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Sidebar: In Vitro Diagnostics (IVD) industry -- more information Manufacturers of devices that test fluids or tissues outside the body say the agency's excessively high standard hinders innovation. Photo: Feit's Photography MAJOR BLOW: National Medical Device Coalition’s Wayne Barlow says delays in FDA approval devastate small companies. The in vitro diagnostics (IVD) industry has long been frustrated by lengthy delays in the United States Food and Drug Administration (FDA) product-approval process. Small, entrepreneurial companies whose researchers have developed innovative IVD products are particularly hard-hit by such delays, agency critics contend. While many in the industry agree that the situation seems to have improved within the last year or two, others are clearly dissatisfied, charging that the agency's policies are stifling innovation and keeping valuable products off the market in the U.S. Further improvements may have to wait until Congress enacts a package of comprehensive FDA reforms. IVDs include all devices that test body fluids or tissues to detect, diagnose, and manage medical conditions. They range from the automated clinical chemistry analyzers used in hospitals to simple home pregnancy tests. According to the Washington, D.C.-based Health Industry Manufacturers Association (HIMA), in 1995 the total value of the U.S. IVD industry's products was $8.9 billion. Regulation of the industry began with the passage of the 1976 Medical Device Amendments to the Federal Food, Drug, and Cosmetic Act. In this legislation, IVDs were lumped together with implantable devices such as cardiac pacemakers. The categorization has been a cause of consternation for industry ever since. "In vitro diagnostics are products that are used outside the body," explains Carolyn Jones, HIMA's director of technology and regulatory affairs. "From our perspective, they don't pose the same risk as an implantable device. But FDA holds them to a standard that's similar to some of those implantable devices." But in 1994 congressional testimony, FDA commissioner David A. Kessler insisted that "the cornerstone of the 1976 device law is the concept of regulation based on risk," and went on to explain that the agency divides medical devices into three classes. Class I devices present the least risk and are subject to the fewest controls; Class II devices carry intermediate risk and are subject to moderate controls; and Class III devices, which include "many implanted and life-supporting and life-sustaining devices," according to Kessler's testimony, "are subject to more stringent controls and requirements, including a comprehensive pre-market review." According to the 1976 legislation, manufacturers must submit all IVD devices and reagents to FDA for review before they are allowed to sell them. Products take one of two pathways through the agency: the 510(K) process (named for a section of the law), or the pre-market approval (PMA) process. FACTORS FOR SPEED: FDA’s Steven Gutman notes that quality of applications and experience have contributed to the decrease in approval times. "A 510(K) is essentially for a new version of an old device, and a PMA is for a fundamentally new device," explains Steven Gutman, director of FDA's Division of Clinical Laboratory Devices. "And the way we decide . . . depends on traceability to a product which was in the marketplace at the time the law was passed in 1976. The bottom-line rubric of both is to assure safety and effectiveness, but for a 510(K) what you're trying to establish is that the product is substantially equivalent to the old device, so we want it to be as safe and effective as the old device. For a new device, you are trying to establish de novo that the product is safe and effective." But all IVDs for which the FDA requires PMAs are automatically assigned to Class III even if they are not "life-supporting and life-sustaining." Under the 1976 law, FDA had 90 days to consider a 510(K) and 180 days to consider a PMA. If manufacturers had not heard from FDA by the end of those "statutory limits," they were allowed to put their devices on the market. But the Safe Medical Devices Act of 1990 and the Medical Devices Amendments of 1992 changed that. The statutory limits remained the same under the new rules, but manufacturers had to wait for approval from FDA before they could start selling their devices in the U.S. FDA soon found itself with a large backlog of applications, and actual approval times soared far beyond the statutory limits. According to FDA's own figures, by fiscal year 1994, manufacturers were waiting an average of 216 days for 510(K) approvals and an astounding 823 days for PMA approvals. (This includes periods when the applications were on hold while FDA waited for manufacturers to respond to queries or to submit amendments.) These delays are devastating to many companies in the IVD industry, maintains Wayne K. Barlow, president and CEO of Wescor Inc., a Logan, Utah, IVD manufacturer. "Ninety-eight percent of the medical device manufacturers registered with the FDA are in fact small businesses," states Barlow, who is also president of the Washington, D.C.-based National Medical Device Coalition. "Sixty percent of those firms have fewer than 20 employees. So in the device industry what you have is a very diverse collection of highly innovative, highly entrepreneurial companies...that are very limited in capital, and are dependent on getting a product to market in order to survive." Moreover, the application process can be baffling, IVD manufacturers contend. In 1985, for example, Wescor submitted a 510(K) for a device used to analyze sweat in diagnosing cystic fibrosis. Barlow, who by that time was highly experienced in dealing with FDA, expected the application to sail through. "We ended up spending nearly two years trying to get this product on the marketplace," he recalls. "It was one of the most frustrating things I've ever had to deal with in my business career. "They treated this 510(K) as though it were a PMA," Barlow continues. "We were required to go out and obtain clinical tests. Now, I was aware that the FDA had the right to call for clinical trials in a 510(K) if it was relevant to the question of substantial equivalence. But it seemed to me that the FDA was requiring us to duplicate medical research that had already been carried out in the 1950s [on the connection between cystic fibrosis and the composition of sweat]. And when I tried to ask the question, 'Where's the relevance? Why are you requiring this?,' I could never get an answer. They refused to allow me to come to Washington to talk to them about it. They refused to answer my written and oral queries." Thomas P. Mac Mahon tells a similar story. Now chairman and CEO of Laboratory Corporation of America Inc., based in Burlington, N.C., Mac Mahon was formerly president of the Roche Diagnostics Group of Branchburg, N.J., one of the world's largest IVD manufacturers and a subsidiary of Basel, Switzerland-based Hoffmann-La Roche Inc. Roche wanted to market a device for the diagnosis of tuberculosis (TB) based on polymerase chain reaction (PCR) technology. "The agency had specific guidelines that indicated it was a 510(K)," Mac Mahon recalls. "When we were about to submit they changed the rules, and that set us back a significant period of time. Their reasoning was that this was basically a new technology, and in re-looking at the whole issue of polymerase chain reaction that they felt this was a technological breakthrough and therefore it should have been treated like a PMA." By the time the TB device was finally approved for sale in the U.S. in November 1996, it had been sold in Europe for more than two years. An FDA spokeswoman declined to answer questions about the approval process for specific products, including the Roche TB device. MARKED COOPERATION: The application process is now "more of a partnership than it is a police state," says Beckman president John Wareham. Despite such stories, things seem to be improving. Total average review times for 510(K)s fell to 145 days in FY1996, although PMA times improved only modestly-to 786 days. Some industry members have noticed other improvements, but there is skepticism about whether they will continue. FDA commissioner Kessler recently submitted his resignation (S. Benowitz, The Scientist, Jan. 6, 1997, page 1), and significant change in the agency will likely depend on the priorities of the new commissioner or on congressional action. "The FDA has gone through cycles as companies have gone through cycles," remarks John P. Wareham. president and chief operating officer of Beckman Instruments Inc., based in Fullerton, Calif. "What I can say is that we are in a cycle where things are getting better....I think there's been great improvements not only with the processing of applications-which still isn't within the statutory limits, but much improved-but also philosophically. It's more of a partnership than it is a police state." "I'm glad to hear he believes that," says FDA's Gutman. "We've tried hard to foster that reality." Gutman says that there are many factors involved in the decrease in application-processing time. "Part of it has to do with experience both on our part and on the part of the people submitting. We are more savvy, and I think that the average person submitting an application probably is more sophisticated than three or four or five years ago. I think we have a little bit larger and better-trained work force." But he notes that "the single most important determinant of how fast the product goes through here is the quality of the submission. A good submission that's based on good science [and] good statistics, that's written in good English [and is] understandable, goes through here very rapidly." For more information about the In Vitro Diagnostics (IVD) industry, contact: Health Industry Manufacturers Association 1200 G St., N.W., Suite 400 Washington, D.C. 20005-3814 (202) 783-8700 ¤ Fax: (202) 783-8750 hima@himanet.com ¤ http://www.himanet.com National Medical Device Coalition c/o Medical Device Manufacturers Association 1900 K St., N.W., Suite 300 Washington, D.C. 20006 (202) 496-7150 ¤ Fax: (202) 496-7756 The Food and Drug Administration's Center for Devices and Radiologic Health, which administers IVD regulations, has a Web site at

In Vitro Diagnostics Firms Frustrated By FDA Delays

Mar 2, 1997

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