Recent warnings about aromatase inhibitors fraudulently marketed as dietary supplements mark a shift in FDA's enforcement against what the agency says is a growing problem of spiked nutritionals.

An industry expert notes the warnings could be a bellwether in enforcement activities by targeting supplements that contain a substance FDA rejected as a new dietary ingredient.

"This is the first time I've seen the agency go back to an objected-to new dietary ingredient notification and basically tell the company, 'We told you guys that you shouldn't go to market and you went anyway.' So that is quite new," said Andrew Shao, science and regulatory affairs senior VP at the Council for Responsible Nutrition.

In separate warnings issued in August, September and October, FDA informed manufacturers Unlimited Nutrition Scivation, Gaspari Nutrition, Kilosports, Genetic Edge Technologies, Advanced Muscle Science, Fizogen Precision Technologies and iForce Nutrition that products they marketed as supplements were violative due to the presence of aromatase inhibitors. Each firm voluntarily recalled the products.

Aromatase inhibitors are active pharmaceutical ingredients that block estrogen production and often are used in treatment of breast and ovarian cancers, the growth of which is stimulated by estrogen.

The so-called supplements, distributed under brands such as Gaspari's Novedex XT , Kilosport's Clomed and Unlimited Nutrition's Off-Cycle II Hardcore , are marketed to bodybuilding enthusiasts who expect to block testosterone, a key element in muscle growth, from being converted into estrogen.

Since Commissioner Margaret Hamburg joined the agency in June 2009, she and other FDA officials have emphasized enforcement against tainted supplements, which most often are marketed for strength training, weight loss or sexual enhancement (¹ Also see "FDA's Flurry Of Food Claim Warnings Sends Bold Enforcement Message" - Pink Sheet, 8 March, 2010.).

Aromatase inhibitors were the subject of NDI notifications made as early as 2003, Shao said. Although FDA rejected the NDI notification, which the agency noted in the warnings, some firms have marketed the products anyway.

He added that marketing products containing a substance from a failed NDI request triggers an adulteration provision of the Dietary Supplement Health and Education Act.

Although the enforcement might reflect poorly on the industry as a whole, it helps level the playing field for responsible manufacturers.

"What we're seeing here is FDA enforcing that provision that they hadn't been enforcing before and going after what are clearly illegitimate products. That would be seen as a good thing from the perspective of the responsible industry," Shao said.

"The mainstream industry would never put these kinds of products out there. That's just asking for trouble."

Marketing of strength-training products containing steroid-like chemicals is proliferating and the ingredients can be difficult to detect, according to Gary Coody, FDA's national health fraud coordinator.

"Steroid chemicals are immensely complicated molecules and there are literally hundreds of variations," Coody said during a presentation at a United Natural Products Alliance seminar Sept. 24.

The enforcement against the firms marketing the aromatase inhibitor products may be illustrative for the industry. "There's a new incentive to use warning letters as a tool, and I think you're going to see that increase," Coody said.

FDA has yet to publish an NDI notification guidance, and the lack of a guidance is considered an impediment to new ingredient development and industry growth.

A Center for Food Safety and Applied Nutrition official said in June that once FDA publishes the guidance, the agency likely will not issue warnings before taking judicial actions against firms that fail to comply with the NDI notification regulation (² Also see "FDA Will Enforce NDI Notification Requirement Without Warning" - Pink Sheet, 21 June, 2010.).

Demand Despite Risks

Coody said many aromatase inhibitors sold as supplements, like other nutritionals adulterated with Rx ingredients, are not tested before being marketed, increasing the likelihood of adverse event. All adverse events linked to the products FDA has noted occurred in men ages 22 to 55, he added.

Adverse events associated with the products could include "decreased rate of bone maturation and growth, decreased sperm production, infertility, aggressive behavior, adrenal insufficiency, kidney failure and liver dysfunction." Consumers with liver, kidney, adrenal or prostate abnormalities are at higher risk, FDA said in a Sept. 20 consumer warning.

Many consumers who purchase adulterated strength-training products likely know what they are getting.

"There's a certain allure to the bodybuilding community about kind of novel, almost drug-sounding ingredients that manufacturers call dietary supplements and basically refer to them as legal steroids," Shao said.

Bodybuilders sometimes use the products to avoid gynecomastia, or the development of female-like breasts, according to James Neal-Kababick, a forensic chemist and director of Flora Research Labs.

But consumers using aromatase inhibitors in untested products are raising the risks of serious and irreversible side effects.

Changing the makeup of a known chemical renders useless all the existing knowledge of a compound's toxicity, interaction with other drugs and other characteristics, Neal-Kababick said. "That makes it even more dangerous," he added.

In addition to adverse events, Shao said he expects other factors influenced FDA's crackdown. For one, the agency is stepping up enforcement across the board, particularly in dietary supplements, he said.

FDA likely learned of the ingredients through good manufacturing practices inspections. Labels made available to FDA officials during inspections would reveal the presence of the unapproved dietary ingredient.

"The way I think these were uncovered is when an inspector went into one of these facilities and asked to see paperwork on the legal status of the dietary ingredients that were being used in the products," Shao said.

The convergence of increased enforcement generally with supplement GMP inspections and the adverse event report "is probably enough to get FDA acting here," he added.

As of June this year, all supplement manufacturers were subject to the GMP final rule (³ Also see "Supplement GMPs Stress Responsibility, Put Firms In Driver’s Seat For Testing" - Pink Sheet, 25 June, 2007.).

Move Puts Industry On Alert

In an interview at the UNPA seminar, Executive Director Loren Israelsen said any supplier's claim that an ingredient works quickly denotes a spiked product.

"If you believe that and you buy a material and you don't test, it has a spiked ingredient in it," said Israelsen

Neal-Kababick pointed out GMP regulations require identity testing for all supplement ingredients and that they be free from "reasonably anticipated contaminants."

Although contaminants are a "moving target" and can be difficult to detect, firms should know to test for aromatase inhibitors due to FDA actions and discussion of the substances in peer-reviewed literature, he added.

However, because changing the chemical structure of aromatase inhibitors and other anabolic steroids is relatively easy, companies may have difficulty detecting the substances, Neal-Kababick said.

"There are no methods where you can just go to a book and get an official method that tells you how to do all of this. You have to have a certain amount of know-how and utilize a certain amount of expertise and method development," he said.

All manufacturers should be on notice that FDA will investigate all aspects of manufacturing.

"They're going to look at other things that are called for in DSHEA, like the legal status of ingredients," Shao said. "Anything is game now."

- Carolyn B. Phenicie ( ⁴ c.phenicie@elsevier.com )

FDA Enters New Enforcement Territory With Warnings Against Failed NDIs

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