Before a drug can be marketed in the United States, its sponsor must demonstrate to FDA that the drug is safe and effective for its intended use. Because no drug is absolutely safe—there is always some risk of an adverse reaction—FDA approves a drug for marketing when the agency judges that its known benefits outweigh its known risks. After a drug is on the market, FDA continues to assess its risks and benefits. FDA reviews reports of adverse drug reactions (adverse events) related to the drug and information from studies about the drug, including clinical trials and studies following the use of drugs in ongoing medical care (observational studies), conducted by the drug’s sponsor, FDA, or other researchers. If FDA has information that a drug on the market may pose a significant health risk to consumers, it weighs the effect of the adverse events against the benefit of the drug to determine what actions, if any, are warranted. This decision-making process is complex and encompasses many factors, such as the medical importance and utility of the drug, the drug’s extent of usage, the severity of the disease being treated, the drug’s efficacy in treating this disease, and the availability of other drugs to treat the same disorder. CDER, the largest of FDA’s five centers, is the organizational entity within FDA that oversees the review of marketing applications for new drugs and the postmarket monitoring of drugs once they are marketed. Within CDER there are several key offices involved in activities related to postmarket drug safety. OND is the largest of the offices with fiscal year 2005 expenditures of $110.6 million and 715 staff. In fiscal year 2005, more than half of OND’s expenditures, or $57.2 million, came from PDUFA funds. OND’s staff evaluate new drugs for efficacy and safety to decide if a drug should be approved for marketing. OND also makes decisions about actions to take when there are postmarket safety issues with a drug (for example, revising the label to include adverse event information or having FDA withdraw approval for marketing). For safety questions, OND interacts with several FDA offices and divisions, but primarily with ODS. ODS is currently located within the Office of Pharmacoepidemiology and Statistical Science (OPaSS), which is organizationally parallel to OND and also contains the Office of Biostatistics. ODS is a much smaller office than OND, with fiscal year 2005 expenditures of $26.9 million and 106 staff. In fiscal year 2005, $7.6 million of ODS’s expenditures were from PDUFA funds. ODS staff evaluate and monitor drug risks and promote the safe use of drugs. While ODS is involved in both premarket and postmarket drug safety issues, its primary focus is on postmarket safety. An important part of the drug approval and postmarket monitoring process is the advice FDA receives from 16 human-drug-related scientific advisory committees, composed of experts and consumer representatives from outside FDA. Considered by FDA as important in helping the agency accomplish its mission and maintaining public trust, these advisory committees provide expert advice to the agency on a range of issues, including safety. The committees are largely organized according to specialized medical areas or conditions such as cardiovascular disease, gastrointestinal conditions, or oncology. In 2002, FDA established the Drug Safety and Risk Management Advisory Committee (DSaRM), 1 of the 16 human-drug-related scientific advisory committees, to specifically advise FDA on drug safety and risk management issues. The committee is composed of individuals from outside FDA with experience in the areas of medication errors, risk communication, risk perception, risk management, clinical trial methodology, evidence-based medicine, biometrics, and pharmacoepidemiology. Since it was established, DSaRM has met nine times, with four of those meetings held jointly with another drug-related scientific advisory committee. DSaRM members have also been asked to participate in other scientific advisory committees when safety issues were discussed. ODS sets the agenda for DSaRM meetings, whereas OND sets the agenda for the other scientific advisory committee meetings. Figure 1 describes the offices and external advisory committees involved in postmarket drug safety at FDA. In terms of postmarket drug safety surveillance, FDA has the authority to require that drug sponsors report adverse events to FDA with different reporting schedules based on the seriousness of the event and whether the event has been previously identified and is included in the drug’s label. Sponsors must report serious, unlabeled adverse events to FDA within 15 days of learning about them. Sponsors are required to report other adverse events quarterly for 3 years, then annually thereafter in the form of periodic adverse event reports. In addition, health care providers and patients can voluntarily submit adverse event reports to FDA through its MedWatch program. Adverse event reports become part of FDA’s computerized database known as the Adverse Event Reporting System (AERS). FDA has the authority to withdraw the approval of a drug on the market for safety-related and other reasons, although it rarely does so. Since 2000 there have been 10 drug withdrawals for safety reasons, and in all of these cases the drug’s sponsor voluntarily removed the drug from the market. FDA does not have explicit authority to require that drug sponsors take other safety actions; however, when FDA identifies a potential problem, sponsors generally negotiate with FDA to develop a mutually agreeable remedy to avoid other regulatory action. For example, if FDA determines that an approved drug may produce adverse events not previously identified, FDA and the sponsor may negotiate on revised labeling for the drug, and then FDA may issue an accompanying Public Health Advisory for patients and health care providers that describes the safety information. FDA may also request that the sponsor restrict the distribution of the drug in order to minimize a significant risk associated with the drug. FDA has limited authority to require that sponsors conduct postmarket safety studies; it may impose such a requirement during the premarket phase of drug development in two situations, and in one during the postmarket phase. In two situations, FDA has the authority to require that sponsors commit to conducting postmarketing studies as a condition of approval. First, FDA’s program for accelerated approval of new drugs for serious or life-threatening illnesses (referred to as “subpart H drugs”) allows FDA to more quickly approve drugs showing meaningful therapeutic benefit with the caveat that the sponsor will conduct or finish studies after the drug is marketed. Such drugs may be made available to the public sooner but with less complete safety information than the normal review process requires for approval. Second, in cases where human efficacy studies of a drug may not be ethical or feasible, FDA may rely on animal studies alone to approve the use of a drug and require postmarket studies as a condition of approval when studies on humans become feasible and ethical. For example, FDA approved a drug in 2003 that is used as a treatment for patients who have been exposed to a chemical nerve agent called Soman. Evidence of the effectiveness of this drug was obtained from animals alone because it is unethical to perform such studies in humans. In either situation, FDA may withdraw approval of these drugs if, for example, postmarket clinical studies fail to verify clinical benefits, the sponsor fails to perform postmarketing studies with due diligence, or postmarketing restrictions (for example, restricted distribution) are inadequate to assure safe use of the drug. Finally, under certain conditions, after a drug is approved, FDA can also require that drug sponsors conduct postmarket studies of marketed drugs when such studies are needed to provide adequate labeling to ensure the safe and effective use of these drugs in children. Two distinct FDA offices are involved in postmarket drug safety activities. While there is some overlap in their activities, they have different organizational characteristics and perspectives on postmarket drug safety. OND is involved in postmarket drug safety activities as one aspect of its larger responsibility to review new drug applications, and it has the decision-making responsibility for postmarket drug safety. ODS has a primary focus on postmarket drug safety and provides consultation to OND. ODS has been reorganized several times over the years, and there has been an absence of stable leadership. FDA’s postmarket drug safety decision-making process is complex, involving iterative interactions between OND and ODS. Since OND is responsible for approving or disapproving drug applications, its staff are involved in safety activities throughout the life cycle of a drug (that is, premarket and postmarket), and it has the ultimate responsibility to take regulatory action concerning the postmarket safety of drugs. OND is organized into six offices that evaluate drugs and drug products, and within these offices are 17 review divisions organized by medical specialty (for example, oncology or dermatology). OND’s staff includes physicians, pharmacologists, toxicologists, and microbiologists. The key decision makers in OND—division directors and office directors—are physicians. In general, OND staff take a clinical perspective in their work. According to the Director of the office, OND’s medical staff have expertise in medical specialties as well as drug regulation, which he said gave them the ability to integrate issues related to the disease, available therapy, effectiveness of the drug, and relative safety. He also told us that OND staff are focused on meeting patient needs and providing health care practitioners and patients with a range of drugs for treatment of a specific disease or condition. Finally, an important characteristic of OND’s organization is that OND’s work and its pace are driven in part by PDUFA goals to complete its review of drug applications within certain time frames. FDA estimates that 51 percent of OND’s work time is devoted to drug safety, either premarket or postmarket. In the drug development or premarket phase, OND staff review safety and efficacy data from sponsors’ animal studies and human clinical trials to decide whether or not to approve a drug.