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13
Findings and Recommendations

The Dietary Supplement Health and Education Act (DSHEA) authorizes the Food and Drug Administration (FDA) to take action only when a dietary supplement ingredient presents a significant and unreasonable risk of illness or injury under conditions of use recommended or suggested in labeling or is adulterated.1 Outlined in the preceding chapters are guiding principles and recommendations for a process by which FDA can use currently available data to evaluate the safety of dietary supplement ingredients. The guiding principles and process are designed to enhance the ability of FDA to protect consumers from unreasonable risk of harm or injury resulting from use of dietary supplement ingredients. This chapter identifies legal and regulatory barriers and provides recommendations for improvement to enhance the evaluation of the safety of dietary supplement ingredients.

ABILITY TO DETERMINE UNREASONABLE RISK

Judgment of Unsafe Versus Unreasonable Risk

For many dietary supplement ingredients, there is little available information about their safety compared with what is available for new drugs or

1  

DSHEA also gives authority the secretary of the U.S. Department of Health and Human Services to declare that a dietary supplement poses an imminent hazard to public health or safety and thus take action.



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Dietary Supplements: A Framework for Evaluating Safety 13 Findings and Recommendations The Dietary Supplement Health and Education Act (DSHEA) authorizes the Food and Drug Administration (FDA) to take action only when a dietary supplement ingredient presents a significant and unreasonable risk of illness or injury under conditions of use recommended or suggested in labeling or is adulterated.1 Outlined in the preceding chapters are guiding principles and recommendations for a process by which FDA can use currently available data to evaluate the safety of dietary supplement ingredients. The guiding principles and process are designed to enhance the ability of FDA to protect consumers from unreasonable risk of harm or injury resulting from use of dietary supplement ingredients. This chapter identifies legal and regulatory barriers and provides recommendations for improvement to enhance the evaluation of the safety of dietary supplement ingredients. ABILITY TO DETERMINE UNREASONABLE RISK Judgment of Unsafe Versus Unreasonable Risk For many dietary supplement ingredients, there is little available information about their safety compared with what is available for new drugs or 1   DSHEA also gives authority the secretary of the U.S. Department of Health and Human Services to declare that a dietary supplement poses an imminent hazard to public health or safety and thus take action.

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Dietary Supplements: A Framework for Evaluating Safety food additives. Because of the limited and variable amount and type of data available, definitive statements judging safety may be difficult to completely substantiate scientifically. However, the standard for demonstrating that a significant or unreasonable risk exists with use of a dietary supplement ingredient does not require the same level of information as is needed to conclusively demonstrate or prove that a substance is unsafe for human consumption. The principles used by the scientific community to determine the risk associated with consumption of various substances should also apply to dietary supplement ingredients, bearing in mind that dietary supplements, by virtue of DSHEA, have been assumed to be safe, but have not been required to be proven safe. Thus, the appropriate scientific standard to be used to overturn this basic assumption of safety is to demonstrate significant or unreasonable risk, not prove that an ingredient is unsafe. Many of these scientific principles are outlined in Chapters 4 through 10, but several warrant additional mention here (see Box 13-1). What Constitutes a Scientific Assessment of Unreasonable Risk? It is important to consider the relevance and value of information presented by other organizations and regulatory bodies to the regulation of dietary supplement ingredients in the United States. Criteria for evaluating the relevance of other approaches are outlined in Chapter 2. These criteria include the importance of reliance on scientifically based data, consideration of all types of data (including animal data, in vitro data, data about chemical and taxonomical relatedness, and as data on human use), and some form of peer review. To be of use in the safety Framework, conclusions of other regulatory bodies or similar organizations as to the safety of particular dietary supplements should be based on primary informational sources rather than reviews, and standardization and similarity of different preparations containing the active ingredient under study needs to be considered when assessing results. Further, if expert judgments play a significant role in the study conclusions, potential biases and conflicts of interest should be noted, and peer review should be part of the evaluative process. Approaches taken by diverse organizations and governmental bodies, both within and outside the United States, which evaluate the safety and, at times, efficacy of dietary supplement ingredients, vary in their relevance to the protection of the American public from risks associated with consumption of dietary supplement ingredients.

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Dietary Supplements: A Framework for Evaluating Safety BOX 13-1 Principles for Evaluating Data to Determine Unreasonable Risk Information that is generally referred to as “safe historical use” should not be used as prima facie evidence that the ingredient does not cause harm. It is important to carefully consider the actual existence of information about historical use and the relevance of this information, taking into consideration whether the preparations are similarly processed, similar in route of exposure and duration of use, the potential for differences in concurrent use with substances, and whether or not the historical use would have revealed any possible adverse event. Appropriate historical use can then be weighed against the strength of other types of evidence suggesting possible harm (human, animal, and in vitro data or information about related substances). Even in the absence of information on adverse events in humans, evidence of harm from animal studies is often indicative of potential harm to humans. This indication assumes greatest importance when the route of exposure is oral, the formulation tested is identical or highly similar to that consumed as an ingredient, and more than one species shows the same or similar toxicity. Validateda in vitro studies can stand alone as independent indicators of risk to human health if a comparative exposure is attained in humans. It is scientifically appropriate and acceptable to use information about safety concerns of related substances to inform a decision about the risk associated with a dietary supplement ingredient, by considering whether: the ingredient’s constituents are compounds with established toxicity, or closely related to compounds with established toxicity, or the plant sources of the botanical dietary supplement are taxonomically related to known toxic plants. a   In this report, in vitro assays are considered validated when their results have been proven to predict a specific effect in animals and/or humans with reasonable certainty. LEGAL AND REGULATORY BARRIERS TO EVALUATION OF THE SAFETY OF DIETARY SUPPLEMENTS Through the process of developing the Framework to evaluate the safety of dietary supplement ingredients, a number of legal and regulatory barriers were identified that hamper FDA’s ability to protect the public’s health. The following findings are designed to enhance the utility of the Framework and enhance the ability of FDA to protect consumers from unreasonable risk of illness or injury.

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Dietary Supplements: A Framework for Evaluating Safety While some constituents of conventional foods are subject to premarket approval, DSHEA excludes all dietary supplement ingredients from this requirement when labeled as dietary supplements, even though some of these ingredients would be subject to premarket approval as food additives if used in conventional foods. Moreover, while new drugs are subject to premarket approval, DSHEA excludes dietary supplements, despite the fact that they may possess biological activities similar, and in some case identical, to those found in medications and are frequently used by consumers for medicinal purposes according to survey data (Blendon et al., 2001; Chang et al., 2003; Johnson et al., 2000; Martin et al., 2002; Najm et al., 2003; Wood et al., 2003). Further, under the provisions of DSHEA, FDA has no authority to require submission of specific safety data from dietary supplement manufacturers or distributors either before or after their products are made available for sale to the public. (The manufacturer decides what information to provide when notifying FDA 75 days in advance of marketing a dietary supplement containing a new dietary ingredient.) It is also very challenging to carry out some of the provisions of DSHEA given the limitations on the quantity and quality of the currently available scientific data related to the safety of dietary supplement ingredients. One of the key premises of DSHEA is that history of use is evidence of safety when applied to dietary supplements; as was indicated in the earlier chapters, significant scientific problems with this assumption have been identified. In line with these findings, some members of the scientific and medical community have strongly advised that the regulatory mechanisms for monitoring the safety of dietary supplements, as currently defined by DSHEA, be revised (Drazen, 2003; Fontanarosa et al., 2003; Marcus and Grollman, 2002; Palmer et al., 2003). These constraints imposed on FDA make it difficult for the health of the American public to be adequately protected. SPECIFIC FINDINGS AND RECOMMENDATIONS Prospective Systematic Monitoring and Tracking Mechanism for Dietary Supplement Ingredients Finding: A prospective, systematic method for recording and monitoring the history of safety issues with specific dietary supplements is necessary to implement a framework for FDA to evaluate the safety of dietary supplement ingredients. During the period of this study, FDA developed a new method of monitoring and tracking adverse event reports—the Special Nutrition/Adverse Event Monitoring System (FDA, 2002). However, a prospective system that enables tracking of information leading to all levels of concern is also needed.

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Dietary Supplements: A Framework for Evaluating Safety Recommendation: FDA should continue to maintain and refine a prospective system for monitoring and tracking reports of adverse events as well as other information related to safety concerns associated with consumption of dietary supplement ingredients. The system should be open, transparent, and useful for establishing varying levels of concern relating to dietary supplements as outlined in the Framework. Relationships with professional societies, scientific journals, other federal agencies, consumer protection groups, and collaborative scientific groups should be continued and enriched to facilitate the ability of FDA to collect and monitor information regarding the use of dietary supplement ingredients. Resources to support these activities should be provided to FDA. Adequate Resources to Protect the Consumer Under DSHEA Finding: While the committee did not conduct an analysis of the cost of implementing this Framework, implementation of any framework for comprehensive safety evaluation generates an additional workload for the responsible staff at FDA. For the framework to be effective, adequate resources must be available to FDA to collect and analyze available information. DSHEA establishes that the determination of the potential for harm from dietary supplement use be done postmarketing, but resources may not be sufficient to fulfill this task. Recommendation: In order to fully protect the public health, Congress should ensure that FDA is provided with adequate personnel and resources to protect the consumer under DSHEA. Adverse Event Reporting Finding: Reports of adverse events are an important source of information by which FDA becomes aware of potential risks to public health from exposure to dietary supplement ingredients. It has been estimated that FDA receives reports of less than 1 percent of all adverse events associated with dietary supplements, according to the Inspector General’s Report, Adverse Event Reporting for Dietary Supplements: An Inadequate Safety Valve, which also documented the limitations in the reports that are received (OIG, 2001). While spontaneous adverse event reports have recognized limitations, they have considerable strength as potential warning signals of problems requiring attention, making monitoring by FDA worthwhile. Under DSHEA, there is no requirement for distributors or manufacturers to collect and maintain records of adverse effects associated with the use of dietary supplements. Further, distributors and manufacturers are not required to submit adverse event reports of which they are aware to FDA,

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Dietary Supplements: A Framework for Evaluating Safety thereby significantly compromising the agency’s ability to actively monitor dietary supplement safety. Recommendation: Congress should amend DSHEA to require that manufacturers and distributors report to FDA, in a timely manner, any serious adverse event associated with use of its marketed product of which the manufacturer or distributor is aware. Given that a 15-calendar-day notification of any serious unexpected adverse event to FDA is the standard for medical products,2 this time frame seems reasonable. Dietary supplements, as for conventional foods, are not expected to be associated with any serious adverse events; therefore, all such events are considered unexpected and should be reported to FDA. Recommendation: FDA should continue to work with the Poison Control Centers as a source of adverse event reports, and sufficient resources to support this activity should be provided. Education of Consumers and Health Professionals about Reporting of Adverse Events Related to Dietary Supplement Ingredients Finding: Consumers and health professionals are not adequately aware of the importance of reporting adverse events to FDA. Recommendation: FDA should increase efforts to inform health care professionals and consumers that they should use the MedWatch adverse event reporting program to report adverse events associated with the use of dietary supplements. Additional outreach efforts should include: Distribution of MedWatch forms with instructions for use for reporting adverse events relating to use of dietary supplements, Education of health care professionals to include questions about dietary supplement use when taking diet and drug histories, and Education of consumers that dietary supplements are not necessarily safe and adverse events should be reported to their healthcare professional or directly to FDA. 2   It is recognized that with the important exception of drugs that have undergone a switch from prescription status to over-the-counter (OTC) drug status, there is no such reporting requirement for OTC drugs. However, premarket approval following expert review is required for OTC drugs, with such assessments incorporating safety, labeling, purity, and manufacturing, but is not required for dietary supplements. Thus there is a required accumulation of evidence for OTC drug safety that is not required for dietary supplements. This difference in regulatory control results in the need for mandatory reporting of serious adverse events associated with the use of dietary supplement ingredients.

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Dietary Supplements: A Framework for Evaluating Safety Recommendation: The FDA MedWatch toll-free telephone number should be provided on product labels to facilitate reporting of adverse events by consumers and health care professionals. Premarket Notification of New Dietary Ingredients Finding: DSHEA requires that a manufacturer or distributor of a new dietary ingredient notify FDA of its intention to market the ingredient at least 75 days before introducing it into interstate commerce. There appears to be ambiguity regarding the nature and amount of information that must be submitted to FDA for their review in the 75-day period. Recommendation: To initiate the 75-day premarketing review period, both the distributor and the manufacturer should be required to provide FDA with all available data in their possession, both favorable and unfavorable, regarding safety of the product. New Formulations and Processes Finding: Under DSHEA, manufacturers and distributors of dietary supplements are required to provide FDA with information establishing the safety of their product only if it contains new dietary ingredients not marketed before October 1994. Dietary supplement ingredients marketed before 1994 are not subject to this requirement. Yet many dietary supplement ingredients on the market today, though not “new dietary ingredients,” are produced in a variety of ways. They have different formulations and are produced through very different processes than related dietary supplement ingredients in traditional products, or even other dietary supplement ingredients bearing the same name. Alterations in formulations and processing of substances that have a history of use as dietary supplements may result in markedly different bioactive substances of potential harm. Recommendation: When the formulation or processing of a dietary supplement ingredient is changed, it should be considered a new dietary ingredient and subject to regulatory oversight as such. FDA Proposed Good Manufacturing Practice Guidelines Finding: While the focus of this report is on developing a framework to evaluate the safety of dietary supplement ingredients per se, and not on safety issues related to good manufacturing practice, these are inseparable because variability in content hampers the evaluation of safety. FDA recently proposed current good manufacturing practices (cGMPs), regulations that may be in place by the time this report is released, but the proposed regulations will not establish uniformity across different manufacturers of the same dietary supplement ingredients. The label verification program (USP, 2004) has been a step in the right direction, but this is a

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Dietary Supplements: A Framework for Evaluating Safety voluntary program. While the U.S. Pharmacopeia has developed some standards for content uniformity for dietary supplements (USP, 2004), to date few standards have been published. Recommendation: The FDA initiative to establish cGMPs for dietary supplement ingredients is supported and additional efforts to develop standards for content uniformity should be undertaken. Sufficient resources to support these efforts should be provided by Congress. Revision in Requirements for Labeling of Dietary Supplements Finding: Required label information that would be of use to the consumer in making informed decisions is limited relative to safety of use. Current regulations related to source of a product only require the name and place of business of the manufacturer, packer, or distributor to be provided on the label. In March 2003, the U.S. Department of Health and Human Services Inspector General presented a template for labeling dietary supplements to provide information in a clear and understandable format to help consumers make informed decisions about the safe and appropriate use of dietary supplements (DHHS, 2003b). Several recommendations that relate specifically to the safe use of dietary supplements are provided in a related report, Dietary Supplement Labels: An Assessment (DHHS, 2003a). Recommendation: Adoption of the labeling changes recommended in the report Dietary Supplement Labels: Key Elements is urged. In addition, the label should contain the name and place of business of both the distributor and manufacturer of the product (e.g., manufactured for Company XX by Company YY) to facilitate tracing the source of the product if adverse events or other problems occur. Additional Research on the Potential to Cause Harm Finding: Based on the experience of preparing the prototype monographs for this report, it is evident that as the process for review of ingredients expands, research needs will be identified to address unresolved issues regarding the potential of certain ingredients to cause harm. There is no legal or regulatory requirement that dietary supplement ingredient manufacturers conduct toxicology or safety pharmacology studies on their products or ingredients. Thus the application of any testing of the types described in Chapters 5, 6, and 8 to dietary supplement ingredients will in most cases be initiated by FDA or other federal agencies. A number of collaborative activities between FDA and other governmental bodies have been undertaken and successfully completed. Recommendation: The continued development of effective working relationships and partnerships between FDA and the National Insti-

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Dietary Supplements: A Framework for Evaluating Safety tutes of Health is encouraged as one means for fostering more research on the safety of dietary supplement ingredients, especially for high-priority needs identified by FDA when utilizing the framework for safety evaluation. Recommendation: FDA should ensure that its own National Center for Toxicological Research and the overall Department of Health and Human Services National Toxicology Program are optimally utilized by FDA’s Center for Food Safety and Applied Nutrition for investigation into specific concerns of dietary supplement safety. In addition, FDA and the National Institutes of Health should establish clear guidelines for cooperative efforts on high-priority safety issues related to the use of dietary supplements. Recommendation: All federally supported research on dietary supplements conducted to assess efficacy should be required to include the collection and reporting of all data related to safety of the ingredient under study. REFERENCES Blendon RJ, DesRoches CM, Benson JM, Brodie M, Altman DE. 2001. American’s views on the use and regulation of dietary supplements. Arch Intern Med 161:805–810. Chang CW, Chu G, Hinz BJ, Grever MD. 2003. Current use of dietary supplementation in patients with age-related macular degeneration. Can J Ophthalmol 38:27–32. DHHS (U.S. Department of Health and Human Services). 2003a. Dietary Supplement Labels: An Assessment. Office of Inspector General, OEI-01-01-0012. Online. Available at http://oig.hhs.gov/oei/reports/oei-01-01-00121.pdf. Accessed June 25, 2004. DHHS. 2003b. Dietary Supplement Labels: Key Elements. Office of Inspector General, OEI 01-01-00120. Online. Available at http://oig.hhs.gov/oei/reports/oei-01-01-00120.pdf. Accessed June 25, 2004. Drazen JM. 2003. Inappropriate advertising of dietary supplements. N Engl J Med 348:777–778. FDA (Food and Drug Administration). 2002. Letter to Stakeholders. Announcing CAERS—The CFSAN Adverse Event Reporting System. Online. Available at http://www.cfsan.fda.gov/_dms/caersltr.html. Accessed June 25, 2004. Fontanarosa PB, Drummond R, De Angelis CD. 2003. The need for regulation of dietary supplements—Lessons from Ephedra. J Am Med Assoc 289:1568–1570. Johnson EM, Wootton JC, Kimzey R, McCullagh L, Wesley R, Byrd DC, Singh KK, Rubino D, Pucino F. 2000. Use of herbal therapies by adults seen in an ambulatory care research setting: An exploratory survey. J Altern Complement Med 6:429–435. Marcus DM, Grollman AP. 2002. Botanical medicines: The need for new regulations. N Engl J Med 347:2073–2076. Martin KJ, Jordan TR, Vassar AD, White DB. 2002. Herbal and nonherbal alternative medicine use in Northwest Ohio. Ann Pharmacother 36:1862–1869. Najm W, Reinsch S, Hoehler F, Tobis J. 2003. Use of complementary and alternative medicine among the ethnic elderly. Altern Ther Health Med 9:50–57.

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Dietary Supplements: A Framework for Evaluating Safety OIG (Office of Inspector General). 2001. Adverse Event Reporting for Dietary Supplements. An Inadequate Safety Valve. OEI-01-00-00180. Boston, MA: OIG, Department of Health and Human Services. Palmer ME, Haller C, McKinney PE, Klein-Schwartz W, Tschirgi A, Smolinske SC, Woolf A, Sprague BM, Ko R, Everson G, Nelson LS, Dodd-Butera T, Bartlett WD, Landszberg BR. 2003. Adverse events associated with dietary supplements: An observational study. Lancet 361:101–106. USP (U.S. Pharmacopeia). 2004. Overview: USP’s Dietary Supplement Verification Program. Online. Available at http://www.uspverified.org/pinfo/overview.html. Accessed March 10, 2004. Wood MJ, Stewart RL, Merry H, Johnstone DE, Cox JL. 2003. Use of complementary and alternative medical therapies in patients with cardiovascular disease. Am Heart J 145:806–812.