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

Cornelis A. van den Bogert; Adam F. Cohen; Hubert G.M. Leufkens; Joop M.A. van Gerven

doi:10.1111/bcp.13422

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

Cornelis A. van den Bogert^*, Adam F. Cohen, Hubert G.M. Leufkens, Joop M.A. van Gerven

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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.

Original language	English
Pages (from-to)	2807-2812
Number of pages	6
Journal	British Journal of Clinical Pharmacology
Volume	83
Issue number	12
DOIs	https://doi.org/10.1111/bcp.13422
Publication status	Published - Dec 2017

Bibliographical note

Publisher Copyright:
© 2017 The British Pharmacological Society

Funding

This work was supported by the Dutch Ministry of Health, Welfare and Sports (grant to H.G.M.L). A.F.C. serves as CEO of the Centre for Human Drug Research at Leiden, the Netherlands. H.G.M.L. received no direct funding or donations from private parties, including the pharmaceutical industry; he has accepted research funding from public-private partnerships [i.e. IMI and Tl Pharma (www.tipharma. nl)] under the condition that no company-specific product or company-related study is conducted; he has received unrestricted research funding from public sources – i.e. the Netherlands Organization for Health Research and Development (ZonMW), the EU 7th Framework Program (FP7), the Dutch Medicines Evaluation Board (MEB), the National Health Care Institute (ZIN) and the Dutch Ministry of Health. C.A.B. and J.M.A.G. declare no other relationships or activities that could appear to have influenced the submitted work.

Funders	Funder number
Medicines Evaluation Board
Dutch Ministry of Health
EU 7th Framework Program
University of Amsterdam
ZonMw
Ministerie van Volksgezondheid, Welzijn en Sport
Seventh Framework Programme
Heath Care Department, Zorginstituut Nederland, Eekholt 4, 1112 XH, Diemen, The Netherlands.

Keywords

clinical trials
drug development, phase I
methodology
statistics and study design

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10.1111/bcp.13422

Cite this

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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.",

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

Abstract

Bibliographical note

Funding

Keywords

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