FDA's Tattered Safety Net for Dietary Supplements
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In August 2011, a Colorado woman was rushed to an emergency room in cardiac arrest a day after her husband injected her with a mineral salt called cesium chloride. For the better part of a year, the 61-year-old had been treating herself for a breast lump by taking a dietary supplement containing the compound as an alternative treatment for breast cancer, until a nutritionist recommended injecting a dose instead.
ER doctors were at first able to stabilize her condition, but after a week the woman was discharged to hospice in a “neurovegetative state,” according to a case report published in the Journal of Alternative and Complementary Medicine. She died three days later.
Her use of cesium chloride—a chemical compound purported to kill cancer cells—probably triggered abnormal heartbeats that stopped her heart, the report’s authors concluded.
Seven years later—citing published accounts of 16 patients who had died, suffered cardiac arrest, or experienced other serious harm after using the products—the consumer advocacy group Public Citizen petitioned the Food and Drug Administration to ban all dietary supplements containing cesium chloride or other cesium salts.
In early February of this year, the FDA agreed to issue an advisory warning consumers about the risks of the supplements. And it has acknowledged that the substance is associated with significant safety risks.
But the agency denied Public Citizen’s request to ban cesium chloride products. One key reason: Only a few adverse events related to those products show up in a little-known FDA database that the agency relies on to police the nation’s $46 billion supplement industry.
That database, called CAERS—which is pronounced “cares” and stands for the Center for Food Safety and Applied Nutrition Adverse Event Reporting System—is meant to alert the agency to potentially dangerous supplements.
But the cesium chloride episode illustrates serious shortcomings in a warning system that doesn’t adequately protect the public, a Consumer Reports investigation has found. As long ago as 2001, when the FDA handled adverse event reports linked to supplements in a precursor to CAERS, a report by the inspector general of the Department of Health and Human Services called the agency’s system (PDF) an “inadequate safety valve” to protect consumers.
Two decades later, that remains the case even with CAERS in place. That’s according to CR’s review of thousands of pages of FDA reports and records obtained through public records requests, and interviews with more than a dozen consumer advocates and experts on supplements.
Consumers overwhelmingly believe that supplements are safe or else they wouldn’t be allowed on the market. And, because of concerns raised by COVID-19, they now may be more likely than ever to seek out supplements that promise to keep them healthy.
Michael Carome, M.D., director of health research at Public Citizen, says that the regulatory structure for dietary supplements is flawed. And he says that relying on reports submitted after a product is on the market into a database known to have issues “puts consumers at risk.”
Dangers Go Unreported
CAERS is a collection of reports of harm linked to dietary supplements and other products. Reports are submitted through an online form or by mail or fax by consumers, healthcare practitioners, and manufacturers.
Doctors and consumers, who may have learned about the system from their healthcare provider or by searching online, submit the reports voluntarily. Manufacturers must submit them whenever they receive reports of people who report serious adverse events, including death or hospitalization, after taking one of their products. About three-quarters of the reports come from supplement makers, according to records obtained by CR.
The reports can’t, on their own, establish a cause-and-effect link between an incident and a product. Rather, the agency periodically scours the database using algorithms to detect signals of potential safety problems.
But the system is plagued by problems, starting with underreporting. Research suggests that only about 2 percent of adverse events possibly related to dietary supplements each year are ever reported to the CAERS database. As a result, it can take years for the FDA to build a case that a supplement is unsafe and, as with cesium chloride, to even consider getting it removed from the market.
Unlike with monitoring of prescription and over-the-counter drugs, the FDA doesn’t have to alert the public when it investigates a potential problem with a supplement. In addition, though the FDA has recently tried to encourage consumers to submit more reports, CR found that report totals are down. And in only a few cases has CAERS clearly played a major role in the recall of dietary supplements.
The FDA acknowledges the challenges of using the database, a reality underscored in a February 2020 memo obtained by CR related to the agency’s handling of cesium chloride supplements. In that memo, an FDA staffer not only pointed to the small number of reports linked to the compound—which wasn’t surprising given the known problem of underreporting—but also said those reports often lacked crucial information about the people reporting problems, including their age, contact details, and relevant medical history.
That’s in part because those details are optional. The FDA requires only that reports include the product name; the possible harm; the name of the person filing the complaint; and, when submitted by a manufacturer, the name of the patient and contact information for the person or company filing the complaint. (Names are not visible in the public database.)
After-the-Fact Oversight
Unlike pharmaceuticals, which must undergo extensive testing before they can be sold or prescribed, federal regulations generally don’t require supplement makers to prove that their products are safe before going to market. Instead, the FDA’s role in identifying and regulating potentially dangerous supplements generally comes after consumers have already purchased and taken them.
The agency does periodically inspect manufacturing facilities and, in a few cases, test products for possible adulterants. But even when it tests and finds problems, the results don’t always lead to action. In June, for example, the FDA published a study on bitter orange weight loss supplements, revealing that about 10 percent of the samples it tested contained illegal stimulants. But as of mid-July, the agency had still failed to warn consumers about the risk.
Mainly, the FDA relies on CAERS—even with its known flaws—to detect potential problems. And the agency considers it a “useful tool,” despite its limitations, says Nathan Arnold, an agency spokesperson. “These reports require careful review and interpretation, and conclusions should be made within the context of all available safety data about a product, with CAERS data being one piece,” Arnold says. He adds that the agency also monitors products through information from manufacturers and healthcare providers and, when the agency finds unsafe or illegal products, it acts “based on public health priorities and available resources.”
Andrea Wong, Ph.D., senior vice president of scientific and regulatory affairs at the Council for Responsible Nutrition, a trade association for the supplement industry, says CAERS works well. “We fully support the system that’s in place,” she says.
But some advocates say CAERS is flawed. “The FDA’s adverse event reporting system may weed out a few dangerous supplements, but only after they’ve been on sale, sometimes for many years,” says Chuck Bell, programs director in CR’s advocacy division, which has pushed for years to reform dietary supplement regulation.
A System's Fatal Flaws
One example of the system’s shortcomings concerns Hydroxycut, a weight loss supplement first popularized in the early 2000s.
In 2004, the FDA banned ephedra—the active ingredient in Hydroxycut—after it received thousands of adverse event reports linking it to heart attacks, strokes, deaths, and other adverse events. But rather than withdrawing Hydroxycut from the market, its manufacturer reformulated the product. Despite that reformulation, reports of liver damage continued.
Martin Robertson, a Maryland resident, claimed in a lawsuit that he developed liver failure in 2008 several months after he started using Hydroxycut. “As a direct and proximate result of using Hydroxycut Regular Rapid Release Caplets,” the lawsuit says, Robertson “suffered severe mental and physical pain and suffering and has sustained permanent injuries and emotional distress.”
Iovate, the maker of Hydroxycut, denied the claims in court. The case was eventually settled.
It took the FDA seven years to compile enough reports—23 in all, including one death—to determine that Hydroxycut was causing the liver injuries, to warn consumers to stop using it, and to get the manufacturer to recall the product line.
In a 2013 report, the Government Accountability Office (GAO), a government watchdog, pointed to Hydroxycut as an example of how difficult it is for the FDA to use CAERS (PDF) to accumulate “enough evidence to discern a clear relationship” between a product and a reported health problem. “Most [reports] do not initiate or support such actions because it is difficult to establish causality between the product and the health problem based on the limited information in an AER,” the report said.
Another case from about a decade ago, with a supplement called OxyElite Pro, illustrates others flaws in the FDA’s oversight. Made by USPlabs, the supplement illegally contained a stimulant called DMAA, an amphetamine derivative linked to high blood pressure and heart attacks.
The Department of Defense, in late 2011, ordered supplements containing DMAA to be removed from stores on military bases after it said the stimulant was a possible factor in the deaths of four soldiers. A subsequent analysis of the CAERS database, captured in a study by FDA staffers, showed that the agency had received several reports citing products containing DMAA the previous year.
Months later, in April 2012, the FDA issued warning letters to firms that manufactured supplements containing DMAA, which led some companies to remove the products from the marketplace. But USPlabs continued to sell its product, reformulating OxyElite Pro with a previously unused supplement ingredient called aegeline.
In the fall of 2013, the Hawaii Department of Public Health identified 21 cases involving adults who developed liver disease after taking OxyElite Pro and submitted reports about them to CAERS. After reviewing those cases plus an additional 12 involving consumers in other states, the FDA determined that OxyElite Pro likely contributed to liver injury. USPlabs agreed to recall the product, saying it was a precautionary measure.
Daniel Fabricant, Ph.D., who led the FDA supplements office at the time and is now CEO of the industry group Natural Products Association, says the agency responded in a timely way, evaluating the reports as they came in.
But a subsequent study by FDA staffers in the journal Public Health Reports highlighted a “significant lag” between the time an incident occurred and when it was reported, and said the value of the system “depends largely on the extent to which potential reporters employ the system.”
A 2014 article in the New England Journal of Medicine by Pieter Cohen, M.D., an assistant professor of medicine at Harvard Medical School who has studied supplements extensively, was more blunt: “The FDA’s delayed response—with its life-threatening consequences—is attributable to our woefully inadequate system for monitoring supplement safety.”
Too Little Data
After the ephedra ban, in 2006 Congress tried to improve the adverse reporting system for supplements by mandating that companies submit reports they receive. But the law required that they submit only “serious” ones, such as those resulting in death, hospitalization, or a “life-threatening experience.” And the only way the FDA can verify that companies submit those reports is by auditing their reports during site inspections, something that happens infrequently.
Of equal concern were reporting rates for adverse events estimated to be around 2 percent, according to a 2017 study in Annals of Pharmacotherapy written by FDA staffers.
In late 2016, the FDA again tried to encourage the submission of more reports, this time by making it possible not just for people to submit them but also for consumers, academics, and others to examine the database itself. The agency hoped that increased access would translate into more people submitting reports.
But since CAERS went public, the FDA has actually received fewer adverse event reports associated with supplements, from 5,355 in 2016 to 2,899 in 2018, the agency confirmed. Arnold, the FDA spokesperson, says, “The FDA cannot speculate why data may be fluctuating, but regardless, CAERS continues to be a useful tool for its intended purposes.”
Harvard’s Cohen says the agency isn’t doing enough to follow up. “Year after year there has been no substantial enforcement action by the FDA to remove dangerous supplements from the marketplace based on adverse event reports,” he says. “Rational consumers and their physicians could reasonably conclude that it is fruitless to submit more reports to an agency that is not following up on the reports.”
The Burden of Proof
An examination of the current publicly available database by CR suggests that it still offers little use to consumers, a critique leveled in the inspector general’s report from two decades ago.
For example, a consumer reviewing the database today might note that a product called Super Beta Prostate is one of the most frequently cited supplements in CAERS, with 1,090 reports, according to a CR review. (It’s hard to know for certain which supplement has the most reports in CAERS because products with the same or similar ingredients are sometimes listed under different names.)
Marketed as an aid for men with urinary frequency problems, Super Beta Prostate contains an ingredient called beta-sitosterol, a substance derived from plants that is sometimes used to lower cholesterol levels but that studies suggest may also help improve urine flow in men with an enlarged prostate. The maker of the product, New Vitality, says that the company has sold 15 million bottles of Super Beta Prostate and a similar supplement, Super Beta Prostate Advanced, since the products were first introduced.
Among the medical research on beta-sitosterol published to date, CR found no convincing evidence that the ingredient or Super Beta Prostate is unsafe. CR even conducted some limited testing of the supplement to see whether it was adulterated with prescription drugs, such as tamsulosin (Flomax) and sildenafil (Viagra), which are sometimes used to treat an enlarged prostate. A drug in a supplement could interact dangerously with other medications. And sildenafil, in particular, has previously been found in some supplements. CR’s tests didn’t find those specific adulterants.
Still, an examination of FDA records on Super Beta Prostate, obtained by CR through a Freedom of Information Act request, offers insight into how the FDA seeks to determine whether there’s a causal relationship between a product and adverse events.
In 2016, records show, FDA staffers mined CAERS and detected a signal potentially tying Super Beta Prostate to reports of hematuria, or blood in urine, prompting the agency to investigate. But as is often the case with those reports, the data was incomplete. For example, only about a third of the Super Beta Prostate reports identify the consumer’s age, according to CR’s analysis.
And documents obtained by CR suggest that the FDA wasn’t even able to posit a theory as to why the product might cause blood in urine—if it did at all—even though it had several hundred reports on file to review. “We have no theory to explain why the effect (if it exists) is so specific to the genitourinary tract,” an FDA investigator said in a document.
One possible reason is that blood in the urine is relatively common among men with enlarged prostates, according to experts and New Vitality itself.
In addition, the company offered several other possible explanations for why its product has many reports in the CAERS database. For example, New Vitality relies heavily on direct marketing, it says, a business model that makes it easy for consumers to pass along potential adverse events they may experience to customer-service representatives. And the company has a policy of submitting to CAERS all adverse event reports it receives, not just those considered serious.
Moreover, New Vitality says that the rate of adverse events reported for its product is low compared with the volume of product it sells and that, after conducting an investigation, the FDA didn’t conclude that the product posed a safety risk. The company told CR that Super Beta Prostate has an “unblemished safety record.”
Behind Closed Doors
In October 2016, records obtained by CR suggest that the FDA’s investigation of Super Beta Prostate ended with the agency taking no enforcement action. But contrary to how the FDA handles prescription drugs, it never alerted the public about the adverse event reports or its investigation. (When asked by CR, an FDA spokesperson declined to comment about the agency’s effort with Super Beta Prostate.)
By law the FDA has to conduct routine screenings of FAERS, the drug counterpart to CAERS, then publicize any “potential signal of a serious risk” associated with a drug. After the agency evaluates signals from that database, it determines whether the drug is associated with the risk and, if so, what regulatory action is required—then publishes an update of the findings on its website.
But with supplements, the FDA isn’t required to publicize the results of its investigation or to even tell the public it conducted one. The FDA didn’t answer CR’s question about why it doesn’t use the same approach for CAERS as it does with FAERS.
Wong, at the Council for Responsible Nutrition, says the system works well because the FDA would notify consumers if CAERS revealed a risky supplement. “FDA’s already analyzed the information, and based on their scientific expertise has determined that information is relevant for consumers to be aware of,” she says.
But the reports in CAERS are public and could also be reviewed by academics, researchers, and consumers. So if there are emerging reports about potential hazards, consumers would want to know that as quickly as possible, says CR’s Bell.
Publicizing the investigation of a signal found in CAERS—especially one that ends with the agency finding no regulatory action is necessary—could also reassure consumers about the safety of a product, he says.
How to Fix the Alarm System
Independent experts and consumer advocates have suggested several ways to improve the system.
Peter Lurie, a former FDA official and president of the Center for Science in the Public Interest, a consumer watchdog in Washington, D.C., suggests the FDA should amend the 2006 law to require supplement makers to submit reports of incidents it receives about all events, not just ones deemed serious.
“It’s always good to have more data, right?” he says. “If it is in the hands of the company to make a determination if something is serious, there’s always the incentive to underreport.”
Another suggestion is for the FDA to better coordinate with other groups that receive reports of adverse events linked to supplements. For example, between 2008 and 2010, poison control centers received an estimated 1,000 more reports of events related to those products than the FDA had received, according to the 2013 GAO study.
The GAO pointed out that the FDA could benefit from such a move. The FDA considered a plan to obtain the data but said it couldn’t afford it in the end. Consumer advocates and researchers have continued to suggest that the FDA explore the option.
Experts and advocates also say the FDA should create a mandatory registry of supplements that includes the name of the product and contact information for the company before they can be sold. Recent cases underscore the problems of not having such a registry, including an August 2019 outbreak of dangerously low blood sugar levels that hospitalized 17 men who took a sexual enhancement supplement called V8. Almost a year after the outbreak, the FDA still won’t even say whether it knows who made the product. Had V8 been registered in such a database, that could have helped the agency more quickly track down who was behind it. The FDA says it supports the creation of a registry.
CR’s Bell adds that an even better fix would be requiring supplement makers, like drug companies, to prove that their products are safe and effective before they are sold. “It would be far preferable to require safety testing and FDA approval up front,” he says. “The current system, in effect, benefits the supplement companies far more than it benefits consumers.”
For more on CR’s work on the FDA’s oversight of the dietary supplement industry, go to CR.org/supplementwatch.
Editor's Note: This article, which was originally published as "FDA's Supplement Warning System Has Deadly Limitations" on ConsumerReports.org on May 27, 2020, also appeared in the September 2020 issue of Consumer Reports magazine. It has been updated since it first published.
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