Rebecca Skloot, journalist, University of Memphis writing professor, and author of the upcoming book, The Immortal Life of Henrietta Lacks (pre-order here), just brought to my attention this commentary by Dr Pieter Cohen in the New England Journal of Medicine entitled, "American Roulette -- Contaminated Dietary Supplements."
In the commentary, Dr Cohen remarks upon the epidemic of adulteration of herbal and non-herbal dietary supplements with undeclared prescription drugs or unapproved drugs:
In July 2009, the FDA expanded its alert to include 75 tainted weight-loss products that contain undeclared medications. Analyses by the FDA have found the stimulant sibutramine in weight-loss supplements at levels amounting to three times the maximum recommended daily dose. Several of the unapproved anorectic ingredients detected in dietary supplements have been linked to serious adverse events: rimonabant to suicide and fenproporex to both addiction and suicide. The inclusion of furosemide and other diuretics in some of these supplements may result in dehydration and hypokalemia; other contaminants, such as benzodiazepines and antidepressants, mask the side effects of stimulants while conferring an increased risk of dependence. Some weight-loss pills, including many from Brazil, combine multiple medications in a single formulation. . .
. . .Recently, unscrupulous manufacturers have made it more difficult for the FDA to detect undeclared ingredients by incorporating pharmaceutical analogues into their products. Analogues are created by modifying the original chemical structure of a compound -- for example, by adding a hydroxyl group. It is suspected that these analogues are developed to evade detection by the FDA, making the products more difficult to regulate, and to reduce the risk of patent-infringement lawsuits. A recent analysis showed that more than half of 26 supplements marketed for the enhancement of sexual function contained analogues of phosphodiesterase type 5 inhibitors.
We've written about such cases at length such as adulterations of erectile dysfunction products (Blue Steel Hero, Zencore) , sibutramine in Confidence apple cider vinegar capsules, body-building supplements with hepatotoxic steroids (various Xtreme products), and eyelash-lengthening cosmeceuticals (RevitaLash,which gave rise to Allergan's Rx product, Latisse®).
I used to say, as Dr Cohen discusses in the commentary, that these cases are due to the Dietary Supplement Health and Education Act of 1994, legislation that permits herbal and non-botanical products top be sold without advance assurance of safety or efficacy. However, the last time I brought up this issue, I gained some additional education by comments, e-mails, and discussions with law experts and others more knowledgable than I about FDA regulations.
These colleagues raised my awareness that the FDA already has the authority to act on companies prior to reports of adverse reactions from supplements containing adulterants. Hence, the problem is not with the legislation but rather FDA's lack of enforcement of existing law stemming from the 1938 Food, Drug, and Cosmetic Act. One comment came from food and drug law attorney, Marc Ullman:
The responsibility is on the manufacturer, marketer, or anyone else who puts the regulated product into interstate commerce. If FDA was serious about enforcement and would refer a couple of these cases to the appropriate US Attorney's Office for prosecution, maybe there would we would see some sort of deterrent effect - the way all law enforcement is supposed to work.
Commenter John had a similar message in response to my 28 July 2009 post, perhaps with an inside take on how large supplement manufacturers view these adulteration cases:
Companies who adulterate supplements with anabolic steroids are committing a serious violation of the law. Most supplement makers would love to see the FDA put these criminals out of business. It's incomprehensible why American Cellular Laboratories receives only a warning letter. The FDA should use its legal authority to take much stronger enforcement action.
Finally, reader Jeff Engel passed along to me a series of detailed and informative links as to how FDA already has the power to act on the barrel dregs of supplement manufacturers:
I wanted to pass on to you this legal discussion concerning ways adulterated dietary supplements can be taken off the market. The standard for adulterated products doesn't require proof that consumers have actually been harmed, or even that a product will harm anyone:
http://www.jissn.com/content/1/1/52#B10
1. The Food, Drug, and Cosmetic Act (FDCA) prohibits introducing adulterated products into interstate commerce. Manufacturers are subject to fines and/or imprisonment. DSHEA doesn't change this law.
2. The other two provisions are included in DSHEA. In both cases adulterated products are subject to seizure and the manufacturer is subject to fines and/or imprisonment.
Products containing anabolic steroids would certainly be banned under the New Dietary Ingredients provision.3. Supplement manufacturing is now highly regulated, due to the new Good Manufacturing Practices:
a. Council for Responsible Nutrition's "Is Your Supplement Really Regulated?" (PDF)
(Yes, I recognize this is from a trade organization but it lays out nicely the current state of legislation - APB)b. Here's the GMP page on the FDA website:
c. Here's an article about plant inpections the FDA is currently carrying out:
FDA Gets Tough on GMP Failures4. Here are two articles concerning the problem of EMA: Economically Motivated Adulteration:
Economically-motivated adulteration remains rife
Many of our regular readers are likely to dismiss these qualifications of dietary supplement regulation since many feel that the clinical science has yet to validate more than a few dietary supplements for human benefit, an issue I've been discussing since I started here at ScienceBlogs.
But what I think are most important to glean from Cohen's NEJM commentary and the detailed information linked to in this post are these two points:
- FDA can act against adulterating dietary supplement companies today.
- Therefore, what is preventing the FDA from doing so? Staffing and resources? Other higher priorities?
I've always kind of walked the middle of the road on these supplements because some of my own NIH-supported research has dealt with the very interesting pharmacologic compounds present in some select supplements. My interests in these supplements come out of my historical respect for The Awesome Power of Natural Products (TAPONP) as some naturally-occurring plant and microbial product have proven both awesome and powerful in human and veterinary therapeutics.
So, for those who think that the FDA is "in bed" with pharmaceutical companies, why wouldn't the same agency then act more aggressively against supplement companies who dope their products with prescription drugs?
Discussion?
Cohen, P. (2009). American Roulette -- Contaminated Dietary Supplements New England Journal of Medicine, 361 (16), 1523-1525 DOI: 10.1056/NEJMp0904768
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An autistic kid under my care dropped 20 lbs over a 3 month period after starting a DAN! supplement regimen. I finally put my foot down over parents' objections and stopped the supplements. Weight then stabilized. I read the list of ingredients on the bottles. Nothing I recognized that might account for a drop in appetite.
Do you think I should send a sample of the stuff to someone for analysis? How much would that cost?
In the Oct. 7 NEJM commentary Dr. Cohen shows his ignorance of current law by stating:
"The DSHEA presents serious obstacles to the FDAâs ability to detect and eliminate contaminated supplements."..."Of particular concern are the dozens of dietary supplements that are contaminated with prescription medications, controlled substances, experimental compounds, or drugs rejected by the FDA because of safety concerns. These potentially hazardous ingredients have been detected in products marketed for patients with diabetes, high cholesterol, or insomnia but are most frequently found in products that promise sexual enhancement, optimal athletic performance, and weight loss."
The FDA has made it clear it considers such products to be unapproved new drugs, NOT dietary supplements. In other words these are illegal products, and as such are not covered under DSHEA.
It is only a matter of time before Congress gives the FDA mandatory recall authority over all dietary supplements, a move supported by the Council For Responsible Nutrition, a supplement trade group. This article explains:
http://www.overthecountertoday.com/2009/02/fda-recall-authority-likely-…
" It is suspected that these analogues are developed to evade detection by the FDA"
How does that work? Do they add an analogue that has no bioactivity in the hopes that only it will be detected and "hide" the real compound? It seems to me, any analytical chemist worth his or her weight in chromatography equipment could easily detect a molecule in a sea of analogues.
Unfortunately, in some peoples minds, nutritional supplements get lumped with dietary supplements. Most people only need to supplement their diet with the proper nutrients in order to loss weight. Too many of us rely on junk food in our stressed and harried lives.
"Do you think I should send a sample of the stuff to someone for analysis? ..." Posted by: titmouse | October 19, 2009 2:23 PM
There are many appetite suppressants, a "supplement" may contain one that is not included in any given screen for them. Thus, a supplement may pass the test for adulteration; that is part of APB's analysis.
"It seems to me, any analytical chemist worth his or her weight in chromatography equipment could easily detect a molecule in a sea of analogues. Posted by: Chemgeek | October 19, 2009 9:46 PM"
I think you miss the point, the analogue is active and is not intended to conceal the presence of another compound. I hope I don't lose readers; but the chromatographic (chemical) profile of an herb varies enormously from batch to batch. Picking-out an adulterating compound is hampered by this variation and by the resolution of the chromatographic system (which varies from compound-to-compound).
Although, as APB has acknowledged, adulterated products were (and are) not (legally) allowed; I think DSHEA opened the floodgates for illegitimate manufacturers. And I think that APB's complaints about DSHEA allowing flooding the market with junk (as I understand him) are fully justified. That is, although DSHEA did not make fraud legal, it gave plenty of opportunity for it.
The problem with the analogues is that you can trade efficacy for detection. If your analogue (might even be known in the literature) is only 20 % as effective as the marketed drug, it is most likely not in the database which checks your HPLC or GCMS results for known signatures, and as such will not trigger an alarm in a routine check. It's just one of the many blips you get, especially if it's unpurified biological stuff. But it still has enough efficacy to give you the wonder supplement everyone is raving about.
It' like typing V1@gra to get by the spam filter.
Heck, if the tobacco industry is allowed to add extra nicotine to cigarettes, who's going to stop the dietary supplement industry from adding drugs to their placebos?
L8R! I'm off to get some Blue Steel Hero.
To elaborate on what Joe@5 said, adulterating dietary supplements has always been illegal. (Well, since 1938.) But since DSHEA, the market has been flooded with dietary supplements which their users expect to have pharmaceutical effects. This greatly reduces the odds that the FDA will actually catch anybody adulterating the products.
Of course, then there's the separate problem of the FDA's weak response when it actually *does* catch somebody doing that. There's definitely room for improvement.
With ever growing competition in the weight loss industry its not surprising companies are going to push the limits on what is safe for people to take to help them lose weight. At the end of the day thought, its the consumer that losses out.