Target selection in drug discovery

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Abstract
The term 'target' carries several connotations in the overall context of drug discovery. For example, disease-linked proteins are commonly referred to as targets, and target selection in a narrow sense could be taken to mean choosing between these. However, here we consider 'target selection' in a broader sense — the decision to focus on finding an agent with a particular biological action that is anticipated to have therapeutic utility. In addition to the question “What is the disease target?”, questions such as “What is the scientific approach?” also need to be addressed. As such, strategic considerations are a crucial component of target selection. Context is also important in target selection. An appropriate balance needs to be struck between stakeholders (investors), consumers (patients/doctors) and other modulating factors, such as legal factors (drug regulators) and political factors (potential payers). To select a proposed research target, a range of issues need evaluation. Perhaps most important is what constitutes an improved medicine. It should be emphasized that better medicines can be obtained in two ways: either by enhancing therapeutic efficacy or efficiency. These considerations lead to the categorization of innovative target-selection strategies into two subclasses: The first can be termed a 'speculative research target' strategy, which represents cases in which the specific biological action sought has not been shown to have therapeutic utility at the inception phase of a research programme; the proof-of-utility of the approach can only be established by Phase II clinical trials. The second can be termed 'innovative improvement', which is a research strategy of which the intention, at the inception phase of the research programme, is to improve on the performance of an agent whose biological activity is already known to have therapeutic utility. Innovative improvement research targets are often underestimated in their utility, both by health consumer groups and regulatory bodies. Furthemore, the risks of the chosen target failing to show improved utility are inherently greater with the speculative research targets than with innovative improvement research targets. Ultimately, there are two pivotal questions facing a research director in deciding whether to accept or reject a new research target. First, what is the probable risk and the likely financial return of the target? Second, will the project provide the Company with the right drug, for the right market niche, at the right time and at the right price? To address these issues, three sets of criteria are commonly used: first, what is the probability of achieving the action(s) sought? Second, what is the probability of maintaining a competitive advantage with the proposed project? Third, what is the probable financial return? To provide a framework for ensuring that the criteria for target selection are consistently applied and that there is transparency in articulating the assumptions underlying decisions about target selection, a range of modelling techniques, many of which are based on models used in predicting future performance in financial markets, have been applied to target selection in pharmaceutical companies.
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