At a Senate hearing on June 8, held 10 years after passage of the Dietary Supplement Act--under which neither the safety nor efficacy of such supplements need to be proven by producers--nearly all witnesses testified that the law needs major reform.
Representatives of the Food & Drug Administration, public interest and consumer groups, the American Medical Association (AMA), and major lobbying organizations for the supplement industry testified. Most of them said mandatory reporting of serious health problems from supplements would help the government better control unsafe products. Under current law, no such reporting is required. Robert E. Brackett, director of FDA's Center for Food Safety & Applied Nutrition, stood nearly alone in asserting that fundamental changes are unnecessary--only vigorous enforcement of the act.
"If the object of the law is to protect Americans, it has failed on its face," said Sen. Richard J. Durbin (D-Ill.), ranking member of the oversight subcommittee of the Committee on Governmental Affairs. Sen. George V. Voinovich (R-Ohio), chairman of the subcommittee, agreed. "I am just as concerned about this as Sen. Durbin is," he said.
When it was passed in 1994, the Dietary Supplement Health & Education Act (DSHEA) changed the prevailing approach to product safety under the Federal Food, Drug & Cosmetic Act. Under FFDC, the manufacturers of food additives, drugs, and medical devices must prove that their products are safe before they can be sold. DSHEA essentially classifies dietary supplements as foods--not food additives--and thus does not require that manufacturers prove their safety or efficacy.
Under DSHEA, FDA has the authority to take dangerous supplements off the shelf if it can prove that they pose a "significant and unreasonable risk." But often, it takes years before the agency can build a case. Ten years passed before FDA had enough evidence to ban the supplement ephedra--the first supplement banned under the act.
Drug manufacturers are legally required to report adverse events--deaths and illnesses associated with their products--to FDA. Under DSHEA, such reporting by supplement producers is voluntary, and few adverse effects of supplements are in fact revealed. According to an FDA-commissioned study, less than 1% of adverse events are reported.
DSHEA stipulates that FDA promulgate rules for Good Manufacturing Practices. Such rules were not proposed until March 2003, however, and have yet to be finalized.
DRUG MANUFACTURERS cannot make health claims on labels or in advertising without rigorous testing and approval by FDA. But supplement makers can place health-related claims--so-called structure/function claims related to the function of some organ--on their labels without FDA approval.
Prescription and over-the-counter drugs must be submitted to FDA or to the U.S. Pharmacopeia to test whether they contain the amount of active ingredient stipulated on the label. DSHEA includes no such requirement for supplements.
At the hearing, one witness after another spelled out how they consider these DSHEA provisions to be flawed.
Ronald M. Davis, an AMA board of trustees member, said the physician members of AMA are very concerned about the quality and safety of dietary supplements. They are especially concerned about herbal products and supplements containing anabolic steroid-like ingredients and their precursors, he explained. AMA believes dietary supplements should be "regulated in the same way as prescription and over-the-counter drugs," he said.
He noted several serious unanswered questions about dietary supplements: Do they contain the amount of active ingredients claimed on the label? Are the structure/function claims for the products based on good science? Does the degree of safety of a supplement change if a patient is taking prescription medication or if he or she has a preexisting condition? Are supplements being used inappropriately to treat diseases or to delay treatment with effective prescription medications?
The answers to these questions are important, Davis noted, because the use of supplements is so widespread--involving more than 29,000 products with an annual market value of at least $18 billion.
A number of published scientific studies suggest that the amount of active ingredient in supplements often deviates from what is listed on the label, Davis said. In an analysis of 24 ginseng products, one-third had no active ingredient. Other studies, he said, have shown that supplements often contain impurities, such as arsenic, lead, mercury, and pesticides, and some are contaminated with medications, such as testosterone, alprazolam, warfarin, and digitalis. "The bottom line is that consumers cannot be sure that what is written on the product label is what is actually in the bottle," he said.
SOME SUPPLEMENTS have been associated with serious life-threatening conditions, Davis said. Those containing aristolochic acid can cause liver failure, and those with comfrey and kava are toxic to the liver. Many of these products are still being marketed, he said. An AMA article published last September [J. Am. Med. Assoc., 290, 1500 (2003)] has convincing data showing that St. Johns wort "could reduce the efficacy of half the prescription drugs on the market," he said.
Even though DSHEA classifies supplements as foods, Davis said that herbal remedies, anabolic steroids, and megadose vitamins have biological activity and are really drugs. The adverse event reporting system for supplements needs to be made mandatory, and supplements must undergo premarket approval for safety and efficacy at FDA, he concluded.
Bruce Silverglade, director of legal affairs for the Center for Science in the Public Interest, noted that "many supplements are undoubtedly beneficial." Examples include calcium to prevent osteoporosis and folic acid in pregnancy to prevent neural tube defects in unborn children, he said. But not all supplements are beneficial, and consumers cannot determine on their own which products are "nothing more than 21st-century snake oil or even dangerous," he said.
Because adverse event reporting is not mandatory, FDA has a great deal of trouble gathering enough information to actually ban a product, Silverglade said. Instead, it must rely on "woefully inadequate remedies, such as using public warnings and requesting voluntary recalls," he observed.
For example, Silverglade said, FDA is trying to gather information on bitter orange, aristolochic acid, and usnic acid, three weight-loss substances with biological effects similar to ephedra's. However, FDA cannot ban these substances under DSHEA without more evidence of harmful health effects, he explained.
Consumers often assume that because supplements are natural, they are safe. "Unfortunately, nothing could be further from the truth," Silverglade said.
He expressed guarded support for S. 722, a bill introduced in the Senate last year by Durbin that would address some problems with supplement safety. The bill would require manufacturers to report adverse health effects to FDA and would require premarket approval for stimulants--a class of supplements that presents some of the greatest problems.
But Congress should go further than S. 722, Silverglade said, and require premarket approval for all supplements intended for pregnant women, children, the elderly, and other vulnerable subpopulations. There should be "significant scientific agreement" about a supplement before a company is allowed to make structure/function claims, he said.
Charles W. F. Bell, program director for Consumers Union, voiced similar concerns. "Under DSHEA, the burden of proof for removing unsafe products [from the market] has been inappropriately shifted from manufacturers to government," he said. FDA can act against a supplement only after "substantial harm has already occurred," he remarked. He called for "premarket safety evaluation, mandatory reporting of adverse events, and increased FDA regulatory authority to take prompt action against known and emerging hazards."
Bell listed seven supplements that remain on the market even though their potentially dangerous effects have been known for more than a decade: aristolochia, yohimbe, chaparral, comfrey, germander, kava, and bitter orange. Five of these are banned in Asia, Europe, or Canada. These and five others listed in a May 2004 Consumer Reports article on supplements should be removed from the market immediately, he said.
But it would be a serious mistake to address the crisis in supplement safety only on an ad hoc, substance-by-substance basis," Bell warned. "It is important for Congress and FDA to take a broad view of supplement safety," he said. By 2000, several years before ephedra was banned, there had been 81 deaths, 32 heart attacks, and 69 strokes associated with its use, according to FDA figures. The dangerous situation similar to that with ephedra should not be allowed to recur, he said
It is possible to effectively evaluate the safety of supplements within the framework provided by DSHEA, said Alice M. Clark, a professor of pharmacognosy and vice chancellor for research at the University of Mississippi. The approach devised by the Institute of Medicine in a report on supplements that was published in April provides a reasonable method for assessment, she said. To make the evaluation process more efficient, however, the supplement law "should be modified to require" reporting of health problems related to supplement use.
Futhermore, health professionals and consumers should be encouraged to report adverse events, Clark said. To facilitate this, FDA's toll-free MedWatch number should be printed on supplement labels, she advised.
Manufacturers should be required to report adverse events associated with their products to FDA, said Anthony L. Young, general counsel for the American Herbal Products Association (AHPA), a trade association. Because FDA does not have the legal authority to require reporting, a change in the law is needed, he said.
In contrast, two witnesses expressed nearly complete satisfaction with DSHEA as it is now written. DSHEA is working well and does not need major revisions, said Annette Dickinson, then-president of the Council for Responsible Nutrition, another trade association of the supplement industry. The law only needs to be fully implemented, she explained.
"The bottom line is that consumers cannot be sure that what is written on the product label is what is actually in the bottle."
DSHEA WAS NECESSARY because FDA had a history of attempting to unreasonably restrict the formulation of dietary supplements, she said, and because then-commissioner David Kessler appeared to be about to impose broad restrictions on supplements. "DSHEA has been successful in maintaining access to a broad range of products," she said.
Dietary supplements have always been considered as a subcategory of food, so DSHEA was maintaining that tradition by categorizing them in the same way, Dickinson said. "The overwhelming majority of dietary supplement products are manufactured by responsible companies operating under stringent Good Manufacturing Practices and providing science-based formulations with substantiated claims," she observed. CRN is, however, considering ways of improving adverse event reporting for supplements, he said.
FDA's Brackett noted that many Americans take some type of dietary supplement, and "there is either strong or suggestive evidence" that many of these products "have important health benefits."
Although supplements are regulated as foods in that premarket approval is not required, there are special requirements for supplements that differ from those applied to conventional foods, he explained. If a claim is made that a supplement affects a structure or function of the body, it must include a disclaimer saying FDA has not evaluated the information, he said. Furthermore, the manufacturer "must have substantiation that the claim is truthful and not misleading," he said.
About a year ago, FDA beefed up its adverse event reporting system for supplements. It now automatically records reports submitted voluntarily by industry, health care providers, and consumers, he said. In addition, FDA has access to many other types of evidence it uses to evaluate the safety of supplements, Brackett said. The agency evaluates published literature, evidence-based reports, and the known pharmacology of compounds to assist in the evaluation of dietary supplements, he explained. He concluded that DSHEA is working well to protect the health of Americans.
But Voinovich was not convinced by these arguments. "How can you meet responsibilities with a law that is so weak?" he asked Brackett.
Voinovich concluded the hearing with an anecdote: "I am personally very concerned about this because I had a brother who took all kinds of dietary supplements and kept urging them on me. He took pill after pill after pill. He died from a massive stroke two years ago. I think there are a lot of Americans out there who for one reason or another think these pills are the thing that will keep them going."
Examples Of FDA Enforcement Actions
April 9, 2004
Warning letter sent to Cytotec Solutions Inc. of Tampa, Fla., for marketing a product called Green Hornet and a number of similar supplements as “street drug alternatives” producing “safe legal highs.” The labels list a variety of herbal and other ingredients, but they are inaccurate. The drugs actually contain dephenhydramine and dextromethorphan. Some teenagers were hospitalized with seizures and excessive heart rates after drinking Green Hornet.
March 11, 2004
Health & Human Services Secretary Tommy G. Thompson announced a crackdown on companies selling androstenedione or “andro.” Advertisements claim these products act like steroids, stimulating muscle growth and testosterone production. FDA issued warning letters to 23 companies asking them to cease selling products that contain androstenedione.
March 9, 2004
Hadi M. Ghandour, owner of Genapharm, Austin, Texas, was convicted of selling tiratricol, a potent thyroid hormone and FDA-designated class 1 health hazard, as a weight-loss supplement.
Feb. 11, 2004
FDA published a regulation declaring supplements containing ephedrine alkaloids (ephedra) illegal because they present an unreasonable risk of illness or injury. The rule is being challenged as unreasonable.
Feb. 5, 2004
FDA seized about 925 bottles of ephedra-containing dietary supplements from Musclemaster.com in Northboro, Mass. The company claimed the products enhanced athletic performance without an adequate scientific basis to support such claims.
FDA blocked entry of 20 kg of bulk germanium sesquioxide that was to be used in dietary supplements. Even at levels of use recommended by the supplement manufacturers, germanium causes kidney injury or death when taken on a regular basis.
FDA warned consumers not to purchase several products manufactured by NVE Pharmaceuticals, in Newton, N.J. The products marketed as dietary supplements for sexual enhancement were found to contain the prescription drug tadalafil, which can cause a drastic lowering of blood pressure when combined with prescription drugs containing nitrates. Tadalafil is the active ingredient in Cialis, a product approved in the U.S. and Europe to treat male erectile dysfunction.