Dietary Supplements A Framework for Evaluating Safety (2005) / Chapter Skim
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11 Applying the Framework: Case Studies Using the Prototype Safety Monographs
11 Applying the Framework: Case Studies Using the Prototype Safety Monographs
Pages 269-291
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From page 269... ...
, after proposing a framework for the safety evaluation of dietary supplement ingredients and releasing it for comment, was to develop at least six prototype monographs for dietary supplement ingredients using the system outlined in the initial framework and, through this process, evaluate the proposed framework and revise it as necessary. Based on this experience and on comments received by industry representatives and other stakeholders about the proposed process (see Appendix B for a summary of the comments received)
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From page 270... ...
The six supplement ingredients selected to serve as the subjects of the prototype monographs were chaparral, chromium picolinate, glucosamine, melatonin, saw palmetto, and shark cartilage. Development of the prototype monographs proved to be a useful tool to assess the practicality and ability of the Framework to guide a dietary supplement ingredient safety evaluation.
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From page 271... ...
Using the Framework, FDA would have considered the nature of the evidence readily available as a result of the signal detected and decided, based on initial review, that a level of concern existed. A decision whether to continue monitoring or to move into the integrative evaluation of the dietary supplement ingredient would then have been made.
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Serious adverse events occurred in individuals 1Special Nutritional Adverse Event Monitoring System, as available on FDA's website. 2This chapter is presented as a review of the prototype monographs as case studies.
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From page 273... ...
The human data considered included information about hepatic adverse events reported to FDA and published as case reports (as discussed in the previous section)
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From page 274... ...
Only one of the human adverse events appeared to be associated with chaparral tea use. Thus the integrative evaluation distinguished between safety problems associated with chaparral consumption as a tea and safety problems associated with other chaparral products likely to contain more NDGA.
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From page 275... ...
Chromium picolinate's widespread prevalence of use, including its common inclusion in many combination dietary supplements, also suggests value in devoting attention to the risk of the use of chromium picolinate as a supplement ingredient. Initial Review: Considering the Nature of the Evidence The renal toxicity cases that signaled chromium picolinate as needing attention were evaluated following the description outlined in Chapter 4.
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From page 276... ...
Following the Framework, a lower to moderate concern suggests that FDA note what was learned about the signals detected, the serious adverse events, and the insulin regulation concern and then continue to monitor until new signals of concern suggest more consideration is warranted. Integrative Evaluation Although not suggested by the review of the two signals above, if FDA did choose to conduct an integrative evaluation of chromium picolinate because of the seriousness of these serious adverse event reports or other reasons, it would be appropriate to follow a broad-based strategy because the serious adverse events reported suggest potential damage to several organ systems.
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From page 277... ...
Therefore, instead of an integrative evaluation, this dietary supplement ingredient could have been designated for monitoring of both new signal-generating information and answers to particularly relevant questions. For example, a periodic search for human data suggesting problems of insulin regulation or reporting blood glucosamine levels following
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From page 278... ...
Office of Dietary Supplements, could request that laboratory indicators of insulin resistance and diabetes, as well as blood glucosamine levels, be monitored in subsequent clinical studies of glucosamine. Integrative Evaluation If FDA chose to proceed with an integrative evaluation for glucosamine, it could follow either a broad-based or a more focused strategy.
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From page 279... ...
In addition, there was concern that adverse events such as seizures and psychiatric problems worsened in persons particularly susceptible to these problems. Integrative Evaluation The integrative evaluation of melatonin began as a focused effort looking at the initial signal of seizure occurrence in an at-risk population, but the preliminary review to gather additional information yielded other areas of concern related to melatonin's physiological role as a hormone.
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: "When data (i.e., in vitro or animal data) suggest that a dietary supplement constituent targets a receptor, enzyme, or other biological target in a manner similar to a compound known to be toxic, concern is warranted, especially if the dietary supplement constituent is known to reach the biological target in a relevant concentration." Finally, the high prevalence of saw palmetto use is a modifying factor, suggesting an evaluation of the safety of this dietary supplement ingredient might be of value even if initial review did not result in higher concern if resources are available for such a proactive integrative evaluation.
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From page 281... ...
Consideration of the limited animal data -- summaries of unpublished animal toxicology available in the published literature -- did not suggest reason for specific concerns given that no overt signs of toxicity were reported. In summary, a lower level of concern would have resulted from an initial review of shark cartilage's liver effects.
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From page 282... ...
The shark cartilage prototype monograph also illustrates the wide difference in preparations of some dietary supplement ingredients. Powders could widely differ from extract preparations.
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From page 283... ...
Others are possible associations between an ingredient and serious adverse events in humans. Some signals of possible risk are not pieces of scientific information per se but information that indicates other knowledgeable organizations have expressed concerns about the safety of the ingredient -- governments in other countries may control the use of the ingredient or secondary sources may describe potential risks.
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to suggest an integrative evaluation is warranted. This step in the process allows FDA to set priorities for determining which dietary supplement ingredients require integrative evaluations and when continued monitoring might be a better use of limited resources.
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Monitoring might also include working with the National Toxicology Program at the National Institute of Environmental Health Sciences or the Office of Dietary Supplements at NIH to initiate research addressing unanswered questions relative to some of the signals detected. Integrative Evaluation Broad-Based Versus Focused Approaches to Integrative Evaluation If the concern level is moderate or higher, a decision may be made to undertake an integrative evaluation.
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From page 286... ...
The most valuable information is studies specifically designed to evaluate toxicity and detect adverse events. Sufficient data of this type rarely exist for dietary supplement ingredients,5 so relevant information found in studies not focused on safety also needs to be collected.
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All human data were included in their prototype monographs, but only the animal, in vitro, and related substances data that were likely to reveal any targeted toxicities were included in their prototype monographs. Given that resources are indeed limited, it is more important to efficiently collect data for integrative evaluations than to produce an exhaustive data collection document.
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From page 288... ...
formation in kidneys effects NDGA Knowledge about structurally related substances, e.g., acetaminophen, which is metabolized to quinones Related substances Proximal tubule Chaparral damage and cyst Adverse liver (not tea) formation in kidneys effects NDGA Animal data FIGURE 11-1 Causal model diagram illustrating a relationship between chaparral and liver effects in animals and humans.
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From page 289... ...
A solid arched arrow illustrates a relationship between chaparral ingestion and adverse liver effects in humans, independent of knowledge about hazards that may be associated with NDGA. Another pathway between chaparral and liver effects is based on the relationship between chaparral and NDGA and knowledge of how chemical structures like NDGA can be metabolized into quinones that subsequently result in adverse liver effects.
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From page 290... ...
For example, it was helpful to have physicians and scientists very familiar with insulin and glucose regulation to consider glucosamine, experts in melatonin biology and endocrinology for melatonin consideration, experts familiar with metal toxicology and carcinogenicity to help with chromium picolinate, and experts in plant chemistry as chaparral and NDGA were considered. The Framework process outlined in Chapter 11 suggests that FDA may also want to involve external experts when data are not clear-cut, when expertise in particular aspects of human physiology is necessary and when the data to be considered require additional expertise to interpret.
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From page 291... ...
1997. American Herbal Product Association's Botanical Safety Handbook.
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