A little over two years ago, the Senate Finance Committee convened to hear testimony sparked by concern over the popular Merck anti-inflammatory drug Vioxx. A few weeks before, Merck had notified the Food and Drug Administration (FDA) that it was withdrawing Vioxx from the market in response to recent study results indicating an increased risk of heart attacks and sudden cardiac deaths among the millions of patients who had been using Vioxx since its introduction in 1999. Senators wanted to find out what had gone wrong and what could be done to prevent it from happening again. This was not the first time that this Congress had reacted to news about dangers posed by drugs that had already reached the market. Earlier that year, the House Committee on Energy and Commerce's Subcommittee on Oversight and Investigations had held hearings because of controversy over the safety of antidepressants when prescribed to children. In both cases, Members were worried that neither the public nor FDA were sufficiently informed by manufacturers—or, in the case of FDA, sufficiently forthcoming—about risks occurring after the drugs had been first approved. At the Finance Committee hearing, David Graham, Associate Director for Science and Medicine in FDA's Office of Drug Safety, was asked whether these concerns were warranted in the case of Vioxx. He stated, "I would argue that the FDA, as currently configured, is incapable of protecting America against another Vioxx. We are virtually defenseless." Pressed to name other marketed drugs he thought troublesome, Graham named five. The February 2005 meeting of two FDA advisory committees—coming three months after Dr. Graham's testimony to the Senate Finance Committee and five months after Merck withdrew Vioxx from the market—also drew intense public attention. After weighing the evidence on the safety and risk-to-benefit of Vioxx and similar drugs, the committees unanimously asserted that the three COX-2 inhibitors then holding FDA approval for sale in the United States—Vioxx, Celebrex, and Bextra—do increase the risk of heart attack and stroke. Illustrating the complexity of decisions that FDA faces, a majority of the committee members, noting that the benefits of the drugs outweigh the risks for certain groups of people, therefore, recommended to FDA that the agency permit the sale of these drugs—with, however, several severe limitations on advertising and strong warnings in consumer and clinician labeling about cardiovascular risk that is likely associated with dose and duration of use. The furor surrounding Dr. Graham's testimony reawakened interest in a variety of regulatory issues that have surfaced periodically ever since the storm of protest over "filthy, decomposed or putrid" food and "worthless" medicines resulted in FDA's creation during Theodore Roosevelt's presidency. Concerns about regulatory agencies' abilities to protect the public are not unique to FDA or public health. The life-and-death issues of medicine, however, strike most closely to home for many Americans. There has not been a decade since FDA's creation without a highly publicized incident involving drug safety that has led to legislation expanding and strengthening FDA's authority to protect the public. Examples include the scores of children killed by an untested antibiotic (elixir of sulfanilamide) marketed by a company in Tennessee in 1937; the mistakes at a plant manufacturing polio vaccine in 1954 that actually caused 260 cases of polio and 11 deaths; and, in 1962, thalidomide, the sleeping pill that eventually resulted in the birth of at least 8,000 severely deformed babies and thousands of prenatal deaths, mostly in Europe. Today, as the 110 th Congress prepares to consider a variety of health issues, Members still share concerns over drug safety and efficacy. The agency most responsible for such issues is the Food and Drug Administration (FDA). In FY2006, FDA operated on a budget of $1.88 billion ($1.49 billion in appropriated funds and $382 million from user fees), more than $6 per U.S. citizen. With that money, FDA was expected to oversee about $1 trillion of goods, which make up about one-quarter of all U.S. consumer spending. Congressional funding for FDA has increased at about half the rate as that of industry user fees, established by Congress as a way to defray the costs of hiring additional agency personnel so that drug approval review could be quicker. Even though the user fees account for somewhat less than 20% of the FDA total, they made up 59% of FDA's Center for Drug Evaluation and Research (CDER) FY2006 budget. Two regulatory frameworks exist for the review of prescription drugs. First, FDA reviews the safety and effectiveness of new drugs that manufacturers wish to market in the United States; this process is called premarket approval or preapproval review . Once a drug has passed that threshold and is FDA-approved , FDA acts through its postmarket or post-approval regulatory procedures. This report examines issues related to drug safety, specifically in the context of the regulatory process that Congress and the FDA have established for ensuring that drugs are safe and effective. It includes a primer on drug approval: how drugs are approved and come to market, including FDA's role in that process. It also describes FDA and industry roles once drugs are on the pharmacy shelves, the postmarket (also called the post-approval ) period. The report then moves on to a discussion of the problems in identifying and resolving the postmarketing safety and effectiveness issues that are raised most frequently in the debate. Finally, it outlines actions that a variety of analysts have suggested to improve the situation, both ones that FDA could adopt on its own and others for which legislation would be necessary. Derived from the Dutch word meaning to boast (quacken) , "quack" was the word Americans commonly used to describe charlatans in medicine. Quacks peddled adulterated and mislabeled medicines throughout the United States without penalty, until 1906, when Congress passed the Food and Drugs Act, outlawing the practice. It was the first in a series of laws intended to assure Americans that the medicines they used did no harm and actually worked—that they are, in other words, safe and effective . Over the next half-century, Congress passed two major pieces of legislation expanding FDA authority in pursuit of those goals. It passed the Federal Food, Drug, and Cosmetic Act (FFDCA) in 1938, requiring that drugs be proven safe before they could be sold in interstate commerce. Then, in 1962, in the wake of the thalidomide tragedy, Congress amended the law to require that drugmakers prove the effectiveness of their products as well. The process has not remained the same since 1962. The 1983 Orphan Drug Act began a series of additional laws passed by Congress in recent decades to boost pharmaceutical research and development, speed the approval of new medicines, or, in some cases, both. The Orphan Drug Act provided incentives for pharmaceutical manufacturers to develop drugs, biotechnology products, and medical devices for the treatment of rare diseases and conditions. Other laws include the 1984 Hatch-Waxman Act, the landmark compromise balancing greater patent protection of manufacturers with quicker public access to lower-priced generic drugs; the 1992 Prescription Drug User Fee Act (PDUFA), which ushered in user fees and performance goals for faster drug approvals; and the 1997 FDA Modernization Act (FDAMA), which relaxed clinical testing requirements, eased access to experimental therapies, and awarded drugmakers six more months of marketing protection for testing drugs in pediatric patients. The 107 th Congress reauthorized the FDAMA pediatric testing provision within the 2002 Best Pharmaceuticals for Children Act, and extended the drug user fee law for five more years under the Public Health Security and Bioterrorism Preparedness and Response Act. All six pieces of legislation inform the U.S. drug approval process, which is supervised by FDA in accordance with the laws from 1938 and 1962. In the following section, we describe the drug approval process as it functions now. A drug cannot be marketed in the United States without FDA approval, for which the manufacturer must demonstrate the drug's safety and effectiveness to FDA's satisfaction, see its manufacturing plant pass FDA inspection, and obtain FDA approval for the drug's labeling—a term that includes all written and electronic material about the drug, including packaging, prescribing information for physicians, and patient brochures. There are four steps leading to FDA approval of a drug for marketing in the United States: Before testing in humans—referred to as clinical testing—the drug's sponsor (usually its manufacturer) must file an IND application with FDA. It includes information about the proposed study protocol, completed animal test data, the lead investigator's qualifications, and the written approval of an Institutional Review Board based on its determination that the study participants will be made aware of the drug's investigative status and that any risk of harm will be necessary, explained, and minimized. The manufacturer will meet with FDA to discuss whether the clinical study design has sufficient statistical power to enable the manufacturer to draw valid estimates of the safety and effectiveness of the drug. The application must include an Indication for Use section that describes what the drug does and the clinical condition and population for which drug use is intended. Trial subjects should be representative of those who would receive the drug if it is approved. The FDA has 30 days to review an IND. If there is no objection, a manufacturer may begin clinical testing after that time. With IND status, researchers proceed to test in a small number of human volunteers the safety they had demonstrated in animals. These trials, called Phase I clinical trials , "try to determine dosing, document how a drug is metabolized and excreted, and identify acute side effects." If the product still seems viable, the sponsor continues with Phase II and Phase III trials to gather evidence of the drug's efficacy and effectiveness in larger groups of individuals with the particular characteristic, condition, or disease of interest, while continuing to monitor safety.