Preclinical efficacy studies in investigator brochures: Do they enable risk-benefit assessment?
Preclinical efficacy studies in investigator brochures: Do they enable risk-benefit assessment?
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DOI：
10.1371/journal.pbio.2004879
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发表时间：
2018-04
期刊：
影响因子：
9.8
通讯作者：
Strech D
中科院分区：
文献类型：
--
作者：
Wieschowski S;Chin WWL;Federico C;Sievers S;Kimmelman J;Strech D
人体保护政策要求在启动临床试验之前进行有利的风险-获益判断。对于I期和II期试验，这种判断的证据通常来自临床前疗效研究（PCES）。我们对I期和II期试验伦理审查的申请材料（研究者手册[IB]）进行了系统研究，以评估其中包含的PCES的内容和性质。使用2010年至2016年期间在德国医学院的3个机构审查委员会最近批准的109个IB样本，我们确定了708个独特的PCES。然后，我们对所有确定的PCES进行了评估，以了解他们对有助于解决有效性威胁的研究元素的报告，他们是否引用了已发表的报告，以及他们的结果的方向。109名IB共报告了708例PCES。不到5%的PCES描述了减少有效性威胁所必需的要素，如随机化、样本量计算和设盲结局评估。对于大多数PCES（89%），未提供已发表报告的参考。只有6%的PCES报告了无影响的结局。对于大多数IB（82%），所有PCES均被描述为报告阳性结果。我们的结果表明，大多数I/II期研究的IB不允许评价者系统地评价支持临床前研究结果的强度。极少数报告证明无影响的PCES引起了对潜在设计或报告偏倚的担忧。不良的PCES设计和报告阻碍了I/II期研究伦理审查期间的风险-获益评估。为了使临床试验符合伦理，监管机构和机构审查委员会必须判断与试验相关的利益（知识增益）是否超过试验固有的风险。对于早期的人类研究，这些风险-效益评估通常基于所谓的“研究者手册”中报告的临床前动物研究的证据。然而，我们的分析表明，绝大多数此类研究者手册缺乏足够的信息来系统地评价支持临床前发现的强度。此外，临床前有效性研究报告显示无影响的情况非常罕见，这引起了对潜在设计和/或报告偏倚的担忧。临床前研究设计和报告的不佳阻碍了早期人类研究伦理审查期间的风险-效益评估。监管机构应制定临床前疗效研究的设计和报告标准，以支持伦理临床试验的开展。
Human protection policies require favorable risk–benefit judgments prior to launch of clinical trials. For phase I and II trials, evidence for such judgment often stems from preclinical efficacy studies (PCESs). We undertook a systematic investigation of application materials (investigator brochures [IBs]) presented for ethics review for phase I and II trials to assess the content and properties of PCESs contained in them. Using a sample of 109 IBs most recently approved at 3 institutional review boards based at German Medical Faculties between the years 2010–2016, we identified 708 unique PCESs. We then rated all identified PCESs for their reporting on study elements that help to address validity threats, whether they referenced published reports, and the direction of their results. Altogether, the 109 IBs reported on 708 PCESs. Less than 5% of all PCESs described elements essential for reducing validity threats such as randomization, sample size calculation, and blinded outcome assessment. For most PCESs (89%), no reference to a published report was provided. Only 6% of all PCESs reported an outcome demonstrating no effect. For the majority of IBs (82%), all PCESs were described as reporting positive findings. Our results show that most IBs for phase I/II studies did not allow evaluators to systematically appraise the strength of the supporting preclinical findings. The very rare reporting of PCESs that demonstrated no effect raises concerns about potential design or reporting biases. Poor PCES design and reporting thwart risk–benefit evaluation during ethical review of phase I/II studies. To make a clinical trial ethical, regulatory agencies and institutional review boards have to judge whether the trial-related benefits (the knowledge gain) outweigh the trial-inherent risks. For early-phase human research, these risk–benefit assessments are often based on evidence from preclinical animal studies reported in so-called “investigator brochures.” However, our analysis shows that the vast majority of such investigator brochures lack sufficient information to systematically appraise the strength of the supporting preclinical findings. Furthermore, the very rare reporting of preclinical efficacy studies that demonstrated no effect raises concerns about potential design and/or reporting biases. The poor preclinical study design and reporting thwarts risk–benefit evaluation during ethical review of early human research. Regulators should develop standards for the design and reporting of preclinical efficacy studies in order to support the conduct of ethical clinical trials.
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影响因子：
9.8
作者：
Macleod, Malcolm R.;McLean, Aaron Lawson;Sena, Emily S.
通讯作者：
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9.8
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