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. FDA approves a drug for marketing when the agency judges that its known benefits outweigh its known risks. However, because premarket evaluations are limited in their ability to always predict safety and efficacy with absolute certainty, FDA continues to assess a drug’s risks and benefits after it has been marketed. If the agency identifies a postmarket safety issue, it makes a decision regarding whether to take a regulatory action, such as withdrawing the approval of a drug, which it rarely does, or communicating new safety information to the public and healthcare providers. The decision-making process for postmarket drug safety is complex, multidisciplinary, and relies on an iterative interaction between OND, OSE, and other FDA components. OND, which primarily conducts premarket reviews of drug applications submitted by drug sponsors, also has postmarket drug safety as one of its responsibilities. Although it interacts with OSE and staff from other offices concerning the postmarket safety of drugs, OND has ultimate responsibility to decide whether to take regulatory action regarding these issues. The office is organized into 17 review divisions that generally reflect certain therapeutic areas, such as gastroenterology or oncology drugs. The review of safety and efficacy data from drug applications is conducted by OND medical reviewers, who typically are physicians who have expertise in specific therapeutic areas and are skilled in the review of clinical trials. OSE’s primary focus is on postmarket safety, although it is also involved in certain premarket drug safety issues. OSE has traditionally operated primarily in a consultant capacity to OND and has not had any independent decision-making responsibility. When a safety issue is identified, OSE staff may conduct an analysis and produce a written report called a “consult” to assist OND. Safety consults could include analyses of adverse event reports and assessments of postmarket study designs. In contrast to OND’s organization by therapeutic area, OSE is organized into five divisions that each reflect different areas of its drug safety responsibilities. Two divisions analyze adverse event reports, one division reviews epidemiologic studies completed by drug sponsors and conducts its own studies, one division reviews risk management plans submitted by drug sponsors, and one division reviews proposed proprietary drug names submitted by drug sponsors for their new products and postmarket studies of medication errors completed by drug sponsors and others. To help it provide oversight of important, high-level safety decisions, FDA established the Drug Safety Oversight Board in spring 2005. The board is comprised primarily of FDA staff, including OND and OSE officials, but also includes officials from other federal agencies, such as the National Institutes of Health. It was established with the goal of providing independent oversight and making recommendations to the CDER Director about the management of important drug safety issues. An important part of the drug approval and postmarket monitoring process is the advice the agency receives from CDER’s 16 drug-related scientific advisory committees composed of external experts. The committees are generally organized into specific therapeutic areas, such as gastrointestinal drugs or oncologic drugs. In 2002, FDA established DSaRM, which is one of the 16 committees. In contrast to the committees focused on a specific therapeutic area, DSaRM was established to advise FDA on drug safety and risk management issues across therapeutic areas. The committee’s charter states that DSaRM is to be composed of 14 members—13 voting members with drug safety expertise and 1 nonvoting member to represent the drug industry. DSaRM members can also be asked to participate in other scientific advisory committee meetings when safety issues are discussed. OSE sets the agenda for DSaRM meetings, whereas OND sets the agenda for meetings of the other 15 committees. Advisory committees may make recommendations to FDA that are not binding on the agency’s decision making. If individuals within CDER have differences of professional opinion or scientific disputes regarding a decision taken by the agency, they are generally expected to try to resolve them through their supervisory chain. If staff cannot resolve the dispute through this process, they can access CDER’s differing professional opinion (DPO) program. First implemented as a pilot program in November 2004, it provides a process through which individuals can protest agency actions or inaction when they believe there is a risk of a significant negative impact on public health. Under this process, a dispute filed by a CDER employee could be reviewed by an ad hoc panel of three to four employees. The panel chair, who is appointed by the CDER Director, appoints the additional members one of whom is nominated by the employee initiating the dispute. The panel would make a recommendation for resolving the dispute to the CDER Director. Several elements of this process are overseen by the CDER Ombudsman’s Office, in consultation with the CDER Director. FDA uses evidence from multiple data sources to inform its postmarket decision-making process, each of which has certain strengths and weaknesses. FDA uses randomized clinical trial data to assess drug safety prior to approval. However, these data have inherent weaknesses. Therefore, the agency uses other data to continue to assess drug safety once drugs are on the market. One method of assessing postmarket drug safety is through the collection and analysis of reports of adverse events associated with drug use. FDA requires drug sponsors to submit adverse event reports for the drugs they market. In addition, healthcare providers and patients may voluntarily submit adverse event reports to FDA’s Medwatch program by telephone, by mailing or faxing a paper form, or through a Web-based application on the Medwatch Web site. In 1997, CDER implemented the Adverse Event Reporting System (AERS), which it uses to store reports of adverse events. Adverse events are often a basis for postmarket safety actions; however, adverse event reporting has limitations that make it hard to establish the magnitude of a safety problem or to compare risks across similar drugs. Therefore, once a “safety signal” is identified for a marketed drug, FDA may use data from observational epidemiologic studies to further examine relationships between a drug’s use and reported adverse events. To conduct these studies, the agency seeks data from large, external databases of electronic health information—including claims data collected by health insurance companies and electronic medical records of care provided through large healthcare systems. (See table 1 for a description of these data sources used to inform drug safety decision making before and after approval.) In 2006, we reported that FDA’s process for overseeing postmarket drug safety was limited by a lack of clarity about OSE’s role in decision making. For example, while OSE often made recommendations to OND in the consults that it completed, the agency had no policy explicitly stating whether this was part of OSE’s role. OSE staff also reported that these consults sometimes fell into a “black hole” or “abyss” and OSE staff would not be informed of the results of their recommendations. Also in 2006, IOM noted that an imbalance in authority, formal role, and resources between OND and OSE constituted a major obstacle to a healthy organizational culture in CDER. Furthermore, IOM reported that FDA’s challenges are reflective of how premarket and postmarket functions have been divided historically. OSE generally takes a population-based perspective in their drug safety work by utilizing adverse event reporting and observational studies, while OND generally takes a clinical perspective that focuses primarily on randomized clinical trials. They reported that OND staff often view the observational data used by OSE as “soft” and unconvincing, while OSE staff view these data as informative and carrying great weight. IOM noted that the imbalance in roles and responsibilities denoted a subservience of the safety function and a devaluation of OSE’s discipline and approach by agency management. We also identified several specific limitations to FDA’s postmarket decision-making process. Several years prior to the release of our 2006 report, FDA started drafting a policy intended to clarify the role of staff, including those from OSE, in the decision-making process. However, the policy had not been finalized and implemented by the time our 2006 report was issued. In addition, we reported that the role of OSE staff in planning for and participating in advisory committee meetings, other than those involving DSaRM, was not clear. We also found that the DPO program had not been used and may not have been viewed as sufficiently independent because it did not offer employees a forum for resolving disputes that was independent of the CDER Director. We reported, for example, that the CDER Director would help decide whether a dispute warranted review and would also make the final decision about how the dispute would be resolved. We also found that OSE management had not effectively overseen postmarket drug safety and lacked systematic information on this process. Specifically, although OSE maintained a database of consult requests it received from OND, the database did not include information about whether OSE staff had made recommendations to OND regarding safety actions. It also did not include information on how the safety issues were resolved, including whether OSE’s recommended safety actions were implemented by OND. In addition, in 2006, OIG found weaknesses in the extent to which FDA tracked another element of postmarket drug safety, the progression of postmarketing studies that FDA had requested drug sponsors to complete. OIG found that FDA could not readily identify whether or how timely these studies were progressing toward completion. We also found in 2006 that FDA faced constraints in its access to data that allow it to monitor the safety of marketed drugs. For example, FDA staff and external drug safety experts told us that OSE did not have enough funding to support the purchase of data for postmarket drug surveillance. Similarly, IOM found that funding for purchasing data was severely limited and had changed little in over 20 years. IOM also found that FDA devoted limited resources for staff training and supportive technology that was needed to fully utilize purchased data.