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Agreement on industry user fees may force the agency to scale back its intramural program, which critics say is fragmented. Intramural research at the United States Food and Drug Administration (FDA) is coming under increasing financial pressure and criticism. In discussions with FDA officials, pharmaceutical manufacturers have won an agreement that the user fees they pay will soon no longer help fund the agency's research. Since 1992, approximately $10 million annually from industry user fees has gone into FDA's research coffers. The decision to end this practice will result in the loss of dozens of research positions. And while a recent report by an external committee expressed strong support for FDA science, it was also highly critical of the fragmentation and uneven quality of the agency's research effort. CORPORATE BENEFIT: FDA’s Bernard A. Schwetz contends that the agency’s research program provides direct advantages to industry. FDA's intramural program, compared with that of other science-based agencies such as the National Institutes of Health or the Centers for Disease Control and Prevention, consumes a relatively small portion of its budget. Although he is unable to provide an estimate of the dollar amount of FDA's research budget, Bernard A. Schwetz, director of the agency's National Center for Toxicological Research and FDA's associate commissioner for science, says that 20 percent of the agency's 9,500 employees are involved in lab work, and 20 percent of that 20 percent (or 4 percent of the total) are involved in "investigator-initiated" research. FDA's total 1997 budget is $996 million. But few if any FDA scientists spend their time exclusively doing research. Virtually all FDA senior scientists are also "reviewers" who spend up to 50 percent of their time performing research and 50 percent of their time reviewing applications for such things as foods, drugs, cosmetics, and medical devices. The percentage of time these reviewers devote to research varies considerably among FDA's six centers. The lion's share of the FDA's intramural research is conducted at just two of these centers: the Center for Biologics Evaluation and Research (CBER) and the National Center for Toxicological Research (NCTR). LESS PURSUED: FDA research often covers areas that are of little interest to academia or industry, maintains CBER’s Neil Goldman. FDA's research is quite diverse, notes Neil D. Goldman, CBER's associate director for research. "In the vaccine area we will have research on pneumococci, meningococci, mycobacteria, pertussis. . . . We really need to understand the pathogenesis to help us understand the safety and efficacy of the various vaccines." This sort of research may not seem innovative enough to interest scientists in academia, since vaccines for diseases caused by these organisms have already been developed, Goldman points out. Another example is the agency's research on mechanisms of rubella arthropathy-joint disease induced by German measles. "No one on the outside seems to be interested in this," notes Goldman, "and this is a safety issue from our point of view. [It's necessary to] make sure that the vaccine strain is not going to cause an adverse reaction." The pharmaceutical industry has been helping to fund FDA's intramural program since the 1992 passage of the Prescription Drug User Fee Act (PDUFA). The act assessed one-time fees for each new drug application, and annual fees for each manufacturing facility and licensed drug. The "user fees" were intended to allow FDA to hire many more reviewers and thus to speed approval of new drug applications, and it has been largely successful. Pharmaceutical and biotech companies are pleased with PDUFA, although, according to the Washington, D.C.-based Biotechnology Industry Organization (BIO), it cost industry $88 million in the current fiscal year. In fact, industry is so pleased with PDUFA that it has agreed to an increase in user fees of 24 percent over the next five years. But the one thing the industry objects to is the $10 million annually that the user-fee program contributes to intramural research. The industry has reached an agreement with FDA that this $10 million will be phased out over the next five years. However, confirmation of this awaits Congress's expected reauthorization of PDUFA, which was originally scheduled to terminate this September. "BIO prefers that the funds from user fees currently going toward research be channeled into improvements in the application-filing process," remarks Alan R. Goldhammer, BIO's director of technical affairs. "In addition to further increases in the number of reviewers, the industry wishes to move toward fully electronic filings, a change that will require the FDA to acquire new hardware and software." DECENTRALIZED AGENDA: Central control of science at FDA has been unpopular since the '70s, states Stanford's Henry Miller. But some industry observers point out that pharmaceutical companies gain direct and indirect benefit from the intramural research program. "There are three advantages to those who review applications doing cutting-edge research," explains Henry I. Miller, senior research fellow at Stanford University's Hoover Institution and a former longtime employee at FDA, where he held several positions, including director of the office of biotechnology. "First, they're scientifically up-to-date, with respect to the data they see coming in from industry. Second, if they're doing high-quality research, they're contributing to the scientific literature themselves. Third, it is much easier to recruit higher-quality scientific/review personnel into a program where research is a primary component." "It is difficult to fully embrace that argument," replies Goldhammer. "One can look at the review activity for the Center for Drugs, which has a very modest-in fact, one might use the word 'minor'-research program . . . and they seem to do a very good job of reviewing new applications." "I understand the importance of research," asserts John D. Siegfried, deputy vice president for science and regulatory affairs at the Pharmaceutical Research and Manufacturers of America (PhRMA), based in Washington, D.C. "And I understand FDA's argument saying this is the way they attract or retain the best reviewers. But if that's the case, then that case has to be made in terms of their own internal management and be funded with the resources they have. If they can't make that case and sustain it and get funding from their internal resources, I don't see why the industry should cough up the money and say, 'Well, rather than approve drugs, let's support your research agenda because that'll make you happy.'" But FDA officials argue that the agency's research provides other, more direct benefits to industry. According to Schwetz, one example of this was the agency's development of genetic analysis techniques for the rapid detection and identification of bacterial contaminants. Previously, products in which contamination was suspected would be held up for several weeks as FDA and the manufacturer waited for bacteria to grow out in traditional culture media. The new techniques can identify suspected contaminants in just a few hours. FOR MORE INFORMATION FDA maintains a Web site at http://www.fda.gov/. The full text of the Korn committee's report can be found at http://www.fda.gov/cber/research.htm. The Biotechnology Industry Organization (BIO) has a Web site at http://www.bio.org/. BIO's address is 1625 K St., N.W., Suite 1100, Washington, D.C. 20006-1604; (202) 857-0244. FAX: (202) 857-0237. Pharmaceutical Research and Manufacturers of America (PhRMA) has a Web site at http://www.phrma.org/. PhRMA's address is 1100 15th St., N.W., Washington, D.C. 20005; (202) 835-3400. FAX: (202) 785-4834. And Goldman points out that much of the intramural research at CBER can be regarded as facilitating the approval of product licenses. "People who are less knowledgeable tend to be overly cautious," he maintains. "And I think that's what's going to happen over time if money keeps getting tighter and tighter and research gets reduced more and more." As a result of the current reductions, says Goldman, CBER will have to eliminate at least 80 research positions. He fears that if Congress reduces FDA's budget any further, he will have to downsize even more. Still, he points out, "We're firing no one." Some temporary appointments will not be renewed, and some permanent positions will not be refilled once they are vacated by scientists transferring or retiring. It is perhaps ironic that this downsizing is coming on the heels of a report by an external committee, issued just this past March, that emphatically affirmed that FDA's intramural research program is vital to the agency's mission (The Science Board Subcommittee on FDA Research, Recommendations to the Science Board of the Food and Drug Administration, March 13, 1997). CALL FOR REFORM: David Korn’s committee found FDA’s research program is "uneven in quality, mission relevance and efficiency." But the committee, which was headed by David Korn, former dean of the Stanford University School of Medicine and currently a distinguished scholar in residence at the Washington, D.C.- based Association of American Medical Colleges, was also highly critical of the intramural research program. It found that FDA "lacks a culture of science and scientific communication" and that the research program is "uneven in quality, mission relevance and efficiency." The committee laid the blame for that state of affairs on the agency's fragmented organization. A big part of the problem, said the committee, is that the FDA's "centers" are anything but central. There are six centers at FDA, for food and cosmetics, biologics, medical devices, human drugs, veterinary medicine, and toxicology. Each operates with a good deal of autonomy. "I joked in the committee that the agency was like the medieval French kingdom," recalls Korn. "It's really run by the dukes, who are the center directors, who have most of the authority and resources of the agency. At the commissioner's level, which would be the analogy to the medieval French king, there isn't a hell of a lot of reach into the centers." Given FDA's various dukedoms, the committee's principal recommendation was the creation of a "virtual science center" under the leadership of a newly appointed "Chief Scientist of the Food and Drug Administration," who would occupy a position near the top of the agency's hierarchy. "We were not talking about building new buildings and moving people all over the place," Korn points out. "We were talking about gathering together the community of scientists that exists in the agency into a true, interactive, communicative group that would be headed by a very distinguished scientist who would have a very high position in the administration of the agency," with authority over personnel, peer review, and budget decisions, and the power to start, stop, or relocate research programs. But Miller is doubtful that the virtual science center will ever become a reality. "Central control and command of science at the FDA has been unpopular at least since the 1970s," he notes. "The [individual] centers dig in their heels. They don't want any part of anyone looking over their shoulder and critiquing their science. The extra-center site for scientific advice or supervision inevitably becomes marginalized." That's precisely the problem the virtual science center is intended to remedy, replies Korn, who notes that the power of the individual centers is "inimical to the sort of scientific potential that I think can and should be in that agency. It leads to fragmentation and isolation and duplication and unevenness in quality of personnel, quality of program, quality of performance review." "The problem is not one of organization," counters Miller. "The problem is one of absence of commitment to the highest-quality science in much of the FDA." Referring to the central control of science, Miller asserts, "It's a good idea in theory, but it hasn't worked. If there were a commissioner who made better and more consistent science his highest priority, and he spent a great deal of time and energy on that issue . . . , it could make a real difference. But that never happens." Nevertheless, according to Schwetz, "there are pockets of researchers throughout the agency" who are even now forming something like a virtual science center despite the absence of a new FDA commissioner to replace the recently departed David Kessler. "For example, there's a group of neurotoxicologists in the agency who are already organized in this virtual manner. They meet on a regular basis and they talk about problems and resources. We also have the same thing in the immunology group [and with] statisticians." Centralizing intramural research is an idea that has been proposed to FDA many times in the last 40 years. The Korn committee chronicled the history of several attempts to reform FDA science in a fascinating appendix to its report. But why have all these past efforts at reform failed? Korn's committee concluded that "the dominant cause was the persistent dilemma posed by well-intentioned scientific aspirations, a burden of ever increasing regulatory mandates and complexities, and annual budgets that were chronically insufficient to meet the desired objectives." With user-fee money drying up as a source of research funds, FDA may well be forced to scale back its scientific aspirations. But Korn declines to blame the pharmaceutical industry. "The financial duress of the agency is not a fault of the industry," he argues. "It is the fault of an inadequate appropriation. I don't believe it's the industry's obligation to have to support activities within the government that the government is not supporting adequately from its own resources." Robert Finn, a freelance science writer based in Long Beach, Calif., can be reached online at finn@nasw.org.

Research By FDA Scientists Faces Fiscal Setback

Jul 6, 1997

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