Abstract
Studies in volunteers are most important in the research and development of a medicinal product or, as defined by the US Food and Drug Administration (FDA), of a drug. The initiation of clinical drug trials in humans requires comprehensive and substantial information about the investigational medical product, particularly toxicology, in order to exclude potential risks for subjects/patients with the greatest probability. Early clinical trials aim to provide first evidence of safety of the investigational medical product. Regulatory and ethical aspects must be taken into account as closely as possible.
Keywords
References
64th WMA General Assembly (2013) WMA declaration of Helsinki – ethical principles for medical research involving human subjects. Fortaleza, Brazil. https://www.wma.net/policies-post/wma-declaration-of-helsinki-ethical-principles-for-medical-research-involving-human-subjects/. Accessed 15 Jan 2021
Brøsen K, Funck-Brentano C, Kroemer H, Pirmohamed M, Schwab M (2017) Open letter on access to the BIA 10-2474 clinical trial data. Lancet 389:156. https://doi.org/10.1016/S0140-6736(16)32515-6
Butler D, Callaway E (2016) Scientists in the dark after French clinical trial proves fatal. Nature 529:263–264. https://doi.org/10.1038/nature.2016.19189
Emanuel EJ, Bedarida G, Macci K, Gabler NB, Rid A, Wendler D (2015) Quantifying the risks of non-oncology phase I research in healthy volunteers: meta-analysis of phase I studies. BMJ 350:h3271. https://doi.org/10.1136/bmj.h3271
European Commission (2005) Commission Directive 2005/28/EC. Off J Eur Union 48:13–19. https://eur-lex.europa.eu/legal-content/EN/TXT/PDF/?uri=CELEX:32005L0028&from=EN. Accessed 15 Jan 2021
European Medicines Agency (2004) Public statement on thiomersal in vaccines for human use – recent evidence support safety of thiomersal-containing vaccines. EMEA/CHMP/VEG/1194/94/Adopted. https://www.ema.europa.eu/en/documents/scientific-guideline/emea-public-statement-thiomersal-vaccines-human-use-recent-evidence-supports-safety-thiomersal_en.pdf. Accessed 15 Jan 2021
European Medicines Agency (2016) Guideline for good clinical practice E6 (R2) – Step 5. EMA/CHMP/ICH/135/1995. https://www.ema.europa.eu/en/documents/scientific-guideline/ich-e-6-r2-guideline-good-clinical-practice-step-5_en.pdf. Accessed 15 Jan 2021
European Medicines Agency (2017) Guideline on strategies to identify and mitigate risks for first-in-human and early clinical trials with investigational medicinal products. EMEA/CHMP/SWP/28367/07 Rev. 1. https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-strategies-identify-mitigate-risks-first-human-early-clinical-trials-investigational_en.pdf. Accessed 15 Jan 2021
European Medicines Agency (2018) First draft guideline on clinical evaluation of vaccines REV1. EMEA/CHMP/VWP/164653/05 Rev. 1. https://pdf4pro.com/view/first-draft-guideline-on-clinical-evaluation-of-vaccines-rev1-316c2c.html. Accessed 15 Jan 2021
European Medicines Agency (2019) ICH guideline E8 (R1) on general considerations for clinical studies Step 2b. EMA/CHMP/ICH/544570/1998. https://www.ema.europa.eu/en/documents/scientific-guideline/draft-ich-guideline-e8-r1-general-considerations-clinical-studies-step-2b_en.pdf. Accessed 15 Jan 2021
Federal Ministry of Justice and Consumer Protection (2012) Verordnung über die Anwendung der Guten Klinischen Praxis bei der Durchführung von klinischen Prüfungen mit Arzneimitteln zur Anwendung am Menschen. https://www.gesetze-im-internet.de/gcp-v/GCP-V.pdf. Accessed 15 Jan 2021
ICH (2021) ICH Official web site: ICH. https://www.ich.org/page/safety-guidelines. Last accessed Jan 20 2021
Jefferson T, Rudin M, Di Pietrantonj C (2004) Adverse events after immunisation with aluminium-containing DTP vaccines: systematic review of the evidence. Lancet Infect Dis 4:84–90. https://doi.org/10.1016/S1473-3099(04)00927-2
Jung D, Boettcher MF, Wensing G (2020) How safe are our studies? Analysis of adverse events in Bayer First-in-Human trials from 2006 to 2016. Int J Clin Pharmacol Ther 58:10–20. https://doi.org/10.5414/CP203390
Karakunnel JJ, Bui N, Palaniappan L, Schmidt KT, Mahaffey KW, Morrison B, Figg WD, Kummar S (2018) Reviewing the role of healthy volunteer studies in drug development. J Transl Med 16:336. https://doi.org/10.1186/s12967-018-1710-5
Lutfullin A, Kuhlmann J, Wensing G (2005) Adverse events in volunteers participating in phase I clinical trials: a single-center five-year survey in 1,559 subjects. Int J Clin Pharmacol Ther 43:217–226. https://doi.org/10.5414/cpp43217
Mandrekar SJ, An MW, Sargent DJ (2013) A review of phase II trial designs for initial marker validation. Contemp Clin Trials 36:597–604. https://doi.org/10.1016/j.cct.2013.05.001
Marchetti S, Schellens JH (2007) The impact of FDA and EMEA guidelines on drug development in relation to Phase 0 trials. Br J Cancer 97:577–581. https://doi.org/10.1038/sj.bjc.6603925
Mellet J, Pepper MS (2021) A COVID-19 vaccine: big strides come with big challenges. Vaccines (Basel) 9:E39. https://doi.org/10.3390/vaccines9010039
Munos B (2009) Lessons from 60 years of pharmaceutical innovation. Nat Rev Drug Discov 8(12):959–968. https://doi.org/10.1038/nrd2961
Singh G (2018) Chapter 5 – target product profile and clinical development plan. In: Vohora D, Singh G (eds) Pharmaceutical medicine and translational clinical research. Academic, London, pp 65–80. https://doi.org/10.1016/B978-0-12-802103-3.00005-5
Suntharalingam G, Perry MR, Ward S, Brett SJ, Castello-Cortes A, Brunner MD, Panoskaltsis N (2006) Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412. N Engl J Med 355:1018–1028. https://doi.org/10.1056/NEJMoa063842. Share
Willhite CC, Karyakina NA, Yokel RA, Yenugadhati N, Wisniewski TM, Arnold IM, Momoli F, Krewski D (2014) Systematic review of potential health risks posed by pharmaceutical, occupational and consumer exposures to metallic and nanoscale aluminum, aluminum oxides, aluminum hydroxide and its soluble salts. Crit Rev Toxicol 44(Suppl 4):1–80. https://doi.org/10.3109/10408444.2014.934439
Young TC, Srinivasan S, Vetter ML, Sethuraman V, Bhagwagar Z, Zwirtes R, Narasimhan P, Chuang T, Smyth BJ (2017) A Systematic review and pooled analysis of select safety parameters among normal healthy volunteers taking placebo in phase 1 clinical trials. J Clin Pharmacol 57:1079–1087. https://doi.org/10.1002/jcph.913
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2021 Springer-Verlag GmbH Germany, part of Springer Nature
About this entry
Cite this entry
Jäger, S., Schwab, M. (2021). Early Clinical Trials. In: Reichl, FX., Schwenk, M. (eds) Regulatory Toxicology. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-36206-4_43-2
Download citation
DOI: https://doi.org/10.1007/978-3-642-36206-4_43-2
Received:
Accepted:
Published:
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-642-36206-4
Online ISBN: 978-3-642-36206-4
eBook Packages: Springer Reference Biomedicine and Life SciencesReference Module Biomedical and Life Sciences