Pharmacological versus classical approaches in the design of first in man clinical drug trials

Aims

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 design elements preclinical information, dose calculation, endpoints and dose escalation were assessed on the justification of the chosen approaches.

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 NOAEL or NOEL as preclinical information. Furthermore, 5 of the 21 (24%) 2007 FIM trials and 12 of the 34 (35%) 2015 FIM trials used unexplained allometric scaling. 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 9 of the 33 (27%) dose escalation trials in 2015.

Conclusions

Trial protocols and investigator's brochures commonly lack PK/PD approaches. Investigators, sponsors and IRBs should require an upfront consideration of pharmacology in these aspects for all FIM-trials.

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