By Paul A. Kimpel
Consumers who enjoy taking dietary supplements should pay close attention to an upcoming federal court case that pits the Food and Drug Administration against a California-based dietary supplement manufacturer, Pharmanex Inc. This pivotal case addresses the question of whether the FDA has the authority to ban from the marketplace a food or dietary supplement that contains a byproduct which happens to also be a FDA-approved drug.
The controversy involves a cholesterol-lowering product called Cholestin, which is sold as a dietary supplement. In June of 1998, the FDA declared Cholestin an unapproved drug because the main active ingredient, lovastatin, is equivalent to the active ingredient in the prescription drug Mevacor, made by Merck & Co., the nation's largest pharmaceutical manufacturer, with $24 billion in sales in 1998.
The FDA impounded several tons of the raw product and requested that Pharmanex stop manufacturing Cholestin. However, in February of 1999, the manufacturer of Cholestin, Pharmanex Inc., a subsidiary of Utah-based Nu Skin Enterprises Inc., appealed the FDA's ruling and won the case in Utah federal court. FDA spokeswoman Judy Foulke said the agency filed an appeal on April 23, 1999, and filed an initial brief on July 20, 1999, in the U.S. Court of Appeals for the 10th Circuit. Cholestin is sold nationwide through select dealers and from Pharmanex, a company that makes 38 supplements sold in 27 countries. Cholestin contains 12 natural substances that the company claims act together to "support healthy cholesterol levels."
The dietary supplement is made from rice treated with a red yeast called Monascus purpurus. When the yeast ferments in about two weeks, the rice is milled into a powder and put in a capsule. Of the naturally occurring active ingredients, 75 percent is lovastatin in either the active form or the pro-drug form, said Dr. Michael Chang, Pharmanex chief scientist and vice-president. A pro-drug, explained Chang, is a substance that is inactive until the body converts it into an active form.
However, Pharmanex president Bill McGlashan said in an earlier conversation that lovastatin makes up only 50 percent of the active ingredients. The FDA based its case on the fact that there is a large amount of lovastatin present in Cholestin, which the agency said makes it a copy of Merck's product, Mevacor. Lovastatin is effective at lowering cholesterol, and sales of Mevacor account for a large part of Merck's $4 billion-a-year in cholesterol drug sales.
Mevacor is made by isolating lovastatin from a fungus called Aspergillus terreus, and then inactive components are added to make a pill. Lovastatin is the only active ingredient in Mevacor, and Merck holds the patent on lovastatin. Merck has protested Cholestin's presence in the marketplace and warned that patients taking lovastatin or other drugs in the statin class should be monitored by their doctor for side effects that can include muscle and liver disease.
Dr. Thomas Baumgartner, a clinical pharmacy specialist for Shands at the University of Florida, said there is also an adherence question with supplements such as Cholestin. Baumgartner said that with Mevacor, patients take one pill a day, but with Cholestin, the dose is two capsules, twice a day. He said the more doses required, the more problems there are with patient compliance. "We have problems with patients remembering to take even one pill a day," Baumgartner said. In addition, Baumgartner said there is the threat that patients desperate to lower their cholesterol may abuse a product like Cholestin because they have unlimited access to purchase the product without a prescription.
Although Merck warns that patients should not self-medicate with Pharmanex's product, Cholestin, Merck spokesman John Bloomfield said Merck is considering its own product, Mevacor, for over-the-counter distribution. Merck would not comment on the safety of Mevacor as an OTC medication, which would be a prescription-strength pharmaceutical drug sold without a prescription. The product would have to be approved by the FDA for OTC distribution. FDA spokeswoman Judy Foulke said Merck's patent on lovastatin expires in 2001.
In the recently ended five-year Texas and Air Force study of 6,605 people, Mevacor reduced first heart attacks by 37 percent, total cholesterol by 18 percent and LDL (bad) cholesterol by 25 percent, which researchers said are significant reductions. The lead researcher, Dr. Antonio Gotto of Cornell University, said that based on these results, six million Americans currently not recommended for drug treatment for elevated cholesterol may benefit by taking Mevacor.
The goal of the study, which was funded by Merck, was to determine if people with only moderately elevated cholesterol levels could also benefit from treatment with Mevacor. About half of America's adults have total cholesterol levels of about 200 milligrams, a number considered by doctors to be "mildly elevated." Elevated cholesterol levels are a prime factor for heart disease, which is the No. 1 killer of Americans, taking about one million lives a year.
|Desireable = 200 or Below|
|Moderate Risk = 200 to 239|
|High Risk = 240 and Above|
Participants in the study were on a diet similar to the National Cholesterol Education Program (NCEP) Step One diet, which limits daily intake of fat to less than 30 percent of calories, intake of saturated fat to less than 10 percent of calories, and cholesterol to less than 300 milligrams daily.
An interesting fact about lovastatin is that it is naturally abundant in oyster mushrooms, which are sold at local supermarkets. In reference to his company's legal battles with the FDA, McGlashan asked, "If I chop up an oyster mushroom and put it in a capsule, is it a food, a dietary supplement or a drug?" But McGlashan conceded that an oyster mushroom will contain whatever amount of lovastatin it contains in nature, whereas Pharmanex concentrates the lovastatin content of its Red-yeast rice product. That is the reason the FDA considers it a drug, not a dietary supplement.
In a recent clinical trial of Cholestin that was published in the "American Journal of Clinical Nutrition," Dr. David Heber, the lead investigator, recommended further studies "to evaluate long-term safety and effectiveness of Cholestin in a larger population." Heber is co-chairman of the Pharmanex medical advisory board. In the Cholestin study, total cholesterol was lowered by 16 percent after eight weeks of treatment, which is considered a significant reduction.
In reference to the study, Dr. Thomas A. Pearson, chairman of the American Heart Association's science committee, said, "In the future, Red-yeast rice may provide clinicians with another tool to lower LDL cholesterol. However, too little is known to make scientifically sound statements about the safety and effectiveness of this substance. Ralph D'Agostino, chairman of the FDA's nonprescription drugs advisory committee, said Cholestin has 11 other active ingredients that have not been adequately tested in long-term studies. Pharmanex has begun further studies.
Proponents of dietary supplements, including Pharmanex president Bill McGlashan, tout the financial advantages of supplements over prescription drugs. But in a cost comparison of Gainesville area drugstores, natural food stores and selected Web sites, a month's supply of Cholestin, which provides a daily dose of 7.5 milligrams of lovastatin, costs $40, while a month's supply of Mevacor, which provides a daily dose of 10 milligrams of lovastatin, sells for $55. Most insurance plans cover Mevacor, but not Cholestin. We found the cost to be about the same.
Washington-based food lawyer Todd Harrison called the Cholestin case "a fine example of linguistic semantics." He said the outcome of the FDA's appeal in the Cholestin case could have a serious impact on the dietary supplement industry, and that he expects the FDA to win its appeal. There are several legal problems with the Cholestin case, and the first one deals with structure-function claims, which are statements about how a product affects the structure or a function of the human body.
These claims are allowed on labels of supplements under the Dietary Supplement Health and Education Act (DSHEA) of 1994, but the statements cannot claim to treat or cure a disease. Pharmanex advertises that Cholestin "supports healthy cholesterol levels." This claim is allowed, but disease claims, such as Cholestin "lowers cholesterol," are not allowed.
However, in a study on Red-yeast rice published in 1998 in the journal "Nutrition Research," Dr. Joseph Chang, a researcher at Pharmanex, and Dr. David Kritchevsky of the Wistar Institute wrote: "In an ongoing research program to discover an agent that can lower cholesterol, we examined fermented rice products used in Chinese medicine."
Doering, the UF pharmacy professor, said it is clear that Pharmanex was seeking a substance that lowers cholesterol and could be marketed as a dietary supplement, and the substance they found is the lovastatin in Cholestin. Doering said the framework of DSHEA, which limits structure-function claims to vague statements about effects on the body, causes supplement companies to play word games. He said if DSHEA allowed disease claims, we would see them for Cholestin and other supplements that are actually drugs, not dietary supplements.
The other legal semantics Harrison referred to address whether the FDA can regulate an individual component of an ingredient of a dietary supplement or only the complete, finished product. This is the aspect of the case that has the supplement industry concerned because if the FDA can prove in its appeal that individual components of ingredients can be individually regulated, that ruling would affect almost every supplement on store shelves. In the Cholestin case, the FDA ruled Cholestin is an unapproved drug and not a dietary supplement. Utah federal Judge Dale Kimball, who overturned the FDA's ruling, said the agency reasoned as follows:
* "Lovastatin, which is the main active ingredient in Cholestin and the active ingredient in the prescription drug Mevacor, was approved by the FDA as a new drug in 1987."
* "Cholestin is manufactured and marketed with a sufficiently great emphasis on its lovastatin content that Cholestin is to be equated with lovastatin."
* "Therefore, Cholestin cannot legally be a dietary supplement because it was not marketed before lovastatin was approved as a drug in 1987."
Under DSHEA, a new dietary supplement cannot be marketed if the same product is already sold as a drug. This section of the law is intended to protect prescription drug patents. But Harrison said that under DSHEA, a dietary supplement that is equivalent to a drug can be marketed after the drug's approval if the ingredients of the supplement were in the food supply before the drug was approved. This is the case with Cholestin because Red-yeast rice was in the food supply as a colorant and preservative in Chinese food prior to 1987. According to Department of Agriculture documents, hongqu, or Red-yeast rice, has been in the U.S. food supply since the 1920s. Harrison said that fact should help Pharmanex win the case.
The FDA argued that Cholestin is not the same product as the Red-yeast rice used in Chinese food. But according to Harrison, because the agency did not follow proper procedure under the Act and take Pharmanex to court on scientific merit, Judge Kimball did not have to address that aspect of the case. Bill McGlashan, president of Pharmanex, said, "Cholestin is the exact same product as the Red-yeast rice sold in Chinese grocery stores. The only difference is we grind it up and put it in a capsule." However, the FDA last year tested 33 samples of traditional Red-yeast rice sold in Chinese grocery stores in the United States and found that, "Thirty samples contained no lovastatin and the three that did had very low levels compared to Cholestin."
Dr. Richard Havel of the Cardiovasular Research Institute at the University of California said that Pharmanex published promotional documents in 1994 that stated the company had "developed a proprietary process to make a Red-yeast rice product containing amounts of lovastatin that could maximize Red yeast's health-enhancing properties." Havel said one of the ways Pharmanex concentrates lovastatin in its product is by "deliberately keeping fermentation production temperatures at optimum levels of about 25 degrees Celsius."
According to Havel, traditional Red-yeast rice is fermented at temperatures that don't allow for the production of significant levels of lovastatin. Havel's statements are taken in part or whole from Public Docket No. 97P-0441. But McGlashan said there are no laws in DSHEA to prevent his company from concentrating the active ingredients in Cholestin, including lovastatin. Doering, the UF pharmacist, said regardless of labeling, products are historically defined by their intended use and Cholestin is clearly intended to lower cholesterol levels, which makes it a drug.
The biggest conflict in the Cholestin case revolves around the intent of Congress when using the word "article." The FDA stated in its ruling that, "In marketing Cholestin, Pharmanex is marketing the "article" lovastatin, and not the traditional food product called Red-yeast rice." The FDA argued that wherever the Act refers to the word article, it means "both a finished product and its individual components (ingredients)."
For example, when defining drugs, DSHEA states drugs are, "articles intended to affect the body or articles intended for use as components of another article." For foods, the law states food can be "articles used as components of any article used for food or drink." However, the law does not address this idea of "articles used as individual components of another article" for dietary supplements, which chronologically follows the definitions of drugs and food in the Act. Whether this part of the law was left intentionally ambiguous is unclear, Harrison said.
However, on March 25, 1999, at a hearing about the dietary supplement industry, Rep. Henry Waxman stated: "It is clear to me that the FDA is doing a good job implementing a complex, challenging, and sometimes deliberately ambiguous law."
Because of the ambiguity of the law, the FDA reasoned that the definition of "article" under the food and drugs section should also apply to supplements, which would mean lovastatin is an article of Cholestin and therefore an illegal drug because Merck holds the patent on lovastatin. However, Judge Kimball, who heard the case, said the use of the word "article" under the definitions for food and drugs did not similarly apply to supplements. Rather, Kimball ruled that the word article, when referring to dietary supplements, only refers to a finished product.
The FDA responded that if Congress wanted the word "article" to refer only to a finished dietary supplement product, it would have used the word "product." However, Kimball said that because Cholestin, and not lovastatin, is the finished product made by Pharmanex, Cholestin is not the same as lovastatin and therefore is not an illegal drug but a dietary supplement.
Harrison said Kimball was wrong in limiting the definition of "article" to refer only to a finished dietary supplement product, and that an "article" could be an individual component of a product.
One of the issues highlighted by this case is whether the FDA is executing its duties properly. Some critics say the agency is not applying the law stringently enough, others say the FDA is heavy-handed in its approach. Marsha Wertzberger, a former FDA legal counselor now working as a food lawyer in Washington, said the FDA might have been able to remove Cholestin from the market if the agency had taken the proper legal approach. "The FDA should have done their homework and proven scientifically that Cholestin was unsafe," Wertzberger said.
The FDA did not question Cholestin's safety or effectiveness in the hearing. Wertzberger said the FDA does not like to go to court and instead looks for shortcuts to the legal process. Other ex-FDA lawyers agreed with this statement. Wertzberger said it was an easier move for the FDA to block the importation of Red-yeast rice and declare Cholestin an illegal drug. This tactic left it to the supplement manufacturer to appeal the FDA's ruling in court, which Pharmanex did.
Waxman said the answer to current regulatory problems is not to criticize the FDA for failing to adhere to the intent of Congress. "The answer is to establish a regulatory framework for dietary supplements that balances the interests of consumer access with public health," Waxman said.
This position is supported by a variety of consumer groups, including the American Dietetic Association, which represents nearly 70,000 food and nutrition professionals.
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