The FDA not only regulates the manufacture of imaging equipment and pharmaceuticals—but it also concentrates on promoting public health.

With a discipline as diverse and complex as medical imaging, it’s no wonder that it takes two of the eight centers under the US FDA umbrella to oversee developments in the field. The Center for Devices and Radiation Health (CDRH) covers the equipment side, while the Center for Drug and Evaluation Research (CDER) handles the drug-development side.

Although the centers have different focuses, both concentrate on safety and effectiveness to ensure that the health benefits of products in both categories outweigh the risks for imaging patients. With the rapid and successful evolution of imaging technology in the past few years, FDA officials look forward to continued advancements in the field.

“Imaging technology really seems to be improving by leaps and bounds,” said Rafel Dwaine Rieves, MD, acting director for the Division of Medical Imaging and Hematology Products (DMIHP), which is within CDER’s Office of Oncology Drug Products. “We’re excited about that, and we’re encouraging its continued development and use across the country.”

Promoting Safe Radiation

When it comes to imaging equipment, the FDA’s role is twofold: to approve devices for use, and to ensure they adhere to the agency’s electronic product radiation standards. Manufacturers seeking approval for medical devices that are similar to others on the market file for 510(k) approval through the CDRH. If the product is entirely new, manufacturers must do much more groundwork, such as proving the device is safe and effective, performing clinical and safety testing, and undergoing a premarket approval process.

On the radiation-control side, CAPT Thomas R. Ohlhaber, deputy director for the Division of Mammography Quality and Radiation Programs under the CDRH’s Office of Communication, Education, and Radiation Programs, oversees all electronic products that can produce ionizing or nonionizing radiation. In addition to medical imaging devices, this includes other products such as television sets, microwave ovens, and lasers.

Manufacturers must come up with the appropriate testing procedures for the devices and certify that they meet the standard. “Our goal here is to keep radiation below the limits of where safe exposure levels have been determined—in other words, no unnecessary radiation to the public,” Ohlhaber said. “When you get to devices that have a beneficial effect from the radiation, such as medical x-ray and CT, our role is to keep the dose as low as possible, consistent with the benefits from the exam.”

The FDA does not actually set the precise dose needed for each procedure—that is a matter for states to decide. Rather, the FDA ensures that the equipment radiation falls within an acceptable range by setting performance standards for manufacturers. “Effectively, what they say is the radiation has to be the right energy, and the field covered has to be the right size so that the majority of the x-rays produced are producing the image,” Ohlhaber said.

For film-based modalities, such as chest x-ray equipment, most devices naturally have a low-radiation dose as only a small number of exposures are needed to get an acceptable image. Digital imaging is a different story, however, as there is a greater range over which these devices can produce a diagnostically significant image.

Although the FDA cannot regulate specific doses for procedures, the agency does have an awareness campaign to get the word out that good diagnostic information can be obtained in the lower-dose range with digital imaging. the FDA allies with professional societies, such as the American College of Radiology (ACR) and the American Association of Physicists in Medicine, to spread the message, and works to influence international standards to adopt stricter low-dose policies. The agency also includes extensive information on its Web site, particularly about areas where dose is generally higher.

“We know that in the country now, CT exams are the number one contributor to the public health dose, followed pretty closely by interventional fluoro procedures,” Ohlhaber said. “Those are the two areas that we’ve targeted as much as we can because the savings are biggest there.” The Web site also emphasizes the important distinction between CT doses used for adult and pediatric patients, and discourages whole-body CT procedures, which could unnecessarily increase exposure without adequate benefit.

The FDA also monitors doses from medical x-ray through a program called Nationwide Evaluation of X-ray Trends (NEXT). Every 2 to 3 years, NEXT collects data on a chosen procedure from a statistically significant sample of hospitals across the country. “We actually measure the doses, with the states going in and performing tests on the equipment and getting the doses,” Ohlhaber said. “That way, we know what kind of doses are given to the public.”

Although regulating specific doses is beyond the FDA’s scope, Ohlhaber said that championing the cause for lower doses is a natural extension of the agency’s concern for public health. “We are the player that regulates the manufacturing, but we don’t regulate the use,” he said. “Yet we do know that there are problems with use. If we were to just ignore those, I think we would not be spending the public’s money wisely. We’ve always had both the compliance side and the side that was concerned with voluntary programs to reduce radiation exposure out in the public.”

As for what’s currently in the device-approval pipeline? That’s a secret even Ohlhaber’s team doesn’t usually know until the products are ready to market. “Certainly, right now they’re talking about CT machines with more and more slices,” he said. “I think everybody is aware that’s coming. But other than that, any big breakthroughs, generally, we can’t talk about them, or we don’t see them a whole lot in advance.”

Still, Ohlhaber expects to see more of the revolutionary changes in imaging that such advances as CT have made to the field. He notes the significant improvements CT has made to emergency departments, the benefits of CT for detecting lung cancer, and the current breakthroughs with using CT for cardiac patients—all of which pave the way for future improvements.

“The FDA has no intention of getting in the way of that,” Ohlhaber said. “In fact, we applaud that because medical care is improving. What we want to do is make sure that the risk is as small as we can make it while you’re getting these tremendous improvements in imaging.”

Monitoring Contrast Agents

The DMIHP regulates investigational new drug applications (INDs), new drug applications, and biologic licensing applications for small-molecule agents and biologics. On the medical imaging side, this encompasses contrast agents and radiolabeled pharmaceuticals, among others.

Under the division, the Office of Surveillance and Epidemiology continuously monitors reports of adverse drug reactions through a system called MedWatch, which allows physicians, pharmacists, and others to report incidents online or by phone or fax. The office also reviews the required annual reports from all manufacturers and maintains contracts with research organizations that track drug usage and medication errors. The office watches for “safety signals” that indicate either a novel reaction or an increase in adverse reactions to a certain drug.

This past spring, the monitoring system alerted the division to an association between gadolinium-based contrast agents, used in common imaging procedures such as MRI, and necrotic systemic fibrosis (NSF) in a small subset of patients. The potentially fatal condition causes the skin of patients to become fibrotic and the patient’s organs to turn to hard connective tissue. “The NSF situation came to light to a large extent because of the novelty,” Rieves said.

There are five gadolinium-based contrast agents on the US market, and they are commonly used. Most patients who receive these contrast agents are not at risk for developing NSF. However, a rare few could be affected if they have severe kidney failure, for example. The FDA reported the issue last spring and emended the labeling on the product packaging to reflect this development. “It’s still not definite; it’s still an association,” Rieves said. “But the association is generally accepted as very strong now.”

Individuals more likely to be affected are patients with acute or chronic severe renal insufficiency, those with acute kidney failure of any severity associated with hepatorenal syndrome, or those with kidney failure of any severity in the setting of liver transplantation.

“The situation with NSF is uncommon,” Rieves said. “In fact, it would be regarded as very rare. However, case-control series have identified patients who appear to be at increased risk.”

Since taking action this past spring, the agency and manufacturers have continued to collect and monitor data on this issue. “All of these companies are cooperating in collecting additional data,” Rieves said. “Large registries are collecting data from people with milder degrees of kidney failure to try to estimate just how common this situation may be in people with less than severe kidney failure.”

Because most patients are unaware that they receive a contrast agent when undergoing an imaging procedure, the communication efforts were directed mainly toward the radiology community. The division spoke with representatives from the ACR prior to making label changes to the gadolinium-based contrast agent products, and the professional societies actively helped build awareness of the changes in the radiology community.

Communicating an association like this to the public requires a diligent effort to provide clearly presented information about the risks and prescribed use of the contrast agent. Simple text formatting helped accomplish this, as bullet and highlighting features emphasized the main points on both the three public advisories on this topic as well as on the labels themselves.

“We tried to make it clear that this was not a risk for most people, that it basically applied to a small subset of the population, and that contrast agents continue to be safe and effective when they’re used according to the prescribing information,” Rieves said.

Since changing the labels of the gadolinium-based contrast agents, there have been no significant developments on this issue to report. However, there has been at least one advisory pertaining to a different set of contrast agents. In October, the division alerted providers to the association between two ultrasound microbubble contrast agents used for echocardiography and fatal cardiac arrest. (The information sheet is available at

“We, with the manufacturers, made some very important changes to those labels to include boxed warnings for fatal cardiac arrest, as well as new warnings related to cardiopulmonary reactions, and modification of the labels to contraindicate use of those products in certain people, including those with acute myocardial infarction or respiratory failure,” Rieves said.

Beyond focusing on reviewing new drug applications and monitoring postmarketing safety of approved drugs, the division also concentrates on standardization of performance of medical imaging in clinical studies as well as interpretation of the imaging data. To this end, the division is working with the Drug Information Association, Horsham, Pa, to develop a white paper describing the standardization procedures for use of imaging end points in clinical studies conducted by hospitals across the country.

“The more variability in those procedures, the less likely a manufacturer can actually show that their therapeutic drug is working,” Rieves said.

Although the imaging equipment side continues to evolve rapidly, Rieves expects that contrast agents will be part of the equation for the long term. He hopes to see more industry interest in developing and advancing safe and efficacious contrast agents. “Something that concerns us is that, compared to drugs that are administered chronically, the incentive for manufacturers to develop these products is probably not as great, specifically one-time-use products,” Rieves said.

Still, he anticipates that his division will continue to expand as more applications are discovered. “I think our division, if anything, is going to start growing,” he said. “Imaging surely will be used more and more in drug developments as end points—for example, cancer, arthritis, and neurology.”

Continuing Improvement

George Mills, MD, served for 14 years at the FDA and is the former director of the DMIHP. In this role, he regulated the development of all contrast agents for x-ray, CT, MRI, and ultrasound.

“When I came to the agency in 1993, they were looking at a single floppy disk containing all of the information for the first diagnostic antibody for imaging a tumor,” said Mills, who is now vice president of medical imaging consulting for Perceptive Informatics, the technology business of PAREXEL, a Boston-based global service provider to the biopharmaceutical industry.

Since 1993, Mills has seen the rapid development of medical imaging into the robust field of today—and he sees no slowing down for imaging in the immediate future. For example, he expects rapid growth in the area of imaging biomarkers, as PET research and the exploratory IND help identify new biomarkers to move various therapeutics forward in clinical trials.

“What we’re trying to do is to make imaging a more uniform application across multicenter clinical trials, as well as for early individual center clinical trials,” Mills said. “Hopefully, in going forward, we can utilize our expertise, experience, and technology in imaging to be able to conduct more effective and more rapid evaluations in these trials.”

Mills also anticipates efforts in exploratory IND applications to weed out ineffective drugs earlier, which will speed effective drug development and cut corporate development costs. The exploratory IND is implemented for human clinical trials to rapidly test whether preclinical results are confirmed—an opportunity to make critical decisions for selecting promising drugs and to concentrate resources.

“When the preclinical results are not confirmed, that individual product is considered less promising and is set aside from the development portfolio so that the sponsor’s attention and resources will be focused elsewhere,” Mills said.

When it comes to radiopharmaceutical development, Mills believes that advances in PET will unlock many opportunities. “This is a very fruitful area that is going to be very exciting because as we develop these various PET imaging biomarkers, they will simultaneously support the development of therapeutic drugs and biologics to advance the entire field of therapeutic medicine,” he said.

He also believes that PET will be effectively combined with MRI and other imaging platforms for simultaneous, dual-modality imaging. “To me, the evolution of PET, which has a very high sensitivity with the high-resolution imaging characteristics of the standard x-ray modalities such as CT, will be an outstanding diagnostic platform for confirmation determinations for clinical trials as well as patient care with current and new therapeutics,” he said.

Throughout these developments in diagnostics and therapeutics, the FDA will play an important role as the industry’s regulatory agency. Mills expects that the FDA will continue to focus on the application of imaging in clinical trial development and to incorporate diagnostics and therapeutics together under the 2004 Critical Path Initiative to encourage the development of new drugs and biologics.

Ann H. Carlson is a contributing writer for  Medical Imaging. For more information, contact .