Guidance for Industry Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers
Guidance for Industry Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers
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2005
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Oprs Alert
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Oprs Alert
该指南由 FDA 药物评价和研究中心 (CDER) 于 2005 年 7 月发布，作为确定成人健康志愿者初始临床试验的估计最大推荐起始剂量 (MRSD) 的行业指南。该过程首先确定受试动物物种的“未观察到不良反应水平 (NOAEL)”，然后将这些 NOAELS 转换为人体等效剂量 (HED)。这通常是通过体表面积换算来完成的；然而，如果更合适的话，可以通过其他措施来推断剂量。该指南指出，这种转换应一步完成：“用适当的体表面积转换因子 (BSA-CF) 除所研究的每种动物的 NOAEL。”结果将是一个将动物物种剂量转换为人类剂量的无单位数字。产生最低 HED 的物种是最敏感的物种。这是选择最合适的动物种类。最后，必须设置至少 10 的安全系数。 MRSD 应通过 HED 除以安全系数来获得。原因之一是某些不良事件（例如偏头痛）在动物中可能无法检测到。
Issued by the FDA's Center for Drug Evaluation and Research (CDER) in July 2005, this serves as the industry guide for determining the estimated maximum recommended starting dose (MRSD) for initial clinical trials in adult healthy volunteers. The process involves first determining the "no observed adverse effect levels (NOAELs)" in tested animal species and then converting these NOAELS to the human equivalent dose (HED). This is usually done by body surface area conversion; however, extrapolating doses may be done by other measures if more appropriate. The guidance states that this conversion should be done in one step: "dividing the NOAEL in each of the animal species studied by the appropriate body surface area conversion factor (BSA-CF)." The result will be a unitless number that converts the animal species dose to human dose. The species that generates the lowest HED is the most sensitive species. This is the selection of the most appropriate animal species. Finally, a safety factor of at least 10 must be put in place. The MRSD should be obtained by dividing the HED by the safety factor. One reason for this is that some adverse events (such as migraines) may be undetectable in animals.