The Integrated Early Drug Development Platform

The landscape of early drug development has changed radically over the last decade. The norms of the past, wherein first-in-human (FIH) studies consisted of a relatively straightforward series of observations following administration of small molecules to normal healthy volunteers, have given way to exponential increases in complexity. As basic science probes deeper into the pathophysiology of disease states, experimental medicines have been discovered that modulate multifunctional biological pathways. Cases in point include inhibitors of Janus kinases, targeted to autoimmune diseases and cancers; inhibitors of histone deacetylases, targeted to cancers, inherited and acquired neuropathies and neurodegenerative diseases; and integrin inhibitors targeted to cancers and immunologic diseases. The result is less predictability of biological effects, increasing probability of undesirable off-target effects, proliferation of biomarkers as "navigational aids," and Phase I study protocols packed with unprecedented numbers of procedures and observations. Increasingly, "umbrella" or "hybrid" study designs are proposed, wherein a single protocol may involve not only single ascending dose (SAD) and multiple ascending dose (MAD) cohorts, but also cohorts to detect the likelihood of drug-drug interactions; food effects; effects on electrocardiographic intervals; effects of age, gender and/or ethnicity; and pharmacodynamic (PD) effects in patients.