Methods and Findings in Experimental and Clinical Pharmacology
Vol. 25, Suppl. A, 2003
ISSN 0379-0355
Copyright 2003 Prous Science, S.A.
CCC: 0379-0355/2003
http://www.prous.com

Strategy and Tactics in Target Validation

J. Beleta

Almirall Prodesfarma

The implementation of successful tactics when the strategy is ill defined is a recipe for failure. Currently this appears to be the case in pharmaceutical target validation. A lot of effort has been put into the "how" part of the process, while the "what" remains unclear.

The problem is one of definitions. Whereas a benchmarking exercise reveals that the "candidate for development" concept is relatively uniform across the industry, this is far from being the case when it comes to defining what is a validated target.

In essence, the aim is to obtain a useful therapeutic effect, in people afflicted by a particular disease, through the modulation of the biochemical activity of a molecular target (usually a protein) by means of a chemical or biological entity. If we define this as the therapeutic hypothesis, then validation can be considered as the extent to which current evidence supports the therapeutic hypothesis for a particular target.

Drugs exert their primary effect at the molecular level, yet the relevance of their benefit can only be demonstrated at the whole body level. This is at the root of the problem of defining target validation. There are many levels of increasing complexity, and all of them have to be considered when evaluating the validation of a given target for a particular disease. Positive evidence in any of them has been claimed to be sufficient proof for validation.

In fact, validation is an incremental concept. Its practical use should be to provide the right amount of information required to progress a given target through the different activities that encompass the discovery and development of a new drug. Presently, there is no clear consensus on what is the right amount of information needed at each stage in order to minimize the risk of failure further along.

Additionally, the validation of new potential targets has been confounded in some instances by an over reliance in high throughput methodological approaches. These have raised some confusion between the amount of information gathered and their real significance. In turn, this has created a certain reaction against new methodologies, putting the blame on the messenger rather than on the message itself, and giving rise to holistic or empirical approaches. Both extremes are probably inappropriate, the truth lying somewhere in the middle: making good use of all available tools, but putting the emphasis on the relevant questions to ask rather than on how to obtain the answer.

Regardless of the reasons, the current situation is that, in spite of the ever increasing expenditure devoted to finding new drugs, industry productivity, measured as submissions of new drugs to the FDA, has hit a historical low.

The talk will try to analyze this paradox and its implications, focusing on the concept of validation, rather then in the particular techniques that are used to demonstrate it.

Methods and Findings in Experimental and Clinical Pharmacology Vol. 25, Suppl. A, 2003
ISSN 0379-0355 Copyright 2003 Prous Science, S.A. CCC: 0379-0355/2003 http://www.prous.com