Using Tolerance Limits to Evaluate Laboratory Data
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Drug Information Journal, Vol. 32, 261-269, 1998 Printed in the USA. All rights reserved.
USING TOLERANCE LIMITS TO EVALUATE LABORATORY DATA DANAJ. NICKENS, MS Biostatistician, Clinical Biostatistics 11, Pharmacia & Upjohn, Inc, Kalamazoo, Michigan
Quantitative laboratory measurements are a large part of the data collected in a clinical trial and the analysis of this type of data is often challenging. The use of tolerance limits and its variations, which describe the concentration and extremes of a distribution, provide useful methods to evaluate laboratory data. The theory of tolerance limits for the gaussian distribution and any unknown continuous distribution ispresented. Tolerance limits provide adequate data reduction while still allowing appropriate interpretation of the results and are useful for evaluating individual patient responses. Examples of the utility of determining limits in which a chosen proportion of the data is likely to be concentrated for interpretation purposes are presented. Using the concept of tolerance limits to determine the size of a clinical trial designed from the safety perspective is also discussed. Key Words: Tolerance limits; Clinical trials; Safety laboratories; Sample size
INTRODUCTION IN ASSESSING THE safety profile of a new therapeutic agent, clinical trials collect extensive data on laboratory measures. Often, these data are collected at the start of a trial and at various study visits over time. Information collected in this way can be difficult to analyze due to the size and complexity of the data sets. The methods used to analyze laboratory data are frequently unsatisfactory and do not answer the questions that are of primary interest to the researcher. In clinical trials, while the emphasis is on efficacy outcomes, assessing the effects of a new therapy on routine laboratory assays is also of major interest. Understanding drug effects on these assays helps to profile the safety of a potential new medicine. A solid grasp of the safety is vital during the approval
Reprint address: Dana J. Nickens, Clinical Biostatistics 11, 9 1 6 2 - 2 2 7 4 , Pharmacia & Upjohn Inc., Kalamazoo MI. 49001.
review process for a new drug as well as its use when it is available in the marketplace for prescription by clinicians. There are currently many methods for analyzing laboratory measurements. These include calculating summary statistics on raw measurements and change-from-baseline statistics. The latter is often used to compare differences between treatment groups. Another method is to determine, using reference ranges, whether a patient’s values during the study were abnormal and then comparing the frequency of abnormalities among the treatment groups. Other analyses focus on abnormal shifts relative to baseline using either reference ranges or a toxicity scale. While these approaches have their utility, they may not adequately address the goals of the safety analysis. For example, the focus of the above approaches is more on the average response of the population and less on an in
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