Productivity shortfalls in drug discovery: contributions from the preclinical sciences?

An inverse relationship between human and financial investment and productivity, in the form of new drug approvals, has been a consistent theme in drug discovery for more than a decade. There appear to be many causes and solutions for this, but few tangible outcomes. Although Food and Drug Administration regulators, the constraints resulting from short-term business decisions, and the harvesting of all "low-hanging fruit," have been cited as the major causes for the decreased productivity, a change in the preclinical research culture is equally culpable. Current trends in biomedical research have led to a decreased emphasis on the null hypothesis/data-driven approach; a trend toward qualitative rather than quantitative science; an implicit assumption that all targets represent a viable starting point for drug discovery efforts; and the replacement of the creativity, objectivity, passion, and logic characteristic of the drug hunter with consensus-dependent, technology-driven research cultures. In addition, the euphoria following the mapping of the human genome and its implicit potential as a source for new drug targets has given way to disillusionment as the relevance, tractability, and complexity of novel disease-associated targets have become recognized as significant challenges. Biomedical research efforts directed toward drug discovery, both in academia and industry, must prioritize genuine innovation over technology and thus allow efforts in preclinical research to play a key role in the solution to the shortfall in new drug applications.