Critical limits to define a lab adverse event during phase I studies: a study in 1134 subjects

The first goal of phase I drug development is the determination of maximal tolerated dose, which must be established by case-by-case analysis, sometimes using a laboratory adverse event. Since no accurate rule defining lab adverse events, has been validated yet, we propose a new "combined method" based on combination of two thresholds: inclusion values and magnitude of variation. Using this combined method, the label "lab adverse event" is applied if any lab value exceeds the inclusion threshold and is associated with a variation from baseline exceeding the variation threshold defined from reference change limit. Thus, this study aimed to test this combined method on a large healthy volunteer population, studied in 19 phase I centres worldwide, and on five lab parameters: alanine amino transferase, aspartate amino transferase, alkaline phosphatases, creatinine and polymorphonuclear leukocytes.

The inclusion threshold from each center was used. Reference change limits were defined from volunteers previously included in comparable studies and were expressed as absolute values: increases of 10 IU.l-1 for alanine amino transferase or aspartate amino transferase, 15 IU.l-1 for alkaline phosphatases, 15 mumol.l-1 for creatinine and a 0.34 10(9).l-1 decrease for polymorphonuclear leukocytes. Comparison between the "combined method" and a normal range method was made using positive predictive value and a ratio between relevant and irrelevant results. This application was implemented in all young healthy volunteers (1134) included in 38 phase I studies sponsored by Rhone Poulenc Rorer from 1991 to 1993.

Seventy seven subjects (6.7%) were indicated in final study reports as having a lab adverse event (reference group). Of 179 subjects with lab abnormalities defined by the normal range method, 77 belonged to the reference group, inducing a poor 0.43 positive predictive value. Of ninety subjects with lab adverse events defined by the "combined method", seventy-five belonged to the reference group, inducing a two-fold higher 0.83 positive predictive value. The combined method produced a high ratio of relevant/irrelevant results (5 = 75/15) compared with the low ratio (0.76 = 77/102) achieved using the normal range method.

This new "combined method", leading to a better definition of lab adverse event, seems an accurate and useful tool for routine case-by-case analysis within phase I drug development studies.