Dietary Supplements A Framework for Evaluating Safety (2005) / Chapter Skim
Currently Skimming:
2 Approaches Used by Others and Existing Safety Frameworks
2 Approaches Used by Others and Existing Safety Frameworks
Pages 43-84
The Chapter Skim interface presents what we've algorithmically identified as the most significant single chunk of text within every page in the chapter.
Select key terms on the right to highlight them within pages of the chapter.
From page 43... ...
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.
|
From page 44... ...
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.
|
From page 45... ...
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 47)
|
From page 46... ...
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)
|
From page 47... ...
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.
|
From page 48... ...
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.
|
From page 49... ...
Type of organization U.S. government Private, nonprofit responsible for resource organization Substances reviewed Many health care Botanicals commonly used in techniques, practices, the United States; and substances, selections are based on including several recommendations of a dietary supplements prioritization committee or monograph sponsorship from interested organizations or companies Product/endpoint Meta-analysis published Summary monographs when completed Focus on safety/risk Both efficacy and safety Identification, handling, are considered standardization, and analytical methods are discussed; safety and efficacy information are considered Reliance on primary data Primary sources are cited, Primary and secondary including foreign sources are used, including language sources foreign language articles Use of nonhuman data Only human data are Human, animal, and in vitro considered in the information are used in examples reviewed 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: The material examined a summary of challenges includes limitations as in conducting and described by the authors of interpreting the research the primary sources is given, difficulties in obtaining and interpreting adverse events are explained continued
|
From page 50... ...
50 DIETARY SUPPLEMENTS TABLE 2-1 Continued Description of literature Well-defined search Strategy was not described search strategy strategy, including in detail databases and key words used Use of current literature Examples reviewed were Monographs published very current at time of periodically since 1997; publication, no older publications, as well explanation of updates as citations within 5 years of publication, were included Starting assumptions/ A lack of information appearance of appears to be interpreted impartiality as safety Use of peer review Peer reviewed Outside peer reviewers are used Focus on a particular Discusses different Preparations are described, standardized product preparations and where but impact of preparation and discussion of effect of preparation on on safety is not preparation impact safety issues is unclear specifically described on safety Description of Ingested amount under Recommended levels are consumption levels consideration is described; it is assumed considered described that the safety conclusions are based on these levels Consideration of data No mention is made of Non-oral data are referred from non-oral routes of how non-oral data were to in some sections, but it exposure handled; in the example is not clear if these data reviewed, non-oral data are considered as possibly were referred to in some relevant for safety of oral sections, but it is not consumption of the clear if these data are ingredient considered as possibly relevant for safety of oral consumption of the ingredient Discussion of biological Addressed Discussion is included, but activity or possible implication for safety is mechanism of action not discussed Discussion of specific No recommendations for Precautions for pregnant and groups within the specific groups in the lactating women are given general population, examples reviewed; for in the examples reviewed, if appropriate ephedra, the panel was but not for children or asked to consider safety other groups in children, adolescents, young athletes, and adults, but conclusions on safety are not specific for these groups
|
From page 51... ...
Dietary Reference Intakes- American Herbal Products Tolerable Upper Intake Association Botanical Levels (ULs) Safety Handbook (IOM, 1997, 1998a, 1998b, Considerations (McGuffin et al., 1997)
|
From page 52... ...
52 DIETARY SUPPLEMENTS TABLE 2-1 Continued Reliance on primary data 30 references are cited for Primary sources are used, over 500 botanicals; including foreign language most are secondary articles sources of information Use of nonhuman data Cannot be determined due Human data primarily, to limited use of primary although animal data are data used on occasion Description of limitations Limitations of primary Limitations regarding studies data for specific used and the review ingredients are generally were well described not described, authors classify some botanicals as "Insufficient Data for Classification" Description of literature Not described Not described search strategy Use of current literature Published in 1997; The ULs have been secondary sources cited published from 1997 to are mostly late 1980s 2004 in groups of to early 1990s 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/ Not possible to discern Caution regarding excess appearance of impartiality due to reliance on intakes is given when no secondary sources 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 Some different Focuses on nutrients present standardized product preparations, including in foods or as and discussion of different plant parts, are concentrates, some of preparation impact on considered (e.g., cooked/ which may be various safety raw, stems/leaves) structural forms; when UL relates to one or more specific forms, discussed in text which forms and why Description of For some substances, a Detailed description included consumption levels "common therapeutic on amounts consumed; considered dose" is included, so how the amount ingested safety conclusions are will impact the safety is assumed to be based on considered, as the purpose these ingestion levels; is to derive a UL however, many substances lack
|
From page 53... ...
APPROACHES USED BY OTHERS AND EXISTING SAFETY FRAMEWORKS 53 TABLE 2-1 Continued information on the common doses to which safety conclusions are relevant Consideration of data According to the text, Only oral routes of from non-oral routes "Information associated administration were of exposure with other forms of considered in safety administration were evaluations; evidence of reviewed but was not adverse effects related to considered as a sole other routes of exposure basis for classification" may be mentioned Discussion of biological Not discussed Biological activity and activity or possible mechanisms for possible mechanism of action harms are discussed Discussion of specific Pregnant and lactating Age, gender, pregnancy, groups within the women, as well as lactation, and sensitive general population, children, are discussed; subpopulations are if appropriate however, only 34 of 600 discussed botanicals are classified as "not for use during lactation" Interaction with other Information on some Overall model for review interventions ingredients includes includes section on comments about interaction with other interactions, but a nutrients; some ULs are discussion of possible based on their known interactions is not interaction with other included for each nutrients (e.g., zinc) substance Other comments and Working assumption is Limited to nutrients considerations for using that "safety concerns for Uses a risk-assessment this resource herbal products need not methodology related to be extrapolated from chronic intake; does not constituent profiles with give guidance related to any more alarm than is acute ingestion appropriate for foods" Useful for assessing safety of Botanicals are classified as: specific nutrient levels used Class 1, which can be as supplements safely consumed when Useful in examining specific used appropriately; Class subpopulations that may 2, for which certain be sensitive or at risk restrictions apply; Class 3, for which significant data exist to recommend special labeling; and Class 4, for which there is insufficient data continued
|
From page 54... ...
that promotes herbal medicines Substances reviewed 380 medicinal plants and 107 medicinal plants and phytomedicines in the phytomedicines common to German marketplace the United States; largely derived from those in the German marketplace Product/endpoint Book of brief monographs Book of monographs Focus on safety/risk Safety and efficacy are Safety and efficacy are considered considered Reliance on primary data Some primary and many Primary and secondary secondary sources were sources are cited in the reported to be used, but text the sources are not cited or available
|
From page 55... ...
assumed to replicate the original Commission E findings Use of peer review -- a Text indicates "streamlined peer review process" was employed, but also indicates additional information provided in the expanded text was not subject to the level of review conducted by Commission E Focus on a particular Preparation impact on Specific preparations were standardized product safety is not specifically not addressed except for and discussion of discussed; safety two botanicals (Echinacea preparation impact on conclusions are assumed and hawthorne) , where safety to be based on confusion existed from standardizations Commission E; safety described because conclusions are based on conclusions were made products standardized for the German for the German marketplace marketplace Description of Recommendations for Recommendations for consumption levels therapeutic doses are therapeutic doses as in the considered included, so it is Commission E translation, assumed that these are so it is assumed that these the intake levels on are the intake levels on which safety judgments which safety judgments are made are made continued
|
From page 56... ...
Lack of references and ability to distinguish reasons for Negative review in the text limit this resource's usefulness; it may be useful for understanding recommended doses, Table 13 may be useful for identifying botanicals of suspected risk (but inclusion of well-known spices in the table without indication of dose is not useful) Usefulness of conclusions depends on similarity of German products to products consumed in the United States
|
From page 57... ...
Focus on safety/risk Includes safety data, but Safety and efficacy are primarily designed for considered; describes efficacy assessment by circumstances in which the regulatory authorities supplement is Likely to be Safe, Possibly Safe, Possibly Unsafe, Likely to be Unsafe, Unsafe Reliance on primary data Primary sources are cited, Primary and secondary including many foreign sources are cited, including language sources foreign language sources Use of nonhuman data Animal and in vitro Safety information is experiments are used generally derived from human data Description of limitations -- a Limitations in interpreting human data are presented Description of literature Not described Not described in database, search strategy but some aspects of strategy are described in description below, from personal communication Use of current literature Late 1990s literature cited Very current; according to the publisher, individual supplements are updated about every 6 months; the book is updated annually Starting assumptions/ The stated purpose is to appearance of "advance the scientific impartiality status of phytomedicines"; continued
|
From page 58... ...
58 DIETARY SUPPLEMENTS TABLE 2-1 Continued ESCOP is an umbrella organization for phytotherapy trade associations, thus conflict of interest cannot be ruled out Use of peer review Peer reviewed Personal communication with NMCD indicated that peer review is conducted Focus on a particular Appears to focus on a Generally does not focus on standardized product standardized product; specific products or impact and discussion of one monograph compares of preparation on safety preparation impact on the effects of the root safety preparation with the syrup on driving impairment Description of consumption The level at which adverse Doses used are described; levels considered effects were reported is impact of dose on safety is described discussed Consideration of data -- a Non-oral data are referred from non-oral routes to in some sections, but it of exposure is not clear if these data were considered as possibly relevant for safety of oral consumption of the ingredient Discussion of biological Addressed, but not Discussed activity or possible necessarily with safety mechanism of action in mind Discussion of specific Considers pregnancy Pregnancy and lactation are groups within the and lactation always included in the general population, safety assessment, children if appropriate are sometimes included; secondary sources are largely used for this discussion Interaction with other Sections for interactions Describes information for interventions are included, but both other supplements, drugs, examples examined and foods, and other stated "none reported" medical conditions; discusses side effects or contraindications observed in the literature, as well as those that might be theorized based on knowledge of the mechanism of action Other comments and Emphasis on European Comprehensive in terms of considerations for using botanical products that the human clinical this resource may not resemble literature and the number
|
From page 59... ...
2000) Type of organization For-profit, not supported For-profit organization responsible for resource by any interest group, professional organization, or pharmaceutical manufacturer Substances reviewed Covers alternative Over 700 botanicals therapies and complementary medicines, including nutrient and nonnutrient dietary supplements Product/endpoint Online monograph Book of brief monographs Focus on safety/risk Safety and efficacy are Both safety and efficacy are considered considered Reliance on primary data Mostly primary sources, Primary sources are cited, some abstracts, including including foreign language foreign language articles sources Use of nonhuman data Mostly human data, some Mostly human data; in vitro data and a limited however, some animal and number of animal studies in vitro data are are considered considered Description of limitations Limitations are described Limitations are somewhat described Description of literature Described thoroughly Search strategy is not search strategy described; many monographs appear to be based upon the Commission E translation continued
|
From page 60... ...
60 DIETARY SUPPLEMENTS TABLE 2-1 Continued Use of current literature Current literature, Mostly current, some updated every historical information 318 months Starting assumptions/ Appears to give favorable appearance of impartiality consideration toward the approved German Commission E monographs (the basis for about half of the monographs) as "approved by the Commission E," without critical evaluation Use of peer review Introductory information No indication of peer review describes an evidenced- found based, consensus-based, peer review Focus on a particular Does not appear to focus A number of different standardized product on specific preparations preparations are described, and discussion of impact on safety is preparation impact on described for some; for safety monographs based on conclusions of Commission E, usefulness of conclusions depends on similarities of German products to products consumed in the United States Description of A recommended use Recommended doses are consumption levels amount is described; it is described considered assumed that safety conclusions are based on this amount Consideration of data No mention is made of No mention is made of how from non-oral routes how non-oral data were non-oral data were of exposure handled in the example handled reviewed Discussion of biological Discussed Addressed, but not activity or possible necessarily with safety in mechanism of action mind Discussion of specific Pregnant and lactating Second edition has separate groups within the women are addressed indexes for herbs not for general population, use during pregnancy or if appropriate lactation or for use only under supervision Interaction with other Thorough section on Interactions discussed and a interventions interactions with Drug/Herb Interaction conventional therapies, Guide is included drugs, other herbs, and supplements
|
From page 61... ...
(Peirce, 1999) Type of organization For-profit organization Nonprofit organization responsible for resource Substances reviewed Vitamins, minerals, amino Botanicals acids, and other nonbotanical dietary supplements Product/endpoint Book Book Focus on safety/risk Safety and efficacy are Safety and efficacy are considered considered Reliance on primary data Many primary sources, Mostly secondary sources some secondary, including foreign language articles Use of nonhuman data Some in vitro and animal Cannot be determined due data are used to reliance on secondary data Description of limitations Limitations are generally Describes insufficiencies in not discussed amount of available data, but discussion of primary data is limited continued
|
From page 62... ...
62 DIETARY SUPPLEMENTS TABLE 2-1 Continued Description of literature Search strategy not Description limited to search strategy described indication that the "National Library of Medicine's biomedical literature, Medline, and NAPRALERT" were used Use of current literature Current for some Some current sources, as supplements, less so well as secondary sources, for others are used Starting assumptions/ appearance of impartiality Use of peer review No indication of peer Board of Reviewers listed review found Focus on a particular Impact of preparation on Describes different forms standardized product safety is not particularly available, but impact on and discussion of addressed; however, safety is not specifically preparation impact on it is focused on nutrients discussed; does not safety preparations, which are describe characteristics of often USP-standardized; the products to which for other natural comments about safety products, does not focus apply on particular standardized products Description of Usual ingested amounts Usual ingested amounts are consumption levels and how substances are described; it is assumed considered supplied is described; it is that the safety conclusions assumed that the safety are based on these ingested conclusions are based on amounts these ingested amounts Consideration of data No mention is made of -- a from non-oral routes how non-oral data of exposure were handled Discussion of biological Discussed for substances Discussed for most activity or possible for which the information substances mechanism of action was known Discussion of specific groups within the Discussed Pregnancy and lactation general population, if issues are discussed when appropriate considered relevant Interaction with other Discussed, when available, Interactions are discussed in interventions for other supplements, some places drugs, and botanicals Other comments and Comprehensive in terms of Book was developed largely considerations for using the number and range of for the consumer, limited this resource supplements described citations Limitations in the compre- Lack of comprehensive hensiveness of the literature search limits literature usefulness
|
From page 63... ...
(Reviewed Radix Valerianae, Radix Ginseng, Herba Considerations Echinaceae Purpureae) Type of organization International, nonprofit responsible for resource organization Substances reviewed Major medicinal plants; selection based on extent of use, worldwide importance, and availability of data Product/endpoint Book of summary monographs Focus on safety/risk Safety, efficacy, and quality control are considered Reliance on primary data Some primary and some secondary sources are cited, including foreign language articles Use of nonhuman data All types of data are considered Description of limitations Data limitations are described for efficacy, but not for safety Description of literature Describes sources of search strategy information searched and timeline of scientific literature search Use of current literature Several volumes have been published since 1999; additional safety concerns may arise well after the review was prepared, due to the length of time it takes to get agreement on a monograph and print it Starting assumptions/ appearance of impartiality Use of peer review Extensive peer review continued
|
From page 64... ...
64 DIETARY SUPPLEMENTS TABLE 2-1 Continued Focus on a particular Defines the medicinal plant standardized product and describes compounds and discussion of to standardize a product; preparation impact on adverse reaction description safety discusses preparation Description of Dose is specified in relation consumption levels to adverse effects; although considered one monograph only states that "large doses may...," many specify how much was associated with the adverse reaction Consideration of data Non-oral data are referred from non-oral routes of to in some sections, but it exposure is not clear if these data were considered as possibly relevant Discussion of biological Discussed activity or possible mechanism of action Discussion of specific Pregnancy, lactation, and groups within the children are considered general population, if appropriate Interaction with other Interactions with drugs are interventions mentioned, if known; many entries say "None reported" Other comments and The section on medicinal uses considerations for using is divided into three parts: this resource Uses Supported by Clinical Data; Uses Described in Traditional Medical Systems, and Uses Described in Folklore; thus, may be a good resource for historic information Some of the safety data references the German Commission E Useful in that the standardized product is carefully defined and adverse reactions are viewed in this context Additional safety concerns may arise well after the review was prepared, due to the length of time it takes to get agreement on a monograph and print it aThis question could not be answered due to limitations in the analysis or lack of description in the available material.
|
From page 65... ...
Information about advanced degrees was helpful, but usually did not indicate whether the individuals had the knowledge needed to conduct a safety evaluation or to evaluate the various types of concerns raised for an ingredient. It may be unrealistic to expect that individuals with in-depth knowledge and expertise in the safety of all dietary supplement ingredients, or even all botanicals, exist.
|
From page 66... ...
As indicated in the table, the committee assumed that specified "recommended" or "typical" ingestion levels were the basis of safety comments, but for resources that made conclusions, it would be useful for the reviews to explicitly state the amounts to which the conclusions apply. Resources Related to Dietary Supplement Safety A number of resources are available that have potential use for aiding in the evaluation of the safety of dietary supplement ingredients.
|
From page 67... ...
. Based on this process, the dietary supplements milk thistle, ephedra, garlic,
|
From page 68... ...
. American Herbal Pharmacopoeia The American Herbal Pharmacopoeia (AHP)
|
From page 69... ...
is a national trade association for the botanical products industry. In response to passage of the Dietary Supplement and Health Education Act (DSHEA)
|
From page 70... ...
. Institute of Medicine In 1997 the Food and Nutrition Board, IOM, National Academies, published its first report on Dietary Reference Intakes (DRIs)
|
From page 71... ...
This resulted in the formation of a series of scientific commissions. Commission E was established by the German Minister of Health to review botanical drugs and preparations from medicinal plants.
|
From page 72... ...
If safety concerns outweighed the potential benefits of a substance, the monograph was assigned a negative (unapproved) rating.
|
From page 73... ...
. Expanded German Commission E The American Botanical Council, which published the English translation of the original monographs from the German Commission E, subsequently expanded upon the original monographs by adding references, some of which were published after the 1994 review by Commission E, for 107 medicinal plants and phytomedicines common to the United States.3 This was published as the book Herbal Medicine: Expanded Commission E Monographs (Blumenthal et al., 2000)
|
From page 74... ...
. 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.
|
From page 75... ...
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)
|
From page 76... ...
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)
|
From page 77... ...
. Each monograph published to date was drafted under the direction of a team of experts in botanical medicines and medicinal plants.
|
From page 78... ...
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, 7Distinct from its development of the USP-NF monographs, USP launched the Dietary Supplement Verification Program (DSVP)
|
From page 79... ...
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.
|
From page 80... ...
A working concept/definition of a framework for safety evaluation of dietary supplement ingredients was developed, having two
|
From page 81... ...
· 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.
|
From page 82... ...
2002. Assessment of the quality of reference books on botanical dietary supplements.
|
From page 83... ...
David Roll, Director, Dietary Supplements, United States Pharmacopeia. Presentation given at the Institute of Medicine Committee on the Frame work for Evaluating the Safety of Dietary Supplements' Open Session on the Proposed Framework for Evaluating the Safety of Dietary Supplements, Washington, DC, Septem ber 26.
|
From page 84... ...
2004. Overview: USP's Dietary Supplement Verification Program.
|
Key Terms
This material may be derived from roughly machine-read images, and so is provided only to facilitate research.
More
information on Chapter Skim is available.