Erik Goldman07.01.10
The first round of data from the federally mandated Adverse Events Reporting System (AERS) for dietary supplements seems to signal two important things: 1) The system works pretty well in enabling FDA to act quickly when there’s evidence of life-threatening side effects, and 2) Serious supplement-associated adverse events are pretty rare given how widely these products are used.
In the end, full participation will increase the knowledge base, and improve the quality, efficacy and safety of products taken by millions of people every day.
That’s good news, and the industry should feel proud of these initial findings. The relatively small number of significant adverse events—1025 reports in 2008, to be exact—should be somewhat reassuring to the general public and the medical community, given the 500,000-plus adverse event reports the FDA received for pharmaceuticals that year.
But we shouldn’t let it go to our heads. The AER system is still very new, and reporting—though required at least in theory—is still more or less voluntary in practice. Most physicians and consumers are unaware that supplement side-effect reporting is even a possibility.
The American Herbal Products Association (AHPA), a trade organization for manufacturers of botanical products, and a major supporter of the legislation establishing the AER system in 2008, obtained the data from FDA under the Freedom of Information Act. Michael McGuffin, AHPA’s president, presented the numbers at the SupplySide East show in May.
Starting in 2008, the federal government mandated that supplement manufacturers list toll-free adverse events reporting phone numbers on product labels, and required them to promptly relay any notices of serious side effects to FDA.
The system, established by the Non-Prescription Drug Consumer Protection Act in 2007 with strong bipartisan political support, uses the same definitions of “serious” as FDA applies to prescription drugs, including: death, life threatening side effect, hospitalization, persistent disability, cognitive dysfunction and congenital anomaly.
Of the total 1025 reports FDA received in the first year, 12 were missing essential information, leaving a total of 1013 evaluable events. Mr. McGuffin noted that 627 reports (61%) came directly from supplement companies, with 287 (28%) coming from consumers and 99 (10%) reported by physicians or other healthcare practitioners.
Roughly two-thirds of the reports concerned AEs in females, which reflects the general demographic pattern of supplement use: women take more supplements and take them more frequently than men.
Direct reports from supplement manufacturers came from 140 different companies. Among the 627 reports were 8 deaths, 64 life-threatening episodes, 229 hospitalizations, 16 incidents requiring medical intervention and 8 that resulted in significant and permanent disability.
Products implicated in the reports represented a broad range 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 Mr. McGuffin stressed that this does not indicate any inherent danger associated with these products. Rather, it reflects their huge popularity, and the fact that these companies, being major pharmaceutical players, already have large and highly sophisticated AER call centers as well as decades of experience in fielding AER calls and reporting them to FDA
What happens when FDA receives a supplement AER report? It gets logged into the Center for Food Safety and Applied Nutrition (CFSAN) database, the same data repository as is used for foods, OTC drugs and cosmetics. CFSAN analysts then assess the strength of the evidence that the product in question could have caused the reported event. They try to rule out confounding variables 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 a strong suggestion of causality, and especially if there is a cluster of similar reports about an individual product or brand, FDA will contact the company in question 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.
He stressed that an AER is a “signal generator, not a final determination of causality.” In isolation, a single report means nothing, and isolated individual reports are seldom if ever even verified by investigators. “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.”
What FDA is looking for is patterns. The 2008 data indicate that the system actually works quite well to facilitate swift investigation and corrective action when a suspicious pattern emerges.
In the first year, there were two signal clusters that moved FDA into action. Early in 2008, the agency received 26 reports, mostly from Florida, of unexpected side effects associated with “Total Body Formulas” brand of liquid vitamins: these included acute muscle cramps, severe diarrhea, joint pain, extreme fatigue and hair loss.
Three months later, FDA issued a consumer warning about the products, which elicited an additional 68 reports. Investigators analyzed the formulas and found that they contained 10 times more selenium than they should have; the reported AEs were related to selenium toxicity. The manufacturer voluntarily recalled the products.
The AER system also showed a cluster of serious side effects related to a muscle-building product called “TREN-Xtreme,” manufactured by American Cellular Laboratories. The FDA tested this product and found anabolic steroids.
TREN-Xtreme was recalled in July 2009, just two months after the widely publicized Hydroxycut recall.
At a time when major pharmaceutical production facilities are under investigation for shoddy manufacture, and every pharmaceutical ad ends with a hyperventilated litany of potential adverse effects, the 2008 AER data sure make the supplement/natural products industry look pretty good.
But let’s face it, under-reporting is the rule not the exception at this point. Though the law does state that failure to report a serious AE to FDA is a punishable criminal offense, there have been no enforcement actions so far. And given how short-handed FDA already is, and the burden of work involved in pharmaceutical oversight, a concerted enforcement effort is unlikely anytime soon.
Further, the AER system—whether for drugs or supplements—depends on input of signals from the field. While most consumers and practitioners are aware they can and should report drug-associated side-effects, far fewer are aware there are similar reporting systems in place for supplements as well. Any industry will look good if few people know how or where to report problems.
Still, AHPA’s Mr. McGuffin said he is pleased by the findings from the first year of AERS, though he said the system definitely needs some tweaking, and more companies need to step up to their responsibility for reporting. As the industry comes to recognize that the system is not intended as a bludgeon, but rather a means by which to improve the safety and value of supplement products, he believes more companies will actively participate.
