Key Advantages of Imaging Biomarkers

As a tool in drug development, imaging biomarkers share several general advantages among all imaging modalities. Imaging biomarkers provide the unique ability to visualize anatomy as well as to spatially localize physiological and molecular function in vivo. Additionally, most imaging modalities have the capability to acquire repeated or temporally resolved images which allow a study of various dynamic biological processes. In vivo image-based evalua tion of disease processes or drug targets occurs in their respective biological microenvironments, accounting for both systemic and local modulators. As in vivo assays, imaging biomarkers also share with in vitro biomarkers the ability to determine drug-target interactions, to help optimize drug dose, and to evaluate longitudinally the response to therapy in vivo [59].

A broad range of sensitivity and spatial resolution is also available, providing great flexibility in the choice of applications. High-resolution CT and MRI anatomical imaging biomarkers can evaluate gross therapeutic effects at the level of organ systems; nuclear, CT, and MRI perfusion imaging biomarkers can probe functional effects at a regional tissue and vascular level; nuclear, MRI, and optical molecular imaging biomarkers can provide readouts down to the level of cellular and molecular effects. This range can sometimes be an advantage when considering the process of clinical qualification. For example, although molecular imaging applications may attain the level of detail necessary to test for proof of mechanism, clinical qualification of imaging biomark-ers will probably be facilitated by coarser biological "resolution" at the macroscopic level of organ systems which may more readily be related to a clinical endpoint.

In addition to the clinical relevance of the various imaging modalities, there is also the possibility for translation of preclinical imaging applications to the clinic, which provides a potential for continuity of readout parameters between preclinical safety and efficacy studies in animal models and eventual clinical evaluations in humans. Furthermore, a majority of hospitals and medical centers (often, the sites participating in later-phase clinical drug trials) typically have direct access to clinical imaging centers or imaging equipment.

Longitudinal assessment of individual subjects provides a potential for reduced statistical variability, and consequently a reduction in the number of study subjects. Clearly, this can benefit drug development through faster studies and reduced costs; however, in practice, many additional factors can influence the net cost savings and efficiency achieved in using an imaging biomarker. These factors are related to the implementation of imaging biomarkers and must be evaluated carefully for each imaging biomarker application.

Limitations of Imaging Biomarkers

There are generally three categories of imaging biomarker limitations. First, there are limitations that are likely to be addressed in the near future by the accelerating rate of imaging biomarker development. The complex and mul-tidisciplinary nature of image acquisition hardware and analysis methods has hindered the translation of promising image-based functional measures into validated and qualified imaging biomarkers. Similarly, a lack of standardization has also impeded imaging biomarker development, since variations in methodologies, as well as hardware platforms with differing capabilities, have made it difficult to compare and evaluate potential imaging biomarkers across sites. Compared to in vitro biomarkers, it may be costly and time consuming to acquire the clinical evidence necessary to establish a biological relationship between an imaging biomarker and a particular disease state. All of these factors have limited the introduction of imaging biomarkers into clinical practice for patient management, diminishing the incentive to commercialize such technologies. Additionally, despite the impressive preclinical accomplishments of molecular imaging to date, expansion of such applications to the clinic has been limited by the fact that relatively few molecular imaging agents have been approved for clinical use in humans [22,60].

However, these limitations are starting to be addressed by novel approaches to imaging biomarker development, broad collaborations to standardize technology, and federal initiatives to foster the development of imaging agents and increase the availability of component tools and methods. In addition, radioisotope production for some important radionuclides, such as 1 8F, UC, 13N, and "O, although complex and expensive, is beginning to be addressed by recent innovations in cyclotron technology [61].

Second, there are limitations in the underlying imaging technologies and methodologies that we might expect to be addressed by ongoing basic research and technology development already occurring independent of imaging bio-marker development. The widespread diagnostic use of imaging motivates continual research and vendor improvements in hardware, software, and acquisition methods. Such improvements have recently included faster imaging and hardware improvements for MRI, innovations that reduce radiation dose in CT, new hardware designs that improve sensitivity and resolution of nuclear imaging modalities, and new capabilities afforded by combining modalities, as in SPECT/CT, PET/CT, and most recently, PET/MRI. Furthermore, many image analysis approaches and tools have been borrowed from ongoing computer vision research. All such advances have the potential to benefit imaging biomarkers' performance; however, careful attention must be paid to the differing criteria for system optimization between diagnostic and biomarker applications.

Finally, there are inherent limitations in imaging biomarkers that are not likely to be fully mitigated by future development. Within the spectrum of potential imaging biomarkers, those that rely on endogenous contrast mechanisms have the advantage of avoiding the added complexity and safety concerns introduced by the use of exogenous imaging agents. However, such image-based functional measures are often inherently nonspecific, relying on biological models in which the connection between measurement and function may not be interpreted easily or directly. In addition, there is a growing perception that the increased use of nuclear and CT modalities, which utilize ionizing radiation, presents a public health concern [62,63]. Diagnostic imaging has been guided by the principle that the risks of ionizing radiation should always be weighed against the benefits of the imaging procedure to the patient [64] i however, in some cases, radiation doses from medical tests may exceed limits known to increase the risk of cancer, particularly in the case of serial imaging [64]. Although progress has recently been made in reducing radiation doses in CT procedures [65] , the image quality of CT depends inherently on a nonnegligible radiation exposure. Additional advantages and limitations specific to different imaging modalities and methods are discussed further in a later section.

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