Food and Drug Administration

FDA logo

The Food and Drug Administration (FDA) is an agency of the U.S. Department of Health and Human Services and is responsible for regulating food, dietary supplements, drugs, biological medical products, blood products, medical devices, radiation-emitting products, veterinary products, and cosmetics in the United States. The FDA also approves some diagnostic tests related to blood safety. As well as being a regulatory agency, it both does research and works with clinical trials.

Organization

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

Until a new Commissioner is appointed by the Obama administration and confirmed by the Senate, the FDA is under the interim leadership of Frank M. Torti. No nominee had been sent to the Senate as of February 3, 2009. A variety of candidate names have been suggested but it is an inherently controversial position to fill, given the FDA has many contituencies, frequently at odds with one another.

During the George W. Bush Administration, the FDA was 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 that are consolidated into the Code of Federal Regulations, Title 21, part 60. 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 randomized controlled 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.

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.

Drugs approved just before deadlines are more likely to have problems after approval.

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, which is almost half of its budget. 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).

Office of Generic Drugs

The Office of Generic Drugs (OGD) is responsible for certifying bioequivalence of generic drugs. The Orange Book contains all approved bioequivalent generic drugs. The OGD also maintains List of authorized generics.

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.

Drug marketing and advertising

Within the Center for Drug Evaluation and Research, the mission of the Division of Drug Marketing, Advertising, and Communications (DDMAC) is:

"To protect the public health by assuring prescription drug information is truthful, balanced and accurately communicated. This is accomplished through a comprehensive surveillance, enforcement and education program, and by fostering better communication of labeling and promotional information to both healthcare professionals and consumers."

The DDMAC oversees direct-to-consumer (DTC) and off-label promotion of drugs under section 906 of the Food and Drug Administration Amendments Act of 2007 (FDAAA).

Off label promotion of drugs is an important problem. An example of off-label promotion of drugs in the promotion of Neurontin (gabapentin) by Pfizer.

The pharmaceutical company Eli Lilly and Company was fined $1.415 billion for off label promotion of Zyprexa (olanzapine).

Postmarket drug safety

his figure illustrates the number of reports received (solid bars) and entered (checkered bars) into AERS by type of report since the year 2000 until the end of the first quarter of 2010.

Various databases of reported drug toxicity are available for analysis. Various signal detection algorithms can be used. The FDA maintains MedWatch and its Adverse Event Reporting System (AERS) for reporting of adverse events. Based on the experience with the withdrawal of rofecoxib, there is concern that the FDA's postmarket drug surveillance is not sufficiently vigilant. Consequently, in 2007, "Title IX, Section 921 of the Food and Drug Administration Amendments Act 2007 (FDAAA) (121 Stat. 962) amends the Federal Food, Drug and Cosmetic Act (FDCA) to add a new subsection (k)(5) to section 505 (21 U.S.C. 355)". The FDA's revised mandate is in Title 21 of the United States Code.

The FDA publishes quarterly a list of active signals in the AERS database.

The AERS data files, albeit one year old, are available for download.

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 coronary stents for percutaneous transluminal coronary angioplasty, 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

History

Selected history establishing public need

• 1862 — President Lincoln appoints chemist, Charles M. Wetherill to the Department of Agriculture. This appointment led to the Bureau of Chemistry.
• 1906 — Upton Sinclair's The Jungle is published: this contributes to the creation of the FDA which received power through the 1906 Pure Food and Drug Act under Theodore Roosevelt.
• 1927 — The "Bureau of Chemistry" is reorganized into two separate entities. Regulatory functions are located in the "Food, Drug, and Insecticide Administration", and non-regulatory research is located in the "Bureau of Chemistry and Soils".
• 1930 — The name of the "Food, Drug, and Insecticide Administration" is shortened to "Food and Drug Administration" (FDA) under an agricultural appropriations act.
• 1937 — Over 100 people died after consuming a raspberry-flavored sulfa elixir which had been rushed to market by the S.E. Massengill Company without any testing. About 70 percent of the elixir was diethylene glycol, which is now known to be poisonous (related to antifreeze). However, the FDA was able to remove the sulfa elixir from the market because elixirs at the time were to contain alcohol as a solvent (not diethylene glycol).
• 1938 — The resulting sulfa elixir scandal and public outcry led to the passage of the Federal Food, Drug, and Cosmetic Act of 1938, which gave the FDA the power to preapprove all new drugs introduced into interstate commerce.
• 1959 — During a 10-week period leading up to Thanksgiving, the FDA recalled cranberry crops that may have been exposed to a weed killer, aminotriazole, which was known to cause cancer. The FDA sampled 3653 batches amounting to over 33,000,000 pounds of cranberries and cranberry products. Samples that were deemed safe and did not contain the weed killer were stamped with FDA approval.
• 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 Amendments 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.
• 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.

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

Controversies

Access to unapproved medications

The case of Abigail Burroughs v. von Eschenbach, 2001-2007 addressed access to unapproved medications. 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 American Society of Clinical Oncology (ASCO) filed an amicus brief to the U.S. Court of Appeals in advance of the March 1 hearing, supporting the FDA. ASCO proposes that the Constitution does not guarantee the right to access unapproved medications, and that the court case threatens the cancer clinical trial enterprise.

Excessive regulatory oversight

During drug development early in the HIV epidemic, the FDA was criticized for slow approvals and harming public health. In response, Congress created the Prescription Drug User Fee Act of 1992 and its renewal in 1997.

Insufficient regulatory oversight

After concerns of slow approvals, the In 2004, the Vioxx controversy revealed that the FDA had instances of insufficient oversight. Drugs approved just before deadlines are more likely to have problems after approval.

Pressure from external influence

The FDA has been reported to be influenced by external forces and conflict of interest.

See also

• European Medicines Agency

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 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