustness of preclinical evidence of drug safety. Combined with recent findings on the presentation of preclinical efficacy studies in IBs, we conclude that the current reporting patterns in IBs strongly limit the independent review of evidential support for early human trials. Regulatory authorities and IRBs should require better reporting in IBs.