The Use of Biomarkers in Human Pharmacology (Phase I) Studies

Cohen, A.F.; Burggraaf, J.; van Gerven, J.M.A.; Moerland, M.; Groeneveld, G.J.

doi:10.1146/annurev-pharmtox-011613-135918

Cited by 55Statistical Methods in Clinical TrialsPharmaceutical studies and practicesPharmacogenetics and Drug Metabolism

The Use of Biomarkers in Human Pharmacology (Phase I) Studies

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Cohen, A.F., Burggraaf, J., van Gerven, J.M.A., Moerland, M., Groeneveld, G.J.·2015·Annual Review of Pharmacology and Toxicology

DOI 10.1146/annurev-pharmtox-011613-135918

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Abstract

The development of a new medicine is a risky and costly undertaking that requires careful planning. This planning is largely applied to the operational aspects of the development and less so to the scientific objectives and methodology. The drugs that will be developed in the future will increasingly affect pathophysiological pathways that have been largely unexplored. Such drug prototypes cannot be immediately introduced in large clinical trials. The effects of the drug on normal physiology, pathophysiology, and eventually the desired clinical effects will need to be evaluated in a structured approach, based on the definition of drug development as providing answers to important questions by appropriate clinical studies. This review describes the selection process for biomarkers that are fit-for-purpose for the stage of drug development in which they are used. This structured and practical approach is widely applicable and particularly useful for the early stages of innovative drug development.

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The FDA Guidance on Maximum Starting Dose from 2005 recommends that the maximum starting dose in humans should primarily be calculated on the basis of safety levels (NOAEL).
“The FDA Guidance on Maximum Starting Dose from 2005 [23] recommends that the maximum starting dose in humans should primarily be calculated on the basis of safety levels (NOAEL).”
From Commentary on the <scp>EMA Guideline</scp> on strategies to identify and mitigate risks for first‐in‐human and early clinical trials with investigational medicinal products (2018) · cites this paper as [23]
The Phase I Studies and Beyond section discusses a 1998 FDA/EMA guideline on how to organize clinical studies, not the 2005 FDA guidance on maximum starting doses. Searches for NOAEL and starting-dose calculations found no passage in our copy stating that the 2005 guidance recommends calculating the human starting dose primarily from NOAEL safety levels. (LLM, conf=0.75)
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Desmopressin as a pharmacological tool in vasopressinergic hypothalamus–pituitary–adrenal axis modulation: neuroendocrine, cardiovascular and coagulatory effects
Jacobs, G. E., Hulskotte, E. G. J., van Gerven, J., Zuurman, L., de Kam, M., Elassaiss‐Schaap, J., Ruigt, G. S. F., PELT, J. V., Peeters, B., Peeters, P. A. M., et al. (2010) · Journal of Psychopharmacology · doi:10.1177/0269881109358203 · Cited by 4 · see citing works
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A pharmacological tool to assess vasopressinergic co-activation of the hypothalamus–pituitary–adrenal axis more integrally in healthy volunteers
Jacobs, G., van Gerven, J., de Kam, M., Elassaiss‐Schaap, J., Ruigt, G. S. F., PELT, J. V., Peeters, B., Peeters, P. A. M., & Hulskotte, E. G. J. (2010) · Journal of Psychopharmacology · doi:10.1177/0269881109358205 · Cited by 3 · see citing works

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Commentary on the <scp>EMA Guideline</scp> on strategies to identify and mitigate risks for first‐in‐human and early clinical trials with investigational medicinal products
van Gerven, J., & Bonelli, M. (2018) · British Journal of Clinical Pharmacology · doi:10.1111/bcp.13550 · Cited by 174 · see citing works
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The return of the prodigal son and the extraordinary development route of antibody TGN1412 ‐ lessons for drug development and clinical pharmacology
Kenter, M. J. H., & Cohen, A. F. (2015) · British Journal of Clinical Pharmacology · doi:10.1111/bcp.12605 · Cited by 17 · see citing works
Self-citation

Authors: Cohen, A. F., Burggraaf, J., van Gerven, J. M. A., Moerland, M., & Groeneveld, G. J.
Affiliations: Leiden University Medical Center (NL)
Leiden University (NL)
Centre for Human Drug Research, 2333 CL Leiden, The Netherlands;
Centre for Human Drug Research (NL)
ORCID: Cohen, A.F.
Burggraaf, J.
Moerland, M.
Groeneveld, G.J.
Venue: Annual Review of Pharmacology and Toxicology
Publisher: Annual Reviews
Published: 2015-01-06
Volume: 55
Issue: 1
Pages: 55-74
ISSN: 0362-1642 (ISSN-L)
1545-4304
DOI: 10.1146/annurev-pharmtox-011613-135918
OpenAlex: W2119617861
Cited by: 55
References: 74
Citations by year: 2026: 1 · 2025: 6 · 2024: 2 · 2023: 6 · 2022: 3 · 2021: 7 · 2020: 3 · 2019: 6 · 2018: 4 · 2017: 7 · 2016: 7 · 2015: 3
FWCI: 0.72
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: The Annual Review of Pharmacology and Toxicology (publishedVersion)
PubMed (publishedVersion)
Pure Amsterdam UMC (publishedVersion, other-oa)
Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
Data Archiving and Networked Services (DANS) (submittedVersion)
Leiden Repository (Leiden University) (submittedVersion)
Topics: Physical Sciences › Mathematics › Statistics and Probability › Statistical Methods in Clinical Trials
Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Pharmaceutical studies and practices
Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
Keywords: biomarkers, human pharmacology, drug development, biomarker selection, early drug development, drug safety assessment
MeSH terms: Animals, Dose-Response Relationship, Drug, Humans, Pharmacokinetics, Pharmacology, Risk Factors, Signal Transduction, Risk Assessment, Endpoint Determination, Biomarkers, Pharmacological, Drug Dosage Calculations, Drug Discovery, Patient Safety, Drug-Related Side Effects and Adverse Reactions

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The Use of Biomarkers in Human Pharmacology (Phase I) Studies

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