Changes Recommended in Adverse Event Reporting on Dietary Supplements
FDA is not authorized to require premarket approval of supplements for safety and efficacy. Instead, the agency identifies safety problems largely through voluntary reporting of adverse events by consumers and health professionals. Research shows that less than 1% of supplement-related adverse events are reported to FDA in this way. When the agency does receive an adverse-event report, it has difficulty obtaining enough information to evaluate the event and take appropriate action to protect consumers.
The OIG report, Adverse Event Reporting For Dietary Supplements, is subtitled "An Inadequate Safety Valve." Released in April, the document contains recommendations for facilitating detection of adverse events, obtaining more information about adverse-event reports and about supplement products, and disclosing more useful information to the public.
FDA authority over supplements. FDA has limited ability to investigate signals of public health problems obtained from reports of supplement adverse events because few clinical data are available on supplement ingredients and products. When problems are linked to a marketed supplement, the burden is on FDA to prove that the product is unsafe or adulterated.
The Dietary Supplement Health and Education Act of 1994 (DSHEA) requires supplement manufacturers to notify FDA 75 days before marketing new supplement ingredientsthose not present before October 1994 in the U.S. food supply "in a form in which the food has not been chemically altered." It is difficult for the agency to determine which ingredients are subject to the requirement, and to date only about 100 premarket notifications have been received.
Supplement products whose labels lack warnings may be misbranded, the OIG noted, and FDA enforcement of false or misleading labeling may be inadequate. Further, supplement ingredients or active constituents can be listed under a variety of names.
More data needed. Six types of key data about adverse events are needed to generate and evaluate signals of potential risk, said OIG: information from the supplement user's medical record, information about the product (e.g., concentration of ingredients, claims, labeling), how to contact the manufacturer, how to contact the consumer for follow-up, information from clinical research, and trend analysis.
OIG found that from 1994 to 1999 FDA followed up on 801 supplement adverse-event reports but could obtain medical records in only 464 cases (58%) and could follow up with consumers on only 214 (27%) of the 801 reports. At least half of all supplement adverse-event reports in FDA's database are from consumers and 20% from health professionals.
Reports of adverse events during that period were associated with 3574 products. For 32% of these products, the manufacturer could not be determined; a consumer may know who the distributor is but not the manufacturer. FDA lacked product labels for 77% of the products and could not determine the ingredients in 32% of the products. FDA told OIG that it had found a product with the same name and packaging in three different locationseach package listing different ingredients. FDA was able to obtain samples of only 69% of the 188 products for which samples were requested.
Supplement manufacturers are not required to report adverse events to FDA, and since 1993 the agency has received fewer than 10 reports from manufacturers. In contrast, said OIG, 90% of adverse-event reports in 1999 to FDA's Center for Drug Evaluation and Research were from manufacturers.
Compounding the lack of information is the inability of FDA's database to analyze trends, said OIG.
Assessing the signals it does receive is a challenge for FDA because of the dearth of clinical data and the limited information on consumer use, said OIG. FDA estimates the potential public health threat associated with an adverse-event report from the size of the consumer population and the dosage used. Since there is little information on how many doses of a supplement product are actually consumed, it is difficult to determine the frequency of adverse events associated with a product or ingredient.
Few safety actions taken. As a result, FDA rarely takes safety actions related to supplement adverse-event reports. From January 1994 to June 2000, 32 safety actions were documented, including 9 consumer warnings (press releases or discussion papers), 2 "Dear Colleague" letters to health professionals or manufacturers, 15 requests for voluntary recalls, and 4 product seizures. "It is quite clear that at a time when more than 100 million people were taking dietary supplements, the number of FDA safety actions was strikingly low," said the OIG report. Some FDA officials told OIG that ensuring compliance with supplement safety actions takes lower priority than use of enforcement resources for other regulated products.
"Without further development of the overall regulatory framework for dietary supplements, the potential of the system to serve as a consumer safeguard is inherently limited," said OIG. "The program simply cannot serve as an adequate safety valve until other measures are taken that will allow FDA to generate and confirm signals of possible public health concerns."
Recommendations to FDA. OIG made the following recommendations to FDA. FDA agreed with most of the recommendations and noted which ones would require more resources, legislative changes, or both. FDA said it was already implementing some of the recommendations but needed more resources to do so comprehensively.
- Require dietary supplement manufacturers to report serious adverse events to FDA for some products. (FDA: More resources needed.)
- Contract with poison control centers to obtain their adverse-event reports on dietary supplements. These centers, which receive more such reports than FDA does, consider product identity private information and have told FDA they would remove product codes from their reports unless FDA agreed not to release product identities to the public. (FDA: More resources needed.)
- Inform health professionals and consumers about the adverse-event reporting system for dietary supplements. Consider requiring manufacturers to list their toll-free telephone numbers on product labels, especially if manufacturers are required to report adverse events to FDA. Consider listing FDA's telephone number on all supplement labels. (FDA: More resources needed; legislative change needed to list FDAs phone number.)
- Educate health professionals about the importance of including medical information in adverse-event reports. Encourage health professionals to obtain consent from patients to release their medical records to FDA.
- Require supplement manufacturers to register their products with FDA. (FDA: Legislative change needed.)
- Notify manufacturers when FDA receives a serious adverse-event report.
- Require supplement manufacturers to register with FDA. (FDA: Legislative change needed.)
- Emphasize to health professionals and consumers the importance of providing a way to identify the alleged injured party in reports. FDA must ensure that the identities of the reporter and the alleged injured party will not be disclosed under any circumstances. (FDA: More resources needed.)
- Develop a new computer database to track and analyze adverse-event reports. (FDA: More resources needed.)
- Issue guidance on the type of safety information that manufacturers should include in the 75-day premarket notification requirement for new dietary supplement ingredients.
- Explore the possibility of a monograph system for dietary supplements.
- Collaborate with the National Institutes of Health in setting a research agenda addressing safety issues.
- Assist industry and the United States Pharmacopeia in standardizing dietary supplement ingredients, particularly botanicals.
- Expedite the development and enactment of good manufacturing practices for dietary supplement manufacturers.
- Disclose more useful information to the public about dietary supplement adverse events. For example, add summary data on particular products to FDA's Web site, and update the site more frequently.
Industry comments. OIG solicited comments from three trade associations: the Consumer Healthcare Products Association, the American Herbal Products Association, and the Council for Responsible Nutrition. The trade groups said FDA's current system would work adequately if internal operating procedures were improved, but OIG strongly disagreed.
Health care professionals received a second letter from FDA in April linking botanical products containing aristolochic acid with renal disease. These products are sold as dietary supplements and "traditional herbal medicines."
"We urge you to review your cases of unexplained renal disease, particularly interstitial fibrosis associated with end-stage renal disease [ESRD], as well as cases of urothelial tract tumors" to determine whether the patients are using supplements containing aristolochic acid, said FDA's Center for Food Safety and Applied Nutrition.
A May 2000 letter from FDA alerted health professionals to concerns about the nephrotoxicity and carcinogenicity of these products. At the same time, FDA urged trade associations representing supplement makers to be sure their products were free of aristolochic acid.
These actions were based on reports from Belgium of 100 cases of renal disease in patients who took a weight-reduction product from 1990 to 1992 and on detection of aristolochic acid-related DNA adducts in renal tissue from five of the patients, plus a 1999 report of two cases of interstitial fibrosis in patients from the United Kingdom who had taken products containing aristolochic acid. Most of these patients required dialysis or renal transplants. In the Belgian cases, Aristolochia fangchi had been inadvertently substituted for the botanical Stephania tetrandra, which has a similar Chinese name.
Since FDA's first letter, urothelial carcinoma was reported in 18 (46%) of 39 of the original Belgian patients with ESRD who had agreed to undergo prophylactic surgery. Seven cases similar to the Belgian cases were identified in French patients who used products contaminated with A. fang chi, and renal malignancies were suspected or confirmed in three of these patients.
Laboratory analysis of products sold in the United States has detected aristolochic acid, and the manufacturers or distributors have been sent warning letters or recall requests. Included are single-ingredient products labeled as Aristolochia (sometimes called Virginia snakeroot) and botanicals likely to be substituted with Aristolochia (e.g., S. tetrandra, Clematis armandii, and akebia extract) and several finished products sold as dietary supplements.
ESRD was reported in two U.S. patients who took products containing aristolochic acid. One of the patients progressed to ESRD within eight months of starting to use herbal medicines in 1994 and had a renal transplant in 1996. Two products she took were found to contain aristolochic acid. The second patient took "stephania tablets" for two years until 1994; the product was found to contain aristolochic acid. She now has ESRD and is awaiting a renal transplant.