Efficient design of integrated and adaptively interlinked early phase drug development programs

[Speaker] Simon Coates:1
[Co-author] Oliver Pohl:2, Jean-Pierre Gotteland:2, Jorg Taubel:1,3, Ulrike Lorch:1
1:Richmond Pharmacology Ltd, UK, 2:Obseva SA, Plan-lesOuates, Switzerland, 3:St Georges, University of London, UK

Background: Current practice favors integrated protocols in early phase clinical trials. Adaptively combining clinical trial protocols has been shown to have advantages in increasing participant safety, the effectiveness of data gathered in the study as well as increasing the speed of completion.
The data presented here shows how an early phase program, from First-in-human (FIH) to proof-of-concept (POC) can be designed and performed efficiently using inter-dependent, integrated, adaptive protocols.
Method: OBE022 is being developed for the treatment of spontaneous pre-term labor. A Phase 1 trial in healthy women was performed to evaluate OBE022's safety, tolerability, pharmacokinetics and proof-of-concept of efficacy. Drug-drug interactions (DDIs) at relevant OBE022 doses with a series of drugs used to treat pre-term labor were also evaluated (Figure 1).
Results: Study parts were designed to overlap - the MAD, FE, POC and DDI started once relevant dose levels/exposures had been tested in the SAD. The feasibility used an active control only so commenced in parallel with the SAD. Considering the distinct risk assessment needed, and the later time point at which the DDI would start, this trial part was split off the main FIH protocol into a separate study for the purposes of simplicity. The adaptive design resulted in significant time savings and reduced number of subjects. Only 11 and 7 months were required for trial set-up to final report and regulatory approval to last subject visit, respectively. The overall program took 11 months. Eighty subjects were included.
Conclusions: The adaptive features enable the flexible dosing regimen selection and the subject numbers to be changed. In addition to the standard SAD, MAD and FE studies, early efficacy POC and DDI studies were integrated. Owing to the adaptive protocol design, no substantial amendments were needed and a more efficient use of data facilitated trial progression.
Early phase protocols can be adaptively interlinked so that entire early phase programs from FIH to DDI and POC can be designed, completed and reported in approximately one year.

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