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What’s in your supplement?

When you pick up a bottle of supplements, should you trust what the label says?  While there is the perception that supplements are effective and inherently safe, there are good reasons to be skeptical. Few supplements are backed by good evidence that show they work as claimed. The risks of supplements are often not well understood. And importantly, the entire process of manufacturing, distributing, and marketing supplements is subject to a completely different set of rules than for drugs.  These products may sit on pharmacy shelves, side-by-side with bottles of Tylenol, but they are held to significantly lower safety and efficacy standards. So while the number of products for sale has grown dramatically, so has the challenge to identify supplements that are truly safe and effective.

It’s been covered in depth before, but is worth repeating, that the Dietary Supplement Health and Education Act of 1994 (DSHEA) was an amendment to the U.S. Federal Food, Drug and Cosmetic Act that established the American regulatory framework for dietary supplements. It effectively excludes manufacturers of these products from virtually all regulations that are in place for prescription and over-the-counter drugs, and puts the requirement to demonstrate harm on the FDA, rather than the onus on the manufacturer to show a product is safe and effective. The goal was to eliminate barriers to sale, and it worked: Within four years of the DSHEA, supplement sales grew from $4 billion to $12 billion. In Canada, the Natural Health Product regulations have had a similar effect at creating a manufacturer-friendly market: Pretty much anything goes, and today even homeopathic rabbit anus is deemed “safe and effective” by the Canadian regulator, Health Canada.

Notwithstanding the lack of good efficacy data for many products, the absence of good product quality standards is a persistent barrier to the science-based use of supplements. With drugs, the standards are rigorous: Any drug product that is approved for sale must be shown to be equivalent to the product studied in the clinical trials that established its efficacy. This allows us to extrapolate the findings from research into expected effects in patients. And manufacturers must meet stringent quality standards for their products, including verifying the consistency and quality of everything they produce. The same can’t be said for supplements. Even if there is promising data from studies, we can’t make the same inference about the expected effects. Lax regulations translate into lax product standards, and more questions about quality standards, safety, and expected effects. So even if I believe a supplement isn’t expected to interfere with someone’s prescription drugs, I’m basing this on the assumption the manufacturer is actually providing a product that delivers what the label says. And the different regulations mean we must have less confidence this is the case.

One of the more troubling signs that there are serious problems with the supplement market are the continued recalls and warnings from regulators. Just last week, Health Canada warned consumers about the following supplements with unlabelled contaminants (among many others):

  • Snake Powder Capsule (for rheumatism) – actually contain piroxicam (an anti-inflammatory), dexamethasone (a steroid), hydrochlorothiazine (a diuretic) and cimetidine (used to treat ulcers). No snake though.
  • Jia Rong Zhuang Gu Tong Bi Jiaonang (for joint pain) – actually contains indomethacin, piroxicam and diclofenac (all anti-inflammatories), prednisone (a steroid), hydrochlorothiazide, metoclopramide, theophylline (used to be used for asthma), trimethoprim (an antibiotic) and phenylbutazone (a now-banned anti-inflammatory which is associated with bone marrow suppression).
  • Long Ren Tang Fu She Gu Rang Jiao Nang (for joint pain) – actually contains indomethacin, piroxicam, diclofenac, naproxen (yep, four NSAIDs), hydrochlorothiazide, cimetidine, metoclopramide and dipyrimadamole.

If you wanted to create supplements that not only had an irrational combination of ingredients, but also maximized the odds of potentially fatal adverse effect, you would have trouble topping the ingredients in these adulterated products.

The FDA maintains its own list, which has warnings that are equally frightening:

FDA continues to warn the public about Reumofan Plus—a product promoted as a dietary supplement for the treatment of arthritis, osteoporosis, bone cancer and other conditions. The product contains hidden prescription drug ingredients that can cause potentially fatal side effects. It could be labeled in Spanish and sold in some retail outlets, at flea markets and on the Internet.

Since June 2012, when FDA first warned the public about the dangers of Reumofan Plus and Reumofan Plus Premium, the agency has received reports of fatalities, stroke, dizziness, difficulty sleeping, high blood sugar levels, problems with liver and kidney functions, and severe bleeding in the esophagus, stomach and intestines, as well as corticosteroid (an anti-inflammatory drug) withdrawal syndrome.

Turns out after the recall, the manufacturer just relabeled it – it’s now called WOW, and still contains three undeclared prescription drugs: dexamethasone, diclofenac, and methocarbamol.

How frequently are supplements adulterated with real drugs? It’s a difficult question to answer given the lack of regulation of this market.  The best signal may be regulator-initiated recalls. A systematic search was recently published by Ziv Harel and colleagues in JAMA Internal Medicine entitled The Frequency and Characteristics of Dietary Supplement Recalls in the United States, it’s a fairly simple review – a descriptive summary of all drug products listed as dietary supplements with class I (dangerous or defective product) recalls. While supplements are not drugs, once they’re identified to contain unapproved ingredients, they’re treated as unapproved drugs for the purpose of a recall. From the perspective of the supplement industry, the results should be concerning:

  • Between 2004 and 2012, 465 products were subject to a class I recall. 51% were supplements – the balance were drugs.
  • Most of the recalls occurred after 2008
  • Every supplement recall was because of unapproved ingredients
  • The majority of the recalled products were manufactured in the United States. Only 24% were imported.
  • Supplements marketed for sexual enhancement were the most commonly recalled product, followed by bodybuilding supplements, and then weight loss products.

table from supplement contamination paper

Remarkably, the authors noted that the FDA does not have accurate manufacturer contact information on file for 20% of all supplement manufacturers.  What’s further, the FDA has found Good Manufacturing Practice violations to be present in nearly half of the firms it has actually inspected. So in light of the lack of regulatory oversight, it’s reasonable to think this list captures only a fraction of the total number of mislabelled and adulterated supplements on the market today.

There are few signals that can guide consumers. Sexual enhancement, weight loss, and body building supplements seem more likely to be adulterated. Given the lack of good evidence to suggest supplements are useful for these purposes, extra caution is warranted.  While no harms were noted in the recall notices posted by the FDA, harms from adulterated supplements have been reported.  Pai You Guo was a Chinese-manufactured weight loss supplement adulterated with two banned drug products, sibutramine and phenolphthalein. Despite warnings from the FDA, sales continued. In a survey, almost all users (85%) reported side effects from use.

Conclusion
A lowered regulatory bar for supplements and natural health products has been a boon to manufacturers, but the same can’t be said for consumer protection. In the absence of regulation that puts safety ahead of manufacturer interests, we shouldn’t expect to see any meaningful improvements in product quality, and the list of adulterated supplements will continue to grow. This double-standard has made it harder, rather than easier, for consumers to use supplements safely. Until a single, rigorous standard is applied across all consumer health products, there will continue to be uncertainty about the safety and quality of supplements.

Reference
Harel Z., Harel S., Wald R., Mamdani M. & Bell C.M. (2013). The Frequency and Characteristics of Dietary Supplement Recalls in the United States. JAMA internal medicine, PMID:

Posted in: Health Fraud, Herbs & Supplements, Politics and Regulation

Leave a Comment (21) ↓

21 thoughts on “What’s in your supplement?

  1. mattyp says:

    Speaking of supplements, what do you make of the use of questionable in certain professional sports in Australia. Supplements such as peptides that haven’t been approved for human use or passed clinical trial stages being used by sports scientists & doctors? Just curious.
    As for supplement regulation – I had naively been of the view that it was regulated with quality control. Thanks for the posting.
    Cheers.

  2. windriven says:

    Costco members are treated to a flyer (read advertising periodical) every month or so. The supplements section of a typical Costco store is less than 5% of the total floor space but at least 20% of the advertising is for supplements. The profit margins on this stuff must be phenomenal.

  3. goodnightirene says:

    Don’t forget the harm to your wallet from buying useless (even if safe) supplements. Thanks for continuing to remind newer readers about the DSHEA and its nasty side effects.

    ——-

    off topic:

    Dr. Gorski, there’s a good article online in the NYT (it’s for the Sunday Magazine) by Peggy Orenstein that summarizes very nicely everything about breast cancer research and treatment that you’ve been telling us for some time. The comments are very positive except for some of the usual “big Pharma and corrupt doctors are just trying to obscure that GMO foods, et al, are causing cancer” sort of thing. I find this a real bright spot in the otherwise often dismal “science” reporting.

  4. Robb says:

    Where to start? I usually respect SBM for presenting a balanced, objective view but this piece is riddled with biased crapola.
    1) Health Canada’s NHPD doesn’t have an “anything goes” policy and cherry picking “rabbit anus” homeopathy as an example is a red flag already. Do you really think rabbit anus homeopathy is generally indicative of supplements and NPN licensing on the whole? I wouldn’t mind if homeopathy disappeared altogether and Health Canada only allows all of it to have the statement “homeopathic remedy” – no health claim at all.
    2) You then go on to try to make the point that approved for sale drugs have better standards than supplements with the example of a foreign produced supplement not approved for sale in Canada that HC recalled. This is Fox news standards of smearing and I’m surprised SBM would stoop this low. Adultered supplements is a problem and HC does catch them and forbid their sale – but this has nothing to do with approved for sale, licensed supplements’ quality control standards at all.
    3) Drugs themselves are more and more commonly encountering poor quality control issues due to them increasingly being manufactured overseas, with lax standards and less ability of the FDA to inspect their manufacturing. This is going to continue to be an issue and you fail to mention it at all in a piece purporting to contrast “high” standards with “low” standards. You can see the dozens of recalls from the past year listed here:
    http://www.fda.gov/drugs/drugsafety/DrugRecalls/default.htm
    and this issue in general discussed here: http://www.washingtonpost.com/wp-dyn/content/article/2007/06/16/AR2007061601295.html

    1. Scott Gavura says:

      @Robb:

      Lest you think I’m cherry picking, here’s a few other homeopathic remedies deemed “safe and effective” by Health Canada:
      homeopathic sea water — DIN-HM 80017767
      homeopathic insulin — DIN-HM 80016480
      homeopathic granite — DIN-HM 80012752
      homeopathic roasted sponge “Spongia Tosta” — DIN-HM 80011377
      homeopathic chloroform DIN-HM 80010524
      homeopathic table salt DIN-HM 80005389
      homeopathic insect repellent – DIN-HM 80031902
      homeopathic lead – DIN-HM 00876119

      And it’s not just homeopathy. Look at the Health Canada approved “recommended use” for other products also deemed “safe and effective”. For example:

      Horny Goat Weed (NPN 80015409): “TCM used to tonify the kidney and fortify the yang, for symptoms such as frequent urination, forgetfulness, withdrawal, and painful cold lower back and knees.”

      But be careful, the same product is “Contraindicated in patients with fire from yin deficiency” according to Health Canada.

      Skeptic North ran a long series of posts where readers were challenged each week to guess which product was approved by Health Canada, and which one was completely made up. Disappointingly, it’s difficult to tell.

      I question how consumers can identify and use supplements in science-based ways when regulators approve sugar pills and herbal remedies based on magical thinking or just plain bad science, and then allow their manufacturing to be subject to lower standards than what’s already in place for drug products.

      You then point to FDA recalls of drug products (approved under those stricter manufacturing requirements) as evidence of what, exactly? Note that 75% of the supplement recalls described in the survey were for US-manufactured products.

      How many FDA-approved drugs (not supplements) have been recalled for being adulterated with other, undisclosed drugs? Any guesses?

  5. DVSousa says:

    Robb,

    Exactly which part of the rabbit would have to be homeopathically diluted and then licensed by Health Canada in order to show that the NHPD indeed does have an “anything goes” policy? Health Canada has handed out about 700 licenses to products containing a homeopathically diluted rabbit part. The regulator provides no warning to consumers either on the label or anywhere else of the true nature of homeopathy. It simply assures them that if a product has a licence, it is “safe, effective and of high quality”.

    Restricting claims to a variation of “homeopathic remedy” doesn’t protect the consumer either. It leaves the door wide open for homeopaths, naturopaths and others to make whatever claim they want about homeopathic products. Nothing on the label warns the consumer about what it *can’t* be used for and under the right circumstances they are likely to believe that the product will work for whatever they’re told it will work for.

  6. windriven says:

    @Robb

    What so totally unhinged you? Health Canada either does or doesn’t tag homeopathic concoctions as “safe, effective and of high quality.” Of the three, only safe passes even a rudimentary sniff test.

    Next you question, “the point that approved for sale drugs have better standards than supplements…” I can’t speak to Canada but that is certainly factual in the US.

    And finally you argue that “[P]oor quality control issues due to [prescription drugs] increasingly being manufactured overseas, with lax standards and less ability of the FDA to inspect their manufacturing.”

    The standards are not lax; the same FDA requirements apply whether the product is made in Mumbai or Shanghai or Patterson, NJ. And FDA has field offices in Mumbai and New Delhi and Shanghai and Beijing and a host of other foreign cities.

    So WTF? Scott wrote a piece questioning the veracity and completeness of supplement labeling based on broad exemptions to regulations that apply to prescription drug manufacturers. I’m struggling to understand your objections.

  7. Robb says:

    I’ll try and make it simpler. Here’s the argument: Health Canada has licensed rabbit anus homeopathy (and whatever other odd homeopathy concoctions) and foreign made not approved for sale adulterated products found their way surreptitiously into the Canadian market, therefore all licensed and approved for sale supplements are suspect and might not be safe and have low quality control standards. This doesn’t strike you as a seriously flawed argument??

    HC licensing homeopathy and whether that signals their efficacy (officially it doesn’t) is one thing. Adulterated, unapproved products is another thing. The safety and quality control that goes into licensed, approved products is totally separate and this piece is trying to smear the one with unrelated issues that go for shock value. Show me actual problems with the GMP regulations and quality control testing of licensed, approved products as compared to those of drugs and then we have an issue. I somehow doubt the author knows the actual differences or what those regulations are or he wouldn’t have the same concerns regarding their safety. Efficacy of homeopathy and adulterated illegal products are all straw men unrelated to the topic he is pretending to address.

  8. Jeff says:

    Scott writes of drug makers: “And manufacturers must meet stringent quality standards for their products, including verifying the consistency and quality of everything they produce. The same can’t be said for supplements.”

    Not true. The GMP standards for supplements are quite stringent. Testing is required at several stages of production:
    http://www.fda.gov/Food/GuidanceRegulation/GuidanceDocumentsRegulatoryInformation/DietarySupplements/ucm238182.htm

    The vast majority of supplements now being sold, especially by the larger companies, are GMP compliant. The final roll-out of supplement GMPs finally occurred in 2010. It’s true some small and medium-sized companies are having trouble meeting those standards. The FDA has made GMP compliance an enforcement priority. Those companies with repeated violations won’t remain in business for long:
    http://www.nutraingredients-usa.com/Regulation/Supplement-maker-Kabco-shut-down-over-GMP-violations

    “While supplements are not drugs, once they’re identified to contain unapproved ingredients, they’re treated as unapproved drugs for the purpose of a recall.”

    Precisely. These illegal products are drugs masquerading as dietary supplements. Those selling them could be subject to criminal prosecution, resulting in fines and jail time. why doesn’t the FDA take stronger action against these companies, instead of merely asking for recalls? This is an enforcement issue, not one of poor regulation.

  9. windriven says:

    @Robb

    “This doesn’t strike you as a seriously flawed argument?? ”

    As you construe it, the argument is flawed. But my reading of the piece is apparently rather different than yours. My takeaway is this:

    Supplements are not required to have the level of FDA oversight that is required of prescription drugs. Supplements have made their way into commerce that are adulterated. It is reasonable to assume that this would not have happened had their facilities been subject to full FDA GMP and ISO 13485 audits (a process not for the faint of heart). Therefore, it is prudent to question supplements until proven pure by some other mechanism.

    You ask, “How many FDA-approved drugs (not supplements) have been recalled for being adulterated with other, undisclosed drugs? Any guesses?”

    I don’t though I can easily enough find out. Because of my business I get a stream of recall notices and warning notices from FDA every day. By far the majority of these are for foods that contain undisclosed milk products, nuts, etc. or that are contaminated with e. coli or listeria. Next most common are devices with some flaw: cables that fail unexpectedly, software glitches, etc. I get notices about prescription drugs but they are by far the least common.

  10. Robb says:

    Scott,
    Yes, Health Canada licenses homeopathic products. What does that have to do with supplements as a whole having lax/unsafe manufacturing practices? You’re ignoring all the criticisms just to list more homeopathic stuff as if that relates to any of the points you were making.

    Your post has done nothing to establish that approved supplements have lower manufacturing standards than drug products. Even if, let’s say, it did come out that Boiron (who makes almost all the homeopathic products sold in Canada) had sub-standard, potentially unsafe manufacturing practices, it would still be unfair to then generalize their example to all other companies making supplements. They’re all completely separate entities, sometimes even owned by pharmaceutical companies themselves.

    As for how consumers can identify and use supplements, personally I think the onus is on the consumer to educate themselves as much as it is Health Canada’s to help them understand, but I might be over optimistic/idealistic in that regard. Health Canada licensing a product vouches for its safety and the claim itself speaks to its efficacy. In the case of homeopathy, as I’ve said they do not endorse it for anything other than being a homeopathic preparation. I agree this begs the question of why even license and sell it then but I guess HC went this route rather than just ban and remove it altogether. Again, totally separate topic and one which I would have no argument with.

    What matters most is, what are consumers actually buying and using (homeopathy is not a big seller in North America at all, except maybe in some cases in Quebec and the number of NPNs they have has no bearing at all on how much is sold or used) and are there are any unsafe/sub-standard manufacturing concerns with those products? Don’t yout think it was underhanded and unrepresentative to choose an illegal unapproved product to try and demonstrate lax standards for licensed approved products?

  11. Jann Bellamy says:

    @ Jeff:

    “GMP standards for supplements are quite stringent. Testing is required at several stages of production . . . “

    Except the manufacturers don’t have to disclose those test results to anyone, including consumers and the FDA. Doesn’t sound very “rigorously binding or exacting; strict; severe,” which is the definition of “stringent.”
    http://www.fda.gov/Food/DietarySupplements/QADietarySupplements/default.htm#responsible

    ”The vast majority of supplements now being sold, especially by the larger companies, are GMP compliant. . . .
    http://www.nutraingredients-usa.com/Regulation/Supplement-maker-Kabco-shut-down-over-GMP-violations.”

    Your source of information doesn’t seem to agree. From the cited article:

    “Is industry getting the message? Both Ullman [an attorney who practices in this area] and LeDoux [an official of a supplement manufacturer] said this [FDA’s enforcement action] should serve to put industry on notice about GMP compliance and enforcement, but it is unclear how many companies are getting the message. ‘This should be a wakeup call, yet, today, we see letters in which FDA is saying, you don’t have ANY manufacturing records,’ Ullman said. ‘I think what is alarming is we are seeing this kind of activity at the baseline of GMP compliance.’”

    “why doesn’t the FDA take stronger action against these companies, instead of merely asking for recalls? This is an enforcement issue, not one of poor regulation.”

    I don’t get it. You just said, “The FDA has made GMP compliance an enforcement priority. Those companies with repeated violations won’t remain in business for long.”

  12. windriven says:

    @Jeff

    You’ll note that the GMP requirements for supplements fall under the general ‘food’ category. I’d like you to compare and contrast the requirements there with ISO 13485 and the GMP requirements for pharmaceutical and medical device manufacturers.

    Is there any particular reason that you believe that companies selling essence of goat urine capsules shouldn’t be held to the same manufacturing standards as companies selling, say, acetaminophen capsules?

  13. Jeff says:

    windriven: Dietary Supplements have their own GMPs, completely separate from any other product regulated by the FDA. All testing records must be kept and provided to FDA when plant is inspected:
    http://www.ecfr.gov/cgi/t/text/text-idx?c=ecfr&SID=53a615e1775fbcf80d75b895372c2c69&rgn=div8&view=text&node=21:2.0.1.1.11.9.1.2&idno=21

    A considerable investment in equipment and personnel is required to meet these new standards. Many smaller companies will be unwilling or unable to make these investments; the FDA has estimated that 25% of supplement companies will be forced out of business due to the high costs of GMP compliance:
    http://www.naturalproductsinsider.com/articles/2012/02/the-cost-of-gmp-compliance.aspx

    Also see this article from Nutraingredients.com: “GMP compliance is a ‘huge opportunity’ for dietary supplements market: Chromadex CEO”

    Jann Bellamy: The FDA’s Daniel Fabricant has stated that drug-spiked products pose the biggest threat to the health of consumers. But the FDA isn’t going after companies selling these products with the same zeal it displays toward GMP compliance.

  14. Narad says:

    Also see this article from Nutraingredients.com: “GMP compliance is a ‘huge opportunity’ for dietary supplements market: Chromadex CEO”

    This doesn’t exactly bolster your “vast majority” argument. Indeed, this thinly disguised press release frankly admits that there is price pressure that favors noncompliance and hoping to be treated leniently should it be detected.

  15. Jeff says:

    This is the link I should have provided showing the complete set of GMP regulations for dietary supplements:
    http://www.ecfr.gov/cgi-bin/retrieveECFR?gp=&SID=53a615e1775fbcf80d75b895372c2c69&n=21y2.0.1.1.11&r=PART&ty=HTML

    Here’s the link to the nutraingredients article mentioned above:
    http://www.nutraingredients-usa.com/Suppliers2/GMP-compliance-is-a-huge-opportunity-for-dietary-supplements-market-Chromadex-CEO

    Virtually all large companies (Now, Vitacost, Natrol, etc.), which supply most of the market, have been GMP compliant for some time.

  16. windriven says:

    @Jeff

    I lack the time (or the inclination) to go through and compare GMPs for for supplements with those for pharmaceuticals. But let’s say for arguments sake that they are the same or similar. That still leaves the huge difference of proof of safety and efficacy. And it leaves the original issue of adulterated supplements hanging in the wind.

  17. Robb says:

    Windriven,
    What huge difference in proof of safety and efficacy?
    Was Vioxx “proven” safe before being sold?
    You can’t make generalizations like that. You’d have to look at each medication or supplement case by case. I don’t doubt that some supplements do not have much clinical backing for efficacy. But others do. It’s a large topic in and of itself. It’s also very different between Canada and the US (and other Commonwealth countries like Australia or quite similar to Canada) in that one has pre-market approval and the other doesn’t. In Canada the government has created guidelines for establishing safety and efficacy.
    http://www.hc-sc.gc.ca/dhp-mps/prodnatur/legislation/docs/modern-eng.php
    People can take issue with these as they do with any government decisions but these are the guidelines manufacturers follow.
    As far as adulterated supplements, many come from overseas and are not manufactured here and enter the country illegally. It has nothing to do with North American manufacturers anymore than a criminal is representative of the general population or those fly-by-night junk email prescription drug sellers are representative of the pharmaceutical industry.

  18. Narad says:

    Virtually all large companies (Now, Vitacost, Natrol, etc.), which supply most of the market, have been GMP compliant for some time.

    So why is compliance a “huge opportunity”?

  19. norrisL says:

    How can the government of a supposedly relatively intelligent country be so sucked in or just plain lazy and uncaring about the poor halfwits who buy and use this garbage have any credibility at all? I just don’t understand! Does HC simply not care whether people become sick or die because HC allowed such complete and utter rubbish into the “medical system”.

    I simply could not believe all of the real drugs that were found in various “medications”, and yet, I could because I know the realms of stupidity that people will go to in order to avoid actually going to see a real doctor who just might make you better and I also know that governments across the world appear to have given up on dealing with these charlatans and quacks who are nothing more than scammers, taking peoples’ money in return for water or in return for dangerous products which are not declared on labels.

    AAAAAAAAAAAARRRRRRRRRRRGGGGGGGGGGGHHHHHHHHHHHHH!!!!!!!!!!!!!!

    Sorry guys, I think I just hit homeopathic overload. Now, where is my rabbit anus?

    But seriously, government has a duty to protect people from charlatans, whether they be medical quacks or any other types of scammers. Governments need to consult people who know about medicine before allowing products onto shelves. They need to know that the latest car made in China is not full of asbestos, as was the case here in Australia……

    http://preview.tinyurl.com/bpdfjxc

    Oops, gotta go, just saw a little pink ring bouncing into the kitchen………..

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