Government, health advocates, lawyers challenge safety of weight-loss supplement.

Once the darling of the "in" crowd, ephedra is now the product that no one wants to sit next to on the school bus. The government has taken up arms against the weight-loss supplement ingredient, also known as ma huang, which contains chemicals that have powerful stimulant effects on the nervous and cardiovascular systems.

The Department of Health and Human Services (HHS) launched a research effort in June to study ephedra's safety, followed shortly by a General Accounting Office (GAO) report that said the federal government has been more concerned with manufacturers' marketing claims than with monitoring the safety and efficacy of supplements containing ephedra. (Dietary Supplements for Weight Loss: Limited Federal Oversight Has Focused More on Marketing Than on Safety, No. GAO-02-985T, July 31,2002.)

While the Federal Trade Commission (FTC) has gone after manufacturers for unfair or deceptive advertising, the FDA cannot by law regulate the product as strictly as it can foods or drugs. It relies on consumer reports of adverse effects to track ephedra's safety.

In July, the FDA asked the Department of Justice (DOJ) to conduct a criminal investigation into the claims of ephedra-supplement manufacturer Metabolife International, Inc. Meanwhile, countless lawsuits have been filed across the country on behalf of plaintiffs who have been injured after taking ephedra supplements.

The dietary supplement industry estimates 3 billion doses of ephedra are sold annually in the United States; Metabolife says it has sold over 4.5 billion tablets in the last five years. Dietary supplements contain ephedrine alkaloids--the active chemicals found naturally in plants that closely mimic the actions of the synthetic norephedrine hydrochloride (ephedrine HCL), which the FDA approved as a drug in 1948.

The problem with ephedra-containing supplements, according to Janet Heinrich, director of public health issues for the GAO, is that they are not proven to aid weight loss, but they are potentially hazardous. The supplement may be contaminated with harmful ingredients or may not state the amount of active ingredients on its label. It can also interact dangerously with medications or foods.

Since the 1990s, the FDA has received reports of ephedra supplements causing seizures, heart attacks, strokes, and psychosis, as well as lesser complications such as nausea, vomiting, insomnia, irritability, dizziness, and severe headaches. The agency warns that no one who is under 18 or pregnant or nursing should take it. Adults should consult their doctors first if they have a history of high blood pressure,

heart or thyroid disease, seizure disorder, depression, diabetes, prostate enlargement, or glaucoma, or if they take any prescription drug or over-the-counter allergy, asthma, or cold medicines.

The FDA cannot enforce these warnings, because under the 1994 Dietary Supplement Health and Education Act (DSHEA) it does not have the authority to evaluate supplements for safety or efficacy before they can be sold. The act entrusts safety to the manufacturer. A supplement's labeling may make "structure and function" claims saying that the product affects a system in the body, but unless the label claims that the supplement treats a particular disease--as drug labels do--the product need not meet the FDA's safety and efficacy standards.

"What started out as an act ensuring the consumer's right to choose has turned into a circus," said Christopher Grell, an Oakland, California, plaintiff attorney involved in ephedra litigation. "Anyone can make products without ever submitting them to the FDA for preapproval, and they can use ingredients not allowed in foods and even deemed unsafe in drugs. Drug companies are starting to market products not as over-the-counter drugs but as dietary supplements--and it's legal as long as they keep the ads and labels free of drug claims. The supplements can be labeled `promotes healthy cholesterol,' but if the label says `will lower cholesterol,' that's a drug claim."

Government oversight

Responsibility for monitoring dietary supplements falls to a patchwork of government agencies. The FTC can order that false, exaggerated, or unsubstantiated claims be removed from advertising, and it can seek monetary penalties. The FDA can issue regulations governing good manufacturing practices to standardize manufacturing, packaging, and storing. The National Institutes of Health (NIH) can conduct research to determine the safety and efficacy of an ingredient.

At the state level, agencies can enforce individual state laws governing the sale and marketing of supplements. Most state laws control the sale of ephedra to prevent its illegal use in manufacturing methamphetamine, not its use as a dietary supplement. Some states prohibit ephedra sales to minors, some have declared it an illegal drug, and others regulate how and to whom it can be sold.

The GAO report found that research is not a government priority, so little is known about whether weight-loss supplements are effective. While many supplements are reported to be associated with potential for physical harm, the FDA depends on voluntary adverse-event reporting that makes safety concerns difficult to identify.

The report cited a 1999 GAO study, which found that only a small number of adverse events are reported and that the information is incomplete and inconsistent. (Dietary Supplements: Uncertainties in Analyses Underlying FDA's Proposed Rule on Ephedrine Alkaloids, No. GAO/HEHS/ GGD-99-90, July 2, 1999.)

Furthermore, manufacturers do not have to identify what products they make or report adverse events to the FDA.

FTC Commissioner Sheila Anthony, speaking at the Food and Drug Law Institute annual conference in April, said there's been a "dramatic increase" in marketing supplements and thus an increase in questionable claims since DSHEA was passed.

The Internet "has made it easier for snake-oil salesmen to sell their products," she said, and marketers believe that the act "provides a green light to make implied health and disease claims and avoid FDA review or approval." The FTC has brought over 60 law enforcement actions in the past five years challenging false or unsubstantiated claims on dietary supplements, with "many more in the pipeline," she said.

On the other hand, the FDA has limited enforcement options: It can work with marketers to correct problems voluntarily and can ask for voluntary recalls. For example, last year it sent warning letters to six firms selling products on the Internet containing the drug ephedrine HCL but labeled as dietary supplements. It gave the companies 15 days to notify the agency that they had corrected the problem. If they failed to do so, the FDA would either go through the courts to seize the products, refuse their entry into the country, seek injunctions against the manufacturers, or pursue criminal penalties.

The agency took such action in October 2001, when it had U.S. marshals seize $2.8 million worth of nonherbal synthetic ephedrine that manufacturer EOLA International intended to market as dietary supplement Nature's Energy. In April 2002, EOLA signed a district court consent decree prohibiting it from holding, making, processing, packing, labeling, promoting, or distributing the product.

In June, HHS Secretary Tommy Thompson made studying the safety of ephedra a priority. The Office of Dietary Supplements and NIH have jointly funded a RAND report on completed studies of the issue, and a draft is currently undergoing review by experts.

HHS will also develop a research agenda for ephedra, including funding valid analysis methods and developing standard reference materials. The National Academies' Institute of Medicine has formed the Committee on the Framework for Evaluating the Safety of Dietary Supplements, which has readied the first of six prototype monographs to test the principles of evaluating dietary supplements for safety. These principles will help the FDA evaluate existing research on dietary supplement ingredients.

"No one's been studying the long-term effects of this product," said California attorney Grell. "The parallels with tobacco are scary. Look at tobacco 40 or 50 years ago. It was another herb, promoted as healthy and good for you with a calming effect. Then, after a run of lung cancers, somebody decided to get an explanation and do epidemiological studies, and they found that smoking increases the risk of lung cancer. For ephedra, we need epidemiological studies. But it's hard to get people to participate because of the human toll that might result."

Metabolife

The FDA's July request for a Justice Department investigation into San Diego-based Metabolife International came after the drug agency had spent five years seeking company records of consumer complaints. The DOJ probe is looking into whether Metabolife knew about dangers but lied to the FDA about the safety of its ephedra product Metabolife 356.

In 1998, Michael Ellis, then Metabolife's president, told the FDA that the company "never received one notice from a consumer that any serious adverse health event has occurred because of the ingestion of Metabolife 356." But a DOJ official told the FDA at that time that court records from private lawsuits showed that the company had received reports of serious illnesses.

FDA Deputy Commissioner Lester Crawford said recently that he was "greatly disturbed" that until September 2002 Metabolife did not offer to turn over 13,000 consumer complaints received between 1997 and September 2001. "Metabolife has refused and resisted us every step of the way. Given their long history of being uncooperative, we view their offer to make these reports available now to be disingenuous," he said.

Metabolife attorney Lanny Davis said the company didn't hand over the records sooner because it was in the middle of a lawsuit and because it wanted scientific experts--hired in 2001--to analyze the reports first. He said only about 80 of the reports mention serious side effects. He defended the product, saying that it carries a warning that people with health problems should consult their doctors before taking it and that people in clinical studies who took recommended doses "showed no different health effects over people who took a placebo."

Last October, the Senate Subcommittee on Oversight of Government Management concluded that Metabolife was aware of complaints even when it told regulators it wasn't. After examining the consumer reports turned over to the FDA, it found that the company's tracking of side effects showed an "indifference to the health of consumers" and that Metabolife maintained incomplete reports on harmful effects, many of which omitted even basic information or were handwritten, sometimes illegibly.

Sidney Wolfe, director of the Public Citizen Health Research Group, which filed a petition with the FDA in 2001 calling for a ban on ephedra supplements, told the panel at an October hearing that 33 military personnel using ephedra had died between 1997 and 2001 and that U.S. Army and Air Force commissaries pulled the product from shelves in August.

"There is no doubt that these products will be banned in the United States. The question is not whether, but when," Wolfe testified. "Delaying tactics ... are costing lives."

The House Committee on Government Reform, which last year conducted an independent analysis of the Metabolife reports, found that the company "took a careless approach to the adverse event reports, did not report them in a timely fashion to the FDA, and routinely failed to obtain medical records necessary to evaluate the safety of its products." The analysis found almost 2,000 of the reports concerned significant adverse reactions, many involving young consumers in good health who took the recommended dosage.

Metabolife President and CEO David Brown said the records were "anecdotal consumer call records [that] cannot and should not substitute for well-controlled scientific studies," contending that "there is not a single well-controlled clinical study that demonstrates that ephedra supplements are unsafe when taken as directed." He said over 30 clinical studies and reports attest to the safety and efficacy of supplements containing ephedrine alkaloids.

Plaintiff victories

That message may be a tough sell in court. In the first federal case against Metabolife to go to trial, a Birmingham, Alabama, jury recently awarded substantial damages to four plaintiffs who had heart attacks or strokes after taking Metabolife 356. The jury found that the company sold a defective product that was unreasonably dangerous to consumers. (McClain v. Metabolife Int'l, Inc., No. CV 01-BU-1801S (N.D. Ala. Nov. 19, 2002).) Judge William Acker Jr. declined to seal the trial records--a boon to plaintiffs in other suits.

The Alabama plaintiffs were represented by attorneys from the Law Offices of Archie Lamb. "This is a great victory for the many people injured by this dangerous and unmonitored supplement," said Lamb, who practices in Birmingham. "The jury agreed that the use of this powerful unregulated product was the direct cause of life-threatening injuries."

Other suits are also under way. Plaintiff attorney John Ruiz has filed a class action against Metabolife in Miami, which he says is the first such action in Florida. (Perez v. Metabolife, No. 02-CV-22850 (S.D. Fla. filed Sept. 25, 2002).) The suit--which claims products liability, strict liability, and violation of the state's Deceptive and Unfair Trade Practices Act--seeks injunctive and equitable relief, including monetary damages, payment refunds, and medical monitoring. One lead plaintiff suffered irregular heartbeat, migraines, and depression--and lost no weight; others were hospitalized after taking the supplement; and some required heart bypass or thyroid surgery.

At least 50 people in the Miami area have joined the suit, and Ruiz estimates there are more than 10,000 class members around the country. He predicts the suits will be consolidated as multidistrict litigation in federal court.