Early in 2008, the Federal government mandated that dietary supplement manufacturers list toll-free adverse events reporting phone numbers on their product labels, and required them to promptly relay to the Food and Drug Administration any notices of serious side effects they receive.
The first wave of data from this new Adverse Events Reporting System (AERS) shows two important things: 1) The system does work, enabling the FDA to act quickly when there’s evidence of life-threatening side effects, and 2) Serious adverse events are rare given how widely supplements are used.
The American Herbal Products Association (www.ahpa.org), a trade organization for manufacturers of botanical products, and a major supporter of the AER legislation, obtained the 2008 data from the FDA under the Freedom of Information Act. Michael McGuffin, AHPA’s president, presented the data at SupplySide East, a natural products industry trade show.
The FDA received a total of 1,025 reports of serious AEs in 2008; 12 reports were missing essential information, leaving a total of 1,013 evaluable events. Even correcting for widespread under-reporting (which is likely with a new system and a still untested enforcement mechanism) the number would still be quite low compared with the 500,000-plus AERs the FDA received for pharmaceuticals that year.
The supplement AER system, established by the Non-Prescription Drug Consumer Protection Act in 2007 with strong bipartisan political support, relies on the same “MedWatch 3500A” reporting form as is used for drug-related AERs. It also uses the same definitions of “serious” as applies to prescription drugs, including: death, life threatening side effect, hospitalization, persistent disability, cognitive dysfunction, and congenital anomaly.
Causality Questions
In one sense, the regulation is more stringent than those governing pharmaceuticals, explained Mr. McGuffin. “Drug marketers are not required to report “expected” AEs to the FDA. That’s not true for supplements.” Companies that fail to relay reports of serious product-associated AEs face potential criminal liability charges.
What happens when FDA receives a report? It gets logged into the Center for Food Safety and Applied Nutrition (CFSAN) database, which also holds reports for foods, OTC drugs, and cosmetics. CFSAN employees encode the information into standardized “Medial Dictionary for Regulatory Activity” terminology.
Analysts then assess the strength of the evidence that the product in question could have caused the reported event. They must rule out confounding factors like prior medical conditions that could have produced the reported symptom, use of other drugs or supplements, foreign travel, or other exposures.
If there’s reasonable evidence of causality, and especially if there is a cluster of similar reports about a product, FDA will contact the company and requisition the original AE report, gather product samples, and if necessary, intensify the investigation. “It’s exactly the same process they use for drug AERs,” said Mr. McGuffin.
Of the 1,013 evaluable reports in 2008, 627 (61%) came directly from supplement companies, with 287 (28%) coming from consumers, and 99 (10%) reported by physicians or other health professionals. Roughly two-thirds of the reports concerned AEs in females, consistent with the overall demographics of supplement use.
Among the 627 reports coming from 140 different supplement companies there were 8 deaths, 64 life-threatening episodes, 229 hospitalizations, 16 incidents requiring medical intervention, and 8 that resulted in significant and permanent disability. Products identified in the reports spanned the gamut of supplement categories, with 249 reports related to vitamin/mineral products, 80 for herbs, 391 for combination (vitamin/mineral/herb) products, and 105 for “Other” supplements (fish oil, amino acids, enzymes, probiotics, etc).
Among the most commonly cited brands were Bayer’s One-a-Day, Centrum, and Flintstones vitamins, but this reflects the massive popularity of these products and the high degree of sophistication of the call centers at these major OTC drug companies, and not any inherent danger associated with them.
Strong Signals, Swift Action
Mr. McGuffin stressed that this raises a very important point. “An AER does not imply admission that a particular product caused that AE. All we can really know from an AER—whether for a supplement or a prescription drug—is that a call was made,” said Mr. McGuffin. “It’s a signal generator, not a final determination of causality.”
So far, there have been two signal that led to swift FDA regulatory action. Early in 2008, the agency received 26 reports, mostly from Florida, of unexpected side effects associated with the “Total Body Formulas” brand of liquid vitamins: the reported AEs included acute muscle cramps, severe diarrhea, joint pain, extreme fatigue and hair loss.
In March of that year, FDA issued a consumer warning about the products, which elicited an additional 68 reports. Further investigation revealed that the formulas contained 10 times more selenium than they should have (200 mg instead of the labeled 2 mg); the AERs reflected selenium toxicity. The manufacturer voluntarily recalled the products. “In this case, the system worked really well,” said Mr. McGuffin.
The AER system also signaled an alarm about significant side effects related to a muscle building product called “TREN-Xtreme,” manufactured by American Cellular Laboratories. The FDA tested the product, which turned out to contain anabolic steroids.
TREN-Xtreme was recalled in July 2009, just two months after the widely publicized recall of Hydroxycut, a line of 14 popular weight loss products that were linked to 23 reports of severe liver damage and one death. Investigators have not yet determined what specific ingredient of these multi-component formulas was causing the problems.
AHPA’s Mr. McGuffin said that while there are tweaks that need to be made to improve the process, and more companies need to step up to their responsibility for reporting, he is pleased by the findings from the first year of the supplement AER system.
His organization, as well as the Natural Products Alliance, the Council for Responsible Nutrition, and many other trade groups, are calling on clinicians to report any suspected AEs related to supplements. In the end, this will increase the knowledge base, and improve the quality, efficacy and safety of these products taken by millions of people every day.
To report any adverse event to the Food & Drug Administration’s MedWatch system, call: 1-800-FDA-1088 or download the online reporting form from this website: http://www.fda.gov/Safety/MedWatch/HowToReport/ucm053074.htm
