Cornelis A van den Bogert1, Adam F Cohen2, Hubert G M Leufkens3, Joop M A van Gerven4. 1. External researcher at the Central Committee on Research Involving Human Subjects, The Hague, The Netherlands. 2. Former vice-chair of the Central Committee on Research Involving Human Subjects, The Hague, The Netherlands. 3. Chair of the Medicines Evaluation Board, Utrecht, The Netherlands. 4. Chair of the Central Committee on Research Involving Human Subjects, The Hague, The Netherlands.
Abstract
AIMS: The aims of the present study were to investigate the role of pharmacology in the design of first-in-man (FIM) trials in the Netherlands, and to evaluate the change in design approaches between 2007 and 2015. METHODS: All FIM drug trials approved by all Dutch Institutional Review Boards (IRBs) in 2007 and in 2015 were selected. The original trial protocols, investigator's brochures and investigational medicinal product dossiers were the data sources. The following four design elements were assessed on the justification of the chosen approaches: preclinical information, dose calculation, endpoints, and dose escalation. RESULTS: In 2007, the Dutch IRBs approved 21 FIM trials, and in 2015 they approved 34 FIM trials (55 in total). Seven out of 21 (33%) of the FIM trials from 2007, and 14 out of the 34 (41%) FIM trials from 2015 discussed only the no-observed-adverse-effect level or no-observed-effect level as preclinical information. Furthermore, five of the 21 (24%) 2007 FIM trials and 12 of the 34 (35%) 2015 FIM trials used unexplained allometric scaling. Pharmacodynamic (PD) parameters were measured in 15 of the 21 (71%) 2007 FIM trials and in 31 of the 34 (91%) of the 2015 FIM trials, and allometric scaling was only guided by safety/tolerability in 11 of the 20 (55%) dose escalation trials in 2007 and in nine of the 33 (27%) dose escalation trials in 2015. CONCLUSIONS: Trial protocols and investigator's brochures commonly lack pharmacokinetic/PD approaches. Investigators, sponsors and IRBs should require an upfront consideration of pharmacology in these aspects for all FIM trials.
AIMS: The aims of the present study were to investigate the role of pharmacology in the design of first-in-man (FIM) trials in the Netherlands, and to evaluate the change in design approaches between 2007 and 2015. METHODS: All FIM drug trials approved by all Dutch Institutional Review Boards (IRBs) in 2007 and in 2015 were selected. The original trial protocols, investigator's brochures and investigational medicinal product dossiers were the data sources. The following four design elements were assessed on the justification of the chosen approaches: preclinical information, dose calculation, endpoints, and dose escalation. RESULTS: In 2007, the Dutch IRBs approved 21 FIM trials, and in 2015 they approved 34 FIM trials (55 in total). Seven out of 21 (33%) of the FIM trials from 2007, and 14 out of the 34 (41%) FIM trials from 2015 discussed only the no-observed-adverse-effect level or no-observed-effect level as preclinical information. Furthermore, five of the 21 (24%) 2007 FIM trials and 12 of the 34 (35%) 2015 FIM trials used unexplained allometric scaling. Pharmacodynamic (PD) parameters were measured in 15 of the 21 (71%) 2007 FIM trials and in 31 of the 34 (91%) of the 2015 FIM trials, and allometric scaling was only guided by safety/tolerability in 11 of the 20 (55%) dose escalation trials in 2007 and in nine of the 33 (27%) dose escalation trials in 2015. CONCLUSIONS: Trial protocols and investigator's brochures commonly lack pharmacokinetic/PD approaches. Investigators, sponsors and IRBs should require an upfront consideration of pharmacology in these aspects for all FIM trials.
Authors: P A Milligan; M J Brown; B Marchant; S W Martin; P H van der Graaf; N Benson; G Nucci; D J Nichols; R A Boyd; J W Mandema; S Krishnaswami; S Zwillich; D Gruben; R J Anziano; T C Stock; R L Lalonde Journal: Clin Pharmacol Ther Date: 2013-03-14 Impact factor: 6.875
Authors: A F Cohen; J Burggraaf; J M A van Gerven; M Moerland; G J Groeneveld Journal: Annu Rev Pharmacol Toxicol Date: 2014-10-06 Impact factor: 13.820
Authors: Cornelis A van den Bogert; Adam F Cohen; Hubert G M Leufkens; Joop M A van Gerven Journal: Br J Clin Pharmacol Date: 2017-10-06 Impact factor: 4.335