title: Determination of the starting dose in the first-in-human clinical trials with monoclonal antibodies: a systematic review of papers published between 1990 and 2013.
abstract: A systematic review was performed to evaluate how the maximum recommended starting dose (MRSD) was determined in first-in-human (FIH) studies with monoclonal antibodies (mAbs). Factors associated with the choice of each MRSD determination method were also identified. PubMed was searched for FIH studies with mAbs published in English between January 1, 1990 and December 31, 2013, and the following information was extracted: MRSD determination method, publication year, therapeutic area, antibody type, safety factor, safety assessment results after the first dose, and number of dose escalation steps. Seventy-nine FIH studies with mAbs were identified, 49 of which clearly reported the MRSD determination method. The no observed adverse effects level (NOAEL)-based approach was the most frequently used method, whereas the model-based approach was the least commonly used method (34.7% vs 16.3%). The minimal anticipated biological effect level (MABEL)- or minimum effective dose (MED)-based approach was used more frequently in 2011-2013 than in 1990-2007 (31.6% vs 6.3%,P=0.036), reflecting a slow, but steady acceptance of the European Medicines Agency's guidance on mitigating risks for FIH clinical trials (2007). The median safety factor was much lower for the MABEL- or MED-based approach than for the other MRSD determination methods (10 vs 32.2-53). The number of dose escalation steps was not significantly different among the different MRSD determination methods. The MABEL-based approach appears to be safer and as efficient as the other MRSD determination methods for achieving the objectives of FIH studies with mAbs faster.
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, College of Medicine, Seoul National University Hospital, Seoul, Korea.
authors.forename: Hoon Young
authors.initials: HY
authors.lastname: Suh
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, School of Pharmacy, University of California, San Francisco, CA, USA.
authors.forename: Carl C
authors.initials: CC
authors.lastname: Peck
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, College of Medicine, Seoul National University Hospital, Seoul, Korea.
authors.forename: Kyung-Sang
authors.initials: KS
authors.lastname: Yu
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, College of Medicine, Seoul National University Hospital, Seoul, Korea; Department of Transdisciplinary Studies, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Korea.
authors.forename: Howard
authors.initials: H
authors.lastname: Lee
mesh_terms: D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000276:immunology / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D004305:Dose-Response Relationship, Drug; D006801:Humans; D058028:Research Report
chemical_list: D000911:Antibodies, Monoclonal
keywords: MRSD; MRSD determination method; first-in-human study with monoclonal antibody; safety factor; starting dose in first-in-human study