Image Awareness
by Sarah Fister Gale
July 2008
Radiological biomarkers hold the potential to be a positive force in pharmaceutical research, but the adoption of imaging techniques as a useful tool for drug development has been slow to materialize.
No one in the pharmaceutical industry would dispute the fact that drug development takes too long and costs too much, and now many industry experts are looking to imaging technologies as a way to shave time and cost from the process. There is increasing evidence that medical imaging can help answer key questions that arise during the drug development process. Imaging modalities such as magnetic resonance imaging (MRI), computed tomography (CT) and positron emission tomography (PET) offer significant insights into the bioactivity, pharmacokinetics and dosing of drugs, in addition to supporting registration applications. But as the technology continues to improve, the industry still has a long way to go to validate the role imaging plays in proving the effectiveness of new therapies.
Merck is one of the companies leading the push to use imaging research as a drug development tool, partnering with other pharmaceutical companies, industry associations and consortia to identify ways in which imaging can validate drug targets, assess drug candidates and evaluate the molecular mechanisms for therapeutic benefit, says Dr. Michael Klimas, Ph.D., executive director of imaging for Merck, in Whitehouse Station, N.J., USA.
Research teams at Merck are currently exploring the use of molecular technologies, such as expression profiling and advanced informatics, to discover novel targets and biomarkers that predict drug activity in a clinical setting with the ultimate goal of treating diseases in a new way. “There is a significant focus in the pharmaceutical industry on researching relatively untreated diseases that are more chronic in nature,” Klimas says. “That research requires a different tool kit and imaging is a part of that.”
Early Identification
Imaging technologies can play a key role at several stages of drug development, notes Dr. Jean-Luc Vanderheyden, global molecular imaging leader at General Electric Healthcare in Waukesha, Wis., USA. “The technology changes so much because it allows pharmaceutical companies to see how their therapies are interacting with receptors.”
In preclinical trials, it can be used to identify and track the activity, metabolism and size of lesions in animals and how therapies impact them. “It’s a great tool for this basic research,” Vanderheyden says. “We can look at multiple parameters simultaneously in real-time and reduce the number of animals sacrificed.”
In early clinical stages, imaging data can possibly identify the drugs that won’t make it to therapy, which can translate into a significant reduction in the cost of research and development, Klimas says. “Imaging results provide better information so we can quickly separate out those research candidates that don’t have the effect we were expecting on the molecular target,” he says. “It provides us additional go/no-go information at an earlier point in the development process, which saves time and expense, particularly in chronic disease therapies that require long development times.”
At later stages of development, imaging can be used to track the specific impact of therapies on human patients, delivering more concrete results than other methods. It also delivers early data on the overall impact of the therapy on the patient using non-invasive strategies. In Alzheimer’s disease patients, for example, Merck is working with several industry groups to research the use of imaging to measure the presence of beta amyloid, a hallmark of Alzheimer’s disease.
Based on imaging results that show levels of beta amyloid—and changes in those levels over the course of months—physicians may be able to personalize therapies, identifying patients who are good candidates for therapies or those who should be switched to other therapies. Klimas notes that this technique is currently being used in preclinical studies.
Imaging also offers early warning signals when something goes wrong at this stage, which offers compelling benefits, Vanderheyden says. It means doctors potentially could detect dangerous side effects before symptoms arise, allowing them to stop or alter the dosage of a therapy more proactively. “This could be used as a differentiator when a drug comes to market,” he says, noting that it would give pharmaceutical companies clear data about the safety of new therapies.
Radiological Real Time
All of these applications have been touted for some time, but advances in imaging technology make them a more realistic strategy. Today’s imaging tools allow for more exact data that can be used to more closely define the amount of a drug needed to treat specific patients and also provide insight into how effective the treatment is, Vanderheyden says.
Having real-time results will give doctors a proactive tool for customizing therapies to patients’ needs and to determine more quickly whether they are working. For example, MRI or PET imaging of patients receiving treatments for cancer could show the drug’s effect on a tumor. “Even two years ago the technology was too rudimentary to do this,” Vanderheyden says, noting that today researchers can see more detail and take advantage of better acquisition signals that have eliminated the image blurring that used to result from natural movements in the body.
“Imaging will continue to help us develop new therapies and increase our probability of success,” Klimas adds.
Falling off the Critical Path
The application of imaging in drug development was a major part of the U.S. Food and Drug Administration’s (FDA) 2004 Critical Path Initiative, which spoke early on about the importance of imaging to hasten the drug approval process, particularly in oncology research. However, not much progress has been made in validating imaging as an FDA-approved regulatory endpoint, says Dr. Bruce Hillman, chief scientific officer for American College of Radiology Image Metrix and a professor of radiology at the University of Virginia in Charlottesville, Va., USA.
“The FDA promoted the Critical Path, but it’s come to a dramatic slowdown,” Hillman says. He blames personnel changes at the FDA and budget cuts in Critical Path projects for the lost momentum. And although individual studies and small trials are being conducted using promising imaging technology, the industry is still a long way from proving that it can deliver meaningful outcomes using these tools.
“There is still a lot of work to be done to validate radiological biomarkers,” he says. “We need to standardize the technology and demonstrate we can get reliable, reproducible results through multi-center studies.”
Hillman is anxious to see what the FDA will do in the next few years and the impact that will have on imaging research for drug development. “There is much we can do in the way of initiating multi-center validation studies, but the support and guidance of the FDA would go a long way in moving things forward.”
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