Food and Drug Administration

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

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 regulating food, dietary supplements, drugs, biological medical products, blood products, medical devices, radiation-emitting devices, veterinary products, and cosmetics in the United States.

Organization

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

Currently, the FDA is divided into eight major centers and offices:

• 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

The FDA is led 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

As an administrative agency in the executive branch of the government of the United States of America, the FDA derives all of its authority and jurisdiction from various acts of the United States Congress. The main source of the FDA's authority is the Federal Food, Drug, and Cosmetic Act. This act gave the FDA various responsibilities including the responsibility of ensuring that no adulterated or misbranded food, drug or medical devices enters into interstate commerce.

The FDA has the power to regulate a multitude of products in a manner that ensures the safety of the American public and the effectiveness of marketed food, medical, and cosmetic products. Regulations may take several forms, including but not limited to outright ban, controlled distribution, and controlled marketing. Additionally, the FDA sets the standards under which individuals may be licensed to prescribe drugs or other medical devices. Regulatory enforcement is carried out by Consumer Safety Officers within the Office of Regulatory Affairs and criminal matters are handled by special agents within the Office of Criminal Investigations (OCI).

Regulation of 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. 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, and Firearms in the U.S. Department of the Treasury), and non-bottled drinking water (regulated by the Environmental Protection Agency).

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.

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

Regulation of 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. 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.

Regulation of drugs

The Center for Drug Evaluation and Research is the branch of the FDA responsible for ensuring the safety and efficacy of new prescription and over-the-counter drugs, overseeing the labeling and marketing of drugs, and regulating the manufacturing and packaging of drugs. The FDA defines a drug as safe and effective for a specific indication if the clinical benefits to the patient are felt to outweigh any health risks the drug might pose. Once a drug has been approved for use, physicians may prescribe it for any indication, referred to as "off label use" and are not restricted to the indications approved by the FDA. The drug may not be marketed for any use other than FDA-approved indications.

The drug approval process

The FDA does not directly test the drugs it regulates. Instead, it is the responsibility of the company seeking to bring a new drug to market, the drug's "sponsor", to submit information to the FDA proving that a new drug is safe and effective. Initially, a U.S.-based researcher or sponsoring company submits an "investigational new drug" (IND) application to the FDA, which includes pre-clinical data about the drug. Approval of this application allows the drug to be shipped across state lines for clinical trials. Once the sponsor has conducted sufficient trials to demonstrate the safety and efficacy of the drug, they submit that information, along with information on manufacturing specifications, drug stability and bioavailablility, and suggested packaging and labeling, as a "new drug application" (NDA) to the FDA. The NDA is then reviewed by teams of FDA employees, including physicians, statisticians, chemists, pharmacologists, and other scientists who assess the validity of the sponsor's claims. FDA inspectors also examine the facilities in which the sponsor intends to manufacture the drug.

The NDA review process is complex, but there are three general outcomes for most drugs after the initial review. First, the FDA may accept the sponsor's application in its entirety and approve the drug for marketing in the U.S. Second, a drug may be declared "approvable," meaning that minor concerns must be worked out between the FDA and the sponsor prior to full approval. For example, the sponsor may be required to provide additional information, or change the proposed labelling of the drug. The FDA may also make approval contingent on an agreement by the manufacturer to conduct specific post-approval studies. Finally, a drug can be declared "not approvable", meaning that the FDA reviewers did not agree that the submitted studies were sufficient to prove the drug's safety and efficacy.

The Prescription Drug User Fee Amendment Program

The Prescription Drug User Fee Amendments (PDUFA) program, established in 1993, allows the FDA to collect fees from drug companies in connection with certain IND and NDA submissions. In 2007, the FDA is expected to collect $259,300,000 in industry user fees. The user fees were intended to allow the FDA to add staff and improve the speed of drug approvals, although the effects of this arrangement on the approval process and on FDA impartiality are controversial (see Criticism).

Accelerated approval processes

The traditional FDA approval process requires that a drug's sponsor prove clinical efficacy of a drug. Because studies showing clear clinical outcomes may take a long time to conduct, the FDA has a special approval track for potentially lifesaving drugs directed at diseases for which satisfactory treatments are lacking. In this track, a drug may receive approval based on its effect on "surrogate markers". For example, a new medication for highly drug-resistant HIV might be approved on the accelerated track if, in short-term trials, it was shown to decrease HIV viral load and increase serum CD4 T-cell counts in AIDS patients, without causing major adverse effects. Under the traditional process, the sponsor would have to show that the drug prevented hospitalizations or saved lives in large, long-term, randomized trials comparing the new drug to older ones.

Following passage of the Drug Price Competition and Patent Term Restoration Act of 1984, the FDA established an abbreviated approval process for manufacturers who wish to produce generic versions of off-patent, previously approved drugs. Generic drug manufacturers are only required to show that the active ingredient in their version of a drug is chemically identical to that of the previously approved drug, that its formulation shows bioequivalence to the previously approved formulation in small human trials, and that the manufacturing, packaging, and labeling of the drug meet FDA standards. There is currently no abbreviated process for approving generic "biologic" agents, such as vaccines or antibody-based drugs.

Regulation of tobacco as a drug

In the 1990s, while under the leadership of former Commissioner David Aaron Kessler, the FDA attempted to regulate tobacco as a pharmaceutical. The courts determined in FDA v. Brown & Williamson Tobacco Corp. that the FDA did not have Congressional authority to regulate tobacco.

Regulation of biologics and blood products

The Center for Biologics Evaluation and Research is the branch of the FDA responsible for ensuring the safety and efficacy of biological therapeutic agents. These include blood and blood products, vaccines, allergenics, protein-based therapeutic agents, 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.

Regulation of medical devices and radiation-emitting devices

The Center for Devices and Radiological Health (CDRH) is the branch of the FDA responsible for the premarket approval of all medical devices, as well as overseeing the manufacturing, performance and safety of these devices. The definition of a medical device is given in the FD&C Act, and it includes products from the simple toothbrush to complex devices such as implantable 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.

Regulation of veterinary products

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

• 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
• 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
• 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

Disabling legislation

• 1994 Dietary Supplement Health and Education Act

History

Origins of Federal Food and Drug Regulation

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

The 1906 Food and Drugs Act and creation of the FDA

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

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

The 1938 Food, Drug, and Cosmetics Act

By the 1930's, 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 congress 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. 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.

Consolidation and Expansion of FDA Authority: 1938-1962

Soon after passage of the 1938 Act, the FDA began to designate certain drugs as safe for use only under the supervision of a medical professional, and the category of 'prescription-only' drugs was securely codified into law by the 1951 Durham-Humphrey Amendment. While pre-market testing of drug efficacy was not authorized under the 1938 FD&C Act, subsequent amendments such as the Insulin Amendment and Penicillin Amendment did mandate pre-market testing for new formulations of specific lifesaving pharmaceuticals. 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, thus confirming extensive powers for the FDA to enforce post-marketing recalls of demonstrably ineffective drugs. Much of the FDA's regulatory attentions in this era were directed towards abuse of amphetamines and barbiturates, but the agency also reviewed some 13,000 new drug applications between 1938 and 1962. While the science of toxicology was in its infancy at the start of this era, rapid advances in experimental assays for food additive and drug safety testing were made during this period by FDA regulators and others.

Outline of history since 1960

• 1960 — Frances Oldham Kelsey, who was in charge of reviewing new drug applications, refused to allow Thalidomide in the United States market. Already being manufactured and sold throughout Europe, Kelsey insisted there was not enough evidence of the drug's safety. Receiving pressure from thalidomide manufacturers, Kelsey would not budge.
• 1961 — November, Germany takes thalidomide, known as kevadon, off the market after several thousand newborns suffered the teratogenic effects — they were born with grave congenital abnormalities.
• 1962 - Partly in response to the thalidomide tragedy, the Kefauver Harris Amendment to the Federal Food, Drug, and Cosmetic Act of 1938 are passed. These laws regulate the marketing and licensure of new drugs. For the first time, rational requirements for the approval of new drugs are enforceable by law.
• 1982 — Cyanide poisoning in Tylenol (a brand of the over-the-counter drug acetaminophen) capsules results in many deaths, leading the FDA to begin tamper-resistant packaging.
• 1990 — The FDA promulgates regulations banning "gifts of substantial value" from drug companies to doctors. Minor gifts (like meals, tickets, and travel) are not banned.
• 1992 — Congress passes a new law creating a faster approvals process to legalize new drugs. The FDA must hire more reviewers and speed up reviews without sacrificing proper study and testing. The drug industry must pay "user fees" with every new drug application. A drug is given "fast-track" status if it meets a medical need not currently being met by any medication. Approval times drop from 30 to 12 months on average. 60% of new drugs come on the market in the U.S. first, before other countries. Before this law, when the approval process was slower, more new drugs came out in other countries first.
• 1997 — The FDA loosens restrictions on consumer advertising. Drug companies are allowed to spend less time describing risks and side effects on TV commercials. A large increase in TV drug ads caused a large increase in drug sales within months.

Historical list of FDA Commissioners

• 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. Govan 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

Court cases

Abigail Burroughs v. von Eschenbach, 2001-2007

Abigail Burroughs was a college student diagnosed with head and neck cancer. During the later phases of her treatment, Abigail's father, Frank Burroughs, sued the FDA for access to cetuximab, case of Abigail Alliance for Better Access to Developmental Drugs v. von Eschenbach. At that time, cetuximab was only available experimentally for patients participating in colon cancer clinical trials. 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 argues that the FDA should license drugs for use by terminally ill patients with "desperate diagnoses," after they have completed Phase I testing.

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. While clinical trials restrict access by terminally ill patients to new drugs, they also protect patients by collecting safety and efficacy data on new drugs under controlled circumstances. The expected success rate of cancer drugs at the Phase I stage of clinical testing is 6%. Implementing the changes proposed by the Abigail Alliance could have the potential to expose terminally ill patients to the toxicity of many unapproved treatments, with a very low expected success rate. From its inception, the US Government has charged the FDA with a mission of overseeing testing of new drugs. Challenges to this core definition, as in the Abigail Alliance court case, would likely require broad changes to the FDA's operating mandate. The Americal 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.

Criticism

The FDA has regulatory oversight over a large array of products that effect the health and life of American citizens As a result, the FDA's powers and decisions are carfully monitored by several governmental and non-governmental organizations. Outlined below are several of the common criticisms and complaints lodged against the FDA from patients, regulatory bodies, and the pharmaceutical industry.

Over-regulation

A diverse group of critics claim that the FDA possesses excessive regulatory authority.

FDA baised towards preventing "visible" casualties

Nobel prize-winning economist Milton Friedman has claimed that the regulatory process is inherently biased against approval of some worthy drugs. He says that it is simply in the self-interest of anyone in the position of an FDA regulator to take any chance whatsoever to refuse to approve a good drug in order to make sure that a bad one is not approved.

His explanation is that if a drug the FDA approves is considered harmful after its approval, then the subsequent error will be highly publicized. This is the definition of a visible casualty. It refers to a publicized discovery of an error on the FDA's part. An error of this variety is called a Type II error, signified by the approval of a harmful drug that causes casualties in it's user base.

On the other hand, Friedman alleges that the FDA is less concerned with invisible deaths caused not by casualties from unsafe drugs, but from useful drugs that were kept of the market because of regulation. This type of death occurrs through what Friedman states is the increased time required to approve helpful drugs. Because a deceased patient has died from their ailment, as opposed to the drug treating them, the death is less notable. These are referred to as Type I errors, where a helpful drug is kept from the market through excessive regulation or it's approval is denied.

He also claims that the bias manifests as the FDA expends more resources to prevent dangerous drugs from enterting the market (as opposed to spending money approving helpful treatments). As a result of these "visible" deaths, the FDA would spare no expense to prevent an accidental death.

Friedman's proposed solution involves the abolition of the FDA as a whole. His opinions state that the bias involved in these deaths in intrinisic to compulsory regulation and more people are harmed than helped by compulsory regulation of drugs. He proposes to replace it with voluntary regulation from private certifiers (and says these would be somewhat analagous to Underwriters Laboratories for electrical equipment), with individuals having the free choice to take approved drugs or unapproved drugs (as long as they have the knowledge that they are unapproved) in accordance with their own risk-aversion standards.

	Drug is safe and effective	Drug is not safe and effective
FDA allows the drug	Correct decision	Type 1 error: Allows a harmful drug. Victims are identifiable and traceable. Highly publicized. Public condemnation and investigations of FDA.
FDA disallows or delays the drug	Type 2 error: Disallows or delays a beneficial drug. Victims are not easily identifiable. Public unaware when it happens. Little, or no, public condemnation or investigations of FDA.	Correct decision

In 1974, FDA Commisioner Alexander Schmidt agreed that individuals in the FDA are under more scrutiny to avoid Type I errors than Type II errors. He said: "In all of the FDA’s history, I am unable to find a single instance where a Congressional committee investigated the failure of FDA to approve a new drug. But, the times when hearings have been held to criticize our approval of new drugs have been so frequent that we aren’t able to count them… The message to FDA staff could not be clearer. Whenever a controversy over a new drug is resolved by its approval, the Agency and the individuals involved likely will be investigated. Whenever such a drug is disapproved, no inquiry will be made." However, in the 1980's the FDA did suffer some criticism for delaying approval of AIDS drugs. When patient advocacy groups get media coverage, the FDA responds because "they make the consequences of delay and rejection more visible."

Allegations regulation harms patients through lack of options

There are trade-offs in regard to regulation. Increase the safety standards increases lag time for drugs to come to market, therefore there is some suffering and deaths during that time that could have been averted if the standard were more relaxed. However, decreasing the safety standards allows dangerous drugs to come to market that would otherwise not have, therefore also causing some suffering and deaths. Increasing standards also makes it more costly to bring drugs to market, which prevent some drugs from coming to market at all. In trying to prevent bad drugs from coming to market, good drugs are slowed or prevented from coming to market. The question is at what level to set the standards so that more suffering is alleviated than caused, or whether to eliminate government from setting the standards at all and leaving it to the market with voluntary approvals either by the FDA or private certifiers. According to economist Daniel B. Kline who researched economists' views, "many economists" would agree with Milton Friedman who said "The FDA has done enormous harm to the health of the American public by greatly increasing the costs of pharmaceutical research, thereby reducing the supply of new and effective drugs, and by delaying the approval of such drugs as survive the tortuous FDA process.” Recently, it has been claimed by other economists that formal studies of the costs and benefits of FDA regulations are largely lacking from the economics literature.

The FDA recognizes that "safety" depends on the potential benefits of a drug, so if a drug with serious side effects can be used to treat a deadly disease it would be approved more easily than a drug with the same side effects to treat a minor ailment. However, Austrian school economist Robert Higgs says that the FDA does allow it to be taken into account that each individual has his own standards of approval in regard to what risks he is willing to take in light of possible benefits, and, instead, imposes its own risk-avoidance preferences on the consumer. Taking this into account, Higg's analysis concluded that "the FDA's regulation of drugs (and likewise its regulation of medical devices), both general and in several of its specific forms, has deterimental effects on consumers' welfare, with consumer welfare being "properly understood" as consumers' prospective and subjective marginal utility.

A national survey of neurologists and neurosurgeons performed The Polling Company by commission of the anti-regulation Competitive Enterprise Institute in 1998 (after the passage of the FDA Modernization Act of 1997) revealed that 67% of them believe that the FDA takes too long to approve new drugs and medical devices. 73% of them believe that unapproved drugs and devices should be made available to them provided there is a warning lable indicating the unapproved status. 58% agree that the approval process costs lives. 80% of them say that on at least on occation that the approval process has prevented them from treating their patients with the best possible care.

Regulation allegedly slows drug development excessively

Prior to passage of the Kefauver Harris Amendment of 1962, the average time from the filing of an investigational new drug application (IND) to approval was seven months. By 1998, it took an average of 7.3 years from the date of filing to approval. Prior to the 1990s, the mean time for new drug approvals was shorter in Europe than in the United States, although that difference has since disappeared. FDA critics such as Nobel prize-winnning economist Milton Friedman acknowledge that the lengthy FDA approval process has saved lives in individual cases, such as that of thalidomide, but argue that "there's enormous evidence that they have caused more deaths by late approvals than they have saved by early approval." Not all scholars agree that economists have substantially addressed this issue however. In 2005, the authors of a new economic methodology for evaluating the effects of changes in FDA approval time wrote "very little quantitative empirical evidence has been put forward to evaluate the degree to which the speed and safety tradeoff facing the FDA is being resolved efficiently." The authors added that they were aware of only a single prior economics study which methodically attempted to address this issue, and it dated to 1973.

Concerns about the length of the drug approval process were brought to the fore early in the AIDS epidemic. In the late 1980s, ACT-UP and other HIV activist organizations accused the FDA of unnecessarily delaying the approval of medications to fight HIV and opportunistic infections, and staged large protests, such as a confrontational October 11, 1988 action at the FDA campus which resulted in nearly 180 arrests. In August 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. Partly in response to these criticisms, the FDA introduced procedures to expedite approval of drugs for life threatening diseases, and exanded pre-approval access to drugs for patients with limited treatment options.

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

"Proof of Efficacy" requirements increases prices of drugs unnecessarily

Studies published in 2003 by Joseph DiMasi and colleagues estimated an average cost of approximately $800 million to bring a new "first-in class" drug to market, while a 2006 study estimated the cost to be $500 million to $2 billion. The consumer advocacy group Public Citizen, using a different methodology, estimated the average cost for development of all new drugs to be under $200 million, about 29% of which is spent on FDA-required clinical trials. Dimasi himself rejects the claim that high drug development costs are responsible for high drug prices. As he wrote in a published letter, "At the time that drug prices are determined, the associated R&D spending for a drug is a sunk cost. Basic economic logic tells us that R&D costs do not determine prices."

In contrast, Nobel prize winning economist Gary S. Becker has written that FDA-required clinical trials for new drugs do contribute to high drug prices for consumers. Prior to the passing of the Kefhauver-Harris Amedment, drugs were only required to obtain FDA certification for safety. That 1962 amendment introduced new regulations went beyond safety standards and required that drugs be proven to be effective, as well, to the FDA. Rejecting government-imposed price controls as a solution to lowering prices, Becker advocates eliminating the regulations introduced in 1962, which would make drugs cheaper to bring to market. He says that this reduced cost in bringing drugs to market will increase the introduction of new drugs, especially from small biotech firms that do not have the capital to invest in extended efficacy trials. Becker says that this will result in more drugs coming to market to compete with each other and will therefore result in lower prices. He says though efficiacy trials would not be mandatory, "fear of lawsuits and the desire to maintain a good reputation would sometimes induce companies to conduct many trials before marketing highly invasive medicines." Another way of saying this is that costly regulations create a barrier to entry for lesser capitalized firms, resulting in less competition in the field. According to one study, the approval process doubles the cost of developing a new drug.

FDA approval procedures negatively affect research and development cycle

A study by Steven N. Wiggins compared pre-1962 data with date after 1962 through the 1970's and found that the 1962 regulations drastically reduced the number of new drugs introduced as well as reduced the amount of research spending. They found that regulations have reduced the rate of introduction of new drugs by 60%. They find a "steep trade-off" between requiring greater certainty about a drugs effectiveness and the rate of new drug introductions.

Importation regulations increase costs

Some claim that the FDA unjustly opposes importation of cheaper drugs from foreign sources, which is held to be an anti-competitive policy that keeps drug prices artificially high in the United States. Prices of almost all pharmaceutical drugs in Europe are significantly lower than in the United States.

Representatives of the pharmaceutical industry, which supports importation restrictions, respond that the lower prices are often due to government imposed price caps, not because of "competition" between markets.

FDA is slow in granting over-the-counter status

An article in the libertarian magazine Reason argued that the FDA should be more aggressive about switching medications to over-the-counter status. They argue that the prescription requirement causes consumers to spend time and money on unnecessary doctor's visits. In the past, the FDA has lagged behind regulator agencies in other major industrialized nations in switching drugs from prescription to over-the-counter status. Unlike some nations, the U.S. does not have a pharmacist-dispensed "behind the counter status" for drugs which are not yet deemed appropriate for over-the counter status, but which do not require a doctor visit for safe and effective usage by patients.

FDA advertising restrictions violate First Amendment and patient safety

Some critics argue that FDA restrictions on speech in drug marketing are harmful or unconstitutional. The drug propranolol was approved in 1968, but was not specifically indicated for the treatment of angina or hypertension until 1973 and 1976 respectively, despite earlier evidence that it might be beneficial in these conditions. A study by Arthur D. Little estimated that approximately 10,000 American died every year that the FDA prohibited manufacturers from disseminating information about these uses, including sending copies of peer-reviewed studies to doctors and advertising. When folic acid was recommended to reduced birth defects by the Centers for Disease Control and Prevention in 1992 , the FDA immediately announced that it would prosecute any food or vitamin manufacturer that placed the CDC recommendation in its advertising or labeling.

The FDA has also been criticized for prohibiting dietary supplement manufacturers from making "drug claims" on the labels of their products. Manufacturers of supplements (which are considered foods for regulatory purposes) are only allowed to make limited claims regarding how the supplement affects the structure or function of the body (structure/function claims), and are prohibited from stating that the supplement can prevent, cure, or mitigate a disease or condition.

One critic, Representative Ron Paul (R-TX), introduced a bill on November 10 2005 titled the "Health Freedom Protection Act " (H.R. 4284), which proposes to stop "the FDA from censoring truthful claims about the curative, mitigative, or preventative effects of dietary supplements, and adopts the federal court’s suggested use of disclaimers as an alternative to censorship. Other critics, such as the Life Extension Foundation, claim that the prohibitions are a violation of the Constitutional right to free speech.

The FDA also prevents providers of foods from making certain "drug claims." For example, the FDA threatened legal action against cherry juice manufacturers for labels with claims such as "If you're plagued with chronic pain of arthritis, headaches, or even gout, pros say a daily bowl of cherries could ease your ache without side effects," and "cherries are packed with... a natural chemical that not only flushes cancer-causing substances out of the body, but also helps stunt the growth of cancerous cells." The FDA has sent letters to cherry distributors saying that when health benefits are mentioned, the cherries then become "drugs" that, among other enforcement actions, are subject to "seizure."

Under-regulation

In contrast to those who see the FDA as a source of excessive regulation, other critics believe that the FDA does not regulate strictly enough. According to this view, the FDA allows unsafe drugs on the market because of pressure from pharmaceutical companies, fails to ensure safety in drug storage and labelling, and allows the use of dangerous agricultural chemicals, food additives, and food processing techniques.

Allegedly releases unsafe drugs

Some critics believe that the FDA has been too willing to overlook safety concerns in approving new drugs, and is slow to withdraw approved drugs once evidence shows them to be unsafe. Troglitazone and rofecoxib (trade name Vioxx) are high-profile examples of drugs approved by the FDA which were later withdrawn from the market for posing unacceptable risks to patients.

Troglitazone is a diabetes drug that was also available abroad at the time the FDA approved it. Post-marketing safety data indicated that the drug had dangerous side-effects (in this case liver failure). The drug was pulled off that market in the UK in 1997, but was not withdrawn by the FDA until 2000, before which time it is claimed that thousands of Americans were injured or killed by the drug.

In the case of Vioxx, a pre-approval study indicated that a group taking the drug had four times the risk of heart attacks when compared to another group of patients taking another anti-inflammatory, naproxen. The FDA approval board accepted the manufacturer's argument that this was due to a previously unknown cardioprotective effect of naproxen, rather than a risk of Vioxx, and the drug was approved. In 2005, the results of a randomized, placebo-controlled study showed that Vioxx users suffered a higher rate of heart attacks and other cardiovascular disorders than patients taking no medication at all. Faced with numerous lawsuits, the manufacturer voluntarily withdrew it from the market in 2004. 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.

David Graham, a scientist in the Office of Drug Safety within the CDER, testified to Congress that he was pressured by his supervisors not to warn the public about dangers of drugs like Vioxx. He argued that an inherent conflict of interest exists when the office responsible for post-approval monitoring of drug safety is controlled by the same organization which initially approved those same drugs as safe and effective. In a 2006 survey sponsored by the Union of Concerned Scientists, almost one-fifth of FDA scientists said they "have been asked, for non-scientific reasons, to inappropriately exclude or alter technical information or their conclusions in a FDA scientific document."

In 2006, a committee was appointed by the Institute of Medicine to review pharmaceutical regulation in the U.S. and to issue reccomendations for improvements. The committee was composed of 16 experts, including leaders in clinical medicine, medical 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 independance of the FDA.

Approved unsafe additives and packaging procedures in foods

Food safety advocates have criticized the FDA for allowing meat manufacturers to use carbon monoxide gas mixtures during the packaging process to prevent discoloration of meat, a process which may hide signs of spoilage from the consumer. The irradiation of food for purposes of safety and longer shelf life is regulated by the FDA. The FDA has concluded that such irradiation is safe, but places a consumer advisory label on all irradiated food.

The FDA has been criticised for allowing the use of recombinant bovine growth hormone (rBGH) in dairy cows. rBGH-treated cows secrete higher levels of insulin-like growth factor 1 (IGF-1) in their milk than do untreated cows. IGF-1 signalling is thought to play a role in sustaining the growth of some tumors, although there is little or no evidence that exogenously absobed IGF could promote tumor growth. The FDA approved rBGH for use in dairy cows in 1993, after concluding that humans drinking such milk were unlikely to absorb biologically significant quantities of bovine IGF-1. A 1999 report of the European Commission Scientific Committee on Veterinary Measures relating to Public Health noted that scientific questions persist regarding the theoretical health risks of milk from rBGH-treated cows, particularly for feeding to infants. Since 1993, all EU countries have maintained a moratorium on rBGH use in dairy cattle.

The FDA has also been criticised for permitting the routine use of antibiotics in healthy domestic animals to promote their growth, a practice which contributes to the evolution of antibiotic-resistant strains of bacteria. The FDA has taken recent steps to limit the use of antibiotics in farm animals. In September 2005, the FDA withdrew approval for the use of the fluoroquinolone antibiotic enrofloxacin (trade name Baytril) in poultry, out of concern that this practice could promote bacterial resistance to important human antibiotics such as ciprofloxacin.

The FDA has received criticism for its approval of certain coal tar derived food dyes such as FDC yellow 5 and 6, which are banned in most European countries. However, many studies of these compounds have failed to demonstrate heath risks. For example, a Japanese group found in 1987 that tartrazine was not carcinogenic even after being fed to mice for two years. In addition, a German group found in 1989 that Sunset Yellow did not induce mutations that could lead to cancer in laboratory animals.

Pharmaceutical industry has too much influence over the FDA

Critics have disputed the claim that the Prescription Drug User Fee Amendment has improved the speed of drug approvals. The advocacy group Consumer Union has claimed that the primary effect of this program has been to increase the influence of the pharmaceutical industry on FDA policy, similar to the effect meat industry user fees have had on the USDA. In contrast, a 2005 analysis published by economists at the National Bureau of Economic Research estimated that the PDUFAs produced a welfare benefit of billions of dollars to producers, and saved hundreds of thousands of patient life-years through more rapid drug approvals.

A 2005 investigation by reporters from the prestigious science journal Nature found that 70% of FDA panels writing clinical guidelines on prescription drug usage contained at least one member with financial links to drug companies whose products were covered by those guidelines. In the most egregious instance, every member of a panel which recommended the use of epoeitin alfa in HIV patients had received money from a manufacturer of that drug. On March 21, 2007, the FDA announced new guidelines for disqualifying experts from serving or voting on advisory committees if they had received financial compensation from a drug company potentially affected by the committee's recccomendations.

The FDA has been criticized regarding its delayed approval of foreign drugs to protect the US pharmaceutical companies from foreign competition. Eli Lilly's Fluoxetine was the first SSRI to be approved by the FDA. Kali-Duphar, the Dutch manufacturer of another antidepressant fluvoxamine, had first attempted to apply for FDA review in the early 1980s (much earlier than Eli Lilly) but fluvoxamine was not approved until the rights were bought by the US pharmaceutical company Reid Rowell. Critics have suggested that the FDA was attempting to protect Eli-Lilly's fluoxetine so it could gain a foothold in the US market before approving fluvoxamine.

FDA discriminates based on sexual preference in blood donations

Blood collecting organizations, such as the American Red Cross, have policies in accordance with FDA guidelines that prohibit accepting blood donations from any "male who has had sex with another male since 1977, even once". The inclusion of homo- and bisexual men on the prohibited list has created some controversy, but the FDA and Red Cross cite the need to protect blood recipients from HIV as justification for the continued ban. Even with PCR-based testing of blood products, a "window period" may still exist in which an HIV-positive unit of blood would test negative. All potential donors from HIV high risk groups are deferred for this reason. The issue has been periodically revisited by the Blood Products Advisory Committee within the FDA Center for Biologics Evaluation and Research. Documentation from these meetings is available.

See also

• Institute of Food and Agricultural Sciences (IFAS)
• Frances Oldham Kelsey
• Kefauver Harris Amendment
• RAFT Program (pharmaceutical)
• Drug Efficacy Study Implementation
• Investigational Device Exemption
• European Medicines Agency
• Health Canada
• Japan Ministry of Health
• Pharmaceutical company

Further reading

• Philip J. Hilts, Protecting America's Health: The FDA, Business, and One Hundred Years of Regulation, ISBN 0-375-40466-X

External links

Food and Drug Administration websites

• 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

Selected news coverage

• Frontline: Dangerous Prescription: watch online |PBS
• US drug safety checks 'slack' from the BBC News
• FDA Scientists Pressured to Exclude, Alter Findings; Scientists Fear Retaliation for Voicing Safety Concerns from the Union of Concerned Scientists.