From Mouse to Man: The Early Clinical Testings
- PDF / 504,608 Bytes
- 8 Pages / 504 x 719.759 pts Page_size
- 90 Downloads / 198 Views
Drug Information J o u m l . Vol. 31. pp. 729-736. 1997 Printed in the USA. All rights reserved.
FROM MOUSE TO MAN: THE EARLY CLINICAL TESTINGS KIMBERLYT. PERRY, PHD Biostatistics Senior Scientist, Clinical Development, Biostatistics I. Pharmacia & Upjohn Company, Kalamazoo, Michigan
In drug development from mouse to man, one of the primary goals of the Phase I studies is to estimate the maximum tolerated dose (MTD). Two considerations in designing Phase I studies are to treat as few patients as possible at doses much above the MTD and to escalate as fast as possible through the portion of the dose-toxicity curve where the chance of toxicity is very low. In some designs such as the Traditional Design, Up-andDown Designs, and Two-Stage Designs, the dose escalation scheme is determined in advance. Whereas, the Stochastic Approximation (SA) Method, the Continual Reassessment Method (CRM), and the Modified CRM Designs are methods where the dose escalation is based on total accumulated patient information. Subsequently, the Extended CRM Design was developed, which is a combination of sampling schemes. The Extended CRM Design uses a traditional type of design to move quickly through the nontoxic dose levels until a toxicity is observed. Once toxicity is observed, the CRM is implemented as it tends to concentrate sampling around the appropriate preset percentile. The above methods were compared in their ability to estimate the MTD and results showed that the designs which used combined sampling schemes were superior. Key Words: Phase I ; Maximum tolerance dose; Study designs; Continual reassessment method; Toxicity
INTRODUCTION THE FIRST ADMINISTRATION of a new drug to man (ie, a Phase I study) at a fixed route (eg, oral or intravenous) and schedule (eg, BID, TID, daily, etc.) is one of the most important steps in the development of a new drug (1,2). The goals of the Phase I study are as follows:
Presented at the DIA 32nd Annual Meeting ‘‘The Challenge of Worldwide Pixumaceutical Development in an Era of Regulatory Change: Accelerated Approval with Quality and Contained Costs,” June 9-13, 1996, San Diego, California. Reprint address: Kimberly Perry, PhD, 9162-227400, Pharmacia & Upjohn Company, 7000 Portage Road, Kalamazoo, MI 49001.
1. To estimate the maximum tolerated dose of a new drug, 2. To determine which organ systems are affected by drug toxicity, 3. To determine the extent, duration, and reversibility of the toxicity, and 4. To observe possible drug activity (3). Once the MTD for a drug has been established in Phase I studies then Phase I1 studies, dose-response studies, are conducted. Phase I1 studies explore different dosages of the new drug and frequently compare the effects of the different doses to that of a placebo to determine which dose(s) has (have) the best efficacy/safety profile. The dose(s) with the best efficacykafety profile are then further investigated in the larger population, a Phase
729 Downloaded from dij.sagepub.com at DALHOUSIE UNIV on May 18, 2015
Kimberly T. Perry
730 111 trial.
Data Loading...
