Medical imaging in trials has been used as a measure of efficacy for more than 20 years. While the clinical practice of radiology
provides sufficient information for managing individual patients, this practice varies geographically within the United States
and globally. It was recognized by FDA that variability in evaluating trial images at the sites necessitated a more standardized
and controlled review process, which was described in the agency's 1994 "Points to Consider for Developing Medical Imaging
Drug and Biologic Products."
Kohkan Shamsi, MD
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In this document, recommendations for the blinded independent central review of images (blinded read) from trials for medical
imaging contrast agents were outlined. This independent review was meant to improve the quality of imaging data evaluations
from clinical trials. The blinded read process used today across therapeutic areas is derived primarily from FDA and diagnostics
industry documents and forums. It is this diagnostics-derived blinded read process which was included in FDA—and other regulatory
agency's—therapeutic guidance documents.
Rick Patt
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In clinical trials of diagnostic imaging agents, a radiologist, not a clinician, is usually the principal/site investigator.
In spite of this, it was recognized that standardizing image review, evaluating reader performance, and eliminating bias in
the reviews was nearly impossible—even with an identified radiologist investigator performing the reads at each site. In today's
therapeutic trials, it is uncommon to have a dedicated radiologist responsible for image interpretation at the site and for
signing 1572 forms. At many sites, a nonradiologist reviews the images to select and measure target lesions and completes
the imaging section of the case report form (CRF). This is either a nonradiologist physician, or even the site coordinator.
While some nonradiologists may believe they can accurately interpret routine CT scans or radiographs, it takes a trained radiologist
to evaluate the complexity of imaging effects seen in pathology (edema, hemorrhage, calcification, arterovenous shunting)
or to distinguish tumor from nontumor imaging effects in cancers with ill-defined margins.
Taming the wild westMethodology issues have always plagued site reads for oncology and other therapeutic drug trials. A radiologist's clinical
interpretation is designed for individual patient management, but rarely meets requirements to enable selection and measurement
of lesions and may use nonstandard terminology. Standardized imaging efficacy criteria used in trials (e.g., Response Evaluations
in Solid Tumors [RECIST] and others) are neither commonly used in clinical radiology practice, nor are they routinely included
in radiology residency training programs. Site reads being performed in oncology studies are also not fully auditable to the
extent of blinded reads. Training of blinded readers on trial-specific imaging efficacy criteria occurs routinely and is accepted
to have a positive impact on the quality of results. However, training of site readers—radiologists or otherwise—is usually
a less rigorous process, not infrequently performed by a CRA or other imaging nonexpert. Because of their relatively uncontrolled
nature, the site read process, particularly in oncology clinical trials, is considered by some to be "the wild west."
There are many factors that influence reader performance, including experience, expertise, evaluation criteria used, viewing
hardware/software, reader fatigue, disease process, drug mechanism of action, and design of blinded read. The evaluation of
reader performance is viewed as a reflection of the quality of imaging data results from a trial. Intra-reader and inter-reader
variability are easily evaluated in blinded reads where CRFs are linked to the image database, measurements made on images
directly populate the CRF, and response is automatically derived. However, similar standard methods to evaluate site reader
performance in multicenter trials for regulatory submission have yet to be established.
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