Research Overview Companion Diagnostics and the Drug–Diagnostic Codevelopment Model Jan Trøst Jørgensen* Dx-Rx Institute, Fredensborg 3480, Denmark Strategy, Management and Health Policy Enabling Technology, Genomics, Proteomics Preclinical Research Preclinical Development Toxicology, Formulation Drug Delivery, Pharmacokinetics Clinical Development Phases I-III Regulatory, Quality, Manufacturing Postmarketing Phase IV ABSTRACT The concept of using a predictive or selective diagnostic assay in relation to drug devel- opment goes back to the 1970s when the selective estrogen receptor modulator, tamoxifen (AstraZeneca) was developed for metastatic breast cancer. Clinical data showed that the estrogen receptor status correlated well with the clinical outcome when the patients were treated with tamoxifen. Although this datum was published more than 35 years ago, the adaption of the drug–diagnostic codevelopment model has been relatively slow, and it is only within the last decade that it has gained widespread acceptance. In this model, the drug and the diagnostic are interdependent, and if the development project proves successful, the companion diagnostic assay (CoDx) will end up determining the conditions for the use of the drug. This gatekeeper role obviously requires that the CoDx assays adhere to the same strict rules and regulations that are known from the development of drugs. For any CoDx assay, it must be documented that it is robust and reliable and that it possesses clinical utility. The article focus on some of the most important aspects of the CoDx development process with emphasis on the clinical validation and clinical utility but also other critical issues such as the biomarker selection process, determination of the cut-off value, and the analytical validation are discussed. Drug Dev Res 73 : 390–397, 2012. © 2012 Wiley Periodicals, Inc. Key words: companion diagnostics; drug–diagnostic codevelopment; clinical validation; clinical utility; personalized medicine; oncology INTRODUCTION The idea about individualizing pharmacotherapy has been a subject within medicine for decades. Before the turn of the century, the talk was about rational pharmacotherapy or rational use of drugs––”the right drug to the right patients in the right dose using the right administration route.” In the 21st century, the goal remains the same, but it has a different name, person- alized medicine/stratified medicine/precision medicine, and very importantly, we have new tools that may enable us to start practicing these ideas. The develop- ments within molecular medicine and molecular diag- nostics have given us new insight into to the basic pathophysiology and have revealed that most diseases are heterogeneous and that a “standard” treatment seldom works for everyone. The philosophy of “one disease–one target–one drug” is now history and the improvement in pharmacotherapy must come from an increased understanding of the underlying molecular mechanisms of the different diseases in the individual patient. These mechanisms are often of a very complex nature, and we are far from a complete understanding. One thing we do understand is that drugs work at the molecular level, and it is here we must seek the solution to a more rational drug development process and the Funding/Support: None. *Correspondence to: Jan Trøst Jørgensen, Dx-Rx Institute, Baunevaenget 76, 3480 Fredensborg, Denmark. E-mail: jan.trost@dx-rx.dk Published online in Wiley Online Library (wileyonlinelibrary. com). DOI: 10.1002/ddr.21029 DRUG DEVELOPMENT RESEARCH 73 : 390–397 (2012) DDR © 2012 Wiley Periodicals, Inc.