Much of the power of modern medicine has resulted from a core of important pharmaceuticals, biologicals, and vaccines developed by the combined efforts of academicians, the pharmaceutical industry, government, clinical investigators, and research subjects during the the past few decades. The proliferation of potential therapeutic targets opened up by genomic and proteomic technologies, the ability of combinatorial chemistry to generate myriad test molecules, and the development of high-throughput technologies to rapidly screen new molecules against new targets promises even more powerful therapies. Yet, massive increases in research and development expenditures have not produced a proportional increase in new therapeutics developed. The relative dearth of new chemical entities has raised significant concerns about the robustness of the pharmaceutical, biotechnology, and vaccine industries. Despite intensive focus in recent years, diseases of the central nervous system (particularly neurodegenerative diseases) have been particularly prominent as a source for recurrent failures of new therapies that are often late in development, with great expense and potential risk to patients.
Three key issues must be addressed to reduce costs and risks while enhancing speed and success rates. (1) Future development of neuroprotective compounds must incorporate the fact of high rates of failures into the strategy of central nervous system development by using technologies to aggressively test key sources of potential failure very early in development. Does the compound penetrate to the target organ? Does it mechanistically do what it is supposed to do? Does it produce biological activity? We should reject inadequate compounds early, without full clinical testing. (2) While approaches based on narrow therapeutic mechanisms are intellectually attractive, many effective compounds affect multiple mechanisms. Approaches using compounds with multimechanistic targets, possibly designed using inferences from disease models, may produce more robust therapies. (3) Technology and more effective management are better sources for time-saving in research than relying on guesswork on dose selection by skipping phase 2.
Gallen C. Strategic Challenges in Neuroprotective Drug Development. Arch Neurol. 2003;60(2):297. doi:10.1001/archneur.60.2.297-a