In the past 10 years, medical imaging devices have made tremendous strides in speed and accuracy, contributing to improved patient care and satisfaction. With many manufacturers sharing a dedication to research and development, more advances can be expected. But before these products in the pipeline can be employed, they must first pass the clearance processes of the regulatory agencies that oversee their use.
In the United States, that body is the Food and Drug Administration (FDA of Rockville, Md). Assigned the mission of protecting the nation’s populace, the organization has the empathy of the manufacturers that must approach it. However, the requirements for approval can be an aggravation, involving a resource-hungry, complicated, and fluid demand for data and documentation. With such disasters as thalidomide1 still fresh in people’s minds, no one is complaining. But when compared to the seemingly faster and easier clearance processes in Europe, the FDA’s requirements can be a source of frustration.
Companies avoid delays and additional costs by planning for regulatory needs early, both within the company and in discussions with the agency. The FDA has made efforts as well to make the process easier with new options, including third-party review, and participation in the global harmonization effort. Founded in 1992, the Global Harmonization Task Force (GHTF) aims to harmonize regulation of medical devices among members and provide a model for medical-device regulation for other countries. Members include the United States, the European Union, Canada, Japan, and Australia.
Protect and Serve
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The FDA is authorized to regulate a host of products, including medical devices and both ionizing and nonionizing radiation-emitting electronic products, through the Federal Food Drug and Cosmetic (FD&C) Act. Its aim is to ensure both the safety and effectiveness of these products. Within the FDA, the Center for Devices and Radiological Health (CDRH) is the body responsible for oversight of this area. It regulates the firms that manufacture, repackage, relabel, and/or import medical devices in the United States as well as radiation-emitting products, both medical and nonmedical.
Products are classified into three groups-Classes I, II, and III-with regulatory control increasing with each class. FDA documentation specifies that “Class I devices are exempt from Premarket Notification 510(k); most Class II devices require Premarket Notification 510(k); and most Class III devices require Premarket Approval (PMA). The basic regulatory requirements that manufacturers of medical devices distributed in the United States must comply with are:
- Premarket Notification 510(k), unless exempt, or PMA;
- Establishment registration on form FDA-2891;
- Medical Device Listing on form FDA-2892;
- Quality System (QS) regulation;
- Labeling requirements; and
- Medical Device Reporting (MDR).”2
Manufacturers that must submit the Premarket Notification 510(k) or a PMA are not permitted to commercially distribute the device in question until the FDA has provided authorization.
The Premarket Notification 510(k), or simply 510(k), is an easier process than that for the PMA. To obtain the 510(k), the manufacturer must demonstrate that the device is substantially equivalent to one legally in commercial distribution in the Untied States before May 28, 1976, or to a device that has been determined by the FDA to be substantially equivalent.2
Class III devices are considered to pose a significant risk of illness or injury, or are not found to be substantially equivalent to previously approved devices. Subsequently, the clearance process is more complicated and requires submission of clinical data, which supports device claims. Examples include mammography and CAD systems.
According to Dawn Lezzer, head of regulatory affairs and quality assurance for the Americas at Agfa HealthCare (Ridgefield Park, NJ), the vast majority of imaging devices are more complicated than Class I but not as risky as Class III. However, as other manufacturers have discovered, some of these devices involve new technology with which the FDA is not familiar; therefore, they’re categorized as Class III.
Early Birds Get the Approval
Whether a product is Class II or III, a company can benefit by beginning the regulatory approval process early. Many do so at the beginning stages of development. “To prepare for the FDA, we need to determine what other products are approved and out there,” says Kathy O’Shaughnessy, VP of regulatory affairs at R2 Technology Inc (Sunnyvale, Calif). “There is no cookie-cutter approach to getting novel products approved through the FDA.”
Lezzer says that Agfa creates a regulatory plan at the same time as the marketing plan. “The two need to be aligned, because the clearance process can impact how quickly a product can be released,” she says. “It could be that one marketing strategy is less complicated than another, and we might want to consider that approach.”
The name of a product is a simple example. “Does the product name include more than one piece of the product?” Lezzer suggests. “For instance, orthopedic solutions versus OT 3000.”
At Eastman Kodak Co (Rochester, NY), the process also starts early. Wido Menhardt, general manager of the CAD business segment, notes that the clearance process has two components: “One is to make sure that the product is safe and effective internally; the second is to prove to the FDA that the product is safe and effective,” he explains.
The company may meet with the FDA early to determine exactly what proof is needed. “Every product is different, depending on its type and how it might impact the treatment process. The highest levels might need clinical trials while others might just need documentation showing similarity to other products already on the market,” Menhardt says. “Sometimes the requirements change over time, even throughout the approval process, so we stay in contact with the FDA to make sure the necessary evidence is documented.”
The FDA encourages this approach and will be flexible. Menhardt shares that the agency is usually very helpful and often reviews submissions ahead of time to make the process as expeditious as possible. This step is important because, as Lezzer notes, sometimes not having and providing all of the data necessary for an FDA filing can cause delays.
O’Shaughnessy agrees, explaining that R2 Technology likes to work interactively with the agency. In fact, the company used this process with its ImageChecker CAD CT software package, which was just approved in July for use in the United States. (See “News Watch” on page 8 for more information.) “The product was launched last year in Europe, was filed in the United States in April 2003, and went up for advisory panel review in early 2004,” he says.
Terry Sweeney, senior VP of quality and regulatory affairs at Philips Medical Systems (Andover, Mass), describes a similar process. “All development efforts that include additional features or new devices have a team that includes regulatory and quality people,” he says. “They develop a regulatory plan for the project that looks at intended use and for predicate products related to a 510(k). If no such products exist and a PMA is necessary, we develop a plan around that to bring the product to the marketplace as well as a schedule for submissions everywhere in the world.”
Around the World in Varying Days
Typically, a company’s schedule for submissions will include the requirements for the regulatory agencies of all the countries where the product is to be released. Each country has its own process, classifications, and requirements.
Sweeney notes that much planning is needed for a worldwide release. “Every year, countries increase their regulations and develop processes similar to the FDA,” he says. “Recent examples include Canada, Japan, and Argentina. Some, such as Brazil and areas of China, even require [US] FDA approval before granting their own. As a result, more countries than just the United States are experiencing delays now. Simple technologies in some regions can take 6 to 9 months for clearance.”
Europe is one of the easier regions in which to obtain approval. In addition to having different classification systems (Europe employs four classes), each category has different requirements. O’Shaughnessy says, “The FDA looks at previous products in the marketplace while European regulatory agencies consider the product itself. For instance, CAD, being a fairly new technology, is a Class III device in the United States, but a Class I in Europe.”
Tim Capehart, senior regulatory consultant at Siemens Medical Solutions (Malvern, Pa), elaborates on the difference between the United States and European requirements: “The European Medical Device Directive [MDD], requires that a manufacturer have a quality management system and meet the defined essential requirements for a device that would require premarket submission and FDA review in the United States. The level and scope of review of the manufacturer and quality documentation by the notified body in Europe is dependent upon the product classification. Product dossiers for European devices of Class I or II are not routinely reviewed; rather, the company signs a declaration of conformity, affixes the CE mark, and is free to distribute the product.” Only Class III products require clinical evaluation in Europe.
Sweeney adds, “The European system relies on the manufacturer to confirm the safety and efficacy of the device and requires certification on design and manufacturing quality that are reviewed by a third party but are not compared to previous products and are not preapproved for marketing. Companies can put a CE mark on a product themselves.”
Consequently, products get to market much more quickly in Europe, sometimes immediately. By contrast, Sweeney estimates that a 510(k) clearance in the United States takes approximately 90-120 days and the PMA 6 months to 1 year.
Capehart notes that Siemens is often selling a product in Europe while awaiting FDA clearance for marketing in the United States. “With the MDD, regulation of products in Europe is done with relation to distribution of the product, while, in the United States, a company can’t promote or advertise a product prior to obtaining FDA approval or clearance,” he says. In Europe, marketing and sales of the product are not delayed by a premarket product review. The situation can be particularly frustrating for the company’s European counterparts who must contend with significant differences in the timing of product introductions.
Says Don Ellis of worldwide regulatory affairs at Kodak’s Health Imaging Group, “Both the European and US systems are based on the simple premise that regulators need a body of information on safety and effectiveness and that the manufacturer can provide this data. Both systems also have a certain amount of built-in flexibility.”
Ellis believes the systems have additional similarities, even more so than differences, particularly in regard to the future. “The FDA is moving closer to third-party review and has begun working with individual European countries to allow their information to be accepted in the United States. It’s a confidence-building exercise to assure that everyone trusts the others’ process with the ultimate dream state being one global review process.”
Modernizing the FDA
Because we have not achieved Ellis’ “dream state” yet, companies and patients can suffer delays in obtaining the right to use devices in the United States. The FDA is not unaware of the problem and has made efforts to alleviate the waits, the most recent being the Medical Device User Fee and Modernization Act of 2002 (MDUFMA). It amends the FD&C with three particularly significant provisions:
- User fees for premarket reviews;
- Establishment inspections by accredited persons or third parties; and
- New regulatory requirements for reprocessed single-use devices.2
The third-party review has done much to speed the review process for 510(k) devices. Items that require clinical trials and a PMA still must be handled directly by the FDA.
Paul Biggins, senior manager of regulatory affairs at Toshiba America Medical Systems (TAMS of Tustin, Calif), has made positive use of the new system. “The third party must be trained and approved by the FDA and completes the same review that the FDA would. Because third-party reviewers charge user fees, they understand that they must turn documentation around quickly, and often, a review is completed in 1 to 2 weeks.”
However, the third party cannot approve the product. Rather, it submits its review to the FDA, which then gives permission to proceed or asks for more documentation. According to Biggins, this process adds an additional 2 weeks, but even so, what once took months can now take weeks.
Capehart agrees. “Using a third party can cut the review time in half for just an additional few thousand dollars.” He notes that the third-party user fees are normally between $5,000 and $10,000 but can vary widely depending on the type of device and chosen reviewer. “Even so,” Capehart says, “it’s small change when compared to the value of an expedited introduction of a new product or technology.”
Coming to America… or Not
Costs and delays can be factors in deciding to bring a product to market in the United States at all. “Just to get the FDA to review a PMA will cost $200,000,” Capehart says, “and that doesn’t mean the product will be approved.” This fee doesn’t include the money spent on clinical trials and the statistical analysis of data. “Sometimes the market won’t support the cost,” he adds, sharing that there have been products not released in the United States as a result.
Philips’ Sweeney, however, feels that the nation’s market is too large to ignore. “For many, the United States is usually about half of the marketplace,” he says. “Medical utility tends to be greater here.” Therefore, the majority of the company’s products are released in the United States, though some at later dates than abroad.
John Strauss, director of marketing for imaging systems at FUJIFILM Medical Systems USA Inc (FMSU of Stamford, Conn) notes that sometimes the decision to not bring a product into the United States has nothing to do with the FDA. “It could be that the market is not appropriate or that the beta units will be released in the corporate home country-for Fuji, it’s Japan-with a final version introduced in the United States several months later.”
The company decided to wait to obtain approval for its digital mammography product, CR for mammography (CRM). First introduced in 1983, the FDA changed the product’s classification to Class III in the 1990s. Andy Vandergrift, FMSU’s national program manager for women’s healthcare imaging, says that the company decided not to apply for approval then, as it was in the midst of developing a device with higher resolution that would require its own approval. Thus, the Profect CS, as it is known in Asia and Europe, handles general radiography and mammography but was not introduced in the United States until late 2003. Here, the general radiography product is called ClearView CS and was one of the first CR systems to require Class III approval. The product can be upgraded to perform mammography (ClearView CSM), but is awaiting clearance for this specific use.
Sweeney has experienced a different problem in trying to get clearance for use of Philips’ MRI systems in combination with cardiac contrast agents. “The products have been available in Europe for some time, but have been held up in the United States because the FDA isn’t quite sure how to handle them,” he explains. “The questions range from which division of the agency should review them to what data is needed to ensure safety and efficacy.” While Philips and the agency negotiate these points, the cardiac contrast agent clinical applications remain unavailable in the United States.
Issues like these can be frustrating, but everyone is loath to condemn the FDA. As Strauss notes, “Some drugs and devices might take a longer time to be made available here, but the FDA also keeps out the snake oil.”
Renee DiIulio is a contributing writer for Medical Imaging.
References
- US Food and Drug Administration/Center for Drug Evaluation and Research page. Thalidomide Information. Available at: http://www.fda.gov/cder/news/thalinfo/. Accessed July 29, 2004.
- US Food and Drug Administration/Center for Devices and Radiological Health page. Overview of Regulations. Available at: http://www.fda.gov/cdrh/devadvice/overview.html. Accessed July 29, 2004.
