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Dietary Supplements: A Framework for Evaluating Safety (2005)

Chapter: 2 Approaches Used by Others and Existing Safety Frameworks

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Suggested Citation:"2 Approaches Used by Others and Existing Safety Frameworks." Institute of Medicine and National Research Council. 2005. Dietary Supplements: A Framework for Evaluating Safety. Washington, DC: The National Academies Press. doi: 10.17226/10882.
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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.

Suggested Citation:"2 Approaches Used by Others and Existing Safety Frameworks." Institute of Medicine and National Research Council. 2005. Dietary Supplements: A Framework for Evaluating Safety. Washington, DC: The National Academies Press. doi: 10.17226/10882.
×

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.

  1. 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.

  2. 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

Suggested Citation:"2 Approaches Used by Others and Existing Safety Frameworks." Institute of Medicine and National Research Council. 2005. Dietary Supplements: A Framework for Evaluating Safety. Washington, DC: The National Academies Press. doi: 10.17226/10882.
×

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.

  1. 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 47), 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.

  2. 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.

  3. 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.

  4. 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.

  5. How current is the information? A good review includes relevant current information, in addition to older information published in repu-

Suggested Citation:"2 Approaches Used by Others and Existing Safety Frameworks." Institute of Medicine and National Research Council. 2005. Dietary Supplements: A Framework for Evaluating Safety. Washington, DC: The National Academies Press. doi: 10.17226/10882.
×

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.

  1. 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.

  2. 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

  3. 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.

  4. 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.”

  5. If appropriate, is variability of specific preparations addressed or acknowledged? Do reviewers address or acknowledge the limitations in

Suggested Citation:"2 Approaches Used by Others and Existing Safety Frameworks." Institute of Medicine and National Research Council. 2005. Dietary Supplements: A Framework for Evaluating Safety. Washington, DC: The National Academies Press. doi: 10.17226/10882.
×

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.

  1. 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.

  2. 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.)

  3. 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.

Suggested Citation:"2 Approaches Used by Others and Existing Safety Frameworks." Institute of Medicine and National Research Council. 2005. Dietary Supplements: A Framework for Evaluating Safety. Washington, DC: The National Academies Press. doi: 10.17226/10882.
×
  1. 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.

  2. 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).

  3. 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.

Suggested Citation:"2 Approaches Used by Others and Existing Safety Frameworks." Institute of Medicine and National Research Council. 2005. Dietary Supplements: A Framework for Evaluating Safety. Washington, DC: The National Academies Press. doi: 10.17226/10882.
×

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

Suggested Citation:"2 Approaches Used by Others and Existing Safety Frameworks." Institute of Medicine and National Research Council. 2005. Dietary Supplements: A Framework for Evaluating Safety. Washington, DC: The National Academies Press. doi: 10.17226/10882.
×

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

Suggested Citation:"2 Approaches Used by Others and Existing Safety Frameworks." Institute of Medicine and National Research Council. 2005. Dietary Supplements: A Framework for Evaluating Safety. Washington, DC: The National Academies Press. doi: 10.17226/10882.
×

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

Suggested Citation:"2 Approaches Used by Others and Existing Safety Frameworks." Institute of Medicine and National Research Council. 2005. Dietary Supplements: A Framework for Evaluating Safety. Washington, DC: The National Academies Press. doi: 10.17226/10882.
×

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

Suggested Citation:"2 Approaches Used by Others and Existing Safety Frameworks." Institute of Medicine and National Research Council. 2005. Dietary Supplements: A Framework for Evaluating Safety. Washington, DC: The National Academies Press. doi: 10.17226/10882.
×

 

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

Suggested Citation:"2 Approaches Used by Others and Existing Safety Frameworks." Institute of Medicine and National Research Council. 2005. Dietary Supplements: A Framework for Evaluating Safety. Washington, DC: The National Academies Press. doi: 10.17226/10882.
×

 

Classification may be helpful for identifying some potential problems, but there is no class that is “Unsafe”

Safety classifications need more justification; the fact that a botanical does not appear on one of the restricted use lists for particular conditions does not indicate that it is safe for the particular condition

 

 

Resource

Considerations

Translation of the German Commission E (Blumenthal et al., 1998)

Expanded German Commission E (Blumenthal et al., 2000)

Type of organization responsible for resource

Commission E, which wrote the original monographs in German, is a German government organization; American Botanical Council (ABC), which translated the Commission E monographs for this resource, is a nonprofit member organization (including corporate members) that promotes herbal medicines

ABC expanded upon the original Commission E monographs in this text

Substances reviewed

380 medicinal plants and phytomedicines in the German marketplace

107 medicinal plants and phytomedicines common to 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 considered

Safety and efficacy are considered

Reliance on primary data

Some primary and many secondary sources were reported to be used, but the sources are not cited or available

Primary and secondary sources are cited in the text

Suggested Citation:"2 Approaches Used by Others and Existing Safety Frameworks." Institute of Medicine and National Research Council. 2005. Dietary Supplements: A Framework for Evaluating Safety. Washington, DC: The National Academies Press. doi: 10.17226/10882.
×

Use of nonhuman data

a

Appeared to rely mostly on human data, although some animal data are mentioned

Description of limitations

a

a

Description of literature search strategy

General types of sources are described, but specifics of the search strategy are not

General types of sources are described but specifics of the search strategy are not

Use of current literature

Original Commission E monographs were completed in 1994; assessment of literature used is not possible because it is not cited

Includes references from the year 2000

Starting assumptions/appearance of impartiality

Translation sponsored by ABC (including corporate members), but it is assumed to replicate the original Commission E findings

Sponsored by ABC (including corporate members)

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 standardized product and discussion of preparation impact on safety

Preparation impact on safety is not specifically discussed; safety conclusions are assumed to be based on standardizations described because conclusions were made for the German marketplace

Specific preparations were not addressed except for two botanicals (Echinacea and hawthorne), where confusion existed from Commission E; safety conclusions are based on products standardized for the German marketplace

Description of consumption levels considered

Recommendations for therapeutic doses are included, so it is assumed that these are the intake levels on which safety judgments are made

Recommendations for therapeutic doses as in the Commission E translation, so it is assumed that these are the intake levels on which safety judgments are made

Suggested Citation:"2 Approaches Used by Others and Existing Safety Frameworks." Institute of Medicine and National Research Council. 2005. Dietary Supplements: A Framework for Evaluating Safety. Washington, DC: The National Academies Press. doi: 10.17226/10882.
×

Consideration of data from non-oral routes of exposure

No mention of how non-oral data were handled

No mention of how non-oral data were handled

Discussion of biological activity or possible mechanism of action

Not discussed in detail

Discussed somewhat

Discussion of specific groups within the general population addressed, if appropriate

Pregnancy and lactation are considered

Pregnancy and lactation are considered, as are contraindications, side effects, and interactions with other drugs

Interaction with other interventions

Discussed

Limited to drug interactions, but the statement “none known” is generally used

Other comments and considerations for using this resource

Medicinal plants only

Safety is considered in light of potential benefit because this was part of a review of all medicines on the German market

Categorized into three classes: Approved, Unapproved-negative (safety concerns outweighed benefit), and Unapproved-null (no risk, but also no substantiated efficacy)

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

Updated review of selected German Commission E monographs

Limited in terms of in-depth evaluation of safety, toxicology, adverse effects, or drug interactions

The “quick look” cross-references included may be useful in establishing a list of supplements for which safety concerns may arise

Suggested Citation:"2 Approaches Used by Others and Existing Safety Frameworks." Institute of Medicine and National Research Council. 2005. Dietary Supplements: A Framework for Evaluating Safety. Washington, DC: The National Academies Press. doi: 10.17226/10882.
×

 

Resource

Considerations

European Scientific Cooperative on Phytotherapy (ESCOP) Monographs on the Medicinal Uses of Plant Drugs (ESCOP, 1996, 1997, 2001) (Reviewed St. John’s Wort and Valerian Root)

Natural Medicines Comprehensive Database (NMCD) (NMCD, 2002) (Reviewed St. John’s Wort and Valerian)

Type of organization responsible for resource

Coalition of international trade associations

Therapeutic Research Center, publisher of the Pharmacist’s Letter and the Prescriber’s Letter; a for-profit organization

Substances reviewed

Botanicals used within the European community

Botanicals, vitamins, minerals, amino acids, glandular products; over 1,000 entries

Product/endpoint

Groups of monographs (Fascicules)

Website and book

Focus on safety/risk

Includes safety data, but primarily designed for efficacy assessment by regulatory authorities

Safety and efficacy are considered; describes circumstances in which the supplement is Likely to be Safe, Possibly Safe, Possibly Unsafe, Likely to be Unsafe, Unsafe

Reliance on primary data

Primary sources are cited, including many foreign language sources

Primary and secondary sources are cited, including foreign language sources

Use of nonhuman data

Animal and in vitro experiments are used

Safety information is generally derived from human data

Description of limitations

a

Limitations in interpreting human data are presented

Description of literature search strategy

Not described

Not described in database, 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/appearance of impartiality

The stated purpose is to “advance the scientific status of phytomedicines”;

 

Suggested Citation:"2 Approaches Used by Others and Existing Safety Frameworks." Institute of Medicine and National Research Council. 2005. Dietary Supplements: A Framework for Evaluating Safety. Washington, DC: The National Academies Press. doi: 10.17226/10882.
×

 

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 standardized product and discussion of preparation impact on safety

Appears to focus on a standardized product; one monograph compares the effects of the root preparation with the syrup on driving impairment

Generally does not focus on specific products or impact of preparation on safety

Description of consumption levels considered

The level at which adverse effects were reported is described

Doses used are described; impact of dose on safety is discussed

Consideration of data from non-oral routes of exposure

a

Non-oral data are referred to in some sections, but it is not clear if these data were considered as possibly relevant for safety of oral consumption of the ingredient

Discussion of biological activity or possible mechanism of action

Addressed, but not necessarily with safety in mind

Discussed

Discussion of specific groups within the general population, if appropriate

Considers pregnancy and lactation

Pregnancy and lactation are always included in the safety assessment, children are sometimes included; secondary sources are largely used for this discussion

Interaction with other interventions

Sections for interactions are included, but both examples examined stated “none reported”

Describes information for other supplements, drugs, and foods, and other 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 considerations for using this resource

Emphasis on European botanical products that may not resemble

Comprehensive in terms of the human clinical literature and the number

Suggested Citation:"2 Approaches Used by Others and Existing Safety Frameworks." Institute of Medicine and National Research Council. 2005. Dietary Supplements: A Framework for Evaluating Safety. Washington, DC: The National Academies Press. doi: 10.17226/10882.
×

 

products sold in the United States

Sponsorship by trade association organization

Starting assumptions of safety; lack of information appears to be interpreted as safety

Preclinical safety data section may be useful for individual botanicals

of supplements that are covered; describes a wide range of dietary

A useful cross-reference to brand names is included

The continuum of safety classifications considered is helpful, as is the attention paid to formulation, plant part, and species

 

Resource

Considerations

Natural Standard (Natural Standard, 2003) (Reviewed Black Cohosh)

Physican’s Desk Reference (PDR) for Herbal Medicines (Medical Economics, 1998, 2000)

Type of organization responsible for resource

For-profit, not supported by any interest group, professional organization, or pharmaceutical manufacturer

For-profit organization

Substances reviewed

Covers alternative therapies and complementary medicines, including nutrient and nonnutrient dietary supplements

Over 700 botanicals

Product/endpoint

Online monograph

Book of brief monographs

Focus on safety/risk

Safety and efficacy are considered

Both safety and efficacy are considered

Reliance on primary data

Mostly primary sources, some abstracts, including foreign language articles

Primary sources are cited, including foreign language sources

Use of nonhuman data

Mostly human data, some in vitro data and a limited number of animal studies are considered

Mostly human data; however, some animal and in vitro data are considered

Description of limitations

Limitations are described

Limitations are somewhat described

Description of literature search strategy

Described thoroughly

Search strategy is not described; many monographs appear to be based upon the Commission E translation

Suggested Citation:"2 Approaches Used by Others and Existing Safety Frameworks." Institute of Medicine and National Research Council. 2005. Dietary Supplements: A Framework for Evaluating Safety. Washington, DC: The National Academies Press. doi: 10.17226/10882.
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Use of current literature

Current literature, updated every 3–18 months

Mostly current, some historical information

Starting assumptions/appearance of impartiality

 

Appears to give favorable 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 describes an evidencedbased, consensus-based, peer review

No indication of peer review found

Focus on a particular standardized product and discussion of preparation impact on safety

Does not appear to focus on specific preparations

A number of different preparations are described, impact on safety is described for some; for 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 consumption levels considered

A recommended use amount is described; it is assumed that safety conclusions are based on this amount

Recommended doses are described

Consideration of data from non-oral routes of exposure

No mention is made of how non-oral data were handled in the example reviewed

No mention is made of how non-oral data were handled

Discussion of biological activity or possible mechanism of action

Discussed

Addressed, but not necessarily with safety in mind

Discussion of specific groups within the general population, if appropriate

Pregnant and lactating women are addressed

Second edition has separate indexes for herbs not for use during pregnancy or lactation or for use only under supervision

Interaction with other interventions

Thorough section on interactions with conventional therapies, drugs, other herbs, and supplements

Interactions discussed and a Drug/Herb Interaction Guide is included

Suggested Citation:"2 Approaches Used by Others and Existing Safety Frameworks." Institute of Medicine and National Research Council. 2005. Dietary Supplements: A Framework for Evaluating Safety. Washington, DC: The National Academies Press. doi: 10.17226/10882.
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Other comments and considerations for using this resource

Brief safety summary describes the situations in which the supplement would be considered Likely Safe, Possibly Safe, Possibly Unsafe, Likely Unsafe

Comprehensive in terms of clinical literature and number of supplements considered

Useful resource to gain understanding of historical uses

Useful cross-reference index of common and scientific names and glossary

Inconsistent reference use

Appears to be a summary of information and not a committee-authored or peer-reviewed activity

Concerns about possible inaccuracies, such as example cited by Chambliss et al. (2002): PDR entry for English hawthorne monograph indicates Commission E approval, but Commission E approved only the leaf with the flower, not the berries, leaf, extracts, powders, etc., as suggested by the PDR

 

Resource

Considerations

PDR for Nutritional Supplements (Medical Economics, 2001)

American Pharmaceutical Association Practical Guide to Natural Medicines (Peirce, 1999)

Type of organization responsible for resource

For-profit organization

Nonprofit organization

Substances reviewed

Vitamins, minerals, amino acids, and other nonbotanical dietary supplements

Botanicals

Product/endpoint

Book

Book

Focus on safety/risk

Safety and efficacy are considered

Safety and efficacy are considered

Reliance on primary data

Many primary sources, some secondary, including foreign language articles

Mostly secondary sources

Use of nonhuman data

Some in vitro and animal data are used

Cannot be determined due to reliance on secondary data

Description of limitations

Limitations are generally not discussed

Describes insufficiencies in amount of available data, but discussion of primary data is limited

Suggested Citation:"2 Approaches Used by Others and Existing Safety Frameworks." Institute of Medicine and National Research Council. 2005. Dietary Supplements: A Framework for Evaluating Safety. Washington, DC: The National Academies Press. doi: 10.17226/10882.
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Description of literature search strategy

Search strategy not described

Description limited to indication that the “National Library of Medicine’s biomedical literature, Medline, and NAPRALERT” were used

Use of current literature

Current for some supplements, less so for others

Some current sources, as well as secondary sources, are used

Starting assumptions/appearance of impartiality

 

 

Use of peer review

No indication of peer review found

Board of Reviewers listed

Focus on a particular standardized product and discussion of preparation impact on safety

Impact of preparation on safety is not particularly addressed; however, it is focused on nutrients preparations, which are often USP-standardized; for other natural products, does not focus on particular standardized products

Describes different forms available, but impact on safety is not specifically discussed; does not describe characteristics of the products to which comments about safety apply

Description of consumption levels considered

Usual ingested amounts and how substances are supplied is described; it is assumed that the safety conclusions are based on these ingested amounts

Usual ingested amounts are described; it is assumed that the safety conclusions are based on these ingested amounts

Consideration of data from non-oral routes of exposure

No mention is made of how non-oral data were handled

a

Discussion of biological activity or possible mechanism of action

Discussed for substances for which the information was known

Discussed for most substances

Discussion of specific groups within the general population, if appropriate

Discussed

Pregnancy and lactation issues are discussed when considered relevant

Interaction with other interventions

Discussed, when available, for other supplements, drugs, and botanicals

Interactions are discussed in some places

Other comments and considerations for using this resource

Comprehensive in terms of the number and range of supplements described

Book was developed largely for the consumer, limited citations

 

Limitations in the comprehensiveness of the literature

Lack of comprehensive literature search limits usefulness

Suggested Citation:"2 Approaches Used by Others and Existing Safety Frameworks." Institute of Medicine and National Research Council. 2005. Dietary Supplements: A Framework for Evaluating Safety. Washington, DC: The National Academies Press. doi: 10.17226/10882.
×

 

Table of side effects and interactions guide may be helpful

 

Useful cross-references and indexes

 

Resource

Considerations

World Health Organization (WHO) Monographs (WHO, 1999, 2001, 2003) (Reviewed Radix Valerianae, Radix Ginseng, Herba 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 search strategy

Describes sources of 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

Suggested Citation:"2 Approaches Used by Others and Existing Safety Frameworks." Institute of Medicine and National Research Council. 2005. Dietary Supplements: A Framework for Evaluating Safety. Washington, DC: The National Academies Press. doi: 10.17226/10882.
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Focus on a particular standardized product and discussion of preparation impact on safety

Defines the medicinal plant and describes compounds to standardize a product; adverse reaction description discusses preparation

Description of consumption levels considered

Dose is specified in relation to adverse effects; although one monograph only states that “large doses may…,” many specify how much was associated with the adverse reaction

Consideration of data from non-oral routes of exposure

Non-oral data are referred to in some sections, but it is not clear if these data were considered as possibly relevant

Discussion of biological activity or possible mechanism of action

Discussed

Discussion of specific groups within the general population, if appropriate

Pregnancy, lactation, and children are considered

Interaction with other interventions

Interactions with drugs are mentioned, if known; many entries say “None reported”

Other comments and considerations for using this resource

The section on medicinal uses is divided into three parts: 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

a This question could not be answered due to limitations in the analysis or lack of description in the available material.

Suggested Citation:"2 Approaches Used by Others and Existing Safety Frameworks." Institute of Medicine and National Research Council. 2005. Dietary Supplements: A Framework for Evaluating Safety. Washington, DC: The National Academies Press. doi: 10.17226/10882.
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of the criteria because (1) information in the material reviewed was insufficient to determine the extent to which a criterion was generally met, and (2) available information was likely to vary from ingredient to ingredient or the available information required in-depth analysis beyond the scope of this report. For example, it is necessary to know what safety data are available and should have been considered to determine whether the authors or organizations paid appropriate attention to all the relevant information when providing a safety conclusion in the resource. Empty cells in the table should be considered limitations in this examination, not in the resource itself.

Several examples of questions that are difficult to answer warrant explanation. Question 4, for example, was not answered at all because conclusions about whether data were weighed appropriately require knowledge of what type of information is available on a particular ingredient and may vary significantly from ingredient to ingredient, especially in the resources that were comprised of monographs authored by different individuals. Of note, however, was the Agency for Healthcare Research and Quality (AHRQ) process, which described in detail how data were analyzed.

Table 2-1 answers Question 7 (“How current is the information?”) by examining whether current literature was cited, but the importance of using current literature will depend on the ingredient being considered and whether there is new information that also should be considered. Question 8 regarding the use of accurate citations cannot be answered until one tries to locate the citations and determine whether they exist and, if so, whether they document the information attributed to them. Question 9, regarding balance and objectivity, was answered for some resources by considering whether there was a tendency toward assuming that an ingredient was safe unless information to the contrary was available. Clearly, there are other aspects of balance and objectivity that will become apparent as more information about a particular ingredient is known.

Question 10 was not answered because it was not possible to assess the backgrounds of those involved in the production of the resources or individual monographs within a resource. 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. While some experts in botanicals may be knowledgeable about historical and current use of botanicals, they may not know enough about the particular safety concerns raised by animal or in vitro studies to be considered an expert in this specific area.

For Question 11, the table indicates whether peer review was con-

Suggested Citation:"2 Approaches Used by Others and Existing Safety Frameworks." Institute of Medicine and National Research Council. 2005. Dietary Supplements: A Framework for Evaluating Safety. Washington, DC: The National Academies Press. doi: 10.17226/10882.
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ducted; most resources indicated that they were. As with Question 10, however, it was not possible to determine if the peer reviewers had adequate expertise in the safety issues raised. It was also not possible to determine the degree to which reviewers’ comments were considered.

Questions 12 and 13, regarding the impact of preparation and focus on particular products, were answered together. The answer varies in importance, depending on whether the preparation of the ingredient varies significantly.

Question 14 asks whether ingested amounts under consideration were specified in the review. 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. The description of the resources that follow are based on information available from the organizations responsible or in published descriptions of the resources. Thus, the descriptions have not been verified further, and their inclusion in this report does not constitute endorsement of the approaches used or the information provided. While readily available resources are included, there are other resources and thus this group should not be considered inclusive of all efforts to consider safety, efficacy, or quality of dietary supplements.

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, 2001). Other federal agencies, private sector agencies, and Congress periodically ask AHRQ to review and evaluate the scientific information on specified topics; their reviews are then used as the basis for clinical guidelines, performance measures, and other quality improvement tools. AHRQ administers the Evidence-based Practice Centers (EPCs), which have produced evidence reports requested by other federal agencies on the effectiveness and safety of a limited number of dietary supplements. The San Antonio EPC at the University of Texas Health Sciences Center, working under contract to AHRQ, has completed reports on garlic and milk thistle at the request of the National Center for Complementary and Alternative Medicine (NCCAM) of the National Insti-

Suggested Citation:"2 Approaches Used by Others and Existing Safety Frameworks." Institute of Medicine and National Research Council. 2005. Dietary Supplements: A Framework for Evaluating Safety. Washington, DC: The National Academies Press. doi: 10.17226/10882.
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tutes of Health (NIH) (AHRQ, 2000a, 2000b). The Southern California EPC/RAND completed an evidence-based report on S-adenosyl-L-methionine (SAMe) in 2002 for NCCAM (AHRQ, 2002b), and an evidence-based report on ephedra, released in February 2003, for NIH’s Office of Dietary Supplements and NCCAM (AHRQ, 2003a).

The EPC reports are based on a systematic analysis of the relevant scientific data (AHRQ, 2002c). The analyses are based on a weighting and ranking methodology and are dependent on judgments based on well-defined criteria. The reports are designed to differentiate the types and strength of evidence (AHRQ, 2002c). Due to the exhaustive nature of the reports, they are resource intensive.

The first step of an AHRQ review is to identify relevant citations following an exhaustive search of the literature in a variety of electronic databases. Additional citations are identified from bibliographies, manufacturers, and technical experts. Both English and non-English references are included in the search. In general, only published full articles are used, but additional unpublished information provided by authors of published studies may also be included (AHRQ, 2000a, 2000b).

Independent reviewers on the EPC staff read the titles and abstracts of all the identified citations and exclude those citations that do not meet defined selection criteria on types of participants, interventions, control groups, outcomes, and study designs. To assess adverse clinical events, all types of human studies are used (e.g., randomized controlled trials, prospective trials, and case-control and cohort studies). Data are abstracted from the literature and analyzed by independent reviewers with clinical and methodological expertise. The analysis includes an assessment of the internal validity and quality of the studies. The data analysis includes generation of evidence tables, graphical summaries, statistical tests, and meta-analyses. The results and conclusions of the analysis are summarized in an evidence report that contains conclusions on the current knowledge on the efficacy and adverse effects of the substance and provides recommendations for future research (AHRQ, 2000a, 2000b).

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 or prevalence in the general population and in special populations … ; significance for the needs of Medicare, Medicaid, and other federal health programs; high cost associated with a condition, procedure, treatment, or technology, whether due to the number of people needing care, high unit cost of care, or high indirect costs; controversy or uncertainty about the effectiveness or relative effectiveness of available clinical strategies or technologies and availability of scientific data to support the systematic review and analysis of the topic” (AHRQ, 2002a). Based on this process, the dietary supplements milk thistle, ephedra, garlic,

Suggested Citation:"2 Approaches Used by Others and Existing Safety Frameworks." Institute of Medicine and National Research Council. 2005. Dietary Supplements: A Framework for Evaluating Safety. Washington, DC: The National Academies Press. doi: 10.17226/10882.
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and SAMe, in addition to over 80 other nondietary supplement topics, had been reviewed as of 2003 (AHRQ, 2003b).

American Herbal Pharmacopoeia

The American Herbal Pharmacopoeia (AHP), a nonprofit organization, develops monographs on the quality, effectiveness, and safety of botanical medicines commonly used in the United States. The monographs include information on traditional use and information from scientific sources (Barrett, 1998). They are designed to provide consumers, health professionals, and botanical manufacturers with the knowledge required for using and manufacturing botanical products safely and effectively, and to provide regulatory bodies and researchers with guidance for integrating botanical products into the health care system (AHP, 2004b).

Botanicals are selected for monograph development based on judgment about the extent of use, the unique value of the botanical, and sponsorship by other interested organizations or companies (AHP, 2004b). Selection of a botanical for monograph development can be made by three methods. The first method is through a prioritization committee consisting of professional herbalists, botanical industry representatives, and herbal educators, which produces a list of priority botanicals based on the extent of their use or their unique values. A second method is through monograph sponsorship. Because AHP seeks funding and technical support for development of monographs from interested organizations or companies, a sponsored botanical may be given higher priority than was assigned by the prioritization committee (AHP, 2004b). Third, AHP considers what other groups have done. If there is an existing monograph of a botanical on the prioritization list, AHP may use relevant sections of that monograph as a starting point for its own monograph development (AHP, 2004b).

The monographs include botanicals with origins in Ayurvedic, Chinese, and Western traditions and include information from both traditional and scientific sources (AHP, 2002; Barrett, 1998). AHP monographs are relatively detailed compared with monographs produced by other organizations. They are released individually as they are completed, and 18 have been released since 1997 (AHP, 2004a).

In preparing the monographs, literature searches are conducted in order to review all reported side effects, contraindications, and negative interactions of the botanical (AHP, 2004b). According to AHP, primary literature is preferred, but secondary literature, such as review articles, may be used if considered acceptable or necessary. The search is not limited to English-language references. According to AHP, a review of the toxicological literature is done to address the safety of the botanical and includes data on acute and chronic toxicity; use during pregnancy, lactation, and fetal

Suggested Citation:"2 Approaches Used by Others and Existing Safety Frameworks." Institute of Medicine and National Research Council. 2005. Dietary Supplements: A Framework for Evaluating Safety. Washington, DC: The National Academies Press. doi: 10.17226/10882.
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development; use during operation of motor vehicles; mutagenicity; teratogenicity; and carcinogenicity.

Next, each section of the monograph is assigned to a writer with expertise in the topic of the section, and the writer is provided with the results of the literature search. Once the sections are drafted, the AHP editor and at least one other expert in the specific field review them. The sections are then incorporated into an initial monograph draft. This draft is then circulated to a peer-review committee of botanists, chemists, herbalists, pharmacists, pharmacologists, pharmacognosists, and physicians (AHP, 2004b). Reviewer comments are incorporated into the draft and the initial authors review and approve their sections. Before it is finalized for publication, the monograph is reviewed by an expert of either the botanical under review or the physiological system that the botanical affects (AHP, 2004b).

American Herbal Products Association

The American Herbal Products Association (AHPA) is a national trade association for the botanical products industry. In response to passage of the Dietary Supplement and Health Education Act (DSHEA), AHPA convened a special subcommittee of its standards committee to address the need for a comprehensive review of safety data for botanical ingredients sold in North America. The committee was made up of natural products scientists and practicing herbalists. According to AHPA, the goal of this committee was to critically evaluate safety and categorize botanicals based on safety. These evaluations are published as The Botanical Safety Handbook (McGuffin et al., 1997).

The committee reviewed over 500 botanicals that were available in the United States, identified primarily by reviewing Herbs of Commerce, another AHPA publication (Foster et al., 1992). After identifying which botanicals to include, AHPA reported that its committee reviewed the available scientific literature for data on human and animal toxicity, traditional use, regulatory status in numerous countries, and current usage of herbs in the United States, China, India, Europe, and Australia. The committee also relied on its own and others’ expertise and clinical experience for the evaluations.

There was no formal weighting of the data used for the evaluations; however, there were some exclusionary criteria. The monographs did not include the following data, conditions, or related products: “… excessive consumption, safety or toxicity concerns based on isolated constituents, toxicity data based solely on intravenous or intraperitoneal administration, traditional Chinese and Ayurvedic contraindications, gastrointestinal disturbances, potential drug interactions, idiosyncratic reactions, allergic reactions, contact dermatitis, well-known toxic plants that are not found in

Suggested Citation:"2 Approaches Used by Others and Existing Safety Frameworks." Institute of Medicine and National Research Council. 2005. Dietary Supplements: A Framework for Evaluating Safety. Washington, DC: The National Academies Press. doi: 10.17226/10882.
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products in trade, homeopathic herbal preparations, essential oils, herbal products to which chemically-defined active substances had been added, or environmental factors, additives or contaminants” (McGuffin et al., 1997).

The AHPA review committee followed guidance from the World Health Organization’s (WHO) Programme on Traditional Medicines (WHO, 1991), which states that regulatory action is not necessary for traditionally used products that have not been shown to be harmful unless new evidence necessitates a risk–benefit assessment. According to AHPA, the safety classification was based on an assumption of rational, informed use of botanicals and the committee reported that it carefully considered the intended use of the substance within the historical context of that use (McGuffin et al., 1997). As listed in the exclusionary criteria above, the committee also reported that it did not extrapolate toxicity data of isolated constituents and did not use data from studies that had excessive or irresponsible consumption patterns (McGuffin et al., 1997).

Once the committee reviewed all available information, the botanicals were assigned to one of four safety classes. Class 1 substances are botanicals that the AHPA committee believes can be used safely when used appropriately. Class 2 substances are botanicals for which certain restrictions apply (see subclasses) unless otherwise directed by an expert qualified in the use of the substance. Class 2a substances are botanicals only to be used externally. Class 2b substances are botanicals not to be used during pregnancy. Class 2c substances are botanicals not to be used while lactating. Class 2d substances are botanicals for which other use restrictions have been specified in the monograph. Class 3 substances are botanicals for which significant data exist to recommend special labeling: “To be used only under the supervision of an expert qualified in the appropriate use of this substance.” Finally, class 4 substances are botanicals for which the AHPA committee found insufficient data for classification (McGuffin et al., 1997).

Institute of Medicine

In 1997 the Food and Nutrition Board, IOM, National Academies, published its first report on Dietary Reference Intakes (DRIs) (IOM, 1997), a set of reference values that grew out of the periodic editions of the Recommended Dietary Allowances (RDAs) for nutrients over the previous 50 years. The RDAs and now the DRIs are to be used as reference values in food and nutrition policy and programs. Included in the DRI set of reference values is the category of Tolerable Upper Intake Levels (ULs), defined as the highest levels of nutrient intake likely to pose no risk of adverse health effects for almost all individuals in a specified life stage group. As

Suggested Citation:"2 Approaches Used by Others and Existing Safety Frameworks." Institute of Medicine and National Research Council. 2005. Dietary Supplements: A Framework for Evaluating Safety. Washington, DC: The National Academies Press. doi: 10.17226/10882.
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intake increases above the UL, the potential risk of adverse effects may increase.

While not recommended intakes, the ULs are based on published data on adverse effects of consuming excess levels of nutrients, usually demonstrated in humans, on a chronic basis over time. Using a risk assessment methodology (IOM, 1998a), uncertainty factors are applied to develop the UL, and depend on the availability of a dataset with dose-response information. In some cases, ULs have not been set where information on chronic ingestion was not available. The reviews are under the direction of an oversight committee of experts, as well as a subcommittee of experts in toxicology and risk assessment. To date, all essential vitamins, minerals, trace elements, macronutrients, and electrolytes have been reviewed (IOM, 1997, 1998b, 2000, 2001, 2002, 2004).

Commission E2

In 1978 the Second Medicines Act in the Republic of Germany went into effect, requiring a scientific review of all medicines in the pharmaceutical market, including conventional drugs, medicinal plants, and phytomedicines. 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. This 24-member committee was made up of physicians, pharmacists, nonmedical practitioners, pharmacologists, toxicologists, and biostatisticians (Blumenthal et al., 1998). According to a Commission E member consulted, at least 60 percent of the commission members had practical experience with phytomedicines (Personal communication, H. Schilcher, Commission E, March 19, 2002). The Commission completed its monograph work in 1994; however, it has met since 1994 to review drug registrations (Blumenthal, 1997; Blumenthal et al., 2000). The monographs produced by Commission E were compiled and published in English in 1998 by the American Botanical Council (Blumenthal et al., 1998). A subsequent publication by the American Botanical Council, Herbal Medicine: Expanded Commission E Monographs, was published in 2000 (Blumenthal et al., 2000).

The stated objective of Commission E was to ensure that approved botanicals were reasonably safe when used according to the product label instructions and to remove unapproved botanicals from the market even if they only posed minor safety risks (Blumenthal et al., 1998). Commission E

2  

Translation of the German Commission E (1998) is a translation of German documents and describes the process used by Commission E. In addition to input from a member of the Commission E, it serves as the basis for this summary.

Suggested Citation:"2 Approaches Used by Others and Existing Safety Frameworks." Institute of Medicine and National Research Council. 2005. Dietary Supplements: A Framework for Evaluating Safety. Washington, DC: The National Academies Press. doi: 10.17226/10882.
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reviewed 378 botanicals used in German folk medicine for both safety and effectiveness (Blumenthal, 1997; Personal communication, H. Schilcher, Commission E, March 19, 2002). It was the manufacturer’s responsibility to provide proof of quality (Blumenthal et al., 1998). Safety and effectiveness were assessed using published scientific literature. Approximately 100 to 200 worldwide references were consulted for each botanical (Personal communication, H. Schilcher, Commission E, March 19, 2002).

The Commission considered data on traditional use, chemical composition, pharmacology, and toxicology and used data from clinical studies, in vitro and in vivo studies, field studies, epidemiological studies, case reports, and unpublished proprietary data submitted by manufacturers that included chemical, toxicological, pharmacological, and clinical testing data. The Commission also reviewed summaries produced by Kooperation Phytopharmaka (an umbrella organization of about 120 pharmaceutical manufacturers). According to Blumenthal, these summaries were based on literature reviews and clinical experience, but did not contain any recommendations about the product under review (Blumenthal et al., 1998).

According to the American Botanical Council’s description, controlled clinical studies appear to have been considered the most useful type of data (Blumenthal et al., 1998). If no controlled studies were available, safety was evaluated based on other types of data, such as well-documented review articles, older clinical trials, and well-documented knowledge of traditional usage (Blumenthal et al., 1998). Commission E did not accept long-term therapeutic or traditional use as sufficient evidence of safety without additional data, and field and case studies were used only when they had been evaluated according to scientific standards (Blumenthal et al., 1998).

Once the Commission finished drafting a monograph for a botanical medicine, it was published and comments were solicited from scientists and other experts. The Commission then prepared a final draft of the monograph. The resulting monographs do not include references. Unpublished justifications with relevant references for the monographs are kept; however, these justifications cannot be accessed except in cases of legal disputes (Blumenthal et al., 1998).

Each substance was assigned one of three approval ratings: (1) positive (approved), (2) negative (unapproved), or (3) negative-null (unapproved). Potential therapeutic benefit was taken into account in the assignment of ratings. Positive (approved) substances were considered reasonably safe when used according to the dosage, contraindications, and other warnings specified in the monograph. If safety concerns outweighed the potential benefits of a substance, the monograph was assigned a negative (unapproved) rating. No dosage recommendations were provided for substances assigned a negative rating, and the intent of the Commission was the immediate withdrawal from the market of substances receiving a negative rating.

Suggested Citation:"2 Approaches Used by Others and Existing Safety Frameworks." Institute of Medicine and National Research Council. 2005. Dietary Supplements: A Framework for Evaluating Safety. Washington, DC: The National Academies Press. doi: 10.17226/10882.
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If no risk was found, but also no substantiation of efficacy, the substance was designated as negative-null (unapproved). If manufacturers could later document the efficacy of such substances, the products could be approved; however, no new monographs would be produced (Blumenthal et al., 1998).

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)

European Scientific Cooperative on Phytotherapy

The European Scientific Cooperative on Phytotherapy (ESCOP) was created in 1989 to promote the scientific status of phytomedicines and the harmonization of their regulatory status in Europe (ESCOP, 1996). ESCOP is an umbrella organization of national trade associations for phytotherapy from countries both within and beyond the European Union. According to ESCOP (2001), monographs are produced by a scientific committee of ESCOP, which consists of a subgroup of delegates from participating member countries with expertise in medicine, phytotherapy, pharmacognosy, pharmacology, and regulatory affairs. The goal is to compile monographs that provide information on the therapeutic uses and safety of botanicals that are widely used in European medicine and pharmacy (Blumenthal, 1997; ESCOP, 2001). Information on quality is not included in these monographs (Blumenthal, 1997).

The ESCOP scientific committee, with assistance from others who do research on specific plants, drafts a monograph by evaluating information from the published scientific literature (ESCOP, 2001). Once a monograph is drafted, it is reviewed by an independent board of supervising editors that consists of academic experts in phytotherapy and medicinal plants. The monographs are then published in groups, as fascicules, each containing 10 monographs; 60 monographs have been published to date (ESCOP, 1996, 1997, 2001).

3  

In response to interest in references, the American Botanical Council developed the book. The editors of this book have included references for statements and expanded the original monographs.

Suggested Citation:"2 Approaches Used by Others and Existing Safety Frameworks." Institute of Medicine and National Research Council. 2005. Dietary Supplements: A Framework for Evaluating Safety. Washington, DC: The National Academies Press. doi: 10.17226/10882.
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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

Suggested Citation:"2 Approaches Used by Others and Existing Safety Frameworks." Institute of Medicine and National Research Council. 2005. Dietary Supplements: A Framework for Evaluating Safety. Washington, DC: The National Academies Press. doi: 10.17226/10882.
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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-

Suggested Citation:"2 Approaches Used by Others and Existing Safety Frameworks." Institute of Medicine and National Research Council. 2005. Dietary Supplements: A Framework for Evaluating Safety. Washington, DC: The National Academies Press. doi: 10.17226/10882.
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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.

Suggested Citation:"2 Approaches Used by Others and Existing Safety Frameworks." Institute of Medicine and National Research Council. 2005. Dietary Supplements: A Framework for Evaluating Safety. Washington, DC: The National Academies Press. doi: 10.17226/10882.
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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).

Suggested Citation:"2 Approaches Used by Others and Existing Safety Frameworks." Institute of Medicine and National Research Council. 2005. Dietary Supplements: A Framework for Evaluating Safety. Washington, DC: The National Academies Press. doi: 10.17226/10882.
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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.

Suggested Citation:"2 Approaches Used by Others and Existing Safety Frameworks." Institute of Medicine and National Research Council. 2005. Dietary Supplements: A Framework for Evaluating Safety. Washington, DC: The National Academies Press. doi: 10.17226/10882.
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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.

Suggested Citation:"2 Approaches Used by Others and Existing Safety Frameworks." Institute of Medicine and National Research Council. 2005. Dietary Supplements: A Framework for Evaluating Safety. Washington, DC: The National Academies Press. doi: 10.17226/10882.
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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

Suggested Citation:"2 Approaches Used by Others and Existing Safety Frameworks." Institute of Medicine and National Research Council. 2005. Dietary Supplements: A Framework for Evaluating Safety. Washington, DC: The National Academies Press. doi: 10.17226/10882.
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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.

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Suggested Citation:"2 Approaches Used by Others and Existing Safety Frameworks." Institute of Medicine and National Research Council. 2005. Dietary Supplements: A Framework for Evaluating Safety. Washington, DC: The National Academies Press. doi: 10.17226/10882.
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Suggested Citation:"2 Approaches Used by Others and Existing Safety Frameworks." Institute of Medicine and National Research Council. 2005. Dietary Supplements: A Framework for Evaluating Safety. Washington, DC: The National Academies Press. doi: 10.17226/10882.
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Next: 3 The Framework »
Dietary Supplements: A Framework for Evaluating Safety Get This Book
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The growing consumer interest in health and fitness has expanded the market for a wide range of products, from yoga mats to the multiple dietary supplements now on the market. Supplements are popular, but are they safe? Many dietary supplements are probably safe when used as recommended. However, since 1994 when Congress decided that they should be regulated as if they were foods, they are assumed to be safe unless the Food and Drug Administration can demonstrate that they pose a significant risk to the consumer. But there are many types of products that qualify as dietary supplements, and the distinctions can become muddled and vague. Manufacturers are not legally required to provide specific information about safety before marketing their products. And the sales of supplements have been steadily increasing—all together, the various types now bring in almost $16 billion per year. Given these confounding factors, what kind of information can the Food and Drug Administration use to effectively regulate dietary supplements? This book provides a framework for evaluating dietary supplement safety and protecting the health of consumers.

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