Food & Drug Administration Commissioner David A. Kessler and his deputies are fond of calling FDA a science-based regulatory agency. But ask those most familiar with the agency - including those who work for it - what research FDA carries out, and one is likely to be met with blank stares.
Toiling under a persistent image of being a foot-dragging bureaucracy and under constant assault for supposedly engaging in unfocused research, it's surprising that FDA doesn't accentuate he positive - the science undergirding its regulatory successes.
Take tryptophan, for example. Many may remember the 1989 - 90 episode during which at least 1,500 Americans taking the dietary supplement became severely ill and 39 died of a painful muscle and blood disorder dubbed eosinophilia-myalgia syndrome. Few will remember - or may ever even have known of - the chemical sleuthing FDA deployed to trap one possible culprit: 1,1'-ethylidene-bis-l-tryptophan.
Eventually, all health problems were traced to one Japanese manufacturer and those supplements were removed from the market. But FDA never really extolled the chemical prowess it had so swiftly marshaled to protect public health.
And "safeguarding America's health" is how Kessler sums up his agency's mission. It's not mere bluster.By law, FDA regulates products that account for 25 cents of every dollar a consumer spends. The agency must guarantee the purity, safety, and effectiveness of foods and food additives, drugs, and the nation's blood supply. It is responsible for overseeing the safety and efficacy of medical devices, cosmetics, animal drugs and feeds, and radiation-emitting products like microwave ovens.
In fiscal 1996, FDA tried to meet these responsibilities with a staff of about 9,000 and a budget of $905 million. About $160 million of these funds support the work of 3,000 or so scientists, estimates Robert Miller, deputy director of FDA's Office of Financial Management. Numbering more than 1,000, chemists make up the largest single block of scientists at the agency.
Many of FDA's research programs exist to satisfy legislative mandates or support agency regulations. Many address scientific questions that others, especially industry, and maybe even universities, are unable or unwilling to tackle or should not tackle - issues in which FDA has special expertise, industry has no legal obligation, or for which industry data need to be more carefully scrutinized.
The aim of the research is to put FDA on a level playing field with industry in resolving regulatory issues and to provide a scientific basis for agency decisions. It provides independent, FDA-generated data that are key to decision making.
FDA's research programs prepare it for rapid responses to crises - like the tryptophan episode - and also help the agency to deal with problems before they become intractable.
FDA accomplishes these goals, says Bernard A. Schwetz, associate FDA commissioner for science and director of the National Center for Toxicological Research (NCTR), in part through the development of testing methods tailored to the regulatory arena and through the generation of research data. But he also notes that FDA meets its objectives by evaluating products in the lab, developing policy for product reviews, and preparing risk assessments.
No matter how vociferously FDA officials stress the importance of a strong research component, critics remain skeptical. If they are not questioning the need for FDA to be doing research, they can be heard questioning the way FDA does it.
On no issue do critics become more vocal than on the time it takes FDA to approve drugs for marketing. They argue that testing and approvals can be sped up by substituting principles of pharmacodynamics for cumbersome clinical trials - exactly the little publicized work being pursued in a lab at the Center for Drug Evaluation & Research.
Still, most critics recognize that if FDA didn't exist it would have to be invented. Its stamp of approval reassures the public that products are safe. "FDA protects both the public and the companies that produce the regulated products," insists Walter R. Benson, former FDA director of the Division of Drug Chemistry in what was called the National Center for Drugs & Biologics.
Acknowledging the need for FDA has done little, however, to quell the persistent concern of critics and supporters alike that something is wrong at the agency. These concerns led in 1990 to the establishment of an advisory panel to study FDA's shortcomings. Headed by former FDA Commissioner Charles C. Edwards, the panel in 1991 found FDA labs and equipment to be profoundly outdated and its review and research staff overwhelmed by expanding regulatory responsibilities. The agency no longer had the scientific capability to keep pace with "revolutionary advances occurring in the biological and medical sciences," the Edwards panel found.
To correct the situation, the panel urged FDA to "reaffirm its commitment to research as an integral component of its activities." But it cautioned that this research "must be linked to the agency's primary functions."
FDA officials took this advice to heart and proceeded to reform and reorganize the agency. Today, they claim that research is more tightly focused on FDA's regulatory mission than at any time in the past.
Research is conducted across the agency in some unexpected places but especially within its five product centers and NCTR where chemists can be found doing mission-oriented projects.
Although more likely to be applied than basic, this research often is published in peer-reviewed journals. And sometimes while in pursuit of a specific goal, an applied research project uncovers some very basic principles, as has happened at the Center for Biologics Evaluation & Research and the Center for Drug Evaluation & Research.
In 1992, with biotech companies pumping out new products at a frenetic pace and AIDS activists clamoring for new therapeutics for the deadly disease, FDA was taking flak for the slow pace of biotech product approvals. To rectify the situation, Kessler promoted widely respected biochemist Kathryn C. Zoon to be director of the center for biologics. Before this appointment, Zoon, a protein chemist with an avid interest in characterizing the structure and function of interferons, was director of the center's Division of Cytokine Biology.
Zoon: basic research is
essentialDuring her four years as center director, Zoon has received accolades from industry and awards from the government for her managerial expertise. But she is still a bench chemist doing cutting-edge research. Her lab has remained a leader in isolating and characterizing natural interferons.
"Using a variety of affinity chromatography and HPLC [high-pressure liquid chromatography], we were able to isolate 21 different &agr;-interferons," Zoon tells C&EN. After structural characterization, her small research group began studies to answer the question: Do the structural variants have different biological activities? These studies revealed that "Yes ... they exhibit basically different biological fingerprints in their activities."
Moreover, clarifying the mechanisms of action at the molecular level has resulted in the development of new methods to measure potency in interferons and other cytokines reviewed by Zoon's center and the Center for Drug Evaluation & Research.
Her research has since shifted to looking for interferon receptors. Evidence now suggests, she says, "that at the very least there is probably more than one binding site, and it may or may not reflect different receptors. But clearly, there is some heterogeneity in the binding-site epitope," the antigenic determinant.
Today, only a few interferons are licensed. So looking at different interferons may uncover some with biological properties that make them more effective and less toxic - safer medicines, Zoon explains. Her research, then, "is related to our regulatory mission because we are looking at the drug development processes of some of these interferons with respect to their efficacy and safety."
Probing the fundamental mysteries of interleukins and growth factors - basic protein chemistry - teaches Zoon and others about the products the center will ultimately review for marketing. It allows them to evaluate the preclinical safety and effectiveness of DNA vaccines before manufacturers undertake clinical trials. And it helps them develop standards and test methods for DNA vaccines, recombinant DNA cytokines, and other products with brave-new-world-sounding names.
The explosive creativity of bioengineering has unleashed a cornucopia of biotech products: cytokines such as interferons and interleukins, subunit vaccine immunogens, thrombolytics, cellular and gene therapies like recombinant viruses, and polynucleotide (DNA) vaccines. And for these the center has "no codified regulations or long-term experience to draw on," explains Neil D. Goldman, acting associate director for research.
So, Zoon argues, the basic research the center conducts is absolutely "essential for us to do our job and do it well."
Goldman elaborates: "To be able to provide relevant advice and guidance to the manufacturer of a state-of-the-art biotechnology product requires [FDA] researchers/reviewers who have hands-on experience in the areas of concern."
Not all areas of concern involve leading-edge products. The center for biologics' 74 chemists, 16% of its total pool of scientists, also conduct more applied research - from assessing the purity and safety of poison ivy allergens, called urushiols, to quantifying and developing standards for hydroxyethyl starches used as blood-volume expanders.
In contrast to the poor conditions of most FDA labs that the Edwards panel found in 1991, the center for biologics' labs are well equipped and state of the art. But, "over the past year we have taken a fairly big decrease in our operating budget and we anticipate [another decrease] next year," says Zoon. Maintaining modern labs "will be a challenge."
Budget cuts also will affect what areas of research the center chooses to pursue in the future. Given sufficient funding, Zoon would like to further explore tantalizing issues in the areas of DNA vaccines, cellular and gene therapy, and molecular developmental biology - biology and its application to medicine.
DNA vaccines are a very hot research area because they are very cheap to make, very stable, and impart both B-cell- and T-cell-mediated immunity, Goldman explains. But a question about their safety has surfaced: If these vaccines are given, will they induce autoimmune conditions like lupus?
With gene therapy, which uses viruses as transporters of genes into recipient cells, "it's important to be able to look at the kinds of viruses being used" to make certain they are truly defective, nonreplicating viruses, Goldman explains.
All this dictates that FDA conduct in-house research. "Lab research is critical for FDA to accomplish its mission," says Zoon.
FDA's senior science adviser, Elkan R. Blout, also appointed in 1992, couldn't agree more. "I'm arguing for an in-house capability, but I'm not arguing for a very large capability. It needs to be at the cutting edge. And it should be related to the agency's needs and regulatory role."
The agency, Blout says, needs to have people "at the forefront of research" to be able to independently evaluate and pass judgment on products coming to the market in the next few years. These products, he points out, "will be very different from the products of the past 10 or 20 years."
Keeping scientists at the frontiers of science means allowing them to do research and attend meetings where the latest research is discussed, Blout explains. Understanding the latest science and knowing the latest methods for evaluating products will allow FDA scientists to process product approvals quickly without sacrificing safety or quality, he insists.
Richard B. Setlow, associate director for life sciences at Brookhaven National Laboratory, who advises FDA, agrees. In-house research is absolutely necessary, "otherwise FDA scientists would have no feel for the data being presented to them [by industry]. Only someone who works in the lab can understand the nuances of the data. But I don't want everyone at FDA doing lab work," he says.
Conducting and publishing research also "establishes the credibility of its people," contends Schwetz. And he notes, "There are certain things we need to know [at FDA] that nobody else will develop for us."
Blout, an eminent chemist with an illustrious career in both industry and academia, intends to boost FDA's scientific efforts by fostering better links between FDA scientists and researchers in the academic and industrial worlds. To accomplish this, he set up the Science Advisory Board in 1992.
The board "is making a real effort to ensure that the scientific judgments FDA makes are as informed and up-to-date as possible," says board member Robert S. Langer, professor of chemical and biomedical engineering at Massachusetts Institute of Technology.
To that end, the board already has recommended that "FDA reevaluate its approach to toxicity and carcinogenicity testing," says Neil L. Wilcox, one of three staff members in FDA's Office of Science.
Among other things, FDA needs to develop new methods to test toxicity and carcinogenicity of products and to develop standards for new biomaterials, the board insists. Such new, improved methods offer the promise of more pertinent answers arrived at more quickly.
A board subcommittee formed to help the agency develop a process to evaluate its own research recently held its first meeting. But before the subcommittee can accomplish its task, it first has to find out what research FDA does. This is a daunting exercise. When Blout is asked what research FDA conducts, he answers: "The spectrum of research is amazingly wide." When pushed for specifics, he says, "It's a black box."
No one C&EN interviewed seems to know all the research programs under way - not even the Office of Science, which might be expected to be a central repository for this type of information.
"Organizations, as they mature, often become more diverse and, sometimes, more diffuse," Blout offers as an explanation.
Advisory Board Chairman David M. Kipnis, professor of medicine at Washington University School of Medicine, St. Louis, puts it a bit differently: "Any organization has an inertia. But recent changes in organization and the identification of an associate commissioner for science are creating an environment conducive to change and enhanced quality."
Responding to this diffuseness or inertia and intent on ensuring the best possible science, FDA's new deputy commissioner for operations, Michael A. Friedman, asked that the subcommittee be formed. After all, when Friedman must respond to congressional inquiries, he needs to know and understand FDA activities before he can justify and support them.
"I want to be absolutely sure that the quality and relevance of the research is of the very highest caliber," says Friedman. "I want to make sure we are using our scientific resources in the most effective way we can. I'm hoping this committee can help us look critically at ourselves and make those judgments."
Friedman says the issue is not whether, but how a regulatory agency should do science. "The question is not so much how research is integrated into the agency, but how the best scientific judgment and knowledge are integrated into the agency." Agency decisions have to be "grounded in scientific information and should be guided by scientific principles and methodologies," he says.
"It's clear the agency cannot have within it all the requisite science it will need to make the necessary decisions in the future," Friedman says. "Therefore, the agency must have available to it the kinds of scientific skills that will assist in regulation, in product approval, in review, and so forth. How does the agency best do that?"
That question, in short, captures the subcommittee's charge.
The panel will try to sort out what types of relationships can be expanded or forged with sister agencies, with academia, and with industry, asking questions such as: What new relationships need to be explored? Which old relationships need to be expanded? Which ones abandoned?
The subcommittee, chaired by David Korn, a distinguished scholar in residence at the Association of American Medical Colleges, is expected to make its recommendations by the end of the year.
Some type of external peer review is likely to continue. "There certainly will be ongoing peer review of individual labs, and of discipline themes within the agency," Friedman says.
Currently, there is no uniform review procedure at FDA. A few centers have formal review processes with external reviewers. At other centers, managers conduct internal reviews, while still others employ a mix of internal and external reviews.
Some centers do a better job than others of weeding out poor projects or research not related to the agency's needs. At the very least, says Schwetz, the eventual review process that grows out of the subcommittee's work will be "more consistent, with defined minimum standards for evaluating research within FDA."
That will be a definite step forward. Currently, Blout admits, "there is a poor understanding of what science is needed to fit the agency's needs," both among FDA staff and close observers of the agency. If the peer review system "is working right, it will, by itself, suggest new areas for the agency to work in, and provide emphasis for the important areas."
The work of Jerry M. Collins, a chemical engineer in the center for drugs, falls into Blout's category of important areas. Collins, director of the Division of Clinical Pharmacology Research, is applying chemical engineering principles - modeling and thermodynamics - to biomedical problems.
Collins: combine development,
regulationCollins takes slight umbrage at the suggestion that as a chemical engineer he's an odd bird in FDA's center for drugs. He says, "FDA actually has a large need for chemical engineers in the product manufacturing and quality control areas." And they can contribute to solutions to problems in food processing and biomaterials and, even conceptually, "to some areas in veterinary medicine when dealing with tiny animals to huge creatures."
For his work, Collins uses his training in thermodynamics, analytical chemistry, and chemical reaction engineering to "solve very interesting problems in drug development with a policy spin in terms of guidelines and guidance development to industry."
He modestly describes his work as "measuring the concentration of drugs in biological systems" using the "tools of HPLC, gas chromatography [GC], and mass spectrometry [MS] to determine either the concentration of a parent drug or its metabolites." Others cite his work as a possible solution to getting drugs through the approval pipeline more rapidly and cheaply.
Recently, Collins' lab has shifted its focus to studies on drug-drug interactions, a concern of patients taking more than one drug. Collins is screening in vitro a large number of potentially interacting drugs to narrow the number "we have to worry about in vivo."
His screening is not large scale. Rather, he has "set up a program to evaluate the tools of screening." As he explains, "Instead of a packed-bed reactor, we are looking at liver homogenates as an in vitro screening tool to predict potential drug-drug interactions in people."
Industrial and academic labs are doing similar work, but Collins' lab concentrates on the niches not filled by these other labs. Academic labs may try to discover the enzyme metabolizing a drug. "We're more interested in saying, 'Okay, this drug is metabolized a particular way, what are the other drugs that are metabolized that way? How does that translate into potential interactions? How can patients and prescribers and drug developers use that information?'" Collins explains.
Industry fixes on developing particular products. Collins says: "We are focusing more on the principles that cut across a wide range of products. ... The unique part here is the focus on translating and pushing these results in the direction of guidelines for how to develop and use drugs."
The work in Collins' lab is applied research. "We are very focused on the interaction of drug development and regulation," he says.
Occasionally, however, applied blurs into basic research, as it did during Collins' studies on the anticancer drug taxol. "Our lab identified the enzyme that metabolizes taxol in humans" - cytochrome P450, subtype 2Ca. This is the first time this enzyme has been linked to the metabolism of a human drug.
Certainly, Collins admits, "that was basic research, but that wasn't the goal of the research." He adds, "Even though it's always fun to be the first [to identify] an enzyme, our focus immediately shifts to, 'Okay, this enzyme doesn't seem to be related to any other drug that's used. Do we have to worry about any particular interaction? Do we change the way we study drug interactions in patients?'
"Our main role is demonstrating technology," Collins explains. If he could use his lab-developed tools in what he calls "real-life drug development situations" he might be able to more directly demonstrate the benefits of the tools. He lists some potential benefits: shorter drug development times, fewer surprises in terms of adverse drug-drug interactions, lower overall costs. All the "things that industry is vitally concerned about," he says.
So, if Collins had more money, he would like to get involved in collaborative clinical studies. To be able to extend his in vitro studies to patient studies - to figure out ways to use fewer patients in clinical trials - "would be most exciting," Collins says.
Collins is not likely to get additional funds for his wish-list research. His 10-person lab - eight chemists, biochemists, and chemical engineers and two pharmacologists - has an operating and salary budget of about $1 million per year. "It's a serious amount of money," he says, but he doesn't expect it to increase next year.
His lab is well equipped, comparable to the best academic lab and almost as good as an industry lab. But he has no equipment budget this year. And if FDA suspends equipment budgets for five years, as it did in the early 1980s, his state-of-the-art lab is "clearly going to fall behind."
In addition to its work on drug metabolism studies, Collins' "lab staff serves as a consultant internally to the [center's] review staff," he explains.
Sometimes reviewers reach an impasse during their assessment of an industry application to take a new drug through clinical trials or to gain approval for marketing. At this point, Collins' lab will be asked to do preliminary studies to decide if additional safety information is needed. If it is determined that none is needed, the application can move forward. Otherwise, the drug sponsor will be asked to supply the additional data.
Another lab, which normally supplies general analytical support to the center for drugs, became, in effect, consultants to FDA Commissioner Kessler on the matter of nicotine in tobacco products. Kessler is considering regulating nicotine as a drug.
The testing and applied lab, headed by Thomas P. Layloff, who is renowned for his analytical expertise, conducted studies to determine the nicotine content and release characteristics of various cigarette brands. That work is mostly completed, but Layloff's lab is still looking at a few related areas. Funding for these tobacco studies comes from discretionary resources.
Layloff says the change of pace was intellectually stimulating. "The staff thought it was exciting and refreshing. Before they worked on pharmaceuticals. Now they were asked to work on tobacco leaves and stems."
Normally, Layloff's 45 chemists, located in St. Louis and Laurel, Md., are busy "checking methods of quality control submitted by companies, and certifying manufacturers of insulin and digoxin," explains Layloff.
The majority of the lab's work is driven by the new drug approval process. A minor portion is propelled by compliance issues. But the lab also develops and perfects techniques - like new "shoot through the bottle" reflectance near-infrared spectroscopy - that address FDA and industry needs.
Although most of the lab's work is applied research, it does "do some minor basic research through contracts with universities," Layloff notes. For example, his lab has conducted studies on the interaction of molecules with the stationary phase in chromatography.
Also with a university, Layloff's lab is exploiting the computer's ability to sort out arrays of data and recognize patterns. Such fingerprinting, as it is called, may be able to help industry detect counterfeit products and regulators detect deviations from approved products.
Layloff says his $2.5 million-per-year operation is "well equipped to do what we do routinely." It's not equipped to do nuclear magnetic resonance or mass spectroscopic work. The lab contracts out for these services.
The lab, like nearly all labs at FDA, has experienced budget cuts. But funding for absolutely essential work - that associated with drug approval - has actually increased, Layloff says.
The cuts, however, have meant curtailment of some research: Raman spectroscopy, correlation studies on spectroscopic data, and photostability testing. Still Layloff maintains, "Even working in a regulated environment allows for intellectual growth. We do a lot of challenging things."
And these challenging things are usually in the realm of research that permits FDA to make better regulatory decisions. "I would hope," says Schwetz, "that what FDA is doing is cutting-edge research in the area of applied questions."
Schwetz: tests tailored to
regulatory arenaAnother part of FDA doing demanding research is NCTR in Jefferson, Ark., which Schwetz has directed since 1993. The center is unique within the FDA umbrella. It is one of the agency's few divisions with no mandate to review products. Prior to Schwetz's tenure, the center did basic research that the Edwards panel said was generally not targeted to agency needs.
There was a reason for this, traceable to the center's origins. In 1971, President Nixon transformed the Army's Pine Bluff Arsenal biological warfare labs into cancer research labs, supported by FDA and the Environmental Protection Agency. But when EPA established its own research labs, it stopped supporting NCTR.
Today, the center is funded wholly by FDA. And over the past few years, NCTR has been restructured to focus its research more tightly on FDA's regulatory mission. Says Schwetz, "There is no doubt the [ongoing] research is much more closely aligned with specific FDA questions than it probably ever has been."
According to its current mission statement, NCTR is to "develop information that will support FDA regulatory needs." And at least 50% of ongoing studies "are direct collaborations with other FDA scientists in the product centers," Schwetz says.
About 25% of the center's $40 million research budget is slotted for analytical chemical studies, with the remainder devoted to studies of a biological nature. The 40 or so chemists at the center ply their skills to develop analytical methods to support FDA field surveillance activities and to verify the purity of materials used in the center's toxicological studies.
The Office of Regulatory Affairs, like NCTR, does not review products. With responsibilities involving surveillance and enforcement, it is "the front line of FDA that reaches out to industry, the consumer, and academia," says Richard A. Baldwin, director of its Division of Field Science.
Baldwin: manning FDA's front
lineBaldwin's division now consists of 18 regulatory labs, whose main function is to analyze samples of products FDA regulates, and five research centers - scattered across the U.S. These research centers develop or improve analytical test methods that are then transferred to the regulatory labs for use in routine analyses.
A sampling of projects under way in the research centers includes chiral chromatography of drug compounds, analysis of ephedrine derivatives in herbal products, and use of mass spectrometric selected ion monitoring to screen for organonitrogen pesticides. The ephedrine study is especially relevant in light of the recent death of a college student in Florida caused by ingesting the herbal supplement ma huang.
FDA plans to modernize and consolidate the 18 regulatory labs and replace them with five scientific centers and four specialized labs. Existing personnel are not expected to lose their jobs because of the consolidations, but they will have to move to new locations.
Modernization is necessary because the regulatory labs have not been able to keep pace with advances in technology. Most of the equipment is rapidly becoming outdated, and increased staffing to meet regulatory needs has caused overcrowding in some labs.
Although his labs are scattered across the U.S., Baldwin is located at FDA's headquarters in Rockville, Md. "I'm the field's presence at headquarters, a broker for getting the resources we need," he explains. He's also there "to remind people that we have certain capabilities."
But his presence at headquarters has not protected Baldwin's division from budget cuts. These cuts mean he doesn't "have the resources to explore cutting-edge technologies" that may have application to his programs, he says.
Intuitively, having lots of chemists performing analyses in field labs makes sense. However, finding chemists in the Center for Devices & Radiological Health seems a bit of a stretch. But there are 14 there - about 11% of all the center's scientists. Most are scattered throughout the center, but a concentrated pocket is involved in a small program in the Division of Mechanics & Materials Science.
"The center for devices is not a powerhouse for chemistry," says physical chemist LeRoy W. Schroeder, chief of the materials chemistry group, which was formed in 1990. As Schroeder explains, chemical stability, not chemical action, has been the hallmark of a medical device.
This is likely to change in the future as implantable devices begin to be made from a combination of materials and begin to look more like "biopolymers" that interact with cells. Take vascular grafts, for example. Here, the surface of the polymer could be coated with polypeptide sequences to promote better adhesion.
Also, until fairly recently there didn't seem to be much of a need for a chemical group in the center. It was not widely recognized that material breakdown leading to device failure could be traced to a chemical action, not simply a fracture.
Over the past six years, Schroeder's group of seven chemists and two engineers has centered its activities on polymer chemistry and technology. The reason is simple: Polymers are increasingly found in medical devices.
Additives in the polymers eventually leach and affect the biocompatibility and toxicology of the polymeric materials. So Schroeder's lab concentrates on polymer stability and degradation - what the body does to the device.
Other parts of the center study "what the materials do to the body. In other words, toxicology," says Elizabeth D. Jacobson, the center's deputy director for science. Jacobson, a microbial geneticist, oversees the efforts of the Office of Science & Technology, where all the center's labs are housed.
Jacobson: applying good
scienceSeveral years ago, a manufacturer made a polyester-urethane-foam-covered silicone breast implant. There was concern that the foam would continually degrade in the body and release suspected carcinogens 2,4- and 2,6-toluene diamine.
The literature was ambivalent, so Schroeder's lab did some testing and found that the foam did slowly degrade. As a result, an expert panel was convened and eventually the company withdrew the product voluntarily. FDA also required that the company do a postmarket surveillance of the more than 100,000 women who had received the implant.
With HPLC and GC/MS, the materials chemistry lab is "pretty well equipped to do what's required. We don't have a [tandem] MS/MS, but if we needed one we could collaborate with other FDA centers that do," Schroeder explains. And with a Fourier-transform infrared spectrometer (FTIR), "we're better equipped for looking at polymers than other parts of the center or the agency," he adds.
Schroeder's group also acts as consultants to other parts of the center. With its FTIR expertise, Schroeder's lab has helped the center's Office of Device Evaluation develop safety and efficacy data guidance for manufacturers of silicone breast implants.
In addition to helping to generate guidance documents, the lab helps develop national and international voluntary standards. For example, the group has been participating in an interlab comparison of analytical methods for determining residual ethylene oxide in sterilized medical devices.
Research in his lab is applied; that is, "directed to obtaining knowledge for specific regulatory problems," Schroeder explains. But his group, like all labs at the center, is charged with doing what he calls proactive research. Falling into the proactive category is a study on the effect of gas plasma sterilization on biodegradable polymers like polylactides. The lab found no significant effect.
What Schroeder calls proactive, Jacobson calls anticipatory research. By whichever name, the aim is to "look down the road" to try to discern "the problems that are going to be hitting us in five years," Jacobson explains.
Quite a few years back, Jacobson's scientists decided they were going to need to know about neural nets - a type of data processing done by computers that tries to mimic the way the nervous system processes information. "So we invested some resources in that area and we are beginning to see people coming in with applications," she says.
Most of the center's research, however, is "targeted toward specific questions that are here and now," Jacobson says. In fact, she says, "a lot of that can even be called testing rather than research."
Still, the Office of Science & Technology does some unexpected research in the area of radiation biology. One study is designed to ferret out the effects of ultraviolet radiation on the human immunodeficiency virus (HIV), which causes AIDS. The center "regulates things like sun tanning booths," Jacobson explains, "which people don't think of when they think of FDA."
Jacobson is responsible for seeing that her labs turn out good science, and "for applying good science to the kinds of regulatory issues that come up - wherever they come up in the center. I just can't conceive of how the agency could get along without having a credible research capability," she says.
If the center for devices has a relatively small chemistry presence, chemistry and chemists are pervasive in the Center for Food Safety & Applied Nutrition. There are about 100 bench chemists and biochemists at that center, and a number of chemical scientists review new product applications there.
"Most of the center's work is directed toward developing methods that can be used by our field laboratories," explains organic chemist Albert E. Pohland, the center's strategic manager for research.
Pohland: develop methods for
field labsAnalytical methods are constantly being developed to measure unwanted substances in foods such as natural contaminants like mycotoxins and saxitoxin, heavy metals, and pesticide residues. A lot of time and effort go into studies on economic adulteration - like fake orange juice, and into the development of test kits for Escherichia coli and Salmonella enteritidis that can be used to monitor the quality of products along a production line.
Chemists also play an important role in the center's more biologically oriented projects. They synthesize compounds that are incorporated into probes used to detect microbiological contaminants. And they produce the pure materials needed for toxicological studies, explains Pohland, who is also acting director for the Division of Toxicological Research.
In addition to internal studies, chemists in the center collaborate with colleagues in the regulatory labs of the Office of Regulatory Affairs. Samples collected by these field labs are sometimes sent to the center for independent confirmation of results, or when there is a particular problem with the sample that the field staff can't handle.
Again, most of the center's research is applied, the nature of the beast when the mission is to keep the food supply safe. But, Pohland asks, when chemists isolate and then identify a contaminant of unknown structure, as they did in the tryptophan crisis in 1990, is that applied or basic research?
Isolation of a putative toxic impurity in the dietary supplement l-tryptophan occurred in the labs of Samuel W. Page, who is director of the Division of Natural Food Products. One of his analytical chemists, Mary W. Trucksess, developed the HPLC method that was widely used by FDA and other organizations to screen for 1,1'-ethylidene-bis-l-tryptophan, an impurity associated with eosinophilia-myalgia syndrome.
The problems associated with food are enormous and expanding. One example: Changes in the technology of food processing are elevating the level of microbial contamination of foods. Another example: More food products are being imported. For lack of resources, FDA "is not testing as much of the [imported] foods for pesticide residues" as is necessary, insists Thomas J. Hartman, manager of the MS lab at Rutgers Center for Advanced Food Technology.
One reason is that Congress has not given FDA the resources that some like Hartman say it needs to keep apace of the problems.
Some claim that lack of resources has hobbled the Center for Food Safety's labs. But the quality of labs varies greatly. The MS labs are well equipped, while the gas and liquid chromatography labs are only adequate. Those that do nuclear magnetic resonance and infrared spectroscopy are not well equipped at all.
Others claim constricted resources have affected technical staffing more than the labs. "The center is badly understaffed," says one observer who asks not to be named. Staffing for the research side of the center has been getting smaller because the demands on the regulatory side are getting larger, he claims.
"If you consider all the problems that are popping up with respect to foods, I don't think you can ever have an excess of resources to put into research," this observer says.
That is especially true if all the new types of food products coming on the market are taken into account. How, for example, asks Blout, should an agency like FDA handle something like the fat substitute olestra?
FDA examined data on olestra over a long period before it approved the product. Yet even now, not all questions have been answered.
Some nutrition researchers have real concerns that olestra will soak up certain vitamins and, if used in quantity over a number of years, will lead to some disease states. "Now how does the agency evaluate that sort of concern?" he asks.
The easy answer is to deny approval, but that is neither realistic nor practical, Blout says. How then "does the agency make sure that, if approval is given, there is a more than reasonable chance that it will be completely safe?" Research and more research, he implies.
Industry is quick to circumscribe that research. "Any research done ought to be focused on regulatory issues," and not on fundamental research problems, says John D. Siegfried, associate vice president for medical affairs at the Pharmaceutical Research & Manufacturers Association. The group is actively lobbying Congress for legislation to reform FDA.
Former FDA general counsel Peter Barton Hutt, now a lobbyist for the drug industry, agrees. "I feel FDA ought to have the capacity to do applied research that is directly relevant to its statutory mission. I do not believe it should do basic research," he says.
As Gerald F. Meyer, former deputy director in FDA's Division of Drugs, points out, "Research on the whole is pretty good at FDA. With the exception of biologics, it is not research in pursuit of new knowledge but research oriented to the regulatory responsibilities of each center.
"Criticism comes mostly from people who don't know what FDA does," Meyer contends.
So, today, there is almost no consensus on the type of research that FDA should be doing, let alone whether it should be doing more research. But there is a growing realization that industry needs FDA because the agency is industry's credibility. And FDA's credibility rests on its scientific expertise.
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