title: Drug designs fulfilling the requirements of clinical trials aiming at personalizing medicine.
abstract: In the current era of stratified medicine and biomarker-driven therapies, the focus has shifted from predictions based on the traditional anatomic staging systems to guide the choice of treatment for an individual patient to an integrated approach using the genetic makeup of the tumor and the genotype of the patient. The clinical trial designs utilized in the developmental pathway for biomarkers and biomarker-directed therapies from discovery to clinical practice are rapidly evolving. While several issues need careful consideration, two critical issues that surround the validation of biomarkers are the choice of the clinical trial design (which is based on the strength of the preliminary evidence and marker prevalence), and biomarker assay related issues surrounding the marker assessment methods such as the reliability and reproducibility of the assay. In this review, we focus on trial designs aiming at personalized medicine in the context of early phase trials for initial marker validation, as well as in the context of larger definitive trials. Designs for biomarker validation are broadly classified as retrospective (i.e., using data from previously well-conducted randomized controlled trials (RCTs) versus prospective (enrichment, all-comers, hybrid or adaptive). We believe that the systematic evaluation and implementation of these design strategies are essential to accelerate the clinical validation of biomarker guided therapy.
authors.affiliation: Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Sumithra J
authors.initials: SJ
authors.lastname: Mandrekar
authors.affiliation: Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Sargent
keywords: All-comers design; adaptive design; biomarker; enrichment design; hybrid design; randomized controlled trial (RCT)