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Friday, February 23, 2024

Americans Took Prevagen for Years—as the FDA Questioned Its Safety

Kimberly Beauregard was terrified of losing her memory as she entered her 60s. When she saw advertisements for Prevagen a few years ago, they impressed her.

“Can a protein originally found in a jellyfish improve your memory?” asks the voice-over in one commercial that used to air on prime-time TV. “Our scientists say yes.” The ad cuts from a swarm of the glowing blue sea creatures to scenes of people in white lab coats, smiling senior citizens, and a final assurance that Prevagen has been clinically shown to improve memory.

“It was enough to make me say this is good, there’s going to be some benefit to it,” Beauregard said. “I thought it was more than just a supplement.”

She wasn’t alone in that faith. Three million people are estimated to have purchased Prevagen since it was first launched by Quincy Bioscience, a Wisconsin-based manufacturer, in 2007. Sales reached $165 million by mid-2015, and the company claims Prevagen is now a “best-selling branded memory supplement in chain drug stores across the United States.” A month’s supply of the “extra strength” variety retails for about $60 at Walgreens, CVS, and Walmart.

Beauregard took Prevagen every day for nine months, spending around $500 in all, but said she hadn’t noticed any memory improvement. Quincy Bioscience has been sued multiple times over allegations of false advertising for Prevagen, including by the government. After hearing about the lawsuits, Beauregard says she felt like her worst nightmare—of losing her memories—had been exploited by Quincy. “They almost played on that fear, really, to make money,” she said. “I was taught that there were people out there that protected us from this kind of stuff.”

She’s not alone there, either. Well over half of American adults take supplements, but there are plenty of misconceptions about the industry and how it’s regulated. In a 2019 survey by Pew Charitable Trusts, more than half the respondents believed that the Food and Drug Administration either tests supplements for safety or must approve products before they are sold. Neither is true. Instead, the FDA largely relies on reporting by the companies and consumers, as well as its own inspections, to spot potential problems once supplements are on the market.

Commercials for Prevagen have insisted that “it’s safe and effective,” an assurance Quincy echoed to regulators. But an investigation by WIRED now shows that for years officials at the FDA questioned the basis for the company’s claims. Multiple FDA inspections, most of which have not been reported before, found significant issues with Quincy’s manufacturing processes, complaint handling, and the quality control testing that was supposed to ensure its products were safe.

And thousands of Americans have reported experiencing “adverse events” while taking Prevagen, including seizures, strokes, heart arrhythmias, chest pain, and dizziness. While the existence of adverse event reports alone don’t prove a product is the cause, the nature and pattern of complaints about Prevagen worried FDA officials, according to agency records. One internal report from 2015 stated that the “numerous adverse events reported” indicated “a serious safety hazard.”

Aside from a warning letter sent to Quincy in 2012, the FDA has not publicly indicated it had any concerns about Prevagen. The agency determined in 2018 that Quincy addressed the violations cited in the warning letter. There is no indication in the records obtained by WIRED that the agency took additional enforcement action.

“Prevagen has been thoroughly tested and has GRAS [Generally Recognized As Safe] status, i.e., it is generally recognized as safe,” a spokesperson for Quincy wrote in a statement. “The FDA issued a close-out letter to Quincy Bioscience which the FDA only issues when, based on its evaluation, a company has taken corrective action to address the issues identified in the Warning Letter to the FDA’s satisfaction.”

The company remains under scrutiny. Earlier this year, Quincy reached a class-action settlement to resolve seven lawsuits brought by customers over false advertising allegations. Anyone who purchased Prevagen in the US before July 21, 2020, is eligible to receive refunds of up to $70; the deadline to file a claim is October 26. The Federal Trade Commission and the New York attorney general are also pursuing a separate lawsuit that alleges Prevagen’s marketers relied on “false and unsubstantiated claims” about its health benefits, violating state and federal law. While a judge initially dismissed the case in 2017, that ruling was vacated last year, and the lawsuit is still ongoing.

Quincy denies the claims made by the Prevagen customers in the lawsuits, and it admits no wrongdoing as part of the settlement. The company denies that it has violated any laws, and maintains that the labeling, packaging, and marketing of Prevagen have always been truthful and not deceptive.

Prevagen shows how a dietary supplement can thrive on the market for years despite accumulating dozens of violations and raising alarm among government regulators, all unbeknownst to most consumers. Critics say the FDA does not police the $40 billion supplement industry effectively, leaving Americans at risk. Even leaders of some of its largest trade associations say they are unhappy with the FDA’s failure to enforce the law.

The product’s persistence is also a testament to the seductive power of its promise—that getting older doesn't have to mean becoming more forgetful—and to Mark Underwood, the man who says he came up with the idea and for years touted it as an unqualified success. Public documents, internal FDA emails, interviews with former employees and FDA officials, as well as interviews with experts and Underwood’s parents, tell a different story.

“We didn't want to wait another 10 years”

The idea that a protein found in jellyfish could improve the human brain occurred to Underwood serendipitously, as he tells it. In his self-published book The Brain Health Guide, he describes how, at the library one evening in the 1990s, he came across an article about a swimmer who developed neurological symptoms after a jellyfish sting. It was then that his inspiration struck, he writes: “Could what was in the jellyfish help to support humans, specifically our brains, in the same way as the jellyfish?”

Underwood’s parents remember it differently.

Diane and Lynn Underwood raised their only son near a small city called Mosinee, Wisconsin. When Underwood graduated from high school there in 1991, the population was less than 4,000. In the yearbook that year, many of the seniors describe starry-eyed but modest professional goals, like going on to college or landing a job they’d enjoy. Underwood’s ambition, noted under his senior photo, was different: “Make a totally obnoxious amount of money at an early age and spend the rest of my life spending it.”

At college, Underwood showed an interest in medicine—a field his mother was also drawn to. Diane has multiple sclerosis, a chronic disease that can attack the central nervous system. It turned her into a “medical junkie,” she says. She would pour over articles in science journals looking for something that could offer hope to patients like herself. There are treatments for MS, but no known cure.

Since the disease limited her body, Diane says she was attracted to the way jellyfish seemed to move so easily. That’s what led her to wonder if the marine animal might hold the key to a medical breakthrough. Diane says she shared her inspiration with her son while he was studying at the University of Wisconsin-Milwaukee, and that he took to the idea “like a dog with a bone.”

After graduating from UWM with a bachelor of arts in psychology, Underwood went to work for Pak Technologies, a chemical packaging firm in Milwaukee. There he met Michael Beaman, a local businessman. The two men started the company that would become Quincy Bioscience in 2004, when Underwood was 30 years old. The following year they filed an application to trademark the name Prevagen.

The Underwoods are no longer on speaking terms with their son. Mark Underwood obtained a restraining order against his father, Lynn, in 2012 over claims the elder Underwood was harassing him. His parents deny any harassment occurred. But Diane says she now hates what her son did with the jellyfish idea she planted in his mind. Her hope had been that his work would lead to a proven medical treatment, she says, “not just a money maker.”

The spokesperson for Quincy called Diane’s claims about coming up with the idea false. Mark Underwood declined to be interviewed on the record for this story when a reporter requested an interview by email in January 2019, and again when the reporter knocked on his door later that month. Underwood then requested through a lawyer that the reporter not contact him further. Representatives for Quincy Bioscience and Underwood did not respond to additional requests for comment at the end of 2019, and Underwood again declined to speak on the record this fall, citing the pending litigation. Beaman did not respond to requests for comment.

Underwood has spoken to the press about Prevagen before, however. Shortly after launching Prevagen in 2007, Underwood told a local reporter at the La Crosse Tribune that Quincy Bioscience decided to sell Prevagen as a supplement, instead of a pharmaceutical, for a practical reason: “We didn't want to wait another 10 years—the time it could take to conduct clinical trials and request approval as a drug.”

Though drugs and dietary supplements are both regulated by the FDA under the Federal Food Drug & Cosmetic Act, they’re held to vastly different standards. The FDA requires drug manufacturers to prove through rigorous testing that their products are safe and effective before they are approved to enter the market. The agency lacks the same authority when it comes to supplements. Instead, the companies are responsible for ensuring their products are safe and lawful, and in many cases they can introduce new dietary supplements to market without even notifying the agency. As a result, supplements are generally presumed safe until proven otherwise.

There’s at least one exception to that rule, however. If a company wants to use what the FDA calls a “new dietary ingredient”—meaning an ingredient that was not marketed in supplements in the US before October 15, 1994—it must have evidence for concluding the substance can reasonably be expected to be safe for people to take in a supplement. Either the supplement's ingredient needs to have been part of the food supply in its current form, or the company needs to provide its evidence for the FDA to assess at least 75 days before it introduces the supplement to the market.

The main ingredient in Prevagen is a synthetic copy of the jellyfish protein called apoaequorin, and is made entirely in a lab. It had never been part of the human diet, let alone sold in supplements. But instead of submitting the documents with the required 75 days’ notice, Underwood signed the necessary forms on August 31, 2007, just one day before Quincy Bioscience started selling Prevagen, according to a copy of the file obtained by WIRED.

In the notification, Quincy explained that the synthetic apoaequorin would be lab-grown from E.coli bacteria in a fermentation process, rather than extracted from the sea animals. Another section of the document hints at why: the ingredient amount in a typical capsule of Prevagen “would be the equivalent of 400-800 lbs of raw jellyfish consumed.”

While Quincy pointed to cases of people eating jellyfish as a reason to believe its synthetic ingredient would be safe, the senior toxicologist at the FDA who reviewed the materials, Linda Pellicore, appeared unconvinced in her response to the company that December.

“It is difficult to rationalize the comparison of your supplement serving size with typical jellyfish consumption,” she wrote. As for other studies Quincy included, Pellicore wrote, “It is unclear how the information submitted is relevant [to] the safe use of your dietary ingredient.”

Her letter concluded that the submission did not provide adequate evidence that the main ingredient in Prevagen would reasonably be expected to be safe. “Therefore, your product may be adulterated,” she wrote. “Introduction of such a product into interstate commerce is prohibited.”

But Prevagen had been on the market for more than three months by the time the letter was dated, and Quincy Bioscience went right on selling the supplements uninterrupted afterwards.

Warning signs

The FDA is not powerless to take action against companies who break the rules, and it has the authority to issue mandatory recalls of supplements. But to do so, the government must first demonstrate there’s significant or unreasonable risk to health. It’s a high standard to meet, and can be difficult given the FDA’s limited oversight.

In 2006, Congress amended the Food Drug and Cosmetic Act to help the government better monitor potential problems on the supplement market. Effective since December of 2007, whenever supplement companies receive a report of a serious adverse event—meaning a life-threatening complication, hospitalization, death, disability, or permanent damage after consuming their products—they must tell the FDA about it within 15 days.

“We asked for it,” said Michael McGufffin, president of the American Herbal Products Association. “We thought that that was an important amendment to the law.”

The FDA’s adverse event reporting systems—currently, there is one for drugs and another one for supplements—aren’t perfect. Reports are submitted by consumers, health care professionals, and manufacturers, and they may lack critical information or can’t be confirmed. For those reasons, reports alone can’t provide definitive proof that a supplement does or does not cause harm.

Not every adverse event associated with a product gets reported, either. Companies are only required to submit the most serious complaints they receive to the government. People who get sick from supplements may not realize what caused their symptoms, don’t take the time to report the problem to the FDA, or don’t know how to, says Tim Blood, a lawyer whose firm specializes in class action lawsuits. “They tend to be just the tip of the iceberg.”

Nonetheless, the reports can help inform FDA surveillance, and with supplements in particular, they can be the agency’s first signal that there’s a potential concern.

When FDA inspectors showed up at Quincy Bioscience’s Madison headquarters in 2011, they found records of “more than 1,000 adverse events and product complaints” that had been reported to the company since May 2008. Only two adverse events had been relayed to the FDA or investigated further by Quincy. In an inspection report known as a Form 483, which documents significant potential violations, or “observations,” investigators listed 18 cases that Quincy had decided not to classify as serious and didn’t share with the FDA. They included five reports of seizures, three of strokes or mini-strokes, and four of vertigo, dizziness, or falling that merited medical attention.

Inspectors found more problems at the company’s manufacturing facilities nearby. Agents observed that steps had been skipped when making the artificial jellyfish protein, and batches had not been tested to verify the identity of ingredients. The company didn’t properly establish written procedures for how it would test for bacteria, nor did they specify how it would control production to ensure the end quality of the supplements.

Together, the two inspections cited six observations and ultimately received the FDA’s worst classification: “Official Action Indicated.” Before leaving Quincy’s headquarters, an investigator met with Mark Underwood to issue their findings. In addition to the conditions inside the facilities, they discussed how Quincy had been promoting Prevagen. Dietary supplement companies are not allowed to advertise that their products can prevent, treat, or cure disease—therapeutic claims like that are reserved for FDA-approved drugs. In the FDA’s view, Quincy was crossing this line by implying that Prevagen could stave off dementia or Alzheimer’s.

Underwood promised to bring his company into compliance. Quincy employees updated their existing operating procedures and created new ones, while those who handled consumer complaints were retrained in the FDA adverse events reporting regulations.

But the FDA’s concerns about Prevagen were not fully addressed. That fall, the agency sent Quincy Bioscience a public warning letter. The letter summarized the manufacturing and adverse event reporting violations from the previous year’s inspections, as well as the steps Quincy had taken to rectify them. “If your Prevagen products were dietary supplements, we would consider your response with regard to our CGMP [Current Good Manufacturing Practices] and adverse event reporting observations to be adequate,” the FDA wrote. But the agency made clear that there was a bigger issue.

“It has also come to our attention that the apoaequorin used in your Prevagen products is produced synthetically,” the FDA wrote. That summer, Quincy had once again submitted a new dietary ingredient notification for apoaequorin. Once again, the FDA responded that “manufacturing for ‘aequorin/apoaequorin’ was reviewed and not considered safe.”

Now, in the warning letter, the agency said that apoaequorin did not meet its definition for a dietary ingredient. Since Quincy was also still making therapeutic claims in its marketing materials, and had conducted clinical investigations with the ingredient—two things only drug manufacturers are allowed to do—the agency stated that it considered Prevagen not to be a supplement at all, but an unauthorized drug. In letters that followed, Quincy disagreed with this assessment vigorously.

Top seller

At the time, Prevagen’s popularity was soaring.

From the beginning, Mark Underwood had been a tireless advocate for the supplement. Before it was picked up by national retail chains, Prevagen was sold directly to consumers, and Underwood would sometimes appear on local radio shows in Wisconsin, speaking enthusiastically on the air about what the product could do for the brain.

"If you don't have the type of protein that's contained in Prevagen, your brain is susceptible to death or injury," Underwood said on one radio show in 2008. “Quite frankly, we’ve raised the bar towards a lot of thinking where some people were pretty satisfied saying well, you know you're just old, you have dementia, you have this issue, there's not much you can do.”

Back at Quincy Bioscience’s corporate office, the sales team would be waiting to field calls from listeners concerned about losing their memories, said former employees.

In those early days, management was “basically hiring anyone with a pulse to join,” recalls Jovan Chavez, who worked for Quincy’s sales team for almost 10 years before he was let go in 2018. Another former Prevagen salesman, Shawn Andrus, said that he joined Quincy in 2012 with little sales experience. “Most of us were in our early twenties and all we cared about was paying our bills,” he said.

The money was good, Andrus said, as long as you made a lot of calls. The team worked on commission, with employees receiving a cut of every successful sale. The system, as Andrus described it, could encourage aggressive product promotion. The more Prevagen someone sold, the more money they made, and Andrus said he was good at selling customers on the company's bigger packages. “A lot of my sales would be the 6-12 bottles at a time,” Andrus said. “There wasn't any free time whatsoever. You were just dialing until basically your fingers bled.”

A spokesperson for Quincy said that the company never encouraged its sales team to pressure customers to purchase as many bottles of Prevagen as they could. “Customers often purchased multiple bottles at a time in order to reduce the cost of shipping or to ensure that they had an adequate supply of Prevagen on hand,” the spokesperson added.

Despite what he remembers as a sometimes stressful working environment, Andrus said he enjoyed his time at Quincy. He was sorry to be let go in 2015, along with his other colleagues on the sales team. Chavez said something similar. He believed that Underwood “had good intentions” with Prevagen.

That belief was bolstered by the studies the company had started conducting on the ingredient in Prevagen. Quincy used the results of one study, called the Madison Memory Study, in advertisements and packaging to claim that Prevagen was clinically shown to improve memory within 90 days. Chavez capitalized on that information in some of his pitches, too, to persuade people to purchase more product, he said. “Ten milligrams shows improvement after, you know, 30 days, but even more after 90 days, so that's why you need a three months' supply,” Chavez remembers telling potential customers on the line. “If you buy the extra strength, that's just going to help you even faster.”

However, the Madison Memory Study didn’t actually show a statistically significant improvement when you look at the study population as a whole, something that Quincy has since acknowledged. The company was able to demonstrate a benefit to taking Prevagen by conducting additional statistical tests on smaller subgroups of participants, a couple of which did show a difference. In its lawsuit, the FTC alleges that this methodology as used by Quincy "greatly increases the probability that some statistically significant differences would occur by chance alone," and that the Madison Memory Study therefore did not "provide reliable evidence" of Prevagen's advertised benefits.

A lot of people did want Prevagen, though. By 2012, Quincy Bioscience reached No. 398 on the Inc. 500|5000 list of the fastest growing private companies in the nation. The company would make the list the next two years, too, as it pivoted from selling through faxes and phones to primetime TV and national pharmacies. Prevagen was now sold in Walgreens, CVS, and Rite Aid, a press release stated in 2014, and was the No. 1 selling branded brain health supplement according to Nielsen data.

"I think the key to its popularity is because the product benefits are so often shared from one person to another,” Underwood was quoted as saying. “There are a lot of people scared about memory loss and they are looking for a solution.”

“Significant concerns for safety”

In the wake of the 2012 warning letter, Prevagen had gained the attention of FDA employees in at least two different branches: the Center for Food Safety and Applied Nutrition, where dietary supplement oversight is based, and the Center for Drug Evaluation and Research, which monitors most drugs.

When FDA investigators returned to Quincy’s headquarters for a follow-up inspection in February and March of 2015, they treated the firm as a drug manufacturer. That meant they cited it under drug regulations, not supplement regulations as in 2011. Quincy told the inspectors that it disagreed with the FDA’s position, because it believed its products were dietary supplements.

Over six days, investigators noted 13 different observations in the 483 inspection form and in a separate written report; copies of both documents were obtained via FOIA and are reported here for the first time. While some of the citations would only apply to drugs, the lead FDA investigator, April Young, wrote that certain observations would have been made under supplement regulations, too.

Some of the observations were similar to what had been identified as objectionable in the 2011 inspections under supplement standards. The protein in Prevagen was still manufactured “without proper controls for contamination or testing in place,” Young noted in the written report. Inspectors observed that Quincy Bioscience failed to sufficiently document their manufacturing processes and adequately test for contaminants.

Many of the problematic conditions identified in the inspection had to do with a failure to properly monitor batches of the ingredient in Prevagen while it was being made, or with neglecting to adequately test finished Prevagen products. When an issue was found in one batch of the ingredient in Prevagen, other batches sometimes weren’t investigated, inspectors noted. Certain controls weren’t established to evaluate the finished quality of Prevagen ingredients. Some of the standards the labs did use weren’t scientifically sound and appropriate standards. And returned bottles of Prevagen were sometimes sent back to other customers without the company first assuring that the product was in good condition.

Inspectors again observed “inadequate controls in place to investigate” consumer complaints. And Quincy had failed to report 24 potentially serious adverse events to the FDA. Again, seizures and strokes were among the most common events that went unreported by Quincy to the FDA.

"After starting Prevagen his number of seizures increased to 4-5 times per week,” read one of the entries Young uncovered in the company’s ledger. One woman had written a personal letter to Quincy to tell the company that she had taken the product just a couple of times before she had a mini stroke. She had seen her family doctor and a neurologist and said “they are pretty positive the product is what caused it.” Neither of the events were reported to the FDA.

Young also observed customer complaints similar to those found during the 2011 inspection: arrhythmia, chest pain, headaches, dizziness, tingling, allergic reactions, high blood pressure, hallucinations, mental decline, blood sugar issues, sleeping issues, and vision problems. During discussion of the inspection with Quincy management, she wrote, “I stated these are not typical complaints associated with supplements. The serious nature and quantity of complaints raises questions about the safety of the product.”

Two additional internal reviews by the FDA that year would also raise concerns about the patterns of complaints associated with Prevagen.

Shortly after Young finished her in-person inspection, the Center for Drug Evaluation and Research’s Office of Surveillance and Epidemiology conducted an overview of Prevagen cases in the adverse reporting system for drugs. The abbreviated review, dated March 19 and obtained via FOIA, covers eight cases, including reports of increased dizziness and loss of balance that resulted in injury. “Despite the fact that the majority of cases do not have medical confirmation, they provide a pattern of events that are temporal with the administration of Prevagen, some of which resolved with discontinuation of Prevagen,” the medical reviewer wrote. Referring to Quincy’s new dietary ingredient notifications, they added, “The evidence supports the FDA’s original notice with significant concerns for safety.”

A few months later, a team over at the Division of Dietary Supplement Programs reviewed a larger set of adverse event reports, this time from the reporting system for supplements and from Quincy itself. Their clinical reviewer reached a similar conclusion, and additionally observed that “a number of consumers who were being treated for seizures experienced an increase in the number of seizures while consuming Prevagen.” The review concluded: “There are numerous adverse events reported pertaining to this ingredient which indicates a serious safety hazard.” The report was sent to Robert Durkin, who was the Acting Director of DDSP at the time, on July 14, and was obtained by WIRED via FOIA.

During its inspection, Quincy’s response to observations about the complaints was, Young wrote, that “they have worked very hard since the previous inspection to be reporting serious adverse events.” They reiterated that they had studies to show Prevagen was safe, Young recorded, and also pointed to their customer demographic. “The firm stated that their customer population is generally an older population with many pre-existing conditions,” she wrote.

But it's precisely because elderly customers have pre-existing conditions that they are more at risk—and need more protection—than other populations, said Maria Caserta, a geriatrician and director of inpatient psychiatry at the University of Illinois at Chicago. “This population is very sensitive to added side effects. Everything has side effects,” she said.

Ultimately, Quincy’s 2015 inspection was classified OAI, Official Action Indicated—once again, the agency’s worst outcome. On the last day of the inspection, Young told management that even if they fixed each of the 13 items within the FDA-483, it wouldn’t resolve the overarching issue: They would still have unapproved drug products. Quincy’s leaders continued to insist that their products were dietary supplements. Young wrote that the basis of their objection was a milkshake: “Mr. Underwood said the ingredient is now a food source because it exists in the market as a food through NeuroShake.”

A controversial GRAS rule

Quincy Bioscience launched NeuroShake in 2013 as “a healthy way to kickstart your mind in the morning.” It was a protein shake mix that also contained 5 mg apoaequorin per serving.

Food additives generally require FDA approval before they hit markets, with a big exception: The agency does not need to review substances that are added to food if they are generally recognized as safe, or GRAS, by experts, and manufacturers may determine an ingredient is GRAS without FDA’s approval or knowledge. Companies can notify the FDA about their determination, but doing so is voluntary. A 2010 report by the US Government Accountability Office found that “FDA’s oversight process does not help ensure the safety of all new GRAS determinations.”

In 2014, Quincy submitted a GRAS notification to the FDA showing that a panel of three scientists had affirmed that apoaequorin, the synthetic jellyfish ingredient, was safe for use in food, based on their read of publicly available studies. These studies included work sponsored by Quincy and in some cases authored by company employees.

The notification appendices also included two reports by medical doctors, both retained by Quincy, who reviewed 26 serious adverse event reports. Both doctors wrote that they saw no pattern or indication of any safety issues. Like Quincy, they cited pre-existing conditions and other medications as more likely causes of problems.

The FDA has not publicly weighed in on Quincy’s GRAS notice, however. Before the agency responded, Quincy quietly withdrew it from the FDA’s consideration on October 21, 2015—something that companies are also able to do. A press officer for the FDA, Nathan Arnold, confirmed that in many cases, a company would not even need to file a notice to claim GRAS in the first place.

Quincy’s decision to publish the notice, even if it was later withdrawn, may have persuaded the agency not to pursue further action, former FDA officials say. “GRAS is pretty compelling, especially if it’s published. My guess is that somebody higher up in the center looked at that and said we can’t make a case,” said Daniel Fabricant, a former director of the Division of Dietary Supplement Programs and current president of the trade group Natural Products Association.

More important, with its introduction via NeuroShake, apoaequorin had officially entered into the US food supply. “Once this happens, the agency’s original position back in ‘07, that the ingredient in question isn’t a dietary ingredient, that argument goes away,” Robert Durkin, Fabricant’s successor at the DDSP, said.

Using GRAS this way is a common practice by supplement manufacturers these days, experts say. After companies notify the food division at the FDA that their product is GRAS, they bypass the need to obtain approval specific to the ingredient’s use in supplements, said McGuffin, the American Herbal Products Association president. Nothing about the practice violates FDA regulations.

Some medical and legal experts believe the GRAS rule is in need of reform, however. The law provides the supplement industry with what is essentially “an alternative route to introduce new drugs to the American public,” said Pieter Cohen, an associate professor of medicine at Harvard Medical School. Referring to the main FDA law that makes this possible, the Dietary Supplement Health and Education Act of 1994, Cohen added that “this is not well understood, how much DSHEA completely undermined the entire drug approval process in the USA.”

“The risk assessment that you do in GRAS is for food use. You’ve never looked at the safety of the supplement uses, but you’re using one to boot-strap the safety of another,” said Laura MacCleery, policy director of the Center for Science in the Public Interest, a nonprofit watchdog that advocates on behalf of consumers on food-related issues. The Center for Science in the Public Interest is one of five organizations currently suing the FDA over the legality of the current rule, which was finalized in 2016.

The FDA maintains that it “can question the basis for an independent GRAS conclusion, whether notified or not,” or even if the notice is withdrawn. And by 2016, the FDA was on Quincy’s case again. Internal emails exchanged by FDA employees that year, obtained by WIRED through FOIA, indicate that by then, a “synthetically produced product being marketed in the form of a shake” was under investigation by the FDA as a potential unapproved food additive.

The agency sent a letter to Mark Underwood dated January 7, 2016, regarding NeuroShake’s ingredient apoaequorin. “We are concerned about the safety of your apoaequorin products because of, among other things, the large numbers of adverse events reported for them,” Steven Musser, the FDA’s deputy director for scientific operations, wrote. He noted that Quincy appeared to be contradicting itself in its public statements: The company’s GRAS self-determination explained that apoaequorin was safe because it was digested like other dietary proteins, but materials marketing Prevagen claimed it could pass through the gastrointestinal system and cross the blood-brain barrier. Musser asked Underwood to explain how both things could be true, and what evidence Quincy had that its ingredient was both safe and effective.

WIRED did not obtain any response the company sent to the FDA about the letter from Musser under FOIA. When asked about the letter directly, the Quincy spokesperson said, “Apoaequorin is GRAS, whether it is in a food like Neuroshake or a dietary supplement like Prevagen. And as previously stated, the FDA issued a close-out letter to Quincy Bioscience which the FDA only issues when, based on its evaluation, the firm addressed the issues identified in the Warning Letter to the FDA’s satisfaction.”

Over 4,000 complaints and counting

Quincy Bioscience’s NeuroShake move appears to have worked well for Quincy in one regard: When FDA investigators showed up in Wisconsin for another inspection in 2016, they were back to evaluating the company for supplement manufacturing practices, not drugs.

The company had undergone some changes, too. During the previous inspection, Quincy management had attributed having a higher proportion of complaints than other manufacturers to all their outbound sales calls, because during calls employees would ask, “How are you feeling?” After the inspection, Quincy discontinued its direct sales strategy and laid off members of its sales team, including Shawn Andrus.

“They just basically severed ties with direct sales,” Andrus said. The layoffs constituted 13 percent of Quincy Bioscience’s staff at the time, according to a complaint an employee filed to the Wisconsin Attorney General’s Office, obtained by WIRED with a FOIA request. (The state determined that no violation occurred.)

A year and a half later, in November 2016, FDA inspectors observed a “noticeable decrease” in the number of adverse event reports Quincy received after they stopped the calls. By that point, the company had received well over 4,000 reports from customers who said they experienced health issues after using its products since they first went on sale, according to the documents WIRED obtained from the FDA.

To understand the meaning of that, the total number of people who took Prevagen should also be considered, Durkin said. “For any particular situation the number of adverse events might sound high, but then you have to step back and say, OK, how many people actually took the product and of that number what was the rate of adverse events,” he said. It’s unclear how many people had taken Prevagen by 2016. That number has been estimated to be three million as of 2020, by lawyers representing a Prevagen customer in Florida.

For all its adverse event complaints, the inspectors in 2016 wrote that Quincy had not identified a single root cause, and that its investigations “did not extend to all relevant batches and records,” as required by law. They noted one example of an assisted living facility that reported 20 residents who fell sick after taking Prevagen. “You did not follow up with a call to find out more about this complaint,” inspectors wrote. “In fact you logged this complaint as one complaint and did not log it as 20 individual complaints. You were provided the lot number … and you did not investigate.”

This time, FDA officials cited 12 different objectionable conditions observed during the inspection. “It would appear that Quincy Bioscience does not have a complete and thorough understanding with respect to the manufacturing operations, key processes … and the Quality Control tests to ensure that the Apoaequorin protein is safe," the inspector wrote in the report.

That 2016 inspection was ultimately classified Voluntary Action Indicated, meaning that “objectionable conditions or practices were found,” but the agency was not prepared to take or recommend regulatory action. FDA records indicate that Quincy had a meeting with regulators in February 2017, and later that year began contracting out its complaint handling operations to a third party. Since then, Quincy seems to have improved its standing with the FDA further. During a follow-up inspection that ended in March 2018, the investigator noted just one issue, regarding insufficient documentation to prove the company reported serious adverse events to the FDA within the required period.

That June, the “FDA determined that the firm’s corrective actions adequately addressed the violations cited in the 2012 warning letter,” said Arnold, the FDA press officer. The agency notified Quincy through what’s known as a close-out letter, which has not been publicly posted.

By then, Prevagen had been on the market for almost 11 years. For more than half of that time, Quincy had been scrutinized by the FDA for safety and marketing violations. Durkin said the agency devoted substantial resources to investigating Prevagen, but that ultimately, the FDA had given it a green flag.

“When the data and information available demonstrate that there's a risk to the public health, the agency does whatever it can to protect the public health, it really does,” Durkin told WIRED. “It's just that sometimes it's not possible to show, to the standard required under the Act, that there's an actionable problem.”

“They cannot possibly adequately monitor this marketplace”

For years, lawmakers, consumer safety advocates, and even agency officials have raised concerns about the FDA’s ability to regulate supplements. “Although FDA has taken some steps to identify and act on safety concerns, limited information hinders FDA’s oversight of the dietary supplement industry,” stated a 2009 report from the US Government Accountability Office. “In addition, FDA dedicates relatively few resources to dietary supplement oversight.” A decade later, little has changed. If anything, the challenge has become more acute in the face of the supplement industry’s enormous growth.

Recognizing the need for reform, the FDA announced plans to modernize its supplement regulations last year. “What was once a $4 billion industry comprised of about 4,000 unique products, is now an industry worth more than $40 billion, with more than 50,000—and possibly as many as 80,000 or even more—different products available to consumers,” said Scott Gotlieb, FDA commissioner at the time. One proposal would for the first time require all supplement products to be registered with the agency; right now it can’t say for sure how many there are.

A comprehensive list of all supplements would be a start. Lack of funding is another part of the problem, experts told WIRED. “The current staff and resources are not even remotely close to what is necessary to adequately police this industry,” said Peter Lurie, a former FDA official who’s now the executive director of the Center for Science in the Public Interest. “They’re not going to be able to go after each infraction that they see.”

The Office of Dietary Supplement Programs employed fewer than 30 people in 2019, and had an annual budget of $6.6 million—all to regulate a $40 billion industry. More recently, the coronavirus pandemic has significantly disrupted the FDA’s normal operations. The agency temporarily suspended routine on-site inspections in March, and the number of compliance actions is much lower so far this year.

McGuffin says the funding problem extends to the Department of Justice, too, which works with the FDA to seize products, issue injunctions, and pursue criminal prosecutions. “We have heard for years that DOJ resources aren’t enough to bring action against every person,” he said.

Lawsuits also have a powerful role in regulating the dietary health supplement marketplace. Prevagen has been the subject of several, primarily concerning false advertising claims. This July, a magistrate judge preliminarily approved the terms of an agreement that would settle open suits brought by private plaintiffs across the country.

According to the current version of the settlement, Quincy would pay a partial refund to anyone who purchased Prevagen products before July 21: up to $70 for individuals with proof of purchase, and up to $12 for individuals without. The current suggested retail price for a 30-day supply of Prevagen extra strength is $59.95. One lawyer who brokered the settlement, Adam Moskowitz, told WIRED that if everyone who was eligible submitted a claim, Quincy “could be responsible for paying $40 or $50 million.”

The terms of the settlement and limited individual payments, however, mean that is unlikely to happen, said Ted Frank, founder of the nonprofit Center for Class Action Fairness. “Nobody will make a claim.” A lawyer involved with the settlement told WIRED that only around 12,000 Prevagen customers had filed claims by the first week of October, more than halfway to the deadline on October 26.

The lawyers are asking for higher awards for the plaintiffs named in the case, ranging from $2,000 to $10,000, and about $4.2 million to cover the legal fees. But “the class is going to end up with less than $1 million. The ratio is supposed to be the other way around,” Frank said.

Moskowitz defended the agreement. “Would we like a perfect settlement when everyone got back 100 cents on the dollar if they didn’t like the product? Sure, but that wasn’t the settlement we negotiated,” he said.

The terms also state that Quincy Bioscience can continue to use the Madison Memory Study to support claims of effectiveness in advertisements, as long as Quincy adds a disclaimer that mentions the company arrived at its numbers by analyzing subgroups. The settlement would also prevent Prevagen customers from suing Quincy over similar claims in the future, unless a person had opted out of the class in writing.

The FTC’s false advertising case against Quincy Bioscience is still ongoing. Recent commercials for Prevagen, meanwhile, don’t give jellyfish as much screen time. But the system that allowed Quincy to make millions of dollars while government officials questioned the safety of Prevagen has not been fixed, Laura MacCleery says.

“Everyone wrings their hands and says it couldn't possibly be that bad,” she said. “And then it happens again.”

Updated 10-20-2020, 9:00 am ET: Pieter Cohen is an associate professor of medicine at Harvard Medical School, not an assistant professor as previously stated.

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