Alex Philippidis Senior News Editor Genetic Engineering & Biotechnology News

Firms are more interested in leveraging the value of this method in clinical development.

Molecular imaging modalities have multiplied over the past couple of generations beyond x-ray, from computed tomography (CT) to positron emission tomography (PET) and from ultrasound to MRI. So too have the number of compounds used and the number of companies with a stake in the industry, not to mention the variations among professionals in interpreting the images they generate.

Since 2008, the Society of Nuclear Medicine through its Clinical Trials Network (CTN) has worked to forge order out of all that chaos. Its aim is to ensure standardization in the use of radiopharmaceuticals in PET imaging studies as part of clinical trials. During that time, CTN has worked to build consensus among the professionals carrying out scans and drug companies as well as academic researchers investigating new treatments.

CTN’s nearly three years of efforts have begun to bear fruit. The network has a pair of clinical trials under way with a pharmaceutical company it won’t identify. Additionally, two years ago CTN collaborated with Siemens Molecular Imaging Biomarker Research on a demonstration project to validate scanner calibration and review the image quality of 12 scanners within 10 clinical sites. Five of the 12 completed all validation requirements the first time. That figure eventually rose to 11 of 12, with the most common problem being inaccurate chest oncology phantoms and lesion standardized uptake value measurements.

Also, CTN has had interest from some 300 sites in getting qualified and getting their scanners validated. The network has validated over 100 PET CT systems, “we’re probably at around 115, at somewhere around 70 or so different sites,” Michael Graham, Ph.D., co-chair of CTN, told GEN.

The goal is to create globally accepted protocols for using radiopharmaceuticals in trials that can be consistently used by multiple pharma companies and give standardized results, Dr. Graham said. Companies are indeed interested in having standardization, since data is then more acceptable by the FDA, he claimed.

 Drug company interest in standardization also reflects a desire to use imaging information to make decisions earlier in their pipeline on whether to pursue approval for a new treatment or note, he added.

Reasons for Variations

CTN got its start as PET imaging was beginning to be used in clinical trials. “The quality of the imaging in a number of these trials was fairly poor, such that pharma companies had to throw out as much as 40% of the studies because of poor imaging,” Dr. Graham recalled.

“We were fairly disturbed by that because we felt, and still feel quite strongly, that this was a powerful methodology that really should be very useful in this setting. But it’s only going to be useful if the studies are done properly,” he pointed out.

Reasons for the poor quality of those early studies vary. In part, it was an issue of clinical design: The PET imaging parts of the studies weren’t specified very carefully. “There was a lack of realization that there was a fair amount of variability about the way different sites do their PET scans.

“Some do it with greater rigor than others, in terms of the accuracy of the quantitation. Some would do the studies as early as 45 minutes after injection. Others would do it 60 to 90 minutes after injection,” Dr. Graham said, noting that the time differential produced varying results. Other factors accounting for variations in results are patient preparation, for e.g., whether they fasted or were sedated before being scanned.

Interestingly, Dr. Graham said, differences in equipment are just a minor factor. Nonetheless, a subcommittee within CTN is working with major manufacturers to standardize image acquisition even further: “The goal there is to have the images essentially equivalent from one system to the next so that you really couldn’t tell the difference which machine it was acquired on.”

Also less critical of a factor is the variability owing in part to the expertise and experience of the readers. Pharma companies try to minimize that through a central read. Until recently, though, firms haven’t paid as much attention to the imaging side of their clinical trials. A traditional approach in trials using CT would simply measure the size of a tumor for signs of shrinkage.

Dr. Graham noted that radiologists at the individual sites conducting clinical trials should get involved. “The way the flow of information has gone in this whole business, the companies work with the oncologists, and the oncologists don’t think very much about the imaging side of things. And if they do think about it, their view is often somewhat naïve.”

Defining Protocols

CTN has offered to review testing protocols for drug development. Such reviews too often occur after protocols have been cemented, even though, in several cases, companies submitted protocols much earlier than their clinical testing started.

FDA is another key player in promoting standardization. In December 2009, the agency approved cGMP regulations for PET drugs marketed for clinical use. That touched off a two-year period during which PET drug makers were required to apply for NDAs and ANDAs for their radiopharmaceuticals. Those applications are due December 12, 2011.

The regulation completes a process dating back to 1995, when the agency said it intended to regulate PET drugs under the Federal Food, Drug, and Cosmetic Act. In 1997, Congress passed the FDA Modernization Act, which clarified that PET drugs are subject to FDA regulation but allowed for a phasing-in of rules.

“Throughout these proceedings, we’ve tried to be sensitive to the fact that we are bringing under regulatory control an industry that had been largely unregulated and an industry with special characteristics, given the short half-lives of the materials involved and the fact that they are often used onsite or within a relatively short distance from the production site because of their half-lives,” Jane A. Axelrad, associate director for policy at FDA’s Center for Drug Evaluation and Research, said at a March 2 public meeting.

Also working on standardization efforts is the Quantitative Imaging Biomarkers Alliance (QIBA), organized in 2007 by the Radiological Society of North America (RSNA) to unite researchers, healthcare professionals, and industry stakeholders in the advancement of quantitative imaging and the use of biomarkers in clinical trials and practice.

Most recently, on June 28, QIBA released for public comment a “profile” or technical document from its Dynamic Contrast Enhanced Magnetic Resonance Imaging (DCE-MRI) Technical Committee. It offers basic standards for site and scanner qualification, subject preparation, contrast agent administration, imaging procedure, image post-processing, image analysis, image interpretation, data archival, and quality control.

CTN says it is close to completing a protocol for the use of fluorodeoxyglucose (FDG), a radiopharmaceutical used in PET imaging. It has obtained some consensus from industry and professionals, CTN reports. Protocols for other PET imaging agents will follow, and rules will differ from one radiopharmaceutical to another. “For instance, the fluorothymidine (FLT) protocol is going to be significantly different than the FDG protocol, though, there will be areas where they are identical,” Dr. Graham said.

“There are other agents that we’ve been talking about. For instance, some of the hypoxia imaging agents are likely to be ones that we work on relatively soon,” he explained.

Amyloid imaging agents, for which clinical trials are getting under way, may be another area of concentration for future CTN protocols. The network’s ultimate direction on which future protocols to pursue won’t be made until after talks with biopharma industry representatives. Dr. Graham added that FDA can help advance standardization by simplifying toxicological requirements for imaging agents, since some have already been used in thousands of patients without incident.

Down the Road

Among companies looking to position themselves well as long-term players in molecular imaging is Cardinal Health. On July 18, it opened an $11 million, 25,000 square foot molecular imaging center in Phoenix. The Center for the Advancement of Molecular Imaging is aiming to accelerate development, testing, and commercialization of new radiopharmaceuticals and PET imaging agents.

Cardinal Health says its scientists, engineers, and manufacturing experts will work with industry and academic professionals through laboratories of multidisciplinary teams. It expects this strategy will cut the time needed to gain FDA approval and foster sharing of commercialization best practices. The center also includes a manufacturing facility, private laboratories for guest researchers, and a PET production control center.

“The launch of the Center for the Advancement of Molecular Imaging is a strategic investment in the future of the molecular imaging and pharmaceutical industries,” John Rademacher, president of Cardinal Health’s nuclear and pharmaceutical services, noted.

On July 18, Texas Children’s Hospital reported that it used real-time MRI-guided thermal imaging and laser technology to destroy lesions in the brain that cause epilepsy and uncontrollable seizures. The technology is considered safer and significantly less invasive compared to craniotomy, currently the most commonly used cranial surgical treatment for epilepsy.

Other hospitals will likely follow over time, increasing the use of molecular imaging. Thus it is all the more important that protocols for the use of radiopharmaceuticals and for scanning processes that use them to be standardized across the field. CTN is among key groups intent on seeing that happen. FDA too has an important role to continue playing even after its final guidance takes effect. And with industry more convinced on the need for consistency in molecular imaging, the next few years should see a codification of standards taking place.

Alex Philippidis is senior news editor at Genetic Engineering & Biotechnology News.

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