Dietary Supplements: FDA May Have Opportunities to Expand Its Use of Reported Health Problems to Oversee Products
Released: 2013-03-18T00:00:00


Highlights: section_title: Why GAO Did This Study
paragraphs: Dietary supplements, such as vitamins and botanical products, are a multibillion dollar industry; national data show that over half of all U.S. adults consume them. FDA regulates dietary supplements and generally relies on postmarket surveillance, such as monitoring AERs, to identify potential concerns. Since December 2007, firms receiving a serious AER have had to report on it to FDA within 15 days. In January 2009, GAO reported that FDA had taken several steps to implement AER requirements and had recommended actions to help FDA identify and act on safety concerns for dietary supplements. GAO was asked to examine FDA's use of AERs in overseeing dietary supplements. This report examines the (1) number of AERs FDA has received since 2008, their source, and types of products identified; (2) actions FDA has taken to ensure that firms are complying with AER requirements; (3) extent to which FDA is using AERs to initiate and support its consumer protection efforts; and (4) extent to which FDA has implemented GAO's 2009 recommendations. GAO analyzed FDA data, reviewed FDA guidance, and interviewed FDA officials.

section_title: What GAO Found
paragraphs: From 2008 through 2011, the Department of Health and Human Services' Food and Drug Administration (FDA) received 6,307 reports of health problems--adverse event reports (AER)--for dietary supplements; 71 percent came from industry as serious adverse events as required by law, and most of these AERs were linked with supplements containing a combination of ingredients, such as vitamins and minerals or were otherwise not classified within FDA's product categories. However, FDA may not be receiving information on all adverse events because consumers and others may not be voluntarily reporting these events to FDA, although they may be contacting poison centers about some of these events. From 2008 to 2010, these centers received over 1,000 more reports of adverse events linked to dietary supplements than did FDA for the same period. FDA officials said that they are interested in determining whether the poison center data could be useful for their analysis and have held discussions with American Association of Poison Control Centers representatives, but cost is a factor.

To help ensure firms are complying with AER requirements (i.e., submitting serious AERs, maintaining AER records, and including firms' contact information on product labels), FDA increased its inspections of supplement firms and took some actions against noncompliant firms. Specifically, FDA increased firm inspections from 120 in 2008 to 410 from January 1 to September 30, 2012. Over this period, FDA took the following actions: 3 warning letters, 1 injunction, and 15 import refusals related to AER violations, such as not including contact information on the product label or submitting a serious AER.

FDA has used AERs for some consumer protection actions (e.g., inspections and warning letters) but may be able to expand their use. FDA officials said that most AERs do not initiate or support such actions because it is difficult to establish causality between the product and the health problem based on the limited information in an AER. However, FDA does not systematically collect information on how it uses AERs for consumer protection actions; by collecting this information, it may be able to assess whether AERs are being used to their fullest extent. In addition, FDA is not required to provide information to the public about potential safety concerns from supplement AERs as it does for drugs. Making such information public, if consistent with disclosure provisions in existing law, could expand FDA's use of AERs and improve consumer awareness and understanding of potential health events associated with dietary supplements.

FDA has partially implemented all of GAO's 2009 recommendations, such as issuing guidance for new dietary ingredients, clarifying the boundary between dietary supplements and conventional foods, and expanding partnerships to improve consumer understanding. Specifically, FDA developed draft guidance in 2009, 2011, and 2012 to address three GAO recommendations about dietary supplement oversight and formed new partnerships to conduct consumer outreach. However, FDA has not issued final guidance in two cases. FDA officials said that they plan to complete implementation, but they have provided no time frame to do so. With final guidance in place, firms may be able to make more informed product development and marketing decisions, which could ultimately reduce FDA's enforcement burden in these areas.

section_title: What GAO Recommends
paragraphs: GAO recommends, among other things, that FDA explore options to obtain poison center data, if determined to be useful; collect information on how it uses AERs; provide more information to the public about AERs; and establish a time frame to finalize guidance related to GAO's 2009 recommendations. FDA generally concurred with each of GAO's recommendations.

section_title: Letter
paragraphs: From 2009 to 2010, almost half of all U.S. adults consumed dietary  supplements—including vitamins, minerals, and herbals—according to  the Centers for Disease Control and Prevention, and dietary supplement  sales surpassed $30 billion in 2011. Furthermore, the number of  supplements on the market has grown exponentially, from an estimated  4,000 products in 1994 to an estimated 55,000 products in 2009,  according to officials from the U.S. Department of Health and Human  Services’ (HHS) Food and Drug Administration (FDA). In some cases,  these products have caused serious health effects, as in the case of  botanical ephedrine alkaloids—an herbal ingredient used in weight loss  supplements that was linked to several deaths and banned from the  dietary supplement market in 2004 and about which we reported in July  2003.

FDA regulates dietary supplements under the Federal Food, Drug, and  Cosmetic Act, as amended by the Dietary Supplement Health and  Education Act of 1994 (DSHEA). Under DSHEA, FDA regulates dietary  supplements, including vitamins, minerals, herbals and other botanicals,  amino acids, certain other dietary substances, and derivatives of these  items. DSHEA directs FDA to require in regulation that dietary  supplement labels include a list of ingredients present in significant  amounts and the quantity of such ingredients in the product. Also, under  DSHEA, FDA does not have the authority to require dietary supplements  to be approved for safety and effectiveness before they enter the market,  as it does for prescription drugs. To identify potential safety concerns  related to dietary supplements, FDA primarily relies on postmarket  surveillance efforts, such as monitoring reports of health problems or  adverse event reports (AER) it receives from industry, health care  practitioners, and individuals; reviewing consumer complaints; and  conducting inspections of dietary supplement firms. Once FDA identifies a  safety concern, it may take an advisory action—such as sending a  warning letter to a firm that manufactures, distributes, or packs a dietary  supplement—or a regulatory action, including refusing entry to an  imported product, seeking an injunction in federal court against a firm, or  initiating a prosecution of a firm. FDA may also ban an ingredient through  the rule-making process, as it did for botanical ephedrine alkaloids. If FDA  decides to remove a product from the market using a regulatory action, it  must demonstrate that the dietary supplement presents a significant or  unreasonable risk of illness or injury or is otherwise adulterated before it  can do so. Collectively, in this report, we are referring to FDA’s  surveillance, advisory, and regulatory actions as consumer protection  actions.

Since botanical ephedrine alkaloids were banned from dietary  supplements in 2004, two major regulatory changes have occurred to  address the oversight of dietary supplements. First, since December  2007, the Federal Food, Drug, and Cosmetic Act, as amended by the  2006 Dietary Supplement and Nonprescription Drug Consumer Protection  Act (the 2006 act), has required dietary supplement manufacturers,  distributors, or packers (dietary supplement firms) with their names  appearing on the supplement label to report information about any  serious AERs they receive to FDA within 15 business days of receiving  the AER. As defined in the act, serious adverse events include any  health-related events that result in, for example, a death, life-threatening  experience, inpatient hospitalization, or birth defect, or that require, based  on reasonable medical judgment, a medical or surgical intervention to  prevent these serious outcomes. The act does not require firms to report  moderate or mild adverse events, such as gastrointestinal distress or  headaches, but firms may do so voluntarily. Under the act, firms are also  required to maintain records on each report of an adverse event (i.e.,  serious, moderate, and mild) for 6 years and allow HHS officials access to  these records during an inspection or other limited circumstances, and  firms must include a domestic address or domestic phone number on the  dietary supplement product label for individuals to submit AERs.  According to a report by the Senate Committee on Health, Education,  Labor, and Pensions on the act, these AER requirements are intended to  enhance FDA’s ability to identify and act on public health issues  associated with the use of dietary supplements. Second, FDA  established Current Good Manufacturing Practice (CGMP) regulations  describing the conditions under which supplements must be  manufactured, packed, and held. These requirements were implemented  in phases, according to company size, and became fully effective in 2010.

In January 2009, we reported that FDA had taken several steps in  response to the new mandatory AER requirements, and we made the  following four recommendations to enhance FDA’s oversight of dietary  supplements with which HHS generally agreed:

FDA should request additional authority to (1) require dietary  supplement firms to self-identify as dietary supplement firms and  provide information on the products they sell annually as part of the  existing process for firm registration and (2) require firms to report all  mild and moderate adverse events to FDA. This recommendation  addressed our finding that FDA’s ability to identify safety concerns  was hindered by a lack of information in three key areas: the identity  and location of dietary supplement firms; the types and contents of  products on the market; and product safety information, such as  adverse event data.

FDA should issue new dietary ingredient guidance clarifying when an  ingredient is considered a new dietary ingredient, the evidence  needed to document the safety of new dietary ingredients, and  appropriate methods for establishing ingredient identity. This  recommendation addressed our finding that FDA recognized the need  to develop guidance on the new dietary ingredient provisions of  DSHEA, but FDA had yet to issue this guidance—an omission  previously highlighted in a report we issued in 2000.

FDA should issue guidance to industry clarifying when products  should be marketed as dietary supplements or conventional foods  formulated with added dietary ingredients. This recommendation  addressed our finding that the boundary between dietary supplements  and foods containing added dietary ingredients, such as a beverage  with kava, was not always clear.

FDA should coordinate with stakeholder groups involved in consumer  outreach to identify, implement, and assess the effectiveness of  additional mechanisms for educating consumers about dietary  supplements. This recommendation addressed our finding that  consumers remained largely uninformed about the safety, efficacy,  and labeling of dietary supplements and that FDA could leverage its  limited consumer outreach resources through partnerships with  stakeholder groups.

You asked us to report on FDA’s use of AERs in overseeing dietary  supplements. We examined the (1) number of AERs FDA has received  since 2008, the source of these reports, and the types of products  identified; (2) actions FDA has taken to help ensure that firms are  complying with the 2006 act’s AER requirements; (3) extent to which FDA  is using AERs to initiate and support its consumer protection actions; and  (4) extent to which FDA has implemented our 2009 recommendations for  enhancing FDA oversight of dietary supplements.

For this report, dietary supplement refers to a product intended for human  consumption as defined in DSHEA—products that, among other things,  are intended for ingestion to supplement the diet, labeled as a dietary  supplement and not represented as a conventional food or as a sole item  of a meal or diet. They must also contain one or more dietary ingredients.  We did not examine FDA’s oversight of products that would otherwise  meet the definition of a dietary supplement in DSHEA but are intended for  veterinary use. We also did not examine FDA’s oversight of products that  would otherwise meet the definition of a dietary supplement in DSHEA  but are available only by prescription. We did include products that are  marketed as dietary supplements but have been deliberately adulterated  (e.g., tainted with active ingredients in FDA-approved drugs or their  analogues to increase their potency). Although such products may not  meet the legal definition of a dietary supplement because they contain  prescription drug ingredients, we included them in our review because  these products are often marketed as dietary supplements and can cause  serious health problems. To identify how many AERs FDA has received  since 2008, and the types of problems reported, we obtained and  analyzed FDA data on the number and type of AERs received from  January 2008 through December 2011. We supplemented our initial  analysis with updated data on the number of AERs FDA received  between January 1 and September 30, 2012. To assess the reliability of  these data, we reviewed related documentation, examined data to identify  obvious errors or inconsistencies, and worked with agency officials to  identify any data problems. We determined the data to be sufficiently  reliable for the purposes of this report. To examine FDA’s actions to help  ensure that firms are complying with the new reporting requirements, we  reviewed the 2006 act, as well as FDA’s procedures, planning  documents, and guidance and obtained and analyzed data on FDA’s  oversight actions, such as inspections and regulatory activities, to identify  which of these actions were related to monitoring or enforcing firms’  compliance. To examine the extent to which FDA is using AERs for its  consumer protection efforts, we used statistical software to match firm  and product names from serious AERs against firm and product names  from other FDA consumer protection actions from January 1, 2008,  through December 31, 2011, such as inspections and warning letters, to  identify which FDA actions were associated with a serious AER. We  established a threshold for matching that gave us confidence we were  capturing most of the potential matches and excluding those that were  definitely not a match. The matches were then manually reviewed to  confirm or reject potential matches. We verified the appropriateness of  this approach with FDA officials. To determine the extent to which FDA  has implemented GAO’s 2009 recommendations for enhancing FDA  oversight of dietary supplements, we reviewed relevant laws, planning  documents, and guidance. We also reviewed proposed legislation to  expand FDA’s oversight authority for dietary supplements. In addition, to  address all of our objectives, we reviewed relevant studies related to  dietary supplements, adverse event reporting, industry compliance, and  using poison center data for public health surveillance, among others. We  reviewed the methodology for each of these studies and assessed them  for reasonableness in accordance with our objectives. We interviewed  officials from FDA’s Center for Food Safety and Applied Nutrition  (CFSAN) who receive and analyze AERs, officials from FDA’s Division of  Dietary Supplement Programs, officials from FDA’s Office of Regulatory  Affairs familiar with the agency’s field operations and regulatory actions,  and officials from FDA’s Center for Drug Evaluation and Research. We  also interviewed a wide range of stakeholders, including officials from  HHS’ Centers for Disease Control and Prevention and National Institutes  of Health; and representatives of industry and trade organizations,  consumer advocacy groups, and the American Association of Poison  Control Centers. A more detailed description of our objectives, scope, and  methodology is presented in appendix I.

We conducted this performance audit from December 2011 to March  2013 in accordance with generally accepted government auditing  standards. Those standards require that we plan and perform the audit to  obtain sufficient, appropriate evidence to provide a reasonable basis for  our findings and conclusions based on our audit objectives. We believe  that the evidence obtained provides a reasonable basis for our findings  and conclusions based on our audit objectives.
subsections: section_title: Background
paragraphs: 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.

section_title: FDA Received More than 6,000 AERs Over 4 Years, but Consumers and Others May Not Be Voluntarily Reporting All Adverse Events to FDA
paragraphs: 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.
subsections: section_title: FDA Received 6,307 AERs from 2008 through 2011, Primarily from Industry, and Mostly for Combination Products or Unclassified Products
paragraphs: 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. During  the same period, AERs submitted voluntarily by consumers, industry,  health care practitioners, and others remained relatively stable, averaging  461 annually. All mandatory AERS from industry involved serious health  problems, and FDA classified roughly 64 percent (1,179) of all voluntary  AERs (1,844) as “serious as reported.” “Serious as reported” means that  the adverse event met the criteria to be classified as serious as it was  reported to FDA (based on the reporter’s responses to standard  questions about it), whether or not FDA’s later medical review classified it  as serious. Appendix II incorporates data on AERs from our 2009 report  to provide information on AERs FDA received from January 1, 2003,  through September 30, 2012.

According to FDA officials, two factors are driving the increase in  mandatory AERs. First, FDA has increased its enforcement efforts  against AER noncompliance. For example, FDA has taken advisory  actions, such as issuing warning letters, against firms that have not  reported serious AERs or failed to include contact information to report an  adverse event on the product label. Second, lawsuits have publicized the  consequences of adverse events and a firm’s decision not to report these  events. Specifically, a number of lawsuits have been filed against firms  that produced and distributed Hydroxycut™—a weight loss supplement  linked to serious liver damage—that cite FDA’s request for a recall  because of AERs as evidence. In addition, in 2011, the Supreme Court  ruled in favor of investors suing a publicly traded drug manufacturing firm  for securities fraud, allowing shareholders to rely on the firm’s decision  not to report, among other things, AERs as grounds for a claim in their  suit. FDA officials stated that these lawsuits have raised firms’ sensitivity  to the risk involved in noncompliance with AER requirements, leading to  the increase in mandatory AERs.

The 6,307 AERs FDA received from 2008 to 2011 reported the following  serious outcomes:

53 percent (3,370) resulted in unspecified important medical events of

29 percent (1,836) resulted in hospitalization,

20 percent (1,272) resulted in serious injuries or illnesses,

8 percent (512) resulted in a life-threatening condition, and

2 percent (92) resulted in death.

When interpreting AERs, FDA officials said that it is important to  understand that an AER by itself does not demonstrate a causal  relationship between the dietary supplement and the reported health  problem. Rather, the officials said that there are several other factors  that must be considered to determine causality, such as the role of other  products consumed at the same time and preexisting health conditions.  Some demographic information on the individuals affected by these and  other outcomes in the AERs was available. Specifically, of the 6,307  AERs, 63 percent (3,980) affected females; however, the age of the  individual affected was missing in about one-third (2,029) of the AERs.  According to FDA officials, the absence of such information can hinder  the agency’s ability to determine whether there is a causal relationship  between the product and the reported health problem.

As shown in figure 4, the vast majority (5,248) of the supplements  identified in the AERs were a combination of different types of dietary  ingredients (e.g., vitamins and minerals) or supplements that were not  otherwise classified by FDA into one of the agency’s existing supplement  categories. Vitamins were the second most frequently reported  supplement, included in 952 AERs, followed by minerals, included in 619  AERs. According to FDA officials, the predominance of combination and  unclassified supplements in AERs reflects the growing number of  complex supplements on the market. These officials said that these  supplements are challenging for FDA because of limited scientific  knowledge on how different supplement ingredients interact and their  effect on consumers’ health. Although product names are not  standardized within CAERs, we matched firm and product names across  AERs data to estimate which types of products were associated with the  most mandatory AERs. According to our analysis, 6 of the 10  supplements receiving the most mandatory AERs were multivitamins; 2  were weight-loss supplements; 1 was an energy supplement, and 1 was  an herbal concentrate. Three supplements were associated with over  roughly 100 AERs; 7 were associated with about 51 to 100 AERs; and 24  were associated with about 26 to 50 AERs. Most of the supplements  identified in the mandatory AERs were associated with approximately one  AER from 2008 to 2011.

FDA relies on consumers, health care practitioners, and others to  voluntarily report adverse events associated with dietary supplements to  FDA and to firms and, in turn, FDA relies on firms to submit to it any  serious AERs it receives from these individuals, as required by law.  However, FDA may not receive information on all adverse events that are  associated with dietary supplements because consumers and others may  not be voluntarily reporting these AERs—either directly or through firms,  as indicated by our analysis and interviews with FDA officials. We found  several potential reasons for this underreporting based on our review of  relevant studies and our prior work. For example, we and others have  reported that consumers, health care practitioners, or others may not  recognize the chronic or cumulative toxic effects of a dietary supplement,  or they may broadly assume dietary supplements to be safe and not  attribute negative effects to them. Additionally, in an October 2012  report, the HHS Office of Inspector General found that 20 percent of a  judgmental sample of 127 weight loss and immune support dietary  supplements did not have contact information that would enable  consumers and health care practitioners to report adverse events. The  HHS Inspector General study is not representative of the dietary  supplement industry but indicates that some firms may not be providing  consumers with the necessary information to report adverse events to  firms, which could lead to underreporting if consumers do not report the  adverse event directly to FDA. FDA officials said that they receive fewer  AERs than they would expect to given the number of dietary supplements  on the market and their widespread use. However, they said that, similar  to other voluntary reporting systems, the extent of underreporting is  unknown because the agency can only know about those adverse events  that are reported to it.

One potential measure of underreporting is the number of dietary  supplement-related health problems managed as poison exposure cases  by poison centers. According to annual reports by the American  Association of Poison Control Centers (AAPCC), poison centers received  145,775 calls from consumers or others related to dietary supplements  from 2008 through 2010. These include cases in which the consumer  took more than the directed amount of a product, accidentally ingested  the product, or used the product as directed but experienced an adverse  event. According to AAPCC reports, there were 4,863 cases of adverse  events from 2008 to 2010, over 1,000 more than the 3,827 AERs FDA  received during the same period. We could not estimate how much  overlap, if any, occurred between cases reported to FDA and the poison  centers or determine whether some of the cases managed by poison  centers were serious and might have also been reported to firms.  However, the greater number of calls received by poison centers  suggests that consumers, health care practitioners, and others may have  contacted poison centers without reporting the adverse event to FDA.

FDA officials said that they are interested in reviewing the poison center  data related to dietary supplements and have held discussions with  AAPCC representatives. Specifically, CFSAN officials said that they want  to review the raw poison center data on dietary supplements to  understand what it includes and whether it would be useful for their  analysis. However, these officials said that they were unable to review the  raw dietary supplement data without purchasing it and said that FDA  should have access to the data at no additional cost given the current  level of federal support for poison centers. For example, a 2012 study  commissioned by the AAPCC, federal funding accounted for an estimated  13 percent (about $17 million) of poison centers’ annual operating budget  in 2011. An FDA official noted that, in a 2004 report, the Institute of  Medicine recommended that poison center data become available to all  appropriate local, state, and federal public health units on a real-time  basis and at no additional cost. In this report, the Institute of Medicine  also recommended that poison centers receive sufficient federal funding  to cover core activities, which at the time were estimated to cost  approximately $100 million annually. According to AAPCC  representatives, AAPCC does not receive federal appropriations to cover  cost of collecting, maintaining, and sharing poison center data at the  national level and generally charges federal agencies to access the  data.

AAPCC representatives also said that they were willing to work with FDA  on reduced pricing. Specifically, based on a May 2012 quote, accessing 4  years’ worth of AAPCC data of about 5,400 product codes would have  cost almost $76 million prior to the AAPCC discount, and $800,000 after  the discount. However, even with the significant AAPCC discount, access  to the data remained more than twice the nearly $400,000 budgeted to  process and perform surveillance of dietary supplement adverse events in  fiscal year 2011. According to CFSAN officials, as of October 2012,  negotiations with AAPCC had stalled at the CFSAN level. CFSAN officials  said that the cost of accessing the data was a factor. They also said that,  although negotiations had stalled at the CFSAN level, as of December,  2012, they were ongoing at the department level, but from their  perspective, progress remained difficult.

According to CFSAN officials, the greatest challenge for identifying  potential safety concerns from AERs is the small number of AERs that  FDA receives related to dietary supplements. Specifically, these officials  said that it is difficult to establish a baseline of doses and responses to  help the agency detect anomalies that might indicate a potential safety  concern using such a small number of AERs. These officials also said  that they could not determine whether the poison center data would be  useful for such signal detection until they could access it. However,  researchers and the HHS Inspector General have concluded that  accessing poison center data may help FDA detect and monitor potential  safety concerns. For example, a 2008 study performed in conjunction  with CFSAN and the San Francisco Division of the California Poison  Control System concluded that active surveillance of poison center  reports of dietary supplement adverse events could enable rapid  detection of potentially harmful products and may facilitate oversight.  Additionally, under contract with the AAPCC, the Centers for Disease  Control and Prevention (CDC)—like FDA, an HHS component—has used  national poison center data to identify and track adverse events related to  dietary supplements. For example, in March 2008, poison centers in three  states (Florida, Georgia, and Tennessee), state health departments, and  FDA began receiving voluntary AERs of muscle cramps, hair loss, and  joint pain related to Total Body Formula and Total Body Mega Formula.  On FDA’s behalf, CDC scientists used national poison center data to  identify which states were reporting similar cases and to track the  geographical extent of the outbreak. If FDA can access more  information about dietary supplement-related adverse events that are  reported to poison centers, FDA may be able to analyze the increased  data on doses and responses to help it identify potential safety concerns.

section_title: FDA Has Increased Its Compliance Monitoring of Firms and Taken Some Advisory and Regulatory Actions
paragraphs: To help ensure firms are complying with AER requirements for submitting  serious AERs, maintaining AER records, and including AER contact  information on supplement labels, from 2008 through 2011, FDA  increased its monitoring of firms through inspections and has taken some  advisory and regulatory actions against noncompliant firms.
subsections: section_title: FDA Has Increased its Monitoring of Firms through Inspections Since 2008
paragraphs: FDA has increased its compliance monitoring of firms through inspections  to help ensure that dietary supplement firms are complying with AER  requirements for (1) reporting serious AERs within 15 business days, (2)  maintaining AER records for 6 years, and (3) including domestic contact  information on product labels for individuals to submit AERs, according to  our analysis of FDA data. Specifically, in 2008, FDA inspected 120 dietary  supplement firms, which represented at least 6 percent of FDA’s total  inventory of dietary supplement firms at the beginning of 2008. In  contrast, from January through September 2012, FDA inspected 410  dietary supplement firms, which represented at least 18 percent of FDA’s  total inventory of dietary supplement firms at the beginning of 2012. FDA  also increased the number of foreign firms it inspected over this period,  from conducting no inspections in 2008 to conducting 35 from January  through September 2012. Figure 5 shows the number of foreign and  domestic inspections of dietary supplement firms FDA or its partners at  the state level conducted annually from January 1, 2008 to September  30, 2012.

According to FDA officials, the key factors underlying this increase in  inspections were the full implementation of dietary supplement CGMP  regulations in 2010 (i.e., describing the conditions under which  supplements must be manufactured, packed, and held) and an increase  in field investigators available to conduct inspections. The dietary  supplement CGMP regulations established new quality control standards  for dietary supplement firms and new compliance criteria for FDA  investigators to use during dietary supplement inspections. The CGMPs  were phased in by firm size starting in 2008, with full implementation  completed in 2010. Additionally, an FDA official said that new field  investigators became available to conduct inspections in 2010 and 2011.  These investigators had been hired following higher appropriations for  FDA in fiscal years 2008 and 2009, but they did not become available to  conduct inspections until 2010 and 2011 because it takes 1 to 2 years of  training before an investigator is ready to perform inspections, according  to this official.

As the CGMPs were being phased in, FDA identified problems or  concerns during inspections, such as a manufacturer not maintaining,  cleaning, or sanitizing equipment. The percentage of inspections where  FDA identified problems or concerns increased from 51 percent in 2008  to 73 percent in 2011, largely resulting from CGMP inspections, according  to our analysis. See figure 6 for the proportion of dietary supplement  inspections where FDA identified problems or concerns from 2008 to  2011.

According to our analysis of FDA inspection results from fiscal years 2008  through 2012, FDA identified 20 problems related to AER requirements  during inspections. In 3 of these instances, FDA found that the firm did  not submit a mandatory AER within the required 15 days. In the 17 other  instances, FDA found that a firm did not submit a mandatory AER. When  FDA identifies a problem during an inspection, firms may decide to take  voluntary corrective action, or FDA may choose to take an advisory or  regulatory action against the firm for the observed violations.

section_title: FDA Took a Total of 19 Advisory and Regulatory Actions Related to AER Noncompliance from January 2008 through December 2011
paragraphs: We identified a total of 19 advisory and regulatory actions that FDA  initiated from 2008 to 2011 for noncompliance with AER requirements.  Specifically, we found three warning letters (advisory actions), one  injunction (regulatory action) to prevent the sale of a firm’s products, and  15 import refusals (regulatory actions). All three of the warning letters  stated that the supplement label did not include domestic contact  information so that individuals could report an adverse event. The  injunction against the dietary supplement manufacturer cited  noncompliance with several sections of the Federal Food, Drug and  Cosmetic Act, including the failure to report serious adverse events as  required by law. It prohibited the firm from producing and distributing over  400 products; this was the first time FDA had taken legal action against a  large manufacturer for CGMP noncompliance, according to FDA  documents. All of the 15 import refusals—spanning nine supplement  companies—that we identified cited violations of supplement labeling  requirements for domestic contact information so that individuals can  report an adverse event. Table 3 provides more information on the 19  advisory and regulatory actions related to noncompliance with AER  requirements that we identified.

According to FDA officials, inspections are the primary way FDA identifies  and develops direct evidence of noncompliance with AER requirements.  However, FDA and others have identified noncompliant firms through  other surveillance actions. Specifically, FDA can also identify and act on  noncompliance with some AER requirements through Internet monitoring.  For example, in March 2012, after reviewing a product label on a firm’s  website, FDA sent a warning letter to the firm for failing to include  domestic contact information to report an adverse event on the product  label. In addition, in October 2012, the HHS Inspector General reported  that 20 percent of a judgmental sample of 127 dietary supplement  products purchased from retail stores or online lacked contact information  to report adverse events. This study is not representative of the dietary  supplement industry, but it indicates that compliance with AER  requirements remains an issue for some firms. According to Inspector  General officials, the Inspector General provided a list of the  noncompliant firms to FDA for the agency’s review.

FDA can estimate noncompliance to some extent using its known  advisory and regulatory actions specific to AER requirements, but the  actual number of noncompliant firms may not be fully reflected by these  data. For example, an FDA official said that companies that deliberately  adulterate supplement products with active pharmaceutical ingredients to  increase their potency probably are also noncompliant with AER  requirements, but FDA can only act on those violations for which it has  direct evidence. Specifically, FDA may be able to identify a supplement  adulterated with such ingredients from voluntary AERs submitted by  consumers, health care practitioners, or others, but it would need to  perform an inspection to determine noncompliance with most AER  requirements. FDA may also have difficulty targeting such firms for  inspections because they may not register with FDA as required by law.  For example, in its October 2012 report, the HHS Inspector General  found that 28 percent, or 22 of the 79 companies in its sample, had not  registered with FDA as required. FDA officials believe that the rate of  noncompliance is greater than the regulatory action data indicate, but  these officials told us that they have not estimated what the  noncompliance rate might be because they cannot make assumptions  about the behavior of firms.

section_title: FDA Has Used AERs for Some Actions but May Have Opportunities to Expand its Use of AERs
paragraphs: FDA has used AERs for some consumer protection actions (i.e.,  surveillance, advisory, and regulatory actions), although the exact number  is largely unknown. FDA officials said that most AERs do not initiate or  support consumer protection actions because it is difficult to establish  causality based on the limited information in an AER. However, FDA does  not collect information on how it uses AERs for its consumer protection  actions; FDA could draw on such information to assess whether AERs  are being used to their fullest extent for consumer protection. FDA could  also expand electronic reporting to firms for mandatory AERs, which  could reduce data entry costs and make more program funds available for  analysis. FDA is not required to provide information to the public about  potential safety concerns from dietary supplement AERs as it is for drugs.  Making such information public, if consistent with disclosure provisions in  existing law, could expand FDA’s use of AERs and improve consumer  awareness and understanding of potential health problems associated  with supplements.
subsections: section_title: FDA Has Used AERs to Initiate or Support Some Consumer Protection Actions
paragraphs: FDA has used AERs to initiate or support some consumer protection  actions, but the exact number of reports used and actions taken is largely  unknown. According to FDA officials, FDA uses AERs to initiate or  support certain consumer protection actions on a case-by-case basis,  such as inspections, consumer alerts, and recalls. FDA officials said they  also use AERs to provide data for general research on products and  ingredients. However, it is difficult to identify the full extent to which FDA  uses AERs to initiate or support consumer protection actions because  FDA does not have mechanisms in place to systematically monitor the  relationship between AERs and these actions.

According to FDA officials, most AERs that are received by FDA do not  initiate or support consumer protection actions because it is difficult to  establish a causal link between supplements and reported health  problems based on the limited information available within an individual  AER. Specifically, AERs typically do not include details on the  consumer’s medical history or other products, such as prescription drugs  that the consumer may have consumed simultaneously. Details such as  underlying medical conditions and allergies are requested as part of the  reporting process, but FDA officials said that there is generally a lot of  missing information in both voluntary and mandatory AERs. For  example, age was not available in 32 percent of the dietary supplement  AERs that FDA received, and pregnancy status was not available in 98  percent of the AERs involving females. Additionally, because AERs  represent a reported association in time between a supplement and a  health problem, FDA must first establish the likelihood that the  supplement caused the health problem before considering it in the  context of consumer protection actions. However, FDA officials told us  that AERs may contain inconclusive and often inconsistent data from  which it may be impossible to draw consistently strong inferences. For  example, FDA was only able to establish a “certain” relationship between  the supplement and reported health problem in 3 percent (212 of 6,307)  of the AERs. For 67 percent (4,211 of 6,307) of the AERs, FDA could not  determine whether the supplement caused the reported health problem  because the AER contained insufficient information. Additionally, FDA  officials told us that AERs may be complete but contain little evidence  necessary for FDA to take action. For example, FDA needs to  demonstrate a known effect from the timing and dosage of the  supplement product in question.

Because FDA has the burden of proof to demonstrate that a product  carries a significant or unreasonable risk of injury or illness for dietary  supplement products on the market prior to 1994 under current law, the  limited information available to FDA based on an individual AER does not  usually provide enough evidence to take action. FDA officials said it is  more common to identify potential problems after analyzing a cluster of  AERs, along with evidence from other sources, such as published  research. For example, a subject matter expert in the Division of Dietary  Supplement Programs may track a cluster of AERs separately in a  spreadsheet and then forward the information to CFSAN’s Office of  Compliance if the expert believes that a regulatory compliance issue or  potential health issue may be present. The Office of Compliance, in turn,  may initiate an advisory or regulatory action, or coordinate with FDA’s  Office of Regulatory Affairs to conduct additional surveillance, such as an  inspection prior to taking an advisory or regulatory action. However,  accumulating enough evidence to discern a clear relationship between a  specific product or ingredient and a reported health problem may take  receiving a number of AERs over a span of months or years. For  example, because liver-related problems associated with Hydroxycut™  were reported infrequently, it took 7 years for FDA to establish a clear  relationship between the Hydroxycut™ products and liver disease. After  establishing a causal relationship in 2009, FDA discussed a voluntary  recall with the manufacturer of Hydroxycut™ products and issued a  consumer advisory against using these products.

To estimate the extent to which FDA uses AERs to initiate or support  consumer protection actions, we compared firm and product names  identified in both mandatory AERs and FDA actions to determine if an  AER preceded a consumer protection action related to a dietary  supplement. Out of the roughly 4,700 consumer protection actions related  to dietary supplements that we reviewed, we found 61 actions (about 1  percent) where FDA received a mandatory AER for the same firm or  product prior to taking action, as detailed in table 4, which supports FDA  officials’ assessment that most AERs do not support consumer protection  actions. However, we could not verify that all of the 61 actions we  identified were necessarily initiated or supported by AERs because FDA  does not systematically monitor this information, and officials could not  verify a relationship between the AERs and the actions taken prior to the  issuance of this report. Additionally, our analysis does not include  situations where FDA used AERs to inform its decisions but did not take  formal action.

According to our analysis, we identified 47 inspections for firms also listed  in an AER, representing 6 percent of all dietary supplement inspections  from 2008 and 2011. Similarly, we found 3 advisory actions for firms also  listed in an AER, which represent less than 1 percent of all such actions.  Two of the advisory actions were warning letters for noncompliance with  CGMP requirements, and another was a consumer alert on Hydroxycut™  products. We also identified 11 regulatory actions for firms also listed in  an AER, representing less than 1 percent of all such actions. The  regulatory actions included 8 import refusals and 3 product recalls, most  of which were for Hydroxycut™ products. (See app. II for more  information on consumer protection actions.) FDA officials told us they  also use AERs to monitor the results of these actions. For example, if  FDA issued a warning letter to a firm based on violations of CGMP  requirements during an inspection, receipt of subsequent AERs may  indicate that the firm has not rectified its practices. Similarly, if FDA  receives an AER for a product that FDA has removed from the market by  a regulatory action such as a recall, FDA’s receipt of AERs subsequent to  the initial action indicates to FDA that further action may be needed.

section_title: More Information on How FDA Uses AERs May Help FDA Expand Their Use
paragraphs: FDA has limited information on how it uses AERs to initiate and support  its consumer protection actions; such information could improve FDA’s  ability to assess whether the agency is using AERs to their fullest extent  in this capacity and make improvements as needed. For example, prior  work has shown that agencies can use data on performance to identify  and mitigate problems, allocate resources, and improve effectiveness.  Currently, FDA uses six separate data management systems to monitor  the consumer protection actions we reviewed apart from AERs, as  outlined in table 5.

FDA can track each type of action in its respective data management  system and tracks certain identifying information, such as firm name,  across all the systems. However, FDA generally does not track AERs  across these systems. Specifically, within the six data management  systems we reviewed, we found that FDA only tracks the relationship  between consumer complaints and AERs. Without having a mechanism  to follow an AER through to other actions, FDA misses the opportunity to  assess how frequently AERs initiate or support consumer protection  actions and to identify ways to potentially broaden their use. For example,  FDA internal guidance states that AERs can be used to demonstrate  potential health risks associated with violative conditions found during  other surveillance activities, such as inspections, and be part of the  evidence gathered to support regulatory actions. Establishing the  potential for harm is particularly important for dietary supplements  because the burden of proof to demonstrate a significant or unreasonable  risk of illness or injury prior to removing a product from the market  through a regulatory action falls upon FDA. However, by not tracking the  relationship between AERs and its other data management systems, FDA  cannot systematically identify the extent to which AERS were used in this  capacity. Having such information could improve FDA’s and  policymakers’ abilities to make fully informed decisions about resource  allocation and AERs’ future role in FDA’s consumer protection activities  related to dietary supplements.

Furthermore, unlike other FDA-regulated products, dietary supplement  firms cannot submit mandatory AERs electronically. Rather, they must  submit these AERs in hard copy by mail. FDA’s requirement that firms  submit mandatory AERs in hard copy form by mail—which must be  entered manually into the CAERS database by CAERS staff—may  reduce the AER system’s effectiveness by diverting resources to data  entry rather than analysis. According to CFSAN officials, FDA has plans  to expand electronic reporting to mandatory AERs for dietary  supplements in mid-2014 as part of its Safety Reporting Portal Program.  However, FDA had similar plans at the time of our prior report in 2009  that have not been realized yet.

section_title: Providing Information to the Public on Dietary Supplement AERs May Improve Consumer Understanding
paragraphs: Communicating effectively about risks related to dietary supplements is a  key part of FDA’s mission to protect and promote public health, according  to FDA’s strategic plan. Specifically, helping consumers better understand  the risks and benefits of regulated products is a key part of FDA’s  responsibilities, as described in the agency’s 2009 Strategic Plan for Risk  Communication. This plan outlines a number of strategies to improve  communication, including identifying and filling gaps in key areas of risk  communication and improving the effectiveness of FDA’s website and  web tools. In addition, guidance from the Office of Management and  Budget and HHS, as well as our prior work, has emphasized providing  greater transparency and participation of federal agencies in publishing  government information online. However, unlike drugs and certain  biologic products—where FDA is required to provide information about  identified potential safety concerns by law—little information on potential  safety concerns from dietary supplement AERs is publicly available and  accessible to consumers, health care practitioners, and others.  Specifically, for dietary supplement AERs, FDA generally provides  information on its website on the number of mandatory AERs it received  and the number of unique firm names from all mandatory AERs on a  monthly basis. This aggregated information, which is located under FDA’s  performance measures for CFSAN and is not directly linked with the  dietary supplement web pages, does not provide any indication to  consumers of potential risks associated with specific dietary  supplements. In November 2012, FDA also posted information on its  website about individual AERs the agency had received from January  2004 through October 2012 associated with four types of “energy  drinks”—three of which were sold as dietary supplements, one as a  conventional food. Individuals may also request information about  adverse events related to dietary supplements by submitting a Freedom  of Information Act request to FDA.

According to FDA officials, there are certain disclosure provisions within  the Federal Food, Drug, and Cosmetic Act that limit FDA’s ability to  provide unredacted information on AERs related to dietary supplements.  However, FDA provides detailed aggregated analysis, including a list of  products with potential safety concerns, and raw disaggregated data on  AERs related to drugs and certain biologic products on its website, even  though some of the same and similar disclosure provisions may apply to  such products. Specifically, in the disaggregated data on prescription  drugs, FDA redacts names and other information that would identify the  individual reporting the adverse event and, occasionally, information on  any ongoing clinical studies or other pending actions, if applicable. The  publicly available disaggregated data, including product names and  health problems, are then used for health and medical research. For  example, researchers have used data available from prescription drug  AERs to study cardiovascular risk, bladder cancer, and tachycardia  (accelerated heart rate). FDA officials told us that they use dietary  supplement-related AERs to conduct safety-related research on dietary  supplement ingredients, and other government researchers have used  AERs in a similar capacity. According to agency officials, FDA already  applies a redaction approach to prescription drug AERs that meets the  nondisclosure provisions within the Federal Food, Drug, and Cosmetic  Act that apply to dietary supplement AERs. An FDA official has stated  publicly that the agency is exploring ways to expand the amount of  publicly available information about AERs for dietary supplements. To  the extent that FDA can do so under existing law—providing greater  information about dietary supplement AERs to the public, such as  potential safety concerns and redacted data on its website—could create  opportunities for external researchers to use AERs and to improve  consumer awareness and understanding of potential health problems  associated with dietary supplements.

section_title: FDA Has Partially Implemented All of Our 2009 Recommendations
paragraphs: FDA has partially implemented each of our four recommendations from  our 2009 report on dietary supplements. Table 6 summarizes our 2009  recommendations and FDA or congressional action.

FDA officials said that the agency is planning to issue final guidance and  complete implementation for most of our recommendations, but they do  not have a time frame for completion. Specifically, FDA officials said they  plan to issue final NDI guidance, but they are still reviewing more than  7,000 distinct comments they received in response to the draft NDI  guidance issued in July 2011. Furthermore, although FDA officials have  indicated they intend to issue final guidance clarifying whether a liquid  product may be labeled and marketed as a dietary supplement and  possibly issuing similar guidance for non-liquid products, they have not  indicated to us where they are in this process. Regarding our  recommendation on consumer outreach, FDA officials said that assessing  the effectiveness of its outreach efforts through the WebMD™ and other  partnerships, consumer updates, and fact sheets on dietary supplement  safety issues would require extensive consumer research, which would  have to be considered in light of FDA’s limited resources and competing  priorities.

Consequently, regulatory uncertainty remains an issue for areas covered  only by draft guidance. As we have previously reported, without final NDI  guidance in place, firms may not notify FDA before marketing products  with ingredients that have drastically different safety profiles than their  historical use. In addition, “energy drinks”—some of which are marketed  as beverages and others as dietary supplements—have raised concerns  about potential health risks among consumer advocacy groups,  academics, government agencies, and members of Congress.  Specifically, concerns raised by these groups include the potential health  risks associated with the level of caffeine in these products, the  combination of caffeine and botanical ingredients with stimulant  properties in these products, and their popularity with youth. Two of the  four top-selling brands of energy drinks in 2012, as identified by a market  research firm, were marketed as dietary supplements, while the others  were marketed as beverages. As we noted in our 2009 report, this  boundary matters because the safety standard for a certain ingredient in  food is different than that for the same ingredient when it is used as a  dietary ingredient in a dietary supplement. The differences in how  products are regulated may lead to circumstances when an ingredient  would not be allowed to be added to a product if it was labeled as a  conventional food but would be allowed in the identical product if it was  labeled as a dietary supplement. Even without final guidance to industry,  the agency has issued warning letters to firms for violations related to NDI  notifications and the distinction between liquid dietary supplements and  conventional foods on a case-by-case basis. With clear guidance to  industry about these issues, firms may have the information necessary to  guide appropriate product development—including the development of  safety information—and marketing, and FDA’s enforcement burden in  these areas may be reduced as a result. Moreover, by assessing its  outreach efforts, FDA would have information on whether its new  approaches are effective, which could help FDA target future efforts,  particularly in the area of increasing voluntary adverse event reporting.

section_title: Conclusions
paragraphs: Because of an increase in mandatory AERs, the number of AERs FDA  has received since 2008 for dietary supplements has more than doubled,  and FDA has used AERs to initiate and support some consumer  protection actions. However, consumers and others may not be  voluntarily reporting information to FDA on all adverse events that occur,  although they may be contacting poison centers about some of these  events. FDA officials said that their greatest challenge to identifying  potential safety concerns from AERs is the relatively small number of  AERs the agency receives, and that—depending on its review of the  poison center data—FDA may benefit from obtaining access to these  data for analysis. According to FDA officials, negotiations to access the  data are ongoing at the HHS level but, as of December 2012, the results  of these negotiations were still pending.

Furthermore, although FDA has used AERs for some consumer  protection actions, FDA may have opportunities to expand its use of  AERs. FDA does not systematically collect information on how it uses  AERs; such information could improve FDA’s ability to assess whether  the agency is using AERs to their fullest extent in consumer protection  actions and make improvements as needed. For example, FDA guidance  states that AERs can be used to demonstrate potential health risks  associated with violations found during other surveillance activities, such  as inspections, and be part of the evidence gathered to support regulatory  actions. However, by not tracking the relationship between AERs and its  other data management systems, FDA cannot identify the extent to which  AERS were used in this capacity. Having such information may also  improve FDA’s and policymakers’ abilities to make fully informed  decisions about resource allocation and AERs’ future role in FDA’s  consumer protection activities related to dietary supplements.

In addition, FDA’s process for collecting and managing mandatory AERs  could be more efficient because dietary supplement firms, unlike other  FDA-regulated products, cannot submit mandatory AERs electronically.  Rather, they must submit these AERs in hard copy by mail. FDA officials  said that they have plans to expand electronic reporting; however, FDA  had similar plans in place at the time we issued our 2009 report that were  never realized. To the extent that FDA can do so under existing law,  providing greater information about dietary supplement AERs to the  public—such as identified potential safety concerns and redacted data on  its website—could create opportunities for external researchers to use  AERs and to improve consumer awareness and understanding of  potential health problems associated with dietary supplements.

Moreover, regulatory uncertainty remains an issue in two key areas of  dietary supplement regulation because FDA has not set a time frame for  issuing final guidance for draft NDI notification guidance and draft  guidance clarifying when liquid products may be marketed as dietary  supplements or conventional foods with added ingredients or for issuing  similar guidance for nonliquid products. With final guidance in these  areas, firms may be able to make more informed marketing and product  development decisions, including the development of safety information,  and ultimately FDA’s enforcement burden in these areas may be reduced  as a result.

section_title: Recommendations for Executive Action
paragraphs: To enhance FDA’s ability to use AERs and to oversee dietary supplement  products, we recommend that the Secretary of the Department of Health  and Human Services direct the Commissioner of FDA to take the  following five actions:

Continue efforts to explore all possible options to obtain poison center  data if the agency determines that the data could inform FDA’s ability  to identify potential safety concerns from adverse event reports for  dietary supplements.

Incorporate a mechanism to collect information on when AERs are  used to support and inform consumer protection actions (i.e.,  surveillance, advisory, and regulatory actions).

Implement the agency’s efforts to facilitate industry reporting of  mandatory AERs electronically.

Determine what additional information FDA can provide to the public  about dietary supplement AERs consistent with existing law and make  the information publicly available and readily accessible on its  website.

Establish a time frame for issuing final guidance for the draft (1) NDI  guidance and (2) guidance clarifying whether a liquid product may be  labeled and marketed as a dietary supplement or as a conventional  food with added ingredients.

section_title: Agency Comments
paragraphs: We provided the Secretary of Health and Human Services with a draft of  this report for review and comment. We received a written response from  the Assistant Secretary for Legislation that included comments from FDA  and is reprinted in appendix III. FDA generally agreed with each of the  report’s recommendations. HHS also sent us technical comments on  behalf of FDA, which we incorporated as appropriate.

We are sending copies of this report to the Secretary of the Department  of Health and Human Services, the appropriate congressional  committees, and other interested parties. In addition, the report is  available at no charge on the GAO website at http://www.gao.gov.

If you or your staff members have any questions about this report, please  contact me at (202) 512-3841 or gomezj@gao.gov. Contact points for our  Offices of Congressional Relations and Public Affairs may be found on  the last page of this report. GAO staff who made key contributions to this  report are listed in appendix IV.

section_title: Appendix I: Objectives, Scope, and Methodology
paragraphs: Our objectives were to determine the (1) number of adverse event reports  (AER) the Food and Drug Administration (FDA) has received since 2008,  the source of these reports, and the types of products identified; (2)  actions FDA has taken to ensure that firms are complying with new  reporting requirements; (3) extent to which FDA is using AERs for its  consumer protection actions; and (4) extent to which FDA has  implemented GAO’s 2009 recommendations for enhancing FDA oversight  of dietary supplements.

For this report, dietary supplement refers to a product intended for  consumption as defined in the Dietary Supplement Health and Education  Act of 1994 (DSHEA)—products that, among other things, are intended  for ingestion to supplement the diet, labeled as a dietary supplement and  not represented as a conventional food or as a sole item of a meal or diet.  They must also contain one or more dietary ingredients. This definition  covers supplements for human consumption. We did not examine FDA’s  oversight of products that would otherwise meet the definition of a dietary  supplement in DSHEA but are intended for veterinary use. We also did  not examine FDA’s oversight of products that would otherwise meet the  definition of a dietary supplement in DSHEA but are available only by  prescription. We did include products that are marketed as dietary  supplements but that have been deliberately adulterated (e.g., tainted  with active ingredients in FDA-approved drugs or their analogues to  increase their potency). Although such products may not meet the legal  definition of a dietary supplement because they contain prescription drug  ingredients, we included them in our review because these products are  often marketed as dietary supplements and can cause serious health  problems.

To determine the number of AERs that FDA received, the source of the  reports, and the types of products identified, we obtained and analyzed  FDA data on the number and type of AERs received since the reporting  requirements went into effect in January 2008 through December 2011.  Some of the data and analyses were provided by FDA in aggregate form,  although FDA also provided us with disaggregate data on serious AERs.  We supplemented our initial analysis with updated data on the number of  AERs that FDA received between January 1 and September 30, 2012. To  count the number of AERs associated with a unique firm or product, we  sorted the data by firm name then manually reviewed the names to  identify firms with similar or related names. We used the same approach  for products, reasoning that products with similar formulations and active  ingredients should be grouped together because they would cause similar  reactions in consumers and may be manufactured in the same facility. In  some cases, we performed additional Internet research to verify the  accuracy of a match between a firm or product name. We also reviewed  and analyzed data on calls about adverse events related to dietary  supplements to poison centers from annual reports of the American  Association of Poison Control Centers (AAPCC) from 2008 through 2010.  Because poison centers classify certain dietary supplement products  differently than FDA, such as including homeopathic agents as dietary  supplements, we worked with AAPCC and FDA officials to make the  appropriate adjustments to the data to make them comparable to FDA  AERs. Similarly, because FDA officials told us that AERs are primarily  associated with product use as directed, we adjusted the poison center  data to include only those cases where an individual experienced an  adverse reaction when using the product as directed and excluded  reports resulting from misuse, abuse, or accidental ingestion. To assess  the reliability of these data, we reviewed related documentation, reviewed  internal controls, and worked with agency or AAPCC officials to identify  any data problems. For the FDA data on serious AERs, which we  received in disaggregate form, we examined the data to identify obvious  errors or inconsistencies. We also reviewed FDA’s laws, rules, and  regulations relevant to collecting and maintaining AERs. We determined  the data to be sufficiently reliable for the purposes of this report.

To determine actions FDA has taken to ensure that firms are complying  with new reporting requirements, we reviewed FDA’s procedures,  planning documents, and guidance and obtained and analyzed data on  FDA’s oversight activities, such as inspections, advisory, and regulatory  actions, to identify which of these actions were related to monitoring or  enforcing firms’ compliance. Specifically, we obtained aggregate data on  the number of dietary supplement inspections from January 1, 2008,  through September 30, 2012 and analyzed record-level data on the type  and results of dietary supplement inspections FDA conducted from 2008  through 2011 from FDA’s Field Accomplishments and Compliance  Tracking System. To determine the number of AER violations observed  during inspections, we obtained and analyzed aggregate data from FDA’s  Turbo EIR system on inspection observations from fiscal year 2008  through fiscal year 2012. To determine the number of advisory and  regulatory actions related to AER violations from January 1, 2008 through  December 31, 2011, we obtained and analyzed data and documents on  warning letters, seizures, and injunctions from FDA’s Compliance  Management System and FDA’s online warning letter database; Class I  recalls from FDA’s Recall Enterprise System and other safety-related  recalls identified from press releases on FDA’s Recalls - Health Fraud  web page and Recalls, Market Withdrawals, and Safety Alerts web page;  import refusals from FDA’s Operational and Administrative System for  Import Support; and prosecutions with charges filed, convictions, or  settlements reached in FDA’s Automated Investigative Management  System. We also reviewed individual firm inspection reports for examples  of specific observations found during dietary supplement inspections, and  accompanied FDA investigators on an inspection of a dietary supplement  manufacturing facility. To assess the reliability of data supporting this  objective, we reviewed related documentation, internal controls,  examined the data to identify obvious errors or inconsistencies, traced  data back to source documents, and identified and removed data that  were outside the scope of our review, such as data related to products for  animal or prescription uses, or data that did not meet the definition of  dietary supplement used for this report, as described above. We  determined the data to be sufficiently reliable for the purposes of this  report.

To determine the extent to which FDA is using AERs to initiate and  support its consumer protection actions, we matched firm and product  names from mandatory AERs against firm and product names in the  following FDA consumer protection actions from January 2008 through  December 2011: inspections, consumer alerts, industry advisories,  warning letters, seizures and injunctions, import refusals, safety-related  recalls, and prosecutions. The matching process was necessary  because FDA does not track how it uses AERs to initiate or support  consumer protection actions across its other data systems. Because  CFSAN officials told us that product and firm names are not standardized  within the CFSAN Adverse Event Reporting System (CAERS) or across  FDA’s systems, we used statistical software to build wild-card searches to  identify potential matches and then reviewed each potential match to  confirm or reject potential matches. Specifically, we used an analytical  software function that measures spelling differences between words to  determine the likelihood that firm and product names from two data sets  matched and to generate possible matches between AERs and actions.  The statistical software returns a numeric value indicating how closely  related the names are. After reviewing the initial results, we established a  threshold for matching that gave us confidence we were capturing most of  the potential matches and excluding those that were definitely not a  match. The matches were then manually reviewed to confirm or reject  potential matches. For matched records, we determined whether an AER  was received prior to the consumer protection action, as an indicator that  the AER may have contributed to FDA’s decision to take action. For  matched records, we tabulated both the number of AERs that contributed  to each action, and the number of actions that matched AERs. We  verified the appropriateness of this approach with FDA officials prior to  conducting the analysis and provided a list of matches to FDA for their  verification. We also reviewed FDA’s guidance and procedures relevant  to using AERs to initiate or support surveillance, advisory, and regulatory  actions.

To determine the extent to which FDA has implemented GAO’s 2009  recommendations for enhancing FDA oversight of dietary supplements,  we reviewed FDA’s laws, planning documents, and guidance. We  reviewed proposed legislation to expand FDA’s oversight authority for  dietary supplements. We also obtained data on the extent to which FDA’s  web-based consumer outreach initiatives were distributed.

In addition, to address all of our objectives, we reviewed relevant studies  related to dietary supplements, adverse event reporting, industry  compliance, and using poison center data for public health surveillance,  among others. We reviewed the methodology for each of these studies  and assessed them for reasonableness in accordance with our  objectives. We also interviewed officials from several FDA offices,  including FDA’s Center for Food Safety and Applied Nutrition (CFSAN)  who receive and analyze AERs, officials from FDA’s Division of Dietary  Supplements Program, officials from the Office of Regulatory Affairs  familiar with FDA’s field operations and regulatory actions related to  dietary supplements, and officials from the Center for Drug Evaluation  and Research. We interviewed a wide range of stakeholders, including  officials from federal agencies, industry and trade organizations, and  consumer advocacy groups. At the federal level outside of FDA, we met  with officials from the Department of Health and Human Services’ (HHS)  Centers for Disease Control and Prevention, the National Institutes of  Health, and the Federal Trade Commission. At the industry level, we  spoke with representatives from the American Herbal Products  Association, the Council for Responsible Nutrition, and the Natural  Products Association. At the consumer advocacy level, we met with  representatives from the Center for Science in the Public Interest,  Consumers Union, and Public Citizen. We also spoke with  representatives from the American Association of Poison Control Centers.

We conducted this performance audit from December 2011 to March  2013 in accordance with generally accepted government auditing  standards. Those standards require that we plan and perform the audit to  obtain sufficient, appropriate evidence to provide a reasonable basis for  our findings and conclusions based on our audit objectives. We believe  that the evidence obtained provides a reasonable basis for our findings  and conclusions based on our audit objectives.

section_title: Appendix II: Data on FDA’s Consumer Protection Actions Related to Dietary Supplements
paragraphs: This appendix combines data collected during this review with data from  our prior report to provide additional detail on FDA’s actions to identify  and respond to safety concerns related to dietary supplements.
subsections: section_title: Data on FDA’s Surveillance Actions Related to Dietary Supplements
paragraphs: FDA actions to identify safety concerns related to dietary supplements  include receiving and analyzing adverse event reports and consumer  complaints and conducting inspections.

Incorporating data from our prior report, figure 7 shows the number of  dietary supplement-related AERs entered into FDA’s database from  January 1, 2003, through September 30, 2012. As shown in 2008,  mandatory reporting had an immediate impact on the number of dietary  supplement-related AERs FDA received.

Incorporating data from our prior report, figure 8 shows the number of  dietary supplement-related consumer complaints with adverse event  results or reported symptoms FDA received from January 1, 2002,  through December 31, 2011. Consumer complaints are not limited to  adverse events. For example, consumers may report a complaint if one or  more pills in a product are discolored.

Incorporating data from our prior report, figure 9 shows the number of  dietary supplement inspections conducted by FDA or its state partners  and the proportion of these inspections where the investigator identified  problems from January 1, 2002, through December 31, 2011. For our  determination for whether FDA identified a problem during an inspection,  we included all inspections where the district determined that: (1) official  action is indicated, (2) voluntary action is indicated, and (3) the case  should be referred to CFSAN’s Office of Compliance. We also included all  cases where the investigator completed an inspectional observation  form—a form used by FDA to document concerns observed during  inspections. The items listed on these forms are preliminary and vary in  severity. Each inspection was counted only once.

Figure 10 shows the type of dietary supplement inspections conducted  from January 1, 2008, through December 31, 2011. Complaint  inspections are conducted to investigate consumer complaints about a  firm. Follow-up inspections are conducted to assess a firm’s progress  after an advisory or regulatory action such as a warning letter or recall.  Compliance inspections are “for-cause” inspections to investigate specific  compliance issues. Surveillance inspections are routine inspections that  generally assess whether a firm is following dietary supplement good  manufacturing practices, as applicable. An inspection may include  product examinations, sampling and testing, as well as the inspection of  the firm and facility involved with dietary supplements, according to FDA  officials.

FDA actions to respond to safety concerns related to dietary supplements  include issuing warning letters to dietary supplement firms, working with  firms on recalls, and refusing imports.

Incorporating data from our prior report, figure 11 shows the number of  warning letters related to dietary supplements FDA issued from January  1, 2002, through December 31, 2011. The relatively low number of letters  issued in 2007 is in part due to the timing of the letters—if we calculated  the number of letters issued by fiscal year, the number would be 43.

Figure 12 shows the number of Class I, health fraud, and other safety- related voluntary recalls related to dietary supplements from January 1,  2008, through December 31, 2011. We focused on these three types of  recalls because FDA determined they (1) are the most likely to cause a  serious health problem, (2) could cause a serious health problem, or (3)  considered them to be of sufficient concern to issue a safety alert press  release.

Figure 13 shows the number of import refusals by product type from  January 1, 2008, through December 31, 2011.

section_title: Appendix III: Comments from the Department of Health and Human Services

section_title: Appendix IV: GAO Contact and Staff Acknowledgments
subsections: section_title: GAO Contact

section_title: Staff Acknowledgments
paragraphs: In addition to the individual named above, Anne K. Johnson, Assistant  Director; Robin Ghertner; Cathy Hurley; Esther Toledo; and Lisa van  Arsdale made key contributions to this report. Important contributions  were also made by Kevin Bray, Michele Fejfar, Dan C. Royer, Carol  Herrnstadt Shulman, and Kiki Theodoropoulos.


Question-summary annotations: questions: question: What complaints regarding dietary supplements did FDA receive?
answer: From 2008 through 2011, the Department of Health and Human Services' Food and Drug Administration (FDA) received 6,307 reports of health problems--adverse event reports (AER)--for dietary supplements; 71 percent came from industry as serious adverse events as required by law, and most of these AERs were linked with supplements containing a combination of ingredients, such as vitamins and minerals or were otherwise not classified within FDA's product categories.
child_questions: question: Why may the real number of adverse events be even higher than the number reported?
answer: However, FDA may not be receiving information on all adverse events because consumers and others may not be voluntarily reporting these events to FDA, although they may be contacting poison centers about some of these events.
child_questions: question: How did numbers of reports to poison centers compare to reports to the FDA?
answer: From 2008 to 2010, these centers received over 1,000 more reports of adverse events linked to dietary supplements than did FDA for the same period.
child_questions: question: What is the current status of data sharing between FDA and poison control centers?
answer: FDA officials said that they are interested in determining whether the poison center data could be useful for their analysis and have held discussions with American Association of Poison Control Centers representatives, but cost is a factor.

questions: question: What actions did the FDA take to help ensure firms are complying with AER requirements?
answer: To help ensure firms are complying with AER requirements (i.e., submitting serious AERs, maintaining AER records, and including firms' contact information on product labels), FDA increased its inspections of supplement firms and took some actions against noncompliant firms.
child_questions: question: As a result of these inspections, what actions did the FDA take?
answer: Over this period, FDA took the following actions: 3 warning letters, 1 injunction, and 15 import refusals related to AER violations, such as not including contact information on the product label or submitting a serious AER.

question: How did FDA inspection numbers in 2012 compare to those from 2008?
answer: Specifically, FDA increased firm inspections from 120 in 2008 to 410 from January 1 to September 30, 2012.

questions: question: How does the FDA currently use AERs for consumer protection actions?
answer: FDA has used AERs for some consumer protection actions (e.g., inspections and warning letters) but may be able to expand their use.
child_questions: question: What is the main difficulty preventing FDA officials from using more AERs?
answer: FDA officials said that most AERs do not initiate or support such actions because it is difficult to establish causality between the product and the health problem based on the limited information in an AER.

question: To what extent does FDA collect information on AERS?
answer: However, FDA does not systematically collect information on how it uses AERs for consumer protection actions; by collecting this information, it may be able to assess whether AERs are being used to their fullest extent.

question: To what extent does FDA make AER information public?
answer: In addition, FDA is not required to provide information to the public about potential safety concerns from supplement AERs as it does for drugs.
child_questions: question: What benefits could making such information public have?
answer: Making such information public, if consistent with disclosure provisions in existing law, could expand FDA's use of AERs and improve consumer awareness and understanding of potential health events associated with dietary supplements.

questions: question: What recommendations from GAO has the FDA implemented?
answer: FDA has partially implemented all of GAO's 2009 recommendations, such as issuing guidance for new dietary ingredients, clarifying the boundary between dietary supplements and conventional foods, and expanding partnerships to improve consumer understanding.
child_questions: question: What was the extent of FDA's action?
answer: Specifically, FDA developed draft guidance in 2009, 2011, and 2012 to address three GAO recommendations about dietary supplement oversight and formed new partnerships to conduct consumer outreach. However, FDA has not issued final guidance in two cases.
child_questions: question: What have FDA officials stated about this gap?
answer: FDA officials said that they plan to complete implementation, but they have provided no time frame to do so.

question: Why will this final guidance be important?
answer: With final guidance in place, firms may be able to make more informed product development and marketing decisions, which could ultimately reduce FDA's enforcement burden in these areas.

questions: question: How widespread are dietary supplements in the U.S.?
answer: Dietary supplements, such as vitamins and botanical products, are a multibillion dollar industry; national data show that over half of all U.S. adults consume them.
child_questions: question: How does FDA identify potential concerns with these supplements?
answer: FDA regulates dietary supplements and generally relies on postmarket surveillance, such as monitoring AERs, to identify potential concerns.
child_questions: question: How must firms respond to AERs?
answer: Since December 2007, firms receiving a serious AER have had to report on it to FDA within 15 days.

question: What did GAO determine regarding FDA's implementation of AER requirements?
answer: GAO was asked to examine FDA's use of AERs in overseeing dietary supplements. In January 2009, GAO reported that FDA had taken several steps to implement AER requirements and had recommended actions to help FDA identify and act on safety concerns for dietary supplements.
child_questions: question: What does GAO's report address?
answer: This report examines the (1) number of AERs FDA has received since 2008, their source, and types of products identified; (2) actions FDA has taken to ensure that firms are complying with AER requirements; (3) extent to which FDA is using AERs to initiate and support its consumer protection efforts; and (4) extent to which FDA has implemented GAO's 2009 recommendations. GAO analyzed FDA data, reviewed FDA guidance, and interviewed FDA officials.