FDA Approvals and Regulations: Overview

Introduction

The United States Food and Drug Administration (FDA) is the government consumer-protection agency responsible for ensuring the safety and effectiveness of drugs, medical treatments and devices, vitamins, food supplies, cosmetics, and other biological products manufactured and/or sold within the country. In order to protect public health and safety, many FDA-regulated products go through an approval process, which varies in complexity and timeliness depending on the type of product.

Approvals for pharmaceutical products, such as prescription drugs, are conducted by the Center for Drug Evaluation and Research (CDER) and are especially strict and extensive. Before a pharmaceutical product may be sold to consumers, it must undergo a process of pre-market review and approval involving several clinical trials. Generic drugs and over-the-counter drugs also are regulated by the FDA, as is the promotion of off-label uses for approved drugs. Other FDA regulations include product-specific safety standards, labeling requirements, and rules governing how products may be advertised.

Since its establishment in 1906, the FDA has been at the center of a number of national controversies. The agency has been criticized by consumers, pharmaceutical companies, and governmental and nongovernmental bodies alike for being too strict, not strict enough, or unfairly biased in its approvals and regulations.

Understanding the Discussion

Center for Drug Evaluation and Research (CDER): The division of the FDA responsible for approving medications.

Clinical Trial: A research study designed to test the safety and effectiveness of medical treatments such as medications, devices, or other therapies. Clinical trials are conducted on human subjects and may focus on answering a specific medical question or determining efficacy of a new treatment.

Consumer Protection: A practice governing the safety and sales of products or services consumed by individuals. Consumer-protection laws provide for controls intended to safeguard consumers’ interests when transacting with businesses in the marketplace.

Generic Drug: A version of a brand-name drug sold under a different name, usually by a different manufacturer from the original patent holder. After a drug’s patent expires, any pharmaceutical company can manufacture and sell the drug under its chemical or generic name for its approved purposes. Generic drugs, by law, differ in name and appearance from the brand-name drugs, but their ingredients, production, and usage indications are identical to the original.

Off-Label Use: The prescription of an FDA-approved drug for a purpose other than that for which it was first approved. Off-label uses cannot be advertised by pharmaceutical companies. The FDA sets specific regulations on how off-label messages are conveyed by medical providers or vendors.

On-Label Use: The prescription of a drug for the purpose for which the FDA first approved it.

Over-the-Counter (OTC) Drugs: Legal therapeutic drugs that consumers may purchase without a prescription, such as aspirin.

Pharmaceutical: Having to do with drugs or medicinal treatment.

Pre-market Approval: The rigorous process of testing and FDA review that takes place before a medical device or technology can be granted safety clearance into the market.

Prescription Drugs: Drugs that can be dispensed only with the signed authorization of a licensed health-care professional; this authorization, written or electronic, is called a prescription.

History

Until the mid-nineteenth century, state and local governments carried most of the responsibility for regulating foods and drugs in the United States. This decentralized system resulted in an inconsistent collection of laws that did not sufficiently ensure either the safety or the efficacy of products.

The first comprehensive attempts to inspect and regulate foods and drugs nationally began in 1883 and were led by Harvey Washington Wiley, chief chemist of the government’s Division of Chemistry. Wiley pushed for a federal law that would prohibit both the use of unsafe chemical preservatives in foods and drugs and the misrepresentation of a marketed product’s properties. Congress passed the Pure Food and Drug Act of 1906 to regulate production and marketing of food and drugs, as well as to allow the government to seize unlawful foods and drugs that were being transported across state lines. In 1927, the Division of Chemistry, then known as the Bureau of Chemistry, was reorganized as the Food, Drug, and Insecticide Administration. Its name was shortened in 1930 to the Food and Drug Administration.

In the late 1930s, the need for a formal testing and approval process for drugs became clear when a pharmaceutical company based in Tennessee began selling a drug that contained a toxic chemical in its preparation. More than one hundred adults and children who ingested the drug died as a result of its poisonous action. As a direct result of this incident, the 1938 Federal Food, Drug, and Cosmetic Act (FFDCA) was passed, requiring pre-market FDA approval for all drugs. The act also required the FDA to set food safety standards and ensure that all drugs be sold with proper labeling and instructions for use.

During the following decades, the FDA’s pre-market approval process for drugs was expanded to include oversight for related clinical trials. This was due to problems associated with the drug thalidomide, which was found to cause deformities in newborns only after it was prescribed widely to European women during pregnancy as a means of alleviating morning sickness. At the time, it had not been approved by the FDA for use in the United States, but thalidomide samples had been distributed to American physicians allegedly as part of the drug company’s internal investigation process, a practice allowable at the time while the drug was undergoing the approval process. As a result of this incident, the Kefauver-Harris Amendment to the FFDCA was passed in 1962, requiring FDA control over clinical trials and requiring that volunteer subjects not only be fully informed, but also sign acknowledgements that they understand the potential hazards of a drug or intervention before participating in a trial.

Other legislation, such as the Food Additives Amendment of 1958, the Drug Abuse Control Amendments of 1965, and the Medical Device Amendments of 1976, added to the authority and responsibilities of the FDA. During this period, some consumer-protection tasks that previously fell under the authority of the FDA were transferred to other government departments. For example, in 1973, the newly created Consumer Product Safety Commission became responsible for the regulation of consumer products such as toys and fabrics.

The FDA has received significant criticism over the years. Some have complained that the agency’s regulations are too exacting and its approval process too extensive and time consuming, unnecessarily delaying potential new therapies for patients. Such criticisms were especially heated in the 1980s, when AIDS activists accused the FDA of taking too long to approve drugs to treat HIV, which can develop into AIDS and for which there is no known cure to date.

In response to the criticism from AIDS activists, the 1992 Prescription Drug User Fee Act shortened the time allowed for the FDA to review most drugs from thirty months to one year. Under the same law, an application fee was instituted for pharmaceutical companies seeking product approval. This fee drew additional criticism from groups such as Consumers Union, which argued that the hundreds of millions of dollars drug manufacturers pay the FDA each year enable the companies to exert unfair influence over the agency’s decisions.

Conversely, in the early twenty-first century, critics accused the FDA of being too quick to approve drugs, claiming that approval was being given without subjecting them to a sufficiently rigorous review process. Between 1992 and 2014, pharmaceutical companies were forced to withdraw, for safety reasons, a total of eighteen drugs that had been approved by the FDA. However, a 2015 study by Kurt R. Karst lists the number of withdrawn drugs in the hundreds, as he notes drugs may be withdrawn under classifications other than safety. The FDA received particularly harsh criticism over its approval of Vioxx, an anti-inflammatory medication that later proved to significantly increase patients’ risk of heart attacks.

FDA Approvals & Regulations Today

The FDA is charged with regulating a vast number of products that, by late 2019, collectively accounted for about one-fifth of all consumer spending in the United States. The agency has responded to critics by emphasizing its many successes in improving the safety and efficacy of health products. It acknowledges that its regulatory measures must develop continuously in order to keep up with scientific and social changes, and it points out that adequate federal funding is needed to continue protecting consumers and patients. The Alliance for a Stronger FDA, formed in 2007 by the merger of the Coalition for a Stronger FDA and the FDA Alliance and consisting of various patient groups, public-health advocates, trade associations, and nonprofit organizations, is one organization that has lobbied the government for larger FDA appropriations in the federal budget.

US president Barack Obama criticized the FDA regulation process as detrimental to the development of American medical innovations, which in turn impacts the US economy. In 2012 Congress passed the Food and Drug Administration Safety and Innovation Act, which, among other provisions, enabled the FDA to expedite development and approval of designated “breakthrough therapies” that, based on preliminary clinical evidence, may represent a significant improvement over existing therapies for serious or life-threatening conditions. It also gave the FDA increased authority to regulate imported drugs and active ingredients for drugs, which constitute nearly 40 percent of all drugs and nearly 80 percent of all active ingredients used in the United States. In December 2016, Obama signed the 21st Century Cures Act, which, among other provisions, created expedited approval programs for regenerative medicines (such as cell and gene therapies) and some breakthrough medical devices. It also allowed "surrogate markers" to be used alongside clinical trial data during the review process.

Under Commissioner Scott Gottlieb, the FDA expedited approvals for generic medications with the intention of increasing competition. It also began allowing "adaptive clinical trial design," meaning that researchers could change how they structured their study partway through testing without restarting their application. Critics argued that faster approvals do not necessarily contain drug prices, as breakthrough therapies essentially constitute monopolies and newer competitor drugs may mirror the high pricing of existing formulations on the market. Undue financial influence from industry on the regulatory agency, such as "pay-later" conflicts of interest, remained another area of concern.

A 2017 JAMA study found that 71 of the 222 new drugs and biologics approved between 2001 and 2010 experienced significant safety problems after FDA approval. Such events were more common among products that had received accelerated approval or approval within two months of the regulatory decision deadline. Several withdrawals, dozens of safety communications, and scores of boxed warnings were issued as a result. The analysis cast further doubt on whether the FDA was sacrificing patient safety for the sake of speed.

Another JAMA analysis, published in 2020, found the average number of annual FDA new-drug approvals between 2010 and 2018 had reached forty-one, up from thirty-four in the 1990s and twenty-five in the 2000s. Eighty-one percent of new drugs approved in 2018 had gone through an accelerated approval, fast-track, and/or priority review program; indeed, by 2017, review times had declined to under one year, as the FDA accepted less rigorous clinical trial data and more surrogate measures.

The ongoing debate of caution versus availability of potentially life-saving devices and treatment gained further salience amid the COVID-19 coronavirus pandemic. In February 2020, the FDA allowed academic hospitals to create and begin using their own test kits ahead of an emergency use authorization, as the nation faced virus-testing shortages. Some medical professionals also urged a COVID-19 vaccine be expedited after initial clinical tests, rather than wait for the completion of the typical three-phase testing process, which could take over twelve months. Others pointed out that a vaccine could receive emergency use authorization (EUA) as well. The FDA opted for the latter approach and granted EUAs for COVID-19 vaccines before approving them. In 2020, the FDA granted EUAs to the first two mRNA COVID-19 vaccines, Pfizer-BioNTech and Moderna, before giving its first approval to the Pfizer-BioNTech vaccine in August 2021. In 2023, the FDA had either approved or given EUA to COVID-19 vaccines from Pfizer-BioNTech, Moderna, and Novavax, which had been updated to provide better protection against variants in circulation in 2023 and 2024.

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