Food and Drug Administration

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Food and Drug Administration

One of the oldest U.S. Consumer Protection agencies, the Food and Drug Administration (FDA) protects the public from unsafe foods, drugs, medical devices, cosmetics, and other potential hazards. As part of the department of health and human services, the FDA annually regulates over $1 trillion worth of products, which account for one-fourth of all consumer spending in the United States. It also protects the rights and safety of patients in clinical trials of new medical products, monitors the promotional activities of drug and device manufacturers, regulates the labeling of all packaged foods, and monitors the safety of the nation's blood supply.

To ensure compliance with its regulations, the FDA employs over 1,000 investigators and inspectors who visit over 15,000 food-processing, drug-manufacturing, and other facilities each year. If it finds violations of law, the FDA first encourages an offending company to voluntarily correct the problem or to recall a faulty product from the market. If the firm does not voluntarily comply with the law, the FDA may take it to court and seek criminal penalties against it. The FDA may also seize faulty products, order product recalls, seek injunctive relief, impose fines, and take other types of enforcement action. Each year, the FDA declares about 3,000 products and 30,000 import shipments to be unacceptable in various ways.

The FDA employs over 2,000 scientists—including 900 chemists and 300 microbiologists—who provide the Scientific Evidence to back up its regulatory and inspection duties. These scientists analyze samples of products for purity and review test results of new products. The FDA itself does not do research for a new medical product. Instead, it evaluates the results of studies undertaken by the manufacturer.

History

Food production in the United States has been regulated since the late eighteenth century. Colonies and, later, states passed laws banning impurities from selected foods. In 1848, the United States began regulating imported drugs, under the Drug Importation Act (Ch. LXX, 9 Stat. 237). The enforcement of food and drug laws was first assigned to the Chemical Division of the new u.s. department of agriculture (USDA) in 1862 (12 Stat. 387).

The need for laws to regulate food and drug purity became increasingly urgent in the late nineteenth century, when substances such as opium, cocaine, and heroin were commonly added to medicinal elixirs and tonics. The need for government regulation was also made evident in Upton Sinclair's book, The Jungle, which exposed the unsanitary conditions of Chicago's meatpacking industry and shocked the nation. On June 30, 1906, Congress, with the support of President Theodore Roosevelt, passed two landmark pieces of Progressive Era legislation that strengthened the government's ability to protect consumers: the Food and Drug Act (34 Stat. 768 [21 U.S.C.A. § 1–15]) and the Meat Inspection Act (21 U.S.C.A. § 601 et seq.). The former prohibited interstate commerce in misbranded and adulterated foods, drinks, and drugs, and the latter addressed the unsanitary conditions and use of poisonous preservatives and dyes in the meatpacking industry.

In 1927, Congress authorized the creation of the Food, Drug, and Insecticide Administration within the U.S. Department of Agriculture. In 1930, the agency's name was changed to the current one, Food and Drug Administration (Agriculture Appropriation Act, 46 Stat. 976).

In 1937, 107 people died after taking the elixir sulfanilamide, a supposedly healing tonic. This tragedy prompted the passage of the next major reform of food and drug law, the Federal Food, Drug, and Cosmetic Act of 1938 (21U.S.C.A. § 301 et seq.). The FDA was then entrusted with the regulation of cosmetics and therapeutic devices and was authorized to do factory inspections. Even more importantly, the act required new drugs to be tested on animals and humans for safety before being marketed. In 1957, the Food Additives Amendment (Pub. L. 85-250, Aug. 31, 1957, Stat. 567) required the evaluation of food additives to establish safety, and in the following year, the Delaney Clause (Pub. L. 85-929, Sept. 6, 1958, 72 Stat. 1784) forbade the use in food of substances found to cause cancer in laboratory animals.

How the FDA Approves New Drugs

The process by which the Food and Drug Administration (FDA) approves drugs as safe and effective is generally long and complicated, though it may vary according to the type of drug and the nature of the illness for which it is being developed. The FDA refers to drugs under development as investigational new drugs, or INDs.

The evaluation of new drugs requires the skills of many different FDA scientists and professionals performing a wide variety of tasks. Biochemists and molecular biologists evaluate the basic chemistry and biology of new chemical compounds and molecular structures. Toxicologists assess the potential harm of proposed drugs, and pharmacologists study how these drugs affect the body and are broken down and absorbed by it. Computer scientists create electronic models that aid in the understanding of new chemicals. Physicians evaluate the results of clinical trials, assessing both the beneficial and adverse effects of the drugs. And statisticians evaluate the design and results of controlled studies.

It is an expensive and time consuming process, particularly for the company developing the drug, called a drug sponsor. A sponsor spends an average of $359 million for each new drug brought to market. Typically, the process takes eight and a half years and may be divided into roughly three stages: preclinical trials, involving animal and other laboratory tests (lasting one and a half years on average); clinical trials, involving tests on humans (five years); and FDA review (two years).

Preclinical Trials Once a sponsor has developed a drug, it must test the drug on animals in the laboratory. In doing so, the drug sponsor must follow FDA guidelines and regulations. These tests, also called preclinical trials, are usually done on more than one species of animals. FDA guidelines call for the inspection of animal laboratories every two years to ensure that they are being operated according to the administration's regulations.

After short-term lab testing has been performed and the sponsor has deemed its results adequate, the sponsor submits test data and plans for future clinical trials to the FDA. FDA scientists, together with a local institutional review board composed of scientists, ethicists, and nonscientists, then conduct a thirty-day safety review to decide whether to allow testing on humans. The vast majority of new drugs tested in the laboratory are rejected by either the sponsor or the FDA because they are unsafe or ineffective.

If the FDA indicates approval, the drug sponsor may begin clinical testing on humans. Even if a drug is approved for clinical trials, the sponsor continues animal testing of the drug in order to better understand the drug's long-term effects.

Clinical Trials Clinical trials are scientifically controlled studies in which the drug being tested is given to one group of patients, while another treatment, often a placebo (an inactive substance that looks like the drug being tested), is given to another group. Ideally, neither group of patients knows which is receiving the new drug and which is receiving the placebo.

The clinical trials, like the animal tests, examine what happens to the drug in the body, including whether it is changed, or metabolized, in the body, how much of it is absorbed into the blood, and how long it remains in the body. If human tests produce unexpected results, researchers may conduct further animal tests to better understand the drug.

Clinical trials proceed in three phases: Phase 1 involves testing primarily for safety and dosage level. Twenty to one hundred healthy patients are assessed over several months. If the results are within FDA safety guidelines, the trials proceed to phase 2.

Phase 2 involves a greater number of patients—up to several hundred—who have the condition that the drug is intended to treat. During this stage, which lasts from several months to two years, researchers attempt to determine the drug's effectiveness in achieving its stated purpose, as well as its safety. At the end of this phase, sponsors meet with FDA officials to discuss the best way to conduct the next phase of testing.

In phase 3, the most crucial stage of testing, the number of patients is expanded still further, to several hundred to several thousand, and the length of the study is increased to one to four years. This phase establishes the correct dosage of the drug and how it will be labeled, and provides further evidence regarding its safety and effectiveness.

Of one hundred drugs submitted for testing in humans, an average of seventy will pass phase 1. Of these seventy, on average, only thirty-three will remain after phase 2 testing, and twenty-five to thirty after phase 3. Finally, an average of only twenty will actually receive FDA approval.

Once the drug sponsor has completed clinical trials, it submits a new drug application (NDA) to the FDA, requesting approval to market the drug. This application consists of documentation detailing the chemical composition of the drug, the design of the trials, the results of the trials, and the means by which the drug is made and packaged.

FDA Review In assessing an NDA, the FDA undertakes its closest scrutiny of all during the drug approval process. Its principal goal during review is to determine whether the benefits of the new drug outweigh the risks. To reach this determination, the FDA examines the documentation provided by the sponsor and looks at samples of the drug.

If inadequacies are discovered in the NDA, the FDA may require additional information, further testing, or modified labeling. In cases where it is difficult to establish clearly whether the benefits of the drug outweigh the risks, a panel of outside experts is often consulted.

If the FDA approves the drug, the sponsor may begin manufacturing and marketing the drug immediately.

The FDA does not stop monitoring a drug once it has been marketed. It continues to evaluate the drug's safety and effectiveness through its program of postmarket surveillance. This program consists of surveys, the testing of product samples, and the analysis of reported adverse reactions.

Speeding Drugs to Those Who Need Them The FDA has longstanding policies allowing what it calls the compassionate use of new drugs for those in desperate need. Innovative cancer treatments, for example, have been made available to patients since the 1970s through the National Cancer Institute.

However, during the 1980s, the FDA came under increasing fire for its slow approval of new drugs. Particularly with the emergence of AIDS during the 1980s, the public outcry for fast delivery of innovative new drugs strengthened. As science produces ever more pharmaceuticals, the FDA is called on to review drug applications as quickly as is reasonably possible.

In response to the growing demand for speedy drug evaluation, the FDA has made significant changes in its review protocols. In 1987, for example, the agency adopted "expanded access" regulations, which permit certain drugs to be designated as treatment INDs. A treatment IND may be administered to patients even while it is still undergoing clinical trials. This program allows patients with no other alternatives to undergo a treatment that may benefit their health. By August 1994, twenty-nine agents had been designated treatment INDs, and by 1995, more than seventy-five thousand patients had received access to new therapies through this program. New drugs used to treat patients with AIDS are made available through a similar process known as the parallel track approach.

Identifying priorities is another method the FDA uses to provide more rapid access to promising new treatments. AIDS drugs, drugs that treat life-threatening or severely debilitating illnesses, and drugs that appear to offer significant improvements over existing therapies are classified as priority drugs and receive faster review than those classified as standard drugs. With priority drugs, the FDA typically becomes involved earlier in the development process, and is thereby able to more quickly review the relevant applications.

Drugs are also classified as to chemical type, so that those closely similar in structure to existing drugs will receive less intensive review than those with a molecular structure that has never been marketed before.

Accelerated approval is another mechanism for faster review of promising new drugs. Under this program, created in 1991, a product may be approved for limited use if it has been shown in trials to achieve particular results—such as lowering blood pressure or cholesterol. Drugs approved under this program include didanosine for AIDS, interferon beta-1B for multiple sclerosis, and DNase for cystic fibrosis.

The Prescription Drug User Fee Act of 1992 (Pub. L. 102-571, Title 1, Oct. 29, 1992, 106 Stat. 4491 to 4500) has also enabled the FDA to speed drug review. Under this law, fees paid by drug manufacturers are used by the agency to hire hundreds of additional review staff and buy improved equipment, including computers that make review more efficient.

The FDA is also attempting to streamline red tape and bureaucracy. In 1995, President bill clinton and Vice President albert gore, Jr., announced that twenty-one separate product license applications used by the FDA would be consolidated into one simplified form. This form would also be available in an electronic format, making it easier to distribute, prepare, and review.

Results indicate that these changes have led to faster approval of important new drugs. One signal success of FDA reform was the prompt approval of taxol, a treatment for advanced ovarian cancer that was approved in December 1992 after a record 5 months. By 1994, all new drugs were being approved by the FDA in a median time of 19 months, and priority drugs with important therapeutic uses were approved in an average of 10.4 months. In the late 1980s, by comparison, the FDA took an average of 27 months to approve new drugs.

In 1995, President Clinton established even more ambitious new goals for FDA approval. These goals, to be met by 1997, require the FDA to approve priority drugs within 6 months and standard drugs within 12 months.

In 1962, the Kefauver-Harris Drug Amendments (Pub. L. 87-781, Oct. 10, 1962, 76 Stat.780) were passed. These laws required drug manufacturers not only to show that their drugs were safe but also to prove that their drugs achieved the effects claimed. That same year, FDA regulations were shown to be effective after the drug thalidomide, for which the FDA had delayed approval, caused thousands of birth defects in western Europe.

In 1979, the FDA was made part of the Department of Health and Human Services (96 Stat. 668, 695). Other laws with major implications for the FDA's activities include the 1990 Nutrition Labeling and Education Act (Pub. L. 101-535, Nov. 8, 1990, 104 Stat. 2353), which requires all packaged foods to carry labels with nutrition information, and the Prescription Drug User Fee Act of 1992 (Pub. L. 102-571, Title 1, Oct. 29, 1992, 106 Stat. 4491 to 4500), which requires drug and biologics manufacturers to pay fees that support FDA assessment of their products.

Effective October 2002, the FDA implemented its National Organic Program (NOP) under the Organic Foods Production Act of 1990 (OFPA), 7 U.S.C. 6501 et. seq. The NOP sets the first national standards for the use of the label term organic on food items and products. Products that qualify as "100 percent organic" under NOP rules may use the "USDA Organic" seal on their principal display panel. The rules specifically prohibit the use of Genetic Engineering methods, ionizing radiation (irradiation), and sewage sludge for fertilization. In addition, all agricultural products that are labeled organic must originate from farms or handling operations that have been certified by a state or private agency accredited by the USDA.

Organization

The FDA carries out its activities through a number of subdivisions. The Center for Drug Evaluation and Research regulates the safety, effectiveness, and labeling of all prescription and over-the-counter drugs intended for human use. It also monitors drug advertising for accuracy, ensures the safety and rights of patients in drug studies, and distributes information on drug products to the medical community and the public.

The Center for Biologics Evaluation and Research regulates biological products, which include blood, vaccines, human tissues, and drugs derived from living organisms. It coordinates an AIDS program, which works to develop an AIDS vaccine and AIDS diagnostic tests. It also conducts research on the safety of blood and blood products and inspects manufacturing plants to ensure compliance with FDA standards.

The Center for Food Safety and Applied Nutrition develops regulations related to food, food additives and colorings, and cosmetics. The Center for Devices and Radiological Health seeks to ensure the safe use of potentially hazardous radiation such as that produced by X rays. It conducts research into the effects of exposure to radiation-producing medical devices and develops manufacturing standards for such devices.

The Center for Veterinary Medicine evaluates the safety of drugs and devices used on animals. The National Center for Toxicological Research assesses the biological effects of toxic chemical substances.

AZT: An Agent of Change for the FDA

Azidothymidine (AZT) is a celebrated example of speedy FDA approval of a new drug. The unusually swift approval of AZT during the early years of the AIDS (Acquired Immune Deficiency Syndrome) epidemic led to the creation of a new FDA category, treatment investigational new drug (treatment IND), that established new procedures for more rapid and flexible drug approval.

The pharmaceutical company Burroughs Wellcome first presented AZT as a new drug to the FDA in June 1985. Public fear of AIDS had increased dramatically during the previous few years, as had protests by AIDS activists who complained of slow FDA movement with regard to promising new treatments. Keenly aware of the need for swift decision making in the face of the deadly AIDS disease, the FDA approved phase 1 clinical trials of the drug within one week of the initial application.

Phase 1 testing of AZT, between July and December 1985, was promising, and phase 2, involving 300 patients in placebo-controlled trials, began in February 1986. After six months, 19 of the 137 patients in the group taking the placebo had died, whereas only 1 of 145 in the group taking AZT had died. The results were encouraging enough for the FDA to forgo further testing. The group taking the placebo was switched to AZT, and phase 3 testing, traditionally the most important step in clinical trials, was deemed unnecessary.

In September 1986, the FDA authorized the treatment of patients who wanted access to AZT, even before it had given approval to the drug. By the time approval for general public use came in March 1987, some 4,000 patients had already been treated with AZT, and thus the drug was already potentially extending the lives of hundreds of people.

Taking an example from its handling of AZT, the FDA in May 1987 created the treatment IND classification to facilitate faster approval and wider distribution of promising new therapies for life-threatening diseases. The rapid approval of AZT also proved greatly encouraging to the pharmaceutical industry, which could now hope to bring AIDS drugs to market much more rapidly and at lower cost.

Cross-references

Acquired Immune Deficiency Syndrome.

Other offices of the FDA include the Office of Policy, the Office of External Affairs, the Office of Management and Systems, the Office of AIDS Coordination, the Office of Orphan Products Development, and the Office of Biotechnology. The administration operates six field offices, 21 district offices, and 135 resident inspection posts throughout the United States and Puerto Rico.

Further readings

Branding, Frederick H. 2003. "Preparing for and Surviving FDA Inspections." Corporate Counsel's Quarterly 19 (January): 28–35.

Burkholz, Herbert. 1994. The FDA Follies. New York: Basic Books.

"Center for Drug Evaluation and Research." 1995. U.S. Food and Drug Administration (March 14). Available online at <www.fda.gov> (accessed March 13, 2003).

Clinton, Bill, and Al Gore. 1995. Reinventing Drug and Medical Device Regulations. National Performance Review series (April). Washington, D.C.: U.S. Government Printing Office.

——. 1995. Reinventing the Regulation of Drugs Made from Biotechnology. National Performance Review series (November). Washington, D.C.: U.S. Government Printing Office.

"FDA Mission Statement: Protect Public Health." 1995. U.S. Food and Drug Administration (March 30). Available online at <www.fda.gov> (accessed March 13, 2003).

Harmon, Daniel E. 2002. The Food and Drug Administration. Philadelphia: Chelsea House Publishers.

"Milestones in U.S. Food and Drug Law History." 1995. U.S. Food and Drug Administration (August). Available online at <www.fda.gov> (accessed March 13, 2003).

Parver, Deborah G. 1999. "Expediting the Drug Approval Process: An Analysis of the FDA Modernization Act of 1997." Administrative Law Review 51 (fall): 1249–66.

U.S. Food and Drug Administration. 1995. FDA Consumer: From Test Tube to Patient: New Drug Development in the United States. 2d ed. Washington, D.C.: U.S. Food and Drug Administration.

U.S. Food and Drug Administration Website. Available online at <www.fda.gov>.

U.S. Government Manual Website. Available online at <www.gpoaccess.gov> (accessed November 10, 2003).

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