What’s on That Label?

Today, we take a deep dive into drugs and supplements that don’t work as advertised. And, we start with a deceptive dementia drug called Prevagen.

Over the last twenty years or so, Big Pharma has invested more than a half trillion dollars into dementia treatment research, but so far to little avail. In light of this, many have turned to supplements. An AARP commissioned survey found that 36 percent of those 74 years and older take a supplement for brain health, to the tune of billions of dollars a year. The most commonly marketed brain supplement was one I’d frankly never heard of before: Prevagen.

Prevagen contains a protein derived from a luminescent jellyfish the company claims “has been clinically shown to improve memory.” According to the company website, “A landmark double-blind and placebo controlled trial demonstrated Prevagen improved short-term memory, learning, and delayed recall over 90 days.” But when you actually pull up the study, not only did Prevagen fail to improve memory, learning, or recall over placebo, it failed to show a significant improvement in any of the nine measured cognitive tasks tested. As an inquiry into Prevagen published by the Center for Science in the Public Interest was titled, “How Can This Memory Supplement Flunk Its One Trial and Still Be Advertised as Effective?” And not just as effective, but the #1 pharmacist recommended brand. Considering the lack of sound clinical evidence, how is that possible? Presumably, they’re just as blitzed with the same kind of advertising as everyone else.

It’s no surprise the supplement didn’t do anything, since the company’s own studies showed the jellyfish protein was rapidly digested by stomach enzymes. Of course, that didn’t stop them from raking in more than $20 million a year. Claiming the “marketers of Prevagen preyed on the fears of older consumers experiencing age-related memory loss,” the Federal Trade Commission and New York State’s Attorney General filed a consumer protection complaint charging the company with making false and unsubstantiated claims. The AARP weighed in, accusing the company of “deceiving millions of aging Americans.”

In a move straight out of the Big Pharma aducanumab playbook, the company went back and conducted more than 30 post hoc analyses of the data, and found a few positive findings on a few tasks for some subgroups. This cherry-picking of subgroups after the fact is a classic example of manipulation, sometimes called “p-hacking” or “data dredging,” that can be described as “placing a bet on a horse after watching the race.”

The makers of Prevagen settled a class action lawsuit in 2020 with the FTC over deceptive business practices and false advertising. Remarkably, though, the settlement allows them to continue to market it, with the court-approved disclaimer that claims are “based on a clinical study of subgroups of individuals…” But with the amount of slicing and dicing of data they did, the chances of finding at least one false positive was estimated at 80 percent.

Prevagen may be more than just a waste of money. The manufacturer was cited for failing to report more than a thousand adverse events related by consumers to the Food and Drug Administration (FDA). Regulators can’t have it both ways, though. If the jellyfish protein is digested away, how can it pose a safety risk? Because dietary supplements are too often adulterated with contaminants. FDA inspectors specifically cited Prevagen’s manufacturing facilities for “objectionable conditions or practices.”

A 2019 survey by Pew found that more than half believed that the Food and Drug Administration requires supplements be tested for safety, but that isn’t true. One study of 24 supplements sold as cognitive performance boosters found that most claimed an ingredient on the label that wasn’t actually in the supplement. And worse, 38 percent contained ingredients not allowed in supplements, like prohibited drugs. Another study of a dozen so-called “brain health supplements” similarly found 8 out of 12 were misbranded (missing an ingredient promised on the label), and 10 out of 12 were deemed adulterated (containing unlisted compounds, for example caffeine in a product that explicitly highlighted all-caps ‘‘DECAFFEINATED’’ on the label). Only 1 out of 12 was certified to contain what it said it did. ​​The bottom line for Prevagen—there is no acceptable evidence that it is effective, and patients should be advised not to take it.

In our next story, we look at the safety and efficacy of two of the newest Alzheimer’s drug treatments.

Aducanumab, sold as aduhelm, is the first new drug approved for Alzheimer’s treatment in nearly 20 years. It involves getting IV infusions of an antibody that targets the amyloid plaque protein, which represents a core brain pathology of the disease. After a phase 1 study found no change in the placebo group, but a dramatic reduction in amyloid plaque burden at different doses of the drug, they jumped straight to phase 3: two randomized controlled trials to put it to the test on thousands of Alzheimer’s patients. Unfortunately, both trials were stopped early after a “futility analysis” deemed them failures, as cognition and function continued to decline in the treatment groups. That shouldn’t be surprising, since over the last 20 years there have been more than 20 amyloid-targeting therapies that have universally failed to offer meaningful cognitive benefit for people with Alzheimer’s disease. In fact, a 2022 investigation into a seminal paper implicating amyloid as a causal factor in Alzheimer’s alleged “shockingly blatant” data fraud, which has further tarnished the reputation of the amyloid theory. So, it’s no surprise aduhelm flopped; but what happened next was surprising indeed.

Just when the drug’s prospects seemed dead, Biogen, the drug company that developed it, launched a secret campaign, code-named “Project Onyx,” to use back channels to convince the Food and Drug Administration (FDA) to approve it anyway. They went back through the data and found a subset of patients in one of the trials that had a 0.39 increase on an 18-point scale of cognitive function. This was well below the minimal standard for clinical significance (judged to be at least one or two full points). And the same subset, at the same dose, in the other study they funded, failed to find even that effect. This kind of post-hoc, after-the-fact data dredging is like “firing a shotgun at a barn and then painting a target around the bullet holes”––as one FDA committee statistician put it.

FDA reviewers thoroughly demolished Biogen’s re-analysis, concluding “there is no compelling substantial evidence of treatment effect or disease slowing… ” The American Academy of Neurology noted that 35 percent of those getting aducanumab suffered swelling or bleeding in the brain within the first four months of treatment; one in three—10 times more than those in the placebo group. So, not surprisingly, not a single member of the FDA expert advisory panel voted in favor of approval (10 out of 11 voted against with one quote-unquote “uncertain”). Yet, the FDA ignored its own advisory committee and in 2021 approved the drug anyway.

The FDA admitted the submitted data “left residual uncertainties regarding clinical benefit,” and so couldn’t give it the standard approval, which involves a designation that the drug is safe and effective. Instead, they used an “accelerated approval” pathway that allows drugs to be accepted on the basis of surrogate markers––in this case, amyloid clearance. But more than two dozen other amyloid-targeting treatments flopped. Despite convincing plaque reduction, there were no clinical improvements or even worsening of the disease.

The FDA approval of aducanumab proved to be one of the most controversial in recent memory. The approval, despite near-unanimous opposition by its own expert committee, is virtually unprecedented, leading three of the committee members to resign in protest––one of whom called it “probably the worst drug approval decision in recent U.S. history.” The response from the scientific community may best be summed up by a commentary written by the head of the American Geriatrics Society entitled “My head just exploded…”

The FDA did stipulate that Biogen would have to run a “post-marketing” trial proving that the drug actually has some benefit, but has until 2030 to report the results. Meanwhile, Biogen is charging $56,000 per person per year for the drug, with out-of-pocket expenses estimated at up to $11,000 annually. And this doesn’t include the costs of IV administration or the sequential $4,000 to $7,000 MRI scans needed to monitor for the brain bleeds and swelling.

Yeah, the risks far exceed any likely benefits, but shouldn’t patients and their families be able to make up their own minds? The problem is that the FDA stamp of approval implies aducanumab is safe and effective, when at the current time it appears to be neither. The official position statement of the American Medical Directors Association, which specializes in long-term care facilities, is that the drug is “likely to have extraordinarily negative consequences” for the millions living with dementia in this country. The European equivalent of the FDA does not seem as easily swayed by Big Pharma, recommending refusal of the drug. I mean, that’s the whole point of drug regulation, as one of the former FDA committee members who resigned put it: “a responsibility to help protect vulnerable patients and their families, not just from sketchy drugs but also from false hopes.”

A congressional investigation concluded FDA approval of aducanumab was “rife with irregularities,” raising “serious concerns about FDA’s lapses in protocol and Biogen’s disregard of efficacy.” Of course, that didn’t stop the FDA from their 2023 accelerated approval of a similar antibody, lecanemab (sold as Lequembi), of similar questionable efficacy and safety.

Did you know that there is little guarantee that a dietary supplement will actually contain what is advertised on the packaging? Here’s the story.

In a video I did a few years ago, I talked about how press releases about the latest science coming out of even top medical centers were filled with overstatements and omissions. Medical journal press releases suffered from similar problems, and press releases from the drug companies themselves were no different, filled with hype and exaggeration. What about press releases issued by the supplements industry? Not even the companies that published the studies, but like trade organizations for the multi-billion dollar dietary supplement industry.

Researchers found that 100 percent of supplements industry press releases contained “spin,” meaning strategies to hype or denigrate findings to distort the results of clinical studies. And here’s the crazy part: industry press releases advocated supplement use in response to >90 percent of even the studies that reported no benefit or harm  A study comes out showing a supplement is actually bad for you, and the vast majority of independent institutions, like the National Institutes of Health or mainstream media stories, are like “don’t take it.” Duh. But the industry trade organizations are like, “Harm? Go for it! Buy an extra bottle.”

It is, therefore, likely that the propagation of the ‘spin’-enriched industry press releases contributes to the ongoing, and even burgeoning, enthusiasm for use of supplements in the face of accumulating evidence of most of their ineffectiveness and, in some cases, harm. In some cases, people are paying to make themselves sick. Sadly, the science may not even matter to many supplement users. Most dietary supplement users said that they would be minimally influenced by independent, taxpayer-funded studies contradicting the efficacy claims of supplement manufacturers. Only a minority of users said they would stop taking a supplement if public health authorities stated that it was just a waste of money.

The iconic image of the snake oil salesman was actually a real dude: Clark “the Rattlesnake King” Stanley, in 1916. Turns out that Stanley’s snake oil, in fact, contained no snake oil at all, but rather just like spicy mothballs and turpentine, prosecuted under the newly enacted Pure Food and Drug Act, and ultimately fined a lofty sum of 20 bucks. And a century later, here we are with snake oil coming out our ears, a vast number of supplements marketed and sold without routine oversight. Now, the supplement industry bristles at such talk, saying that the supplement industry is regulated to protect consumers. And it’s true there are definitely laws on the books, but the ability of regulators to successfully carry out this mission is hampered by the sheer number of products.

The FDA estimates that there are more than 85,000 dietary supplement products currently available in the U.S. alone. So, there’s the sheer number, the underreporting of adverse side effects, the difficulty of successfully prosecuting cases against offenders, and the ease with which suppliers can rebrand products removed from the shelves have led to a largely unregulated environment. In the real world, there is little guarantee that a supplement will even contain what is advertised on the packaging and not contain unlisted ingredients, potentially leading to significant harms, resulting in an estimated 23,000 ER visits every year. Now, of course, prescription drugs don’t just sicken but kill many more, making them perhaps the third leading cause of death, wiping out more than 100,000 Americans. But still, the less death and disability, the better.

Dietary supplements are often adulterated with undeclared pharmaceuticals, which could represent an enormous risk to consumers, most often found in erectile dysfunction, weight loss, diabetes, and high blood pressure supplements. But wait a second, what about supplement manufacturers who say they have independent, 3rd party certification of purity? There is a practice called dry labbing, a dirty little secret of the supplements industry, where quality assurance labs just rubber stamp fake documents. And if you think that’s outrageous, check out the story of BMPEA.

A researcher at Harvard published a paper replicating prior research from the FDA detecting a designer amphetamine-like stimulant, β-methylphenylethylamine in various U.S. supplements sold in the United States. In response, one of the offenders, Hi-Tech Pharmaceuticals, manufacturers of weight loss supplements like Black Widow and Yellow Scorpion, sued the Harvard researcher for libel, slander, and product disparagement, originally to the tune of $200 million in damages.

This was all documented in a piece by STAT, which is an excellent source of medical journalism that I recommend. The head of Hi-Tech openly admitted that he was “hoping that we were able to silence this guy,” and while ultimately unsuccessful in court, Hi-Tech’s lawsuit effectively sent a warning to other researchers. In fact, Hi-Tech’s CEO is attributed as saying, he “hope[s] that the long and costly legal battle will scare away other academics from investigating the supplement industry.”