Docket Management
Docket: 95N-0304 - Dietary Supplements Containing Ephedrine Alkaloids
Comment Number: EC -1370

Accepted - Volume 326

Comment Record
Commentor Mr. Scott Kumpf Date/Time 2003-04-04 18:49:36
Organization Natural Balance, Inc.
Category Dietary Supplement Industry

Comments for FDA General
Questions
1. General Comments March 27, 2003 Dockets Management Branch HFA-305 Food and Drug Administration 5630 Fishers Lane, Room 1061 Rockville, MD 20852 Dear Sir or Madam: Background We thank the FDA for the opportunity to provide public comment regarding Docket: 95N-0304 - Dietary Supplements Containing Ephedrine Alkaloids. Natural Balance, Inc. was one of the original companies in the dietary supplement industry to sell ephedra-containing products. Over the 20 years we have been in business, we have sold literally millions of ephedra-containing tablets and capsules and have had literally thousands of customers who have testified to the success they have had with our ephedra-containing products. We believe, based on our extensive actual experience with these products, that ephedra-containing products are safe and effective when used properly. We have been dismayed by the increasingly negative media coverage of ephedra-containing products. Much of it is sensationalistic and uninformed. Despite the negative coverage, it is the FDA’s responsibility to make decisions about the products it regulates based on sound scientific evidence and not sensationalized news stories. It is exactly because of the lack of a sound scientific basis on which to proceed that the FDA was forced to withdraw the prior proposed regulation regarding ephedra. The GAO’s analysis of the AER’s upon which FDA was relying clearly established the lack of any credible and scientifically sound connection between these largely anecdotal reports and the action FDA proposed taking. From our perspective, little has changed on the scientific front which would support the action FDA now proposes. In fact, if anything, the evidence has gotten stronger that ephedra-containing products can indeed to be used safely and effectively, especially for weight loss. Therefore, we urge the FDA to withdraw the proposed regulation, which would represent the single most onerous regulatory scheme imposed on any non-prescription food, drug or supplement. It is hard to logically reconcile the warning proposed by the FDA on ephedra-containing products, with their demonstrated benefits, while tobacco products with no health benefit whatsoever and which have claimed the lives of millions, are sold with virtually no warning at all. We call upon the FDA to have the courage to act correctly, not politically. As a supplement manufacturer, it has always been our position that claims and public policy regarding dietary supplements should be based on a thorough analysis of the scientific literature. It is our view that the best way to enhance performance and/or improve body composition profiles is through prudent exercise and dietary modification. Most people can reach their fitness, health, and/or body composition goals through proper diet and exercise. However, we also know that that some nutrients have been shown in clinical studies to enhance exercise and/or training adaptations. Further, in obese populations, exercise and diet interventions alone may not be enough to promote as much weight loss as needed to reduce the medical risk related to obesity. Therefore, we understand that there may be medical interest in determining additive and/or alternative means of helping people gain and/or lose weight. It is our view that recommendations about exercise, training, supervision of athletes, and dietary supplementation should be based on science not speculation or political pressure. A decision whether or not to use nutritional supplements should be based on analysis of available clinical studies that have evaluated the safety and efficacy of the nutrient as well as whether use of a supplement is legal or not in a particular sport. It is our view that athletes should only consider use of supplements that have been shown to be effective and safe in clinical trials and that are legal for use in their sport. Individuals that are not regulated by sport governing bodies should also only consider use of supplements that have been shown to be safe and effective. We recommend that anyone starting an exercise program, diet, and/or considering use of a dietary supplement consult with a knowledgeable physician that is familiar with the scientific literature in order to determine if any underlying medical condition may be contraindicated for the exercise, diet, and/or a supplementation program. Research over the last 20 years has revealed that some nutrients may play a role in reducing risk to certain diseases. Physicans and health care practitioners are gradually becoming educated on this point and we believe that the traditional medical community is increasingly educated on the proper role supplements can play in human health. We believe it is part of our responsibility, as a leading manufacturer of dietary supplements, to help educate individuals about the safety and efficacy of nutritional supplements so they can make an informed decision about whether or not to use them. Obviously, we feel that people should have the right to take dietary supplements as long as they are aware of the potential risks and benefits and so long as the supplement does not pose a significantly greater health risk than other over-the-counter medications and common lifestyle practices. We join with other manufacturers and the leading trade associations in our industry in calling upon the Federal government to increase funding to examine the safety and efficacy of nutrition products. Products found in research to be unsafe and/or ineffective should be banned from sale and/or include sufficient warning labels to properly inform the public about the associated risk of taking nutritional supplements. We feel, however, it is important to place risks of taking nutritional supplements, if any, in proper perspective among the many common products that are available on the market and widely used by Americans. Comments Regarding Proposed FDA Regulations Regarding Ephedra We understand that the issue of availability of dietary supplements containing ephedra alkaloids is controversial. The easy and politically expedient position might simply be to concur with the FDA’s proposed warning and limitations on marketing claims regarding dietary supplements containing ephedra. Nevertheless, we feel it is important for the FDA to consider the following points regarding the proposed FDA regulations regarding use of dietary supplements containing ephedra: (1) As the Rand report concurs, numerous studies indicate that dietary supplementation of ephedrine/caffeine or herbal ephedra can safely promote weight loss in healthy but overweight populations [1-21]. Ephedrine/caffeine supplementation typically allows for about a 1-2 pounds per month greater weight loss than individuals taking placebos with or without exercise and dietary modification. The Rand report indicated that studies have only been conducted for up to 6 months. However, it should be noted that in a recent study presented at the IX International Congress on Obesity in Sao Paolo, Brazil supplementation of ephedrine/caffeine (20 mg/day of ephedrine and 200 mg/day of caffeine) for 11 months after a 4-week dietary weight loss program allowed subjects to maintain weight loss while subjects taking a placebo regained the weight [22]. No side effects were reported. Generally, when side effects were reported in these studies, they have been minor and consistent with the incidence of side effects reported in placebo groups. (2) The primary mechanisms of weight loss appears to be due to synergistic effect of ephedrine/caffeine on modestly increasing resting energy expenditure (typically 5 – 10 kcal/hour or 120 – 240 kcals/day), an increase in fat metabolism, and suppression of appetite. While this increased energy expenditure may help promote a slow loss in body fat (i.e., 1-2 pounds per month), such an increase in caloric expenditure in response to ephedrine/caffeine supplementation would have minimal, if any, measurable effects on core temperature. In comparison, exercise typically increases energy expenditure by 600 – 1,200 kcals/hour depending on intensity. It is our view that claims suggesting that ephedrine/caffeine supplementation significantly increases thermal load is not supported by available literature. (3) Studies have shown that ephedrine or ephedra supplementation either mildly increases heart rate (an average of less than 5 beats/min) or blood pressure (an average less than 4 mmHg) [18] or has no impact on resting cardiovascular dynamics [20]. There is no evidence from clinical studies that ephedrine supplementation increases peak heart rate, peak blood pressure, or increases the prevalence of cardiac arrhythmias in comparison to subjects taking placebos [18]. Further, there is no evidence that short-term ephedra supplementation causes a marked increase in resting heart rate, blood pressure, or cardiovascular function as is commonly describe in media reports [20]. The changes in heart rate and blood pressure are small in consideration that cardiac reserve is typically 100 – 140 beats/min above resting heart rate and systolic reserve is typically 60 – 80 mmHg above resting during maximal exercise in normal individuals. (4) Studies comparing the safety of ephedrine/caffeine supplementation to other weight loss medications and/or over-the-counter drugs have revealed similar or greater efficacy and/or safety [23-25]. It is our view that any warnings about ephedra must be placed in proper context to the risks of common behaviors like taking aspirin, ibuprofen, other weight loss medications, and/or consuming alcohol and smoking cigarettes. Further, if the FDA places warning labels on dietary supplements containing ephedra alkaloids, it should also do so on over-the-counter medications that contain ephedrine and common products that have been reported to have similar or greater risk profiles (e.g., aspirin, ibuprofen, alcohol, etc). (5) Concerns over the safety of ephedra containing supplements have been voiced for a number of years. The basis of this concern has primarily come from case reports submitted to the FDA’s Adverse Event Monitoring System (AEMS). The AEMS was a voluntary system of reporting perceived side effects related to taking nutritional supplements. Approximately 1,500 reports to the AEMS since 1993 have indicated that individuals who were taking ephedra containing supplements (with or without other supplements) experienced some type of symptom, side effect, and/or adverse event including approximately 88 suspected deaths. In context, according to the Nutrition Business Journal, approximately 12 million people purchased dietary supplements containing ephedra alkaloids last year alone with an estimated 3 billion doses taken. Based on these types of reports, the FDA issued a warning about ingesting ephedra containing dietary supplements in 1995 and attempted to ban sale of ephedra containing supplements in 1997. The attempt to ban sale of ephedra supplements was rescinded by Congress who found that there was insufficient data to support FDA claims that ephedra was not a safe nutritional supplement. (6) A paper that was published in the New England Journal of Medicine in the fall of 2000 renewed warnings about ephedra supplements [26]. This study evaluated 141 cases reported to the AEMS from 1997-1999 that involved ephedra supplements. The researchers reported that it was their view that 31% of cases were considered definitely or probably related to the use of supplements containing ephedra alkaloids and 31 percent were deemed possibly related. Of these, 47 percent involved cardiovascular symptoms and 18 percent involved the central nervous system. Hypertension was the single most frequent adverse effect (17 reports), followed by palpitations and/or tachycardia (13); stroke (10); and seizures (7). According to these reviewers, 10 events resulted in death and 13 events produced permanent disability. In some instances, excessive amounts of ephedra or ephedrine were apparently consumed (i.e., more than the apparent upper limit of safety of 90 mg/d) often with other supplements and/or medications. The authors concluded that use of dietary supplements that contain ephedra alkaloids may pose a health risk to some persons. Critics of this report suggested that since findings were based on incomplete, unsubstantiated, and/or uncorroborated reports to the FDA’s Special Nutritional AEMS, it was unclear whether any of these purported adverse events were or were not related to ephedra supplementation. It should be noted that the FDA removed the SNAEMS effective August 29, 2002 stating the following: “Data from the Special Nutritional Adverse Event Monitoring System website for dietary supplements has not been added to or updated since 1999, and the website has now been removed. The information previously available on dietary supplement adverse event reports on this website was very limited and was provided in a manner that made it difficult for users to appropriately interpret the adverse events.” Since the publication of this report, a number of case reports and/or review papers have questioned the safety of ephedra supplementation [19,27-41]. We concur with the findings in the Rand report that although these reports and concerns deserve careful, well-controlled clinical study to examine a possible relationship to ephedra supplementation, these reports are too incomplete to make any definitive clinical judgment as to the safety of ephedra supplementation. In this regard, if the FDA considers reports to their Special Nutritional AEMS as “difficult for users to appropriately interpret the adverse events” then there is little merit in analyzing these reports in an attempt to make any conclusions about the safety of ephedra supplementation from these reports. The same holds true for reports to the U.S. Poison Control Center that have been recently described in the literature [27]. There is simply no way of verifying whether the adverse events reported were related in any way to ephedra supplementation or not. Further, we are aware of several letters to the editor that have been submitted questioning the methods and conclusions of recent studies described as by the FDA as “new medical information” justifying in part actions against ephedra. When reviewing these reports, it is important to note that the significant media attention regarding the possible side effects of ephedra supplements may have influenced the reporting of side effects and/or association of non-related side effects to ephedra. In our view, the best evidence as to the possible side effects of ephedra supplementation come from available clinical studies that compared reported side effects in ephedrine/ephedra users to those on placebos. The most thorough study conducted to date on the safety of herbal ephedra and caffeine supplements was an NIH funded, 6-month study reported last year by Boozer and colleagues [18] which concluded that “herbal ephedra/caffeine supplementation, when used as directed by healthy overweight men and women in combination with healthy diet and exercise habits, may be beneficial for weight reduction without significantly increased risk of adverse events.” This study involved a comprehensive analysis of side effects including 24-hour Holter monitoring for arrhythmias, ambulatory blood pressure readings, and comprehensive medical examinations to assess side effects. At worst, the researchers reported that a greater frequency of participant dropouts occurred in subjects taking herbal ephedra/caffeine supplements. This study did not support contentions that herbal ephedra/caffeine supplementation produces untoward side effects. (7) We concur with findings in the Rand report that there is too little data to conclude that herbal ephedra provides ergogenic benefit for athletes. If there is any ergogenic benefit, it most likely is associated with the caffeine often found in herbal ephedrine/caffeine supplements rather than the ephedra. (8) We do not concur with the FDA’s position that ephedra supplementation is dangerous “especially under conditions of strenuous exercise and in combination with other stimulants, including caffeine”. While this may be a prudent recommendation, we are aware of no data supporting the view that ephedra supplementation affects maximal heart, myocardial function, promotes dehydration, or significantly increases core temperature during exercise. We assume that this warning has been issued in response to several high profile deaths among athletes suspected of taking dietary supplements containing ephedra while training in hot/humid environments. However, it is currently unclear whether ephedra supplementation played a role in the deaths of any of these athletes. (9) We concur with the FDA recommendation that warnings should indicate that anyone under 18 should not take ephedra containing supplements. There is simply too little evidence as to efficacy and/or safety in younger populations. However, since the Molnar and associate [15] paper showed efficacy and safety in obese adolescent patients participating in a medically supervised weight loss program, it is our view that a qualifier should include “unless directed by their physician.” (10) We believe that the new warnings should highlight possible side effects attributed to ephedra supplementation as described in the Rand report including “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”. We do not believe there is sufficient evidence to conclude at this time that ephedra supplementation increases “risks of serious adverse events, including heart attack, seizure, stroke, and death”. We recommend that this statement be modified to indicate that these side effects have been reported to occur in rare instances among people claiming to have taken ephedra containing dietary supplements but that this relationship has yet to be medically proven. (11) While we support appropriate warning labels of possible side effects associated with taking dietary supplements containing ephedra, we do not believe that available data shows that ephedra supplements “present a significant and unreasonable risk of illness and injury”. Dietary supplements containing ephedra are clearly not for everyone. However, research shows they can be safely used by healthy populations to promote a modest amount of weight loss. While some Americans may feel that the possible risk of taking ephedra containing dietary supplements outweigh the potential benefits, millions of people have safely used ephedra containing dietary supplements without any apparent side effects. We feel that as long as the public is made aware of the possible risks and benefits, then it should be up to the consumer, in consultation with their physician, as to whether they should or should not take dietary supplements containing ephedra. Further, when one compares the safety record of ephedra to such common practices as taking aspirin, pain medications, cold medications, weight loss medications, and alcohol, ephedra supplementation appears to be a relatively safe practice. Comments Regarding “Additional Legislative Authorities” The proposed rule seeks comments regarding “what additional legislative authorities, if any, would be necessary or appropriate to enable FDA to address this issue most effectively.” We do not believe that any additional legislative authority is necessary to address the matter of how ephedra-containing products should be regulated. Congress delegated to the FDA all of the authority it needs to regulate dietary supplements when it passed, after careful deliberation, the Dietary Supplement Health and Education Act of 1994. It is important that the FDA not forget that the matter of dietary supplement regulation had a full hearing before the United States Congress in 1993 and 1994. The full United States Congress, representing the entire populous of the country, made several key findings embodied in DSHEA. Specifically, Congress found that “dietary supplements are safe within a broad range of intake, and safety problems with the supplements are relatively rare.” Congress also deliberately delegated to the Secretary of Health and Human Services, not the FDA, the ability to declare a dietary supplement an imminent hazard to public health or safety. This deliberate and thoughtful delegation by Congress should not now be undone simply because FDA wants more power in this area. Its powers were purposefully and deliberately restricted in order that consumers enjoy the benefits of access to supplements that the FDA might otherwise find a way to restrict. For the reasons stated above, we believe that ephedra-containing products are safe. However, if the FDA disagrees, it has a whole arsenal of weapons available to use in order to restrict or even ban the sale of these products. These weapons include declaring that the product is adulterated under the Food, Drug and Cosmetic Act if the product, due to the inherent dangerousness of one or more of its ingredients, presents a significant or unreasonable risk to health. Since the passage of DSHEA in 1994, we are unaware that the FDA has ever used this authority. Yet, without every having used this powerful regulatory tool, the FDA seeks comment on whether it should be given “additional legislative authorities.” Likewise, the Secretary of HHS can declare a supplement to be an imminent hazard to public health or safety. Again, without every using its already delegated powers, comments is sought on additional powers. It seems as if the FDA wants Congress to make it easier to regulate access to these products when in fact Congress has very recently decided that access to supplements should be maximized from a regulatory perspective not minimized. It thus placed the burdens for action where there currently resided—with the FDA and not with consumers. While it is clear FDA has seized upon the recent ephedra controversy to open the door for reform of DSHEA, this is not its place. Moreover, we do not believe that the recent controversy over ephedra represents any legitimate reason to expand the power of FDA over supplements when the finding underpinning DSHEA remains true—supplement are safe within a broad range of intake. Summary Comments about nutritional supplements should be based on science and not political and media pressure. Research has indicated that ephedrine/ephedra supplementation can safely promote weight in appropriate populations. The adverse events reported deserve study to see if a relationship actually exists to supplementation with dietary supplements containing ephedra. However, as the Rand report concludes, it is difficult to make definitive clinical conclusions based on these reports due to a lack of information and/or presence of potential confounding variables and medical history. We therefore call on the FDA and Federal government to conduct a large-scale, multi-site clinical trial to investigate the safety and efficacy of dietary supplements containing ephedra. This can be accomplished by developing entrance criteria; having physicians perform a comprehensive medical exam; randomly and blindly assigning patients to a placebo (e.g., caffeine) or ephedra group (ephedra + caffeine); and, conducting follow-up medical assessment at 3-month intervals for a year. This would provide sufficient data to document changes in medical status in comparison to a placebo. Until such a study is conducted to show a statistically greater incidence of side effects among ephedra users, we cannot support a ban on the sale of ephedra supplements. Rather, we support efforts to better educate consumers as to the potential risks of taking ephedra containing supplements through proper labeling of risk as described in the Rand report. In our view, this should include: 1. Recommending that children under 18 not take dietary supplements containing ephedra, unless directed by their physician; 2. Recommending that individuals with pre-existing medical conditions (e.g., high blood pressure, heart disease, pulmonary disease, liver disease, thyroid disease, etc) and/or or who are pregnant not take dietary supplements containing ephedra; 3. Recommending that anyone considering taking dietary supplements containing ephedra should consult a knowledgeable physician to discuss possible risks and benefits; 4. Warning people of an increased risk to “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” as described in the Rand report; 5. Indicating that in rare instances, people who purportedly have taken dietary supplements containing ephedra have had heart attacks, strokes, seizures, and/or died but that these risks have yet to be confirmed in medical studies; and, 6. Indicating that it is not advisable to diet and/or take stimulants such as ephedra and caffeine when engaged in intense training particularly in hot/humid environments. Respectfully Submitted, /Scott D. Kumpf/ Scott D. Kumpf General Counsel Natural Balance, Inc. References 1. Dulloo, A. G., D. S. Miller. Ephedrine, caffeine and aspirin: over-the-counter drugs that interact to stimulate thermogenesis in the obese. Nutrition 5:7-9., 1989 2. Dulloo, A. G., D. S. Miller. Reversal of obesity in the genetically obese fa/fa Zucker rat with an ephedrine/methylxanthines thermogenic mixture. J Nutr 117:383-389., 1987 3. Krieger, D. R., P. A. Daly, A. G. Dulloo, B. J. Ransil, J. B. Young, L. Landsberg. Ephedrine, caffeine and aspirin promote weight loss in obese subjects. Trans Assoc Am Physicians 103:307-312, 1990 4. Astrup, A., B. Buemann, N. J. Christensen, S. Toubro, G. Thorbek, O. J. Victor, F. Quaade. The effect of ephedrine/caffeine mixture on energy expenditure and body composition in obese women. Metabolism 41:686-688., 1992 5. Astrup, A., L. Breum, S. Toubro, P. Hein, F. Quaade. The effect and safety of an ephedrine/caffeine compound compared to ephedrine, caffeine and placebo in obese subjects on an energy restricted diet. A double blind trial. Int J Obes Relat Metab Disord 16:269-277., 1992 6. Daly, P. A., D. R. Krieger, A. G. Dulloo, J. B. Young, L. Landsberg. 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EC -1370