Experience with extrapolating efficacy and safety data across indications to improve/accelerate dose selection: Opportunities and challenges

Music City Center 

A question of interest in clinical development is whether evidence establishing that a drug is efficacious and safe in one indication can be leveraged to accelerate the development of that drug in another indication, either by minimizing the amount of efficacy and safety data to support dose selection in the second indication, or at the extreme, by avoiding a new study in that indication. Generally speaking, this kind of extrapolation can be conducted by bridging the two indications at the level of the drug exposure, of the target, or of a downstream biomarker. We argue here that such extrapolations require assumptions, which are not dissimilar to those required for surrogacy and in pediatric development, and we use direct acyclic graphs to depict those assumptions. We discuss how those assumptions could be supported, e.g., with existing data in the second indication (at the targeted dose level or at a different dose level), with data from another drug with same mechanism of action, or with informed pharmacological principles. We conclude by presenting our experience of situations where extrapolations were successfully used, e.g., extrapolation across treatment lines in chronic myeloid leukemia, or when the assumptions could not be supported, e.g., extrapolation for skin efficacy endpoints from psoriasis to psoriatic arthritis, or safety extrapolation from psoriasis to hidradenitis suppurativa..

Extrapolation

PK/PD

Pharmacometrics