Abstract
In the process of new drug discovery and development, understanding the dose–response relationship is one of the most challenging tasks. It is also critical to identify the right range of doses in early stages of clinical development so that Phase III trials can be designed to confirm some doses within this range. Usually at the beginning of Phase II, there is not a lot of available information to help guide the study design. At this stage, Phase II clinical studies are needed to establish proof-of-concept (PoC), to identify a set of potentially effective and safe doses, and to estimate dose–response relationships. Challenges in designing these studies include: selection of the dose frequency and the dose range, choice of clinical endpoints or biomarkers, and use of control(s), among others. Consequences of bad Phase II study designs may lead to the delay of the entire clinical development program or the wastage of R&D investment. In fact, the entire drug development process can be viewed as a scientific search of right doses—starting from discovery, up to clinical Phases I, II, III, and IV—is a process to find one or a few efficacious and safe doses.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Bornkamp, B.; Bretz, F.;Dmitrienko, A.; Enas, G.; Gaydos, B.; Hsu, C.H.; König, F.; Krams, M.; Liu, Q.; Neuenschwander, B.; Parke, T.; Pinheiro, J.; Roy, A.; Sax, R.; Shen, F. Innovative approaches for designing and analyzing adaptive dose-ranging trials. J. Biopharm. Stat. 2007, 17 (6), 965–995.
Bretz, F., Pinheiro, J.C., and Branson, M., Combining Multiple Comparisons and Modeling Techniques in Dose-Response Studies, Biometrics, 2005; 61(3):738–748
Chang, M., and Chow, S.C. (2006) Power and sample size for dose response studies; Dose Finding in Drug Development, Springer, New York
Chow, S.C., and Liu, J.P. (1999) Design and Analysis of Bioavailability and Bioequvalence Studies, Marcel Dekker, Inc. New York
Deng, Q, N. Ting, Sample Size Allocation in a Dose-Ranging Trial Combined with PoC. Statistical Applications from Clinical Trials and Personalized Medicine to Finance and Business Analytics. (2016) Springer pp 77–90
Dette, H., Bretz, F., Pepelyshev, A., & Pinheiro, J. (2008, Optimal designs for dose-finding studies. Journal of the American Statistical Association, 103, pp. 1225–1237.
Dmitrienko, A., Offen, W., and Westfall, P., Gatekeeping strategies for clinical trials that do not require all primary effects to be significant, Statistics in Medicine, 2003; 22, 2387–2400.
Hamlett, A., N. Ting, C. Hanumara, J.S. Finman, Dose Spacing in Early Dose Response Clinical Trial Designs. Drug Information Journal (2002) Vol. 36, Issue 4, pp 855–864
Krams M, KR Lees, W Hacke, AP Grieve, JM Orgogozo, GA Ford, and for the ASTIN Study Investigators. ASTIN: An adaptive dose-response study of UK-279, 276 in acute ischemic stroke. Stroke. (2003). 34, 2543–254.
MacDougall, J., Analysis of dose-response studies—Emax model. In: Ting, N., ed. Dose Finding in Drug Development, 2006 Springer, Berlin, New York.
Pereira TV, Horwitz RI, Ioannidis JPA. Empirical evaluation of very large treatment effects of medical intervention. Journal of the American Medical Association, (2012); 308(16):1676–1684.
Pukelsheim, F. (1993). Optimal Design of Experiments. Wiley.
Tamhane, A.C., Statistical Analysis of Designed Experiments: Theory and Applications, 2009 Wiley
Thomas, N. Hypothesis testing and Bayesian estimation using a sigmoid Emax model applied to sparse dose-response designs J. Biopharmaceutical Statistics, 2006; 16(5):657–677
Thomas, N., Sweeney, K., and Somayaji, V. Meta-analysis of clinical dose response in a large drug development portfolio, Statistics in Biopharmaceutical Research, 2014; Vol. 6, No. 4, 302–317.
Thomas, N., and Roy, D. Analysis of clinical dose-response in small-molecule drug development: 2009-2014. Statistics in Biopharmaceutical Research, 2016; 137–146.
Ting, N. Practical and Statistical Considerations in Designing an Early Phase II Osteoarthritis Clinical Trial: a Case Study, Communications in Statistics – Theory and Methods, (2009) Vol. 38, # 18, pp 3282–3296
Wang, X., N. Ting. A Proof-of-concept Clinical Trial Design Combined with Dose- Ranging Exploration. Biopharmaceutical Statistics, (2012) wileyonlinelibrary.com. https://doi.org/10.1002/pst.1525
Wu, J., Banerjee, A., Jin, B., Menon, S., Martin, S., Heatherington, A. Clinical dose–response for a broad set of biological products: A model-based meta-analysis, Statistical Methods in Medical Research, 2017; 0(0) 1–28
Yuan, G, N. Ting, First Dose Ranging Clinical Trial Design – More Doses? Or a Wider Range? Clinical Trial Biostatistics and Biopharmaceutical Applications (2014), Taylor & Francis
Zhang, Y., Q. Deng, S. Wang, N. Ting. A Simple and Efficient Statistical Approach for Designing an Early Phase II Clinical Trial: Ordinal Linear Contrast. New Advances in Statistics and Data Science. Springer 2017 pp 179–196
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2019 Springer Nature Switzerland AG
About this chapter
Cite this chapter
Deng, Q., Ting, N. (2019). Phase II Dose Finding. In: Fang, L., Su, C. (eds) Statistical Methods in Biomarker and Early Clinical Development. Springer, Cham. https://doi.org/10.1007/978-3-030-31503-0_14
Download citation
DOI: https://doi.org/10.1007/978-3-030-31503-0_14
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-030-31502-3
Online ISBN: 978-3-030-31503-0
eBook Packages: Mathematics and StatisticsMathematics and Statistics (R0)