It's all about the test: the complexity of companion diagnostic co-development in personalized medicine.

These words distill the essence of the topic we present in this CCR Focus section. The idea of "personalizedmedicine"asaparadigminoncologyhas captured the imaginationofphysiciansand patients alike. A Google search finds 940,000 hits on the term, and another 109,000 for the term "precisionmedicine." In this paradigm, a cancer is analyzedbyone ormore tests thatwill direct the patient and the physician toward amore effective therapy, and hopefully one that is also less toxic thanthe "unselected therapies"painstakinglydevelopedbeforeweunderstood theheterogeneityof themolecularbasisofhumantumors.Andsotherehasbeenanincreasing focus tofindandvalidate molecular targets for cancer therapy, and then to make drugs for those targets. Notable successes havebeenachieved inparticular cancer types—suchas trastuzumabinHER2-positivebreast cancer, imatinib for BCR–ABL in chronicmyelogenous leukemia, c-KIT in gastrointestinal stromal tumors, vemurafenib for B-RAF mutations in melanoma, erlotinib and gefitinib for the EGF receptor (EGFR) mutation in non–small cell lung cancer (NSCLC), and crizotinib for the ALKmutation in NSCLC.With the development of drugs against these targets has come the recognition that not all tests are equally accurate, although incredibly important decisions are being based on these tests. Although quality, safety, and efficacy standards must be met before a drug can be prescribed to patients, the value of a laboratory test does not have to be proven. Investigators may argue that another layer of oversight in the development of cancer therapies is not desirable, and will limit innovation. However, the wide array of commercially available molecular tests doctors can order and patients and payers can purchase, often lacking the scientific rigor we want, undermines this argument. We are at the threshold of using next-generation sequencing platforms to assess cancers inpatientsoutsideof theclinical trial setting. If these testsbecomewidely employedanddoctorsuse the results to support their use of approved agents off-label in "creativeways,"we riskhaving a "lost generation" of information that should be available to future investigators. ThisCCR Focus section addresses these issues and highlights the approaches regulatory bodies in both the United States and Europe have taken in companion diagnostic development. These are complex issues in drug development—the receiver–operating characteristic curve of a test is surely less exciting than the waterfall plot of best responses. Eric Rubin and I, asGuest Editors, have brought together experts to challenge our thinking on this subject. Parkinson and colleagues highlight the importance of proving clinical utility before a test becomes commercially available. Senderowicz and Pfaff examine the differences in regulatory approaches in the United States and Europe that have led todifferent outcomes for drugapprovals.Mansfielddiscusses the evolutionof FDAthinkingon this topic, including themandate that a targeted drug should be co-developed with a test. Pignatti and colleagues discuss the evolution of thinking at the European Medicines Agency. Finally, Byron, Crabb, and theirNICE coauthors lay out theHealth TechnologyAssessments that are performed to determine whether tests and drugs will provide sufficient clinical benefit to be routinely used, coming full circle back to clinical utility. These are thoughtful articles meant to inform those workingonnewcancer therapeutics, andmeant topromptearlier attention to the importanceof codeveloping both diagnostic test and drug.