FDA is emphasizing statistical outcomes over protocol standardization when assessing imaging studies, according to Division of Medical Imaging Drug Products Director George Mills.

"What the sponsor and the agency are looking for is the outcome of the assessment. And so we don't grade, if you will, the technical quality" of a trial's protocol, Mills said in a recent interview with "The Pink Sheet."

"If they've met their prospectively defined statistical analytical plan, then they have a path forward towards approval or licensure."

However, standardization remains a key contributor to achieving statistical significance. The agency has been stressing the utility of standardization in imaging studies through informal recommendations to industry.

Many times, "because the sponsor and the clinical sites did not align their clinical imaging as well as they could have through standardization, they have had data that's not been as strong as it could have been," Mills said. "With improved imaging standardization, the clinical trial results may have been able to statistically demonstrate the effect that had been proposed."

FDA considers rheumatoid arthritis therapies as one area that has significantly benefited from standardization of imaging studies.

"We've been able to demonstrate very fine, very minimal changes in the radiographic outcome assessments for these various clinical trial populations," Mills noted.

Improved standardization of imaging studies also could facilitate comparative effectiveness assessments of RA treatments, he stated.

"The radiographic findings across these multiple clinical trials, with multiple...sponsors across multiple centers, could readily be compared," Mills said. "They are so well standardized that...we know that the independent reviewers could compare these images quite nicely."

In public forums, FDA has taken a cautious stance on the use of imaging studies for RA.

During a Drug Information Association meeting in May on Critical Path opportunities for medical imaging, FDA Division of Therapeutic Biological Internal Medicine Products Medical Team Leader Jeffrey Siegel noted that "challenges remain."

Siegel suggested that imaging studies are likely to continue to be used as an additional assessment tool rather than replacing clinical evaluations.

FDA's emphasis on standardization of imaging studies has received a degree of pushback from industry.

Following the second "approvable" letter for its vascular imaging agent Vasovist (gadofosveset), Epix maintained that the product had been caught between what it described as a "paradigm shift" taking place at FDA.

[Editor's note: In-depth coverage of the approvable letter appeared in ¹ "The Pink Sheet" DAILY Nov. 23, 2005. To sign up for a free trial, visit www.ThePinkSheetDAILY.com.]

Mills said that the agency is moving in the direction of issuing a guidance on standardization of imaging studies couched in the Critical Path initiative.

However, in light of the availability of the related exploratory IND draft guidance and the final guidance on developing medical imaging drugs and biologics, release of such a guidance is not imminent (² Also see "Exploratory INDs Will Better Serve Large Companies, PDL Exec Says" - Pink Sheet, 2 May, 2005., p. 29).

Mills believes the imaging community has been open to the agency's push toward greater standardization.

"The community [has been] very receptive and understands that these are issues that are there for them to work with and to help them improve the performance of their therapeutic as well as diagnostic trials," he said. "This community understands...that imaging performance can be improved through standardization."

Mills singled out the Society of Nuclear Medicine as a group that has responded to its message. SNM, in return, sees FDA's efforts as a long-term benefit that will accelerate drug development.

"The major accomplishment has been the open communications with FDA on these issues....In the long run, it will provide some stimulus to the radiopharmaceutical industry to produce new products," the society said.

FDA Stressing Statistical Outcomes Over Standardization In Imaging Trials

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