Determining Maximum Recommended Starting Dose of Systemically Administered Biologics in First in Human Clinical Trials
Asian Oncology Research Journal,
Page 11-15
Abstract
Determining Maximum Recommended Starting Dose (MRSD) in first in human (FIH) studies is a crucial milestone in the development path of a new pharmaceutical drug. It is imperative to determine what is the safe starting dose in these trials, as the drug would be introduced for testing in humans for the first time. There are guidelines from United States Food and Drug Administration (US-FDA) and European Medicines Agency (EMEA) that help in determining this dose. Several determination methods for calculating MRSD are in practice, including Minimal Anticipated Biological Effect Level (MABEL), No Observed Adverse Effects Level (NOAEL), and Minimum Effective Dose (MED) approach. This paper elucidates NOAEL and MABEL methods for calculating the starting dose. This paper also discusses the factors that help in determining which method to choose for a particular study.
Keywords:
- MABEL
- NOAEL
- MRDS
- maximum recommended starting dose
- FIH
- first in human clinical trial
How to Cite
Mark Churchill, B. (2022). Determining Maximum Recommended Starting Dose of Systemically Administered Biologics in First in Human Clinical Trials. Asian Oncology Research Journal, 5(1), 11-15. Retrieved from https://journalaorj.com/index.php/AORJ/article/view/30143
References
US Food and Drug Administration. Guidance for industry: Estimating the maximum safe starting dose in initial clinical trials for thera¬peutics in adult healthy volunteers. Rockville, MD: Food and Drug Administration; 2005. Available:https://www.fda.gov/media/72309/download
Accessed on: 7 April 2022.
Committee for Medicinal Products for Human Use (CHMP). Guideline on strategies to identify and mitigate risks for first-in-human and early clinical trials with investigational medicinal products. London, UK. European Medicines Agency (EMEA); 20 July, 2017. Available:https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-strategies-identify-mitigate-risks-first-human-early-clinical-trials-investigational_en.pdf
Accessed on: 7 April 2022.
Suh HY, Peck CC, Yu KS, Lee H. Determination of the starting dose in the first-in-human clinical trials with monoclonal antibodies: A systematic review of papers published between 1990 and 2013. Drug Des Devel Ther. 2016;10:4005-4016. DOI: 10.2147/DDDT.S121520.
PMID: 27994442; PMCID: PMC5153257.
Muller PY, Milton M, Lloyd P, Sims J, Brennan FR. The minimum anticipated biological effect level (MABEL) for selection of first human dose in clinical trials with monoclonal antibodies. Curr Opin Biotechnol. 2009;20(6):722-9. DOI: 10.1016/j.copbio.2009.10.013.
Epub 2009 Nov 5. PMID: 19896825.
Sims J. Calculation of the Minimum Anticipated Biological Effect Level (MABEL) and 1st dose in human [Presentation]. The Association of the British Pharmaceutical Industry; 15 June, 2007.
Available:https://www.ema.europa.eu/en/documents/presentation/calculation-minimum-anticipated-biological-effect-level-mabel-1st-dose-human-jennifer-sims_en.pdf .
Accessed on: 8 April 2022.
Tam K. Estimating the “First in human” dose – a revisit with particular emphasis on oncology drugs. ADMET & DMPK. 2013;1(4):63-75. DOI: 10.5599/admet.1.4.10
Shen J, Swift B, Mamelok R, Pine S, Sinclair J, Attar M. Design and Conduct Considerations for First-in-Human Trials. Clin Transl Sci. 2019;12(1):6-19. DOI: 10.1111/cts.12582
Schaller TH, Snyder DJ, Spasojevic I, et al. First in human dose calculation of a single-chain bispecific antibody targeting glioma using the MABEL approach. Journal for Immuno Therapy of Cancer. 2020;8:e000213. DOI: 10.1136/jitc-2019-000213
Liao KH, Chen X, Beaupre DM, Yin D, Udata C. Assessment of current approaches of starting dose selection and dose escalation for oncology biologics in first-in-patient trials. Journal of Clinical Oncology. 2020;38(15_suppl):e14093-e14093.
Elmeliegy M, Udata C, Liao K, Yin D. Considerations on the Calculation of the Human Equivalent Dose from Toxicology Studies for Biologic Anticancer Agents. Clin Pharmacokinet. 2021;60:563–567. Available:https://doi.org/10.1007/s40262-021-00987-2
Suntharalingam G, Perry MR, Ward S, Brett SJ, Castello-Cortes A, Brunner MD, Panoskaltsis N. Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412. N Engl J Med. 2006; 355:1018-1028. DOI: 10.1056/NEJMoa063842
Harper J, Adams KJ, Bossi G, Wright DE, Stacey AR, Bedke N, et al. An approved in vitro approach to preclinical safety and efficacy evaluation of engineered T cell receptor anti-CD3 bispecific (ImmTAC) molecules. PLoS ONE. 2018;13(10): e0205491. Available:https://doi.org/10.1371/journal.pone.0205491
Van den Bogert CA, Cohen AF, Leufkens HGM, van Gerven JMA. Pharmacological vs. classical approaches in the design of first in man clinical drug trials. Br J Clin Pharmacol. 2017;83:2807–2812.
Frank R. Brennan, Laura Dill Morton, Sebastian Spindeldreher, Andrea Kiessling, Roy Allenspach, Adam Hey, Patrick Müller, Werner Frings & Jennifer Sims. Safety and immunotoxicity assessment of immunomodulatory monoclonal antibodies, mAbs. 2010;2(3): 233-255. DOI: 10.4161/mabs.2.3.11782
Accessed on: 7 April 2022.
Committee for Medicinal Products for Human Use (CHMP). Guideline on strategies to identify and mitigate risks for first-in-human and early clinical trials with investigational medicinal products. London, UK. European Medicines Agency (EMEA); 20 July, 2017. Available:https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-strategies-identify-mitigate-risks-first-human-early-clinical-trials-investigational_en.pdf
Accessed on: 7 April 2022.
Suh HY, Peck CC, Yu KS, Lee H. Determination of the starting dose in the first-in-human clinical trials with monoclonal antibodies: A systematic review of papers published between 1990 and 2013. Drug Des Devel Ther. 2016;10:4005-4016. DOI: 10.2147/DDDT.S121520.
PMID: 27994442; PMCID: PMC5153257.
Muller PY, Milton M, Lloyd P, Sims J, Brennan FR. The minimum anticipated biological effect level (MABEL) for selection of first human dose in clinical trials with monoclonal antibodies. Curr Opin Biotechnol. 2009;20(6):722-9. DOI: 10.1016/j.copbio.2009.10.013.
Epub 2009 Nov 5. PMID: 19896825.
Sims J. Calculation of the Minimum Anticipated Biological Effect Level (MABEL) and 1st dose in human [Presentation]. The Association of the British Pharmaceutical Industry; 15 June, 2007.
Available:https://www.ema.europa.eu/en/documents/presentation/calculation-minimum-anticipated-biological-effect-level-mabel-1st-dose-human-jennifer-sims_en.pdf .
Accessed on: 8 April 2022.
Tam K. Estimating the “First in human” dose – a revisit with particular emphasis on oncology drugs. ADMET & DMPK. 2013;1(4):63-75. DOI: 10.5599/admet.1.4.10
Shen J, Swift B, Mamelok R, Pine S, Sinclair J, Attar M. Design and Conduct Considerations for First-in-Human Trials. Clin Transl Sci. 2019;12(1):6-19. DOI: 10.1111/cts.12582
Schaller TH, Snyder DJ, Spasojevic I, et al. First in human dose calculation of a single-chain bispecific antibody targeting glioma using the MABEL approach. Journal for Immuno Therapy of Cancer. 2020;8:e000213. DOI: 10.1136/jitc-2019-000213
Liao KH, Chen X, Beaupre DM, Yin D, Udata C. Assessment of current approaches of starting dose selection and dose escalation for oncology biologics in first-in-patient trials. Journal of Clinical Oncology. 2020;38(15_suppl):e14093-e14093.
Elmeliegy M, Udata C, Liao K, Yin D. Considerations on the Calculation of the Human Equivalent Dose from Toxicology Studies for Biologic Anticancer Agents. Clin Pharmacokinet. 2021;60:563–567. Available:https://doi.org/10.1007/s40262-021-00987-2
Suntharalingam G, Perry MR, Ward S, Brett SJ, Castello-Cortes A, Brunner MD, Panoskaltsis N. Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412. N Engl J Med. 2006; 355:1018-1028. DOI: 10.1056/NEJMoa063842
Harper J, Adams KJ, Bossi G, Wright DE, Stacey AR, Bedke N, et al. An approved in vitro approach to preclinical safety and efficacy evaluation of engineered T cell receptor anti-CD3 bispecific (ImmTAC) molecules. PLoS ONE. 2018;13(10): e0205491. Available:https://doi.org/10.1371/journal.pone.0205491
Van den Bogert CA, Cohen AF, Leufkens HGM, van Gerven JMA. Pharmacological vs. classical approaches in the design of first in man clinical drug trials. Br J Clin Pharmacol. 2017;83:2807–2812.
Frank R. Brennan, Laura Dill Morton, Sebastian Spindeldreher, Andrea Kiessling, Roy Allenspach, Adam Hey, Patrick Müller, Werner Frings & Jennifer Sims. Safety and immunotoxicity assessment of immunomodulatory monoclonal antibodies, mAbs. 2010;2(3): 233-255. DOI: 10.4161/mabs.2.3.11782
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