Predictive Biomarkers for Linking Disease Pathology and Drug Effect

Curr Pharm Des. 2017;23(1):29-54. doi: 10.2174/1381612822666161006153639.


Background: Productivity in drug R&D continues seeing significant attrition in clinical stage testing. Approval of new molecular entities proceeds with slow pace specifically when it comes to chronic, age-related diseases, calling for new conceptual approaches, methodological implementation and organizational adoption in drug development.

Methods: Detailed phenotyping of disease presentation together with comprehensive representation of drug mechanism of action is considered as a path forward, and a big data spectrum has become available covering behavioral, clinical and molecular characteristics, the latter combining reductionist and explorative strategies. On this basis integrative analytics in the realm of Systems Biology has emerged, essentially aiming at traversing associations into causal relationships for bridging molecular disease specifics and clinical phenotype surrogates and finally explaining drug response and outcome.

Results: From a conceptual perspective bottom-up modeling approaches are available, with dynamical hierarchies as formalism capable of describing clinical findings as emergent properties of an underlying molecular process network comprehensively resembling disease pathology. In such representation biomarker candidates serve as proxy of a molecular process set, at the interface of a corresponding representation of drug mechanism of action allowing patient stratification and prediction of drug response. In practical implementation network analytics on a protein coding gene level has provided a number of example cases for matching disease presentation and drug molecular effect, and workflows combining computational hypothesis generation and experimental evaluation have become available for systematically optimizing biomarker candidate selection.

Conclusion: With biomarker-based enrichment strategies in adaptive clinical trials, implementation routes for tackling development attrition are provided. Predictive biomarkers add precision in drug development and as companion diagnostics in clinical practice.

Keywords: Clinical phenotyping; big data; causality; disease pathology; drug development; precision medicine; study design.

Publication types

  • Review
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomarkers, Pharmacological*
  • Disease* / genetics
  • Humans
  • Pharmaceutical Preparations*
  • Systems Biology


  • Biomarkers, Pharmacological
  • Pharmaceutical Preparations