FDA Turns 100
From its inception, the Food & Drug Administration has been under siege. The public has always expected more of the agency than could be accomplished with its limited resources. FDA regulates human and animal drugs, biological products, cosmetics, medical and radiation-emitting devices, and all foods except meat and poultry. It currently employs fewer than 0.5% of the nation's 2 million government workers, yet it must regulate products worth 29 cents of every dollar spent in the U.S.
Despite its chronically inadequate resources, the agency has many accomplishments to celebrate during this centennial year. It has grown from a small cadre of chemists called the Bureau of Chemistry, housed in the Agriculture Department, to an agency with about 9,000 employees that is part of the Department of Health & Human Services. Its standards for drug evaluation and approval are arguably the highest in the world. Though there are exceptions, FDA's green light for a prescription drug generally guarantees that the European Union and most other countries will also agree to market it.
In addition, FDA is the most transparent drug agency in the world. No other government body involved in drug approval makes transcripts of its advisory committee deliberations available to the public, according to Arthur Daemmrich, director of the Center for Contemporary History & Policy at the Chemical Heritage Foundation (CHF).
FDA has no time to bask in its limelight, though. For every problem it addresses, another either has cropped up or will soon. In some cases, the agency is hampered by misplaced priorities, weak laws, and insufficient resources.
Some could argue that the agency has also been hampered by problems in leadership. Since the beginning of the George W. Bush Administration nearly six years ago, FDA has had confirmed commissioners for just 18 months, and the current acting commissioner, Andrew C. von Eschenbach, has been waiting 11 months for his confirmation.
Other causes of problems are the outgrowth of relatively new technologies that were not in widespread use or did not exist a few decades ago. And still others result from new understandings of how toxicants and infectious organisms affect human health.
For example, the agency is struggling with how to deal with acrylamide in starchy foods cooked at high temperatures. Acrylamide, a probable carcinogen, has always existed in some foods, such as potato chips and french fries, because it is created when natural starch and proteins are heated (C&EN, Aug. 14, page 43). But before 1970, FDA had no way to detect acrylamide at the parts-per-billion levels existing in food, and even in 2000, it had to refine its techniques to be able to measure acrylamide accurately.
Benzene in soft drinks is a similar issue. Generated by a reaction between citric acid (vitamin C) and the preservative sodium benzoate in the drink at parts-per-billion levels, benzene, a carcinogen, was undetectable at such low levels until a few decades ago. Now, FDA is deliberating over how to respond to this issue (C&EN, April 24, page 10).
FDA is also wrestling with how to prevent people from buying drugs over the Internet without a prescription. This problem could not have been widespread even 10 years ago when the majority of U.S. adults did not have Internet access (C&EN, Nov. 10, 2003, page 36).
Counterfeit drugs have always existed, but today, with the Internet and relatively cheap techniques of producing pills and packages that look exactly like the genuine articles, fake medicines have become a pervasive U.S. and international concern. If a U.S.-based website hawking a counterfeit drug is shut down, a similar site may spring up a few days later in Russia or India, for example.
Throughout its history, FDA has had to deal with adulterated food and drinks, but now that problem crosses international borders via the Internet. For example, in 2002, a California firm began selling nicotine-laced water called NicLite as a substitute for cigarettes. FDA ordered the firm to stop marketing the product, and the company shut down its business. But NicLite is still available on the Internet, shipped from some undisclosed location. A website advertises it as a pure, harmless "organic" noncarcinogenic supplement with a slight hint of lemon.
Even though FDA confronts difficult problems today, they are minuscule compared with what the agency faced at its inception in the early 1900s. The Pure Food & Drug Act of 1906 that created FDA was passed after a long struggle. According to FDA's History Office, the act would not have been enacted at that time without the strong support of President Theodore Roosevelt, who had become convinced that something must be done to curb the sale of dangerous medicines and adulterated and rotten food.
The first national drug law was passed in 1848. It banned the importation of adulterated drugs, a chronic health threat during the 19th century, but it did nothing about adulterated, fake, and dangerous domestic patent medicines (nonprescription drugs of secret composition). Toward the end of the 19th century, food laws also became necessary as vast numbers of rural residents moved to large cities and could no longer grow their own food or have direct contact with the farmers who were raising crops and livestock.
As the population became more urbanized, processed foods came to substitute for fresh produce in the U.S. diet. There were no refrigerated trucks or railroad cars to bring produce to city dwellers. If someone tried to transport fruits and vegetables to the city and the trip took more than a day, the food was usually rotten by the time it arrived. "The use of processed food then was even greater than it is today," Daemmrich said.
Food processing in the late-19th and early-20th centuries involved a great deal of deception. Chemicals were used to heighten color, modify flavor, soften texture, and delay spoilage, according to FDA. Jars labeled strawberry jam often contained no strawberries, only glucose, red food coloring, grass seed, and gelatin. Jars of honey were sometimes diluted with glucose. Rotten eggs were deodorized, rancid butter was revived. "Soothing syrups" for babies were often laced with morphine. "Olive oil" was sometimes made with cottonseed.
States exercised the principal control over domestically produced foods and drugs, but control was inconsistent from state to state. The state laws punished food and drug retailers, but processors and manufacturers were the greater problem. Agricultural chemists who had been trained in Germany worked for some states and informed farmers about fraudulent practices.
The food law that was eventually introduced in Congress in 1881 was based on an 1875 British food law. It would not have gained much support without the efforts of Harvey W. Wiley, a chemist and physician who then headed the Division of Chemistry in the Agriculture Department. (Its name was later changed to the Bureau of Chemistry.)
Wiley carried on a 25-year crusade, forming coalitions among agricultural chemists, state food and drug officials, women's club members, the medical profession, and some journalists. The more legitimate canners who felt they would not be able to compete with firms that were selling fake and adulterated foods also joined the coalition.
The Pure Food & Drug Act, which the FDA's predecessor, the Bureau of Chemistry, was charged to administer, prohibited the interstate transport of unlawful foods and drugs. Unlawful products could be seized and responsible parties prosecuted.
The safe food and drug system created by the law was based on product labeling, not premarket approval. Drugs had to comply with the standards of strength in the U.S. Pharmacopoeia and the National Formulary. They were not subject to FDA approval before they were marketed. In fact, FDA was not unusual in this respect. According to Peter Barton Hutt, senior counsel at the Washington, D.C.-based law firm Covington & Burling and former chief counsel at FDA, no government prior to 1900 "had ever required that an article of commerce first be approved by the government before it could be marketed."
The 1906 law prohibited the sale of filthy or decomposed food and the addition of ingredients, such as sawdust, that would substitute for food or pose a health hazard. Food or drug labels had to list alcohol, heroin, morphine, and cocaine if they were present. The law did not apply to false therapeutic claims unless it could be proven that the manufacturer intended to defraud customers.
Furthermore, the law did not require that the weight or volume of the food or drug be listed on the label. "There was no affirmative requirement to put on anything, anything at all on the label. The law simply prohibited adulteration and misbranding," Hutt said at a conference on FDA's centennial held in May at CHF. In 1913, the Gould amendment was passed; it stipulated "that the net quantity of contents appear on every food package in clear form," he said.
The 1938 Food, Drug & Cosmetic Act filled in many of the loopholes of the 1906 law. It put cosmetics and medical devices under FDA's control. It mandated premarket notifiication for the safety of new drugs and prohibited false therapeutic claims. It required that the name and address of the manufacturer and adequate instructions for use of the drug be included on the label. It was, however, still inadequate in many respects. The Federal Trade Commission retained control over advertising of medicines, for example. To extend FDA's authority under the 1938 law, it has been amended more than 100 times, Hutt said.
In the early-20th century, FDA considered law enforcement one of its primary missions. "In the 1920s, for example, every year FDA would bring between 500 and 1,000 criminal prosecutions of companies," Hutt said. In recent years, there have been about five prosecutions annually. And in the 1920s, FDA carried out 2,000 to 3,000 seizures of unlawful products annually. It now averages about 20 seizures per year, he said. "Can you imagine, with a small agency and a minuscule budget, the amount of work that took and the priority that represented?" he asked.
More recently, one of the major turning points in FDA's evolution was the advent of user fees, which are paid by companies and partially fund FDA's work in processing new drug and device applications. A law for prescription drug user fees was passed in 1992, a law for medical device user fees in 2002, and a law for animal drug user fees in 2003. "FDA now says it needs user fees for generic drugs and for food applications, and indeed there have been proposals to fund all of enforcement activity with user fees," Hutt said.
User fees are highly controversial, however. Peter Lurie, deputy director of Public Citizen's Health Research Advisory Group, told C&EN he believes user fees should be revoked in all areas. Since the advent of user fees, "people at FDA now see the medical device and drug industries as their customers, their partners. That is the wrong posture toward regulated industries," he said. "The industries do not need to be your enemies, but they need to be a group you regard skeptically," he observed. "The right solution is to adequately fund the agency, not keep expanding user fees to new sectors."
But Hutt considers user fees absolutely necessary and a boon to FDA's overall mission. "I do believe that the fear of people that user fees will somehow subvert FDA is completely and totally misplaced," he said at the CHF conference. He claims, however, that user fees can't be used to make up all the deficiencies in the agency's resources. "There is a limit to which you can fund FDA's activities out of user fees. The agency today is being starved to death by the U.S. Congress and by the people of this country," Hutt said.
Even though most developed countries passed drug legislation during the 20th century, "FDA remains the only food and drug regulatory body in the world whose origins lay solely in science," said FDA's historian Suzanne White Junod at the CHF conference. For example, from 1910 to 1930, "standardized methods of lead and arsenic analysis, new knowledge concerning botulism in processed olives, and the discovery of the role of vitamins in human health largely determined and dominated the agency's regulatory agenda," she explained.
In the 1940s, FDA's Division of Pharmacology began to give guidance to industry on toxicological testing applicable to food regulation. In the 1950s, FDA's microbiological work led to a revolution in the way grain was stored. Because of the agency's research, farmers were eventually forced to replace decrepit and decaying storage bins with modern steel silos, she observed. From FDA's earliest days, chemistry has been central to its work.
Experts who spoke after Junod and Hutt at the CHF conference discussed contemporary problems facing FDA. They talked about challenges with prescription drugs. These issues were discussed at length in the June 19 issue of C&EN (page 80).
Since the agency's beginning, food safety has always been a compelling public health problem, Robert E. Brackett, director of FDA's Center for Food Safety & Applied Nutrition (CFSAN), told conference attendees. Despite progress, the problem has not been solved, and food safety poses "many new difficult challenges," he said. Today, "we have almost 80 million cases of food-borne illness every year in this country, resulting in hundreds of thousands of hospitalizations and many deaths," he said.
One new challenge is the potential use of food contamination as a terrorist weapon, Brackett said. "Never before in the history of this country have we had to consider how to prevent intentional, wide-scale massive poisoning of the public," he explained. It presents "new and quite complicated and difficult challenges for not only regulatory agencies but for other public health agencies as well," he explained.
Another new challenge is parasites that previously were problems only in developing countries, Brackett said. People are traveling more, both for business and pleasure, he said. They sometimes bring back parasites that physicians in the U.S. fail to recognize. As a consequence, "once-rare illnesses, such as cyclosporiasis contracted from infected food or water, are becoming endemic in this country." The first U.S. case of cyclosporiasis was reported in 1979, but now the illness is found all over the U.S. and the world.
New knowledge about microorganisms is also changing the way foods are regulated, Brackett said. In the past, scientists believed that all pathogens of a particular variety, such as Escherichia coli, were the same. "Now, we know that different strains of the same organism differ greatly in their virulence," he explained.
Many nontraditional foods that were not commonly eaten in the U.S. until a few decades ago also have been associated with recent outbreaks of food-borne illness, Brackett said. Examples are puffer fish with its naturally occurring toxins, Salmonella-contaminated mangoes, and typhoid-contaminated mamey, a tropical fruit. With rapid and widespread use of air freight, "what may have been picked in southern Mexico this morning may be on somebody's plate in Los Angeles this afternoon," he said.
"Another trend is that more and more foods are prepared outside the home," Brackett said, so preparation is increasingly beyond the consumer's control. And food processing is more centralized than it was in the past. Mistakes made in preparing lettuce in California's Salinas Valley, for example, may cause illness in New England and the Southeast, he said.
FDA has seen many additions to its statutory authority over the past 100 years, Brackett concluded. "Some of the regulations have helped us, but some of them haven't caught up to modern trends in society."
One such trend, for example, is the increasing attention paid to the health effects of food. At the CHF conference, Idamarie Laquatra, director of global nutrition at H. J. Heinz Co., suggested several changes that FDA might make to improve the U.S. diet.
"It might be time for FDA to facilitate the development of a voluntary visual logo that can result in quick and easy decisions for consumers who want to choose foods that help them follow dietary guidelines to reduce the risk of chronic disease," she said. About 80% of people over 65 years of age have at least one chronic condition, and half have at least two, she said. As the population ages, "the burden of chronic disease is going to be magnified."
When FDA issued regulations for a revamped nutrition label in the 1990s, food-service establishments were exempt, Laquatra said. But since Americans are spending about half of every food dollar on meals eaten outside of the home, the idea of requiring nutrition information for restaurants will "probably need to be explored again," she said.
Furthermore, as technology increases the ability to detect substances in food at ever-more-minute levels, she said, the potential exists for unnecessary panic and alarm. It is important for FDA to remain steadfast to the science and establish no-effect thresholds for substances, such as acrylamide, she warned.
Michael F. Jacobson, executive director of the Center for Science in the Public Interest (CSPI), told C&EN that FDA's regulation of food has been highly deficient. With all the attention pharmaceuticals receive because of their potential for saving lives and taking lives, "most FDA commissioners have treated the foods division as an afterthought," he said. In fact, "the diet we eat has a tremendous potential for good."
The two most dangerous ingredients in the food supply are trans fat, from partially hydrogenated vegetable oil, and salt, Jacobson said. FDA considers both ingredients as generally recognized as safe, or GRAS, he explained. Yet, according to experts at the Harvard School of Public Health, trans fat causes 70,000 to 230,000 heart attacks a year, and about 50,000 are fatal, he observed. FDA has finally decided to require trans fat to be placed on nutrition labels, Jacobson said, but it should eliminate trans fat from the U.S. diet.
Another large problem is overconsumption of salt, Jacobson said. The National Heart, Lung & Blood Institute estimates that cutting the salt content of restaurant and packaged foods by 50% would prevent about 150,000 heart attacks and strokes each year. CSPI has sued FDA to make sodium reduction a top priority. Today, not a single agency employee is working on the issue, he said.
Jacobson is also concerned about Salmonella in eggs. In 2004, FDA proposed rules to improve on-farm conditions to prevent contaminated eggs from getting into grocery stores. But the rules have not been finalized.
Quorn, a line of fake meat labeled as comparable to mushrooms, is another dangerous food in the U.S. diet, according to Jacobson. Its basic ingredient is a fungus, called Fusarium venenatum, which is grown in vats. According to a survey conducted in England, 3 to 5% of the population is severely allergic to Quorn. It causes sudden, violent vomiting in most who are allergic and anaphylactic shock in some victims, he explained. Yet FDA refuses to require warnings about allergic reactions on Quorn packages, he said. Experts have said that calling Quorn a mushroom is like calling a rat a chicken, he noted.
Another trend FDA must contend with is the use of dietary supplements. At the CHF conference, Barbara Schneeman, director of CFSAN's Office of Nutritional Products, Labeling & Dietary Supplements, told attendees that dietary supplements present two major challenges: their definition and the nature of the claims that can be made about these products.
Two laws have affected dietary supplements, Schneeman said. One is the 1990 Nutrition, Labeling & Education Act, which made nutrition labeling mandatory on foods and allows for nutrient claims about which there is significant scientific agreement. The second is the 1994 Dietary Supplement, Health & Education Act (DSHEA), which defined dietary supplements and established a new framework for ensuring their safety. It also gave FDA authority to establish Good Manufacturing Practices for dietary supplements.
In DSHEA, supplements are defined as products other than tobacco that contain one or more dietary ingredients and are intended to supplement the diet, Schneeman said. Supplements can be vitamins, minerals, amino acids, herbs, or other botanicals. Before introducing a new supplement, the manufacturer must notify FDA and provide information to establish the safety of the product, she said. But the manufacturer does not have to prove that the supplement is safe or efficacious.
Claims that supplements reduce the risk of certain diseases are allowed in packages under the laws, but claims that a supplement cures disease are not allowed, Schneeman said. The agency will soon publish good manufacturing guidelines for supplements, she observed. However, safety issues with supplements remain unresolved, she said.
"It's becoming more and more important to develop widely accepted analytical methods for identifying pharmacologically relevant components of these dietary ingredients," said Steven Mister, president of the Council for Responsible Nutrition, at the CHF conference. Currently, manufacturers do not have to report adverse events from dietary supplements to FDA. However, Mister said, he, as well as the manufacturers, would like such reporting to be mandatory.
Public Citizen's Lurie has a different view. "Dietary supplements remain essentially unregulated," he told C&EN. "We have no idea what's in them, and it's extremely difficult to get them off the market," he said. "We examined the data for the 13 largest selling dietary supplements, and in each and every case, we concluded there was inadequate data for effectiveness," he explained. "There are no standardized methods of production and no consumer protection in the sense of any assurance of efficacy. It is just the Wild West out there, and all sorts of unscrupulous people are stepping into the field."
FDA has solved many problems since its inception, but the agency still faces serious difficulties in food and drug regulation. The prevailing view is that although the agency's regulatory system is far from perfect, it is challenged, not broken. Speaking at the CHF conference, Ronald Krall, senior vice president and chief medical officer at GlaxoSmithKline, summed up the views of many FDA observers: "If we are not happy with every one of our medicines or with every one of FDA's regulatory decisions, let's be careful that changes we make to the system reap more happiness, not havoc."