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(monitors and predictors of disease risk, progression, improvement, and severity); surrogate endpoints (substitutes or correlates with measurable clinical endpoints such as how a patient feels, functions, or survives, e.g., viral titer, serum cholesterol, blood pressure); pharmacogenomic biomarker (monitors or predicts drug response, e.g., Her2/neu, EGFR single nucleotide polymorphisms (SNPs), CYP2D6 variants); pharmacodynamic biomarkers (demonstrates that a drug is on target and correlates with drug plasma levels in vivo, e.g., receptor occupancy, kinase phosphorylation) and functional response biomarkers (demonstrates a functional effect of the drug on a relevant pathway or mechanism of action, e.g., apoptosis markers).

Disease biomarkers are usually based on large population studies that monitor diseases such as cancer (CEA, PSA),69 diabetes (hemoglobin A1c), and autoimmunity (rheumatoid factor).73 These markers not only allow the possibility for early detection that may influence success of treatment, but also serial analysis to potentially indicate whether disease

Figure 3 Types of biomarkers. CEA, carcinoembryonic antigen; CA-125, cancer antigen-125; PSA, prostate-specific antigen; SNPs, single nucleotide polymorphisms; EGFR, epidermal growth factor receptor; kinase-P, kinase phosphorylation; PARP inhibition, poly(ADP-ribose) polymerase inhibition.

is stable, progressing, or in remission. However, both inter- and/or intrapatient variability can complicate the interpretation of results.

Clinical endpoints are direct variables attributed to a response to therapeutic intervention and the gold standard in cancer trials is increase in long-term survival.75 However, this takes time to achieve and can only be evaluated at the end-stages of a study. Consequently, surrogate endpoints are attractive since they could provide early signals of therapeutic benefit and aid in treatment decisions that could save time and suffering. However, not all surrogate endpoints may accurately predict clinical outcomes because only one parameter or effect of the drug is evaluated.64 Although this may be of benefit in monitoring therapeutic treatment in devastating diseases such as cancer, it may be less useful in chronic diseases when drugs are taken over a long duration or there is no certainty of clinical benefit. Therefore, validation of surrogate markers must reflect the mechanism of action of the drug, pathophysiology of disease, or treatment benefit that correlates with clinical outcomes. Evaluating other drugs with similar mechanisms is important and can better ensure predictability. With the acceptance of imaging (DCE-MRI, high-resolution CT, positron emission tomography (PET), and multimodal PET-CT) that more accurately measures lesion size and/or metabolic assessment (use of tracers) for tumor growth,76 the evaluation of efficacy of treatment regimens has increased. However, further validation of these technologies is still necessary. Owing to the difficulties associated with demonstrating definite predictive value, few biomarkers have attained US FDA approval as surrogate endpoints. Exceptions include blood pressure monitoring and cholesterol screening for cardiology; tumor shrinkage for oncology; and the CD4+ cell count for human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS).77

Recently, molecular profiles that can potentially predict drug response have been possible with advances in gen-omics. Examples of pharmacogenomic biomarkers are polymorphisms for enzymes involved in drug metabolism (i.e., CYP2D6 of the cytochrome P450 system and thiopurine S-methyltransferase or TPMT).78 In December 2004, the FDA approved the first DNA microarray test (Amplichip Cytochrome P450 Genotyping Test: Roche Molecular Systems) for genetic variations in the 2D6 and 2C19 genes that have been associated with the predictive phenotypes of drug metabolism that affect drug efficacy and potential adverse reactions with certain drugs.79

Other genomic markers, such as Her2/neu expression in tumors are being screened to select patients more likely to respond to trastuzumab, the therapeutic monoclonal antibody to the (Her2/neu)/ErbB2 receptor (Herceptin: Genen-tech/Roche).80'81 Similarly, imatinib (Gleevac: Novartis), a small-molecule inhibitor of the mutant in bcr-abl kinase, is an example where a subset of patients with a translocation in bcr-abl kinase predicts response to therapy.58 EGFR/ ErbB1/Her1 mutations appear to correlate with a response to the small-molecule EGFR tyrosine kinase inhibitor, erlotinib (Tarceva: Genentech/OSI Oncology).82-84 Additionally, the Oncotype Dx test (Genomic Health),85 profiling 21 genes from tumor samples predicting recurrence in certain breast cancers and response to chemotherapy, is now on the market. These examples and many others in development have and will impact disease outcomes.

PD markers have long been used in phase I studies to determine the optimal dose by assessing serum/plasma levels of the drug in conjunction with safety and toxicology parameters. Other analytes in either blood or urine associated with disease can also be evaluated if the pathogenesis of disease is understood and it is in this context where discovery of novel biomarkers of disease may be greatly aided by genomic, proteomics and metabolomics.67,86 Functional biomark-ers, an extension of a pharmacodynamic type of biomarker, are biochemical measures that indicate the drug is reaching its target and affecting its proposed mechanism of action. Evaluating cell death in cancer therapies may soon be possible using an enzyme-linked immunosorbent assay (ELISA)-based assay measuring caspase 3-mediated apoptosis in solid tumors (Cyclacel, UK),75 but it will be limited to accessible tumor types. Recently, functional biomarker assays for PARP inhibition were demonstrated in metastatic melanoma from patients in a phase I study.87 Potentially, the correlation of PK and functional biomarkers could shed light on cancer treatments where variable efficacy is observed and thereby influence treatment decisions earlier in the clinical development process.

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