Quantitative imaging test approval and biomarker qualification: interrelated but distinct activities

Abstract

Quantitative imaging biomarkers could speed the development of new treatments for unmet medical needs and improve routine clinical care. However, it is not clear how the various regulatory and nonregulatory (eg, reimbursement) processes (often referred to as pathways) relate, nor is it clear which data need to be collected to support these different pathways most efficiently, given the time- and cost-intensive nature of doing so. The purpose of this article is to describe current thinking regarding these pathways emerging from diverse stakeholders interested and active in the definition, validation, and qualification of quantitative imaging biomarkers and to propose processes to facilitate the development and use of quantitative imaging biomarkers. A flexible framework is described that may be adapted for each imaging application, providing mechanisms that can be used to develop, assess, and evaluate relevant biomarkers. From this framework, processes can be mapped that would be applicable to both imaging product development and to quantitative imaging biomarker development aimed at increasing the effectiveness and availability of quantitative imaging.

Supplemental material: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.10100800/-/DC1.

Figure 1:

Flowchart shows interrelated activities, with feedback. From a regulatory point of view, the introduction of new technology solutions for medical purposes is generally considered as applying to either clinical research or clinical practice. In the United States, these activities generally follow different requirements and are administered by different departments within the agency. Quantitative imaging is relevant to both clinical research and clinical practice, but in the absence of an organized effort to do so it is generally difficult to utilize evidence across both of these uses owing to differences in expectations and requirements related to the collection and interpretation of evidence. To meet constraints imposed in both the use and the business models of sponsors, it may be possible to organize efforts that enable efficient and effective study designs to address multiple needs from collective activities. CMS = Centers for Medicare and Medicaid Services.

Figure 2:

Chart shows quantitative imaging biomarker qualification process. A detailed following of the FDA process is shown, where steps outlined on the right are steps within the regulatory agency and steps outlined on the left are steps that a collaborative activity of industrial sponsors, practicing clinicians, and academic stakeholders may take to pursue biomarker qualification. Processes in other geographic areas such as Europe and Asia differ somewhat, but cooperative activities across the agencies have worked to minimize differences and ideally allow parallel or near parallel pursuit in multiple countries at the same time. BQDS = Biomarker Qualification Data Submission.

Figure 3:

Volumetric image analysis with CT serves as an example of how the interrelated activities outlined in Figure 1 may be pursued for this marker. The numbered sequence refers to the chronologic order in which steps may be accomplished, on the basis of the current state of the marker and projecting possible steps that may be undertaken by the community to advance the marker. CMS = Centers for Medicare and Medicaid Services.

Figure 4:

Standardized uptake value in FDG PET serves as an example of how the interrelated activities outlined in Figure 1 may be pursued. This image may be read by itself, as well as compared with Figures 3 and 5 to highlight the differences in sequence that may be pursued by the community as appropriate for each marker. CMS = Centers for Medicare and Medicaid Services.

Figure 5:

The use of FMISO PET to evaluate hypoxia serves as a third example highlighting the different sequence of activities that may be pursued, in this case as applying to a marker that has been the subject of considerable interest but that may not be as mature as the examples given in Figures 3 and 4. CMS = Centers for Medicare and Medicaid Services.