Statistical Approaches to Detecting Dose-Response Relationships
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STATISTICAL APPROACHES TO DETECTING DOSE-RESPONSE RELATIONSHIPS TOSHIMITSU HAMASAKI, MSc, PHD Clinical Biometrics, Biometrics. Pfizer Pharmaceuticals Inc., Tokyo, Japan
TATSUYAISOMURA,MSc Clinical Biometrics. Biometrics, Pfizer Pharmaceuticals Inc.. Tokyo, Japan
MITSUMASA BABA Biometrics Office, Product Development Department, Pharmaceuticals Division, Teikoku Chemical Industries Co., LTD., Osaka, Japan
MASASHIGOTO,MSc, PHD Department/Division of Informatics and Mathematical Science, Graduate School of Engineering Sciences, Osaka University, Osaka, Japan
A dose-response study, which is performed to determine whether or rwt there is any effect
of a new drug related to dose, plays a very important role in the clinical development of a drug. Finding evidence of the dose-response relationship is usually done based on hypothesis testing, which has been considered an appropriate way to analyze a doseresponse study. Hypothesis testing does nor provide information about certain structures of the dose-response relationship, especially the shape and location of the dose-response curve, though the information is most helpful in determining the clinical dose of a drug. In this papel: the model-based approach with data-adaptive distribution is introduced to infer the dose-response relationship. We also introduce the statistical descriptive use of the empirical cumulative distribution function, Furthermore, methods to compare two dose-response curves are considered.
Key Words: Nonmonotone relationship; Data-adaptive approach; Statistical graphics; Empirical cumulative distribution function; Asymmetric power-transformation model; Loggamma model
INTRODUCTION THE ASSESSMENT OF relationship (systern) between dose and clinical response (&sirable and undesirable effects) is the most Reprint address: Toshimitsu Hamasaki, Clinical Biometrics, Biometrics, Wizer Pharmaceuticals Inc., P. 0. Box 226 Mitsui Bldg.. 2-1-1, Nish-Shinjuku. Shinjuh-ku, Tokyo, 163-0461, Japan. E - ~ ~hamas&@ I : pfizer.co.jp.
important study in the drug development process. The relationship is called the “doseresponse relationship” and the curve of the dose-response may be described as a monotone curve such as sigmoid and s-shape curves. The dose-response curve is considered useful in identifying an appropriate starting dose, adjusting dosage to a particular patient, and identifying the lowest dose with a discernibly useful effect (mini-
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Toshimitsu Hamasaki, Tatsuya Isomura, Mitsumasa Baba, and Masashi Goto
mum effective dose) or a maximum dose beyond which no further beneficial effects are seen (maximum useful dose). The International Conference on Harmonization harmonized tripartite guideline on “Dose-Response Information to Support Drug Registration” (ICH-M Guideline) (1) mentions that practical study designs do not exist for precise determination of the minimum effective dose and the maximum useful dose. It also me
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