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Strategies and Recommendations for Using a Data‐Driven and Risk‐Based Approach in the Selection of First‐in‐Human Starting Dose: An International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) Assessment
Author(s) -
Leach Michael W.,
Clarke David O.,
Dudal Sherri,
Han Chao,
Li Chunze,
Yang Zheng,
Brennan Frank R.,
Bailey Wendy J.,
Chen Yingxue,
Deslandes Antoine,
Loberg Lise I.,
Mayawala Kapil,
Rogge Mark C.,
Todd Marque,
Chemuturi Nagendra V.
Publication year - 2021
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1002/cpt.2009
Subject(s) - selection (genetic algorithm) , risk analysis (engineering) , medicine , quality (philosophy) , ambiguity , table (database) , computer science , data mining , philosophy , epistemology , artificial intelligence , programming language
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.