Biomarkers can take many different forms. In preclinical screening, for example, they may entail studies of gene expression or cell systems. Animal studies can make use of genomic and proteomic techniques, thereby increasing the probability that initial administration to humans will be safe, or help establish the relevance of animal findings to humans. Biomarker findings in clinical trials and postmarket data also can provide information about mechanisms of drug toxicity or benefit and suggest the need for additional nonclinical studies to fully elucidate the relevant mechanisms. In a clinical setting, such information can be used, for example, to monitor reactions to drugs in individuals or to deselect individuals from trials who may be at risk from a treatment.

In considering the use of biomarkers for drug development, additional issues arise, said Alastair Wood of Symphony Capital, LLC. To be useful, a biomarker for toxicity found to be elevated by an investigational drug in preclinical studies must provide some level of confidence that carrying such a drug forward into clinical trials will produce toxicity in a proportion of patients. This proportion must be significant enough to alter decision making about developing the drug, to point to a different course of action in patient selection for clinical trials, or to necessitate more detailed studies prior to marketing so that safety signals can be assessed. Conversely, the absence of elevation of a biomarker should imply confidence that a safety problem will not occur in more than a known (low) proportion of patients. In this way, the use of a biomarker can provide risk assessment and risk mitigation, both to patients who are likely to receive the drug clinically and to the development program carrying that drug forward.

Beyond these broad considerations lie more detailed questions. If a biomarker is elevated in a small number of people in early clinical studies, what is the overall risk to any given individual or to a population? If the absolute degree of elevation is small, does this mean that the likely toxicity will be mild when the drug is given to a large population of patients, and/or does it mean that only a small proportion of patients will develop severe toxicity? Unfortunately, the answers to these questions are seldom known with any degree of certainty. Does the absence of a biomarker signal necessarily predict long-term safety?

The use of biomarkers potentially could address several major problems associated with drug development. The costs of new drug development have risen rapidly even as the number of new molecular entities (NMEs) submitted to the FDA has fallen (Figure 2-1). In addition, a number of drugs have been withdrawn from the market because of safety concerns. By enhancing the ability to assess whether drug candidates are promising early in development, biomarkers could reduce the costs of developing drugs and bringing them to the market, enhance the safety of new drugs, and improve

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