9
Dietary Supplements

Dietary supplements have become a prominent part of American popular health culture, a fact attested to by the ready supply of supplements in pharmacies; chain stores such as Sam’s Club, Costco, and Walmart; supermarkets; and health food stores. Vendors advertise cut-rate prices for dietary supplements on the Internet. Since the 1960s, the prevalence of vitamin, mineral, and herbal product use has increased in the United States (Kessler et al., 2001). Today, dietary supplements comprise a major industry, responsible for $18.7 billion in sales in 2002 (Nutrition Business Journal, 2003). Herbal product use increased 380 percent between 1990 and 1997 (Eisenberg et al., 1998), and recent survey data indicate that 14 percent of Americans have taken an herbal product or supplement within the last week (Kaufman et al., 2002) and that 18.9 percent have taken one in the past year (Barnes et al., 2004). The use of dietary supplements is primarily self-initiated rather than practitioner based and presents unique regulatory, safety, and efficacy challenges to consumers, researchers, and practitioners. These challenges are an integral part of the committee’s charge to identify major scientific, policy, and practice issues related to complementary and alternative medicine (CAM) and are the focus of this chapter.

DIETARY SUPPLEMENT USE IN THE UNITED STATES

Kaufman and colleagues (2002) have described the patterns of medication use (for both prescription and nonprescription drugs) by the ambulatory adult population of the United States. Among their findings were the observations that (1) 40 percent of the population routinely used one or



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Complementary and Alternative Medicine in the United States 9 Dietary Supplements Dietary supplements have become a prominent part of American popular health culture, a fact attested to by the ready supply of supplements in pharmacies; chain stores such as Sam’s Club, Costco, and Walmart; supermarkets; and health food stores. Vendors advertise cut-rate prices for dietary supplements on the Internet. Since the 1960s, the prevalence of vitamin, mineral, and herbal product use has increased in the United States (Kessler et al., 2001). Today, dietary supplements comprise a major industry, responsible for $18.7 billion in sales in 2002 (Nutrition Business Journal, 2003). Herbal product use increased 380 percent between 1990 and 1997 (Eisenberg et al., 1998), and recent survey data indicate that 14 percent of Americans have taken an herbal product or supplement within the last week (Kaufman et al., 2002) and that 18.9 percent have taken one in the past year (Barnes et al., 2004). The use of dietary supplements is primarily self-initiated rather than practitioner based and presents unique regulatory, safety, and efficacy challenges to consumers, researchers, and practitioners. These challenges are an integral part of the committee’s charge to identify major scientific, policy, and practice issues related to complementary and alternative medicine (CAM) and are the focus of this chapter. DIETARY SUPPLEMENT USE IN THE UNITED STATES Kaufman and colleagues (2002) have described the patterns of medication use (for both prescription and nonprescription drugs) by the ambulatory adult population of the United States. Among their findings were the observations that (1) 40 percent of the population routinely used one or

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Complementary and Alternative Medicine in the United States more vitamin or mineral supplements; (2) 14 percent of the population had taken herbals and supplements during the previous week; and (3) among prescription drug users, 16 percent also took an herbal or supplement. Tables 9-1 and 9-2 summarize data on the most common supplements consumed by the American public. One shift in supplement usage is instructive. The use of St. John’s wort declined significantly between 2000 and 2001. A plausible reason for this is the negative attention that this herbal medicine received in both scientific journals and the popular press (Piscitelli et al., 2000; Shelton et al., 2001). To the extent that this is true, it demonstrates that the American public is responsive to reports of adverse events and scientific evidence involving the safety and efficacy of supplements as well as product adulteration disseminated in the press. Market sensitivity to scientific reports as well as drug advertisements related to CAM therapies need to be further examined, as they have for conventional medicine. The American public’s views on the federal regulation of dietary supplements are also instructive. Blendon et al. (2001) reported on Americans’ views on dietary supplements determined in multiple randomized surveys, each with a sample size of greater than 1,000, performed from 1996 to 1999. The investigators found that approximately half (48 percent) of all American adults surveyed reported that they regularly take some type of nonprescription vitamin or dietary or mineral supplement. One in six (16 to 18 percent) reported that they regularly use dietary supplements, such as echinacea, ginseng, amino acids, or nonprescription hormones. Respondents with higher levels of education reported greater use than those with TABLE 9-1 Ten Most Commonly Used Vitamins/Minerals and Herbal Supplements Vitamin or Mineral Percent Use Herbal Supplement Percent Use Multivitamin 26 Ginseng 3.3 Vitamin E 10 Gingko biloba 2.2 Vitamin C 9.1 Garlic 1.9 Calcium 8.7 Glucosamine 1.9 Magnesium 3.0 St. John’s wort 1.3 Zinc 2.2 Echinacea 1.3 Folic acid 2.2 Lecithin 1.1 Vitamin B12 2.1 Chondroitin 1.0 Vitamin D 1.9 Creatine 0.9 Vitamin A 1.8 Saw palmetto 0.9 Any vitamin or mineral 40 Any herbal supplement 14 SOURCE: Adapted from Kaufman et al. (2002).

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Complementary and Alternative Medicine in the United States TABLE 9-2 Top-Selling U.S. Dietary Supplements Vitamins and Mineralsa $ Millionsa Nonherbal Dietary Supplementsa $ Millionsa Herbal Supplementsb $ Millionsb Percent Change from January 2002 to January 2003b Multivitamins 839 Glucosamine/chondroitin 288 Garlic 34.5 –1.5 Calcium 340 CoenzymeQ-10 41 Ginkgo biloba 32.9 –28.9 Vitamin C 230 Melatonin 31 Echinacea 32.4 –18.9 Vitamin B complex 90 Amino acids 21 Soy 28.2 +1.6 Vitamin B 82 Fish oil/omega-3 fatty acid 14 Saw palmetto 23.1 –7.1 Iron 57 DHEA 11 Ginseng 21.6 –30.6 Vitamins A and D 34 Acidophilus 11 St. John’s wort 14.9 –38.4 Zinc 28 Lecithin 10 Black cohosh 12.3 +27.4 Potassium 14 Gelatin 8 Cranberry 11.8 +13.0 Glucose 7 Valerian 8.1 –31.4 Shark cartilage 6 Milk thistle 7.7 +9.2 Evening primrose 6.0 +2.1 Kava kava 4.4 –52.9 Bilberry 3.3 –4.9 Grape seed 3.0 –24.1 Yohimbe 2.4 +12.3 Green tea 1.7 +1.0 Ginger 1.0 –9.8 Pycnogenol 0.9 –36.0 Aloe vera 0.5 +1.1 Multiple herbs 8.5 +27.1 All other herbs not listed above 33.7 –5.9 SOURCES: aEisenberg (2001); bBlumenthal (2003a).

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Complementary and Alternative Medicine in the United States less education. Regular users were also more likely to be white and non-Hispanic. Americans older than age 45 years were more likely to use supplements regularly than those who were younger (44 and 24 percent, respectively). The investigators also reported that uninsured Americans were significantly more likely than those with insurance to use dietary supplements (21 and 15 percent, respectively). Of note, they comment that one of six parents (18 percent) reported that they give dietary supplements to their children. Blendon and colleagues (2001) noted that a 1997 survey found that one-third (36 percent) of adults thought that there was a dietary supplement that could help them live longer. Overall, 85 percent of regular users reported that dietary supplements are good for people’s health and well-being. That proportion was lower for those who were not regular dietary supplement users. Regular users believed that dietary supplements could help with the treatment of a wide range of medical conditions. About half of regular users believed that supplements are helpful for people with colds (61 percent), arthritis (53 percent), depression (52 percent), and influenza (49 percent). Some regular users viewed dietary supplements as helpful in the treatment of cancer (35 percent) and HIV infection-related immunodeficiency syndromes (16 percent). Another study that the investigators identified found that 82 percent of Americans surveyed said that they would seriously consider trying alternative treatments such as herbal medicines if they were terminally ill. Importantly, Blendon and colleagues (2001) also found that those who were regular users believed strongly in the usefulness of various dietary supplements, irrespective of the scientific evidence. When asked what they would do if a government agency said that the supplement that they used most often was ineffective, 71 percent of regular users reported that they would continue to use it. In a follow-up survey, respondents were asked what they would do if the Food and Drug Administration (FDA) specifically said that the supplement that they used most was ineffective to see if use of the FDA name versus an unknown government agency would alter the results. Specific mention of the FDA did not lead to different responses. Once again, two-thirds (67 percent) of regular users of dietary supplements said that they would continue to take the supplement. Regular users had more confidence in the safety of these products than nonusers: the majority of regular users (53 percent) believed that people are “rarely or never” harmed by taking dietary supplements; in contrast, 51 percent of nonusers reported that people are “often or sometimes” harmed by these supplements (Blendon et al., 2001). Blendon and colleagues (2001) also queried the respondents about their attitudes towards governmental regulation of dietary supplements. A substantial percentage of respondents were confused about the role that the

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Complementary and Alternative Medicine in the United States government currently plays in regulating supplements. Slightly more than half (53 percent) were aware that supplements are not regulated by the government. One-third (35 percent) believed that supplements are currently regulated, and 12 percent reported that they did not know (Blendon et al., 2001). However, the investigators reported that even with this level of public confusion, a majority of respondents expressed support for increased government regulatory efforts to ensure that dietary supplements are not harmful and are pure, that doses are consistent, and that advertising claims are true (Blendon et al., 2001). Eighty-one percent of respondents supported giving FDA the authority to allow new supplements to be sold only if the safety of the supplements has been tested by FDA; 80 percent supported giving FDA the authority to remove dietary supplements from the market if they are proven to be unsafe. Despite the large percentage of people in support of greater regulation, Blendon et al. (2001) also note, “a substantial number of respondents were not prepared to be denied access to existing dietary supplements that have not been previously tested for safety.” Similar levels of support were found among those who were regular users and those who were not (Blendon et al., 2001). As such, the matter of federal regulation of dietary supplements is clearly one for which there is currently much confusion on the part of the American public. REGULATION OF DIETARY SUPPLEMENTS Dietary Supplement Health and Education Act The capstone of herbal medicine regulation is the Dietary Supplement Health and Education Act of 1994 (DSHEA, 1994). As seen from the survey data presented above, dietary supplements encompass many products, including herbs, vitamins, and minerals. DSHEA formally defined dietary supplements as a product (other than tobacco) intended to supplement the diet that bears or contains one or more of the following dietary ingredients: a vitamin; a mineral; an herb or other botanical; an amino acid; a dietary substance for use by man to supplement the diet by increasing the total dietary intake; or a concentrate, metabolite, constituent, extract, or combination of any ingredient described above. Dietary supplements are further defined as products that are labeled as dietary supplements and are not represented for use as a conventional

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Complementary and Alternative Medicine in the United States food or as a sole item of a meal or the diet. Supplements can be marketed for ingestion in a variety of dosage forms including capsule, powder, softgel, gelcap, tablet, liquid, or indeed, any other form so long as they are not represented as conventional foods or as sole items of a meal or of the diet. (DSHEA, 1994) DSHEA had enormous consumer support as evidenced by the approximately 2 million letters sent to members of the U.S. Congress in support the act (Soller, 2000). The legislation sought to be responsive to the public and was passed in the spirit of improving the health of Americans and empowering consumers to make their own choices about preventive health care practices. In doing so, however, DSHEA designated that supplements be regulated similarly to foods. This crucial distinction exempted manufacturers from conducting premarket safety and efficacy research and eliminated FDA’s premarket regulatory authority. Before DSHEA, FDA attempted to regulate dietary supplements as foods evaluating the safety of all new ingredients, including those used in dietary supplements. DSHEA eliminated this requirement, and as a result, the dietary ingredients used in dietary supplements are no longer subject to the premarket safety evaluations required of other new food ingredients or for new uses of old food ingredients. They must, however, meet the requirements of other safety provisions (FDA, 1995). Table 9-3 shows how dietary supplements are regulated in comparison to foods and drugs. The establishment of dietary supplements as foods limited FDA’s premarketing regulatory authority and placed FDA in a reactive, postmarketing role. If FDA can prove that a supplement presents a significant or unreasonable risk of injury or illness when it is used as recommended on the label, it may remove a product from the market. This occurred in 2004, when FDA prohibited the sale of dietary supplements containing ephedrine alkaloids. To substantiate its ruling, FDA conducted a risk-benefit analysis of ephedra and examined evidence from the known pharmacology of ephedrine alkaloids, the peer-reviewed literature on effects of ephedrine alkaloids, and reported adverse events after consumption of the product. Review “showed little evidence of ephedra’s effectiveness except for short-term weight loss, while confirming that the substance raises blood pressure and stresses the heart” (http://nccam.nih.gov/health/alerts/ephedra/consumeradvisory.htm). FDA determined that data did not indicate a health benefit sufficient to outweigh the short- and long-term risks of use (e.g., increased blood pressure, and heart rate) (FDA, 2004). Adverse event analysis is complicated by the fact that supplement manufacturers are not required to report adverse events. DSHEA authorized FDA to establish good manufacturing practice regulations specific to dietary supplements, and these are in development (FDA, 2003a). However, until these practices are implemented, manufacturers are

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Complementary and Alternative Medicine in the United States TABLE 9-3 FDA Regulation of Foods, Drugs, and Dietary Supplements Status Dietary Supplements Foodsa Food Additives New Drugsb Premarket approval required Noc Nod Yes Yes Risk-benefit analysis conducted by FDA before marketingNo No No Yes   Postmarketing reporting or surveillance by industry required No No Rarely Yes Burden of proof for demonstrating safety or lack thereof FDA FDA Manufacturer Manufacturer aFoods (including conventional foods and dietary supplements), unlike drugs, are considered safe (reasonable certainty of no har m), and thus risk-benefit analysis is not applicable. bThis description applies to“new” drugs. Many over-the-counter drugs are regulated under FDA’s Over-The-Counter Drug Review procedures, which do not provide for postmarketing surveillance. cA 75-day premarketing notification, but not premarketing approval, is required for dietary supplements containing ingredients n ot marketed before 1994. dIn 2001, FDA proposed a rule requiring marketers of food developed through biotechnology to notify the agency at least 120 days before commercial distribution and to provide information to demonstrate that the product is as safe as its conventional counterpart (FDA, 2001). SOURCE: Adapted from IOM (2005).

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Complementary and Alternative Medicine in the United States accountable to consumers only on the basis that they have made a good faith effort to ensure that their products contain pure substances and are not contaminated, weakened, or mislabeled. Dietary Supplement Labels DSHEA also included labeling guidelines for supplements and prohibited products from containing information on the label that claims that the product can treat or cure a disease. Three categories of claims for food and dietary supplement labels are allowed: (1) health claims, (2) structure-function claims, and (3) nutrient content claims. Table 9-4 provides examples of each type of claim. Health Claims Health claims can be established by three methods: (1) authorization by FDA after a careful review of the scientific literature, (2) an authoritative TABLE 9-4 Label Claims for Dietary Supplements Health Claim Structure-Function Claim Unallowable Disease Claim Nutrient Content Claim or Percentage Claim Regular exercise and a healthy diet with enough calcium helps teens and young adult white and Asian women maintain good bone health and may reduce their high risk of osteoporosis later in life. Supports the immune system Supports the body’s ability to resist infection Excellent source of choline; contains 55 mg of choline per serving, which is 10 percent of the daily value for choline (550 mg) Healthful diets with adequate folate may reduce a woman’s risk of having a child with a brain or a spinal cord defect. Maintains healthy lung function Protective against the development of cancer More, added, extra vitamin C Some scientific evidence suggests that consumption of antioxidant vitamins may reduce the risk of certain forms of cancer. However, FDA has determined that this evidence is limited and not conclusive. Helps promote digestion Promotes low blood pressure  

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Complementary and Alternative Medicine in the United States statement of a scientific body of the U.S. government or National Academy of Sciences,1 or (3) the results of the 1999 Pearson v. Shalala court decision (FDA, 2003b). The Pearson case challenged FDA’s denial of four health claims: dietary fiber may reduce the risk of colorectal cancer, antioxidant vitamins may reduce the risk of certain cancers, omega-3 fatty acids may reduce the risk of coronary heart disease, and 0.8 milligram (mg) of folic acid in dietary supplement form is more effective than a smaller amount obtained through foods for reducing neural tube defects. The final decision stated that FDA could not “reject health claims that the agency determines to be potentially misleading unless the agency also reasonably determines that no disclaimer would eliminate the potential deception” (FDA, 1999). The court also called for FDA to clarify the meaning of the “significant scientific agreement” standard. Most health claims are applicable only to foods, for example, “low-fat diets rich in fiber-containing grain products, fruits, and vegetables may reduce the risk of some types of cancer, a disease associated with many factors.” However, two health claims for dietary supplements have been approved: folate reduces the risk of neural tube defects, and calcium reduces the risk of osteoporosis (FDA, 2000). Structure-Function Claims The second category created by DSHEA for foods and dietary supplements labels is structure-function claims. Such claims may only contain statements about how a product affects maintenance of normal functioning or describe general well-being because of the “consumption of a nutrient or dietary ingredient.” Structure-function claims may also describe the means by which a nutrient or dietary ingredient acts to maintain a particular structure or function. Examples include “calcium builds strong bones” and “fiber maintains bowel regularity.” Because manufacturers are responsible for the truthfulness and accuracies of these claims, if a product label contains a structure-function claim, it must also include the disclaimer, “This statement has not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure, or prevent any disease.” An additional requirement of structure-function claims is that FDA must be notified of the claim within 30 days after such a product is marketed. 1   At present, this method of oversight for health claims cannot be used for dietary supplements, as Congress did not include dietary supplements in the provisions for health claims based on authoritative statements.

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Complementary and Alternative Medicine in the United States Nutrient Content Claims The final category of product labels is nutrient content claims. These claims describe the level of a nutrient or dietary substance in a product, using terms such as “good source,” “high,” or “free.” With few exceptions, nutrient claims may be used only for nutrients or dietary substances that have an established daily value, such as fat, cholesterol, calories, and sodium. However, since many dietary ingredients, including most dietary supplements, lack established or recommended daily intake values, a subcategory called percentage claims also exists. These claims describe the percentage of a product, such as “40 percent omega-3 fatty acids” or make a comparative percentage claim, such as “twice the omega-3 fatty acids per capsule (80 mg) as in 100 mg of manhaden oil (40 mg)” (FDA, 2003b). Off-Label Use of Dietary Supplements For the majority of dietary supplements, particularly herbal products, inadequate evidence exists to qualify them for health or nutrient content claims. Consequently, many dietary supplements are subject to structure-function claims. However, despite all the attention given to proper labeling, recent survey data and clinical trials indicate that dietary supplements are not being used according to label claims (Blendon et al., 2001; Kaufman et al., 2002). Instead, many supplements are being taken for specific health concerns and health promotion, even though the effectiveness of the supplements has not yet been demonstrated. In response to this problem, several research efforts have been launched to evaluate the efficacies of supplements for off-label health uses, for example: Echinacea and colds (Grimm and Muller, 1999; Turner et al., 2000) Hypericum perforatum (St. John’s wort) and major depressive disorder (Hypericum Depression Trial Study Group, 2002; Shelton et al., 2001) Black cohosh and red clover for the relief of menopausal symptoms (ongoing National Center for Complementary and Alternative Medicine [NCCAM]-funded study at the University of Illinois, Chicago) Effects of garlic on cholesterol (ongoing NCCAM-funded study at Stanford University) Glucosamine, chondroitin sulfate, and the combination of glucosamine and chondroitin sulfate for knee pain associated with osteoarthritis (ongoing multisite NCCAM-funded study) Chelation with EDTA (ethylenediaminetetraacetic acid) to treat heart disease (ongoing multisite NCCAM-funded study)

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Complementary and Alternative Medicine in the United States Federal Trade Commission In addition to FDA’s responsibilities for ensuring safety, the Federal Trade Commission (FTC) regulates product advertising. For all products, FTC maintains two guiding principles: (1) advertising must be truthful and not misleading, and (2) before an advertisement is disseminated, all objective product claims must be adequately substantiated (FTC, 2001). In accordance with its goal of ensuring that consumers receive accurate information about dietary supplements so that they may make informed decisions about the use of products, FTC released Dietary Supplements: An Advertising Guide for Industry (FTC, 2001). The guidelines are intended to clarify how FTC policies and enforcement practices relate to dietary supplement-related advertising. In addition to FTC’s standard substantiation requirements, the document outlines the type of evidence needed to support both expert endorsements and claims based on traditional use, as well as appropriate use of the DSHEA disclaimer and third-party literature. In addition to the guidance document, FTC launched Operation Cure. Although the campaign is not limited to dietary supplements, it aims to enforce FTC regulations and educate consumers on recognizing health fraud. However, as evident in the literature (Bonakdar, 2002; Morris and Avorn, 2003) and acknowledged by Howard Beales, director of FTC’s Bureau of Consumer Protection, “unfounded and exaggerated claims for dietary supplements have proliferated,” and the FTC has partnered with FDA to increase its enforcement activities (Beales, 2003). Dietary Supplement Regulation Outside of the United States The use of herbal products is prevalent throughout the world (WHO, 2002), and several countries have been addressing the use and regulation of dietary supplements for many years, whereas others like the United States are in the early years of their regulatory efforts. Canada New Natural Health Products (NHP) regulations came into effect in Canada on January 1, 2004. The intent of the regulations is to “ensure a balance between Canadians’ freedom of choice with respect to natural health products and the assurance of consumer safety” (HealthCanada, 2003). The regulations establish NHPs as a subset of drugs. Before the establishment of the regulations, NHPs could be sold as either foods or drugs, depending on whether a health or therapeutic claim was made. In

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Complementary and Alternative Medicine in the United States Assessing Product Safety and Quality Because research on the efficacies of herbal products requires consistent products, NCCAM recently established a policy on the quality of natural products to provide guidance for researchers seeking NCCAM funding (NCCAM, 2003). The policies are intended to help researchers identify and use products of sufficient quality for their investigations. NCCAM recommends that the natural products used in a study be described in sufficient detail and that the results be understood and independently reproduced. Studies must prove that the test material has been reliably identified, and the content should be described by analysis of putative active ingredients and by chromatographic analysis of the whole material by the commercial company or independent laboratory. Also, depending on the study design, verification of the samples at the start and end of the study may be necessary to ensure product stability (NCCAM, 2003). With the lack of federal standards for dietary supplements, several organizations have initiated efforts to improve and test the safety, quality, and efficacy of supplements. The following overview focuses on approaches taken by organization- or government-sponsored committees or a peer-reviewed process.2 The list should not be considered inclusive of all efforts to consider safety, efficacy, or quality of dietary supplements, nor should it be considered committee endorsement of the approaches used. The Agency for Healthcare Research and Quality (AHRQ) of the U.S. Department of Health and Human Services is authorized to sponsor, conduct, and disseminate research to improve the quality and effectiveness of health care. AHRQ administers evidence-based practice centers (EPCs), which have produced reports on the effectiveness and safety of a limited number of dietary supplements requested by other federal agencies. The EPC reports are based on a systematic analysis of the relevant scientific data and are designed to differentiate the types and strengths of a comprehensive body of evidence. Nominations for clinical topics to be reviewed by an EPC are solicited through notices in the Federal Register. Topics must meet specific selection criteria, including high incidence; significance for the needs of users of Medicare, Medicaid, or other federal health programs; high cost; controversy about effectiveness; and availability of scientific data. On the basis of this process, reports on six dietary supplements3 have been reviewed as of October 2003. 2   A comprehensive discussion of these private and public safety assessments is available in Dietary Supplements: A Framework for Evaluating Safety (IOM, 2005). 3   The topics of the six reports are: Antioxidant supplements for prevention and treatment of cancer (October 2003); Antioxidant supplements for prevention and treatment of cardio-

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Complementary and Alternative Medicine in the United States The American Herbal Pharmacopoeia (AHP), a nonprofit organization, develops monographs on the quality, effectiveness, and safety of botanical products commonly used in the United States. The monographs are intended to provide consumers, health care professionals, and botanical manufacturers with the knowledge required to use and manufacture botanical products safely and effectively and to provide regulatory bodies and researchers with guidance on the integration of botanical products into the health care system (AHP, 2004a). Botanicals are selected for review and description in a monograph on the basis of the extent of use, the unique value of the botanical, and sponsorship by other interested organizations or companies (AHP, 2004a). The monographs are relatively detailed compared with the monographs produced by other organizations and are released as they are completed. Eighteen monographs have been published4 since 1994, and 7 more have been proposed. The American Herbal Products Association (AHPA) is a national trade association for the botanical products industry. AHPA reviewed safety data for 600 herbs and published the information in the American Herbal Products Associations’ Botanical Safety Handbook (McGuffin et al., 1997). The publication assigned botanicals to one of four safety classes. Class 1 contains botanicals that AHPA believes can be used safely when they are used appropriately. Class 2 contains botanicals for which certain restrictions apply (e.g., external use only and not recommended for use during pregnancy). Class 3 contains botanicals for which significant data exist to recommend special labeling. Class 4 contains botanicals for which AHPA found insufficient data for classification. The Natural Medicines Comprehensive Database (NMCD) is a private effort and was first published in 1999 by the Therapeutic Research Center. It is designed to bring together the consensus of the available data on natural medicines so that practitioners do not need to search multiple sources to find scientifically reliable and clinically practical information on botanical medicines and supplements for their patients. Products are evaluated on the basis of several factors: safety, effectiveness, mechanism of     vascular disease (CVD) (July 2003); Ephedra and ephedrine for weight loss and athletic performance enhancement (March 2003); S-adenosyl-L-methionine (SAMe) for depression, osteoarthritis, and liver disease (August 2002); Garlic and CVD (October 2000); and Milk thistle effects (September 2000). 4   The monographs published by AHP covered astragalus root, hawthorn berry, hawthorn leaf and flower, schisandra berry, valerian root, willow bark, ashwaganda root, black haw, chaste tree, cramp bark, goldenseal root, reishi mushroom, bilberry fruit, cranberry fruit, dang gui root, garlic powder, ginkgo leaf, black cohosh (AHP, 2004b).

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Complementary and Alternative Medicine in the United States action and active ingredients, adverse reactions, interactions, drug influences on nutrient levels and depletion, and dosage and administration (NMCD, 1999). Natural Standard was founded by clinicians and researchers as a multi-institution initiative in January 2000 to provide evidence-based information about CAM therapies (Natural Standard, 2004). The organization is a private, independent service that is not supported by any interest group, professional organization, or pharmaceutical manufacturer. Each monograph assigns a letter grade (A to F) pertaining to the level of evidence of effectiveness for specific indications. Information on safety, toxicology, precautions, contraindications, interactions, and mechanism of action is also provided; but these do not contribute to the letter grade. In 1998 the Physician’s Desk Reference (PDR) organization, a private, for-profit group, expanded its publications to include a PDR for Herbal Medicines. The second edition was published in 2000 and contains monographs on approximately 700 herbs. Of the 700 monographs, 300 are based on the German Commission E monographs. The monographs contain information on efficacy, safety, potential interactions, effects, contra-indications, precautions, adverse reactions, and dosage. In addition, PDR published a reference volume for nonprescription drugs and dietary supplements in 2003 and a PDR for nutritional supplements in 2001. The World Health Organization (WHO) has undertaken several efforts related to the safety, efficacy, and quality control of herbal medicines and has published three volumes of monographs since 1999, with a fourth volume in development. Each volume contains approximately 30 monographs. For each medicinal plant, information is included about purity tests, chemical constituents, uses, clinical studies, pharmacology, contraindications, warnings, precautions, adverse reactions, and posology (i.e., pharmacological determination of appropriate doses of drugs and medicines). In addition, in 2004 WHO published Guidelines on Good Agricultural and Collection Practices for Medicinal Plants, as well as several other reports related to quality control, appropriate use, and regulations pertaining to herbal medicines. The U.S. Pharmacopeia-National Formulary (USP-NF), a non-government, nonprofit organization, develops and provides standards of identity, strength, quality, purity, packaging, and labeling of drugs sold in the United States. However, unlike the previously discussed monographs, USP-NF standards do not evaluate safety. Their standards were recognized by the U.S. Congress in the Federal Food, Drug, and Cosmetic Act of 1938 as the official compendium of the United States, making its established standards for drugs essentially similar to federal regulations. As a separate effort, USP-NF also developed the Dietary Supplement Verification Program (DSVP) in November 2001. DSVP is designed to

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Complementary and Alternative Medicine in the United States ensure that dietary supplement products contain the declared ingredients in the declared quantities. USP collaborates with manufacturers who voluntarily submit their products for testing. The USP certification award is granted if the product meets five quality standards: (1) contains the ingredients stated on the label; (2) has the declared amount of ingredients; (3) will disintegrate or dissolve effectively to release nutrients for absorption into the body; (4) has been screened for harmful contaminants such as pesticides, bacteria, and heavy metals; and (5) has been manufactured by safe, sanitary, and well-controlled procedures. In addition, USP performs an initial screening so that products with known safety concerns are not certified and conducts random tests of marketed products carrying the mark for the USP certification award to ensure that they continue to meet USP standards over time. SAFETY Under the current DSHEA legislation, supplements are not subject to the same safety precautions as prescription and over-the-counter medications. Instead of premarketing testing, FDA must prove that a supplement is unsafe to remove it from the market. For medications, manufacturers are required to comply with the Federal Food, Drug, and Cosmetic Act and ensure the safety of their products before marketing. For new dietary supplement ingredients (those not marketed before the passage of DSHEA), before marketing manufacturers must provide FDA with the information that forms the basis on which the manufacturer has concluded that the product is safe. Although many supplement manufacturers recognize that the industry can be sustained only if they market safe products that perform in accordance with their claims (Young, 2000), product inconsistency has been demonstrated for several herbs (Gilroy et al., 2003; Raloff, 2003). De Smet (2002) identified three safety concerns: adverse effects of the herb, drug-herb interactions, and an indirect risk of delaying or replacing conventional treatment with treatment with an herb with unestablished efficacy. Even though they are natural products, herbs contain biological and chemical properties that may lead to rare, acute, or chronic adverse effects. Drug-herb interactions also present a potential risk to many consumers, given that one in six people take prescription or over-the-counter medications and dietary supplements concurrently (Kaufman et al., 2002). The interactions of a popular herb, St. John’s wort, with cyclosporine, indinavir, nevirapine, oral contraceptives, and amitriptyline have been reviewed in the literature (Ioannides, 2002). To address the question of product safety, the FDA recently asked the Institute of Medicine (IOM) to develop a framework for evaluating the safety of dietary supplement ingredients. The framework was published in

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Complementary and Alternative Medicine in the United States 2005 and includes a process for evaluating and describing the available information to establish the risk of harm and science-based principles to serve as guidance for evaluating the risk to human health (IOM, 2005). The IOM framework suggests a three-step process for determining the risk of harm. Because FDA evaluation of every dietary supplement ingredient is unrealistic, the first step of the framework relies on “signal detection” to indicate that there may be a safety concern warranting further examination. If a signal is found, the second step is to conduct a review of the available information, such as the quality of the adverse event report, its applicability to humans, or the route of exposure. In addition to reviewing this information, it may be feasible to collect information to place the signal in context. If a safety concern remains after completion of this initial review, IOM recommended the performance of an integrative evaluation consisting of an in-depth literature search and review, drafting of a safety monograph, integration of the data into an analysis to complete the monograph, and possibly, referral of the monograph to an advisory body for additional input before FDA decides whether to take regulatory action. If the integrative evaluation results in a lower level of concern, FDA should continue to monitor the supplement for safety concerns through ongoing assessments of the literature. This responsibility rests on FDA, because DSHEA does not require postmarketing surveillance. The committee supports several of the conclusions and recommendations in the IOM framework that address the legal and regulatory barriers affecting FDA’s ability to protect the health of the public: It is very challenging to carry out the mandate of DSHEA given the limitations it imposes on the quantity and quality of the currently available scientific data related to the safety of dietary supplement ingredients … In line with these findings, members of the scientific and medical community have strongly advised that the regulatory mechanisms for monitoring the safety of dietary supplements, as currently defined by DSHEA, be revised. The constraints imposed on the FDA with regard to ensuring the absence of unreasonable risk associated with the use of dietary supplements make it difficult for the health of the American public to be adequately protected. (IOM, 2005) An additional conclusion from the 2005 framework report states, “DSHEA should be amended to require that a manufacturer and distributor report to the FDA, in a timely manner, any serious adverse event associated with use of its marketed product of which the manufacturer or distributor is aware” (IOM, 2005). Both the IOM framework and a recent review on the quality of dietary supplement reference books (Chambliss et al., 2002) conclude there is a wide variation among references, and multiple sources should be consulted to obtain the most comprehensive information about product safety and

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Complementary and Alternative Medicine in the United States quality. This uncertainty about safety, the lack of premarketing safety data, and the proliferation of misleading and unfounded claims about dietary supplements place researchers, consumers, and conventional medical practitioners in a unique situation. It is a challenge to guide and advise patients about their use of supplements in the absence of evidence on their safety, quality, efficacy, and cost-effectiveness. Only when products are consistently manufactured, characterized, and evaluated for safety and efficacy will physicians be able to judiciously advise their patients about their use. RESEARCH ON DIETARY SUPPLEMENTS Office of Dietary Supplements Another component of DSHEA established the Office of Dietary Supplements (ODS) within the National Institutes of Health to promote, conduct, and coordinate scientific studies on dietary supplements. As discussed in Chapter 1, the ODS 2004–2009 Strategic Plan sets five overarching goals related to research, information communication, and education. To achieve these goals, ODS plans to place greater emphasis on the use of emerging technologies, cross-disciplinary studies, training and education of investigators, translation of research, and establishment of a process for regular evaluation of ODS programs and activities. In the last 5 years, ODS has initiated many efforts to improve the quality of dietary supplement research. It established a program to improve analytical methodologies and develop standard reference preparations of dietary supplements and has created two databases that are publicly accessible: the Computer Access to Research on Dietary Supplements (CARDS) database and the International Bibliographic Information on Dietary Supplements (IBIDS) database. The CARDS database currently contains information on federally funded dietary supplement research and is continually updated. The IBIDS database provides access to bibliographic citations and abstracts from the published international scientific literature on dietary supplements. An additional resource for the research community and the public is evidence-based review reports, commissioned through a partnership with NCCAM from AHRQ’s EPCs. Another instance of ODS partnerships involves NCCAM, the National Institute for Environmental Health Sciences, the Office of Research on Women’s Health, and the National Institute of General Medical Sciences. Together, they fund six Centers for Dietary Supplement Research. The centers emphasize botanicals and aim to identify and characterize botanicals, assess their bioavailabilities and activities, explore their mechanisms of action, conduct preclinical and clinical evaluations, establish training and

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Complementary and Alternative Medicine in the United States career development, and help select the botanicals to be tested in clinical trials. NCCAM Research Efforts As part of its effort to understand which CAM therapies work and which ones are safe, NCCAM supports research on herbal products. Recently, NCCAM noted that much of its research portfolio was devoted to clinical trials and in the future, it plans to place greater emphasis on studies that will help provide an understanding of the mechanisms of CAM modalities. It is hoped that such research will aid with the acceptance of CAM therapies by conventional medicine, as well as clarify research markers and design questions. For dietary supplements in particular, NCCAM notes that poorly characterized products and unknown optimal dosage schedules may cause premature efficacy studies to fail and may limit further research. Therefore, NCCAM is interested in determining “active ingredients, dosing, pharmacology, stability, and bioavailability; to identify surrogate markers; and to assess study feasibility” (NCCAM, 2003). The committee believes that more preclinical and clinical trials on dietary supplements are needed and that it is crucial for the products being evaluated to adhere to a seed-to-shelf quality control system. NCCAM supports five Centers for Dietary Supplement Research, which are located at Purdue University, the University of Illinois at Chicago, the University of California at Los Angeles, the University of Arizona, and the University of Missouri-Columbia. Each center has a unique focus: age-related diseases, women’s health, botanicals, phytomedicines, and phytonutrients, respectively. Examples of ongoing NCCAM-funded research include interactions between olive leaf extract and anti-HIV drugs, phytoestrogens for multiple sclerosis, ginger for chemotherapy-induced nausea and emesis, Ginko biloba and vascular function, and herb-drug interactions. Research abstracts for all research funded by the National Institutes of Health are available through an online database, CRISP (Computer Retrieval of Information on Scientific Projects [http://crisp.cit.nih.gov/]). Research Needs and Disincentives Reliable products are necessary to conduct quality research, and at present, most herbal supplements are not available in reliable or consistent forms. As stated above, unlike prescription drugs and over-the-counter medicines, manufacturers of dietary supplements are not required to test their products for safety or efficacy. In addition to this missing legal requirement, there is a financial disincentive for such research. Because dietary supplements are ineligible for patent protection, manufacturers have a

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Complementary and Alternative Medicine in the United States financial disincentive to invest in research on these products. Without patent protection and an ensuing period of exclusivity, a manufacturer’s results would be publicly available for use by its competitors, thus jeopardizing the manufacturer’s ability to regain the money invested in safety and efficacy testing (Richter, 2003a). Despite this disincentive, research on the efficacy of dietary supplements is crucial, and for future studies to be most useful, dietary supplements should be evaluated in comparison with conventional medicines and the studies must use well-characterized products. Even when a reliable product is used, there is still a challenge in synthesizing the research results and performing meta-analyses, given the multiple brands and product characteristics. Future product reviews that identify safe and effective herbs and that stratify the research results by brand or manufacturer would add meaning and value. CONCLUSIONS AND RECOMMENDATIONS The committee is concerned about the quality of dietary supplements in the United States. There is little product reliability (Raloff, 2003), and because patent protection is not available for natural products, there is little incentive for manufacturers to invest resources in improving product standardization. In addition to the confusion that this introduces to consumers, the lack of reliable and consistent products is a challenge to the research and clinical practice communities. Without consistent products, research is extremely difficult to conduct or generalize. Furthermore, without high-quality research, evidence-based clinical recommendations cannot be made to guide patients. As a result of their pharmacological properties, dietary supplements, particularly botanical products, carry a risk of adverse effects and interactions. Unlike vitamins and minerals, herbal supplements are composed of many active compounds, and often, the primary active ingredient is unknown. Without knowing the active ingredient(s), it is a challenge for manufacturers to set standards that bear any therapeutic meaning. As such, consistency and quality checks throughout the manufacturing process garner even more importance (Berman and Straus, 2004). To improve product consistency and reliability, the committee recommends that the U.S. Congress and federal agencies, in consultation with industry, research scientists, consumers, and other stakeholders, amend the Dietary Supplement Health and Education Act of 1994 and the current regulatory scheme for dietary supplements, with emphasis on strengthening: Seed-to-shelf quality control, Accuracy and comprehensiveness in labeling and other disclosures, Enforcement efforts against inaccurate and misleading claims,

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Complementary and Alternative Medicine in the United States Research into how consumers use supplements, Incentives for privately funded research into the efficacies of products and brands, and Consumer protection against all potential hazards. REFERENCES AHP (The American Herbal Pharmacopeia). 2004a. Monographs Defined. [Online]. Available: http://www.herbal-ahp.org/mgdefine.html [accessed April 9, 2004]. AHP (The American Herbal Pharmacopeia). 2004b. American Herbal Pharmacopeia Home Page. [Online]. Available: http://www.herbal-ahp.org/ [accessed April 9, 2004]. Barnes PM, Powell-Griner E, McFann K, Nahin RL. 2004. Complementary and alternative medicine use among adults: United States, 2002. Vital Health Stat 343:1–19 (advance data). Beales H. 2003. Prepared statement of the Federal Trade Commission: The Commission’s role in policing deceptive marketing of dietary supplements. U.S. Senate Committee on Commerce, Science and Transportation, Washington, DC. Berman JD, Straus SE. 2004. Implementing a research agenda for complementary and alternative medicine. Annu Rev Med 55:239–254. Betz J. 2003. Characterization of Dietary Supplements: Research Considerations. Presentation to the Institute of Medicine Committee on the Use of Complementary and Alternative Medicine by the American Public, Washington, DC. Blendon RJ, DesRoches CM, Benson JM, Brodie M, Altman DE. 2001. Americans’ views on the use and regulation of dietary supplements. Arch Intern Med 161(6):805–810. Blumenthal M. 2003a. Herbs continue slide in mainstream market: Sales down 14 percent. HerbalGram 58:71. Blumenthal M. 2003b. Industry increasingly nervous about drug orientation of FDA’s proposed GMPs for dietary supplements: High costs threaten smaller companies. HerbalGram 59:57–58, 74. Blumenthal M, Busse WR, Goldberg A,Gruenwald J, Hall T, Riggins CW, Rister RS. 1998. The Complete German Commission E Monographs: Therapeutic Guide to Herbal Medicines. Austin, TX: American Botanical Council. Bonakdar RA. 2002. Herbal cancer cures on the Web: Noncompliance with The Dietary Supplement Health and Education Act. Fam Med 34(7):522–527. Chambliss WG, Hufford CD, Flagg ML, Glisson JK. 2002. Assessment of the quality of reference books on botanical dietary supplements. J Am Pharm Assoc 42(5):723–734. Dentali S. 2003. Characterization of Dietary Supplements: Industry Considerations. Presentation to the Institute of Medicine Committee on the Use of Complementary and Alternative Medicine by the American Public, Washington, DC. De Smet PA. 2002. Herbal remedies. N Engl J Med 347(25):2046–2056. DSHEA (Dietary Supplement Health and Education Act of 1994). 1994. Public Law No. 103-417, 108 Stat. 4325, 21 U.S.C. ss. 301 et seq. 1994. Eisenberg DM, Davis RB, Ettner SL, Appel S, Wilkey S, Van Rompay M, Kessler RC. 1998. Trends in alternative medicine use in the United States, 1990-1997: Results of a follow-up national survey. JAMA 280(18):1569–1575. Eisenberg DM. 2001, November 5. Complementary, Alternative and Integrative Medical Therapies: Current Status and Future Trends. Institute of Medicine Rosenthal Lecture. FDA (Food and Drug Administration). 1995. Dietary Supplement Health and Education Act of 1994. [Online]. Available: http://vm.cfsan.fda.gov/~dms/dietsupp.html [accessed March 6, 2004].

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