Successful drug development despite adverse preclinical findings part 1: processes to address issues and most important findings

Abstract

Unexpected adverse preclinical findings (APFs) are not infrequently encountered during drug development. Such APFs can be functional disturbances such as QT prolongation, morphological toxicity or carcinogenicity. The latter is of particular concern in conjunction with equivocal genotoxicity results. The toxicologic pathologist plays an important role in recognizing these effects, in helping to characterize them, to evaluate their risk for man, and in proposing measures to mitigate the risk particularly in early clinical trials. A careful scientific evaluation is crucial while termination of the development of a potentially useful drug must be avoided. This first part of the review discusses processes to address unexpected APFs and provides an overview over typical APFs in particular classes of drugs. If the mode of action (MoA) by which a drug candidate produces an APF is known, this supports evaluation of its relevance for humans. Tailor-made mechanistic studies, when needed, must be planned carefully to test one or several hypotheses regarding the potential MoA and to provide further data for risk evaluation. Safety considerations are based on exposure at no-observed-adverse-effect levels (NOAEL) of the most sensitive and relevant animal species and guide dose escalation in clinical trials. The availability of early markers of toxicity for monitoring of humans adds further safety to clinical studies. Risk evaluation is concluded by a weight of evidence analysis (WoE) with an array of parameters including drug use, medical need and alternatives on the market. In the second part of this review relevant examples of APFs will be discussed in more detail.

Keywords: adverse preclinical finding; hazard identification and characterization; mode of action; risk evaluation and management; safety ratio; weight of evidence.

Fig. 1

Beta-cell vacuolization in the pancreas of a SIV 50 rat. H&E, lens 25×.

Fig. 2

The main aspects of a simplified risk evaluation as part of the weight of evidence analysis (WoE, for details see text) for significant adverse preclinical findings (APFs) with drug candidates: Mode of action (MoA) assessment combined with calculation of safety ratios (NOAEL exposure in most sensitive and relevant animal species vs. maximal human therapeutic exposure). For the definition of a sufficient safety ratio see text.

Fig. 3

Risk/benefit ratio. Greater benefit justifies higher risk.