Drug Safety Research and Development, Pfizer, Inc., Cambridge, Massachusetts, USA.
Nonclinical Safety Assessment, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana, USA.
Clin Pharmacol Ther. 2021 Jun;109(6):1395-1415. doi: 10.1002/cpt.2009. Epub 2020 Nov 3.
Various approaches to first-in-human (FIH) starting dose selection for new molecular entities (NMEs) are designed to minimize risk to trial subjects. One approach uses the minimum anticipated biological effect level (MABEL), which is a conservative method intended to maximize subject safety and designed primarily for NMEs having high perceived safety risks. However, there is concern that the MABEL approach is being inappropriately used for lower risk molecules with negative impacts on drug development and time to patient access. In addition, ambiguity exists in how MABEL is defined and the methods used to determine it. The International Consortium for Innovation and Quality in Pharmaceutical Development convened a working group to understand current use of MABEL and its impact on FIH starting dose selection, and to make recommendations for FIH dose selection going forward. An industry-wide survey suggested the achieved or estimated maximum tolerated dose, efficacious dose, or recommended phase II dose was > 100-fold higher than the MABEL-based starting dose for approximately one third of NMEs, including trials in patients. A decision tree and key risk factor table were developed to provide a consistent, data driven-based, and risk-based approach for selecting FIH starting doses.
各种用于选择新分子实体（NME）首次人体（FIH）起始剂量的方法旨在将试验对象的风险降至最低。一种方法使用预期最小生物学效应水平（MABEL），这是一种旨在最大程度提高受试者安全性的保守方法，主要用于具有高感知安全风险的 NME。然而，有人担心 MABEL 方法被不适当地用于风险较低的分子，对药物开发和患者获得药物的时间产生负面影响。此外，MABEL 的定义和确定方法存在歧义。国际药品研发创新与质量联盟召集了一个工作组，以了解当前 MABEL 的使用情况及其对 FIH 起始剂量选择的影响，并就未来的 FIH 剂量选择提出建议。一项全行业调查表明，大约三分之一的 NME 包括患者试验，其基于 MABEL 的起始剂量与实际或估计的最大耐受剂量、有效剂量或推荐的 II 期剂量相比，高出 100 倍以上。已制定决策树和关键风险因素表，以提供一种一致的、基于数据的、基于风险的方法来选择 FIH 起始剂量。
