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{{redirect|FDA}}
[[Image:Food and Drug Administration logo.svg|thumb|right|200px|FDA logo]]
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 [[food]]s, [[dietary supplement]]s, [[Medication|drug]]s, [[vaccine]]s, [[Biopharmaceutical|biological medical products]], [[blood transfusion|blood products]], [[medical device]]s, [[Electromagnetic radiation|radiation]]-emitting devices, veterinary products, and [[cosmetics]]. The FDA also enforces section 361 of the Public Health Service Act and the associated regulations, including [[sanitation]] requirements on interstate travel as well as specific rules for control of disease on products ranging from pet [[turtles]] to [[semen]] donations for assisted reproductive medicine techniques.
==Organization==
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 Criminal Investigations]] (OCI)
* The [[Office of Regulatory Affairs]] (ORA)
* The Office of the [[FDA commissioner|Commissioner]] (OC)

===Leadership===
The FDA is headed by [[FDA 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==
Most federal laws administered through the FDA are codified into the Food, Drug and Cosmetic Act, <ref> Food, Drug and Cosmetic Act Web Version [http://www.fda.gov/opacom/laws/fdcact/fdctoc.htm]</ref> 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==
===Federal budget===
The FDA's federal budget request for 2008 totaled $2.1 billion, a $105.8 million increase from what they received in 2007.<ref>[http://www.fda.gov/oc/oms/ofm/budget/2008/summary.html Summary of FDA’s FY 2008 Budget<!-- Bot generated title -->]</ref><!-- This section is a stub, and I think it's relevant to the article, should be expanded -->

====User fees====

FDA is also funded by user fees submitted with [[New Drug Applications]] under the Prescription Drug User Fee Act (PDUFA) in which the industry pays a fee for the review of the new product. A similar process is used for medical devices under the Medical Device User Fee and Modernization Act (MDUFMA) and for animal drugs under a similar act. These fees are typically waived or reduced for small businesses.

==Regulatory Programs==
===Food and dietary supplements===
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.<ref>http://www.cfsan.fda.gov/~lrd/cfsan4.html Overview of the Center for Food Safety and Applied Nutrition</ref> 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 [[United States Department of Justice|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 supplement]]s as foods, rather than as drugs. Therefore, dietary supplements are not subject to safety and efficacy testing and there are no approval requirements. 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.<ref name="dshea text">[http://www.fda.gov/opacom/laws/dshea.html Text of the Dietary Supplement Health and Education Act of 1994]. Accessed 5 Feb 2007.</ref>

Bottled water is regulated in America by the FDA.<ref>{{PDFlink|[http://a257.g.akamaitech.net/7/257/2422/04nov20031500/edocket.access.gpo.gov/cfr_2001/aprqtr/pdf/21cfr165.110.pdf]|106&nbsp;[[Kibibyte|KiB]]<!-- application/pdf, 108847 bytes -->}} Title 21 of the Code of Federal regulations</ref> 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.<ref>{{PDFlink|http://www.dwrf.info/documents/recent_dev_bw_quality.pdf|217&nbsp;[[Kibibyte|KiB]]<!-- application/pdf, 223029 bytes -->}}</ref>
Water bottlers in the US are subject to inspection similar to other food firms, but quality controls for the bottled water industry are not nearly as stringent as those for municipal water supplies.

===Drugs===
{{Regulation of therapeutic goods in the United States}}
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 drugs====
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. New drugs are available only by prescription by default. A change to Over the Counter (OTC) status is a separate process.

=====Approval for testing in humans=====

To test a new drug experimentally in humans, a sponsor must first file an 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.<ref> 21 CFR Part 312: Investigational New Drug Application </ref>

=====Approval to market a new drug=====

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]]. <ref name='FDCA'>Food, Drug, and Cosmetic Act, Section 502; 21 USC 355]</ref>
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 minimal weight in this process. Data for the submission must come from rigorous clinical trials. The second critical requirement is that the sponsor must prove the drug is safe "by all scientific means applicable." <ref name='FDCA'> </ref>This places the burden on the sponsor to conduct whatever tests may be needed to establish the safety of the drug product.

The trials are typically conducted in three phases:

*Phase 1: The drug is tested in a few healthy volunteers to determine if it is acutely toxic.
*Phase 2: Various doses of the drug are tried to determine how much to give to patients.
*Phase 3: The drug is typically tested in [[double-blind]], [[placebo]] controlled trials to demonstrate that it works. Sponsors typically confer with FDA prior to starting these trials to determine what data is needed, since these trials often involve hundreds of patients and are very expensive.

The legal requirements for safety and efficacy have been interpreted as requiring scientific evidence that the benefits of a drug outweigh the risks and that adequate instructions exist for use, since many drugs are toxic and technically not "safe" in the usual sense. Many approved medications for serious illnesses (i.e. cancer) have severe and even life-threatening side effects. Even relatively safe OTC drugs such as [[aspirin]] can be dangerous if used incorrectly.

The results of the testing program are codified in an FDA-approved public document that is called the ''product label,'' package insert or Full Prescribing Information. <ref>21 CFR 201.5: Labeling Requirements for Prescription Drugs and/or Insulin</ref>The prescribing information is widely available on the web, from the FDA, <ref name="DailyMed">{{Cite web|url=http://dailymed.nlm.nih.gov/dailymed/about.cfm|title=Daily Med: Current Medication Information|accessyear=2007|accessmonthday=October 10}}</ref>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=====
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=====
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<ref> 21 CFR 202: Prescription Drug Advertising.</ref> 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. "Off-label use", using a drug for other than its approved purpose, is common in medical practice. Also, an advertisement must contain "fair balance" between the benefits and risks of a drug.

=====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. <ref>21 CFR 314.80: Postmarketing Reporting of Adverse Drug Experiences</ref>
The FDA also receives directly adverse drug event reports through its MedWatch program.<ref>MedWatch: The FDA Safety Information and Adverse Event Reporting Program[http://www.fda.gov/medwatch/index.html]. Accessed October 9, 2007</ref>
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 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. <ref name="Therapeutic Equivalance of Generic Drugs">{{Cite web|url=http://www.fda.gov/cder/news/nightgenlett.htm|title=Therapeutic Equivalence of Generic Drugs|accessdate=2007-10- 10|publisher=U.S. Food and Drug Administration|year=1998}}</ref> This is called an "ANDA" (Abbreviated New Drug Application).

====Over-the-counter drugs====
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.
<ref>FDA CDER Handbook: Over-the- Counter Drug Products [http://www.fda.gov/cder/handbook/otcintro.htm] Accessed October 9, 2007</ref>

===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.<ref>[http://www.fda.gov/cber/about.htm FDA/CBER - About CBER<!-- Bot generated title -->]</ref> 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 device]]s, as well as overseeing the manufacturing, performance and safety of these devices.<ref>{{PDFlink|[http://www.fda.gov/cdrh/radhealth/initiative/rhprogram.pdf 2005 report of the CDRH Radiological Health Program Core Group]|90.3&nbsp;[[Kibibyte|KiB]]<!-- application/pdf, 92516 bytes -->}}</ref> 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 pacemaker]]s. 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 security|airport baggage screening equipment]], [[television|television receivers]], [[microwave oven]]s, [[tanning booth]]s, and [[laser|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===
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.

===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 [[USDA]].

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

On [December 19], 2007, the FDA announced plans to create a database to track cloned animals through the food system and enable an effective labeling process [http://www.chron.com/disp/story.mpl/ap/fn/5392722.html]. This system will be part of the National Animal Identification System, which will track all livestock in the United States from farm to fork [http://www.thenation.com/doc/20071231/pentland_gumpert].

===Important Enabling legislation===
* 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
* 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 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

==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 [[muckraker|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]].<ref name="FDAHist">[http://www.fda.gov/oc/history/historyoffda/section1.html] A History of the FDA at FDA.gov</ref> The 1902 Biologics Control Act was put in place after tetanus antitoxin was collected from a horse named Jim who also had [[diphtheria]], resulting in several deaths.

====The 1906 Food and Drugs 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.<ref name="FDAHist"/> 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.<ref>[http://www.fda.gov/opacom/laws/wileyact.htm] Original Text of the 1906 Food and Drugs Act and Amendments</ref> The responsibility for examining food and drugs for such "adulteration" or "misbranding" was given to Wiley's USDA Bureau of Chemistry.<ref name="FDAHist"/>

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 of the United States|Supreme Court]] decision ruled that the 1906 act did not apply to false claims of therapeutic efficacy,<ref>{{cite court |litigants= United States v. Johnson |vol= 221 |reporter=U.S. |opinion=488 |pinpoint= |court=31 S. Ct. 627 |date=May 29, 1911, decided |url=[http://web.lexis-nexis.com/universe/document?_m=45e93d4ecf899e8ddacfc1288d2b2e55&_docnum=3&wchp=dGLbVlb-zSkVA&_md5=0c2cf1f63b450204 6df1b297de555a5c] }}</ref> 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.<ref name="FDAHist"/> 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.<ref name="milestones">[http://www.fda.gov/opacom/backgrounders/miles.html] Milestones in U.S. Food and Drug Law History at FDA.gov</ref>

====The 1938 Food, Drug, and Cosmetics 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 [[Federal Food, Drug, and Cosmetic Act|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.<ref name="FDAHist"/>

===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|prescription-only]]' drugs was securely codified into law by the 1951 [[Durham-Humphrey Amendment]].<ref name="FDAHist"/> 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.<ref name="milestones"/> 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.<ref name="FDAHist"/> 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.<ref name="FDAHist"/>

====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.<ref>[http://www.library.arizona.edu/exhibits/udall/congrept/87th/620817.html] Report of Congressman Morris Udall on thalidomide and the Kefauver hearings.</ref>

The 1962 [[Kefauver-Harris Amendment]] to the FD&C act represented a "revolution" in FDA regulatory authority.<ref>{{cite journal |author=Temple R |year=2002 |title=Policy developments in regulatory approval |journal=Statistics in Medicine |volume=21 |pages=2939-2948}}</ref> 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 drug|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 [[pharmacokinetics|pharmacokinetic]] properties ("bioequivalence") as the corresponding brand-name drug. This act has been credited with essentially creating the modern generic drug industry.<ref name="HatchWaxman">{{cite journal |author=Karki L |year=2005 |title=Review of FDA Law Related to Pharmaceuticals: The Hatch-Waxman Act, Regulatory Amendments and Implications for Drug Patent Enforcement |journal=Journal of the Patent & Trademark Office Society |volume=87 |pages=602-620}}</ref>

====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.<ref>[http://www.actupny.org/documents/cron-88.html] ACT-UP NY timeline</ref> In August of 1990, [[Louis Lasagna|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.<ref> 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</ref>

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.<ref>[http://www.fda.gov/oashi/aids/expanded.html] FDA Website: Expanded Access and Expedited Approval of New Therapies Related to HIV/AIDS</ref> 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.<ref>{{cite journal |author=Orlando V |year=1999 |title=The FDA's Accelerated Approval Process: Does the Pharmaceutical Industry Have Adequate Incentives for Self-Regulation? |journal=American Journal of Law and Medicine |volume=25 |pages=543-68}}</ref>

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.<ref>[http://www.fda.gov/fdac/special/newdrug/speeding.html] FDA report on accelerated approval process</ref> Three of the first five drugs targeting HIV were approved in the United States before they were approved in any other country.<ref>[http://www.fda.gov/bbs/topics/NEWS/NEW00519.html] FDA press release on [[3TC]] approval</ref>

==Recent and ongoing reforms==
===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.<ref>{{PDFlink|[http://www.abigail-alliance.org/WLF_FDA.pdf]|119&nbsp;[[Kibibyte|KiB]]<!-- application/pdf, 122020 bytes -->}} Abigail Alliance Citizen Petition to FDA</ref> The case won an initial appeal in May 2006, but that decision was reversed by a March 2008 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===
{{update}}
The widely publicized recall of [[Vioxx]], a [[non-steroidal anti-inflammatory drug]] now estimated to have contributed to fatal [[myocardial infarction|heart attack]]s 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.<ref>[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=15713943&query_hl=10&itool=pubmed_docsum] The APPROVe study (Pubmed)</ref> 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<ref name="Graham">{{PDFlink|[http://www.senate.gov/~finance/hearings/testimony/2004test/111804dgtest.pdf]|28.3&nbsp;[[Kibibyte|KiB]]<!-- application/pdf, 29017 bytes -->}} David Graham's 2004 testimony to Congress</ref> 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 [[drug company|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.<ref>{{cite news |first=Diedtra |last=Henderson |title=Panel: FDA needs more power, funds |work= Boston Globe |date=September 23, 2006}} [http://www.webcitation.org/5NkCrjdpd]</ref><ref>{{PDFlink|[http://books.nap.edu/execsumm_pdf/11750.pdf]|279&nbsp;[[Kibibyte|KiB]]<!-- application/octet-stream, 286424 bytes -->}} Executive Summary of the 2006 IOM Report ''The Future of Drug Safety: Promoting and Protecting the Health of the Public''</ref> Some of 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===
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 [[pediatrician]]s 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.<ref name="PedReg">{{cite journal |author=Politis P |year=2005 |title=Transition From the Carrot to the Stick: The Evolution of Pharmaceutical Regulations Concerning Pediatric Drug Testing |journal=Widener Law Review |volume=12 |pages=271}}</ref>

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.<ref name="PedReg">{{cite journal |author=Politis P |year=2005 |title=Transitiion From the Carrot to the Stick: The Evolution of Pharmaceutical Regulations Concerning Pediatric Drug Testing |journal=Widener Law Review |volume=12 |pages=271}}</ref>

===Rules for generic biologics===
Since the 1990s, many successful new drugs for the treatment of [[cancer]], [[autoimmunity|autoimmune disease]]s, and other conditions have been [[protein]]-based [[biologics|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 [[Imiglucerase|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 [[Drug Price Competition and Patent Term Restoration Act|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<ref>[http://www.webcitation.org/5Nz4qt1oo] H. R. 1038: Access to Life-Saving Medicine Act. (Introduced 2/14/2007)</ref> and Senate<ref>[http://www.webcitation.org/5Nz4sPPMP] S. 623: Access to Life-Saving Medicine Act. (Introduced 2/14/2007)</ref> 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.<ref>[http://www.webcitation.org/5Nz6SMDEP] Pear R. Congress Seeks Compromise on Generic Drugs. New York Times (April 7, 2007)</ref>

==Criticism==
{{main|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.<ref name="FDAHist">[http://www.fda.gov/oc/history/historyoffda/section1.html] A History of the FDA at FDA.gov</ref> 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.

== See also ==
* [[Criticism of the Food and Drug Administration]]
* [[Drug Efficacy Study Implementation]]
* [[European Medicines Agency]]
* [[International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use|ICH]]
* [[Investigational Device Exemption]]
* [[Institute of Food and Agricultural Sciences (IFAS)]]
* [[Kefauver Harris Amendment]]
* [[Pharmaceutical company]]
* [[The Medical Letter on Drugs and Therapeutics]]
* [[Medicines and Healthcare products Regulatory Agency]] (UK)

==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.

==References==
{{reflist}}

==External links==
===Food and Drug Administration websites ===
* [http://www.fda.gov/ Food and Drug Administration Home Page]
** [http://www.fda.gov/oc/history/makinghistory/100yearsofbiologics.html Biologics Centennial: 100 Years of Biologics Regulation] — from the Food and Drug Administration Home Page
** [http://www.fda.gov/cder/ U.S. FDA CDER Home Page] — the Center for Drug Evaluation and Research
** [http://www.fda.gov/cber/ CBER — Center for Biologics Evaluation and Research, FDA]
** [http://www.fda.gov/oc/commissioners/default.htm Past FDA Commissioners]
* [http://www.oceana.org/mercury Communication of FDA Advice on Consumption of Fish Like Tuna and Swordfish]
{{HHS agencies}}

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Revision as of 20:11, 7 May 2008

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