Sievers Sören, Wieschowski Susanne, Strech Daniel
Hannover Medical School, Institute for Ethics, History, and Philosophy of Medicine, Hannover, 30625, Germany.
QUEST - Center, Berlin Institute of Health (BIH), Berlin, 10178, Germany.
Br J Clin Pharmacol. 2021 Jul;87(7):2723-2731. doi: 10.1111/bcp.14615. Epub 2020 Nov 20.
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.
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.
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.
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.
有意义且符合伦理的I/II期试验只有在进行支持性的前瞻性风险效益评估后才能开展。这在很大程度上依赖于针对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）中进行报告，以便为伦理审查委员会和监管机构提供信息。我们的研究调查了IB中汇编的临床前安全性研究（PCSS）的范围、报告质量和可获取性。
我们分析了2010年至2016年在德国一所领先的大学医学中心批准的46项I/II期试验的IB样本。我们提取了46份IB中呈现的所有PCSS，并评估它们在减少有效性威胁的方法措施报告方面的情况。
46份IB包含777项PCSS。不到1%的研究报告了盲法结果评估、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文献。52%的PCSS报告了符合良好实验室规范（GLP）指南，但GLP文件本身并未包括任何减少有效性威胁的相关方法学要求。
IB中的报告稀少，且关于PCSS的公开可用数据非常有限，这使得研究人员几乎无法批判性地评估药物安全性临床前证据的稳健性。结合近期关于IB中临床前疗效研究呈现情况的发现，我们得出结论，IB中目前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。监管机构和机构审查委员会应要求在IB中有更好的报告。
