Food and Drug Administration

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [20]

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The Food and Drug Administration (FDA) is an agency of the United States Department of Health and Human Services and is responsible for the safety regulation of most types of foods, dietary supplements, drugs, vaccines, biological medical products, blood products, medical devices, radiation-emitting devices, veterinary products, and cosmetics.

## Contents

* 1 Organization
* 1.1 Leadership
* 2 Authorization and regulatory mandate
* 3 Funding
* 3.1 Federal budget
* 3.1.1 Prescription drug user fees
* 4 Regulatory Programs
* 4.1 Food and dietary supplements
* 4.2 Drugs
* 4.2.1 New prescription drugs
* 4.2.1.1 Approval for testing in humans
* 4.2.1.2 Approval to market a new drug
* 4.2.1.3 Chemistry and manufacturing
* 4.2.1.4 Advertising and promotion
* 4.2.1.5 Post market safety surveillance
* 4.2.2 Generic drugs
* 4.2.3 Over-the-counter drugs
* 4.3 Biologics and blood products
* 4.4 Medical and radiation-emitting devices
* 4.5 Cosmetics
* 4.6 Veterinary products
* 4.7 Enabling legislation
* 5 History
* 5.1 Early history
* 5.1.1 Origins of federal food and drug regulation
* 5.1.2 The 1906 Food and Drugs Act and creation of the FDA
* 5.1.3 The 1938 Food, Drug, and Cosmetics Act
* 5.2 Regulation of human drugs and medical devices after 1938
* 5.2.1 Early FD&C Act amendments: 1938-1958
* 5.2.2 Expansion of premarket approval process: 1959-1985
* 5.2.3 FDA reforms in the AIDS era
* 6 Recent and ongoing reforms
* 6.1 Patients' rights to access unapproved drugs
* 6.2 Post-marketing drug safety monitoring
* 6.3 Pediatric drug testing
* 6.4 Rules for generic biologics
* 7 Criticism
* 8 FDA commissioners
* 9 See also
* 10 Further reading
* 11 References
* 12 External links
* 12.1 Food and Drug Administration websites

## Organization

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The FDA is an agency within the United States Department of Health and Human Services.

The agency is currently organized into the following major subdivisions,each focused on a major area of regulatory responsibility:

* The Center for Food Safety and Applied Nutrition (CFSAN)
* The Center for Drug Evaluation and Research (CDER)
* The Center for Biologics Evaluation and Research (CBER)
* The Center for Devices and Radiological Health (CDRH)
* The Center for Veterinary Medicine (CVM)
* The National Center for Toxicological Research (NCTR)
* The Office of Regulatory Affairs (ORA)
* The Office of the Commissioner (OC)

### Leadership

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The FDA is headed by Commissioner Andrew von Eschenbach, who was confirmed by the Senate on December 7 2006 after serving as Acting Commissioner for fourteen months. Von Eschenbach succeeded Lester Crawford, who resigned on September 23 2005, just two months after his final Senate confirmation.

## Authorization and regulatory mandate

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Most federal laws administered through the FDA are codified into the Food, Drug and Cosmetic Act, [1] also called Title 21, Chapter 9 of the United States Code (21 USC 9).

The programs for FDA 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. It regulates other products with a set of published standards enforced with a modest number of facilities inspections.

## Funding

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### Federal budget

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The FDA's federal budget request for 2008 totalled $2.1 billion, a $105.8 million increase over 2007.[2]

Before the 1990s, the FDA was funded solely by appropriations from the federal government. In response to a variety of issues, Congress adopted various laws in the 1990s that imposed a fee on entities that applied for FDA approval of a drug, biologic or medical device.

#### Prescription drug user fees

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The Prescription Drug User Fee Act (PDUFA) of 1992 was the most significant statutory attempt in the 1990s to accelerate the FDA drug approval process. The Act provided that the FDA was entitled to collect a substantial application fee from drug manufacturers at the time an NDA was submitted, with those funds designated for use only in CDER or CBER drug approval activities. In order to continue collecting such fees, the FDA is required to meet certain performance benchmarks, primarily related to the speed of certain activities within the NDA review process. A 2002 GAO report found that PDUFA funds allowed the FDA to increase the number of new drug reviewers by 77 percent in the first eight years of the act, and the median approval time for non-priority new drugs dropped from 27 months to 14 months over the same period.[3]

In response to concerns that the PDUFA mandates had unintentionally reduced the resources available to the FDA for non-approval-related activities, the second congressional reauthorization of the act in 2002 (PDUFA III) included amendments allowing 7% of user fees to be allocated for post-marketing surveillance of drug safety as well.[3] Another 2002 statute extended user fee policies to cover the approval process for medical devices. In 2007, the FDA is expected to collect $259.3 million in industry user fees.[4]

The PDUFA program has been criticized in the mainstream medical literature as creating conflicts of interest between the pharmaceutical industry and the FDA. The high number of mandated post-approval safety studies that have not been completed by drug manufacturers, 71%, is cited as evidence that the PDUFA is more focused more on the rapid approval of drugs, and less upon patient safety.[5]

PDUFA was reauthorized in October 2007 with an increase in user fees as well as a series of new initiatives intended to strengthen the FDA's regulation of drug advertising, give it additional authority to require drug testing after initial market approval, and establish a new system for monitoring the safety of drugs once they are on the market.[6] While earlier renewals of PDUFA focused primarily on speeding the initial approval of drugs through deadlines for action and provision of additional staff, the 2007 reauthorization focused on safety regulation.

## Regulatory Programs

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### Food and dietary supplements

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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.[7] One exception is 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 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)).

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 prior to approval, and the FDA can take action against dietary supplements only after they are proven to be unsafe. However, the 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.[8]

Bottled water is regulated in America by the FDA.[9] 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.[10] Water bottlers in America must make their facilities available to yearly compliance checks by FDA officials, to document that required protocols are followed. Regulated water quality control in the bottled water industry is not nearly as publicly accountable or transparent as municipal water works, due to the emphasis on drug regulation in the FDA budget.

### Drugs

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The Center for Drug Evaluation and Research has different requirements for the three main types of drug products: new prescription drugs, generic drugs and over-the-counter drugs. The most rigorous requirements apply to new prescription drugs.

#### New prescription drugs

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New drugs receive extensive scrutiny before FDA approval and some continuing surveillance after marketing. The following sections outline the basic elements of the regulatory program.

##### Approval for testing in humans

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To test a new drug experimentally in humans, a sponsor must first file Investigational New Drug Application (IND). The sponsor must show it has learned enough about the drug from animal and laboratory studies to give the drug safely to healthy volunteers. An IND is automatically approved unless the FDA objects. After an initial IND filing, a sponsor must submit annual reports, scientific reports about every study conducted and reports of adverse events.[11]

##### Approval to market a new drug

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A New Drug Application (NDA) is request for approval to market a new drug for a specific indication or medical use. The first pivotal hurdle for approval is the legal requirement for "substantial" evidence of efficacy demonstrated through controlled clinical trials. [12] This standard lies at the heart of the regulatory program for drugs. It means that the clinical experience of doctors, the opinion of experts, or testimonials from patients, even if they have experienced a miraculous recovery, have no weight in this process. The second critical requirement is that the sponsor must prove the drug is safe "by all scientific means applicable." [12]This places the burden on the sponsor to conduct whatever tests may be needed to establish the safety of the drug product. A drug that effects the electrical system of the heart--where a unexpected result could result in cardiac arrest-- could require more extensive testing than a cortisone skin cream that differed only slightly from exiting products.

However, prescription drugs are not completely safe. The legal requirement for safety and efficacy have been interpreted as requiring scientific evidence that the benefits of a drug exceed its risks, and that adequate instructions exist for its safe use.

The results of the testing program are codified in a FDA-approved public document that is called the product label, package insert or Full Prescribing Information. [13]The prescribing information is widely available on the web, from the FDA, [14]drug manufacturers, and frequently inserted into drug packages.The main purpose of a drug label is to provide doctors with adequate information and directions for the safe use of the drug.

##### Chemistry and manufacturing

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The FDA initial review of an NDA also includes a chemical assessment of the drug molecule. The sponsor must demonstrate a capacity to manufacture and package the drug at the specified potency without contamination or impurities and the with specified chemical characteristics (such as dissolution).

##### Advertising and promotion

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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[15] 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.

##### Post market safety surveillance

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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. [16] The FDA also receives directly adverse drug event reports through its MedWatch program.[17] 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 is requiring risk management plans for some drugs that may provide for other kinds of studies, restrictions, or safety surveillance activities.

#### Generic drugs

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Generic drugs are prescription drugs whose patent protection has expired, and therefore may be manufactured and marketed by other companies. For approval of a generic drug, the FDA requires scientific evidence that the generic drug is interchangeable or therapeutically equivalent with the originally approved drug. [18]

#### Over-the-counter drugs

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Over-the-counter (OTC) drugs are biologically active 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 physician's supervision. [19]

### Biologics and blood products

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The Center for Biologics Evaluation and Research is the branch of the FDA responsible for ensuring the safety and efficacy of biological therapeutic agents.[20] 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

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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.[21] 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. The 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. The CDRH also conducts limited amounts of direct product testing.

### Cosmetics

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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. 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.

### Veterinary products

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The Center for Veterinary Medicine is the branch of the FDA which regulates food additives and drugs that are given to animals, including agricultural animals and pets.

### Enabling legislation

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* 1902 — Biologics Control Act
* 1906 — Pure Food and Drug Act
* 1938 — Federal Food, Drug, and Cosmetic Act
* 1944 — Public Health Service Act
* 1951 — Food, Drug, and Cosmetics Act Amendments PL 82–215
* 1953 — Flammable Fabrics Act PL 83–88
* 1960 — Federal Hazardous Substances Labeling Act PL 86–613
* 1962 — Food, Drug, and Cosmetics Act Amendments PL 87–781
* 1965 — Federal Cigarette Labeling and Advertising Act PL 89–92
* 1966 — Fair Packaging and Labeling Act PL 89–755
* 1966 — Child Protection Act PL 89–756
* 1970 — Federal Cigarette Labeling and Advertising Act Amendments PL 91–222
* 1972 — Consumer Products Safety Act PL 92–573
* 1976 — Medical Device Regulation Act PL 94–295
* 1986 — Comprehensive Smokeless Tobacco Health Education Act PL 99–252
* 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 Modernization Act 105-115
* 2002 — Bioterrorism Act 107-188
* 2002 — Medical Device User Fee and Modernization Act (MDUFMA) PL 107-250
* 2002 — Best Pharmaceuticals for Children Act PL 107-109
* 2003 — Animal Drug User Fee Act PL 108-130
* 2003 — Pediatrict Research Equity Act PL 108-155
* 2004 — Project BioShield Act 108-276
* 2004 — Minor Use and Minor Species Animal Health Act PL 108-282
* 2004 — Food Allergen Labeling and Consumer Protection Act PL 108-282

## History

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### Early history

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#### Origins of federal food and drug regulation

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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.[22]

#### The 1906 Food and Drugs Act and creation of the FDA

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In June 1906, President Theodore Roosevelt signed into law the Food and Drugs Act, also known as the "Wiley Act" after its chief advocate.[22] 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.[23] The responsibility for examining food and drugs for such "adulteration" or "misbranding" was given to Wiley's USDA Bureau of Chemistry.[22]

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,[24] 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.[22] 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.[25]

#### The 1938 Food, Drug, and Cosmetics Act

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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. President Franklin Delano Roosevelt signed the new Food, Drug, and Cosmetic Act (FD&C Act) into law on June 25, 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.[22]

### Regulation of human drugs and medical devices after 1938

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#### Early FD&C Act amendments: 1938-1958

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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.[22] 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.[25] The FDA began enforcing its new powers against drug manufacturers who could not substantiate the efficacy claims made for their drugs, and the 1950 Court of Appeals ruling in Alberty Food Products Co. v. U.S. 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.[22] 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.[22]

#### Expansion of premarket approval process: 1959-1985

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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.[26]

The 1962 Kefauver-Harris Amendment to the FD&C act represented a "revolution" in FDA regulatory authority.[27] 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.

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.[28]

#### FDA reforms in the AIDS era

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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.[29] In August of 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.[30]

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.[31] 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.[32]

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.[33] Three of the first five drugs targeting HIV were approved in the United States before they were approved in any other country.[34]

## Recent and ongoing reforms

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### Patients' rights to access unapproved drugs

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An ongoing court case, Abigail Alliance v. von Eschenbach, has the potential to force radical changes in FDA regulation of unapproved drugs. Abigail Burroughs]was a college student diagnosed with head and neck cancer. During the later phases of her treatment, Abigail's father sued the FDA for access to the novel biotechnology drug cetuximab. At that time, cetuximab was available experimentally only for patients participating in colon cancer clinical trials (it has since been approved for colon cancer, as well as head and neck cancer when combined with radiation therapy). The argument made by the Abigail Alliance in court is that terminal cancer patients have a Constitutionally protected right to access to experimental medications before the FDA approves them. Specifically, the Abigail Alliance argued that the FDA should license drugs for use by terminally ill patients with "desperate diagnoses," after they have completed Phase I testing.[35]

In May 2006, the U.S. Court of Appeals for the District of Columbia ruled in favor of the Abigail Alliance, and found that the US Constitution protects the right of terminally ill patients to access treatments that are not approved by the FDA. On March 1, 2007, the U.S. Court of Appeals was scheduled to rehear the case at the request of the FDA. This case has the potential to radically alter the conduct of clinical cancer research, since the initial Court of Appeals ruling essentially condones unfettered access to experimental drugs by terminally ill patients, who would then have little incentive to enter Phase II and Phase III clinical trials testing new cancer drugs. The American Society of Clinical Oncology (ASCO) filed an amicus brief to the U.S. Court of Appeals in advance of the March 1 hearing, supporting the FDA. ASCO proposes that the Constitution does not guarantee the right to access unapproved medications, and that the court case threatens the cancer clinical trial enterprise.[36]

### Post-marketing drug safety monitoring

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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 gastrointestinal 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.[37] 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[38] 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.[39][40] Some the committee’s recommendations have been incorporated into drafts of the PDUFA IV bill which is expected to be passed by Congress in 2007.

### Pediatric drug testing

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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.[41]

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.[41]

### Rules for generic biologics

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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 of 2007, identical bills were introduced into the House[42] and Senate[43] with bipartisan cosponsorship to create an ANDA process for the approval of generic biologics. The bills face opposition from biologic drug manufacturers, and other lawmakers are working to create compromise legislation.[44]

## Criticism

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Main article: Criticism of the Food and Drug Administration

The FDA has regulatory oversight over a large array of products that affect the health and life of American citizens.[22] 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.

## FDA commissioners

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* Andrew von Eschenbach — current commissioner
* Lester Crawford 7/2005 - 9/2005
* Mark McClellan 11/2002 - 3/2004
* Jane E. Henney 1/1999 - 1/2001
* David Aaron Kessler 11/1990 - 2/1997
* Frank Edward Young 7/1984 - 12/1989
* Arthur Hull Hayes 4/1981 - 9/1983
* Jere E. Goyan 10/1979 - 1/1981
* Donald Kennedy 4/1977 - 6/1979
* Alexander M. Schmidt 7/1973 - 10/1976
* Charles C. Edwards 12/1969 - 3/1973
* Herbert L. Ley 7/1968 - 12/1969
* James L. Goddard 1/1966 - 7/1968
* George P. Larrick 8/1954 - 12/1965
* Charles W. Crawford 6/1951 - 7/1954
* Paul P. Dunbar 5/1944 - 5/1951
* Walter G. Campbell 7/1927 - 4/1944 and 7/1921 - 6/1924
* Charles A. Browne 7/1924 - 6/1927
* Carl L. Alsberg 12/1912 - 7/1921
* Harvey W. Wiley 1/1907 - 3/1912

## See also

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* Drug Efficacy Study Implementation
* European Medicines Agency
* ICH
* Investigational Device Exemption
* Kefauver Harris Amendment
* Pharmaceutical company
* The Medical Letter on Drugs and Therapeutics

## Further reading

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* 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.

## References

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1. ↑ Food, Drug and Cosmetic Act Web Version [1]
2. ↑ [2]
3. ↑ 3.0 3.1 Template:PDFlink GAO-02-958 Effect of User Fees on Drug Approval Times, Withdrawals, and Other Agency Activities
4. ↑ [3] Information about the PDUFA program from the FDA
5. ↑ Avorn J (2007). "Paying for drug approvals--who's using whom?". N. Engl. J. Med. 356 (17): 1697–700. PMID 17435083.
6. ↑ Text of House Bill 3580 [4]
7. ↑ http://www.cfsan.fda.gov/~lrd/cfsan4.html Overview of the Center for Food Safety and Applied Nutrition
8. ↑ Text of the Dietary Supplement Health and Education Act of 1994. Accessed 5 Feb 2007.
9. ↑ Template:PDFlink Title 21 of the Code of Federal regulations
10. ↑ Template:PDFlink
11. ↑ 21 CFR Part 312: Investigational New Drug Application
12. ↑ 12.0 12.1 Food, Drug, and Cosmetic Act, Section 502; 21 USC 355]
13. ↑ 21 CFR 201.5: Labeling Requirements for Prescription Drugs and/or Insulin
14. ↑ "Daily Med: Current Medication Information". Unknown parameter `|accessyear=` ignored (`|access-date=` suggested) (help); Unknown parameter `|accessmonthday=` ignored (help)
15. ↑ 21 CFR 202: Prescription Drug Advertising.
16. ↑ 21 CFR 314.80: Postmarketing Reporting of Adverse Drug Experiences
17. ↑ MedWatch: The FDA Safety Information and Adverse Event Reporting Program[[5]]. Accessed October 9, 2007
18. ↑ "Therapeutic Equivalence of Generic Drugs". U.S. Food and Drug Administration. 1998. Retrieved 2007-10- 10. Check date values in: `|accessdate=` (help)
19. ↑ FDA CDER Handbook: Over-the- Counter Drug Products [6] Accessed October 9, 2007
20. ↑ http://www.fda.gov/cber/about.htm
21. ↑ Template:PDFlink
22. ↑ 22.0 22.1 22.2 22.3 22.4 22.5 22.6 22.7 22.8 [7] A History of the FDA at FDA.gov
23. ↑ [8] Original Text of the 1906 Food and Drugs Act and Amendments
24. ↑ Template:Cite court
25. ↑ 25.0 25.1 [9] Milestones in U.S. Food and Drug Law History at FDA.gov
26. ↑ [10] Report of Congressman Morris Udall on thalidomide and the Kefauver hearings.
27. ↑ Temple R (2002). "Policy developments in regulatory approval". Statistics in Medicine. 21: 2939–2948.
28. ↑ Karki L (2005). "Review of FDA Law Related to Pharmaceuticals: The Hatch-Waxman Act, Regulatory Amendments and Implications for Drug Patent Enforcement". Journal of the Patent & Trademark Office Society. 87: 602–620.
29. ↑ [11] ACT-UP NY timeline
30. ↑ Faster Approval of AIDS Drugs Is Urged, The New York Times, August 16, 1990, Thursday, Late Edition - Final, Section B; Page 12, Column 4; National Desk, 830 words, By ROBERT PEAR, Special to The New York Times, WASHINGTON, Aug. 15
31. ↑ [12] FDA Website: Expanded Access and Expedited Approval of New Therapies Related to HIV/AIDS
32. ↑ Orlando V (1999). "The FDA's Accelerated Approval Process: Does the Pharmaceutical Industry Have Adequate Incentives for Self-Regulation?". American Journal of Law and Medicine. 25: 543–68.
33. ↑ [13] FDA report on accelerated approval process
34. ↑ [14] FDA press release on 3TC approval
35. ↑ Template:PDFlink Abigail Alliance Citizen Petition to FDA
36. ↑ Template:PDFlink Amicus brief by ASCO, filed February 2007
37. ↑ [15] The APPROVe study (Pubmed)
38. ↑ Template:PDFlink David Graham's 2004 testimony to Congress
39. ↑ Henderson, Diedtra (September 23, 2006). "Panel: FDA needs more power, funds". Boston Globe. [16]
40. ↑ Template:PDFlink Executive Summary of the 2006 IOM Report The Future of Drug Safety: Promoting and Protecting the Health of the Public
41. ↑ 41.0 41.1 Politis P (2005). "Transition From the Carrot to the Stick: The Evolution of Pharmaceutical Regulations Concerning Pediatric Drug Testing". Widener Law Review. 12: 271.
42. ↑ [17] H. R. 1038: Access to Life-Saving Medicine Act. (Introduced 2/14/2007)
43. ↑ [18] S. 623: Access to Life-Saving Medicine Act. (Introduced 2/14/2007)
44. ↑ [19] Pear R. Congress Seeks Compromise on Generic Drugs. New York Times (April 7, 2007)

## External links

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### Food and Drug Administration websites

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* Food and Drug Administration Home Page
* 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
* Communication of FDA Advice on Consumption of Fish Like Tuna and Swordfish

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