Commentary: Regulatory Toxicology and the Critical Path: Predicting Long-term Outcomes from Short-term Studies

Abstract

Much attention and angst have been focused on the decline in new drug approvals, the increased failure rate of drug candidates in late stage development, and the soaring costs of developing new drugs. The causes for this crisis have been much discussed and debated. Oft cited are the following: consolidation in the pharmaceutical industry; more complicated multigenic diseases such as cancer, diabetes, and obesity; competition with generics; and perhaps a lower tolerance for adverse side effects. It is abundantly clear however that advances in applied science have not kept pace with the frenetic speed of developments in basic sciences (http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.pdf). This discrepancy is especially true for the discipline of regulatory toxicology. In spite of the tremendous advances in our ability to assess xenobiotic-induced changes in gene expression, protein and metabolite levels, the tools that are routinely employed in preclinical safety testing have changed little in the last quarter of a century. Many of the endpoints we routinely evaluate are subjective and only semiquantitative such as clinical signs, functional observations, gross pathology, and histopathology. This article is designed to identify specific advances in applied regulatory toxicology that could help facilitate the movement of new drugs from discovery to the clinic. It is instructive to consider which advances in toxicology would provide the greatest benefit in advancing drug development. While nonclinical studies still comprise a relatively small percentage of overall drug development costs, the rate of increase for this aspect of drug development is rising dramatically along with other development costs (http://csdd.tufts.edu/InfoServices/ OutlookPDFs/Outlook2008.pdf). This is especially true for biologics, which frequently rely on costly nonhuman primate studies. For small molecules, the costliest studies, in terms of time and resources are chronic studies which have in-lives of 6 to 24 months. Clearly, a major contribution to the field of regulatory toxicology would be the ability to predict chronic outcomes from relatively shortterm studies. Arguably, this would be the most important contribution of the new ‘‘omics’’ endpoints. One of the costliest, and certainly the most timeconsuming requirement in nonclinical safety testing is the 2-species, 2-year chronic bioassay for carcinogenicity. In addition to the time and resource requirements, cancer bioassays are often criticized as being overly sensitive (subject to false positives), especially for drugs that induce tumors at only 1 site, in 1 sex or in 1 species. Perhaps the most frustrating aspect of this assay is its lack of mechanistic information. Often when drugs are found to induce tumors, the basis for the result is not known, and therefore little useful information is provided for designing the next generation drug that does not induce tumors. Shorter drug development timelines in the pharmaceutical industry have resulted in the need to start these studies earlier in the development cycle. Since many drugs will fail in phase 1 and phase 2 clinical trials, early initiation of cancer bioassays can result in wasted resources and needless use of animals. Predicting carcinogenicity from short-term assays is a challenge. It was both a surprise and disappointment when in the late 1980s it was learned that while most mutagens are carcinogens, the opposite is often not true, especially for pharmaceuticals. Pharmaceutical companies screen drug candidates early in development and generally discard genotoxic molecules except for life-threatening indications such as oncology. Nevertheless, approximately one third of the drugs in the Physicians’ Desk Reference (PDR) for which carcinogenicity data are