Fig. 1

Operational phases and associated challenges for translational research. Translational research has many layers (T0-T4) and associated operational obstacles that must be overcome. T0, basic science research that define cellular mechanisms, their relationship to disease and, consequently, the identification of therapeutic targets and development of methods of treatment (new molecular entities). T1, is the proof of concept studies conducted in volunteer human subjects as phase 1 clinical trials that aim to define proof of safety, mechanism, and concept. T2, phase 2 and 3 clinical (ideally randomized) trials that are necessary to test the proof of efficacy of the therapeutic agent in cohorts of patients representing the relevant disease that may include control groups. T3, phase 4 clinical trials that are associated with optimizing the therapeutic use of a therapeutic agent in clinical practice. T4, Population-level outcomes research or comparative effectiveness research aims to determine the ultimate utility and cost effectiveness of a therapeutic agent relative to others currently in use. Translation from basic science to human studies form the critical path, as defined by the FDA, or the “valley of death”, as defined by the pharmaceutical industry. This “valley of death” encompasses T0-T2 phases of research. However, each of these phases have overlapping sets of challenges as discussed in the text. Adapted from [15, 16]