For medical-imaging equipment, progress is frequently made and regulated in baby steps. Many of the industry's new products are cleared by the US FDA (Rockville, Md) for marketing in the United States with a Premarket Notification 510(k), which is given after comparability is established with older products. Only when the use, technology, or risk has significantly changed, or taken a giant leap, does the FDA undertake a more rigorous approval process, requiring clinical data to prove company claims (Premarket Approval, or PMA).

Neither clearance nor approval is all-encompassing—if the use, technology, or risk changes just enough, a company might need to apply for a new 510(k) or PMA supplement. Off-label uses, therefore, stay off the record until a company submits an application and the FDA clears it.

The regulatory process itself isn't necessarily difficult; it's determining exactly what the process is that can be challenging. The FDA offers a wealth of information online, but the information can be overwhelming and dry with the confusion reflected in disorganized submissions.

Throw in the varying policies of other countries, and regulation becomes a complex machine that businesses must plan, budget, and schedule time to manage. For this reason, companies begin regulatory preparation alongside product development.

Most likely, this process will never change. Ensuring the safety and effectiveness of the many products that fall under FDA purview is a mission that the organization takes seriously. No one is "against" the safety of the American people, and everyone understands that the FDA must do its job. Still, even the FDA has admitted that improvements could be made, and it has been proactive about making the clearance and approval processes quicker and easier.

In an effort to improve turnaround, the organization has implemented third-party reviews, user fees, and decision-making time frames. The FDA continues to be open to providing answers to companies with questions and is in the process of revamping its Web site to make it more user-friendly. The administration also has led efforts to harmonize medical device regulatory practices internationally. It is a founding member of the Global Harmonization Task Force (GHTF of Brussels, Belgium) and currently participates in all five study groups, chairing one. (For more information about the GHTF, see "Five-Part Harmony".)

Perfect Harmony

Although international regulations have not yet converged, more similarities are beginning to appear, and, more frequently, companies are able to reuse information. "In some occasions, an entire product, or a portion of one, has not yet cleared the FDA but is available in Europe—but that is gradually changing. No matter where you go, you still need to save evidence and testing. The differences are disappearing," says Rishi Gadagkar, director of product development at Neurognostics Inc (Milwaukee).

Vy Tran, director of regulatory affairs at Varian Medical Systems (Palo Alto, Calif), agrees that the documentation is similar. "In Europe, the same documentation is required. The difference is that you self-certify to CE mark requirements to begin marketing and are audited later. There is no review process to complete beforehand like that at the FDA," she says.

Some products, however, take a more complicated path. According to Don Ellis, senior director of regulatory affairs and clinical affairs quality at Eastman Kodak Co (Rochester, NY), a new mammography product from the company is expected to be available in Europe long before it's available in the United States. The product falls into Class III and will require a PMA. "This product does present more risk and so needs to be approved by the FDA for use in the United States," Ellis explains. "In Europe, no intervention is required, so the processes are very different." (For more information on Class structure, see "The Fine Print," below.)

Early Starts

In the Works Doug Tucker, CEO of startup Neurognostics, brought on a team member with FDA experience to help navigate regulatory requirements. Most sources wanted to keep their works in progress (WIPs) close to the vest, but Neurognostics Inc CEO Doug Tucker shared that his company has been reading the FDA Web site for information on how to obtain clearance for a new CAD-type application for functional MRI. "A lot of our preparation for clearance is driven by developing a normative database that includes performance over normal and abnormal patients. How do we use this information to develop the product and the documentation needed for the FDA? How do we publish it? Will the database provide good objective evidence for the product's performance?" Tucker asks. As the company nears implementation, it plans to meet with the FDA to review its plan and gather feedback.

Because there is no standard approach to the application process, most companies develop a plan on a case-by-case basis, and they start early. Often, regulatory teams are involved at the earliest stages of development.

"From a regulatory point of view, the company must understand the intended use of the product and the technology used to accomplish imaging," says John Smith, MD, JD, an attorney and diagnostic radiologist at law firm Hogan & Hartson LLP (Washington).

The FDA uses that information to determine if a predicate device exists as well as the data that is necessary to demonstrate substantial equivalence (SE). It could be obvious—the predicate and existing device could be the same, and the company is seeking clearance for modifications. Or, the predicate device might need to be found among the competition. Once found, a company must make its case for SE.

"The data depends on the comparison. If it's straightforward, it might be that only nonclinical data is needed, maybe bench or animal data. Another level might require human clinical data," Smith explains.

If no predicate device can be found, the company will need to apply for a PMA and will need to collect more data, often through clinical trials. Kodak's Ellis always sends a draft protocol to the FDA before conducting any study. "We want to verify that we are conducting the right trials," he says.

If in doubt, companies should contact the FDA. "In general, the earlier the better, particularly if a company or the product area is new," says Donna-Bea Tillman, director of the office of device evaluation at the FDA. "If a company is spending money—for instance, on a clinical trial—[someone within the organization] should contact the FDA first." Companies can then more efficiently gather information and documentation for either the 510(k) or PMA during the design-control process.

Device Advice

Kodak's Don Ellis verifies planned clinical trials by first sending the protocol to the FDA. Rishi Gadagkar of Neurognostics notes that global regulatory differences are converging. Rishi Gadagkar of Neurognostics notes that global regulatory differences are converging.

To avoid contacting the FDA with information that is too abstract, most companies seek their first guidance from the organization's Web site (www.fda.gov/cdrh). Tillman recommends that those unfamiliar with FDA procedures begin with the "Device Advice" section, which is written specifically for first-timers. The ability to drill down makes the information more manageable. In addition, "Efforts to make the Web more approachable are under way," Tillman assures.

Albert Xthona, product manager of digital mammography products at Barco (Beaverton, Ore), suggests visiting the site more than once. "The information doesn't change, but you might need another look, maybe using a different search word," he says, noting that the information can provide a starting point for discussions with the FDA. "You can tell them what you've read, and they can direct you to additional resources."

The process is easier to navigate with experience, and new companies can hire consultants to help. Neurognostics decided to create a position that required FDA experience, according to CEO Doug Tucker. "We are a startup and wanted to be sure we put in place quality systems and processes that would allow us to meet FDA regulations," he says.

Once a company has determined what it will need, it must gather and present the information. Surprisingly, this area is where companies often fail, Tillman says.

"The biggest problem we see with applications is disorganization. Companies need to be very clear about why they have submitted the application. Is it a new device? Are they adding an indication?" she explains.

Submissions should include a table of contents and a cover letter, with an executive summary. "This should summarize the application up front. This is my device. These are my changes. These are the risks. This is how they have been addressed. This is how we've proven equivalency. These are the tests we've run. And then refer to tabs for the tests," Tillman suggests.

Typical Turnarounds

More than Maintenance: International Service Agreements "There is no such thing as an international service agreement. Service agreements are very local," says Mike Swinford, general manager of Americas services at GE Healthcare (Waukesha, Wis), who suggests that global infrastructures allow such diversification. "We are able to leverage our scale, network, and technology to provide service around the world." In every market, local offices focus on the customer needs, learning their typical demands, challenges, and regulatory requirements. Service agreements have extended beyond service and have become flexible enough to help clients optimize their assets. "We can offer not only remote maintenance options, but also staff and patient education, training, and consulting," Swinford notes. Service agreements are tailored to each company and budget. GE Healthcare just completed segmenting its many different offerings to different customers in the marketplace, though the effort provides just an initial agreement from which to start. Customer types include large national GPOs, research institutes, and imaging center chains. GE Healthcare's goal for any service agreement is to minimize, if not eliminate, unplanned downtime. Machine diagnostics are expected to help to achieve this goal. "GE is continuing to invest in machine diagnostics, which leverage the remote platform to predict failures," Swinford says. "For instance, predictive diagnostics of a CT scanner will know its tube is going to fail next week, and the replacement—which will take four to eight hours, depending on the scanner—can be scheduled at a convenient time rather than having to be completed urgently while diverting patients," he says. The benefits are obvious and available wherever clients are able to get online. Remote monitoring also helps with compliance. "Our clients will be prepared for the unannounced audits that JCAHO will begin in 2006," says Swinford, referring to the Joint Commission on Accreditation of Healthcare Organizations (JCAHO of Oakbrook Terrace, Ill). Information on the device is collected in real time, and reports, such as device history and maintenance schedules, can be accessed easily. "We want our customers to get more from their service agreements than just maintenance," says Swinford, whose company is leveraging its global infrastructure to offer just that. —WD

The 510(k) process takes 90 days, but it can be shortened to 30 days if the application is submitted by a third party. The FDA has accredited 12 organizations to conduct reviews of 670 device types. These submissions are exempt from 510(k) application fees, although companies will have to pay the third party.

The initiation of user fees has helped to improve FDA turnaround. "The changes implemented over the years have sped up the process dramatically. The process can take as few as 30 days for products with modifications that do not change the intended use or fundamental scientific technology. More complex submissions take about 90 days," says Varian's Tran. She notes that often, the FDA will return questions within 45 days if it has them, at which point, the clock is stopped and restarted when the answers have been received.

PMA submissions take longer, frequently extending beyond the FDA's self-imposed 180-day turnaround. If a submission is missing any required data, is inconsistent, or is poorly organized, the review process will be extended, and approval will be delayed until all questions have been answered.

Off-Label Uses

The ability to market a product in the United States, however, is just that. "FDA clearance or approval is not a ranking nor an assertion," says Xthona, providing this example: "PACS displays have been approved since the early 1990s, and the more than 100 products—some with monitors featuring two megapixels, some three megapixels, some five megapixels—all have the same clearance."

But the FDA is not concerned with ranking; its mission is to ensure safety and effectiveness. It wants to see that products do what their makers claim in a safe and effective manner. If a new use is found, then its safety and efficacy must be proven separately before a company can market the product for that use.

Companies know this rule and are careful not to break it. Often, it's the customers who use products in a manner not included on the label. Tillman's only comment? "The FDA does not regulate the practice of medicine and cannot comment on off-label uses."

Legal expert Smith notes, "Off-label uses are tricky. Physicians use devices off-label all the time. The practice-of-medicine exemption allows it—a licensed provider can use any legal, available product to treat a patient in whatever way he or she sees fit. The FDA regulates only device marketing and not medical practice."

Companies frequently are faced with independently published articles describing off-label uses and subsequent requests for these studies. "A company can provide peer-reviewed articles studying an off-label use at the direct request of a healthcare provider as long as the company also includes a disclaimer that the use described in the article is not approved or cleared," Smith explains.

If a company is unsure if a use is off-label, it's best to check with the FDA. "The process of clearing an off-label use starts with evaluation of whether the use actually is off-label and, if yes, which regulatory channels it will need to go through. A predicate device might need to be found; clinical data might need to be collected," says Varian's Tran.

The use might not have a market large enough to justify the expense, and the company can decide to leave it off-label. "When we install a system, the customer is made aware of the intended use and is asked to inform Neurognostics if the product will be used for other activities. We want to be able to help them understand the safety issues," Gadagkar says. Ultimately, it is the customer's choice.

Xthona notes that Barco's customers have the final say in how they use purchased products. For instance, a company in Europe did not want to use the approved CRT for digital mammography and used a 3-megapixel flat-panel display instead. "They were not even using a five-megapixel panel. We discovered this but could not push the customer to change. A few months later, they decided on their own to exchange the three-megapixel display for five megapixels," Xthona says.

Instrument-acquisition decisions often are based on the expected volume. Without enough demand to justify the purchase of new equipment, a facility could extend current devices beyond their intended use. "We have gone back and sought additional approvals before, but in some cases, we have been denied because the product was determined not to be as good as those already out there. We'll ask questions and might agree that the FDA has made the right decision. Customers can still decide to use the device off-label," Xthona says.

"It's a safety issue," says Neurognostics' Tucker, whose company is too new to have encountered off-label uses yet. "Is there a good scientific basis for the use? What is its efficacy?" Most companies, large or small, will address the issue on a case-by-case basis, deciding whether to take the next step or stay still—which can work too.

Wren Davis is a contributing writer for Medical Imaging.