Food and Drug Administration

"FDA" redirects here. For other uses, see FDA (disambiguation).

Food and Drug Administration
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FDA Logo
Agency overview
Formed	1906
Preceding agencies	Food, Drug, and Insecticide Administration (July 1927 to July 1930) Bureau of Chemistry, USDA (July 1901 through July 1927) Division of Chemistry, USDA (Established 1862)
Jurisdiction	Federal government of the United States
Headquarters	10903 New Hampshire Ave, Silver Spring, MD 20903
Employees	9,300 (2008)
Annual budget	$2.3 billion (2008)
Agency executive	Margaret A. Hamburg, Commissioner of Food and Drugs
Parent agency	Department of Health and Human Services
Website
fda.gov

The Food and Drug Administration (FDA or USFDA) is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments, responsible for protecting and promoting public health through the regulation and supervision of food safety, tobacco products, dietary supplements, prescription and over-the-counter pharmaceutical drugs (medications), vaccines, biopharmaceuticals, blood transfusions, medical devices, electromagnetic radiation emitting devices (ERED), veterinary products, and cosmetics.

The FDA also enforces other laws, notably Section 361 of the Public Health Service Act and associated regulations, many of which are not directly related to food or drugs. These include sanitation requirements on interstate travel and control of disease on products ranging from certain household pets to sperm donation for assisted reproduction.

The FDA is led by a Commissioner of Food and Drugs, appointed by the President with the advice and consent of the Senate. The Commissioner reports to the Secretary of Health and Human Services. The 21st and current Commissioner is Dr. Margaret A. Hamburg. She has served as Commissioner since February 2009.

The FDA has its headquarters at Silver Spring, Maryland and has 223 field offices and 13 laboratories located throughout the 50 states, the United States Virgin Islands, and Puerto Rico. In 2008 the FDA started opening offices in foreign countries, including China, India, Costa Rica, Chile, Belgium, and the United Kingdom.

Organization

The FDA comprises several offices and centers. There are

• Office of the Commissioner

• Center for Biologics Evaluation and Research

• Center for Devices and Radiological Health (CDRH)
  • Office of the Center Director
  • Office of Communication, Education, and Radiation Programs
  • Office of Compliance
  • Office of Device Evaluation
  • Office of In Vitro Diagnostic Device Evaluation and Safety
  • Office of Management Operations
  • Office of Science and Engineering Laboratories
  • Office of Surveillance and Biometrics

• Center for Drug Evaluation and Research (CDER)
  • Office of the Center Director
    • Advisory Committee Staff
    • Controlled Substance Staff
  • Office of Compliance
    • Division of Compliance Risk Management and Surveillance
    • Division of Manufacturing and Product Quality
    • Division of New Drugs and Labeling Compliance
    • Division of Scientific Investigations
  • Office of Medical Policy
    • Division of Drug Marketing, Advertising and Communications8
  • Office of New Drugs
  • Office of Nonprescription Products
  • Office of Oncology Drug Products
    • Radioactive Drug Research Committee (RDRC) Program
  • Office of Pharmaceutical Science
    • Office of Biotechnology Products
    • Office of Generic Drugs
    • Office of New Drug Quality Assessment
    • Office of Testing and Research
      • Division of Applied Pharmacology Research
      • Division of Pharmaceutical Analysis
      • Division of Product Quality Research
        • Informatics and Computational Safety Analysis Staff (ICSAS)
  • Office of Surveillance and Epidemiology (formerly Office of Drug Safety)
  • Office of Translational Sciences23
    • Office of Biostatistics
    • Office of Clinical Pharmacology
      • Pharmacometrics Staff
  • Division of Drug Information
    • FDA Pharmacy Student Experiential Program
  • Botanical Review Team
  • Maternal Health Team

• Center for Food Safety and Applied Nutrition
• Center for Tobacco Products
• Center for Veterinary Medicine
• National Center for Toxicological Research
• Office of Regulatory Affairs

In recent years the agency began undertaking a large-scale effort to consolidate its operations in the Washington Metropolitan Area from its main headquarters in Rockville and several fragmented office buildings in the vicinity to the former site of the Naval Ordnance Laboratory in the White Oak area of Silver Spring, Maryland. When the FDA arrived, the site was renamed from the White Oak Naval Surface Warfare Center to the Federal Research Center at White Oak. The first building, the Life Sciences Laboratory, was dedicated and opened with 104 employees on the campus in December 2003. The project is slated to be completed by 2013.

While most of the Centers are located around the Washington, D.C., area as part of the Headquarters divisions, two offices - the Office of Regulatory Affairs (ORA) and the Office of Criminal Investigations (OCI) - are primarily field offices with a workforce spread across the country.

The Office of Regulatory Affairs is considered the "eyes and ears" of the agency, conducting the vast majority of the FDA's work in the field. Consumer Safety Officers, more commonly called Investigators, are the individuals who inspect production and warehousing facilities, investigate complaints, illnesses, or outbreaks, and review documentation in the case of medical devices, drugs, biological products, and other items where it may be difficult to conduct a physical examination or take a physical sample of the product. The Office of Regulatory Affairs is divided into five regions, which are further divided into 13 districts. Districts are based roughly on the geographic divisions of the federal court system. Each district comprises a main district office, and a number of Resident Posts, which are FDA offices located away from the district office to serve a particular geographic area. ORA also includes the Agency's network of laboratories, which analyze any physical samples taken. Though samples are usually food-related, some laboratories are equipped to analyze drugs, cosmetics, and radiation-emitting devices.

The Office of Criminal Investigations was established in 1991 to investigate criminal cases. Unlike ORA Investigators, OCI Special Agents are armed, and are not focused on the technical aspects of the regulated industries. OCI agents pursue and develop cases where criminal actions have occurred, such as fraudulent claims, or knowingly and willfully shipping known adulterated goods in interstate commerce. In many cases, OCI will pursue cases where Title 18 violations have occurred (e.g. conspiracy, false statements, wire fraud, mail fraud), in addition to prohibited acts as defined in Chapter III of the FD&C Act. OCI Special Agents often come from other criminal investigations backgrounds, and work closely with the Federal Bureau of Investigation, Assistant Attorney General, and even Interpol. OCI will receive cases from a variety of sources, including ORA, local agencies, and the FBI, and will work with ORA investigators to help develop the technical and science-based aspects of a case. OCI is a smaller branch, comprising of about 200 agents nationwide.

The FDA frequently works in conjunction with other federal agencies including the Department of Agriculture, Drug Enforcement Administration, Customs and Border Protection, and Consumer Product Safety Commission. Often local and state government agencies also work in cooperation with the FDA to provide regulatory inspections and enforcement action.

Scope and funding

The FDA regulates more than $1 trillion worth of consumer goods, about 25% of consumer expenditures in the United States. This includes $466 billion in food sales, $275 billion in drugs, $60 billion in cosmetics and $18 billion in vitamin supplements. Much of the expenditures is for goods imported into the United States; the FDA is responsible for monitoring a third of all imports.

The FDA's federal budget request for fiscal year (FY) 2008 (October 2007 through September 2008) totaled $2.1 billion, a $105.8 million increase from what it received for fiscal year 2007. In February 2008, the FDA announced that the Bush Administration's FY 2009 budget request for the agency was just under $2.4 billion: $1.77 billion in budget authority (federal funding) and $628 million in user fees. The requested budget authority was an increase of $50.7 million more than the FY 2008 funding - about a three percent increase. In June 2008, Congress gave the agency an emergency appropriation of $150 million for FY 2008 and another $150 million for FY 2009.

Legal authority

Most federal laws concerning the FDA are part of the Food, Drug and Cosmetic Act, (first passed in 1938 and extensively amended since) and are codified in Title 21, Chapter 9 of the United States Code. Other significant laws enforced by the FDA include the Public Health Service Act, parts of the Controlled Substances Act, the Federal Anti-Tampering Act, as well as many others. In many cases these responsibilities are shared with other federal agencies.

Important enabling legislation for the FDA includes:

• 1902 – Biologics Control Act
• 1906 – Pure Food and Drug Act
• 1938 – Federal Food, Drug, and Cosmetic Act
• 1944 – Public Health Service Act
• 1951 – 1951 Food, Drug, and Cosmetics Act Amendments PL 82–215
• 1962 – 1962 Food, Drug, and Cosmetics Act Amendments PL 87–781
• 1966 – Fair Packaging and Labeling Act PL 89–755
• 1976 – Medical Device Regulation Act PL 94–295
• 1987 – Prescription Drug Marketing Act
• 1988 – Anti–drug Abuse Act PL 100–690
• 1990 – Nutrition Labeling and Education Act PL 101–535
• 1992 – Prescription Drug User Fee Act PL 102–571
• 1994 – Dietary Supplement Health and Education Act
• 1997 – Food and Drug Administration Modernization Act 105-115
• 2002 – Bioterrorism Act 107-188
• 2002 – Medical Device User Fee and Modernization Act (MDUFMA) PL 107-250
• 2003 – Animal Drug User Fee Act PL 108-130
• 2007 – Food and Drug Administration Amendments Act of 2007
• 2009 – Family Smoking Prevention and Tobacco Control Act

Regulatory programs

The programs for safety regulation vary widely by the type of product, its potential risks, and the regulatory powers granted to the agency. For example, the FDA regulates almost every facet of prescription drugs, including testing, manufacturing, labeling, advertising, marketing, efficacy and safety, yet FDA regulation of cosmetics is focused primarily on labeling and safety. The FDA regulates most products with a set of published standards enforced by a modest number of facility inspections. Inspection observations are documented on Form 483.

Food and dietary supplements

Main article: Regulation of food and dietary supplements by the U.S. Food and Drug Administration

The Center for Food Safety and Applied Nutrition is the branch of the FDA which is responsible for ensuring the safety and accurate labeling of nearly all food products in the United States. One exception is meat products derived from traditional domesticated animals, such as cattle and chickens, which fall under the jurisdiction of the United States Department of Agriculture Food Safety and Inspection Service. Products which contain minimal amounts of meat are regulated by FDA, and the exact boundaries are listed in a memorandum of understanding between the two agencies. However, medicines and other products given to all domesticated animals are regulated by the FDA through a different branch, the Center for Veterinary Medicine. Other consumables which are not regulated by the FDA include beverages containing more than 7% alcohol (regulated by the Bureau of Alcohol, Tobacco, Firearms and Explosives in the Department of Justice), and non-bottled drinking water (regulated by the United States Environmental Protection Agency (EPA)).

CFSAN's activities include establishing and maintaining food standards, such as standards of identity (for example, what the requirements are for a product to be labeled, "yogurt") and standards of maximum acceptable contamination. CFSAN also sets the requirements for nutrition labeling of most foods. Both food standards and nutrition labeling requirements are part of the Code of Federal Regulations.

The Dietary Supplement Health and Education Act of 1994 mandated that the FDA regulate dietary supplements as foods, rather than as drugs. Therefore, dietary supplements are not subject to safety and efficacy testing and there are no approval requirements. The FDA can take action against dietary supplements only after they are proven to be unsafe. Manufacturers of dietary supplements are permitted to make specific claims of health benefits, referred to as "structure or function claims" on the labels of these products. They may not claim to treat, diagnose, cure, or prevent disease and must include a disclaimer on the label.

Bottled water is regulated in America by the FDA. State governments also regulate bottled water. Tap water is regulated by state and local regulations, as well as the United States EPA. FDA regulations of bottled water generally follow the guidelines established by the EPA, and new EPA rules automatically apply to bottled water if the FDA does not release an explicit new rule.

Drugs

Regulation of therapeutic goods in the United States

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Prescription drugs Over-the-counter drugs Law Federal Food, Drug, and Cosmetic Act Comprehensive Drug Abuse Prevention and Control Act of 1970 Controlled Substances Act Prescription Drug Marketing Act Drug Price Competition and Patent Term Restoration Act Hatch-Waxman exemption Government agencies United States Department of Health and Human Services Food and Drug Administration Drug Enforcement Administration Center for Drug Evaluation and Research Process Drug discovery Drug design Drug development New drug application Investigational new drug Clinical trial (Phase I, II, III, IV) Randomized controlled trial Pharmacovigilance Abbreviated New Drug Application Fast track approval Off-label use International coordination International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use Uppsala Monitoring Centre World Health Organization Council for International Organizations of Medical Sciences Single Convention on Narcotic Drugs Non-governmental organizations. Institute of Medicine Research on Adverse Drug events And Reports

The Center for Drug Evaluation and Research has different requirements for the three main types of drug products: new drugs, generic drugs and over-the-counter drugs. A drug is considered "new" if it is made by a different manufacturer, uses different excipients or inactive ingredients, is used for a different purpose, or undergoes any substantial change. The most rigorous requirements apply to "new molecular entities": drugs which are not based on existing medications.

New drugs

New drugs receive extensive scrutiny before FDA approval in a process called a New Drug Application or NDA. New drugs are available only by prescription by default. A change to Over the Counter (OTC) status is a separate process and the drug must be approved through an NDA first. A drug that is approved is said to be "safe and effective when used as directed."

Advertising and promotion

The FDA reviews and regulates prescription drug advertising and promotion. (Other kinds of advertising, including for over-the- counter drugs, are regulated by the Federal Trade Commission). The drug advertising regulation contains two key requirements. Under most circumstances, a company may only advertise a drug for the specific indication or medical use for which it was approved. Also, an advertisement must contain "fair balance" between the benefits and risks of a drug.

The term "off-label" refers to drug usage for indications other than those approved by the FDA.

Post market safety surveillance

After approval of an NDA, the sponsor must review and report to the FDA every patient adverse drug experience of which it learns. Unexpected serious and fatal adverse drug events must be reported within 15 days; other events on a quarterly basis. The FDA also receives directly adverse drug event reports through its MedWatch program. These reports are called '"spontaneous reports" because reporting by consumers and health professionals is voluntary. While this remains the primary tool of postmarket safety surveillance, FDA requirements for postmarketing risk management are increasing. As a condition of approval, a sponsor may be required to conduct additional clinical trials, called Phase IV trials. In some cases the FDA requires risk management plans for some drugs that may provide for other kinds of studies, restrictions, or safety surveillance activities.

Generic drugs

Generic drugs are chemical equivalents of name-brand drugs whose patents have expired. Generally they are less expensive than their name brand counterparts, are manufactured and marketed by other companies and, in the 1990s, accounted for about a third of all prescriptions written in the United States. For approval of a generic drug, the U.S. Food and Drug Administration (FDA) requires scientific evidence that the generic drug is interchangeable or therapeutically equivalent with the originally approved drug. This is called an "ANDA" (Abbreviated New Drug Application).

Generic drug scandal

In 1989 a major scandal erupted involving the procedures used by the FDA to approve generic drugs for sale to the public. Charges of corruption in generic drug approval first emerged in 1988, in the course of an extensive congressional investigation into the FDA. The oversight subcommitee of the United States House Energy and Commerce Committee resulted from a complaint brought against the FDA by Mylan Laboratories Inc. of Pittsburgh. When its application to manufacture generics were subjected to repeated delays by the FDA, Mylan, convinced that it was being discriminated against, began its own private investigation of the agency in 1987. Mylan eventually filled suit against two former FDA employees and four drug-manufacturing companies, charging that corruption within the federal agency resulted in racketeering and in violations of antitrust law. "The order in which new generic drugs were approved was set by the FDA employees even before drug manufacturers submitted applications" and according to Mylan this illegal procedure was followed to give preferential treatment to certain companies. During the summer of 1989 three FDA officials pleaded guilty to criminal charges of accepting bribes from generic drugs makers and two companies pleaded guilty to giving bribes. Furthermore, it was discovered that several manufacturers had falsified data submitted in seeking FDA authorization to market certain generic drugs. Vitarine Pharmaceuticals of New York, which sought approval of a generic version of the drug Dyazide, a medication for high blood pressure, submitted Dyazide, rather than its generic version, for the FDA tests. In April 1989 the FDA investigated 11 manufacturers for irregularities; and later brought that number up to 13. Dozens of drugs were eventually suspended or recalled by manufacturers. In the early 1990s the U.S. Securities and Exchange Commission filed "securities fraud charges against the Bolar Pharmaceutical Company, a major generic manufacturer based in Long Island, New York.

Over-the-counter drugs

Over-the-counter (OTC) drugs are drugs and combinations that do not require a doctor's prescription. The FDA has a list of approximately 800 approved ingredients that are combined in various ways to create more than 100,000 OTC drug products. Many OTC drug ingredients had been previously approved prescription drugs now deemed safe enough for use without a medical practitioner's supervision.

Vaccines, blood and tissue products, and biotechnology

The Center for Biologics Evaluation and Research is the branch of the FDA responsible for ensuring the safety and efficacy of biological therapeutic agents. These include blood and blood products, vaccines, allergenics, cell and tissue-based products, and gene therapy products. New biologics are required to go through a pre-market approval process similar to that for drugs. The original authority for government regulation of biological products was established by the 1902 Biologics Control Act, with additional authority established by the 1944 Public Health Service Act. Along with these Acts, the Federal Food, Drug, and Cosmetic Act applies to all biologic products as well. Originally, the entity responsible for regulation of biological products resided under the National Institutes of Health; this authority was transferred to the FDA in 1972.

Medical and radiation-emitting devices

The Center for Devices and Radiological Health (CDRH) is the branch of the FDA responsible for the premarket approval of all medical devices, as well as overseeing the manufacturing, performance and safety of these devices. The definition of a medical device is given in the FD&C Act, and it includes products from the simple toothbrush to complex devices such as implantable brain pacemakers. CDRH also oversees the safety performance of non-medical devices which emit certain types of electromagnetic radiation. Examples of CDRH-regulated devices include cellular phones, airport baggage screening equipment, television receivers, microwave ovens, tanning booths, and laser products.

CDRH regulatory powers include the authority to require certain technical reports from the manufacturers or importers of regulated products, to require that radiation-emitting products meet mandatory safety performance standards, to declare regulated products defective, and to order the recall of defective or noncompliant products. CDRH also conducts limited amounts of direct product testing.

Cosmetics

Cosmetics are regulated by the Center for Food Safety and Applied Nutrition, the same branch of the FDA that regulates food. Cosmetic products are not generally subject to pre-market approval by the FDA unless they make "structure or function claims" which make them into drugs (see Cosmeceutical). However, all color additives must be specifically approved by the FDA before they can be included in cosmetic products sold in the U.S. The labeling of cosmetics is regulated by the FDA, and cosmetics which have not been subjected to thorough safety testing must bear a warning to that effect.

Cosmetic products

Though the cosmetic industry is predominantly responsible in ensuring the safety of its products, the FDA also has the power to intervene when necessary to protect the public but does not generally require pre-market approval or testing. Companies are required to place a warning note on their products if they have not been tested. Experts in cosmetic ingredient reviews also play a role in monitoring safety through influence on the use of ingredients, but also lack legal authority. Overall the organization has reviewed about 1,200 ingredients and has suggested that several hundred be restricted, but there is no standard or systemic method for reviewing chemicals for safety and a clear definition of what is meant by ‘safety’ so that all chemicals are tested on the same basis.

Veterinary products

The Center for Veterinary Medicine (CVM) is the branch of the FDA which regulates food, food additives, and drugs that are given to animals, including food animals and pets. CVM does not regulate vaccines for animals; these are handled by the United States Department of Agriculture.

CVM's primary focus is on medications that are used in food animals and ensuring that they do not affect the human food supply. The FDA's requirements to prevent the spread of bovine spongiform encephalopathy are also administered by CVM through inspections of feed manufacturers.

History

Early history

Origins of federal food and drug regulation

Up until the 20th century, there were few federal laws regulating the contents and sale of domestically produced food and pharmaceuticals, with one exception being the short-lived Vaccine Act of 1813. A patchwork of state laws provided varying degrees of protection against unethical sales practices, such as misrepresenting the ingredients of food products or therapeutic substances. The history of the FDA can be traced to the latter part of the 19th century and the U.S. Department of Agriculture's Division of Chemistry (later Bureau of Chemistry). Under Harvey Washington Wiley, appointed chief chemist in 1883, the Division began conducting research into the adulteration and misbranding of food and drugs on the American market. Although they had no regulatory powers, the Division published its findings from 1887 to 1902 in a ten-part series entitled Foods and Food Adulterants. Wiley used these findings, and alliances with diverse organizations such as state regulators, the General Federation of Women's Clubs, and national associations of physicians and pharmacists, to lobby for a new federal law to set uniform standards for food and drugs to enter into interstate commerce. Wiley's advocacy came at a time when the public had become aroused to hazards in the marketplace by muckraking journalists like Upton Sinclair, and became part of a general trend for increased federal regulations in matters pertinent to public safety during the Progressive Era. The 1902 Biologics Control Act was put in place after diphtheria antitoxin was collected from a horse named Jim who contracted tetanus, resulting in several deaths.

The 1906 Food and Drug Act and creation of the FDA

In June 1906, President Theodore Roosevelt signed into law the Food and Drug Act, also known as the "Wiley Act" after its chief advocate. The Act prohibited, under penalty of seizure of goods, the interstate transport of food which had been "adulterated", with that term referring to the addition of fillers of reduced "quality or strength", coloring to conceal "damage or inferiority," formulation with additives "injurious to health," or the use of "filthy, decomposed, or putrid" substances. The act applied similar penalties to the interstate marketing of "adulterated" drugs, in which the "standard of strength, quality, or purity" of the active ingredient was not either stated clearly on the label or listed in the United States Pharmacopoeia or the National Formulary. The act also banned "misbranding" of food and drugs. The responsibility for examining food and drugs for such "adulteration" or "misbranding" was given to Wiley's USDA Bureau of Chemistry.

Wiley used these new regulatory powers to pursue an aggressive campaign against the manufacturers of foods with chemical additives, but the Chemistry Bureau's authority was soon checked by judicial decisions, as well as by the creation of the Board of Food and Drug Inspection and the Referee Board of Consulting Scientific Experts as separate organizations within the USDA in 1907 and 1908 respectively. A 1911 Supreme Court decision ruled that the 1906 act did not apply to false claims of therapeutic efficacy, in response to which a 1912 amendment added "false and fraudulent" claims of "curative or therapeutic effect" to the Act's definition of "misbranded." However, these powers continued to be narrowly defined by the courts, which set high standards for proof of fraudulent intent. In 1927, the Bureau of Chemistry's regulatory powers were reorganized under a new USDA body, the Food, Drug, and Insecticide organization. This name was shortened to the Food and Drug Administration (FDA) three years later.

The 1938 Food, Drug, and Cosmetic Act

By the 1930s, muckraking journalists, consumer protection organizations, and federal regulators began mounting a campaign for stronger regulatory authority by publicizing a list of injurious products which had been ruled permissible under the 1906 law, including radioactive beverages, cosmetics which caused blindness, and worthless "cures" for diabetes and tuberculosis. The resulting proposed law was unable to get through the Congress of the United States for five years, but was rapidly enacted into law following the public outcry over the 1937 Elixir Sulfanilamide tragedy, in which over 100 people died after using a drug formulated with a toxic, untested solvent. The only way that the FDA could even seize the product was due to a misbranding problem: an "Elixir" was defined as a medication dissolved in ethanol, not the diethylene glycol used in the Elixir Sulfanilamide.

President Franklin Delano Roosevelt signed the new Food, Drug, and Cosmetic Act (FD&C Act) into law on June 24, 1938. The new law significantly increased federal regulatory authority over drugs by mandating a pre-market review of the safety of all new drugs, as well as banning false therapeutic claims in drug labeling without requiring that the FDA prove fraudulent intent. The law also authorized factory inspections and expanded enforcement powers, set new regulatory standards for foods, and brought cosmetics and therapeutic devices under federal regulatory authority. This law, though extensively amended in subsequent years, remains the central foundation of FDA regulatory authority to the present day.

Regulation of human drugs and medical devices after 1938

Early FD&C Act amendments: 1938-1958

Soon after passage of the 1938 Act, the FDA began to designate certain drugs as safe for use only under the supervision of a medical professional, and the category of "prescription-only" drugs was securely codified into law by the 1951 Durham-Humphrey Amendment. While pre-market testing of drug efficacy was not authorized under the 1938 FD&C Act, subsequent amendments such as the Insulin Amendment and Penicillin Amendment did mandate potency testing for formulations of specific lifesaving pharmaceuticals. The FDA began enforcing its new powers against drug manufacturers who could not substantiate the efficacy claims made for their drugs, and the United States Court of Appeals for the Ninth Circuit ruling in Alberty Food Products Co. v. United States (1950) found that drug manufacturers could not evade the "false therapeutic claims" provision of the 1938 act by simply omitting the intended use of a drug from the drug's label. These developments confirmed extensive powers for the FDA to enforce post-marketing recalls of ineffective drugs. Much of the FDA's regulatory attentions in this era were directed towards abuse of amphetamines and barbiturates, but the agency also reviewed some 13,000 new drug applications between 1938 and 1962. While the science of toxicology was in its infancy at the start of this era, rapid advances in experimental assays for food additive and drug safety testing were made during this period by FDA regulators and others.

Expansion of premarket approval process: 1959-1985

In 1959, Senator Estes Kefauver began holding congressional hearings into concerns about pharmaceutical industry practices, such as the perceived high cost and uncertain efficacy of many drugs promoted by manufacturers. There was significant opposition, however, to calls for a new law expanding the FDA's authority. This climate was rapidly changed by the thalidomide tragedy, in which thousands of European babies were born deformed after their mothers took that drug - marketed for treatment of nausea - during their pregnancies. Thalidomide had not been approved for use in the U.S. due to the concerns of an FDA reviewer, Frances Oldham Kelsey. However, thousands of "trial samples" had been sent to American doctors during the "clinical investigation" phase of the drug's development, which at the time was entirely unregulated by the FDA. Individual members of Congress cited the thalidomide incident in lending their support to expansion of FDA authority.

The 1962 Kefauver-Harris Amendment to the FD&C act represented a "revolution" in FDA regulatory authority. The most important change was the requirement that all new drug applications demonstrate "substantial evidence" of the drug's efficacy for a marketed indication, in addition to the existing requirement for pre-marketing demonstration of safety. This marked the start of the FDA approval process in its modern form. Drugs approved between 1938 and 1962 were also subject to FDA review of their efficacy, and to potential withdrawal from the market. Other important provisions of the 1962 amendments included the requirement that drug companies use the "established" or "generic" name of a drug along with the trade name, the restriction of drug advertising to FDA-approved indications, and expansion of FDA powers to inspect drug manufacturing facilities.

These reforms had the effect of increasing the time required to bring a drug to market. In the mid-1970s, 13 of the 14 drugs the FDA saw as most important to approve were on the market in other countries before the United States.

One of the most important statutes in establishing the modern American pharmaceutical market was the 1984 Drug Price Competition and Patent Term Restoration Act, more commonly known as the "Hatch-Waxman Act" after its chief sponsors. This act was intended to correct two unfortunate interactions between the new regulations mandated by the 1962 amendments, and existing patent law (which is not regulated or enforced by the FDA, but rather by the United States Patent and Trademark Office). Because the additional clinical trials mandated by the 1962 amendments significantly delayed the marketing of new drugs, without extending the duration of the manufacturer's patent, "pioneer" drug manufacturers experienced a decreased period of lucrative market exclusivity. On the other hand, the new regulations could be interpreted to require complete safety and efficacy testing for generic copies of approved drugs, and "pioneer" manufacturers obtained court decisions which prevented generic manufacturers from even beginning the clinical trial process while a drug was still under patent. The Hatch-Waxman Act was intended as a compromise between the "pioneer" and generic drug manufacturers which would reduce the overall cost of bringing generics to market and thus, it was hoped, reduce the long-term price of the drug, while preserving the overall profitability of developing new drugs.

The act extended the patent exclusivity terms of new drugs, and importantly tied those extensions, in part, to the length of the FDA approval process for each individual drug. For generic manufacturers, the Act created a new approval mechanism, the Abbreviated New Drug Application (ANDA), in which the generic drug manufacturer need only demonstrate that their generic formulation has the same active ingredient, route of administration, dosage form, strength, and pharmacokinetic properties ("bioequivalence") as the corresponding brand-name drug. This act has been credited with essentially creating the modern generic drug industry.

FDA reforms in the AIDS era

Concerns about the length of the drug approval process were brought to the fore early in the AIDS epidemic. In the mid- and late 1980s, ACT-UP and other HIV activist organizations accused the FDA of unnecessarily delaying the approval of medications to fight HIV and opportunistic infections, and staged large protests, such as a confrontational October 11, 1988 action at the FDA campus which resulted in nearly 180 arrests. In August 1990, Dr. Louis Lasagna, then chairman of a presidential advisory panel on drug approval, estimated that thousands of lives were lost each year due to delays in approval and marketing of drugs for cancer and AIDS.

Partly in response to these criticisms, the FDA issued new rules to expedite approval of drugs for life threatening diseases, and expanded pre-approval access to drugs for patients with limited treatment options. The first of these new rules was the "IND exemption" or "treatment IND" rule, which allowed expanded access to a drug undergoing phase II or III trials (or in extraordinary cases even earlier) if it potentially represented a safer or better alternative to treatments currently available for terminal or serious illness. A second new rule, the "parallel track policy", allowed a drug company to set up a mechanism for access to a new potentially lifesaving drug by patients who for various reasons would be unable to participate in ongoing clinical trials. The "parallel track" designation could be made at the time of IND submission. The accelerated approval rules were further expanded and codified in 1992.

All of the initial drugs approved for the treatment of HIV/AIDS were approved through accelerated approval mechanisms. For example, a "treatment IND" was issued for the first HIV drug, AZT, in 1985, and approval was granted just two years later in 1987. Three of the first five drugs targeting HIV were approved in the United States before they were approved in any other country.

Challenges to FDA authority by states

In two instances, state governments have sought to legalize drugs which have not been approved by the FDA. Because federal law passed pursuant to Constitutional authority overrules conflicting state laws, federal authorities still claim the authority to seize, arrest, and prosecute for possession and sales of these substances, even in states where they are legal under state law.

The first wave was the legalization by 27 states of laetrile in the late 1970s. This drug was used as a treatment for cancer, but scientific studies both before and after this legislative trend found it to be ineffective. Federal law enforcement prevented interstate shipment, making the drug infeasible to manufacture and sell. Further studies based on a Mexican formulation also showed no effectiveness in treating cancer, but did find that some patients experienced symptoms of cyanide poisoning. Though the political movement died out in the 1980s, FDA enforcement actions against laetrile purveyors continued into the 2000s.

The second wave concerned medical marijuana in the 1990s and 2000s. Though Virginia passed a law with limited effect in 1979, a more widespread trend began in California in 1996. The Obama Administration de-prioritized enforcement of federal law against patients using the drug in compliance with state law, resulting in a de facto legalization. Recreational marijuana remains illegal (but not necessarily criminal) in all states and at the federal level, as of 2009.

Further information: Medical cannabis in the United States

Recent and ongoing reforms

Critical Path Initiative

The Critical Path Initiative is FDA's effort to stimulate and facilitate a national effort to modernize the sciences through which FDA-regulated products are developed, evaluated, and manufactured. The Initiative was launched in March 2004, with the release of a report entitled Innovation/Stagnation: Challenge and Opportunity on the Critical Path to New Medical Products [1].

Patients' rights to access unapproved drugs

A 2006 court case, Abigail Alliance v. von Eschenbach, would have forced radical changes in FDA regulation of unapproved drugs. The Abigail Alliance argued that the FDA must license drugs for use by terminally ill patients with "desperate diagnoses," after they have completed Phase I testing. The case won an initial appeal in May 2006, but that decision was reversed by a March 2007 rehearing. The US Supreme Court declined to hear the case, and the final decision denied the existence of a right to unapproved medications.

Post-marketing drug safety monitoring

The widely publicized recall of Vioxx, a non-steroidal anti-inflammatory drug now estimated to have contributed to fatal heart attacks in thousands of Americans, played a strong role in driving a new wave of safety reforms at both the FDA rulemaking and statutory levels. Vioxx was approved by the FDA in 1999, and was initially hoped to be safer than previous NSAIDs, due to its reduced risk of intestinal tract bleeding. However, a number of pre- and post-marketing studies suggested that Vioxx might increase the risk of myocardial infarction, and this was conclusively demonstrated by results from the APPROVe trial in 2004. Faced with numerous lawsuits, the manufacturer voluntarily withdrew it from the market. The example of Vioxx has been prominent in an ongoing debate over whether new drugs should be evaluated on the basis of their absolute safety, or their safety relative to existing treatments for a given condition. In the wake of the Vioxx recall, there were widespread calls by major newspapers, medical journals, consumer advocacy organizations, lawmakers, and FDA officials for reforms in the FDA's procedures for pre- and post- market drug safety regulation.

In 2006, a congressionally requested committee was appointed by the Institute of Medicine to review pharmaceutical safety regulation in the U.S. and to issue recommendations for improvements. The committee was composed of 16 experts, including leaders in clinical medicinemedical research, economics, biostatistics, law, public policy, public health, and the allied health professions, as well as current and former executives from the pharmaceutical, hospital, and health insurance industries. The authors found major deficiencies in the current FDA system for ensuring the safety of drugs on the American market. Overall, the authors called for an increase in the regulatory powers, funding, and independence of the FDA. Some of the committee’s recommendations have been incorporated into drafts of the PDUFA IV bill which was signed into law in 2007.

Pediatric drug testing

Prior to the 1990s, only 20% of all drugs prescribed for children in the United States were tested for safety or efficacy in a pediatric population. This became a major concern of pediatricians as evidence accumulated that the physiological response of children to many drugs differed significantly from those drugs' effects on adults. The reasons for the dearth of clinical drug testing in children were multifactorial. For many drugs, children represented such a small proportion of the potential market, that drug manufacturers did not see such testing as cost-effective. Also, because children were thought to be ethically restricted in their ability to give informed consent, there were increased governmental and institutional hurdles to approval of these clinical trials, as well as greater concerns about legal liability. Thus, for decades, most medicines prescribed to children in the U.S. were done so in a non-FDA-approved, "off-label" manner, with dosages "extrapolated" from adult data through body weight and body-surface-area calculations.

An initial attempt by the FDA to address this issue was the 1994 FDA Final Rule on Pediatric Labeling and Extrapolation, which allowed manufacturers to add pediatric labeling information, but required drugs which had not been tested for pediatric safety and efficacy to bear a disclaimer to that effect. However, this rule failed to motivate many drug companies to conduct additional pediatric drug trials. In 1997, the FDA proposed a rule to require pediatric drug trials from the sponsors of New Drug Applications. However, this new rule was successfully preempted in Federal court as exceeding the FDA's statutory authority. While this debate was unfolding, Congress used the 1997 Food and Drug Administration Modernization Act to pass incentives which gave pharmaceutical manufacturers a six-month patent term extension on new drugs submitted with pediatric trial data. The act reauthorizing these provisions, the 2002 Best Pharmaceuticals for Children Act, allowed the FDA to request NIH-sponsored testing for pediatric drug testing, although these requests are subject to NIH funding constraints. Most recently, in the Pediatric Research Equity Act of 2003, Congress codified the FDA's authority to mandate manufacturer-sponsored pediatric drug trials for certain drugs as a "last resort" if incentives and publicly funded mechanisms proved inadequate.

Rules for generic biologics

Since the 1990s, many successful new drugs for the treatment of cancer, autoimmune diseases, and other conditions have been protein-based biotechnology drugs, regulated by the Center for Biologics Evaluation and Research. Many of these drugs are extremely expensive; for example, the anti-cancer drug Avastin costs $55,000 for a year of treatment, while the enzyme replacement therapy drug Cerezyme costs $200,000 per year, and must be taken by Gaucher's Disease patients for life. Biotechnology drugs do not have the simple, readily verifiable chemical structures of conventional drugs, and are produced through complex, often proprietary techniques, such as transgenic mammalian cell cultures. Because of these complexities, the 1984 Hatch-Waxman Act did not include biologics in the Abbreviated New Drug Application (ANDA) process, essentially precluding the possibility of generic drug competition for biotechnology drugs. In February 2007, identical bills were introduced into the House to create an ANDA process for the approval of generic biologics, but were not passed.

Criticism

Main article: Criticism of the Food and Drug Administration

The FDA currently has regulatory oversight over a large array of products that affect the health and life of American citizens. As a result, the FDA's powers and decisions are carefully monitored by several governmental and non-governmental organizations. There are many criticisms and complaints lodged against the FDA from patients, economists, regulatory bodies, and the pharmaceutical industry. A $1.8 million 2006 Institute of Medicine report on pharmaceutical regulation in the U.S. found major deficiencies in the current FDA system for ensuring the safety of drugs on the American market. Overall, the authors called for an increase in the regulatory powers, funding, and independence of the FDA.

Nine FDA scientists appealed to then president-elect Barack Obama over pressures experienced during the George W. Bush presidency, from management to manipulate data, including in relation to the review process for medical devices. Characterized as "corrupted and distorted by current FDA managers, thereby placing the American people at risk," These concerns were also highlighted in the 2006 report on the agency as well.

A recent analysis of the economic discourse regarding certain FDA-administered restrictions finds that published statements by economists very preponderantly support liberalization. The three FDA restrictions under analysis are the permitting of new drugs and devices, the control of manufacturer speech, and the imposition of prescription requirements. Additionally, some economists have argued that in the increasingly complex and diverse food marketplace, the FDA is not equipped to adequately regulate or inspect food.

However, when asking the question whether economists or fundamental economic reasoning favor liberalization of the restrictions, the consensus is disagreement. Economist Daniel Klein suggests, "taboos surround the issue, particularly taboos against the critical examination of fundamentals." He contends, "that there is no market-failure rationale for the restrictions.” Many economists that publish statements regarding the FDA "exhibit a sort of intellectual schizophrenia. In their heart of hearts, they seem to agree that there is no respectable market-failure rationale." Perhaps, certain factors surrounding the political and sociological culture of the regulations keep some economists from speaking openly.

Regulation of living organisms

With acceptance of premarket notification 510(k) 033391 in January 2004, the FDA granted Dr. Ronald Sherman permission to produce and market Medical maggots for use in humans or other animals as a prescription medical device. Medical maggots represent the first living organism allowed by the Food and Drug Administration for production and marketing as a prescription medical device.

In June 2004, the FDA cleared Hirudo medicinalis (Leeches) as the second living organism to be used as a medical devices.

See also

• 12px Media related to Food and Drug Administration (United States) at Wikimedia Commons
• Criticism of the Food and Drug Administration
• Drug Efficacy Study Implementation
• European Medicines Agency
• Food Administration
• Food and Drug Administration Amendments Act of 2007
• International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)
• Investigational Device Exemption
• Kefauver Harris Amendment
• Medicines and Healthcare products Regulatory Agency (UK)
• Pharmaceutical company
• The Food Defect Action Levels, an FDA publication
• Wilhelm Reich
• Office of Criminal Investigations

Further reading

• Michael Givel (December 2005) Philip Morris’ FDA Gambit: Good for Public Health? Journal of Public Health Policy (26): pp. 450–468.
• Philip J. Hilts. Protecting America's Health: The FDA, Business, and One Hundred Years of Regulation. New York: Alfred E. Knopf, 2003. ISBN 0-375-40466-X
• Thomas J. Moore. Prescription for Disaster: The Hidden Dangers in Your Medicine Cabinet. New York: Simon & Schuster, 1998. ISBN 0-684-82998-3.

External links

• Food & Drug Administration homepage
• Strategic Plan (in XML) - from StratML
• Biologics Centennial: 100 Years of Biologics Regulation – from the Food and Drug Administration Home Page
• U.S. FDA CDER Home Page – the Center for Drug Evaluation and Research
• CBER – Center for Biologics Evaluation and Research, FDA
• Past FDA Commissioners
• Agency Presentations

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