Testimony of
Cynthia T. Culmo, R.Ph., Chairperson
Drugs, Devices, and Cosmetics Committee
Association of Food and Drug Officials
Before
Subcommittee on Oversight of
Government Management, Restructuring, and the District of Columbia
Committee on Governmental Affairs
United States Senate
Washington, D.C.
July 31, 2002
Testimony: When Diets Turn Deadly: Consumer Safety and Weight Loss Supplements
The Association of Food and Drug Officials Board of Directors, hereinafter referred to as AFDO, is pleased to offer written comments in addition to the oral comments presented by Cynthia Culmo, on July 31, 2002, to the Senate Governmental Affairs Subcommittee on Oversight of Government Management, Restructuring, and the District of Columbia hearing entitled, “When Diets Turn Deadly: Consumer Safety and Weight Loss Supplements.”
AFDO is a 106 years old not for profit association that represents federal, state, and local regulatory members as well as industry associate members. AFDO develops and promotes uniform laws, regulations, and guidelines that result in more efficient and effective regulation along with enhanced cooperation and communication. AFDO has been a leader and active participant in many regulatory initiatives during the past many years at both state and federal levels. An activity of particular interest to this committee relates to our efforts to address the public health issues associated with products containing ephedrine; especially those labeled as dietary supplements which are advertised and promoted for weight loss, performance enhancement, and increased energy.
Our membership has many longstanding concerns related to the public health risks associated with dietary supplement products containing ephedrine alkaloids (hereinafter referred to as ephedrine) and other dietary supplements promoted for weight loss that contain stimulants. We last adopted a resolution in June 2001, urging the FDA to expedite a policy decision on this issue and to provide effective regulatory guidance on this difficult public health problem. We have submitted other resolutions concerning ephedrine containing dietary supplements in previous years. Considering the extensive documentation of serious adverse health effects associated with ephedrine-containing dietary
supplement products along with more recent developments, AFDO believes it is critical that FDA take strong and decisive actions regarding products that contain ephedrine. We submitted our June Resolution and request to Dr. Bernard Schwetz, then Acting Principal Deputy Commissioner, on September 18, 2001.
In an effort to stay focused on the issues at hand, we offer comments to the questions you posed regarding dietary supplements promoted for weight loss:
As a public health official, what has been your experience with weight loss supplements?
The States and the FDA continue to receive serious adverse event reports (AERs). There are hundreds, if not thousands, of serious AERs for a plethora of products containing multiple pharmacologically active ingredients (multiple stimulants, diuretics, laxatives, metabolic blockers or stimulators, hormones, etc.). Many of the weight loss supplements contain herbs which have laxative effects such as senna, cascara, aloe, and rhubarb root. Labels of these supplements frequently do not warn consumers that ingredients in the product have laxative effects. Nor is there any mention of the dangers related to the daily consumption of such cathartic laxatives (e.g., severe electrolyte disturbances and heart arrhythmias). There are several supplements (some containing "chitin") that claim to "bind" fat so you can eat anything you want and "still not gain weight." This claim is not only unsound, but also provides potentially unsafe advice. Furthermore, the chitin in these products is commonly extracted from shellfish, but contains no warning of this fact on the product labels to alert those with shellfish allergies.
To support this concern with polyingredients in dietary supplement formulations, Bill J. Gurley, Ph.D., Associate Professor, Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences has reported that Ephedra-containing dietary supplements are rarely formulated as single ingredient products. Along with ephedrine alkaloids (ephedrine, pseudoephedrine, methylephedrine, norephedrine [phenylpropanolamine]) present in ma huang, most products also contain natural sources of caffeine (guarana, kola nut, green tea), additional stimulants (synephrine), and a host of other botanicals and amino acids (1). The pharmacokinetics (blood levels) of ephedrine following ingestion of supplements formulated as concentrated ephedra extracts is indistinguishable from that of synthetic ephedrine found in conventional dosage forms (2, 3). Thus, ephedrine and other sympathomimetic amines from botanical sources share the same risks for and consequences of interactions with conventional stimulants, hypoglycemic agents, antihypertensives, and monamine oxidase inhibitors that have been experienced with pharmaceutical products containing these ingredients. There are additional safety concerns for ephedra-containing supplements because of interactions among the individual phytochemical components. Thus these dietary supplement products pose risks above and beyond those seen with drugs containing ephedrine.
From a pharmacodynamic standpoint, ephedrine and caffeine each potentiate the other’s cardiovascular and central nervous system stimulant effects, thereby increasing the risk of adverse events in susceptible individuals (1). Because of this enhanced health risk, the FDA has not allowed ephedrine/caffeine combinations in conventional OTC products since 1983 (1). Other phytochemical components in ephedra-containing dietary supplements appear to exacerbate ephedrine/caffeine pharmacodynamics. Catechins, a class of polyphenolic compounds found in high concentrations in guarana and green tea enhance the sympathetic activity of ephedrine and caffeine by inhibiting catechol-O-methyltransferase (4). Catechins are also readily absorbed into the systemic circulation and elicit their own inotropic effect on the heart (5, 6). Another common ingredient, Citrus aurantium (bitter orange) extract, provides an additional source of sympathomimetics (synephrine, octopamine), and has been shown to be arrhythmogenic in laboratory animals (1, 7). Recently, it was shown that multi-component ephedra-containing dietary supplements containing caffeine, catechins, and Citrus aurantium are more toxic in animal models than ephedra alone (8). St. John’s Wort is yet another ingredient in some weight loss products, which when combined with ephedrine can increase the risk for serotonin syndrome. Taken together, these findings lend credence to adverse events reported in the medical literature and those submitted to the FDA’s MedWatch program (9, 10).
As reported many times over the last eight years, dietary supplements containing ephedrine alkaloids from ephedra and other botanicals are commonly marketed for weight loss. People continue to experience serious adverse reactions from these products, including disabling or fatal heart attacks, strokes, seizures, and psychoses. The misleading and deceptive labeling and marketing for these products, which will be discussed later in the comments, may also be contributing to these adverse events.
Some weight loss dietary supplements make outrageous claims, e.g., "Exercise in a Bottle" marketed by former Dodger Steve Garvey claimed to be equivalent to exercising, or “Body Solutions” and the “Hollywood Diet” that each claim “Lose weight while you sleep.” People at a minimum were and are defrauded by the advertising for these products. Eventually “Exercise in a Bottle” was removed from sale, but only after extensive resources were devoted to these efforts by the regulatory agencies.
Drug manufacturers have requested permission to make claims similar to those made for dietary supplements. Claims for over-the-counter (OTC) drugs cannot go outside a prescribed set of scientifically validated indications. Therefore, drug regulatory requirements prohibit such claims due to inadequate substantiation, yet dietary supplements routinely make these unsubstantiated claims and promotions. Consumers confuse dietary supplements promoted for weight loss with over-the-counter drugs which must be proven to be safe and effective while there are no comparable requirements for their dietary supplement counterparts. Nonetheless, dietary supplement products make safety and efficacy claims in their labeling and advertising.
Also, data on complaints from dietary supplements cannot be adequately evaluated since dietary supplement manufacturers are not required to record, investigate, or report complaints and/or injuries, unlike drug manufacturers. Because of civil proceedings involving personal injury, regulatory agencies are aware that dietary supplement companies are receiving thousands of reports of injuries related to their products, none of which have ever been reported to the FDA by the manufacturers. Yet they continue to report/advertise publicly that their products are safe and they haven’t received reports of serious injuries. This was somewhat addressed two years ago, at the US Public Health Service meeting, on August 8, 2000, by Mr. Michael McGuffin, President, American Herbal Products (AHPA). He summarized an ephedra survey conducted by Arthur Andersen, LLP auditors on behalf of AHPA. He reported at this meeting the survey reflected a total of 25 serious AERs which were reported to the 14 respondents in 1999 and a total of 66 serious AERs were reported to the 14 respondents for the five-year period from 1995 to 1999. Upon questioning, he didn’t know if they had been reported to the FDA, but FDA can confirm they’ve never received an AER from a dietary supplement manufacturer on these products. Interesting to note on this topic, Mr. McGuffin stated on ABC’s Nightline, July 2000, “…but it would be just in—in—unbelievable if a manufacturer had any evidence that its product had—if, in fact, produced serious adverse effects, to think that they would not inform the agency. “ Hard to believe, but true. Additionally, and perhaps not so surprising now, many problems with the validation and accuracy of that survey were discovered and disclosed.
Another issue concerning weight loss dietary supplements is that the industry routinely claims their products are not drugs, but they do advertise them as drugs under the guise of medical advice. Several firms have opted to print their product information in the Physician’s Desk Reference for Nonprescription Drugs and Dietary Supplements (PDRNDDS) (previously the Physician’s Desk Reference for Nonprescription Drugs). It should be noted that all material published in the PDR is provided to the publication and paid for by the manufacturers and is not reviewed or edited for content. The foreward to the 1999 PDRNDDS states:
“ The function of the publisher is the compilation, organization, and distribution of product information obtained from manufacturers. Each product description has been prepared by the manufacturer and edited and approved by the manufacturer’s medical department, medical director, and/or medical consultant.
In organizing and presenting the material in Physicians’ Desk Reference for Nonprescription Drugs and Dietary Supplements the publisher does not warrant or guarantee any of the products described, or perform any independent analysis in connection with any of the product information contained herein. Physician’s Desk Reference does not assume, and expressly disclaims any obligation to obtain and include any information other than that provided to it by the manufacture.”
Therefore, the PDRNDDS is clearly a source of advertising and product information for dietary supplement manufacturers since there is no regulatory requirement for a patient package insert or labeling beyond that described in the Dietary Supplement Health and Education Act. The primary concern is that consumers will review this material and assume the ‘science’ of the content is equivalent to the information in the product descriptions submitted to PDR for prescription drug products; content that is guaranteed to have been previously reviewed by a source other than the manufacturer. A mislead consumer may well be the result.
DSHEA has resulted in a gross contradiction to its authors’ prediction of a healthier nation pursuant to the total unregulated availability of dietary supplements. The reality seems to be quite contrary to the predictions. As the industry has grown enormously since DSHEA, and the types and numbers of “dietary supplement” labeled products have proliferated, there is no evidence that the health of Americans has improved due to increased access to supplements. As much as the dietary supplement industry has proclaimed the efficacy of their weight loss products, obesity remains a critical public health issue, and in fact, one that continues to increase in numbers. Not only has there not been any reportable improvement in the country’s overall health, but quite the contrary, since the passage of DSHEA, reports of AERs have poured into the States and the U.S. Food and Drug Administration (FDA), even though it is estimated by Dr. Alexander Walker that less then one percent (1%) of the adverse events are reported to the FDA voluntary reporting system. Prior to DSHEA, most States report few if any AERs associated with dietary supplements to their agencies. In addition, the American Association of Poison Control Centers (AAPCC) did not record AERs for dietary supplements or herbs prior to DSHEA. (Attachment 1) If they did receive any, they were coded as drug AERs.
Did the passage of DSHEA in 1994 affect your ability to perform your job?
YES! DSHEA placed the burden of determining and proving health risks and disproving claims for weight loss products on regulatory agencies rather than on the firms marketing the products. This has made enforcement difficult and costly. For drugs, FDA can collect data on safety via the mandated pre-market safety studies and the post-marketing AERs. For dietary supplements, neither is required and both mechanisms are vehemently objected to by the dietary supplement industry.
DSHEA prevents regulatory agencies (and also discourages manufacturers) from evaluating risks versus benefits of dietary supplements. Risk/benefit evaluations are important components in this country’s regulation of drugs, but are not required for these dietary supplement labeled products that also contain potent pharmacologically active ingredients, many of which are exactly the same synthetic ingredients found in drugs. DSHEA has added confusion because dietary supplements regulated as foods should not pose recognized health risks and should not be promoted to prevent or treat diseases. Yet serious risks and safety concerns have arisen with the proliferation of products labeled as dietary supplements which contain pharmacologically active ingredients.
Many products use DSHEA to market conventional foods, e.g., beverages, cereals, and snack bars, that contain ingredients like ginkgo biloba, ephedrine, senna, and yohimbine commonly found in dietary supplements, but not specifically allowed in conventional foods where, prior to DSHEA, all ingredients had to be either approved food additives, generally recognized as safe, or prior sanctioned for safety.
DSHEA did not change the regulation of conventional foods, but has prompted manufacturers of some conventional foods, in their desire to obtain a portion of the dietary supplement market, to include these unapproved ingredients in their products and now label them as dietary supplements. Consumers, regulators, prosecutors, and juries are confused by the distinctions and overlaps between conventional foods and dietary supplements making states reluctant to take actions unless faced with flagrant violations that impact public health. Even then there are resultant political battles which adversely affect the abilities of the regulatory agencies to take these actions. The enforcement actions by the States are labor and time intensive, are done with great difficulty and fierce battles with industry and their political supporters. There are ongoing conflicts between good public health and industry’s economic needs with politics frequently serving as the referee. The States and the federal government's failure or inability to take regulatory actions results in more conventional foods and dietary supplements in the marketplace containing ingredients that have not been thoroughly evaluated for safety. These conventional foods often display label claims allowed for dietary supplements under DSHEA, but not allowed for conventional foods. States also fail to take actions because of the confusion about the distinctions and overlaps between conventional foods and dietary supplements. Any attempt by FDA to clarify the confusion via regulations seems to be pre-empted or prevented by HHS, Congress, and/or the White House.
Dietary supplements are intended for human consumption. There is no provision in DSHEA for the use of the dietary supplements in animal feed, yet members of the American Association of Feed Control Officials report the appearance of vast numbers of these products on the market. The content of animal feed is tightly regulated. Any product designed for ingestion by animals is either a food or a food additive. Products marketed as dietary supplements must fit into one of those two categories, and frequently, they do not. Of special concern are those products targeted towards food producing animals that are intended for human consumption. A significant portion of time is now spent by feed control officials “chasing down” products that are in violation of feed regulations.
It is a federal responsibility to address DSHEA regulations. The States look to FDA and FTC, since they have (potential) resources that are unavailable to the States, to address these problems. But, politics and bureaucratic entanglements have prevented FDA and FTC from accomplishing their responsibilities. It is easier for the states to ignore small problems, hoping FDA or FTC will act, than to expend resources in long, drawn-out investigations including possible industry lawsuits on a case-by-case basis. As AFDO has stated before, it’s time to place the politics and money aside and act as the responsible public health agency that the general public considers FDA to be, and to which it is charged.
Have you seen evidence of harmful outcomes related to supplement use? What evidence?
Yes! AFDO would be more than remiss if Ephedrine wasn’t discussed as the first example of harmful outcomes related to supplement use and the evidence associated with these harmful outcomes. As a quick reminder, ephedrine is extremely close in chemical structure to phenylpropanolamine and methamphetamine. (attachment 2) It is essentially a legal amphetamine-like substance and becomes even more so when combined with other stimulants.
Many States have received AERs associated with weight loss supplements which contain ephedrine, and/or other stimulants. These include ingredients such as caffeine, theobromine, synephrine, forskolin, sida cordifolia, epitonin, citrus aurantium, yohimbe/yohimbine, and others. (attachment 3) Most of these the consumer, and others (medical professionals, public health officials, even some industry members), are completely unaware that they are potent stimulants. Some products (i.e. Xenadrine, NoPhedra, EAS Beta Blast, CytoTrim, etc.), or product regimes (Herbalife’s Quick Start Gold Pack), may contain up to 161 ingredients or more! (attachment 2) Who knows what these multitudes of ingredients are doing within your body! They are quite simply a chemical soup waiting to have a time-bomb effect on unsuspecting persons. The ingredients interact with themselves, interact with other drugs, and there are drug-disease interactions.
California and other states have received reports and investigated serious injuries and deaths from dietary supplements. A woman in California used many different dietary supplements. She suffered from liver failure and subsequently died before receiving a liver transplant. Her death certificate listed the cause of death as polypharmacy from dietary supplements. This is not unlike other reports received by other states.
In California, two other deaths were investigated from bufotoxin, sold as an herbal product. One was due to misidentification of the bufotoxin and the other was due to accidental overdose. California also has investigated several cases of renal failure resulting from lack of Good Manufacturing Practices (GMP) leading to incorrect use of an herb that contained aristolochic acid, a renal toxin.
Other evidence of harmful outcomes has been related to contamination of these dietary supplements. FDA conducted a random sampling of products containing one of the 40 herbs commonly misidentified as artistolochic acid. 38 products were sampled and 18 of these products had aristolochic acid. There are more examples of heavy metal(s) contamination, filth contamination, and other adulterations.
Consumers are not only physically harmed and at risk with some of these products, but they are also harmed and deceived by the fraud associated with many of the products. When products containing ingredients like sea salt or dissolved oxygen are promoted to improve health and slow aging at a cost of hundreds of dollars a month for products with no nutritional or therapeutic value, and there is no science to back their claims, many suffer economic harm. Reports have been received where consumers stop using conventional vitamin and mineral supplements that provide real health benefits at minimal costs in favor of hyped supplements purported to contain some "wondrous" ingredient(s), or worse, discontinue prescription medications in favor of these miracle dietary supplements.
As a representative of the Association of Food and Drug Officials can you tell us what is happening at the state level with respect to weight loss supplement products (examples of states that are attempting to regulate, different approaches, obstacles to appropriate regulation, successes, shortcomings)?
More than half the states have enacted or attempted to enact some form of legislation regarding ephedrine, some of which addressed dietary supplements with ephedrine. (attachment 4) Ohio and Nebraska had legislation regulating dietary supplements as prescription drugs, but were extensively lobbied by the dietary supplement industry and legislation was repealed or amended to include much lesser regulation. Texas, over a period of six years, attempted unsuccessfully to restrict dietary supplements containing ephedrine to a practitioner’s prescription. Obstacles to this regulation included heavy lobbying by the industry and their representatives, intervention of state and federal legislators, and documentation of extensive spending on these efforts by industry and their lobbyists. Texas’ fourth attempt to regulate dietary supplements with ephedrine did not propose to restrict the availability of ephedrine containing products, nor did they set dose restrictions. The rules outlined labeling requirements and warnings. Although the warning and labeling requirements represented some progress in protecting the public health, and in essence resulted in a national outcome for most of these products (the majority of these products are now labeled pursuant to Texas’ requirements and are distributed nationwide), the States and the FDA continue to receive serious AERs. Additionally, industry continues to challenge efforts to appropriately label products with warnings, and opposes efforts to require mandatory reporting of adverse events.
In 1998, California, after great effort, adopted regulations requiring dietary supplements containing ingredients with stimulant laxative effects, of which the most common products were those marketed as weight loss products, to display a label notice informing consumers not to use the product if they developed diarrhea, abdominal pain, or loose stools. Additionally there is legislation pending in California that would require dietary supplements containing ephedrine alkaloids, commonly marketed for weight loss, to list on the label the quantity of ephedrine alkaloids from herbal extracts, specific warnings, and FDA's MedWatch adverse event reporting line. This legislation would also prohibit sales to minors of dietary supplements containing ephedrine alkaloids. The Governor of California vetoed similar legislation two years ago stating that the regulation of dietary supplements was a matter of interstate commerce and the responsibility of the U.S. Congress. This veto also just happened to coincide with the documented significant contribution by Metabolife, Inc. to the Governor’s campaign. The obstacles encountered by the States, FDA, and the FTC clearly demonstrate the issue of economics and politics versus public health.
The California Department of Health Services (DHS), along with many other states, works closely with their poison control centers in monitoring adverse reactions related to dietary supplements. Once an adverse reaction related to a dietary supplement has been identified, DHS, or the other state agencies, conducts a thorough investigation to identify the cause of the adverse reaction including obtaining the medical history of the patient, laboratory analysis, epidemiology study if necessary, and follow up with the distributor, importers and/or manufacturer. AFDO emphasizes that only regulatory agencies are equipped to conduct appropriate and complete dietary supplement adverse event investigations. Only regulatory agencies have lawful authority to oversee the manufacturing, distribution, professional practice, and public health areas. They can provide unbiased evaluations of the adverse events and share the results with the dietary supplement industry and the public.
California DHS reports also working closely with the dietary supplement industry to seek their cooperation on different issues. DHS initiated the Asian Medicine Operation Cooperation in the early 1990’s to educate the users on the risk of Asian herbal products and to convince retailers and importers to remove unsafe products from sale, and manufacturers to reformulate and relabel their products to make them safe for use. This cooperative effort has achieved success in reducing exposure within the ethnic communities to unsafe herbal medicines, which have been associated with illness, death, and injury, and to do so with minimal impact upon cultural traditions.
Can you comment on how the US system of regulation for weight-loss supplements compare with other nations?
The United States (US) has developed a rigorous and widely emulated system for evaluation and approval of new drugs. The United States, however, never emulated such countries as Japan and Germany, which accommodated national traditions by developing special regulations for traditional medicines (and dietary supplements in general). In Europe, the European Union (EU) is developing specific regulations on botanical products under their DRUG system. The EU Directives regulate the manufacturing, distribution, marketing and approval of herbal products in addition to requirements for post market surveillance. Dietary supplements are generally prescription products in Europe and they aren’t formulated, promoted, marketed, nor sold as they are in the US.
In China, one of the world’s largest herbal producers, herbs used in Traditional Chinese Medicine are regulated as drug products. China has GMP regulations in place for manufacturers of herbal and dietary supplement products. China has also recently adopted good agricultural practices (GAP) for herbal products. In the U.S., dietary supplements are regulated as foods. There are currently no adopted GMPs and no proposal on GAPs.
In January 2002, Health Canada requested a recall of certain ephedrine containing products because a risk assessment concluded that these products posed a serious public health threat. Reports of adverse events included stroke, heart attacks, heart rate irregularities, seizures, psychoses and deaths. Currently in Canada, the maximum allowable dose for Ephedra/ephedrine in products is 8 mg ephedrine per single dose or 32mg ephedrine per day. Products containing Ephedra which were marketed for traditional medicine, were allowed to continue to be available, provided the products did not contain caffeine, and that the ephedrine content did not exceed 8 mg per dose up to a maximum of 32 mg per day. A previous press release issued by Health Canada in June 2001 advised Canadians not to use products containing the herb Ephedra, in combination with caffeine and other stimulants, for purposes of weight loss, body building or increased energy.
In 1999, Health Canada established the Office of Natural Health Products to ensure the safety of traditional herbal products, vitamins and mineral supplements, and homeopathic preparations. Currently, natural health products are regulated in Canada as either foods or drugs, however, new rules and modifications to Canada's Food and Drug Law will separate these products into their own regulatory category with a separate framework of enforcement. A proposed regulatory framework was set out in December 2001. The latest action of the Office of Natural Health Products was the April 2002 issuance of a draft guidance document entitled "Good Manufacturing Practices for Natural Health Products."
Are there any changes to the current law that you think would help ensure greater consumer protection?
There are several changes to the current law that AFDO believes would ensure greater consumer protection:
• Prohibit multi-ingredient products, or limit to only one active ingredient per product. The polypharmacy within a bottle is a significant contribution to the harmful effects of these dietary supplements;
• Require manufacturers and distributors to register with the FDA. Register products with FDA so that information about these products and their ingredients is readily available. If there is a formulation change, companies must submit a new registration before distribution;
• Mandate AER reporting;
• Create a single adverse event system within FDA so that product interactions can be readily identified and appropriately addressed. Make information from this system publicly available in a manner that health professionals, consumers and industry can readily access and use.
• Create an EXPERT panel within FDA with the appropriate scientific expertise to review new dietary supplement ingredients applications. Provide authority for FDA to write regulations for new dietary supplement ingredient approvals;
• Fund FDA! Fund FDA! Fund FDA! – user fees from this multi-billion dollar industry to support the program;
• Create a specific Center within FDA for traditional medicines and Dietary Supplements for regulatory oversight – the public health focus for these products should be FDA, not NIH. Change NIH’s authority and emphases so that research efforts focus on safety first, in addition to effectiveness research. When these changes are made, include funding for it;
• Support the utilization of AERs through all Congressional actions and publications. Congress funded FDA MedWatch & AERs – these are used repeatedly by FDA in actions to assure product safety. However, for dietary supplements it has been repeatedly stated that AERs cannot be used as the basis of actions to protect the public health. If the FDA can’t use AERs, then the gold standard for safety should apply – i.e., adequate and well-controlled clinical trials affirming safety before the product can be marketed. The language for “significant or unreasonable risk” needs clarification and interpretation. AFDO also believes creating an EXPERT Medical Panel to review AERs would be beneficial, if the panel actually carries some authority for action.
• Labels of all supplements except those containing only vitamins and minerals at 100 percent or less of the Reference Daily Intake should display FDA's MedWatch number and Internet address in a phrase similar to: "To report serious adverse events call 1 800 332-1088 or via the Internet at some short, convenient Internet address.” Requiring that labels of dietary supplements display FDA's MedWatch number and Internet address, if they contain ingredients not essential in human nutrition, assures that consumers know who to call if they experience a serious adverse reaction. This requirement would improve FDA's awareness of adverse events experienced by individuals using these supplements.
These changes would at a minimum improve the safety of these products for the general population and still allow the industry to sell their dietary supplements.
FDA has already effectively removed phenylpropanolamine, a compound with similar pharmacological effects and a partial metabolite of ephedrine, from the marketplace based on recommendations of its own Advisory Committee and a Yale University School of Medicine study linking the drug to strokes. Yet since 1994, more strokes associated with ephedrine containing dietary supplements have been reported to FDA's MedWatch than for the almost 30 year period phenylpropanolamine was on the market. AFDO believes ephedrine should be considered equally dangerous for the same reasons and evidence.
On September 9, 2001, the National Football League (NFL) announced it has added ephedra, a genus of herbs from which the dietary supplement ephedrine is extracted, to its list of banned substances. The league based their decision on the available scientific evidence and the fact that three NFL players who died this year were found, on autopsy, to have ephedra in their systems. NFL league spokesman Greg Aiello, quoted in a Los Angeles Times article stated that “the purpose is to protect our players who operate in a very unique and stressful environment”. Aiello also said “because of the research that’s out there on ephedra, the commissioner [Paul Tagliabue] has reached the conclusion that it shouldn’t be used by our players.”
As evidenced by the previous paragraph, a non-healthcare professional, when presented with the evidence, concluded that ephedrine-containing dietary supplements promoted and marketed as "safe and natural" for uses such as weight loss, body building and increased energy, are dangerous.
It has also been alleged that there are healthcare professionals who tout the safety of these products are paid by industry to review the research, data, and FDA ephedra docket. AFDO believes that those healthcare professionals without such ties who have reviewed the research, data, and docket have concluded the products are dangerous, even when taken as directed. There are important issues of endorsements, professional conflict and appropriate disclosure, of which the public is generally unaware, that should be addressed.
Trustee J. Edward Hill, M.D., of The American Medical Association (AMA) stated, “Tobacco is the only product sold in America that kills when used as directed by the manufacturer.” 2 Based upon the data and the statistics documented in the FDA docket on ephedrine adverse events reported, over 90% of the adverse events occurred when the products were taken as directed or at lesser doses. These statistics would seem to indicate that tobacco is no longer the only product that should be considered dangerous when used as directed by the manufacturer.
Another organization, the Public Citizen Health Research Group, very recently petitioned FDA via Secretary Thompson to ban the production and sale of dietary supplements containing ephedrine alkaloids. Their petition thoroughly and adequately addresses the data, statistics, research and science associated with our mutual concern regarding these products.
We would like to thank you for the opportunity to provide you with our comments, and for your time and consideration of this request. It is in the interest of public health safety that AFDO urges Congress to assist the FDA, to act expeditiously, and to take actions in the true sense of good public health protection.
References
1. Gurley BJ, Gardner SF, Hubbard MA. Content Versus Label Claims in Ephedra-containing Dietary Supplements. Am J Health Syst Pharm. 2000; 57:963-969.
2. Gurley BJ, Gardner SF, White LM, Wang P. Ephedrine Pharmacokinetics After the Ingestion of Nutritional Supplements Containing Ephedra Sinica (ma huang). Ther Drug Monit. 1998; 20:439-445.
3. Gurley B. Extract Versus Herb: Effect of Formulation on the Absorption Rate of Botanical Ephedrine from Dietary Supplements Containing Ephedra (ma huang). Ther Drug Monit. 2000; 22:497.
4. Dulloo AG, Seydoux J, Girardier L, Chantre P, Vandermander J. Green Tea and Thermogenesis: Interactions Between Catechin-polyphenols, Caffeine and Sympathetic Activity. Int J Obesity. 2000; 24:252-258.
5. Van Amelsvoort JMM, Van Het of KH, Mathot JNJJ, Mulder TPJ, Wiersma A, Tijburg LBM. Plasma Concentrations of Individual Tea Catechins After a Single Oral Dose in Humans. Xenobiotica. 2001; 31:891-901.
6. Kubota Y, Umegaki K, Tanaka N, Mizuno H, Nakamura K, Kunimoto M, Shinozuka K. Safety of Dietary Supplements: Chronotropic and Inotropic Effects on Eat Atria. Biol Pharm Bull. 2002; 25:197-200.
7. Calapai G, Firenzouli F, Saitta A. Antiobesity and Cardiovascular Toxic Effects of Citrus Aurantium Extracts in the Rat: A Preliminary Report. Fitoterapia. 1999; 70:586-592.
8. Gurley BJ, Ali S. Toxicity of Multi-component Ephedra-containing Dietary Supplements. [poster #W4075] Presented at the American Association of Pharmaceutical Scientists annual meeting, Denver, CO, October 24, 2001.
9. Haller CA, Benowitz NL. Adverse Cardiovascular and Central Nervous System Events Associated with Ephedra Dietary Supplements Containing Ephedra Alkaloids. N Engl J Med. 2000; 343:1833-1838.
10. Samenuk D, Link MS, Homoud MK, Contreras R, Theohardes TC, Wang PJ, Estes NAM. Adverse Cardiovascular Events Temporally Associated with Ma Huang, an Herbal Source of Ephedrine. Mayo Clin Proc. 2002; 77:12-16.
