Scope Of Imaging Biomarkers In Drug Development

Parallel developments in our knowledge and understanding of biology and disease, and advances in biomedical technologies, have dramatically increased our ability to discover and develop new therapies as well as to evaluate the biological effects of disease interventions. Imaging technologies have played an important role across the spectrum of drug discovery and development [9,20] . Apart from basic biological research, the roles of imaging biomarkers in drug development generally fall into two categories: supporting internal decision making, and to support the demonstration of efficacy in pivotal clinical trials for registration.

Within the category of imaging biomarkers used for decision making in drug development, there are three fundamental applications that imaging biomarkers have in common with in vitro biomarker technologies: confirming that a drug candidate hits the intended biological target, testing whether hitting the target, alters the disease process (proof of mechanism), and testing whether altering the disease process affects the clinical status of the patient (proof-of-therapeutic concept) [40,45]. Imaging biomarkers have provided early critical information at each of these development stage gates through in vivo molecular imaging studies of competitive binding or receptor occupancy [45], imaging of target distribution and radiolabeled drug distribution [68,69], lead optimization, and preclinical and early clinical efficacy testing [ 19,70] . Other tasks in early clinical development that imaging biomarkers have addressed include appropriate dose and regimen selection and in vivo phar-macokinetic/pharmacodynamic studies [71,72],patient stratification, and study population enrichment [40].

Importantly, imaging biomarkers for internal industry decision making have demonstrated value for drug development without comprehensive vali dation or clinical qualification [ 67] . Indeed, many such biomarkers may be proprietary and specific to a particular development program, therapeutic target, or mechanism [ 45] . However, achieving a stage of assay validation appropriate to a given task and the associated risk is a crucial but often time-consuming process. The use of novel imaging biomarkers is most effective if development and characterization activities, such as PET radiotracer development or MRI pulse sequence and method development, are begun as early as possible and ideally in tandem with the corresponding drug development program [45] .

Although imaging biomarkers have proven useful in many aspects of drug development without being fully clinically qualified, there is renewed interest from multiple stakeholders to develop qualified surrogate endpoints and expedite the lengthy and costly drug approval process [39]. In addition to the well-documented difficulties of clinical qualification [45] . the potential impact of such tools for regulatory decision making will be limited unless they achieve some measure of standardization and cost-effectiveness, and become widely accepted and widely available. In the next section we examine in some detail a few of the imaging biomarkers that are currently, or are poised to become, such high-impact tools for drug development in oncology.

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