Dietary Supplements: Adverse Event Reporting and Review
By Robert Mozersky, D.O., and Vasilios H. Frankos, Ph.D.
The Center for Food Safety and Applied Nutrition (CFSAN) within the Food and Drug Administration (FDA or the Agency) is responsible for regulating food, food and color additives and cosmetics. The primary law CFSAN administers to ensure these products are safe and properly labeled is the Federal Food, Drug and Cosmetic Act (the FD&C Act). Under the FD&C Act, dietary supplements are considered foods, although there are regulations that are unique and specific to dietary supplements.
Unfortunately, consumers do occasionally experience adverse effects from consuming a food or dietary supplement, or after using a cosmetic. It is important to understand what caused these effects and, for this reason, FDA accepts reports of adverse events. By analyzing these reports, FDA may be able to identify products or product ingredients that present a health concern and take action to protect consumers from potential harm. This article describes adverse event reporting requirements for dietary supplements, explains how dietary supplement adverse event reports (AERs) are handled by FDA and lists impediments to adverse event reporting.
Background and Reporting Requirements
On October 15, 1994, the Dietary Supplement Health and Education Act (DSHEA) of 1994 was signed into law, amending the FD&C Act. This amendment defines a dietary supplement as a product (other than tobacco) that is intended to supplement the diet and that bears one or more of the following dietary ingredients: 1) a vitamin; 2) a mineral; 3) an herb or other botanical; 4) an amino acid; 5) a dietary substance for use by man to supplement the diet by increasing the total dietary intake; or 6) a concentrate, metabolite, constituent, extract or combination of any of the above ingredients.[1-5] DSHEA states that dietary supplements that contain dietary ingredients that were not marketed in the United States prior to October 15, 1994, are considered adulterated unless: 1) the supplement contains only dietary ingredients that have been present in the food supply as an article used for food in a form in which the food has not been chemically altered; or 2) there is a history of use or other evidence of safety establishing that the dietary ingredient when used under the conditions recommended or suggested in the labeling of the dietary supplement will reasonably be expected to be safe; or 3) at least 75 days before the supplement enters interstate commerce the manufacturer or distributor of the dietary ingredient provides FDA with the information which was the basis to determine that the dietary supplement is safe. Two effects of the law were that it removed previous impediments to marketing dietary supplements and expanded the universe of lawful dietary supplement products. DSHEA, though, was silent about how adverse events associated with dietary supplements were to be handled. There was no requirement that adverse events be reported to FDA. Still, FDA accepted voluntarily submitted reports of adverse events from consumers, health care professionals and state health departments among others, just as it did for other FDA-regulated products.
However, over the more than 10 years that elapsed after DSHEA was enacted, many individuals, consumer protection groups and members of Congress became concerned that FDA was not receiving sufficient information regarding serious adverse events associated with the use of dietary supplements, and that relying on a voluntary reporting system was inadequate to detect a harmful dietary supplement. On December 9, 2006, Congress passed the Dietary Supplement and Non-prescription Drug Consumer Protection Act, and on December 22, 2006, the President signed it into law. This law established a definition for serious adverse events and set both labeling and mandatory adverse event reporting requirements for the dietary supplement industry. The law defines a serious adverse event as: a death; a life-threatening experience; a hospitalization; a persistent or significant disability or incapacity; a congenital anomaly or birth defect; or an event that requires a medical or surgical intervention to prevent one of the preceding outcomes.
This law also mandates that the name and address of a party (i.e., a manufacturer, packer, distributor or retailer) responsible for collecting information about adverse events appear on the label of a dietary supplement. It also states that the same party is responsible for reporting any serious adverse event associated with the product to the FDA via a MedWatch 3500A form within 15 business days of learning of the adverse event, and that a product’s label must accompany the MedWatch report. Additionally, if the party learns of any new medical information related to a serious adverse event report submitted in the previous 12 months, it must be provided to FDA within 15 business days of receiving that information. The information that companies must submit to FDA includes: a) an identifiable injured person; b) the identity of the person who reported the injury to the manufacturer, packer, distributor or retailer responsible for collecting adverse event information for the product; c) the identity and contact information the person responsible for submitting the information to FDA; d) the name of the suspect dietary supplement(s); and e) a description of the serious adverse event or fatal outcome. The party must also maintain records of a serious adverse event for six years and permit FDA access to the records.
FDA has published three documents intended to assist dietary supplement manufacturers and others in complying with the provisions of the Dietary Supplement and Non-prescription Drug Consumer Protection Act. In October 2007, FDA published Instructions for Completing the MedWatch Form 3500A To Report a Serious Adverse Event Associated with a Dietary Supplement and the draft guidance document Guidance for Industry: Questions and Answers Regarding Adverse Event Reporting and Recordkeeping for Dietary Supplements as Required by the Dietary Supplement and Non-prescription Drug Consumer Protection Act. In December 2007, FDA published a second draft guidance document titled Guidance for Industry: Questions and Answers Regarding the Labeling of Dietary Supplements as Required by the Dietary Supplement and Non-prescription Drug Consumer Protection Act. Each of these documents can be found on FDA’s web site.
FDA AER Review
Although industry must submit serious adverse events via mail using the MedWatch Form 3500A, consumers and health care providers (and industry member submitting non-serious adverse events) can report adverse events to FDA office via phone, e-mail, letter or on-line using MedWatch Voluntary Reporting Form 3500. This is the same procedure used to provide FDA with adverse event information that may be linked to any product FDA regulates.
Regardless of the method by which a report is received, it gets a unique identification number and the adverse event is coded using the Medical Dictionary Regulatory Activities (MeDRA) standardized terminology developed by the International Conference on Harmonization (ICH) and logged into an electronic database. Next, the adverse event is forwarded to the appropriate CFSAN reviewer. The reviewer evaluates the report and characterizes the adverse event as either serious or non-serious. Examples of serious adverse events include heart attacks, strokes, liver or kidney failure, aplastic anemia, Stevens-Johnson syndrome and death.
In some instances, the reviewer will request additional information from the individual who filed the adverse event report. Requests for additional information may occur when the adverse event is serious, as an investigation of a product’s safety might be warranted. As part of such an investigation, FDA may contact the Centers for Disease Control and Prevention (CDC), the Department of Defense or other federal agencies to determine whether they have evaluated similar cases. FDA may also consult with foreign regulatory agencies, including Health Canada, MedSafe of New Zealand and Therapeutic Goods of Australia, among others.
The reviewer may also check the medical literature to determine whether similar adverse events have been reported in the past. If the reviewer identifies similar adverse events related to a product, the reviewer may contact the author of the paper to obtain more details regarding the case(s). Next, the reviewer evaluates literature regarding animal studies to see whether any animals exposed to the product in question experienced similar adverse events. Review of the pharmacology literature can also inform the reviewer whether the adverse reaction experienced by the consumer is biologically plausible.
Finally, FDA generates weekly, monthly, biannual and annual reports from the information stored in its electronic database of adverse events to help to identify trends that would otherwise not be seen. These types of reports help FDA determine whether there is an association between a specific product/ingredient and certain types of adverse events. Although serious adverse events often grab immediate attention, non-serious adverse event reports can be a signal that a serious adverse event could arise from using a dietary supplement.
Unfortunately, many of the voluntary adverse event reports FDA received in the past were missing information that could have been helpful to FDA. At a minimum, a voluntarily submitted adverse event report should contain: the name and contact information for both the reporter and the injured consumer; the name of the CFSAN-regulated product believed to be associated with the adverse event; and a description of the adverse event. It is also helpful to include a list of the product’s ingredients including the amount of each ingredient specified on the label. However, many supplements contain "proprietary blends" and the specific amounts of ingredients included in the proprietary blend are not indicated on the label, making it difficult to determine a product’s exact formulation.
Notwithstanding any information gaps in voluntarily submitted adverse event reports, such reports have helped FDA identify several problematic dietary supplements over the years, leading to a number of FDA actions intended to protect consumers, including: a letter to industry, health care providers and a consumer advisory regarding the safety of aristolochic acid (April 2001); similar warnings about the safety of Lipokinetix (November 2001) and kava (December 2001 and March 2002); and the banning of the sale of ephedrine alkaloids (February 11, 2004). In the spring of 2008, a combination of voluntary and mandatory adverse event reporting prompted FDA to warn consumers about supplement products that were eventually found to contain dangerously high levels of selenium and chromium. Additional FDA warnings about dietary supplement products can be found at www.cfsan.fda.gov/~dms/ds-warn.html.
Barriers to Reporting
Common reasons dietary supplement adverse events are not reported to FDA include the following: the consumer does not think it is important to report the adverse event to a health care provider; many consumers and health care providers do not know where or how to report the adverse event; consumers may be less likely to report an adverse event after taking herbal supplements because many consumers believe dietary supplements are inherently safe or "natural;" and patients may be embarrassed to tell their health care provider that they were trying to self-treat a medical condition using a dietary supplement. Often a consumer informs the physician that he or she experienced an adverse event and assumes the physician will share that information with FDA. However, the physician may not report the event to the Agency so it is important for a consumer to fill out a MedWatch form to ensure that FDA is aware of the adverse event.
It is the manufacturer’s responsibility to ensure that its products are safe for consumption before marketing them. However, FDA’s review of adverse events provides an additional measure of protection for consumers. By tracking and analyzing adverse events, FDA may be able to identify potentially harmful ingredients and warn both consumers and industry of any health hazard. Regardless of where that hazard originated, the FDA, the consumer and members of industry all benefit from the identification of potential hazards so they may be avoided or prevented in the first instance. Of course FDA’s ability to detect signals in the adverse event data is best when it has access to the most current adverse events that have occurred. A combination of mandatory serious adverse event reporting by industry members and encouraging consumers and health care professionals to relay similar information will help provide FDA with robust data from which it can better further the public health.
Robert Mozersky, D.O., is a medical officer in CFSAN’s Division of Dietary Supplement Programs. He has worked for FDA for over 8 years and is responsible for reviewing clinical data related to adverse event and new dietary ingredients.
Vasilios H. Frankos, Ph.D., is a toxicologist and the director of CFSAN’s Division of Dietary Supplement Programs. He has worked for FDA for over 10 years.
Series Editor Sebastian Cianci is a public affairs specialist and a member of CFSAN’s Office of Food Defense, Communication and Emergency Response. He has worked for FDA for 18 years and serves as the Center’s trade press liaison.
Nancy Yanish is a policy analyst for CFSAN and a member of the Center’s Executive Operations Staff. She has worked for FDA for 6 years.
1. This definition is consistent the criteria FDA had been using to identify serious adverse events for many years.
6. www.accessdata.fda.gov/scripts/ medwatch/medwatch-online.htm
7. www.fda.gov/bbs/topics/NEWS/2008/ NEW01812.html and www.fda.gov/bbs/topics/NEWS/2008/NEW01818.html
8. Dietary supplements are not intended to diagnose, treat, cure or prevent any disease.
9. FDA cross-checks reports to detect when a duplicate report of the same adverse event is received.