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1 From the Division of Dietary Supplement Programs, Center for Food Safety and Applied Nutrition, US Food and Drug Administration, College Park, MD
2 Presented at the conference "Multivitamin/Mineral Supplements and Chronic Disease Prevention," held at the National Institutes of Health, Bethesda, MD, May 15–17, 2006. 3 Reprints not available. Address correspondence to JJY Woo, the Division of Dietary Supplement Programs, Center for Food Safety and Applied Nutrition, US Food and Drug Administration, 5100 Paint Branch Parkway, HFS-810, College Park, MD 20740. E-mail: jason.woo{at}fda.hhs.gov.
ABSTRACT
A study commissioned by the Food and Drug Administration (FDA) estimated that the FDA is notified of <1% of all adverse events associated with dietary supplements. Among the factors that may contribute to underreporting are that many consumers presume supplements to be safe, use these products without the supervision of a health care professional, and may be unaware that the FDA regulates them. In 2001 an Office of the Inspector General report identified many of the difficulties in evaluating adverse events in a voluntary system and the barriers to effective analysis of these reports to generate possible signals of concern. These include factors such as limited medical information, limited product information, limited manufacturer information, limited information on dietary supplement consumers, and limited ability to analyze trends. In addition, for dietary supplements, vital premarket information (which is available for drug products) is often missing so that possible public health concerns generated by the adverse event reporting system, such as limited clinical information, product identification, and information on consumer use, cannot be adequately assessed. Thus, the FDA is inherently limited in its ability to investigate signals of public health problems generated by the system. However, the FDA can use adverse event reports to identify areas of concern warranting further investigation. The FDA then initiates collaboration with federal partners to identify knowledge gaps in the safety of individual dietary ingredients and products and works with these partners to fill these information gaps to support appropriate regulatory action.
Key Words: Adverse events • dietary supplements • multivitamins • minerals
INTRODUCTION
Estimated sales of dietary supplements increased nearly 100% between 1992 and 1996, and in 2004 the industry grossed an estimated $20.3 billion (1). Today, dietary supplements are widely available in grocery stores, retail pharmacies, and health food stores and on the Internet. More than 70% of the American population uses some form of dietary supplement every day, of which vitamin and mineral supplements are the most commonly used (2). In the words of a former Food and Drug Administration (FDA) commissioner (3), "A small but disturbing number of these products have a potential for harm or bear unsupported claims. In this context, a rapidly expanding industry and a changing demographic of consumers eager to manage their own health care needs provide a significant regulatory challenge."
The FDA regulates dietary supplements under a different set of regulations from those covering conventional foods and either prescription or over-the-counter drug products. In other countries, where the definitions and regulations for product categories are different, products marketed and sold as dietary supplements in the United States may be marketed more like drugs and may be required to meet more extensive premarket requirements. Under the Dietary Supplement Health and Education Act of 1994 (DSHEA), in the United States, it is the dietary supplement manufacturer who is responsible for ensuring that a dietary supplement is safe before it is marketed (4). The FDA is responsible for taking action against any unsafe dietary supplement product only after it reaches the market. Manufacturers do not need to register their dietary supplement products with the FDA or to obtain FDA approval before producing or selling them (5). The FDA's postmarketing responsibilities, in addition to monitoring product and ingredient safety, include monitoring product information, such as labeling, claims, package inserts, and accompanying literature (6).
ADVERSE EVENT REPORTING SYSTEMS
As with differences in premarket regulations, the FDA's postmarket authority for receiving adverse event information is also different from that for drugs or devices. Adverse event reporting systems typically detect only a small proportion of the events that actually occur. An FDA-commissioned study estimated that the FDA is notified of <1% of all adverse events associated with dietary supplements (A Walker, unpublished observations, 2000). Among the factors that may contribute to underreporting are that many consumers presume supplements to be safe, use these products without the supervision of a health care professional, and may be unaware that the FDA regulates them. In 2001 an Office of the Inspector General report identified many of the difficulties in evaluating adverse events in a voluntary system and the barriers to effective analysis of these reports to generate possible signals of concern (7). These include factors such as limited medical information, limited product information, limited manufacturer information, limited information on dietary supplement consumers, and limited ability to analyze trends. In addition to these postmarket information limitations, for dietary supplements, vital premarket information that is available for drug products is often missing, such as clinical indications, product identification, and consumer or user information, so that possible public health concerns generated by the adverse event reporting system cannot be adequately assessed.
Since 2001, the FDA and the Center for Food Safety and Applied Nutrition (CFSAN) have updated the system for receiving, storing, and evaluating adverse event reports for dietary supplements. The CFSAN Adverse Event Reporting System (CAERS) was initiated in 2004 and allows more efficient review of adverse event reports submitted to the agency. CAERS is a postmarket surveillance system that collects voluntary adverse event reports and product complaints that are allegedly related to CFSAN-regulated products. Because adverse event reports submitted to the FDA are voluntary, they vary in the quality and reliability of the information provided. Information in some reports cannot be verified for accuracy of the symptoms, products, or ingredients. Furthermore, in many reports, individuals may have used other products, and many products contain multiple ingredients, which further complicates the evaluation of adverse event reports. There is no certainty that a reported adverse event can be attributed to a particular product or ingredient. However, CAERS does give the FDA the ability to organize, store, and review submitted adverse event reports more efficiently and effectively by using electronic storage, coding, and query software. The adverse event reports themselves only reflect information as reported and do not represent any conclusion by the FDA regarding a causal relation or association with the product or ingredient. Because of the continuous inclusion of new or updated information into the CAERS system, reports released from CAERS containing adverse event data may change over time. This ability to track and monitor changes improves the CFSANs ability to better analyze trends in the reporting of adverse events for dietary supplements.
SIGNALS OF SAFETY CONCERNS
Signals of a possible safety concern may originate from a variety of sources, including federal, state, and local sources; foreign regulatory actions; media reports; information from consumer groups; consultation with experts; and adverse event reports. Factors affecting the utility of adverse event reports as signals of a possible safety concern include the source of the information, details of the product and clinical event, timing of the exposure, and reproducibility of the event as well as consideration of confounding factors. Adverse event reports in and of themselves typically cannot generate conclusive evidence about the safety of a product or ingredient. Rather, the system can generate signals of possible public health problems.
For dietary supplements, the FDA has relatively few clinical data on ingredients and products. Adding to the challenge of identifying possible safety concerns of individual dietary ingredients is the increasing number of dietary supplement products containing multiple ingredients. Thus, the FDA is inherently limited in its ability to investigate signals of public health problems generated by the system. However, the FDA can use adverse event reports to identify areas of concern warranting further investigation. The FDA then initiates collaboration with federal partners to identify knowledge gaps in the safety of individual dietary ingredients and products and works with these partners to fill these information gaps to support additional regulatory actions. The FDA does this by sometimes seeking independent expert third-party review and evaluation of the risks and benefits of the ingredient or supplement. The FDA considers any independent report and other evidence as appropriate to determine whether an adequate basis exists for a finding of significant or unreasonable risk or whether additional research, labeling, or outreach efforts are needed. Regulatory actions are subsequently based on the totality of the scientific evidence available, including the pharmacology of the substance, scientific literature, adverse event reports, and evidence-based reviews (8).
SUMMARY
Multivitamin and mineral dietary supplements are widely available and used by the public in the United States. The FDA's implementation of the CFSAN Adverse Event Reporting System has improved the agency's ability to analyze trends in adverse events for dietary supplements reported to the FDA. However, limitations in the premarket and postmarket information available for dietary supplements limit the FDA's ability to investigate possible public health problems generated by the system. The FDA does use adverse event reports to identify areas of concern warranting further investigation and initiates regulatory actions based on the totality of the scientific evidence available.
ACKNOWLEDGMENTS
The author had no financial or personal interest in any company or organization sponsoring the research, including advisory board affiliations.
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