Importance of Context Disease Therapeutic Strategy Development Stage and Alternative Approaches

The development or implementation of any particular imaging biomarker must be preceded by consideration of the current research environment, the local availability of technology and resources, and an attempt to evaluate the relative utility, efficiency, and cost-effectiveness of alternative approaches. Local implementation of an imaging biomarker is a time-consuming process, even for methods validated and published previously. Commercially available imaging systems are generally tailored toward diagnostic rather than quantitative applications, and as a consequence, the implementation of an imaging biomarker often involves applying customized acquisition, radiotracer synthesis, or analysis methods that must be locally optimized and compared to published results. In a preclinical setting, the implementation process places great demands on the local availability of resources such as MRI pulse sequences and acquisition methods, radiotracer production facilities, appropriate animal models, and image analysis tools, among many others. In a clinical research setting, an imaging biomarker may have to be implemented across multiple centers. An overriding concern in the usability of any particular imaging bio-marker once implemented is the overall throughput that can be achieved [66].

Alongside these practical concerns are various scientific questions about which technique among several will be optimal. Within any one imaging biomarker application, there may be multiple methods for acquiring similar data, and multiple approaches for image reconstruction, processing, and quantification. Similarly, there may be multiple imaging or in vitro biomarkers that address the same biological function or clinical endpoint. Such choices typically have to account for incomplete data comparing the methods and limited available resources.

When considering the use of imaging biomarkers, the dominant focus is often on the technology, implementation issues, or necessary tools. Although implementation choices must be weighed carefully, it is important to emphasize that imaging biomarkers, like any other biomarker, should be specified in terms of the disease context and therapeutic strategy, as well as the development stage and questions to be answered. Defining the clinical context of a given imaging biomarker is part of the process of biomarker validation, which answers the question: What are the biological conditions, disease states, and therapies under which the use of the imaging biomarker will result in the empirically determined reliability and validity? For example, the location of a tumor may limit our ability to obtain a robust quantitative assessment of treatment effects due to excessive respiratory or cardiac motion. An imaging biomarker that is validated and qualified for a given tumor type and therapeutic class cannot be assumed to be validated and qualified for tumors of other types or anatomical locations or other therapies without additional validation data.

Conversely, in drug development, time efficiency and the value of investing in imaging technology resources can be maximized by selecting and implementing cross-mechanism imaging biomarkers [67]. For example, multiple imaging biomarkers may share a common MRI pulse sequence or acquisition method, such as T2*-weighted dynamic imaging for dynamic susceptibility contrast (DSC) bolus tracking and blood - oxygenation - level- dependent (BOLD) functional MRI, or T2 mapping for measuring peripheral edema or liver iron concentration. Similarly, a custom PET radiotracer may be developed for a specific development program but may have utility in other therapeutic areas [45]. Such coordination requires significant planning and broad alignment across discovery and development groups and therapeutic areas, which may be difficult to achieve in large organizations.

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