Translational Medicine Guide transforms drug development processes: the recent Merck experience

Abstract

Merck is implementing a question-based Translational Medicine Guide (TxM Guide) beginning as early as lead optimization into its stage-gate drug development process. Initial experiences with the TxM Guide, which is embedded into an integrated development plan tailored to each development program, demonstrated opportunities to improve target understanding, dose setting (i.e., therapeutic index), and patient subpopulation selection with more robust and relevant early human-based evidence, and increased use of biomarkers and simulations. The TxM Guide is also helping improve organizational learning, costs, and governance. It has also shown the need for stronger external resources for validating biomarkers, demonstrating clinical utility, tracking natural disease history, and biobanking.

Opportunities and Challenges for Drug Development: Public–Private Partnerships, Adaptive Designs and Big Data

“…Therefore, new models for a more effective and less costly drug development are needed. Some reported models focus on use of non-clinical or translational data to improve predictions of safety (Bowes et al, 2012) or efficacy (Dolgos et al, 2016). Others focus on target-centric approaches, particularly for new biological entities (Swinney and Anthony, 2011), more rapid paths to clinical proof-of-concept (Owens et al, 2015), or attempts to identify candidates for early termination, i.e., before the most expensive late-stage clinical development starts (Peck et al, 2015), or more systematic portfolio review to systematically challenge development candidates (Cook et al, 2014).…”

IGF‐1R pathway activation as putative biomarker for linsitinib therapy to revert tamoxifen resistance in ER‐positive breast cancer

“…Our data suggest that the subset of high‐risk postmenopausal ER+ breast cancer patients characterized by PI3K/MAPK pathway activation via IGF‐1R may have more benefit from adjuvant tamoxifen to which linsitinib is added than from adjuvant tamoxifen alone. Naturally, the latter should be validated in an independent prospective randomized clinical trial …”

“…Naturally, the latter should be validated in an independent prospective randomized clinical trial. 47 Currently, postmenopausal ER+ breast cancer patients generally receive tamoxifen in sequence with an AI, or 5 years of an AI as adjuvant endocrine therapy for at least 5 years. 3 Patients in our retrospective study received a maximum of 3 years of tamoxifen and no additional AI.…”

Translational Science: Turning Discovery into Health

“…Complex multifactorial phenomena of interaction of human disease and response to treatment are highly under the influence of individuals genetically determined characteristics. If this issue of interaction of individuals genetics, diseases and reaction of treatment is resolved it will lead to costefficient approaches to therapeutic interventions ultimately will help in implementing "personalized medicine" [25,26].…”