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Dietary Supplements: A Framework for Evaluating Safety 2 Approaches Used by Others and Existing Safety Frameworks In its charge, the committee was specifically asked to consider methods other expert bodies have used to categorize and review supplement safety and efficacy issues. Considering the strengths and weaknesses of other organizations’ approaches was an initial step in developing the framework described in this report. Assessing the relevance of other organizations’ efforts to safety evaluation by the Food and Drug Administration (FDA) was also important because these resources may be referred to by some as authoritative sources on the safety of dietary supplements. A list of considerations was developed for evaluating the usefulness to FDA of existing and future resources of dietary supplement information. These considerations, which are not part of the proposed framework, are summarized in the first part of this chapter. Frameworks developed for reviewing the safety of other substances (i.e., in foods, in pharmaceuticals, and in the environment) were also considered to prepare the committee to undertake its charge. The objective was to identify aspects applicable to developing a framework for evaluating dietary supplement ingredient safety. Brief descriptions of the frameworks the committee reviewed are provided in Appendix A. The knowledge gained from reviewing existing dietary supplement resources and frameworks for other substances, as well as discussions in open sessions with many individuals, informed the development of a list of attributes of a framework for setting priorities and evaluating the safety of dietary supplement ingredients. These attributes are summarized in the second part of the chapter.
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Dietary Supplements: A Framework for Evaluating Safety RESOURCES ON DIETARY SUPPLEMENTS Several organizations have compiled resources that review the safety, efficacy, and/or quality of dietary supplements. A list of considerations was developed for assessing the relevance of different resources to a safety review, and samples of these resources were reviewed. The considerations are described below, followed by a table indicating how each resource met these considerations and a narrative description of each resource. This discussion focuses on resources that appeared to be the product of organization or government-sponsored committees or a peer-reviewed process. Inclusion does not constitute endorsement of resources, nor should this review be considered inclusive of all efforts to consider safety, efficacy, and/ or quality of dietary supplements. Additional publications, although not reviewed here, may also be informative (Ernst, 2000; Foster and Tyler, 1999; Grieve, 1996). Considerations for Evaluating Resources Eighteen considerations were developed to assess the relevance of various resources to safety/risk evaluation. They address the objectives and focus of the resource, the authors and review process, the literature procurement and type of information considered, and the limitations of product-specific evaluations. Was review of safety/risk a primary goal of the document? Does the review have a clear focus on safety, rather than a focus on quality or potential therapeutic uses? For example, some resources focus mainly on efficacy, with safety issues seemingly an afterthought. Also, some reviews focus on objectives, such as verifying that the label is accurate and determining whether the substance is contaminated. These are useful approaches because quality and purity issues are important and can impact the safety of dietary supplements to a significant degree, but they are product focused, rather than focused on a particular dietary supplement ingredient’s inherent safety. Does the review rely on primary sources of information rather than secondary sources? Primary sources are original research articles that generate data, while secondary sources are compilations that may include statements of opinion in addition to facts. A review that summarizes data from primary sources is a more appropriate resource for assessing safety. If a resource’s conclusion about safety is based on scientific evidence from the primary literature, then it is more likely to be factual and less likely to be an opinion. Use of primary literature to support statements is a daunting task, but when it is possible, it minimizes the risk of carrying forward anecdotal
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Dietary Supplements: A Framework for Evaluating Safety statements that are not possible to document. Use of primary literature also increases credibility of resources when persons or organizations involved in producing them might be perceived to have a bias or conflict of interest. Does the review consider all types of information available, including data from in vitro studies and animal studies, as well as information about the safety of closely related plants or substances? A review that attempts to integrate a variety of data types, especially in the absence of good quality human data, will be a more appropriate resource for assessing safety. Because it is scientifically appropriate to consider concerns raised by animal data, in vitro studies, or information about related substances (see Chapters 4–7), reviews that conclude a substance is safe by focusing exclusively on human data should not be considered as adequate sources of safety conclusions. The converse is not true. That is, reviews that conclude a risk exists by exclusively focusing on human data are acceptable. Has appropriate scientific expertise and objectivity been used in weighing different types of information? Good reviews will explain why some information is considered more important than other information in reaching overall conclusions. Clearly stating the logic that underpins the data interpretation enables other experts to understand the basis for the evaluative judgment and determine whether appropriate objectivity and scientific expertise were used. What are the limitations to the safety review? Does the review explain why it may be difficult to make a conclusion about the safety of an ingredient? Does the review describe where insufficient, inconsistent, or inadequate data preclude an accurate assessment of safety? Discussion of limitations in data, such as how much is known and how definitively it is known, is useful in understanding safety. Also, an appropriate discussion about the limitations in interpreting the available data lends credibility to the review. Limitations may be of two types. First is the individual study’s limitations, such as limitations in interpreting the data or in experimental design, sometimes described by the study authors themselves. Another type is derived from developing the review itself, such as difficulty in interpreting data from foreign language sources or inconsistent data from different sources. Were the strategies used to search the literature adequately described? A good review will describe how the search for pertinent data was performed. Ideally, this description will include a list of databases searched, when they were searched, what search terms were used, and if there was a strategy for selecting information to review. This allows the user of the information to determine if the breadth and depth of the search was appropriate. How current is the information? A good review includes relevant current information, in addition to older information published in repu-
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Dietary Supplements: A Framework for Evaluating Safety table journals and historic information. Of course, all published reviews cannot claim to be current after they are published, but some will be updated with new information, if available. Evaluations that use resources that do not consider recent data should be supplemented with information available after publication of the review to determine if new data might have affected safety conclusions. Are the primary sources cited accurately and completely? Accurate citations are one indication that the original literature is being used and support the accuracy of the interpretation of the data. Incomplete or incorrectly cited references take away from the credibility and usefulness of the resource. Is the review well balanced and objective? Is there a conflict of interest (financial or otherwise) relative to the outcome of the safety evaluation? Conflicts of interest should lead the user to be more skeptical in interpreting the review’s assessment of safety as unbiased and appropriate. In considering the objectivity of a particular evaluation, the starting assumptions should be identified. For example, there is a difference between concluding that a substance can be consumed without safety concerns because the data reviewed included relevant safety information and it was determined to be of little concern, compared with concluding that a substance can be consumed without concern but not having any data that provided information related to safety. Guidelines for authors of scientific journals include the importance of disclosing financial relationships (Campbell, 2001), underscoring the importance of full disclosure relative to the information included in the review Do the authors have the depth and breadth of expertise necessary to assess the primary sources, weigh the data, and make conclusions as to the adequacy of the data for safety assessment? Persons knowledgeable in safety assessment should be included in the evaluations. In addition, particular types of expertise may be needed depending on the safety issues being considered for the particular supplement. Was the authored information peer-reviewed by knowledgeable experts? A good safety review will utilize the expertise of a variety of appropriate experts. Peer review is an essential component and, as such, the review should be critically reviewed by experts from a variety of disciplines. As the National Research Council (NRC, 1998) has stated, “External experts often can be more open, frank, and challenging to the status quo than internal reviewers, who may feel constrained by organizational concerns. Evaluation by external reviewers thus can enhance the credibility of the peer review process by avoiding both the reality and the appearance of conflict of interest.” If appropriate, is variability of specific preparations addressed or acknowledged? Do reviewers address or acknowledge the limitations in
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Dietary Supplements: A Framework for Evaluating Safety extrapolating across different parts of a botanical (i.e., roots, stems, flowers, and leaves) in the safety assessment? A safety review should attempt to explain different dietary supplement ingredient preparations and how those different preparations might change the safety assessment. For some ingredients that are well characterized this is not an issue, but for many botanical ingredients it is important to understand the plant part used, as well as the effect of different methods of preparation that may concentrate active compounds or otherwise alter the activity of the ingredient. Does the review focus on the safety of a particular standardized product? Frequently, reviews from another country describe the safety of standardized preparations of supplements available in that country; however, the relevance of such reviews to the safety of nonstandardized products consumed in the United States should be addressed for such reviews to be considered relevant to U.S. consumers. Reviews describing the safety of a standardized product are helpful in understanding some safety concerns inherent in the ingredient, but less relevant to safety concerns that vary with preparation. Similarly, good reviews will convey limitations inherent in extrapolating from studies suggesting safety of one standardized product to other products of the same ingredient. That is, they acknowledge that extrapolation to other products to mitigate safety concerns may be inappropriate. Is the ingested amount (or range of ingested amounts) under consideration specified in the review? Does the review address the relevance of the amount used in the evaluated research studies and published data to the amount commonly ingested or recommended for ingestion? Given the basic tenet of toxicology, “the dose makes the poison,” a good review of safety will describe the relevance of ingredient levels that produce safety concerns to the ingredient levels commonly consumed by or recommended to humans. (Many resources available to consumers specify recommendations for consumption, even if the labeling per se does not include recommended ingestion levels.) Does the review consider the relevance of data that describes results of non-oral administration of the ingredient? While safety issues with oral consumption are obviously the most relevant, some safety issues that come to light with other routes of administration may also be relevant. The relevance of such issues should be considered on a case-by-case basis, but expressly disregarding any safety information derived from non-oral exposure is not appropriate for some dietary supplement ingredients, especially when sufficient, quality data about oral ingestion are lacking. A review that considers non-oral data in its evaluation will have more value to FDA than one that ignores this type of information regardless of relevance. In many of the resources described, it was not evident whether non-oral data were considered.
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Dietary Supplements: A Framework for Evaluating Safety Does the review address the possible biological activity or mechanism of action of the ingredient and its implications for human safety? Knowledge of the mechanism of action may be useful in understanding the biological basis for possible harm. Does the review address whether the ingredient might pose safety problems for specific groups within the general population? Does the review address specific concerns related to pregnant or lactating women, children, the aged, or those with specific diseases or other physiological conditions? A good review will address vulnerable populations and may be helpful in targeting safety concerns that may apply to a subpopulation, but that may not cause a significant safety concern for the general population (see Chapter 9). Does the review address the potential for interaction with other supplements, drugs, foods, or other medical interventions? A useful review will address potential interactions (see Chapter 8) and explain whether possible interactions have actually been observed from human use, or if interactions described are predicted based on other types of information (e.g., in vitro assays, chemical structure). Inclusion of both demonstrated and theoretical interaction information is important to understanding the safety profile of an ingredient. If considering potential interactions is not within the authors’ expertise or capabilities, then the review should acknowledge that the potential for interactions with other substances was not evaluated. Strengths and Weaknesses of Available Dietary Supplement Resources Table 2-1 provides an overview of many of the available resources that address dietary supplements and characterizes each based on the considerations listed in the previous section. The summaries following the table1 provide a general description based on the general information reviewed. As is apparent from the table, the resources vary in their relevance to FDA’s mission of identifying dietary supplements that would present risk of significant or unreasonable harm. Of the resources that do sufficiently focus on safety, some are not ideally transparent or unbiased. Other resources fall short in other areas. Nevertheless, the different resources are valuable even when their conclusions are less relevant to FDA’s task—they can serve as starting points of information about concerns and as sources of primary literature references. In preparing Table 2-1, it was difficult to provide descriptions for some 1 The descriptive summaries and Table 2-1 are largely based on information from the resource itself via websites or books, or descriptions written by others (Barrett, 1998); they are not based on verification of the statements included in those resources.
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Dietary Supplements: A Framework for Evaluating Safety TABLE 2-1 Brief Characterization of 13 Secondary Resources and How They Meet the Described Considerations Resource Considerations Agency for Healthcare Research and Quality (AHRQ) (AHRQ, 2000a, 2000b, 2002b, 2003a) American Herbal Pharmacopoeia (AHP, 2002, 2004a, 2004b; Upton, 1997, 1999) (Reviewed St. Johns Wort and Valerian Root monographs) Type of organization responsible for resource U.S. government Private, nonprofit organization Substances reviewed techniques, practices, Many health care and substances, including several dietary supplements Botanicals commonly used in the United States; selections are based on recommendations of a prioritization committee or monograph sponsorship from interested organizations or companies Product/endpoint Meta-analysis published when completed Summary monographs Focus on safety/risk Both efficacy and safety are considered Identification, handling, standardization, and analytical methods are discussed; safety and efficacy information are considered Reliance on primary data Primary sources are cited, including foreign language sources Primary and secondary sources are used, including foreign language articles Use of nonhuman data Only human data are considered in the examples reviewed Human, animal, and in vitro information are used in efficacy assessment; however, from the examples reviewed, it is not clear the degree to which various types of information are generally used Description of limitations Limitations are described: a summary of challenges in conducting and interpreting the research is given, difficulties in obtaining and interpreting adverse events are explained The material examined includes limitations as described by the authors of the primary sources
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Dietary Supplements: A Framework for Evaluating Safety Description of literature search strategy Well-defined search strategy, including databases and key words used Strategy was not described in detail Use of current literature Examples reviewed were very current at time of publication, no explanation of updates Monographs published periodically since 1997; older publications, as well as citations within 5 years of publication, were included Starting assumptions/appearance of impartiality A lack of information appears to be interpreted as safety Use of peer review Peer reviewed Outside peer reviewers are used Focus on a particular standardized product and discussion of preparation impact on safety Discusses different preparations and where effect of preparation on safety issues is unclear Preparations are described, but impact of preparation on safety is not specifically described Description of consumption levels considered Ingested amount under consideration is described Recommended levels are described; it is assumed that the safety conclusions are based on these levels Consideration of data from non-oral routes of exposure No mention is made of how non-oral data were handled; in the example reviewed, non-oral data were referred to in some sections, but it is not clear if these data are considered as possibly relevant for safety of oral consumption of the ingredient Non-oral data are referred to in some sections, but it is not clear if these data are considered as possibly relevant for safety of oral consumption of the ingredient Discussion of biological activity or possible mechanism of action Addressed Discussion is included, but implication for safety is not discussed Discussion of specific groups within the general population, if appropriate No recommendations for specific groups in the examples reviewed; for ephedra, the panel was asked to consider safety in children, adolescents, young athletes, and adults, but conclusions on safety are not specific for these groups Precautions for pregnant and lactating women are given in the examples reviewed, but not for children or other groups
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Dietary Supplements: A Framework for Evaluating Safety Interaction with other interventions Interaction with caffeine discussed extensively in the ephedra report; not discussed in other examples reviewed Interactions discussed in the examples reviewed Other comments and considerations for using this resource AHRQ reviews are extensive reviews of health care practices Thorough resource for those supplements considered; less useful due to small number of supplements included to date: garlic, milk thistle, SAMe (S-adenosyl-L-methionine), and ephedra Only 18 monographs are available to date; starting assumption appears to be one of safety, therefore a lack of information appears to be interpreted as safe This is a useful resource to understand use levels, stability, and analytical methods, but the literature search on safety information may not be sufficiently comprehensive for all ingredients considered Resource Considerations American Herbal Products Association Botanical Safety Handbook (McGuffin et al., 1997) Institute of Medicine (IOM) Dietary Reference Intakes—Tolerable Upper Intake Levels (ULs) (IOM, 1997, 1998a, 1998b, 2000, 2001, 2002, 2004) Type of organization responsible for resource Nonprofit trade association representing the herbal products industry Prepared by expert panels assembled by the IOM of the National Academies (Nonprofit organization chartered to give advice to the government) Substances reviewed Botanicals sold in North America Essential vitamins, minerals, and electrolytes, as well as macronutrients and water Product/endpoint Book; safety classifications of botanicals Chapter sections; component of Dietary Reference Intakes publications Focus on safety/risk Safety is primary focus Safety is primary focus; specifically, determining the level at which nutrient intake may cause adverse effects
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Dietary Supplements: A Framework for Evaluating Safety Reliance on primary data 30 references are cited for over 500 botanicals; most are secondary sources of information Primary sources are used, including foreign language articles Use of nonhuman data Cannot be determined due to limited use of primary data Human data primarily, although animal data are used on occasion Description of limitations Limitations of primary data for specific ingredients are generally not described, authors classify some botanicals as “Insufficient Data for Classification” Limitations regarding studies used and the review were well described Description of literature search strategy Not described Not described Use of current literature Published in 1997; secondary sources are mostly late 1980s to early 1990s The ULs have been cited published from 1997 to 2004 in groups of nutrients; at the time of their publication, the authors considered the most recent literature; when and if they will be updated has not been determined Starting assumptions/ appearance of impartiality Not possible to discern due to reliance on secondary sources Caution regarding excess intakes is given when no UL is provided Use of peer review Reviewers are listed in text External peer reviewers were used and are listed in the report Focus on a particular standardized product and discussion of preparation impact on safety Some different preparations, including different plant parts, are considered (e.g., cooked/raw, stems/leaves) Focuses on nutrients present in foods or as concentrates, some of which may be various structural forms; when UL relates to one or more specific forms, discussed in text which forms and why Description of consumption levels considered For some substances, a “common therapeutic dose” is included, so safety conclusions are assumed to be based on these ingestion levels; however, many substances lack Detailed description included on amounts consumed; how the amount ingested will impact the safety is considered, as the purpose is to derive a UL
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Dietary Supplements: A Framework for Evaluating Safety information on the common doses to which safety conclusions are relevant Consideration of data from non-oral routes of exposure According to the text, “Information associated with other forms of administration were reviewed but was not considered as a sole basis for classification” Only oral routes of administration were considered in safety evaluations; evidence of adverse effects related to other routes of exposure may be mentioned Discussion of biological activity or possible mechanism of action Not discussed Biological activity and mechanisms for possible harms are discussed Discussion of specific groups within the general population, if appropriate Pregnant and lactating women, as well as children, are discussed; however, only 34 of 600 botanicals are classified as “not for use during lactation” Age, gender, pregnancy, lactation, and sensitive subpopulations are discussed Interaction with other interventions Information on some ingredients includes comments about interactions, but a discussion of possible interactions is not included for each substance Overall model for review includes section on interaction with other nutrients; some ULs are based on their known interaction with other nutrients (e.g., zinc) Other comments and considerations for using this resource Working assumption is that “safety concerns for herbal products need not be extrapolated from constituent profiles with any more alarm than is appropriate for foods” Botanicals are classified as: Class 1, which can be safely consumed when used appropriately; Class 2, for which certain restrictions apply; Class 3, for which significant data exist to recommend special labeling; and Class 4, for which there is insufficient data Limited to nutrients Uses a risk-assessment methodology related to chronic intake; does not give guidance related to acute ingestion Useful for assessing safety of specific nutrient levels used as supplements Useful in examining specific subpopulations that may be sensitive or at risk
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Dietary Supplements: A Framework for Evaluating Safety Natural Medicines Comprehensive Database The publisher of Pharmacist’s Letter and Prescriber’s Letter created the Natural Medicines Comprehensive Database (NMCD) which is available online and in print (NMCD, 2002). This database reviews many “natural medicines” on the market in North America, and it reviews safety and efficacy for a large number of dietary supplement ingredients. Its goal is 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 (NMCD, 2002). NMCD reports that it covers nearly every natural medicine on the market in North America. New product reviews are prioritized based on market saturation and requests by health professionals (Personal communication, P. Gregory, NMCD, February 21, 2002). For each product that is reviewed, a research team of pharmacists, physicians, and pharmacologists begins the process with a literature search. Initially, when the database was first being developed, the research team consulted reference textbooks, such as the Commission E Monographs, the Physicians’ Desk Reference (PDR), and AHPA’s Botanical Safety Handbook, for their evaluation of the literature. However, the research team soon turned to the primary literature using electronic databases (e.g., MEDLINE and TOXLINE) to find the pertinent literature (Personal communication, P. Gregory, NMCD, February 21, 2002). For the most part, the research team limits their search to Englishlanguage references. However, non-English articles of special significance are also included. For the safety evaluation, the team relies mainly on human data; animal data are rarely used (Personal communication, P. Gregory, NMCD, February 21, 2002). After completion of the literature review, the information is evaluated, a consensus on any relevant issues is reached by the research team, and then a single author drafts the review. The draft is sent out for review to two or three pharmacists and physicians who are not on the research team. After this review, the final draft is added to the database (Personal communication, P. Gregory, NMCD, February 21, 2002). Each product is rated according to specific criteria as: likely safe, possibly safe, possibly unsafe, likely unsafe, or unsafe. Natural products that are rated likely safe are those for which there is general agreement among reliable references that the product is safe when used appropriately or those for which a governmental body has approved their use. A product is rated possibly safe if the reputable references suggest that the product might be safe when used appropriately or there are human studies that report no serious adverse effects. A rating of possibly unsafe requires that there are some data suggesting product use might be unsafe. Likely unsafe indicates
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Dietary Supplements: A Framework for Evaluating Safety agreement among reputable references that the product can be harmful or there are reliable reports of harm to product users. A rating of unsafe is based on finding general agreement among reliable references that the product should not be used, reliable reports of clinically significant harm to product users, or safety warnings for the product issued by a reliable agency. Special mention is made if use during pregnancy, lactation, or in children presents special concerns (NMCD, 2002). Natural Standard Natural Standard was founded as a multi-institution initiative in January 2000 by clinicians and researchers to provide evidence-based information about complementary and alternative therapies (Natural Standard, 2003). It considers itself an impartial service and is not supported by any interest group, professional organization, or pharmaceutical manufacturer. Paid subscriptions to its website, NaturalStandard.com, are the only visible means of support. According to Natural Standard, for each therapy (dietary supplement or other), a research team gathers scientific data and expert opinions. To prepare each monograph, electronic searches are conducted in several databases, including AMED, CANCERLIT, CINAHL, CISCOM, the Cochrane Library, EMBASE, HerbMed, International Pharmaceutical Abstracts, MEDLINE, and NAPRALERT, without restrictions on language or quality of publications. Additionally, industry warnings are regularly monitored. When clinically relevant new data emerge, best efforts are made to immediately update the content. In addition, regular updates with renewed searches occur every 3 to 18 months; the exact interval varies by topic. Rating scales based on the Jadad scoring technique are used to evaluate the quality of the evidence (Jadad et al., 1996). Grading scales “reflect the level of available scientific evidence in support of the efficacy of a given therapy for a specific indication” (Natural Standard, 2003). In addition, “Expert opinion and folkloric precedent are not included in this assessment, and are reflected in a separate section of each monograph” (Natural Standard, 2003). Evidence of harm is considered separately and the grading applies only to evidence of benefit. Monographs undergo blinded peer review prior to inclusion in the database. In cases of editorial disagreement, a three-member panel addresses conflicts and consults experts when needed (Natural Standard, 2003). Physicians’ Desk Reference for Herbal Medicines In 1998 the PDR organization broadened its scope from producing a widely used collection of information on prescription drugs to also produc-
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Dietary Supplements: A Framework for Evaluating Safety ing a collection of information on botanical medicines. This publication was the first edition of the PDR for Herbal Medicines (Medical Economics, 1998). A second edition of PDR for Herbal Medicines was published in 2000 that provides monographs for approximately 700 medicinal herbs (Medical Economics, 2000). The monographs contain information on efficacy, safety, potential interactions, precautions, adverse reactions, and dosage. For 300 of these monographs, the findings and assessments were taken from the German Commission E report. There are useful cross-referencing indices for information such as names, indications, side effects, and interactions. This collection of monographs does not appear to be the product of direct committee effort or to involve a peer review in a consistent manner given the variety of origins of information included. Physicians’ Desk Reference for Nutritional Supplements The PDR for Nutritional Supplements contains over 200 monographs of nearly 1,000 nutritional products, including amino acids, fatty acids, metabolites and cofactors, nucleic acids, proteins, glycosupplements, phytosupplements, hormonal products, and probiotics (Medical Economics, 2001). Crude botanicals or herbal medicines are not included in the 2001 book. Each monograph contains trade names, description, actions and pharmacology, indications and usage, research summary contraindications, interactions, warning signs of overdose, dosage and administration, how supplied, and literature cited. Inaccuracies and typographical errors were noted in some of the references. Like the PDR for Herbal Medicines, there are useful cross-referencing indices. This publication appears to be a summary of information rather than a committee-authored or peer-reviewed activity. The American Pharmaceutical Association’s Practical Guide to Natural Medicines The American Pharmaceutical Association (APhA) is a national professional society of pharmacists that is dedicated to helping pharmacists help consumers. The book, Practical Guide to Natural Medicine, was written for the consumer by a writer for APhA (Peirce, 1999). It is a compilation of information on many substances (mostly botanicals), but includes other substances, such as melatonin. For each substance, the monograph describes what it is, what it is used for, the forms available, and the dosage commonly reported. Sections include, “Will it work for you? What the studies say”; and “Will it harm you? What the studies say” (Peirce, 1999). Given its orientation to the lay reader, the evaluation of the literature does not appear to be as extensive or rigorous as some of the other resources.
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Dietary Supplements: A Framework for Evaluating Safety General sources and text citations are listed at the end of each monograph. Also included is a list of the board of reviewers for the book. World Health Organization4 WHO has begun to develop international specifications for the most widely used medicinal plants in an effort to fill the need for current, authoritative information on their safety and efficacy (WHO, 1999). WHO published the first volume of monographs on selected medicinal plants in 1999 (WHO, 1999); second and third volumes were published in 2000 and 2003. The medicinal plants and products in each volume were selected by a WHO advisory group based on the extent of each plant’s use and importance throughout the world and on the sufficiency of the data available to evaluate safety and efficacy. The goal is to include information on safety, effectiveness, and quality control of botanical medicines. The monographs present descriptive information, purity tests, chemical constituents, medicinal uses, clinical studies, pharmacology, contraindications, warnings, precautions, adverse reactions, and posology5 (WHO, 1999). Each monograph published to date was drafted under the direction of a team of experts in botanical medicines and medicinal plants. Information for the monographs was collected from a review of the literature, bibliographies, review articles, pharmacopoeias from several countries, reference books, and the NAPRALERT database.6 Once drafted, the monographs were reviewed by a number of additional basic scientists, physicians, pharmacologists, pharmacognosists, and toxicologists throughout the world with expertise in traditional medicine, drug regulation, drug evaluation, and pharmaceutical sciences. WHO convenes a Consultation on Selected Medicinal Plants that consists of 16 experts in medicinal plants and drug regulation to give final approval, modification, or rejection of the proposed monographs. WHO plans to periodically supplement and update the monographs as new data are made available (WHO, 1999). 4 As a matter of disclosure, the author of the WHO specifications is committee member Norman Farnsworth. 5 From the Greek, posos (how much), representing the science or doctrine of dosing. 6 NAPRALERT, an acronym for Natural Products ALERT, is a relational database of world literature describing the ethnomedical or traditional uses, chemistry, and pharmacology of plant, microbial, and animal (primarily marine) extracts. In addition, it contains considerable data on the chemistry and pharmacology (including human studies) of secondary metabolites of known structure, derived from natural sources. NAPRALERT is available by subscription from the University of Illinois (Farnsworth, 2003).
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Dietary Supplements: A Framework for Evaluating Safety U.S. Pharmacopeia-National Formulary7 The U.S. Pharmacopeia-National Formulary (USP-NF), a nongovernmental, nonprofit organization, develops and provides standards of identity, strength, quality, purity, packaging, and labeling of drugs sold in the United States in the form of standards monographs; these monographs do not consider the inherent safety of the substance. The USP-NF standards were recognized by Congress in the Federal Food, Drug, and Cosmetic Act of 1938 (21 U.S.C. § 321 et seq.) as the official compendium of the United States, making its established standards for drugs essentially similar to federal regulations (USP, 2002a, 2002b). In its first publication in 1820, the USP contained monographs for hundreds of botanicals; however, most of them were removed by the end of the 1930s due to diminishing use in medical practice following the appearance of synthetic medicinal compounds in the U.S. marketplace (Barrett, 1998; Blumenthal, 1997). In 1990, in response to a USP Convention Resolution, the USP Committee of Revision, an independent body of elected scientific experts representing industry, academia, and government agencies, established public standards for vitamins, minerals, and their combination products. These standards monographs, along with general chapters that include manufacturing practices for nutritional supplements, were grouped together and published within a separate section of the USP called Nutritional Supplements (Roll, 2002). In 1995, after passage of DSHEA, the USP Convention, in recognition of the resurgence in the use of botanicals by the American public, adopted a resolution that encouraged the USP Committee of Revision to establish public standards for botanical dietary supplements. In response to the Convention resolution, the USP Committee of Revision generated a list of approximately 20 widely used botanicals for public standards monographs. Criteria for identification of these botanicals included lack of safety risk, 7 Distinct from its development of the USP-NF monographs, USP launched the Dietary Supplement Verification Program (DSVP) in November 2001. Manufacturers sponsor products that are tested and reviewed by USP. If the product meets the DSVP requirements, the product is granted a USP certification mark. This mark is intended to signify that the product (1) contains the ingredients stated on the label in the declared amount and strength, (2) meets stringent standards for product purity, (3) meets specified limits on known contaminants, and (4) has been manufactured under good manufacturing practices according to the USP-NF General Chapter on Manufacturing Practices for Nutritional Supplements and the FDA’s Advance Notice of Proposed Rulemaking for Good Manufacturing Practices (Personal communication, S. Srinivasan, USP, February 14, 2002; USP, 2004). Importantly, the DSVP certification mark is not intended to imply safety or efficacy of dietary supplement ingredients. The USP-DSVP is not included in Table 2-1 due to the program’s emphasis on quality and label verification, rather than inherent ingredient safety. Similar work of NSF International and other organizations is not described for the same reason.
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Dietary Supplements: A Framework for Evaluating Safety extent of use by consumers, interest from regulatory agencies, positive assessment by recognized pharmacognosists, and the ability of the botanical to meet typical requirements for USP monographs. History of traditional use and pharmacological action were also considered. According to USP, standards monographs are not developed for botanicals that USP believes may be associated with a significant safety risk (Roll, 2002). Once a botanical has been approved for inclusion in the USP or the NF,8 analytical methods are requested from several manufacturers and reviewed by the USP Expert Committee relating to dietary supplements. Before official adoption into USP-NF, public comment on proposed standards is generated by publicizing them in Pharmacopoeia Forum (Personal communication, V.S. Srinivasan, USP, February 11, 2002). An evaluation of USP or USP-NF was not included in Table 2-1 due to the emphasis on ingredient quality rather than safety. CONSIDERATION OF FRAMEWORKS FOR EVALUATING THE SAFETY OF OTHER SUBSTANCES In the previous section, resources that address the safety of dietary supplements were considered. There are also numerous frameworks in place that the FDA and other organizations have used to evaluate the safety of other substances to which humans may be exposed. Assessment of the scope, characteristics, and processes used in other frameworks can aid in the development of a workable framework for dietary supplement safety evaluation. Frameworks that FDA already has in place to evaluate food additives and pharmaceuticals were reviewed, as well as mechanisms for considering the safety of cosmetic ingredients and of flavors and extracts. The Environmental Protection Agency (EPA) has also developed a system for considering possible human and environmental impacts of toxic substances. Detailed summaries of the different frameworks, as described by the organizations, are included in Appendix A. Role of Premarket Approval and Postmarket Surveillance Consideration of frameworks used to evaluate the safety of other substances contributed to an understanding of different types of “frameworks.” For most of the frameworks that were evaluated, the scientific principles 8 Whether a substance’s monograph is admitted into the USP or its companion guide, the NF, currently depends on its approval status, as determined by USP. If the substance has an FDA- or USP-approved use, then standards are developed for it and it is published in the USP; otherwise, the standards for the substance are published by USP in the NF.
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Dietary Supplements: A Framework for Evaluating Safety associated with the framework operate in a context that utilizes some aspects of premarket approval or requirements for postmarket surveillance. DSHEA does not include provisions for either of these conditions in its regulation of dietary supplement ingredients, although it provides the agency with the requirement for conducting postmarket review of dietary supplement safety (see Chapter 1). Consequently, the existing frameworks reviewed could not simply be adapted to dietary supplement ingredients; this resulted in the need to define the use of the scientific principles in the context of postmarket review of safety. The postmarket versus premarket difference is apparent from reviewing the FDA process for approval of a new food additive. The Redbook, periodically published by FDA (OFAS, 2001, 2003), outlines the types of testing expected in order to receive food additive approval, thus specifically defining the types of premarket testing that must be conducted. No such requirement exists for dietary supplement ingredients. Likewise, the generally recognized as safe (GRAS) notification procedure (see Table 1-1) identifies certain types of information that a manufacturer must present in order for a food ingredient to be considered GRAS. In this context it is clear that manufacturers are responsible for demonstrating the safety of an additive before it is allowed in the marketplace. In contrast, DSHEA places the burden of proof on FDA to provide evidence that a dietary supplement ingredient currently on the market is associated with significant or unreasonable risk. In the EPA new chemicals program, the manufacturer submits a premanufacturing notification. Often little or no data are available on the new substance, so an expert team considers the chemical structure and substructure to look for health-based “structural alerts,” based on safety concerns of analogous chemicals. If a chemical is categorized in one of the structural alert categories, it is treated as if it causes the health effects of concern unless demonstrated otherwise. Such a structure-based approach was considered difficult to adapt to the dietary supplement system as a whole because many of the dietary supplements, such as botanicals, are complex mixtures of many substances that may or may not be known, and health concerns may be very dependent on the level ingested. Nonetheless, aspects of this approach remain in the principles regarding structural relatedness (see Chapter 6). Conceptualization of a Framework Review of other resources on dietary supplements and consideration of other frameworks assisted in the development of the framework described in the next chapter. A working concept/definition of a framework for safety evaluation of dietary supplement ingredients was developed, having two
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Dietary Supplements: A Framework for Evaluating Safety basic elements that must work together: (1) principles for how to assess risk in a scientifically valid way, using the types of data and information that are likely to be available to FDA, and (2) a process by which FDA gathers this information and increases its level of scrutiny to make decisions of whether significant risk exists, overturning the assumption of safety and determining if regulatory action is needed. SUMMARY In reviewing the methods used by other expert bodies to consider dietary supplements and in reviewing the discussions with the sponsor and other interested representatives, the following attributes of a framework to evaluate the safety of dietary supplements were identified: It must be workable and able to be integrated into the agency’s program of work and resources available. It should provide guidance on organizing diverse information that is already available. It should provide for the scientifically valid categorization, based on priority, of the diverse substances classified as dietary supplements. It should establish a database for the collection of information regarding potential safety concerns that can be updated as new information becomes available. It should provide a method to integrate diverse information into a priority-setting scheme so that efforts and resources can be maximally directed toward those dietary supplement ingredients with the greatest safety concerns. It should provide a mechanism for public input. It should be consistent with the provisions of DSHEA. Once the definition and key attributes of a safety framework were identified, a framework that focused on the safety of dietary supplements was developed. This approach is described in the following chapter, with the basis for the scientific principles incorporated into the framework discussed in detail in the succeeding chapters. REFERENCES AHP (American Herbal Pharmacopoeia). 2002. Mission Statement: The American Herbal Pharmacopoeia. Online. Available at http://www.herbal-ahp.org/mission.html. Accessed November 20, 2002. AHP. 2004a. Monographs: American Herbal Pharmacopoeia and Therapeutic Compendium: Standards of Analysis, Quality Control, and Therapeutics. Online. Available at http://www.herbal-ahp.org/. Accessed February 12, 2004.
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Representative terms from entire chapter: