The trouble with translational medicine.

Increasingly more reports in the literature are reflecting on the hurdles of effective translation from promising results of biomedical research into useful therapeutics. A recurrent theme is that good intentions are frustrated by extrinsic factors upon which 'translationalists' have little control. It is possible that the problem resides, at least in part, within the translational community itself, which has failed to prioritize the steps required to approach the problem systematically. Most importantly, there is disproportionate emphasis on bench-to-bedside efforts, rather than confronting a priori the need to increase the understanding of human pathophysiology. Thus, therapeutic concepts based on experimental conditions that may not and indeed often do not represent the nature of human genetics lead to drug development that is not sufficiently applicable to the human condition. The damage is then amplified when these ill-fated concepts are tested in clinical trials at great cost. The use of surrogate biomarkers that could allow early assessment of efficacy currently requires long-term assessment of clinical benefit. This can delay by years or decades essential feedback about clinical efficacy. Moreover, scant effort is applied to learning whether a drug has achieved its biological endpoint, or why it failed its clinical endpoint. Thus, the feedback loop is not only delayed, but is often uninformative. As a consequence, researchers continue to produce novel therapeutic candidates based on experimental models without the essential benefit of lessons learned from previous failures. Biomedical research will succeed when drug development is guided by experience gained through informative clinical trials with the purpose of not only testing the effectiveness of treatment but also providing mechanistic insights into the differences between expected and observed results. This can only be achieved through the courageous effort of the research community to change the way biomedical research is funded, published and rewarded.