RISK AND BENEFIT EVALUATION IN DEVELOPMENT OF PHARMACEUTICAL PRODUCTS

Pharmaceutical products are intended to cure disease, reduce pain and suffering, prolong life, and correct metabolic deficits in patients. However, the potential patient population is intrinsically genetically heterogenous, and this factor complicates the evaluation of data on all aspects of safety evaluation of new drugs. Often the genetic heterogeneity is related to drug metabolizing capacity, but recent evidence suggests that heterogeniety in repair capacity as well as structural integrity of the chromatin (fragile X) have been shown to be relevant. Because drugs are biologically active and may have more than one type of effect, the evaluation of a large number of parameters is necessary in arriving at a rational estimate of potential risk. In this paper, several specific examples of risk assessments and some generic genotoxicity questions that are recurrent, including the question of the relevance of in vitro chromosomal aberration induction at high dose/sampling time, are raised. Other examples of the kinds of concerns from the safety evaluation of U-18753E, U-54461, and U-68,553B are discussed. The drug U-48753E was discovered to be slightly mutagenic in the AS52 assay, and significant efforts were expended in evaluation of the metabolism-based generation of a reactive intermediate. The drug U-54,461 was shown to be capable of breaking chromosomes in vitro but extensive in vivo data as well as a variety of other studies served to reduce the level of concern substantially. The induction of apparent chromosome breaks and gaps by U-68553B was shown to be an artifact that was restricted to a single cell line of rodent cells. These diverse examples of risk assessments illustrate the complexity of risk/benefit analysis in drug development.