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United States Government Accountability Office: 
GAO: 

Report to Congressional Requesters: 

March 2013: 

Dietary Supplements: 

FDA May Have Opportunities to Expand Its Use of Reported Health 
Problems to Oversee Products: 

GAO-13-244: 

GAO Highlights: 

Highlights of GAO-13-244, a report to congressional requesters. 

Why GAO Did This Study: 

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. 

What GAO Found: 

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. 

What GAO Recommends: 

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. 

View [hyperlink, http://www.gao.gov/products/GAO-13-244]. For more 
information, contact J. Alfredo Gómez at (202) 512-3841 or 
gomezj@gao.gov. 

[End of section] 

Contents: 

Letter: 

Background: 

FDA Received More than 6,000 AERs Over 4 Years, but Consumers and 
Others May Not Be Voluntarily Reporting All Adverse Events to FDA: 

FDA Has Increased Its Compliance Monitoring of Firms and Taken Some 
Advisory and Regulatory Actions: 

FDA Has Used AERs for Some Actions but May Have Opportunities to 
Expand its Use of AERs: 

FDA Has Partially Implemented All of Our 2009 Recommendations: 

Conclusions: 

Recommendations for Executive Action: 

Agency Comments: 

Appendix I: Objectives, Scope, and Methodology: 

Appendix II: Data on FDA's Consumer Protection Actions Related to 
Dietary Supplements: 

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

Appendix IV: GAO Contact and Staff Acknowledgments: 

Tables: 

Table 1: Examples of FDA Surveillance Actions in Addition to AERs: 

Table 2: Examples of FDA Consumer Protection Actions in Response to 
Identified Potential Safety Concerns for Dietary Supplements: 

Table 3: Identified Advisory and Regulatory Actions on AER Requirement 
Violations, 2008 through 2011: 

Table 4: Mandatory AERs Preceding Certain FDA Consumer Protection 
Actions Related to Dietary Supplements, 2008 through 2011: 

Table 5: Examples of FDA Data Management Systems to Monitor Consumer 
Protection Actions Related to Dietary Supplements: 

Table 6: 2009 GAO Recommendations on Dietary Supplements and FDA or 
Congressional Action: 

Figures: 

Figure 1: Process for Reporting a Health Problem as an Adverse Event 
for Dietary Supplements: 

Figure 2: Process for Reviewing AERs and Using AERs for Consumer 
Protection Actions: 

Figure 3: The Number of Voluntary and Mandatory Industry AERs Related 
to Dietary Supplements FDA Received, 2008 through 2011: 

Figure 4: Most Commonly Reported Types of Supplements Associated with 
Adverse Events, 2008 through 2011: 

Figure 5: Number of Foreign and Domestic Inspections of Dietary 
Supplement Firms FDA or Its State Partners Conducted, January 1, 2008 
through September 30, 2012: 

Figure 6: Proportion of Dietary Supplement Inspections for Which FDA 
Identified Problems or Concerns, 2008 through 2011: 

Figure 7: Voluntary and Mandatory AERs Related to Dietary Supplements 
Received by FDA, 2003 through September 30, 2012: 

Figure 8: Dietary Supplement-Related Consumer Complaints with Adverse 
Event Results or Reported Symptoms Received by FDA, 2002 through 2011: 

Figure 9: Proportion of Dietary Supplement Inspections for Which FDA 
Identified Problems or Concerns, 2002 through 2011: 

Figure 10: Type of Dietary Supplement Inspections, 2008 through 2011: 

Figure 11: Number of Warning Letters Related to Dietary Supplements, 
2002 through 2011: 

Figure 12: Number of Class I, Health Fraud, and Other Safety-Related 
Dietary Supplement Recalls, 2008 through 2011: 

Figure 13: Dietary Supplement Import Refusals by Product Type, 2008 
through 2011: 

Abbreviations: 

AAPCC: American Association of Poison Control Centers: 

AER: adverse event report: 

CAERS: CFSAN Adverse Event Reporting System: 

CDC: Centers for Disease Control and Prevention: 

CGMP: Current Good Manufacturing Practices: 

CFSAN: Center for Food Safety and Applied Nutrition: 

DSHEA: Dietary Supplement Health and Education Act: 

FDA: Food and Drug Administration: 

FSMAFDA: Food Safety Modernization Act of 2011: 

GRAS: generally recognized as safe: 

HHS: Department of Health and Human Services: 

NDI: New Dietary Ingredient: 

OEI: Official Establishment Inventory: 

RSS: Really Simple Syndication: 

[End of section] 

March 18, 2013: 

The Honorable Henry A. Waxman: 
Ranking Member: 
Committee on Energy and Commerce: 
House of Representatives: 

The Honorable Richard J. Durbin: 
United States Senate: 

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.[Footnote 1] Furthermore, the 
number of supplements on the market has grown exponentially, from an 
estimated 4,000 products in 1994[Footnote 2] 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.[Footnote 3] 

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.[Footnote 4] 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.[Footnote 5] 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[Footnote 6] 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.[Footnote 7] 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.[Footnote 8] 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,[Footnote 9] 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.[Footnote 10] 

* FDA should issue guidance to industry clarifying when products 
should be marketed as dietary supplements or conventional foods 
formulated with added dietary ingredients.[Footnote 11] 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. 

Background: 

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.[Footnote 12] 
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.[Footnote 13] 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.[Footnote 14] 

* 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. 
[Footnote 15] 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.[Footnote 16] 

Alternatively, consumers, health care practitioners, or others can 
call a poison center about a health problem.[Footnote 17] 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.[Footnote 18] Poison exposures can 
result from a variety of circumstances and substances, including 
adverse reactions to dietary supplements under use as 
directed.[Footnote 19] 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.[Footnote 20] 

Figure 1: Process for Reporting a Health Problem as an Adverse Event 
for Dietary Supplements: 

[Refer to PDF for image: illustration] 

Consumer, health care practitioner, or others: 
Reports health problem to: FDA Consumer Complaints Coordinator; 
Submits voluntary adverse event report (AER) FDA's MedWatch webpage; 
Reports health problem: Firm[B]; 
Calls to receive advice about health problem: Poison center[A]. 

FDA Consumer Complaints Coordinator: 
Health problem entered as voluntary AER: FDA CFSAN. 

FDA's MedWatch webpage: Voluntary AER faxed to CFSAN: FDA CFSAN. 

Firm[B]: 
If serious, submits mandatory AER; if not serious, may submit 
voluntary AER[C]: FDA CFSAN. 

Source: GAO. 

[A] Dietary supplement manufacturer, packer, or distributor identified 
on product label as the contact for AERs. 

[B] As defined by the Federal Food, Drug, and Cosmetic Act, as amended 
by the 2006 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. As provided in the 
2006 act, the manufacturer, packer, or distributor of a dietary 
supplement with their name appearing on the label of a dietary 
supplement marketed in the United States, shall submit to the 
Secretary of HHS any report received of a serious adverse event 
associated with such dietary supplement when used in the United 
States, accompanied by a copy of the label on or within the retail 
packaging of such dietary supplement. The 2006 act does not require 
firms to report moderate or mild adverse events, such as 
gastrointestinal distress or headaches, but firms may do so 
voluntarily. 

[End of figure] 

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.[Footnote 21] 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.[Footnote 22] 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. 

Figure 2: Process for Reviewing AERs and Using AERs for Consumer 
Protection Actions: 

[Refer to PDF for image: process map] 

FDA CFSAN: 

AERs received by CFSDAN: 
All AERs are sent for review and analysis to: 
CAERS data analysts, or: 
Program subject matter experts; 
If AER involves a product adulterated with pharmaceutical drug: sent 
to FDA Center for Drug Evaluation and Research. 

CAERS data analysts: Epidemiology analysis: If regulatory compliance 
issue or health issue with product ingredients: sent to: Office of 
Compliance. 

Program subject matter experts: If AER a product adulterated with 
pharmaceutical drug: sent to FDA Center for Drug Evaluation and 
Research. 

Office of Compliance: If additional surveillance is necessary: 
FDA Office of Regulatory Affairs: 
To district office for inspection of firm: 
Advisory action; or: 
Regulatory action. 

Office of Compliance: If additional surveillance is not necessary: 
Advisory action; or: 
Regulatory action. 

Source: GAO. 

Note: Consumer complaints that involve health problems and are entered 
into CAERS as voluntary AERs, are sent directly to the Office of 
Compliance. Additionally, foreign inspections of firms are coordinated 
through the Office of Regulatory Affairs' headquarters, according to 
FDA officials. 

[End of figure] 

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. 

Table 1: Examples of FDA Surveillance Actions in Addition to AERs: 

Type of Action: Consumer complaints; 
Description: Consumers or other parties can contact FDA to submit 
complaints about FDA-regulated products by phone. Complaints may 
address any aspect of a product including, but not limited to, an 
adverse event. In one instance, a complaint indicated that the dropper 
dispenser in a liquid dietary supplement broke during use. In another 
instance, a fish oil dietary supplement had a rotten fish smell. 

Type of Action: Import screening; 
Description: FDA reviews imported dietary supplement products entering 
the country. There were approximately 546,603 dietary supplement 
shipments entering the country from 2008 to 2011. A small percentage 
of these products is examined or sampled.[A] 

Type of Action: Inspections; 
Description: FDA inspects firms that manufacture, pack, or hold 
dietary supplements. There are four general types of inspections: 
routine surveillance, consumer complaint investigations, for-cause 
compliance inspections, and follow-up to a regulatory action. 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. 

Type of Action: Internet monitoring; 
Description: FDA monitors the Internet to identify products that 
purport to be dietary supplements but may be fraudulently promoted for 
treating disease. 

Source: GAO. 

[A] We did not collect data on the percentage of dietary supplement 
import entries that FDA examined, sampled, or tested for this report. 
However, in our prior work on dietary supplements (GAO-09-250), we 
found that FDA sampled or examined, on average, approximately 3 to 5 
percent of dietary supplement import entries from fiscal year 2002 
through March 24, 2008. According to FDA, an import entry line is each 
portion of an import shipment that is listed as a separate item on an 
entry document. Items in an import entry having different tariff 
descriptions must be listed separately. 

[End of table] 

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. 

Table 2: Examples of FDA Consumer Protection Actions in Response to 
Identified Potential Safety Concerns for Dietary Supplements: 

Advisory: 

Type of Action: Warning letter; 
Description: FDA issues a letter to a firm citing violations of 
statute or regulations. FDA may pursue a regulatory action if a firm 
does not correct violations in response to a warning letter. 

Type of Action: Consumer alert; 
Description: FDA issues a public alert about types of products, 
ingredients, unlawful marketing practices, or other areas of concern. 

Type of Action: Industry advisory; 
Description: FDA issues an industrywide advisory urging firms not to 
market products containing certain ingredients or to address other 
areas of concern. 

Regulatory: 

Type of Action: Product recall; 
Description: FDA works with firms to voluntarily remove a product from 
the market through a recall. According to FDA officials, the agency 
may also use its new mandatory recall authority for dietary supplement 
products. FDA received this authority in 2011 with the passage of the 
FDA Food Safety Modernization Act.[A] 

Type of Action: Refusal of imported product; 
Description: Imported products can be detained and subsequently 
refused entrance into the U.S. market at the port of entry. 

Type of Action: Legal action; 
Description: FDA can take legal action against firms, such as issuing 
seizures or injunctions, and the initiating of criminal charges 
against responsible parties. 

Type of Action: Ban ingredient; 
Description: FDA may issue a regulation banning an ingredient from the 
market.[B] 

Source: GAO. 

Note: This table is not an exhaustive list of potential consumer 
protection actions FDA could take. For example, FDA could hold a 
regulatory meeting with a firm to discuss voluntary action. However, 
we focused on these actions for the purposes of this report because 
(a) FDA maintained data on these actions or data were publicly 
available, or (b) we had reviewed these actions as part of our prior 
work on FDA's oversight of dietary supplements, GAO-09-250. 

[A] In January 2011, the FDA Food Safety Modernization Act amended the 
Federal Food, Drug, and Cosmetic Act to give FDA authority to order 
the recall of food products (other than infant formula) that present a 
reasonable probability of being adulterated or misbranded, with regard 
to a major food allergen, when a company fails to voluntarily recall 
the products. FDA already had authority to order the recall of infant 
formula. 

[B] To date, FDA has banned one ingredient--botanical ephedrine 
alkaloids--in 2004. 

[End of table] 

According to FDA officials, products or ingredients of greatest 
concern for public health are subject to regulatory actions. In 
addition, FDA may pursue a regulatory action against a firm if the 
firm does not correct violations in response to an advisory action, 
such as a warning letter. 

FDA Received More than 6,000 AERs Over 4 Years, but Consumers and 
Others May Not Be Voluntarily Reporting All Adverse Events to FDA: 

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. 

FDA Received 6,307 AERs from 2008 through 2011, Primarily from 
Industry, and Mostly for Combination Products or Unclassified Products: 

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.[Footnote 
23] 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.[Footnote 24] 

Figure 3: The Number of Voluntary and Mandatory Industry AERs Related 
to Dietary Supplements FDA Received, 2008 through 2011: 

[Refer to PDF for image: vertical bar graph] 

Adverse event reports: 

Year: 2008; 
Voluntary: 442; 
Mandatory: 689. 

Year: 2009; 
Voluntary: 604; 
Mandatory: 726. 

Year: 2010; 
Voluntary: 415; 
Mandatory: 1,004. 

Year: 2011; 
Voluntary: 464; 
Mandatory: 2,040. 

Source: GAO analysis of FDA data. 

Note: In some cases, FDA received both voluntary and mandatory AERs 
for the same adverse event. To avoid double-counting, we included 
these cases in the mandatory AER total. FDA received from 12 to 24 
AERs per year as both mandatory and voluntary from 2008 through 2011. 

[End of figure] 

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.[Footnote 25] 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. 
[Footnote 26] 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 a serious nature, 

* 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.[Footnote 27] 

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.[Footnote 28] 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.[Footnote 29] 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.[Footnote 30] 

Figure 4: Most Commonly Reported Types of Supplements Associated with 
Adverse Events, 2008 through 2011: 

[Refer to PDF for image: vertical bar graph] 

Product type: Combination products and products not elsewhere 
classified; 
Reported events: 5,249. 

Product type: Vitamins; 
Reported events: 953. 

Product type: Minerals; 
Reported events: 619. 

Product type: Fats and lipid substances; 
Reported events: 358. 

Product type: Animal by-products and extracts, protein, or fiber; 
Reported events: 188. 

Product type: Herbal and botanical; 
Reported events: 375. 

Source: GAO analysis of FDA data. 

Note: Combination products included were a combination of different 
types of ingredients, such as vitamins and minerals. 

[End of figure] 

Consumers and Others May Not Be Voluntarily Reporting All Adverse 
Events to FDA, but May Be Contacting Poison Centers about Some Events: 

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.[Footnote 31] 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.[Footnote 32] 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.[Footnote 33] 

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.[Footnote 34] 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.[Footnote 35] 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.[Footnote 36] 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.[Footnote 37] 
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.[Footnote 38] 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.[Footnote 39] 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.[Footnote 40] 
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.[Footnote 41] 

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.[Footnote 42] 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.[Footnote 43] 
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. 
[Footnote 44] 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.[Footnote 
45] 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.[Footnote 
46] 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. 

FDA Has Increased Its Compliance Monitoring of Firms and Taken Some 
Advisory and Regulatory Actions: 

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. 

FDA Has Increased its Monitoring of Firms through Inspections Since 
2008: 

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.[Footnote 47] 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.[Footnote 48] 

Figure 5: Number of Foreign and Domestic Inspections of Dietary 
Supplement Firms FDA or Its State Partners Conducted, January 1, 2008 
through September 30, 2012: 

[Refer to PDF for image: stacked vertical bar graph] 

Inspections: 

Year: 2008; 
Domestic: 120; 
Foreign: 0. 

Year: 2009; 
Domestic: 136; 
Foreign: 0. 

Year: 2010; 
Domestic: 194; 
Foreign: 1. 

Year: 2011; 
Domestic: 262; 
Foreign: 33. 

January 1-September 30, 2012; 
Domestic: 375; 
Foreign: 35. 

Source: GAO analysis of FDA data. 

Note: FDA contracts with states to conduct domestic facility 
inspections for foods and other regulated products. During this period, 
states conducted 40 dietary supplement inspections on FDA's behalf. 

[End of figure] 

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.[Footnote 49] 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. 

Figure 6: Proportion of Dietary Supplement Inspections for Which FDA 
Identified Problems or Concerns, 2008 through 2011: 

[Refer to PDF for image: stacked vertical bar graph] 

Inspections: 

Year: 2008; 
Problem: 61; 
No problem: 59. 

Year: 2009; 
Problem: 70; 
No problem: 66. 

Year: 2010; 
Problem: 141; 
No problem: 54. 

Year: 2011; 
Problem: 214; 
No problem: 81. 

Source: GAO analysis of FDA data. 

Note: Dietary supplement CGMPs were phased in by firm size from 2008 to 
2010. For firms with 500 or more full-time equivalent employees, they 
became effective in June 2008; for firms with at least 20 but fewer 
than 500 full-time equivalent employees, they became effective in June 
2009; and for firms with fewer than 20 full-time equivalent employees 
they became effective in June 2010. 

[End of figure] 

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. 

FDA Took a Total of 19 Advisory and Regulatory Actions Related to AER 
Noncompliance from January 2008 through December 2011: 

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. 

Table 3: Identified Advisory and Regulatory Actions on AER Requirement 
Violations, 2008 through 2011: 

Advisory actions (warning letters): 

Initiation date[A]: 2/25/11; 
Action date: 6/17/11; 
Firm: BioSan; 
AER violation: Did not include contact information to report an 
adverse event on product label; and did not submit mandatory AER to 
FDA within 15 days. 

Initiation date[A]: 7/13/11; 
Action date: 10/11/11; 
Firm: Nordimex; 
AER violation: Did not include contact information to report an 
adverse event on product label. 

Initiation date[A]: 12/7/2011; 
Action date: 4/2/12; 
Firm: Theta Brothers Sports Nutrition; 
AER violation: Did not include contact information to report an adverse 
event on product label. 

Regulatory actions (injunction): 

Initiation date[A]: 4/22/11; 
Action date: 3/9/12; 
Firm: ATF Fitness Products and Manufacturing ATF Dedicated Excellence, 
Inc.; 
AER violation: Did not report serious AERs to FDA. 

Regulatory actions (import refusals): 

Initiation date[A]: 6/27/11; 
Action date: 9/7/11; 
Firm: Bio-minerals; 
AER violation: Did not include contact information to report an 
adverse event on product label. 

Initiation date[A]: 6/22/11; 
Action date: 9/15/11; 
Firm: Hayashi Industria E Comercio D; 
AER violation: Did not include contact information to report an adverse 
event on product label. 

Initiation date[A]: 5/31/11; 
Action date: 9/20/11; 
Firm: Forza Vitale Italia SRL; 
AER violation: Did not include contact information to report an adverse 
event on product label. 

Initiation date[A]: 5/9/11; 
Action date: 10/4/11; 
Firm: Guangzhou Tian Yi Import & Export Company Limited; 
AER violation: Did not include contact information to report an adverse 
event on product label. 

Initiation date[A]: 10/9/11; 
Action date: 12/5/11; 
Firm: Metabolics Limited; FDA refused 7 different imported product 
shipments from this firm on this date; 
AER violation: Did not include contact information to report an adverse 
event on product label. 

Initiation date[A]: 4/20/11; 
Action date: 12/12/11; 
Firm: Tatsuhiko Kono; 
AER violation: Did not include contact information to report an 
adverse event on product label. 

Initiation date[A]: 4/19/11; 
Action date: 12/12/11; 
Firm: Hipernatural.Com; 
AER violation: Did not include contact information to report an 
adverse event on product label. 

Initiation date[A]: 1/31/11; 
Action date: 8/12/11; 
Firm: Hersol Manufacturing Laboratories; 
AER violation: Did not include contact information to report an 
adverse event on product label. 

Initiation date[A]: 12/29/09; 
Action date: 6/16/10; 
Firm: Stephen Health Agency; 
AER violation: Did not include contact information to report an 
adverse event on product label. 

Source: GAO analysis of FDA data. 

[A] For warning letters and injunctions, the initiation date is the 
date the shipment was offered for entry into U.S. commerce. For import 
refusals, the initiation date is the date that the import shipment was 
processed by the U.S. Customs Service. 

[B] Data provided to GAO as of April 13, 2012. 

[C] The refusals shown in this table are those for which FDA 
specifically cited an AER-related violation, not other more general 
types of violations, such as labeling. 

[End of table] 

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.[Footnote 
50] 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.[Footnote 51] 

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.[Footnote 52] 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.[Footnote 53] 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. 

FDA Has Used AERs for Some Actions but May Have Opportunities to 
Expand its Use of AERs: 

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. 

FDA Has Used AERs to Initiate or Support Some Consumer Protection 
Actions: 

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.[Footnote 54] 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.[Footnote 55] 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.[Footnote 56] 
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.[Footnote 
57] 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.[Footnote 58] 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.[Footnote 59] 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. 
[Footnote 60] Additionally, our analysis does not include situations 
where FDA used AERs to inform its decisions but did not take formal 
action. 

Table 4: Mandatory AERs Preceding Certain FDA Consumer Protection 
Actions Related to Dietary Supplements, 2008 through 2011: 

Type of action: Surveillance; 
Description: We identified 47 inspections for firms also listed in an 
AER, representing 6 percent of all dietary supplement inspections from 
2008 through 2011. These inspections included compliance, 
surveillance, and follow-up inspections. 

Type of action: Advisory; 
Description: We identified 3 advisory actions for firms or products 
also listed in an AER, representing less than 1 percent of dietary 
supplement advisory actions from 2008 through 2011. The advisory 
actions included two warning letters and 1 consumer alert for firms or 
products also listed in an AER. 

Type of action: Regulatory; 
Description: We identified 11 regulatory actions for firms or products 
also listed in an AER, representing less than 1 percent of dietary 
supplement regulatory actions from 2008 through 2011.The regulatory 
actions included 8 import refusals and 3 voluntary product recalls 
initiated by firms. 

Source: GAO analysis of FDA data. 

Note: We also reviewed seizures, injunctions, criminal investigations, 
and industry alerts to identify consumer protection actions that might 
have been preceded by a mandatory AER. However, we did not find any 
matches between mandatory AERs and these actions. 

[End of table] 

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 appendix 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. 

More Information on How FDA Uses AERs May Help FDA Expand Their Use: 

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.[Footnote 61] Currently, FDA uses six separate 
data management systems to monitor the consumer protection actions we 
reviewed apart from AERs, as outlined in table 5. 

Table 5: Examples of FDA Data Management Systems to Monitor Consumer 
Protection Actions Related to Dietary Supplements: 

Data management system: Automated Investigative Management System; 
Action monitored[A]: Criminal investigations; 
FDA office: Office of Regulatory Affairs. 

Data management system: CFSAN Adverse Event Reporting System (CAERS); 
Action monitored[A]: AERs; 
FDA office: CFSAN. 

Data management system: Compliance Management System; 
Action monitored[A]: Warning letters, seizures, and injunctions; 
FDA office: Office of Regulatory Affairs. 

Data management system: Field Accomplishments and Compliance Tracking 
System; 
Action monitored[A]: Consumer complaints and inspections; 
FDA office: Office of Crisis Management and Office of Regulatory 
Affairs. 

Data management system: Operational and Administrative System for 
Import Support; 
Action monitored[A]: Import screenings and refusals; 
FDA office: Office of Regulatory Affairs. 

Data management system: Recall Enterprise System; 
Action monitored[A]: Product recalls; 
FDA office: Office of Regulatory Affairs. 

Source: GAO analysis of FDA documents. 

[A] This column includes those consumer protection actions that we 
reviewed as part of this report and not necessarily all of the 
activities monitored by the data management systems. 

[End of table] 

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. 

Providing Information to the Public on Dietary Supplement AERs May 
Improve Consumer Understanding: 

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. 
[Footnote 62] 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. 
[Footnote 63] 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.[Footnote 64] 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.[Footnote 65] 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,[Footnote 66] bladder cancer, 
[Footnote 67] and tachycardia (accelerated heart rate).[Footnote 68] 
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.[Footnote 69] 
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. 

FDA Has Partially Implemented All of Our 2009 Recommendations: 

FDA has partially implemented each of our four recommendations from 
our 2009 report on dietary supplements.[Footnote 70] Table 6 
summarizes our 2009 recommendations and FDA or congressional action. 

Table 6: 2009 GAO Recommendations on Dietary Supplements and FDA or 
Congressional Action: 

GAO recommendation: FDA should request additional authority to: (1) 
require firms to self-identify as dietary supplement firms as part of 
existing registration requirements, provide information on the products 
they sell, and update this information annually and (2) require firms 
to report all adverse events; 
FDA or congressional action: (1) FDA officials told us they requested 
additional authority as part of the FDA Food Safety and Modernization 
Act of 2011 (FSMA) to modify the list of required food categories that 
FDA uses to identify firms by industry as part of existing 
registration requirements. In August 2012, FDA published draft 
guidance expanding the list of food categories required at 
registration to include dietary supplement categories that were 
previously optional. FDA issued final guidance in October 2012. 
Requiring dietary supplement firms to provide information on the 
products they sell has been part of multiple proposed legislative 
efforts but has not become law.[A]; (2) Mandatory reporting of all 
adverse events for dietary supplement firms was proposed in S. 3002, 
the Dietary Supplement Safety Act of 2010, sponsored by Senators McCain 
and Dorgan, but did not pass the Senate. 

GAO recommendation: FDA should issue new dietary ingredient (NDI) 
notification guidance; 
FDA or congressional action: As part of FSMA, FDA was required to 
issue draft NDI notification guidance no later than 180 days after 
enactment. FDA published its draft guidance in July 2011. An FDA 
official said the agency is still reviewing the over 7,000 comments it 
received in response to the draft guidance. 

GAO recommendation: FDA should issue guidance to industry clarifying 
when products should be marketed as dietary supplements or conventional 
foods formulated with added dietary ingredients; 
FDA or congressional action: FDA issued draft guidance to industry 
clarifying when liquid products may be marketed as dietary supplements 
or conventional foods with novel ingredients in December 2009.[B] FDA 
has indicated it is developing final guidance but has not set a time 
frame for its issuance. 

GAO recommendation: 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; 
FDA or congressional action: FDA coordinated with stakeholder groups 
by expanding its partnership with the website WebMD™ to include 
vitamin-and supplement-specific pages and formed new stakeholder 
partnerships with EverydayHealth™ and Drugs.com™ websites to educate 
consumers about dietary supplements. FDA also expanded the consumer 
education content on its own website and implemented new mechanisms 
for reaching consumers such as a Really Simple Syndication (RSS) feed 
on tainted (i.e., adulterated) products marketed as dietary 
supplements and consumer updates. FDA collects information about the 
number of RSS feed subscribers and page views that can be used to 
measure distribution.[C] 

Source: GAO. 

[A] The Food Safety Enhancement Act of 2009, H.R. 2749, 111th Cong. 
(passed by the House of Representatives July 30, 2009); the Dietary 
Supplement Safety Act of 2010, S.3002, 111th Cong. (sponsored by 
Senators McCain and Dorgan); the Dietary Supplement Labeling Act of 
2011, S. 1310, 112th Cong.(sponsored by Senators Durbin and 
Blumenthal). In addition to these efforts, individual legislators have 
also introduced amendments with provisions regarding product 
registration to other legislation under consideration. 

[B] The Federal Food, Drug, and Cosmetic Act (21 U.S.C. §§ 321(s), 
348(a) generally requires that when a company adds an ingredient to a 
food product, that ingredient must either be generally recognized as 
safe (GRAS) or go through FDA's review and approval process as a food 
additive. The GRAS standard is defined as a general recognition among 
qualified experts that the substance is reasonably certain to be safe 
under conditions of its intended use. See GAO, FDA Should Strengthen 
Its Oversight of Food Ingredients Determined to Be Generally 
Recognized as Safe (GRAS), GAO-10-246 (Washington, D.C.: Feb. 3, 2010) 
for more information. 

[C] According to FDA data, as of July 31, 2012, the number of page 
views for the dietary supplement pages ranged from 22,687 views for 
the "Tainted Sexual Enhancement Products" page to 249,783 views for 
the "Overview of Dietary Supplements" page. There are 58,633 
subscribers to the tainted products marketed as dietary supplements 
govdelivery e-mail subscription service. There are 135 subscribers to 
the tainted products RSS feed and 828 subscribers to the consumer 
update RSS feed. According to FDA officials, FDA is precluded from 
collecting similar metrics for content on its partnership pages owing 
to Freedom of Information Act restrictions on the release of 
commercial confidential information. 

[End of table] 

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.[Footnote 71] 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.[Footnote 72] 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. 

Conclusions: 

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. 

Recommendations for Executive Action: 

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. 

Agency Comments: 

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 [hyperlink, 
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. 

Signed by: 

J. Alfredo Gómez: 
Director, Natural Resources and Environment: 

[End of section] 

Appendix I: Objectives, Scope, and Methodology: 

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.[Footnote 73] 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[Footnote 74] 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[Footnote 75]; 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.[Footnote 76] 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. 

[End of section] 

Appendix II: Data on FDA's Consumer Protection Actions Related to 
Dietary Supplements: 

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.[Footnote 77] 

Data on FDA's Surveillance Actions Related to Dietary Supplements: 

FDA actions to identify safety concerns related to dietary supplements 
include receiving and analyzing adverse event reports and consumer 
complaints and conducting inspections. 

Data on Adverse Event Reports Related to Dietary Supplements: 

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. 

Figure 7: Voluntary and Mandatory AERs Related to Dietary Supplements 
Received by FDA, 2003 through September 30, 2012: 

[Refer to PDF for image: vertical bar graph] 

Year: 2003; 
Voluntary: 739. 

Year: 2004; 
Voluntary: 657. 

Year: 2005; 
Voluntary: 491. 

Year: 2006; 
Voluntary: 317. 

Year: 2007; 
Voluntary: 350. 

Year: 2008; 
Voluntary: 442; 
Mandatory: 689. 

Year: 2009; 
Voluntary: 604; 
Mandatory: 726. 

Year: 2010; 
Voluntary: 415; 
Mandatory: 1,004. 

Year: 2011; 
Voluntary: 464; 
Mandatory: 2,040. 

Year: January 1-September 20, 2012; 
Voluntary: 420; 
Mandatory: 2,043. 

Source: GAO analysis of FDA data. 

Note: Although mandatory reporting went into effect on December 22, 
2007, FDA did not receive its first mandatory report until January 
2008. In some cases, FDA received both voluntary and mandatory AERs 
for the same adverse event. To avoid double-counting, we included 
these cases in the mandatory AER total. FDA received from 12 to 24 
AERs per year as both mandatory and voluntary from January 1, 2008, 
through September 30, 2012. 

[End of figure] 

Data on Consumer Complaints Related to Dietary Supplements: 

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. 

Figure 8: Dietary Supplement-Related Consumer Complaints with Adverse 
Event Results or Reported Symptoms Received by FDA, 2002 through 2011: 

[Refer to PDF for image: vertical bar graph] 

Year: 2002; 
Complaints: 91. 

Year: 2003; 
Complaints: 68. 

Year: 2004; 
Complaints: 44. 

Year: 2005; 
Complaints: 29. 

Year: 2006; 
Complaints: 41. 

Year: 2007; 
Complaints: 49. 

Year: 2008; 
Complaints: 68. 

Year: 2009; 
Complaints: 52. 

Year: 2010; 
Complaints: 54. 

Year: 2011; 
Complaints: 42. 

Source: GAO analysis of FDA data. 

[End of figure] 

Data on Inspections Related to Dietary Supplements: 

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 9: Proportion of Dietary Supplement Inspections for Which FDA 
Identified Problems or Concerns, 2002 through 2011: 

[Refer to PDF for image: stacked vertical bar graph] 

Year: 2002; 
Problem: 43; 
No problem: 28. 

Year: 2003; 
Problem: 62; 
No problem: 54. 

Year: 2004; 
Problem: 102; 
No problem: 112. 

Year: 2005; 
Problem: 103; 
No problem: 84. 

Year: 2006; 
Problem: 68; 
No problem: 73. 

Year: 2007; 
Problem: 53; 
No problem: 73. 

Year: 2008; 
Problem: 61; 
No problem: 59. 

Year: 2009; 
Problem: 70; 
No problem: 66. 

Year: 2010; 
Problem: 141; 
No problem: 54. 

Year: 2011; 
Problem: 214; 
No problem: 81. 

Source: GAO analysis of FDA data. 

Note: Current good manufacturing practices (CGMP) specific to dietary 
supplement firms were phased in by firm size from 2008 to 2010. For 
firms with 500 or more full-time equivalent employees, they became 
effective in June 2008; for firms with at least 20 but fewer than 500 
full-time equivalent employees, they became effective in June 2009; 
and for firms with fewer than 20 full-time equivalent employees they 
became effective in June 2010. According to FDA officials, prior to 
the establishment of dietary supplement-specific CGMPs, FDA inspected 
dietary supplement firms according to food CGMPs. 

[End of figure] 

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. 

Figure 10: Type of Dietary Supplement Inspections, 2008 through 2011: 

[Refer to PDF for image: pie-chart] 

Surveillance: 64%; 
Compliance: 23%; 
Follow-up: 8%; 
Complaint: 6%. 

Source: GAO analysis of FDA data. 

Note: 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. 

[End of figure] 

Data on FDA's Advisory and Regulatory Actions Related to Dietary 
Supplements: 

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. 

Data on Warning Letters Related to Dietary Supplements: 

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 11: Number of Warning Letters Related to Dietary Supplements, 
2002 through 2011: 

[Refer to PDF for image: vertical bar graph] 

Year: 2002; 
Warning letters: 29. 

Year: 2003; 
Warning letters: 64. 

Year: 2004; 
Warning letters: 60. 

Year: 2005; 
Warning letters: 59. 

Year: 2006; 
Warning letters: 69. 

Year: 2007; 
Warning letters: 12. 

Year: 2008; 
Warning letters: 48. 

Year: 2009; 
Warning letters: 76. 

Year: 2010; 
Warning letters: 56. 

Year: 2011; 
Warning letters: 89. 

Source: GAO analysis of FDA data. 

[End of figure] 

Data on Recalls Related to Dietary Supplements: 

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 12: Number of Class I, Health Fraud, and Other Safety-Related 
Dietary Supplement Recalls, 2008 through 2011: 

[Refer to PDF for image: vertical bar graph] 

Year: 2008; 
Recalls: 9. 

Year: 2009; 
Recalls: 21. 

Year: 2010; 
Recalls: 27. 

Year: 2011; 
Recalls: 30. 

Source: GAO analysis of FDA data. 

[End of figure] 

Data on Imports Related to Dietary Supplements: 

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

Figure 13: Dietary Supplement Import Refusals by Product Type, 2008 
through 2011: 

[Refer to PDF for image: vertical bar graph] 

Product type: Herbal and botanical; 
Refusals: 1,729. 

Product type: Products not elsewhere classified; 
Refusals: 980. 

Product type: Vitamins; 
Refusals: 537. 

Product type: Animal by-products and extracts, proteins, or fiber; 
Refusals: 156. 

Product type: Minerals; 
Refusals: 70. 

Product type: Fats and lipid substances; 
Refusals: 36. 

Source: GAO analysis of FDA data. 

Note: To be consistent with our prior report, GAO-09-250, these data 
only include products classified as dietary supplements and do not 
include products that were initially classified as dietary 
supplements, then reclassified as drugs by FDA. (FDA reclassifies 
dietary supplements as drugs if the products contain an active 
pharmaceutical ingredient or if their labeling contains claims or 
other evidence that would cause them to be regulated as drugs.) FDA 
did not provide information on how many dietary supplements were 
reclassified as drugs and, therefore, refused entry to the United 
States. These data are current as of April 13, 2012. 

[End of figure] 

[End of section] 

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

Department of Health & Human Services: 
Office of the Secretary: 
Assistant Secretary for Legislation: 
Washington, DC 20201: 

February 25, 2013: 

J. Alfredo Gomez: 
Director, Natural Resources and Environment: 
U.S. Government Accountability Office: 
441 G Street NW: 
Washington, DC 20548: 

Dear Mr. Gomez: 

Attached are comments on the U.S. Government Accountability Office's 
(GAO) report entitled, "Dietary Supplements: FDA May Have 
Opportunities to Expand Its Use of Reported Health Problems to Oversee 
Products" (GAO-13-244). 

The Department appreciates the opportunity to review this report prior 
to publication. 

Sincerely, 

Signed by: 

Jim R. Esquea: 
Assistant Secretary for Legislation: 

Attachment: 

General Comments Of The Department Of Health And Human Services (HHS) 
On The Government Accountability Office's (GAO) Draft Report Entitled, 
"Dietary Supplements: FDA May Have Opportunities To Expand Its Use Of 
Reported Health Problems To Oversee Products" (GAO-13-244): 

The Department appreciates the opportunity to review and comment on 
this draft report. 

HHS acknowledges that the current AER system is inherently limited. 
The core limitation of this system and all post market passive 
surveillance systems for consumer products is the challenge in 
determining whether reports in the system reflect cause-and-effect 
relationships between specific products and specific harms. Because of 
this limitation, AER data are only one component of the evidence the 
Agency uses when assessing a potential safety problem with a dietary 
supplement or supporting regulatory action against an adulterated 
product. FDA will continue to use AER data as one basis for 
investigating potentially unsafe products, and will track whether the 
AER signal turns out to be valid and leads to regulatory action. 

GAO Recommendation: 

Continue efforts to explore all possible options to obtain poison 
control 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. 

HHS Response: HHS and the American Association of Poison Control 
Centers (AAPCC) will continue to discuss the feasibility and costs of 
sharing data from AAPCC's system. Additional high-quality data could 
enhance FDA's ability to accurately estimate background rates of
illnesses and injuries, establish temporal relationships where signals 
of a possible safety problem exist, and detect more subtle safety 
signals. Additionally, FDA is working with both the U.S. Substance 
Abuse and Mental Health Services Administration's Drug Abuse Warning 
Network and the Centers for Disease Control and Prevention on whether 
data on CFSAN-regulated products in their systems could be integrated 
with the FDA system. 

GAO Recommendation: 

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). 

HHS Response: HHS strongly agrees that establishing whether and when 
AERs are being used to support and inform the Agency's consumer 
protection actions is useful. Such assessments can be divided into two 
types: (1) assessments that use analytical criteria to evaluate 
whether a signal from the AER system is more or less likely to reflect 
illness or injury from a specific product or type of product; and (2) 
assessments that measure the extent to which AER collection and 
analysis end up supporting FDA actions to protect public health, 
including surveillance, advisory, and regulatory actions. These 
measurements should provide important information to HHS, GAO, and the 
public on the value of the system over time. For example, last year, 
FDA issued a press release informing consumers how it investigates 
adverse event reports allegedly related to energy drinks and 
supplements. 

GAO Recommendation: 

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

HHS Response: FDA is building a Web-based data entry form, similar in 
content to the MedWatch 3500A paper form for adverse event reporting. 
This electronic form will allow industry to submit mandatory adverse 
event reports online, and the data will automatically populate the 
Center for Food Safety and Applied Nutrition's Adverse Event Reporting 
System (CAERS). HHS expects the data entry form to be available for 
online submissions by mid-2014. We are confident that Web-based data 
entry can be implemented within this timeframe. 

GAO Recommendation: 

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. 

HHS Response: FDA will continue to make available dietary supplement 
adverse event data in response to FOIA requests from the public. To 
promote transparency and user-friendliness, FDA is streamlining the 
process for locating and processing documents for Freedom of 
Information Act (FOIA) requests in order to provide the requested 
documents as quickly as possible. The Agency has contracts in place to 
implement a number of changes to its CAERS business processes and IT 
systems. These changes will free up resources for processing FOIA 
requests as quickly and as accurately as possible. 

GAO Recommendation: 

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. 

HHS Response: HHS regards the completion of both guidances as a 
priority. The comments received on the NDI draft guidance revealed 
that certain parts of the draft guidance were widely
misinterpreted; therefore, FDA concluded that the best course of 
action would be for the Agency to reissue the guidance as a second 
draft containing key clarifications on certain matters, and seek 
public input on the revised draft before proceeding to issue final 
guidance. A revised draft NDI guidance is currently being developed. 
The final liquid product guidance is currently undergoing Agency 
review. 

Links to additional information: 

Draft Guidance on NDI: [hyperlink, 
http://www.fda.gov/Food/GuidanceComplianceRegulatoryInformation/Guidance
Documents/DietarySupplements/ucm257563.htm] 

Draft Guidance on Liquid dietary supplements: [hyperlink, 
http://www.fda.gov/Food/GuidanceComplianceRegulatorvInformation/Guidance
Documents/DietarySupplements/ucm196903.htm] 

[End of section] 

Appendix IV: GAO Contact and Staff Acknowledgments: 

GAO Contact: 

J. Alfredo Gómez, (202) 512-3841 or gomezj@gao.gov: 

Staff Acknowledgments: 

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. 

[End of section] 

Footnotes: 

[1] Nutrition Business Journal, NBJ's Supplement Business Report 2012 
(Boulder, CO: Penton Media Inc: 2012) at [hyperlink, 
http://newhope360.com/research/supplement-business-report] (accessed 
December 12, 2012). 

[2] According to the Dietary Supplement Health and Education Act of 
1994, the estimated 600 dietary supplement manufacturers in the United 
States produced approximately 4,000 products, with total annual sales 
of such products alone reaching at least $4 billion at that time. 

[3] GAO, Dietary Supplements Containing Ephedra: Health Risks and 
FDA's Oversight, [hyperlink, http://www.gao.gov/products/GAO-03-1042T] 
(Washington, D.C.: July 23, 2003). 

[4] Products may include "proprietary blends," which must list all 
ingredients but do not need to list the amount of each ingredient. 

[5] Although FDA does not approve dietary supplements, a dietary 
supplement manufacturer or distributor of a supplement with a "new 
dietary ingredient"--an ingredient that was not marketed in the United 
States before October 15, 1994--may be required to notify FDA at least 
75 days before marketing the product, depending on the history of use 
of the ingredient. 

[6] The significant risk of illness or injury standard applies under 
conditions of recommended or suggested use, or if no conditions are 
recommended or suggested, under conditions of ordinary use. 

[7] Firms are required to report serious adverse events to FDA that 
occur on or after December 22, 2007, but since the law allows firms 15 
days to file a report with FDA, the agency did not receive its first 
mandatory report until January 2008. Firms are also required to report 
follow-up medical information received about serious adverse events 
within 1 year after the initial report. 

[8] S. Rep. No. 109-324 (2006). 

[9] GAO, Dietary Supplements: FDA Should Take Further Actions to 
Improve Oversight and Consumer Understanding, [hyperlink, 
http://www.gao.gov/products/GAO-09-250] (Washington, D.C.: Jan. 29, 
2009). 

[10] GAO, Food Safety: Improvements Needed in Overseeing the Safety of 
Dietary Supplements and "Functional Foods," [hyperlink, 
http://www.gao.gov/products/GAO/RCED-00-156] (Washington, D.C.: July 
11, 2000). 

[11] The Federal Food, Drug, and Cosmetic Act generally requires that 
when a company adds an ingredient to a food product, that ingredient 
must either be generally recognized as safe (GRAS) or go through FDA's 
review and approval process as a food additive. The GRAS standard is 
defined as a general recognition among qualified experts that the 
substance is reasonably certain to be safe under the conditions of its 
intended use (21 U.S.C. §§ 321(s), 348). See GAO, FDA Should 
Strengthen Its Oversight of Food Ingredients Determined to Be 
Generally Recognized as Safe (GRAS), [hyperlink, 
http://www.gao.gov/products/GAO-10-246] (Washington, D.C.: Feb. 3, 
2010) for more information. 

[12] According to FDA officials, CAERs also collects data on adverse 
events related to cosmetics. 

[13] Other responsibilities include managing reviews of regulatory 
actions recommended by field offices and guiding field offices' 
activities, when necessary, in developing scientifically and legally 
supportable actions. 

[14] According to FDA officials, the Office of Regulatory Affairs also 
coordinates with FDA's Office of Chief Counsel for advisory and 
regulatory actions. 

[15] Individuals may also call or e-mail health problems directly to 
CFSAN; however, CFSAN officials told us relatively few do so. 

[16] Consumer complaints are not limited to health problems but may 
include problems with products, such as foul odors or bottles 
containing a pill that is different than the other pills in the 
container. 

[17] These centers were formerly known as poison control centers. In 
addition to receiving calls about poison exposures where there is an 
identifiable exposed person, poison centers also receive calls where 
there is no identifiable exposed person, which poison centers treat as 
information cases. 

[18] Poison centers are typically affiliated with state government 
agencies or academic medical centers, according to American 
Association of Poison Control Centers (AAPCC) representatives. 

[19] The AAPCC manages a 24-hour hotline that provides free medical 
advice from toxicology specialists including nurses, pharmacists, 
physicians, and poison information providers. All local poison centers 
can be reached through the 24-hour hotline. 

[20] According to AAPCC representatives, poison centers have shared 
information with FDA and other public health agencies, such as the 
Centers for Disease Control and Prevention, when they detect potential 
signals of an outbreak, such as a foodborne illness, based on a 
pattern of calls to their centers. 

[21] FDA uses product codes to classify the products it regulates. For 
dietary supplements, these codes contain information about the 
industry, the type of ingredient, the delivery mechanism (e.g., 
capsule, topical), and whether the product is intended for human or 
animal use. The general categories for types of supplement ingredients 
are vitamin, mineral, protein, herbal and botanical, animal byproducts 
and extracts, fats and lipid substances, fiber, and a category for 
products that either combine different types of ingredients, such as 
vitamins and botanicals, or are otherwise not classified into one of 
the other categories. A vitamin C supplement with Echinacea is an 
example of a combination product that would fall into this category. 
Royal jelly--a byproduct of honey bees--is an example of a not 
elsewhere classified supplement that would fall into this category. 

[22] CFSAN officials noted that the program subject matter experts in 
the Division of Dietary Supplement Programs are medical officers. 

[23] This average does not include cases where both a voluntary and a 
mandatory AER were submitted independently for the same adverse event. 
To avoid double-counting, we included these cases in our mandatory AER 
total. 

[24] [hyperlink, http://www.gao.gov/products/GAO-09-250]. 

[25] See e.g., In re Hydroxycut Marketing and Sales Practices 
Litigation, No. 09 2087 (S.D. Cal. Oct. 16, 2009). 

[26] The case considered whether a plaintiff could state a claim for 
securities fraud under §10(b) of the Securities Exchange Act of 1934, 
as amended, and Securities and Exchange Commission Rule 10b-5, based 
on a pharmaceutical firm's not disclosing reports of adverse events 
and pending lawsuits associated with a product if the plaintiff did 
not allege statistically significant evidence linking adverse effects 
to the use of the product. Matrixx Initiatives, Inc. v. Siracusano. 
563 U.S. ___, No. 09 Civ.1156. (Mar. 22, 2011). 

[27] Because each AER can report multiple outcomes, numbers and 
percentages of outcomes should not be totaled. 

[28] Specifically, under the Federal Food, Drug, and Cosmetic Act, the 
submission by a firm of an AER in compliance with the requirements of 
the statute is not to be construed as an admission that the dietary 
supplement involved caused or contributed to the adverse event. 

[29] FDA officials told us they are in the process of standardizing 
product names across AER records. 

[30] These numbers are approximate for the following reasons. First, 
product names may change over time, as firms alter their labeling 
without changing the underlying product. For example, a firm may 
decide to relabel its product line by age ranges (e.g., children, 
adults, seniors). Although we incorporated these changes into our 
analysis to the extent they were identifiable within the product names 
themselves, we did not conduct extensive research to verify these 
changes were not present otherwise. Second, FDA officials told us that 
their method for determining how many AERs are associated with a 
particular product varies depending on the purpose of the analysis. In 
some cases, it might be appropriate to consider products with the same 
active ingredients but different flavors to be the same product. In 
other cases, FDA would consider products with different flavor 
formulations to be separate products. 

[31] J.K. Glisson and L.A. Walker, "How physicians should evaluate 
dietary supplements," American Journal of Medicine 123, No. 7 (2010): 
577-582. M. Cellini et al., "Dietary Supplements: Physician Knowledge 
and Adverse Event Reporting," Medicine and Science in Sports and 
Exercise, 45, No. 1 (2013): 23-28. [hyperlink, 
http://www.gao.gov/products/GAO-09-250]. 

[32] Department of Health and Human Services, Office of Inspector 
General, Dietary Supplements: Companies May Be Difficult To Locate in 
an Emergency (Washington, D.C.: Oct. 2012). 

[33] Underreporting to adverse event systems is not unique to dietary 
supplements. In our prior work, we noted that similar problems exist 
for FDA's adverse event reporting system for pharmaceutical drugs. See 
GAO, Drug Safety: FDA Has Begun Efforts to Enhance Postmarket Safety, 
but Additional Actions Are Needed, [hyperlink, 
http://www.gao.gov/products/GAO-10-68] (Washington, D.C.: Nov. 9, 
2009). 

[34] Poison centers do not define dietary supplements according to the 
Federal Food, Drug, and Cosmetic Act. Therefore, we worked with AAPCC 
representatives and FDA officials to make the appropriate adjustments 
to the data to make them comparable to FDA's AERs. For more 
information on our scope and methodology, see appendix I. 

[35] Based on discussions with FDA officials, we focused our analysis 
on adverse events under use as directed, since these types of cases 
were most similar in nature to the types of AERs FDA received. 

[36] 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. 

[37] AAPCC representatives said that they had offered to provide FDA 
with a smaller, targeted analysis of the dietary supplement data at no 
charge to temporarily meet FDA's needs while a longer-term agreement 
was negotiated, but CFSAN officials told us that they needed to see 
the raw data for such an analysis to be informative and prior to 
agreeing to a longer-term arrangement. AAPCC representatives told us 
that since they do not own the poison center data--only the national 
database where it is stored--they cannot release it without the 57 
poison centers' permission. 

[38] The Lewin Group, Final Report on the Value of the Poison Center 
System, (Falls Church, VA: The Lewin Group: 2012) [hyperlink, 
http://production-aapcc.dotcloud.com/about/lewin-group-report/] 
(accessed January 7, 2013). The report notes that its findings do not 
include recent reductions in federal funding to poison centers. 
Additionally, according to AAPCC representatives, AAPCC funding and 
data management costs were not included in this report. 

[39] National Academy of Sciences, Institute of Medicine, Forging a 
Poison Prevention and Control System (Washington, D.C.: 2004). 

[40] According to the 2012 Lewin Group Report, total expenditures to 
maintain the poison center services nationwide were an estimated $136 
million in 2011. 

[41] According to AAPCC representatives, AAPCC does not own the data 
collected by poison centers, but owns and operates the national 
database where the data are stored. These representatives said that 
there are large costs for collecting, maintaining, analyzing, 
organizing and reporting on the national data which are borne by AAPCC 
and its members, and that the sales of the national data support these 
costs. As of February, 2013, the annual operating budget for the 
national database was approximately $3 million, according to an AAPCC 
representative. 

[42] This number does not include resources for CAERS staff, as they 
perform center-wide surveillance activities and are budgeted 
separately. FDA officials said that there is also a concurrent 
negotiation effort underway at the department level to obtain access 
to AAPCC data for multiple HHS components, including CDC and FDA. 

[43] FDA received more than 1.8 million AERs related to prescription 
drugs from 2008 to 2010, in comparison to the 3,827 FDA received 
related to dietary supplements from 2008 to 2010. Prescription drug 
AERs include those that are submitted directly to FDA and four types 
of AERs submitted to FDA by manufacturers for health problems, 
depending on the nature of the health problem, whether the health 
problem is described as a potential side effect in the product 
labeling, and the type of product. 

[44] Wolkin et al., "Using Poison Center Data for National Public 
Health Surveillance for Chemical and Poison Exposure and Associated 
Illness," Annals of Emergency Medicine 59, no. 1 (2011): 56-61. 
Department of Health and Human Services, Office of Inspector General, 
Adverse Event Reporting for Dietary Supplements: An Inadequate Safety 
Valve (Washington, D.C.: April 2001). 

[45] Haller et al., "Dietary Supplement Adverse Events: Report of a 
One-Year Poison Center Surveillance Project," Journal of Medical 
Toxicology 4, no. 2 (2008): 84-92. This paper considered active 
surveillance to include prompt follow-up of symptomatic cases, 
laboratory analysis, and a causality assessment by a case review 
panel. CFSAN officials said that they will contact firms and voluntary 
reporters to follow up on incomplete AERs, but often they are unable 
to obtain the missing information. 

[46] According to CDC officials, CDC has also performed limited, 
targeted surveillance of poison center data for adverse events related 
to Hydroxycut™ and "Miracle Mineral Solution" products. 

[47] For the purposes of this report, we requested data on inspections 
of firms that produce dietary supplements for human food use. FDA 
officials told us that they do not distinguish between firms that 
produce dietary supplements for human food use as opposed to dietary 
supplement firms that produce products that otherwise meet the 
statutory definition of dietary supplements but are for animal or drug 
uses, within their firm inventory database. Accordingly, the number of 
dietary supplement firms in the inspection inventory includes firms 
that produce such products for animal and drug uses. Consequently, the 
percent of dietary supplement firms for human food use represented by 
the inspections is presented as a minimum estimate. 

[48] FDA contracts with states to conduct domestic facility 
inspections for foods and other regulated products. From January 1, 
2008, to September 30, 2012, states conducted 35 domestic inspections 
of dietary supplement firms on FDA's behalf. 

[49] Investigators from FDA district offices conduct inspections. For 
our determination for whether FDA identified a problem or concern 
during an inspection, we included all cases with a district decision 
of Official Action Indicated--OAI (A); Voluntary Action Indicated--VAI 
(E); and Referred to Center (P)--for dietary supplements, CFSAN--plus 
all cases where the investigator completed an inspectional observation 
form--a form used by FDA to document concerns observed during 
inspections. Concerns identified on the inspectional observation forms 
are preliminary findings and vary in severity. Each inspection was 
counted only once. 

[50] Department of Health and Human Services, Office of Inspector 
General, Dietary Supplements: Companies May Be Difficult To Locate in 
an Emergency (Washington, D.C.: October 2012). 

[51] According to Office of Inspector General officials, they asked 
FDA if retail-based product surveillance was a viable method for 
monitoring firms' compliance with AER requirements. According to these 
officials, FDA officials said that FDA would need too many staff 
resources to do the same type of study. 

[52] For example, FDA officials said that supplements adulterated with 
active pharmaceutical ingredients or their analogues can become 
apparent through AER surveillance because of telltale symptoms 
associated with adverse reactions to these ingredients, such as 
cardiovascular issues and color blindness associated with the presence 
of prescription male sexual enhancement medications. 

[53] In addition, of the 57 companies with registered facilities, 16 
had inaccurate addresses listed in the registry. According to FDA 
officials, FDA identifies facilities for inspection from its Official 
Establishment Inventory (OEI), not the food facility registry. 
However, new or updated information about facilities entered into the 
food facility registry does inform FDA's maintenance of its OEI. 

[54] The Federal Food, Drug, and Cosmetic Act establishes that a 
firm's submission of an AER cannot be construed as an admission that 
the dietary supplement product caused the adverse event. 

[55] According to FDA guidance, these details are not part of the 
minimum data elements required for submitting a serious adverse event 
report. 

[56] The causality determinations are based on a World Health 
Organization classification system. During the course of our review, 
FDA revisited prior reviewer evaluations for consistency--which 
reduced the causality determinations from: certain - 14 percent; 
probable - 14 percent; and possible - 35 percent. Most of these cases 
were moved to the insufficient information category for the final 
evaluations. 

[57] Consumer complaints that involve health problems are entered into 
CAERS and sent directly to the Office of Compliance, according to FDA 
officials. Additionally, if a medical reviewer believes that a dietary 
supplement associated with an AER might be adulterated with an FDA-
approved drug or its analogue, the reviewer will forward the report to 
FDA's Center for Drug Evaluation and Research. 

[58] FDA received more than 20 reports over the 7-year period leading 
up to the firm's voluntary recall of Hydroxycut.™ 

[59] Outside of trying to establish whether or not an AER was part of 
the basis for taking a consumer protection action, we did not identify 
the individual basis for each of the roughly 4,700 consumer protection 
actions we reviewed. 

[60] In 2001, the HHS Inspector General reported that it was able to 
document only 32 safety actions based on FDA's adverse event reporting 
system for dietary supplements between January 1994 and June 2000. 
According to the Inspector General, this number was strikingly low 
given that more than 100 million people were using dietary supplements 
at the time. Department of Health and Human Services, Office of 
Inspector General, Adverse Event Reporting for Dietary Supplements: An 
Inadequate Safety Valve (Washington, D.C.: April 2001). 

[61] GAO, Managing for Results: Enhancing Agency Use of Performance 
Information for Management Decision Making, [hyperlink, 
http://www.gao.gov/products/GAO-05-927] (Washington, D.C.: Sept. 9, 
2005). For information on using performance data to improve IT 
strategic planning and investment management, see [hyperlink, 
http://www.gao.gov/products/GAO-12-346], Information Technology: FDA 
Needs to Fully Implement Key Management Practices to Lessen 
Modernization Risks (Washington, D.C.: Mar. 15, 2012). 

[62] OMB, Memorandum for the Heads of Executive Departments and 
Agencies: Open Government Directive, M-10-06 (Washington, D.C.: Dec. 
8, 2009); HHS Open Government Plan Version 2.0 (Washington, D.C.: Apr. 
9, 2012); GAO, Information Technology: OMB's Dashboard Has Increased 
Transparency and Oversight, but Improvements Needed, [hyperlink, 
http://www.gao.gov/products/GAO-10-701] (Washington, D.C.: July 16, 
2010); and GAO, Electronic Government Act: Agencies Have Implemented 
Most Provisions, but Key Areas of Attention Remain,[hyperlink, 
http://www.gao.gov/products/GAO-12-782] (Washington, D.C.: Sept. 12, 
2012). 

[63] 21 U.S.C. § 355(k)(5). 

[64] Information on AERs related to dietary supplements is found on 
FDA's performance measures webpage for CFSAN, under the archived 
version of performance measures for CFSAN's Office of Food Defense, 
Communication, and Emergency Response at [hyperlink, 
http://www.fda.gov/AboutFDA/Transparency/track/ucm240881.htm] 
(accessed December, 11, 2012). 

[65] One such example provided by FDA officials is the "Protected 
Information" provision of section 761 of the Federal Food, Drug, and 
Cosmetic Act, as added by the 2006 act and codified at 21 U.S.C. § 
379aa-1(f). 

[66] Navin K. Kapur and Kiran Musunuru, "Clinical efficacy and safety 
of statins in managing cardiovascular risk," Vascular Health and Risk 
Management 4, no. 2 (2008): 341-353. 

[67] Carlo Piccinni et al., "Assessing the association of pioglitazone 
use and bladder cancer through drug adverse event reporting," Diabetes 
Care 34, no. 6 (2011): 1,369-71. 

[68] Elisabetta Poluzzi et al., "Antimicrobials and the risk of 
Torsades de Pointes: The contribution from data mining of the U.S. FDA 
Adverse Event Reporting System," Drug Safety 33, no. 4 (2010): 303-314. 

[69] Increasing the amount of publicly-available information on its 
website about AERs for all FDA-regulated products was also the focus 
of a draft proposal under FDA's Transparency Initiative in May, 2010. 
We asked FDA officials if expanding public access to dietary 
supplement AERs was under consideration as part of this initiative, 
and they said it was not. 

[70] [hyperlink, http://www.gao.gov/products/GAO-09-250]. 

[71] [hyperlink, http://www.gao.gov/products/GAO-09-250]. For example, 
bitter orange--historically used as a flavoring--could be reformulated 
into a product that is 95 percent synephrine, a powerful stimulant. 
FDA officials said that even without guidance, firms must meet their 
statutory obligation to notify FDA. However, the preamble to the draft 
NDI guidance states that the purpose of the guidance is to assist 
industry in deciding when a premarket safety notification for an NDI 
is necessary; the chemical alteration of historical ingredients is one 
of the questions addressed. 

[72] Consumer Reports, "The Buzz on Energy-Drink Caffeine" at 
[hyperlink, http://www.consumerreports.org/cro/magazine/2012/12/the-
buzz-on-energy-drink-caffeine/index.htm] (accessed December 10, 2012); 
Higgins et al., "Energy Beverages: Content and Safety," Mayo Clinic 
Proceedings 85, no. 11(2010); and Substance Abuse and Mental Health 
Services Administration, Center for Behavioral Health Statistics and 
Quality, The Dawn Report: Emergency Department Visits Involving Energy 
Drinks (Rockville, MD: Nov. 22, 2011). 

[73] FDA officials told us their basis for grouping products together 
depends on the particular analytical need. For example, in some cases, 
products with the same active ingredient but different flavors would 
be grouped similarly and, in other cases, products with different 
flavors would be grouped separately. 

[74] Class I recalls involve a reasonable probability that the use of 
or exposure to a violative product will cause serious adverse health 
problems or death. Class II recalls involve violative products that 
may cause temporary or medically reversible adverse health problems or 
where the probability of serious adverse health problems is remote. 
Class III recalls involves violative products not likely to cause 
adverse health problems. 

[75] We collected data on Class II and Class III recalls from FDA's 
Recall Enterprise System related to dietary supplements. However, we 
could not verify that the data were complete because of 
inconsistencies in how tainted supplement products are classified 
within the database. In some cases, they are classified as drugs, in 
other cases; they are classified as dietary supplements. We were able 
to verify the universe for Class I recalls against FDA press releases 
on its Recalls, Market Withdrawals, and Safety Alerts web page and 
Recalls - Health Fraud web page, but did not verify Class II and Class 
III recalls because according to FDA they are less likely to cause a 
serious health problem. 

[76] We did not include consumer complaints in this analysis because 
consumer complaints with adverse events are uploaded into the CAERS 
database as voluntary AERs and thus the matching process would yield 
false positives. 

[77] [hyperlink, http://www.gao.gov/products/GAO-09-250]. 

[End of section] 

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