Deadly Delay

ean Riggins' parents traveled from their Peoria, Ill., home to bring their son to tae kwon do tournaments as far afield as Indiana and Wisconsin. They and Sean were proud of the roomful of trophies he'd won. In high school, Sean joined the wrestling and football teams and his mother and father attended many of these events.

Sean wanted to win. He lifted weights to improve his strength. He also used money from his part-time job at the local Steak 'n Shake to buy the pills a coroner later said caused him to die, at 16, of a heart attack. Sean's father, Kevin Riggins, told a Senate committee last year that the pills, an herbal supplement called ephedra, never should have been available to kids. But when Sean died in September 2002, anyone could buy a three-pill pack for $1.50 at the local gas station.

Ephedra has been marketed to people hoping to lose weight or improve their athletic performance. The Food and Drug Administration considered the supplement dangerous for nearly a decade, but in 1997 aborted a proposed regulation that would have restricted its sale and use. Last December, nearly six years later and after the FDA had linked ephedra to more than 160 deaths, the agency announced that it would seek to ban ephedra from the marketplace.

The decision struck many public health advocates as too little too late. "We know they think they have the evidence because they did act. It's very legitimate to ask why they did not act sooner," says William Schultz, who was deputy commissioner of the FDA from 1994 to 1998. Even now, while the FDA is allowing comment on its rule prior to final approval, ephedra products remain-legally-in the marketplace. Sidney Wolfe, director of the health research group of the consumer advocacy organization Public Citizen, puts it more bluntly. The FDA's decision to wait six years to take action is "an inexcusable dereliction of responsibility," he says.

The answer to the question of why the FDA waited is far from a simple one. But if the agency is right about ephedra, then the story is undoubtedly a sad one.

There is no doubt that a lack of funding and staffing derailed the FDA's efforts to regulate ephedra. And after years of inaction, it looks like the regulatory train got rolling again only in response to Riggins' death, as well as the February 2003 death of Baltimore Orioles pitching prospect Steve Bechler, who was taking ephedra to lose weight. Members of Congress held a series of hearings in 2002 and 2003 in which they raised questions about the agency's response to ephedra. But Congress also has much to answer for. A decade ago, it passed the Dietary Supplement Health and Education Act (DSHEA), which allows natural products like ephedra to be sold without any government pre-approval, and which does not even require that companies that sell the products report problems that they discover to the FDA.

Ephedra is a naturally occurring substance derived from the Chinese herb ma huang. Its principal active ingredient is ephedrine, a stimulant which, when chemically synthesized, is regulated by the FDA as a drug. Synthetic ephedrine has long been available in FDA-approved over-the-counter and prescription drugs without reports of health risks. Products containing ephedra have been used to treat respiratory symptoms in traditional Chinese medicine. American manufacturers have promoted ephedra products for weight loss, enhanced sports performance and increased energy.

BUCKING A BAN

The story of how the FDA has reacted to the spread of ephedra starts with the 1994 DSHEA law. The dietary supplement industry pressed for the legislation, arguing that people should be allowed to take supplements-which include vitamins and natural herbal products like ephedra-without a doctor's prescription. These products should be treated like food, not drugs, the industry argued. One famous industry-sponsored advertisement featured actor Mel Gibson playing a person being arrested in his home by FDA agents for possessing a bottle of vitamin C.

Congress unanimously passed the DSHEA legislation, and President Clinton signed it. The supplement industry began to expand rapidly, and ephedra manufacturers were the principal beneficiaries. Consider Metabolife International, a San Diego-based firm founded by Michael Ellis, a former police officer who'd served jail time in the 1980s for manufacturing and selling the illegal street drug methamphetamine. Synthesized ephedrine is the street drug's principal ingredient.

The signature product of Ellis' firm was Metabolife 356, a weight-loss supplement containing ephedra. Between 1996 and 1999, the company's sales grew from $2 million to nearly $1 billion annually.

Under DSHEA, companies cannot make unproven claims that their supplements will cure diseases. But general health claims-even if debatable-are permitted. Companies can claim, for example, that a supplement helps respiration, but not that it cures asthma. Marketers of dietary supplements do not, under the law, have to prove the efficacy of their products before putting them on the market. But the FDA can order a supplement pulled from stores if the agency determines its use creates a significant or unreasonable risk, or an imminent hazard to public health.

The problem was-and is-that supplement manufacturers are not required to report consumer health problems, known in medical parlance as "adverse events," to the FDA. For years, Ellis and Metabolife denied that they had ever received a call from a consumer reporting health problems after using the company's products. "DSHEA tied the hands of the FDA," says Ilene Ringel Heller, senior staff attorney for the Center for Science in the Public Interest.

Nevertheless, in 1997, the FDA developed a proposal to regulate ephedra based on adverse event reports it had obtained directly from consumers, poison control centers and health care providers. The FDA proposed a requirement that ephedra manufacturers label their products with recommended doses much smaller than was the norm at that time. The label also would have instructed consumers not to use ephedra for longer than one week.

Supplement companies, led by Metabolife, launched another lobbying campaign to beat back the proposal. The companies hired the Dutko Group, a Washington lobbying firm then headed by Dan Dutko, a top Democratic Party fund-raiser. Dutko convinced Reps. George Brown, D-Calif., and James Sensenbrenner, R-Wis., to request a General Accounting Office study examining the FDA's rule. GAO's July 1999 report said that while the FDA had reviewed several hundred reports of health problems related to ephedra, the thrust of its rule-the dosage limits-was actually "based on information associated with only 13 adverse event reports." GAO recommended that the agency do additional research to support its rule.

TREADING WATER

The FDA pulled back its rule and requested that Congress boost its budget by $2.5 million to enable it to improve its system for gathering reports of adverse events. Congress said no. At the time, the agency's budget for monitoring dietary supplements was only $6.6 million a year, making it the FDA's smallest program.

In 2002, the FDA reported that it would need $45 million to $65 million and 133 to 244 employees to effectively run the supplement program. Two years later, amidst congressional outrage surrounding ephedra, the program is budgeted at $10.4 million with 59 employees.

After the first regulatory effort failed, the FDA found itself treading water without the ability to compel manufacturers to provide adverse event reports. The agency arranged some inconclusive roundtables, where most experts agreed that ephedra should be restricted. Each time, the agency determined that it still needed more proof. Clinical trials-the kinds of studies that are done to test the safety and effectiveness of drugs-were out of the question. Given the agency's belief that ephedra was harmful, such studies were viewed by FDA officials as unethical. Besides, clinical trials are expensive, and the agency didn't have the money to fund them.

Experts in food and drug law sympathize with the agency. "They were trying to be careful," says Peter Reichertz, an FDA expert at the Washington law firm Sonnenschein Nath & Rosenthal. "They knew they were going to be challenged [in court] by somebody."

In the meantime, Metabolife and its allies boosted their efforts. The firm hired lobbyists with Patton Boggs, one of Washington's most prestigious firms. Among the advocates hired were Brian Lopina, who previously headed the Washington office of the Christian Coalition, and Lanny Davis, who was a member of Bill Clinton's damage-control team during the Monica Lewinsky scandal. The industry paid lobbyists more than $3 million between 1998 and last year and made generous campaign contributions.

The lobbying effort hinged on getting the FDA to take action based on "real science." That approach would likely stymie regulation since the agency was unable to perform clinical trials, the only scientific method of proving causation.

In 2002, the FDA teamed with the Office of Dietary Supplements at the National Institutes of Health, a division created by DSHEA, to commission a study of ephedra. RAND, a California think tank, was asked to review existing adverse event reports, as well as scientific studies about the way ephedra affects the human body. From the start, the FDA knew that such an analysis could not prove causation the way a clinical trial would. But in the agency's view, it was the next best thing and would show to any court that the FDA had gone to extremes to study ephedra's risks and benefits.

The report came out in February 2003. It held no smoking gun, but bolstered the agency's belief that ephedra posed risks and offered few benefits. The study indicated that ephedra had no benefit for athletes and only limited benefit for dieters.

After reviewing 16,000 reports of adverse health events, RAND cited 21 cases-two deaths, four heart attacks, nine strokes, one seizure and five psychiatric cases-where no explanation other than ephedra use was apparent. The study found 160 cases in which ephedra users died, but use of the supplement was not the only factor that could have caused death. The FDA had received many of those adverse event reports in 2002, only after the Justice Department began an investigation into a 1998 claim by Metabolife's Ellis, in a letter to the FDA, that the firm had received no such reports.

RE-REGULATION

After Sean Riggins' and Steve Bechler's deaths, Congress began to change its attitude about dietary supplement enforcement. Both events prompted angry congressional hearings. Much of the ire was directed at the FDA. But Congress did accept some of the blame. "By taking the FDA out and leaving it up to the industry to be responsible, we found perhaps we made a terrible mistake," said Rep. Billy Tauzin, R-La.

After the RAND report, the FDA reopened its 1997 rule for more comments. Then FDA Commissioner Mark McClellan said the agency was "committed to finding the right public health solution" even though "the standard for regulating the safety of dietary supplements is largely untested."

McClellan, who took over the agency in late 2002 and has since been confirmed by the Senate to head the Centers for Medicare and Medicaid Services, decided to take on ephedra manufacturers directly. Prior to his arrival, the FDA had sent only eight cease-and-desist letters to manufacturers, accusing them of making false claims on their packaging. After the RAND report, it issued more than 30, primarily to companies advertising ephedra products as athletic enhancers.

In addition, McClellan launched a revamped version of the agency's adverse event reporting system in an effort to cull more accurate data from poison control centers, reports from consumers and health care providers, and complaints from companies about their competitors. And the FDA teamed with the Federal Trade Commission to coordinate the two agencies' enforcement efforts against health care fraud. One major joint initiative, Operation Cure-All, aims to stop Internet promotion of dietary supplements that make false or misleading claims about their benefits.

What may have ultimately turned the tide was McClellan's decision to abandon efforts to prove conclusively that ephedra can cause serious ailments and death, and to focus instead on demonstrating that the product's risks outweigh its benefits. The FDA's current proposal to ban ephedra is derived from the agency's authority under DSHEA to regulate supplements that pose an "unreasonable" risk to consumers. The agency also had the option of declaring ephedra an "imminent hazard" to the public health under the 1938 Food, Drug and Cosmetic Act. But FDA officials were much less confident in their ability to take action under this standard, believing that it required proof of causation.

"We are interpreting our standard . . . not to require the kind of scientific proof that is required for a drug to be brought to market," McClellan said in December 2003. "We have to consider evidence that's not quite at that level of proof."

Whether McClellan's approach will hold up in court-should there be a challenge to the FDA's proposed ban-remains to be seen. The comment period on the proposed regulation was scheduled to run out at the end of March, after which time the agency could issue a final rule. Whatever happens, the Center for Science in the Public Interest's Hiller says, "The FDA has been creative in trying to get to the problem. It's the first time that anybody has [done] a balancing test for whether the harm outweighs the benefit."

Meanwhile, many dietary supplement manufacturers say they are willing to see ephedra go, in the hope of averting further changes to DSHEA. They may not be so lucky. Sen. Richard Durbin, D-Ill., has sponsored a bill that would shift the burden of proof from the FDA to the manufacturers, requiring that they prove that their products are safe before they can be sold. Rep. Susan Davis, D-Calif., has proposed legislation to require manufacturers to send adverse event reports that they receive to the FDA. Judging by the ephedra hearings held in Congress last year, the proposals have substantial GOP support.