Phase I Studies: Innovations and Issues.

ABSTRACT

INTRODUCTION: Emeritus Editor-in-Chief, Richard Shader, published 2 editorials in 2014 to state that Clinical Therapeutics' would no longer consider simple innovator vs generic bioequivalence studies for publication and would require a rationale for the choice of agents when submitting drug-drug interaction studies for consideration. The intervening decade of developments in this field provides an opportunity to comment on these trends. Lewis Scheiner anchors the subsequent discussion in a "Learn and Confirm" super-structure of thinking about the goals of early development of pharmaceutical agents. Subsequent experience with newer agents that are focused on immunological targets has led to a shift from the simple No Observable Effect Level (NOEL) model to the Minimal Anticipated Biological Effect Level (MABEL) model for biologically focused effects to assess pre-clinical data in guiding the selection of a starting dose for First-in-Human studies. ELEMENTS OF PHASE I STUDIES The primary tasks of Phase I activities are to describe the pharmacokinetics (determination of absorption, distribution, metabolism, and excretion) and essential pharmacodynamics (the dose correlation with the physiological responses, plus any untoward effects, including idiosyncratic responses) keeping in mind reporting requirements. Other Phase I activities usually conducted later in the development cycle include evaluation of drug interactions with food and other pharmaceutical agents and thorough QT studies. INNOVATIONS Phase I studies have been evolving in response to the unrelenting pressures to improve access and efficiencies in time, cost, and effort. Changes have been occurring in the characteristics of the participating populations, the starting dose, and shifts in the enrollment schedule to a more flexible, data-driven, adaptive design. ISSUES Additional issues have gained attention in the recent past, including Phase 0/microdosing, use of Phase I studies explicitly for treatment in the case of oncological products, involvement of Data Safety Monitoring Committees especially for first-in-class molecules, and improved means of optimizing selection of candidate agents for advancement to subsequent stages of development. Of final importance is the need for greater transparency of the presently inaccessible, early development study data maintained in commercial corporate legacy databases. Taken together, these developments and innovations by a broad range of stakeholders point to continuing opportunities for clinical investigators to explore the potential of Phase I studies to contribute to their own specialties.