By Ann Neuer
December 14, 2009 | As clinical trial protocols call for more imaging of all types, a big controversy is brewing as to whether efficacy can be based on site evaluation of images, or if the images should be read centrally, by trained and independent professionals. Much of the brouhaha centers on oncology trials and whether sites are able to adequately identify “progression-free survival (PFS)”, an image-based surrogate endpoint that indicates whether a patient’s disease has progressed.
“Making this kind of determination requires training and consistent methodology in acquiring and interpreting the images,” says radiologist Rick Patt, principal of RadMD, a provider of “blinded reader services” and consultants for implementing medical imaging endpoints in clinical trials. Blinded read is shorthand for blinded independent central review (BICR), the form of review advocated by the Food and Drug Administration for radiographic exams used in oncology studies when PFS is the primary endpoint.
Applying consistent and unbiased methodology to BICR is essential because image interpretation is one part of determining the efficacy of investigational compounds. Patt explains that too frequently, this critical work is left in inadequately trained hands. “There are instances in which the non-radiologist site investigator or even the study coordinator is completing the imaging case report form. It would be better to have the images read by a radiologist who should be included on the (Statement of Investigator Form) 1572, but this costs money,” he says. Patt comments further that even if the site does engage a radiologist to read images, many are not trained in clinical trials and are not familiar with RECIST—Response Evaluation Criteria in Solid Tumors—which are rules for objectively determining PFS in solid tumors.
And the challenges don’t stop there. Patt says that site reads may be acceptable and image interpretation may be similar to findings made by a BICR, but if there is a faulty methodology at the site-level or inconsistencies in reading, results can’t be compared. To address these issues, RadMD has a cadre of more than 600 experts, including radiologists, oncologists, medical imaging physicists and other professionals. Anyone of the 600 who reads images for a trial goes through the Blinded Reader and Investigator Training Institute (BRITI), RadMD’s sister company, which teaches standardized reading of medical images for clinical trials.
Despite what may appear to be the obvious advantages of using a provider that can offer a BICR, there is a contingent that maintains that BICR does not remove all biases from evaluations of treatment effectiveness. Some suggest that BICR may actually introduce bias because of a practice known as “informative censoring”. The term “censoring” refers to the concept that if a subject is removed from a study because the site determines that his or her disease has progressed, the data linked to that subject is removed from the clinical trial. Informative censoring means that if censoring has occurred but cannot be confirmed through a central read, censoring will make the survival course of those still on treatment appear more favorable than it actually is.
The topic of independent review as compared to site-determined evaluation was explored in an October meeting entitled Progression-Free Survival Oncology Workshop. Sponsored by the Drug Information Association (DIA) in cooperation with FDA and the Pharmaceutical Research and Manufacturers of America, presentations on this subject were largely given by biostatisticians, not clinicians or clinical investigators. One session proposed performing an audit comparing image interpretations by sites to those provided by centralized blinded read. In this scenario, 10 percent of the images would be “over-read” meaning that an independent central review team would read images that the site had read, and if results were similar, some propose there would be no reason to do a complete independent review.
Much of the perceived problem between a site determining PFS and receiving confirmation from an independent radiologist stems from the fact that oftentimes, independent confirmation is not performed in real time. Patt contends that much of this gap can be substantially reduced. “Current technology enables fast turnaround on confirmation of disease progression—24-48 hours. If the site feels that the patient has progressed, those images can be sent to us immediately for independent review before removing a patient for suspected progression,” he says.