7
Attributes and Limitations of the Proposed Framework

The previous chapters propose a framework for screening/flagging, priority setting, and conducting a full safety evaluation for dietary supplement ingredients. This framework was drafted after considering systems used by other organizations for reviewing the safety and effectiveness of dietary supplement ingredients, and after considering frameworks that have been established to evaluate the safety of other types of substances, as described in Chapter 2.

ATTRIBUTES OF THE PROPOSED FRAMEWORK

There are a number of attributes of the proposed framework, and there are also a few limitations. This framework integrates the variety of available evidence about safety, balancing the value of different types of evidence and also integrating prevalence of use information to enhance the public health impact of the process. Using the framework, FDA can be both proactive and reactive, as well as provide an open and transparent process helpful to the general public and industry.

First and foremost, it is important to note that this framework focuses on how to consider the safety of dietary supplement ingredients rather than offering guidance on how to consider their benefits and role in health. This was a key point of the request to the Institute of Medicine from FDA, as is appropriate since dietary supplements are regulated as foods that are assumed to be safe, rather than as drugs requiring a risk-benefit analysis.

As mentioned above, a strength of the proposed framework is that it incorporates several different types of data that may be available, providing a mechanism to evaluate the totality of the available data—not just relying on one type, such as human data. Utilizing the diverse types of data available (i.e., the different “factors”) is especially important because the extent of the types of data available are vastly different from one dietary supplement ingredient to another. Since FDA has no authority to require specific types of studies or data in advance of marketing, it is not possible to have available for safety review the same types of information regardless of the ingredient. Thus the integrative approach proposed is more useful than centering a framework on one type of data in establishing priorities and subsequently reviewing safety.

A somewhat distinct aspect of this framework, compared to the approaches taken by other organizations, is that it reflects a public health perspective that a supplement ingredient used by more individuals warrants greater attention, given similar safety concerns. The framework



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For Comment: Proposed Framework for Evaluating the Safety of Dietary Supplements 7 Attributes and Limitations of the Proposed Framework The previous chapters propose a framework for screening/flagging, priority setting, and conducting a full safety evaluation for dietary supplement ingredients. This framework was drafted after considering systems used by other organizations for reviewing the safety and effectiveness of dietary supplement ingredients, and after considering frameworks that have been established to evaluate the safety of other types of substances, as described in Chapter 2. ATTRIBUTES OF THE PROPOSED FRAMEWORK There are a number of attributes of the proposed framework, and there are also a few limitations. This framework integrates the variety of available evidence about safety, balancing the value of different types of evidence and also integrating prevalence of use information to enhance the public health impact of the process. Using the framework, FDA can be both proactive and reactive, as well as provide an open and transparent process helpful to the general public and industry. First and foremost, it is important to note that this framework focuses on how to consider the safety of dietary supplement ingredients rather than offering guidance on how to consider their benefits and role in health. This was a key point of the request to the Institute of Medicine from FDA, as is appropriate since dietary supplements are regulated as foods that are assumed to be safe, rather than as drugs requiring a risk-benefit analysis. As mentioned above, a strength of the proposed framework is that it incorporates several different types of data that may be available, providing a mechanism to evaluate the totality of the available data—not just relying on one type, such as human data. Utilizing the diverse types of data available (i.e., the different “factors”) is especially important because the extent of the types of data available are vastly different from one dietary supplement ingredient to another. Since FDA has no authority to require specific types of studies or data in advance of marketing, it is not possible to have available for safety review the same types of information regardless of the ingredient. Thus the integrative approach proposed is more useful than centering a framework on one type of data in establishing priorities and subsequently reviewing safety. A somewhat distinct aspect of this framework, compared to the approaches taken by other organizations, is that it reflects a public health perspective that a supplement ingredient used by more individuals warrants greater attention, given similar safety concerns. The framework

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For Comment: Proposed Framework for Evaluating the Safety of Dietary Supplements reflects this perspective by integrating estimates of prevalence of use with the available safety information as part of the priority-setting step. In addition to providing a method for integrating various types of information, the framework is also practical in that it allows FDA to be both proactive and reactive. The screening/flagging and priority-setting steps are reactive in nature, providing a mechanism for FDA to integrate new safety concerns into the existing priority scheme. The priority-setting mechanism can be initiated with limited information, but as additional resources are devoted to proactively searching for data, the level of concern characterized by the priority group to which a dietary supplement ingredient is assigned becomes increasingly accurate. As additional information about flagged ingredients becomes available, the information is used to update “scores” of dietary supplement ingredients that have not yet reached Step Three (the critical safety evaluation), easily updating and thus revising the ingredient’s priority ranking. For example, it is easy to envision that a new clinical study may report serious adverse events for an ingredient, changing its score for human data from an NAD (no appropriate data) to a 3. The priority ranking of this ingredient relative to the others is easily adjusted to reflect this new information. The practical nature of the framework is also reflected in the fact that it allows FDA to score each ingredient one factor at a time. Relative priorities can be set without having to simultaneously consider the entire array of each ingredient’s safety concerns. The critical safety evaluation step is designed to be as open and transparent as possible, so a mechanism for the public and the relevant industry to provide data and other input is provided. Keeping the activity open and transparent also allows the general public to be able to access safety conclusions made by scientists devoid of conflicts of interest. For this reason, the framework stresses the value of making safety reviews readily available to the public. LIMITATIONS OF THE PROPOSED FRAMEWORK In addition to the framework’s attributes outlined above, there are also limitations inherent to the framework. By definition, the framework cannot be used to consider the possible benefits of consuming dietary supplement ingredients. Another limitation is that, as with any evaluation of dietary supplement ingredients under the current regulatory scheme, the framework’s evaluation of safety depends on publicly available data or data voluntarily made available by industry and other groups. Another limitation of this framework is that a major component of it is human data, which unfortunately can be highly variable in quality and quantity. The framework, especially through the priority-setting scoring process, seeks to evaluate explicitly the different components of the data—considering the evidence or possible risk, seriousness of harm, the hierarchy of data types, and the potential public health impact as distinct variables. This approach attempts to guide judgments made at the screening/flagging and priority-setting steps, but judgment of safety is in the end a subjective determination dependent upon expert interpretation of the totality of evidence. The use of expert judgment via an external advisory committee may itself be another limitation, in that the number of qualified experts not associated with industry or the regulatory agency may be limited. An additional limitation of the framework is the extent to which evaluation of the safety of any combination of dietary supplement ingredients can be conducted when the review is limited to available data. In the absence of having the authority to require manufacturers to present specific evidence of safety, the burden of conducting studies to ascertain adverse effects is

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For Comment: Proposed Framework for Evaluating the Safety of Dietary Supplements placed on FDA, which has limited resources compared to the number of the dietary supplements currently marketed. SUMMARY While the framework approach outlined here is not based entirely on empirical data, it should provide a mechanism for FDA to accomplish its goal of using a science-based approach to set priorities for evaluating the safety of dietary supplement ingredients given its available resources and the legislative authority under which it regulates the industry.

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