Local Laboratory Reference Intervals in Clinical Trials
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loop H. M. Diikmon, MD, MBA, PPM Senior Director at Covance, Zeist. The Netherlands
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Local Laboratorv Reference Intervals in Clinical Trials J
Professor Callrn G. Fraser, PLD, FAACB Consultant Clinical Biochemist at the Scottish Bowel Screening Centre Laboratory. Dundee, United Kingdom
F. Peter Treasure, PLD, cstot Director at Peter Treasure Statistical Services Ltd. King’s Lynn, United Kingdom
Gordon F. Kopke, PLD Senior Director Biomarkers at Covance. Indianapolis, Indiana
Assessment of whether laboratory results in clinical studies are abnormal relies heavily on the laboratory upper or lower reference limits. While centml labomtories use a single reference interval for an entire study population, local labomtories apply their own reference intervals. Due to bias caused by method differences between local laboratories, such reference intervals are not interchangeable. We have compared the reference intervals of local labomtm’es after harmonizing their test results, using an ana!vtml calibration stepfor routine clinical biochemistry
Key Words Local laboratory: Reference interval: Calibration: Safety monitoring
Correspondence Address Jaap H. M. Dijkman, Sr. Director, Covance VCL BY Driebergseweg 26, 3708 JC. Zeist, The Netherlands (email: [email protected])
INTRODUCTION LITERATURE !XUDY Laboratory data are of major importance in drug safety assessments since they are considered objective tools to supplement clinical judgments and the transfer of results across study populations. Moreover, the spectrum of available biomarkers to assess drug safety and efficacy is continuously being developed and refined. Although central laboratories are widely used in clinical trials, local laboratories continue to play an important role for trials where the use of such central laboratories is not practical or feasible. Local laboratories are primarily performing safety testing. The collection and analysis of these data remain a challenge in view of differences in reference intervals, analytical methods, and reporting units. These challenges are widely recognized. Other factors that may account for differences between local and central laboratories are differences in population characteristics, such as ethnicity or nutrition. While such differences should be reflected by differences between local and central laboratory reference intervals, analysis of central laboratory data in global clinical studies has shown these differences to be insignificant (see next section). Al-
analytes. Chr results show that differences in local reference intervals could result in significantly variable criteria being used for assessment of normality versus abnormality-up to more than 30%. Significant differences were observed for most analytes used in routine safdy monitoring. We condude that local reference intervals are not useful for drug taxicity trend analysis. Instead, a single reference interval after data harmonization can be used with advantage in addition to assessment of changes in individuals versus their baseline result
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