April 2, 2014
WASHINGTON—The number of adverse events reports (AERs) connected to dietary supplements that must be reported to FDA has risen for six consecutive years.
Last year, FDA received 3,289 AERs, an increase of 445 from 2012 (2,844) and more than quadruple the number from 2008 (687). From 2008 through 2013, dietary supplement firms submitted 10,585 mandatory AERs to FDA, or an average of 1,765 annually, according to figures from the agency.
AERs reflect hospitalizations, life-threatening illnesses, deaths and other serious adverse events that are connected to supplements.
Mandatory adverse event reports (supplements) submitted to FDA
The growing numbers are actually a credit to the supplement industry, demonstrating that it has become more compliant with a mandatory AER law that Congress passed in late 2006, according to Rick Kingston, co-founder and president of scientific and regulatory affairs with SafetyCall International, an AER specialist that focuses on adverse event management and post-market surveillance.
"As we start to see more companies engage in best practices, which includes being open to receiving information from their consumers, you are going to see more reports of adverse events," Kingston said.
FDA stepped up enforcement activity and increased its vigilance through its inspections to verify companies are following AER requirements, said Steve Mister, president and CEO of the Council for Responsible Nutrition (CRN), which represents dietary supplement manufacturers and ingredient suppliers. FDA checks compliance with AER requirements during its inspections of dietary supplement firms for cGMPs (current good manufacturing practices). Inspections for cGMPs have soared from 87 in fiscal year 2010 to 416 last year, as Natural Products INSIDER previously reported.
FDA also has attributed increases in mandatory AERs to lawsuits that publicize the consequences of failing to report adverse events, according to a 58-page report from the U.S. Government Accountability Office (GAO).
"I think you are getting increased compliance, and so you are getting more reports," Mister said. "That certainly does not suggest the marketplace is getting more dangerous or anything like that."
Pieter Cohen, M.D., an assistant professor of medicine at Harvard Medical School who has advocated for regulatory changes to require FDA preapproval of supplements, credited supplement manufacturers with increased compliance; however, he said it's possible the number of AERs could increase substantially in the coming years.
"I would not be surprised if in the years to come, we find that these 3,300 AERs are only the tip of the iceberg," he said.
Mister noted predictions made years earlier that the number of AERS would double every year proved to be wrong.
The supplement law governing AERs—the Dietary Supplement and Nonprescription Drug Consumer Protection Act—was passed by Congress in late 2006 and required compliance one year after its enactment.
Under the law, dietary supplement firms must disclose to FDA "serious" AERs within 15 days that result in the following: (1) death, (2) a life-threatening experience, (3) inpatient hospitalization, (4) a persistent or significant disability or incapacity, (5) a congenial anomaly or birth defect, or (6) a condition that requires a medical or surgical intervention to prevent one of the outcomes mentioned above based on reasonable medical judgment.
According to GAO, between 2008 and 2010, only 10 percent of supplement AERs resulted in a life-threatening condition (8 percent or 512 reports) or death (2 percent or 92 reports) while roughly half resulted in hospitalization (29 percent or 1,836 AERs) or serious injuries or illnesses (20 percent or 1,272 AERs). During that same time period, more than half of AERs (3,370) resulted in serious events that were not specified. (The percentages don't add up for a reason: GAO cautioned each AER can report multiple outcomes).
Such reports must be kept for six years, and firms have an obligation to submit to FDA new medical information related to the AERs.
Early this year, FDA announced that distributors, manufacturers and packers of dietary supplements could submit AERs through an electronic filing system, representing an alternative to the MedWatch 3500A paper form.
The law does not require reporting of more mild adverse events such as headaches, although supplement firms, consumers and medical professionals have that option. According to GAO, from 2008 through 2011, the number of AERs voluntarily submitted to FDA averaged 461 annually. FDA could not provide the total number of voluntary AERs submitted to the agency from 2008 through 2013.
FDA and its equal north of the border—Health Canada—pointed out such reports don't constitute medical proof that the regulated products caused the adverse event.
"Inclusion of a particular reaction does not necessarily mean that it was caused by the suspected health product(s)," Health Canada explained on its website before consumers can access an online database on adverse reactions. "The data presented reflects, as much as possible, the reporter's observations and opinions, and does not reflect any Health Canada assessment of association between the health product and the reaction(s)."
A person who suspects a dietary supplement as the cause of an adverse reaction may have taken a number of foods, as was the case with a 19-year-old, 173-pound male who was hospitalized last year and had ingested Monster Energy, a muscle-building milk shake and a creatine powder, according to Health Canada's "Canada Vigilance Adverse Reaction Online Database." Other victims may have taken a combination of pharmaceutical drugs, alcohol, illegal substances and dietary supplements.
Establishing whether an isolated AER stems from ingestion of a dietary supplement can be challenging, particularly if the patient has been taking a supplement for months or years. Kingston, who also teaches as a clinical professor of pharmacy at the University of Minnesota, contrasted the latter situation with a person who has taken an antibiotic for a little over a week and develops an adverse reaction.
"Often times, you have to take them [AERs] with a grain of salt" because there is insufficient information to determine whether a product caused an adverse effect, said Bill Gurley, Ph.D., a College of Pharmacy pharmaceutical sciences professor at the University of Arkansas for Medical Sciences.
But an increasing number of reports describing the same event or types of events could indicate a problem, as was the case with the hepatitis outbreak last year connected to a fat-burning supplement manufactured by USPlabs.
Enforcement actions in response to AERs are rare, Kingston said, because few safety issues related to dietary supplements warrant government intervention. According to the professor, Daniel Fabricant, Ph.D., director of FDA's division of dietary supplement programs, said only between 1 percent and 2 percent of AERs are likely to trigger safety concerns. Kingston said those numbers are "realistic" based on his own research.
FDA could not confirm whether Fabricant made that statement and whether it was accurate. Arthur Whitmore, an FDA spokesman, said "even a single percentage—or single number—of people being injured from a conventional food or dietary supplement is not acceptable."
Of the 6,037 supplement AERs FDA received from 2008 through 2011, the agency only established a "certain" relationship between the product and the reported health problem in 3 percent of the cases, according to GAO.
Clearly, FDA faces a difficult task: determining what role, if any, supplements play in its review of AERs, and deciding when to take enforcement action in order to protect public health.
In a phone interview, Fabricant acknowledged AERs don't always include medical history, such as underlying conditions that afflict a person. For two-thirds of the 6,037 supplement AERs FDA received through 2011, "FDA could not determine whether the supplement caused the reported health problem because the AER contained insufficient information," GAO observed in the report. AERs typically exclude other products that a consumer may have taken simultaneously with a supplement, such as a pharmaceutical drug, the report noted.
FDA said it reviews all AERs to track safety issues that warrant intervention. "If we can establish a temporal relationship between the product and adverse event, that's generally when we move to take action immediately," Fabricant said.
In order to take enforcement action, FDA must show the product is "adulterated," which the Dietary Supplement and Health Education Act of 1994 (DSHEA) partly defines as a supplement or ingredient presenting "a significant or unreasonable risk of illness or injury under conditions of use recommended or suggested in labeling."
Fabricant said the agency acts swiftly when the public encounters such risks from a product. He cited last year's hepatitis outbreak connected to USPlabs' OxyElite Pro. In a letter to USPlabs, FDA declared an ingredient (aegeline) in OxyElite Pro was adulterated. USPlabs subsequently destroyed USD $22 million in products, according to the agency.
Canadian and U.S. regulators acknowledge post-market surveillance systems don't capture all adverse reports because not all adverse events are reported. According to a recent investigation by the Atlanta Journal-Constitution, only five of 10 deaths linked to the controversial stimulant DMAA over three years were reported to FDA.
The extent of such underreporting is unknown, according to GAO and industry representatives.
"We still see products this day that don't have an address or a phone number to which a firm can receive an adverse event report," Fabricant said. "We have seen evidence people aren't submitting serious adverse events to the agency, and that's concerning," he added.
A 2012 government report from the Health and Human Services' Office of Inspector General (OIG) discovered 26 out of 127 labels on dietary supplements didn't contain phone numbers or complete addresses, making it difficult for consumers to reach a company in an emergency. The Dietary Supplement and Nonprescription Drug Consumer Prescription Act renders a supplement "misbranded" in violation of federal law if it fails to include such information.
"If a company doesn't make it easy for a consumer to report adverse events then obviously they are not going to have any adverse events to report," Kingston said.
Supplement firms aren't entirely to blame. GAO noted "consumers, health care practitioners or others may not recognize the chronic or cumulative toxic effects of a dietary supplement, or they may broadly assume dietary supplements to be safe and not attribute negative effects to them."
Gurley agreed. "Most health care professionals often times don't have a tendency to consider botanical supplements to be potentially problematic and certainly consumers don't," said the professor, who has studied supplement AERs for several years.
"Clearly a lot of things are underreported because people just don't want to take the time to describe," he added.
Also, consumers who associate supplements with an illness often contact poison control centers rather than FDA, according to GAO's analysis. From 2008 through 2010, the American Association for Poison Control Centers (AAPCC) reported 4,863 cases of adverse events related to dietary supplements; the figure represented 1,000-plus more cases than FDA received during the same period, according to GAO. FDA officials said they were unable to access the poison control data without purchasing it.
Alvin Bronstein, M.D., medical director of the Rocky Mountain Poison and Drug Center in Denver, who presented data at an Institute of Medicine workshop on calls related to energy drinks, said it would be helpful to share the poison control data with FDA.
"Poison centers data is a very valuable resource for learning more about energy drink exposures," Brownstein said in a phone interview. "It would be very useful for FDA to have and review this data. That is my personal opinion."
Cohen and Kingston will further explore the topic of post-market surveillance and regulatory reporting on Wednesday, April 16 during the 13th Annual Oxford International Conference on the Science & Regulation of Botanicals in Oxford, MS. They will be joined by Victor Navarro, M.D., chairman of the Division of Hepatology and medical director of Liver Transplantation at the Einstein Healthcare Network.
For more information on this topic, check out INSIDER's previous Digital Summit where attorney Claudia Lewis of Venable LLP delved into AER requirements.
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