Responsibility for dietary supplement oversight is shared among several offices at FDA: FDA’s Center for Food Safety and Applied Nutrition (CFSAN) manages the CFSAN Adverse Event Reporting System (CAERS), which collects and stores AERs related to foods and dietary supplements. CFSAN also houses the Division of Dietary Supplement Programs, within its Office of Nutrition, Labeling and Dietary Supplements, which is responsible for developing guidance, providing scientific and technical expertise, and directing dietary supplement priorities across the agency. Additionally, CFSAN’s Office of Compliance has primary responsibility for compliance and enforcement of FDA regulations and federal laws within FDA’s jurisdiction with respect to foods—such as dietary supplements— including coordinating compliance and regulatory actions within the center and with other FDA components. Among other responsibilities, the Office of Compliance reviews incoming investigational findings and recommendations to determine if a proposed action or remedy is supported by the documented observations and other evidence; assesses the integrity and relevance of the evidence; and obtains necessary scientific verification from appropriate subject matter experts. FDA’s Office of Regulatory Affairs is responsible for managing the agency’s field operations in 25 regional and district offices for each of FDA’s centers, including CFSAN. Among other responsibilities, the Office of Regulatory Affairs supports FDA centers by performing inspections and import operations. The Office of Regulatory Affairs also takes advisory and regulatory actions for dietary supplements, but generally these actions are coordinated with CFSAN’s Office of Compliance. FDA’s Center for Drug Evaluation and Research is responsible for oversight of over-the-counter and prescription drugs, including generic drugs and some biological therapeutics. Center for Drug Evaluation and Research officials work with other FDA offices to identify products that are marketed as dietary supplements but that have been deliberately adulterated with active ingredients in FDA-approved drugs or their analogues. Once identified, FDA alerts the public and takes action to protect the public through a variety of consumer protection actions, such as working with firms on voluntary product recalls. Table 2 provides examples of consumer protection actions FDA may take in response to identified safety concerns. According to FDA officials, the estimated resources for all dietary supplement activities across FDA grew slightly from $14.6 million in fiscal year 2009 to a projected $18.9 million in fiscal year 2012. These activities include regulatory and technical review, policy and guidance development, research, education and outreach, compliance and inspection activities, and associated administrative support activities, including infrastructure costs. There are three different paths consumers, health care practitioners, or others can follow for reporting any serious, moderate, or mild health problem related to a dietary supplement to FDA. First, consumers, health care practitioners, or others can complete an electronic voluntary AER form at FDA’s MedWatch webpage—FDA’s agencywide safety information and adverse event reporting program—and submit it to FDA. The information is then sent to CFSAN via fax. Second, consumers, health care practitioners, or others can report the health problem to the dietary supplement firm listed on the product label. The firm evaluates the problem and, if it determines it to be serious in accordance with the 2006 act, it is to complete a hard copy mandatory AER form and submit the form to FDA by mail, along with a copy of the product label. If the firm determines the problem is not serious, it can complete and submit a voluntary AER form at its discretion. Third, consumers, health care practitioners, or others can report the health problem to an FDA Consumer Complaint Coordinator. The coordinators are located in FDA district offices and document and follow up on a variety of health and nonhealth-related complaints about FDA-regulated products. Coordinators enter health problems reported by consumers into a database from which the health problems are later uploaded into the CAERS database as voluntary AERs, as shown in figure 1. Alternatively, consumers, health care practitioners, or others can call a poison center about a health problem. Poison centers are independently operated and provide free medical advice from health care professionals who are trained in the toxicological management of poison exposures and can address toxic exposure situations and adverse events. Poison exposures can result from a variety of circumstances and substances, including adverse reactions to dietary supplements under use as directed. Calls received at the 57 poison centers covering the United States and its territories are uploaded into a national database for analysis. However, the 57 poison centers are not an adverse event reporting system. Consequently, individual health problems involving dietary supplements and managed as poison exposure cases by poison centers are generally not sent to CFSAN. When reporting a health problem to FDA, individuals are asked to provide a short description of the reported health problem; a brief description of the affected person, such as age, gender, weight, and any preexisting medical conditions; and information about the dietary supplement, such as the product name and manufacturer, as well as dosage associated with the health problem. Firms submitting mandatory AERs are also asked to provide the above information. However, to avoid duplication in its database, FDA asks for the following five data elements at a minimum for mandatory AERs: (1) an identifiable patient, (2) an identifiable individual who is reporting the health problem to the firm, (3) identity and contact information for the responsible firm submitting the serious AER to FDA, (4) a suspect dietary supplement, and (5) a serious adverse event or fatal outcome. Once FDA receives an AER for a serious, moderate, or mild health problem, contractors enter the information into the CAERS database, either electronically or manually, and record information by product, industry code, ingredient(s), medical symptom(s) and other information. CAERS staff review the AERs for accuracy and then distribute them to subject matter experts within CFSAN’s program offices, including the Division of Dietary Supplement Programs, for their review. These subject matter experts review the AERs to determine the extent of the relationship between the reported health problem and the product. In addition, CAERS data analysts use statistical tools to analyze relationships across all AERs to detect potential indicators of unsafe products, including patterns or relationships among health problems, products, and ingredients that are found to be significant, according to CFSAN officials. These officials said that, if CFSAN’s subject matter experts find that a product in an AER contains active ingredients in FDA- approved drugs or their analogues, the AER is shared with FDA’s Center for Drug Evaluation and Research, which shares oversight responsibility for supplement products that have been deliberately adulterated with active ingredients in FDA-approved drugs or their analogues. If an issue related to compliance with dietary supplement regulations is identified— such as CGMPs describing the conditions under which supplements must be manufactured, packed, and held—CFSAN’s subject matter experts pass the AER or cluster of AERs to CFSAN’s Office of Compliance, which works with FDA’s Office of Regulatory Affairs to determine if consumer protection actions are needed, as shown in figure 2. FDA uses other postmarket surveillance approaches in addition to AERs to identify potential safety concerns and conduct oversight related to dietary supplements. Examples of these approaches are listed in table 1. According to FDA officials, inspections of dietary supplement firms constitute the agency’s primary method for monitoring compliance with requirements to report adverse events. According to CFSAN guidance, FDA investigators take several steps during inspections to monitor compliance with AER requirements, including determining whether a firm has a process in place to report serious adverse events, determining whether the firm has any serious AERs that it did not submit to FDA, and reviewing labels to determine if the product has contact information for reporting AERs. As table 2 shows, once FDA has identified a potential safety concern or a violation for dietary supplements, it has a range of consumer protection actions available, from advisory actions, such as issuing a warning letter, to regulatory actions, such as seizing adulterated dietary supplements. According to FDA officials, products or ingredients of greatest concern for public health are subject to regulatory actions. In addition, FDA may pursue a regulatory action against a firm if the firm does not correct violations in response to an advisory action, such as a warning letter. FDA received more than 6,000 AERs from 2008 through 2011, primarily from industry, and most of these AERs were for supplements containing a combination of different types of ingredients (e.g., vitamins and minerals) or supplements that were otherwise not classified into one of FDA’s existing product categories, according to our analysis of FDA data. However, FDA may not have received information on all adverse events that are associated with dietary supplements because consumers and others may not be voluntarily reporting them to FDA—either directly or through firms—although they may be contacting poison centers about some of these events. Specifically, poison centers received over 1,000 more reports of adverse events from 2008 through 2010 than FDA did. From 2008 through 2011, FDA received a total of 6,307 AERs related to dietary supplements; 71 percent of these AERs came from industry for serious health problems (i.e., based on consumer, health care practitioner, or others’ reports), and most of these AERs were linked with dietary supplements containing a combination of ingredients—such as products containing both vitamins and minerals or otherwise unclassified dietary supplements—according to our analysis of FDA data. Specifically, the total number of AERs FDA received annually more than doubled over the period, from 1,119 in 2008 to 2,480 in 2011. This rise in AERs was driven by a large increase in the number of mandatory industry AERs, according to our analysis. As shown in figure 3, mandatory AERs almost tripled from 2008 through 2011, from 689 in 2008 to 2,040 in 2011.