The dose selections for phase 1 assessments which aim to investigate
intrinsic and extrinsic factors of pharmacokinetic variability as well
as safety is a central and challenging question in long drug development
programs. The dose of an investigational product are selected with
respect to regulatory guidances, stage of program, feasibility and
maximization of information for later regulatory submission. This review
selected 37 development programs of drugs recently approved in the EMA-
and FDA-covered regions to explore the doses selected in these trials
and also supporting modeling activities with focus on drug interaction,
renal and hepatic impairment, food effect and concentration-QTc
assessment. This survey found that most sponsors followed regulatory
guidance documents, with some interesting deviations. Particular
oncology drugs programs but also some cardiovascular programs which have
a drug associated safety risks were not able to test supratherapeutic
dose levels. Drugs using a titration scheme in development or label were
often tested using a dose range. Drugs from combination treatments
incorporated the expected exposure increase through interactions or
tested the combination in patients. Sponsors included multiple food
effect studies due to ongoing formulation developments. Incomplete
programs were subject of post market commitments. In this retrospective
review, the discrepancies from conventional approaches may give
interesting insights into strategic consideration and regulatory
acceptability for drug development programs.