scope:

The successful utilization of biomarkers in clinical development and, indeed, realization of personalized medicine require a close collaboration among different stakeholders: clinicians, biostatisticians, regulators, commercial colleagues, and so on. For this reason, we invited experts from different fields of expertise to address the opportunities and challenges and discuss recent advancements related to biomarkers and their translation into clinical development. The first four chapters discuss biomarker development from a clinical perspective ranging from introduction to biomarkers to recent advances in RNAi screens, epigenetics, and rare disease as targets for personalized medicine approaches. Chapters 5 through 10 are devoted to considerations from a statistical perspective, and the last chapter addresses the regulatory issues in biomarker utilization.

A biomarker is a characteristic that can be objectively measured and evaluated as an indicator of a physiological as well as pathological process or response to a therapeutic intervention. Although there is nothing new about biomarkers such as glucose for diabetes and blood pressure for hypertension, the current focus on molecular biomarkers has taken the center stage in the development of molecular medicine. Molecular diagnostic technologies have enabled the discovery of molecular biomarkers and are assisting in the definition of the pathogenic mechanism of diseases. Biomarkers represent the basis of the development of diagnostic assays as well as the target for drug discovery. Biomarkers can help monitoring drugs' effect in clinical trials as well as in clinical practice.

There is a tremendous amount of literature about biomarkers and their utility and potential in clinical development, but there is no comprehensive source of information that integrates and blends the clinical and statistical components together. Of the thousands of biomarkers that are being discovered, very few are being actually validated. This book, which covers a wide spectrum of personalized medicine-related topics, is an overview of the state-of-the-art techniques and advances in the application of biomarkers in drug discovery and development. It represents an important source of information for clinical developers such as biostatisticians, clinicians, scientists, and those involved in drug discovery and development.

The utilization of biomarkers provides great opportunities and tremendous challenges in statistics. One of the major challenges, among many, is the control of false-positive rates due to multiple testing. Multiple testing comes from a larger number of hypotheses tests involving different genes, biomarker subgroup analyses, multiple endpoints, and biomarker adaptive designs. Failing to handle this issue adequately will either increase the likelihood of the false-positive findings in the studies or result in the studies losing their utility and efficiency to the extent that the value of biomarker utilization is completely nullified.

Chapter 1 gives a bird's-eye view of the history, life cycle, and types and applications of biomarkers along with an overview of patient stratification for personalized medicine. Chapter 2 discusses the RNAi screen triumphs and tribulations in the context of drug target development. Chapter 3 presents one of the most exciting and fastest-expanding fields of biology, that is, epigenetics, which is frequently described as a phenomenon of heritable changes in gene expression in the absence of changes in the DNA sequence. Today, human disorders are thought to be driven by combinations of genetic and epigenetic abnormalities. It is the epigenetic component that proves to be most relevant to all aspects of personalized medicine. Chapter 4, which is the final clinical chapter, focuses on rare diseases, which are now becoming targets for personalized medicine approaches, owing to the view that individual susceptibility might now be explained by the subject genetic background and by epigenetic changes. Chapter 5 discusses the new biomarker- informed adaptive design, providing guidance when biomarkers may be used to increase the efficiency of clinical trials. Chapter 6 discusses an adaptive dose-finding design, in which the "dose-arms" are actually different doses potentially efficacious to one subgroup enrolled in the study. Thus, the goal is to select the best dose for this subgroup identified by the genomic marker. Chapter 7 discusses the use of predictive biomarkers in adaptive design. Chapters 8 and 9 present the multiplicity issues in biomarker identification at different stages of clinical trials. Chapter 10 discusses the importance of the patient-report outcomes (PROs) in personalized medicine, where the PRO may be very different for patients with different genomic markers. Chapter 11 addresses the regulatory issues in the utilization of biomarkers for drug development with case studies.

We would like to extend our sincere gratitude to all the authors and reviewers for their sincere tireless effort and time to help us make this project a reality. We would like to thank David Grubbs and Stephanie Morkert from CRC Press for their guidance and coordination. Finally, we would like to dedicate this book to our colleagues in the scientific community and our family and friends.