Testimony

Statement by
Mark B. McClellan, M.D., Ph.D., Commissioner
Food and Drug Administration

on
Hearing: Regulation of dietary supplements particular those containing: Ephedra or Ephedrine Alkaloids
before the
The Subcommittee on Commerce, Trade and Consumer Protection and The Subcommittee on Oversight and Investigations, Committee on Energy and Commerce

July 24, 2003

Introduction

Thank you Mr. Chairmen for this opportunity to come before your subcommittees to testify about the authority of the Food and Drug Administration (FDA or the Agency) to regulate dietary supplements, and in particular those containing ephedra or ephedrine alkaloids.

Background on Regulation of Dietary Supplements

More than half of the population of the United States use "dietary supplements". The Dietary Supplement Health and Education Act of 1994 (DSHEA) (P.L. 103-417) set up a unique regulatory framework in an attempt to strike the right balance between providing consumers access to dietary supplements that they may choose to use to help maintain and improve their health, and giving FDA the necessary regulatory authority to take action against supplements or supplement ingredients that present safety problems, have false or misleading claims, or are otherwise adulterated or misbranded. Although dietary supplements are generally regulated as foods, in addition to food regulations there are special statutory provisions and implementing regulations for dietary supplements that differ in some respects from those covering "conventional" foods. Moreover, the regulatory requirements for dietary supplements also differ from those that apply to drug products (prescription and over-the-counter).

Congress defined the term "dietary supplement" as a product that, among other things, is ingested, is intended to supplement the diet, is labeled as a dietary supplement, is not represented as a conventional food or as a sole item of a meal or the diet, and contains a "dietary ingredient." The "dietary ingredients" in these products may include vitamins, minerals, herbs or other botanicals, amino acids, and dietary substances such as enzymes. Dietary ingredients also can be metabolites, constituents, extracts, concentrates, or combinations of the preceding types of ingredients. Dietary supplements may be found in many forms, such as tablets, capsules, liquids, or bars. DSHEA placed dietary supplements in a special sub-category under the general umbrella of "foods," but products that meet the drug definition are subject to regulation as drugs.

Labeling of Dietary Supplements

Under the Federal Food, Drug, and Cosmetic (FD&C) Act and FDA's implementing regulations, the label of a dietary supplement must bear a statement of identity (product name) that identifies the product as a dietary supplement; nutrition information in the form of a Supplement Facts panel; a list of any ingredients not listed in the Supplement Facts panel; the name and address of the manufacturer, packer, or distributor; and the net quantity of contents. In addition, if the labeling includes a claim to affect the structure or function of the body, a claim of general well-being, or a claim of a benefit related to a classical nutrient deficiency disease, the product must also bear a disclaimer stating that FDA has not evaluated the claim and that the product is not intended to diagnose, treat, cure, mitigate, or prevent any disease.

Products containing ephedrine alkaloids have unusual features and present complex regulatory issues. If the product is a botanical, it may meet the definition of a dietary supplement regulated under DSHEA. On the other hand, if it contains synthetic ephedrine, that ingredient and other ephedrine alkaloids (including pseudoephedrine) are regulated as drugs, which are only marketed for indications where safety and effectiveness have been demonstrated. Synthetic ephedrine and pseudoephedrine are available as components of various over-the-counter and some prescription drug products for treating allergies, asthma, nasal congestion, and related upper respiratory symptoms. None of these drug products include other ephedrine alkaloids, caffeine, or other stimulants that may interact with their effects. Synthetic ephedrine drug products are subject to stringent manufacturing, labeling, and dosing requirements. Non-prescription ephedrine drug products must be kept behind the counter in retail stores. There are no synthetic ephedrine drug products approved for long-term use. Some dietary supplements have been found to contain synthetic ephedrine and FDA has taken enforcement action against their use.

Adverse Event Reporting

DSHEA's regulatory framework is primarily a postmarket program like the bulk of food regulation. Thus, like most foods, there is no requirement for manufacturers to provide evidence of product safety to FDA prior to marketing ephedra-containing products. In contrast, drug regulation involves an extensive premarket evaluation of safety and effectiveness with explicit standards of evidence. This evidence provides a basis to guide not only approval decisions but also conditions of use to manage benefits and risks. In addition, there are postmarket reporting requirements for drugs to support product safety monitoring. These requirements do not exist for dietary supplements.

As a result, adverse event reports (AERs) are the primary means FDA has for identifying potential safety problems with dietary supplements. Under DSHEA, FDA must rely on adverse event reports as a major component (i.e.-signal generator) of its post-market regulatory surveillance efforts under DSHEA. Also unlike drugs, FDA cannot compel reporting of adverse events by dietary supplement manufacturers. Because the Department of Health and Human Services (HHS) Inspector General estimated that the number of reports actually reported to FDA is less than 1% of actual occurrences, a lot of time and resources have been devoted to making this system as effective as possible.

FDA's Center for Food Safety and Applied Nutrition (CFSAN) has recently put in place the CFSAN Adverse Event Reporting System (CAERS) to monitor adverse event reports on food, cosmetics and dietary supplement products. CAERS includes a comprehensive single computerized system that captures and analyzes all reports of consumer complaints and adverse events related to CFSAN-regulated products. This state-of-the art system started collecting reports after June 15, 2003, and combines all existing CFSAN adverse event-reporting systems and logs reports into one portal within CFSAN.

Dietary Supplements Containing Ephedrine Alkaloids

A number of plant genera, including ephedra, are known to contain ephedrine alkaloids. Ma huang is a common name given to Chinese Ephedra, which is used in traditional Chinese medicine. Ephedra has been shown to contain various chemical stimulants, including the alkaloids ephedrine, pseudoephedrine and norpseudoephedrine, as well as various tannins and related chemicals. The concentrations of these alkaloids depend upon many factors, such as the species, parts of the plant used, time of harvest, growing location, and production methods. Ephedrine and pseudoephedrine are used in some over-the-counter and prescription drugs, where they have been demonstrated to be safe and effective for the labeled use. Many of these stimulants have known, and potentially serious, side effects. While ephedra has been used in herbal medicine preparations for thousands of years, in recent years ephedra has been sold primarily in dietary supplement products for weight control, as well as in products promoted to boost energy levels or to enhance athletic performance. These products often contain other stimulants, such as caffeine, that may have synergistic effects and increase the potential for adverse effects.

A number of adverse effects, including hypertension (elevated blood pressure), palpitations (rapid heart rate), neuropathy (nerve damage), myopathy (muscle injury), psychosis, and memory loss, and even the more serious adverse effects of heart attacks, stroke, seizure and death, have been reported to FDA associated with the use of products containing ephedra or other botanical sources of ephedrine alkaloids.

As the tragic death of the Baltimore Orioles' pitching prospect Steve Bechler has reminded Americans, ephedra has raised concerns about safety and has long posed difficult issues for health care professionals, regulators, and for consumers. These concerns stem from both the mechanism of action of ephedrine alkaloids on the sympathetic nervous system, and accumulating evidence of potentially serious adverse events after use of ephedra-containing products.

While there has been considerable debate about the safety and effectiveness of dietary supplements like ephedra, as well as the most effective approach to regulating them, one thing is clear: Although dietary supplements are regulated as foods and not drugs because they are botanical or natural ingredients, the consumer should not presume they are always safe to use. In particular, botanical and herbal products may have active ingredients with pharmacologic properties similar to, or in the case of ephedra identical to, drug products.

Use of Ephedra By Athletes

I want to take this opportunity to applaud the National Football League, National Collegiate Athletic Association, and the International Olympic Committee for banning the use of ephedra by their players. Although FDA is reviewing ephedrine alkaloids under the purview of DSHEA to assess the safety concerns, FDA has particular concerns about the use of ephedra by persons engaged in strenuous exercise. A study by RAND concluded that ephedra has minimal if any proven benefit for enhancing sports performance. Yet ephedra acts like an adrenaline boost, stressing the heart, raising blood pressure, and increasing metabolism, so its risks are potentially much more serious for competitive athletes than for the general population. Moreover, the stimulating effects of ephedra may mask the signs of fatigue, causing even the most well conditioned athletes to push beyond their physical limits. Thus, for any ephedra products that remain on the market, FDA has proposed a strong warning. It should not be used by people who engage in strenuous activity.

Major league baseball players and other athletes want to do the best job possible, and they push themselves to the limit to excel. Even though ephedra is a natural product, that does not mean it has a "natural" effect on the body. There is good reason to think that it might push some athletes over the limit of what their bodies can tolerate and adverse event reports reviewed by RAND indicate that in some instances "sentinel" events have been identified as a result of ephedra use.

Because of the special risks of ephedra use in athletes, I believe that the sports leagues that have acted to restrict ephedra use are making a prudent decision. Even as the Agency evaluates the safety of ephedra use in the population more generally, including its use for weight loss, I have clearly and repeatedly indicated that ephedra poses special risks in the context of sports performance with little or no identified benefit for athletes.

FDA's Proposed Rule on Ephedrine Alkaloids

Right now, the Agency's professional, scientific and legal staff are working hard to address the extraordinary challenges presented by these products. As you know the Agency proposed a rule earlier this year seeking comment on proposed label changes to strengthen the warning label for ephedra and assess whether ephedra poses a significant or unreasonable risk. These changes would make it clear to users, via a black-box warning on the front of the product, as well as additional information in the product labeling, that serious adverse events and death have been reported after using ephedra, and that risks of adverse events are particularly high with strenuous exercise and/or use of stimulants including caffeine. In addition, the agency reopened the comment period on its proposed 1996 regulation to restrict ephedra use. While that regulation was not finalized, there is now considerably more evidence available on ephedra's risks and benefits. FDA announced that it was seeking comments from health professionals, the supplement industry, and the general public on any additional data on ephedra's safety, so that we can acquire the most complete picture possible of the product's potential risks, as a basis for appropriate further regulatory action.

Our Federal Register announcement also sought comments on the whether and at what level the evidence of significant safety concerns is sufficient for further regulation of ephedra products under DSHEA under which a product can be considered adulterated if it present a significant or unreasonable risk of injury at the recommended level of use. "Unreasonable risk" clearly implies a risk-benefit calculus. Such a calculus should examine the best available scientific evidence and take it into account in assessing whether the product's known or suspected risks outweigh its known or suspected benefits, in light of the claims the product makes or under ordinary conditions of use. The "sentinel" events identified by RAND coupled with the adverse event information we have collected at the Agency has raised concerns about ephedra's mechanism of action.

This March 5, 2003 Federal Register announcement also sought comment on additional relevant evidence on ephedra's safety based on FDA's more extensive pharmaceutical regulation of synthetic ephedrine, which is identical to the main active ingredient in ephedra. Ephedrine has been available in certain FDA-approved over-the-counter and prescription drugs. It appears that the more controlled availability of synthetic ephedrine products, which are available primarily for approved uses for respiratory symptoms, carry mandatory warning labels, and (in its single-ingredient form) is sold as a "behind-the-counter drug," has not been associated with the same volume of adverse events as have occurred with dietary supplements containing ephedra. This long experience with synthetic ephedrine (in over-the-counter drug products) suggests that restrictions on labeling, marketing, and/or access to ephedrine may more effectively address potential risks associated with usage of botanical ephedrine alkaloids.

Seeking public comments on these issues helps give DSHEA the meaning in practice that many of its supporters say it should have, by clarifying that public health authorities can take actions to protect the public from unreasonable but uncertain safety risks associated with ephedra. We intend to establish an up-to-date public record for further, legally sustainable actions based on the latest scientific evidence. We are currently in the process of analyzing the over 16,000 public comments we received earlier this summer. We are in the final stages of our deliberative review related to finalizing our rule, so I cannot discuss the specifics of that process or the anticipated outcome. However, I want to emphasize that we are committed to moving forward expeditiously to make a determination that is well grounded in the scientific evidence we have and that is protective of the public health in accordance with DSHEA

Meanwhile, under my leadership, the Agency has dramatically increased its enforcement actions against ephedrine alkaloids and other dietary supplement products making false or misleading claims. I believe these actions, many of which have been undertaken in collaboration with the Federal Trade Commission, are having a real impact on the marketing of dietary supplements in general and ephedra in particular.

Enforcement Actions (Working Jointly with FTC)

At the core of FDA's effort is its commitment to enhance the legitimate manufacture, sale, and use of dietary supplements while maintaining a zero-tolerance for fraudulent product claims and other illegal practices. Achieving these goals relies on a number of strategies, including cooperation and coordination with other Federal, state, and international law enforcement agencies in protecting consumers against unapproved and potentially harmful products offered by Internet outlets, some of which are based abroad.

With a mutual goal of consumer protection, FDA and FTC formed a Dietary Supplement Enforcement Group to closely coordinate their enforcement efforts against health care fraud. In addition, FDA and FTC chair an interagency health fraud steering committee that meets regularly to coordinate activity on these issues. The workgroup currently includes federal agencies in the U.S. and Canada. Mexico has been invited to join the group. As part of its effort to curb Internet health fraud, the FDA has conducted several "surfs" to identify fraudulent marketing of health care products over the Internet. These actions were carried out in partnership with the FTC and other law enforcement and public health authorities in United States and abroad.

FDA Enforcement Actions In the Past Year

Improving the Evidence Base For Action On Ephedra - RAND Review

On February 28, 2003, Secretary Tommy Thompson and I held a press conference and announced the conclusions from the RAND review. In evaluating potential benefits of ephedra, the RAND report found only limited evidence of an effect of ephedra on short-term weight loss, and minimal evidence of an effect on performance enhancement in certain physical activities. Also, the RAND study concluded that ephedra is associated with higher risks of mild to moderate side effects such as heart palpitations, psychiatric and upper gastrointestinal effects, and symptoms of autonomic hyperactivity such as tremor and insomnia, especially when it is taken with other stimulants. Moreover, its review of some 16,000 adverse event reports revealed two deaths, four heart attacks, nine strokes, one seizure, and five psychiatric cases involving ephedra in which the records appeared thorough and no other contributing factors were identified. RAND called such cases "sentinel events," because they may indicate a safety problem but do not prove that ephedra caused the adverse event. The study recognized that such case studies are a limited form of scientific evidence. The study also identified other such events potentially associated with ephedra, in which other factors may have contributed to the adverse events or in which records were inadequate.

Additionally, on February 28, 2003, FDA announced a number of actions to address concerns about ephedra's safety. First, based on the conclusion of the RAND review, warning letters were sent to over two dozen ephedra manufacturers challenging them to remove unproven claims or substantiate those claims, with a particular focus on athletic performance enhancement claims. As a result of FDA's enforcement actions, all but one of these products are no longer being marketed for sports enhancement. Since performance enhancement was one of the two principal ways in which ephedra has been marketed, the impact of these warning letters has been substantial.

On March 31, 2003, FDA announced new guidance to curb the use of alternatives to illicit street drugs. In a Federal Register notice we announced guidance for the industry entitled "Street Drug Alternatives." This guidance outlines FDA's response to the proliferation of various products promoted as alternatives to illicit street drugs. These products, which are intended to affect psychological states, are generally labeled as containing botanicals, and some are alleged to include vitamins, minerals, or amino acids. FDA does not consider street drug alternatives to be dietary supplements because they are intended for recreational purposes to affect psychological states (e.g., to get high) and are not intended to supplement the diet. The guidance was implemented immediately without prior public comment and states that street drug alternatives are unapproved and misbranded drugs that can be subject to regulatory action, including seizure and injunction. In addition, we initiated six new enforcement cases against products that were making such marking claims. These six letters went to manufacturers of products that contain the drugs ephedrine or norephedrine hydrochloride labeled as dietary supplements for use in weight loss, suppression of appetite, enhanced libido, and the like. Also, FDA warned another company about illegally promoting its herbal ephedra product as an alternative to street drugs.

Additional Enforcement Actions On Dietary Supplements, Including Ephedra

Effective enforcement is an essential part of FDA's ongoing "Consumer Health Information for Better Nutrition" initiative, which is designed to improve the health of consumers by providing them with scientifically accurate, FDA-approved information about the health effects of foods and dietary supplements. False health claims that mislead Americans endanger their health and undermine the goals of the FDA health information initiative while enriching irresponsible manufacturers. As FDA expands and enhances its efforts to help consumers get better product information, it will continue its aggressive law enforcement against false and misleading health claims on all regulated products.

On December 18, 2002, FDA announced a significant enforcement initiative targeted at misleading claims about dietary supplement-associated health benefits. Dietary supplements are used by an estimated 158 million Americans, and so misleading claims about their health benefits may have significant consequences - not only for wasting consumers' money but also for luring consumers interested in improving their health in wrong directions. While FDA's enforcement goals related to truthful and nonmisleading statements about health benefits apply to all of the products the agency regulates, this initiative was especially focused on products that in recent years have been the subject of important misrepresentation.

As part of this December announcement, FDA released the "Dietary Supplement Enforcement Report" which pledged to closely scrutinize and bring enforcement actions against products identified as "clearly problematic." This included dietary supplements that falsely claim effectiveness as treatments for life-threatening diseases; overweight; autism; behavioral disorders; mental retardation and Down's syndrome; as well as colloidal minerals; supplements for smokers and drinkers; and colloidal silver products. In one joint action by FDA and the Federal Trade Commission (FTC), a Federal District Court ordered marketers of a dietary supplement to cease making unsubstantiated disease treatment claims and froze the company's assets, while FDA seized $7 million worth of these products at two warehouse sites. Since December, FDA has issued 40 Warning Letters and Cyber Letters to firms for making misleading claims about their products for treatment of life-threatening diseases such as cancer, lupus and heart disease. FDA also seized approximately $9 million worth of dietary supplement products which were promoted to treat a variety of serious medical conditions. Altogether, FDA issued 73 warning letters and Cyber letters to marketers of dietary supplement products, seized products worth almost $9 million, refused import of 368 shipments of dietary supplement products offered for entry, and supervised the voluntary destruction of $515,000 worth of dietary supplements promoted with unsubstantiated structure/function claims. By comparison, in 2001 FDA issued 21 warning letters and seized unlawful dietary supplement products worth $2 million. From October 1, 2002 to May 31, 2003 FDA issued 368 refusals of dietary supplement products offered for entry. From October 1, 2003, to May 31, 2003 FDA carried out approximately 72 inspections of manufacturers and distributors of dietary supplements.

Nature's Nutrition Formula One - July 2000

FDA determined that this pre-DSHEA product, which was marketed between 1992 and 1994, as an all natural "nutritional supplement" that contained plant ingredients, was actually made with two pharmaceutical-grade chemicals, ephedrine hydrochloride and caffeine anhydrous. FDA received more than 100 reports of injuries and adverse events related to the product, ranging from serious and life-threatening conditions, such as irregular heartbeat, heart attack, stroke, seizures, hepatitis and psychosis, to more minor and temporary conditions such as dizziness, headache and gastrointestinal distress. At least one death was associated with the use of this product.

This case was developed by the alerts provided from the adverse event reports, by ORA's field staff, and by the work of FDA's Office of Criminal Investigation (OCI) with DOJ. As a result, the government launched a criminal prosecution against the company and its president.

On July 7, 2000, a Federal judge sentenced its president to 21 months in jail and fined him and his corporation $4.7 million. In his plea agreement, the company admitted it labeled Formula One as "all natural" but spiked the product with synthetic ephedrine hydrochloride and caffeine anhydrous. It also admitted that the product's labeling failed to disclose the use of the chemicals on the list of ingredients, and that he and his employees had misled FDA investigators and hindered inspections of the manufacturing plant, Chemins. The sentence marked the culmination of a three-year investigation.

E'OLA International, Inc. - April 2002

FDA has seized products marketed as dietary supplements that contain synthetic ephedrine. In March of this year, for example, FDA filed a consent decree signed by the parties in United States v. 1009 cases et al., No. 2:01CV-820C (D. Utah). This case involved the seizure of nearly $3 million worth of Amp II Pro Drops from a company doing business as E'OLA International. Although labeled as a supplement, the product contained synthetic ephedrine. FDA alleged that the product violated the law because synthetic ephedrine is not a dietary ingredient. Accordingly, a product containing synthetic ephedrine is not a dietary supplement. The agency also alleged that the product, which was marketed to treat obesity, had made illegal disease claims. The consent decree required the product's destruction and prohibited E'OLA from manufacturing or distributing products that violate the FD&C Act.

Yellow Jackets

In September 2002 FDA became aware of a death of a 16-year-old boy who had taken the product Yellow Jackets. Yellow Jackets capsules and Black Beauties capsules are herbal products sold as alternatives to street drugs. These products contain ephedra extract and other herbal ingredients, including kola nut extract, a source of caffeine. There is no legitimate dietary supplement use for these products and their sale as a substitute for controlled substances is illegal. On October 4, 2002 FDA issued a Cyber Letter to Mr. Xoch Linnebank, Sjamaan Internet Department, The Netherlands, regarding the U.S. sale of Yellow Jackets as street drug alternatives. Further, FDA placed the company's products on import alert on October 7, 2002. FDA held weekly meetings over the Fall of 2002 and early Winter of 2003 to coordinate and evaluate its enforcement efforts regarding Yellow Jackets. In January 2003, after an inspection of the New Jersey manufacturer of Yellow Jackets, NVE Pharmaceuticals, FDA witnessed the voluntary destruction of Yellow Jackets and Black Beauties valued at $4 million.

FDA Efforts to Obtain Scientific Data

In order to acquire the best available scientific data to support its regulatory decisions relating to ephedra, the Agency has undertaken numerous credible and appropriate steps to gain access to information, in the form of adverse event information, clinical studies and other scientific reviews that could be helpful in evaluating the safety concerns identified by adverse event reports on ephedrine alkaloids. These successful efforts have put the Agency in a better position to make meaningful science based decisions about these products. In particular, FDA has sought unredacted complaints from Metabolife as well as the raw data from the six month Boozer Daly study that was conducted at the request of the makers of dietary supplements containing ephedra. These data are being reviewed by the Agency and its outside experts, along with the adverse event information the Agency has received from Metabolife and in its own CAERs system. All three of FDA's outside reviewers of the Boozer Daly weight loss study have raised serious concerns about that study's ability to prove the safety of these dietary supplements containing ephedra.

At this time, we have massed a significant data set and conducted substantial analyses on ephedrine alkaloids, and as you know we have issues a proposed rule on labeling that also takes the unprecedented step of asking for comment on whether data exists to indicate that these products pose a significant and unreasonable risk to the public health. This data set includes AERs from FDA's Medwatch and from Metabolife as well as detailed assessments by Agency experts and outside experts at RAND that have identified ephedra as product of particular concern. But as GAO noted, AERs while indicative of sentinel events are not alone enough to make a scientific determination about the safety of ephedra. In addition, our review of the Boozer Daly study has raised additional significant concerns about the mechanisms of action for ephedra and we are taking a hard look at this. At this point, we are in the final stages of our deliberative review related to finalizing our rule, so while I cannot get into the specific of that process or the anticipated outcome, I want to emphasize that we are committed to moving forward expeditiously to make a determination that is well grounded in the scientific evidence we have and that is protective of the public health in accordance with DSHEA. Meanwhile, under my leadership the Agency will continue to use available resources to target false and misleading dietary supplement claims

Mr. Chairman, thank you for this opportunity to testify. I am happy to answer your questions.

Last Revised: November 14, 2003