title: Randomized clinical trials with biomarkers: design issues.
abstract: Clinical biomarker tests that aid in making treatment decisions will play an important role in achieving personalized medicine for cancer patients. Definitive evaluation of the clinical utility of these biomarkers requires conducting large randomized clinical trials (RCTs). Efficient RCT design is therefore crucial for timely introduction of these medical advances into clinical practice, and a variety of designs have been proposed for this purpose. To guide design and interpretation of RCTs evaluating biomarkers, we present an in-depth comparison of advantages and disadvantages of the commonly used designs. Key aspects of the discussion include efficiency comparisons and special interim monitoring issues that arise because of the complexity of these RCTs. Important ongoing and completed trials are used as examples. We conclude that, in most settings, randomized biomarker-stratified designs (ie, designs that use the biomarker to guide analysis but not treatment assignment) should be used to obtain a rigorous assessment of biomarker clinical utility.
authors.affiliation: Biometric Research Branch, EPN-8122, National Cancer Institute, Bethesda, MD 20892, USA. freidlinb@ctep.nci.nih.gov
authors.forename: Boris
authors.initials: B
authors.lastname: Freidlin
authors.forename: Lisa M
authors.initials: LM
authors.lastname: McShane
authors.forename: Edward L
authors.initials: EL
authors.lastname: Korn
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000097:blood*; D002289:Carcinoma, Non-Small-Cell Lung / Q000097:blood* / Q000188:drug therapy; D017326:Clinical Trials, Phase III as Topic; D004268:DNA-Binding Proteins / Q000378:metabolism; D004720:Endonucleases / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D066246:ErbB Receptors / Q000378:metabolism; D000069347:Erlotinib Hydrochloride; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005971:Glutamates / Q000627:therapeutic use; D006147:Guanine / Q000031:analogs & derivatives / Q000627:therapeutic use; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000201:enzymology*; D008175:Lung Neoplasms / Q000097:blood* / Q000188:drug therapy; D009154:Mutation; D000068437:Pemetrexed; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011799:Quinazolines / Q000627:therapeutic use; D016032:Randomized Controlled Trials as Topic; D012107:Research Design / Q000592:standards / Q000639:trends; D019311:Staurosporine / Q000031:analogs & derivatives / Q000627:therapeutic use; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D005971:Glutamates; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000068437:Pemetrexed; D006147:Guanine; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3; C071447:ERCC1 protein, human; D004720:Endonucleases; D019311:Staurosporine; C059539:midostaurin