Benchmark Dose-Response Analyses for Multiple Endpoints in Drug Safety Evaluation

Hazard characterization during pharmaceutical development identifies the candidate drug's potential hazards and dose-response relationships. To date, the no-observed-adverse-effect-level (NOAEL) approach has been employed to identify the highest dose which results in no observed adverse effects. The benchmark dose (BMD) modeling approach describes potential dose-response relationships and has been used in diverse regulatory domains, but its applicability for pharmaceutical development has not previously been examined. Thus, we applied BMD-modeling to all endpoints in three sequential in vivo studies in a drug development setting, including biochemistry, hematology, organ pathology and clinical observations. In order to compare the results across such a broad range of effects, we needed to standardize the choice of the critical effect size (CES) for the different endpoints. A CES of 5%, previously suggested by the European Food Safety Authority, was compared with the study NOAEL and with the General Theory of Effect Size, which takes natural variability into account. Compared to the NOAEL approach, the BMD-modeling approach resulted in more informative estimates of the doses leading to effects. The BMD-modeling approach handled well situations where effects occurred below the lowest tested dose and the study's NOAEL, and seems advantageous to characterize the potential toxicity during safety assessment. The results imply a considerable step forward from the perspective of reducing and refining animal experiments, as more information is yielded from the same number of animals and at lower doses. Taken together, employing BMD-modeling as a substitute, or as a complement, to the NOAEL approach seems appropriate.