A FRAMEWORK FOR EVALUATING SAFETY
Alice M. Clark, Ph.D.
Vice Chancellor for Research and Sponsored Programs
Frederick A.P. Barnard Distinguished Professor of Pharmacognosy
Research Professor of the Research Institute of Pharmaceutical Sciences
The University of Mississippi
Member, Committee on the Framework for Evaluating the Safety of Dietary Supplements
Food and Nutrition Board, Institute of Medicine
and Board on Life Sciences, National Research Council
The National Academies
Subcommittee on Oversight of Government Management, the Federal Workforce and the District of Columbia
Committee on Governmental Affairs
June 8, 2004
Good afternoon, Mr. Chairman and members of the Subcommittee. My name is Alice M. Clark. I am the Vice Chancellor for Research and Sponsored Programs of the University of Mississippi as well as a Frederick A.P. Barnard Distinguished Professor, Professor of Pharmacognosy, and Research Professor in the Research Institute of Pharmaceutical Sciences at the University. I also served as a member of the Committee on the Framework for Evaluating the Safety of Dietary Supplements of the Institute of Medicine and National Research Council.
The Institute of Medicine and the National Research Council are part of the National Academies, which also include the National Academy of Sciences and the National Academy of Engineering. The Institute of Medicine operates under the 1863 charter by Congress to the National Academy of Sciences to advise the government on matters of science, technology, and health. The National Research Council is the principal operating agency of both the National Academy of Sciences and the National Academy of Engineering in providing service to the government, the public, and the scientific and engineering communities.
I am here to talk about the report of the Committee on the Framework for Evaluating the Safety of Dietary Supplements. The report, Dietary Supplements: A Framework for Evaluating Safety, was released in April 2004. My comments will focus on the key findings and recommendations of the report.
The work of the committee was conducted under a contract initiated by the Food and Drug Administration (FDA). Over several decades, the agency tried several approaches to regulating supplements, sometimes meeting resistance from industry and the public. In 1994 Congress passed the Dietary Supplement Health and Education Act, known as DSHEA, in order to define FDA’s authority to regulate dietary supplements. DSHEA states that supplements are to “supplement the diet” and are thus to be regulated like foods, meaning that they are assumed to be safe. Therefore, like food processors, supplement manufacturers are not required to conduct specific and defined safety tests on their ingredients or to provide the FDA documentation on the safety of their products. Many of the supplements on the market are probably safe. However, to identify and take action on the occasional problem product, the FDA must rely on available evidence and information to evaluate whether the ingredient in question poses an unreasonable risk. To aid the FDA, the committee was asked to devise a science-based approach to evaluating the safety of supplement ingredients under the authority of current statutes.
Framework for Evaluating Safety
The committee’s report offers the FDA a science-based approach by which the agency can use different kinds of available data to better identify supplements of concern, and then evaluate the safety of these ingredients. This approach works within the parameters of the current law governing how dietary supplements are regulated. This approach, called the framework, characterizes the nature of the scientific evidence that FDA is likely to encounter and describes a process for organizing that evidence to assess where a dietary supplement ingredient lies on a spectrum of concern.1. As the level of concern rises, so does the potential for a “significant or unreasonable risk,” the standard warranting regulation under the Food Drug and Cosmetic Act, as amended by DSHEA.
The framework consists of three major components: signal detection, initial review of the signal, and integrative evaluation. The first component is signal detection and signals can come from many sources and originate from many types of scientific data. Given the significant number of dietary supplements the FDA’s attention should focus on signals that indicate that a serious2. health problem may result due to ingestion of a dietary supplement or ingredient. The second component of the framework is to conduct an initial review of available information. This allows the FDA to focus its efforts on the few dietary supplement ingredients that are strong candidates for regulation. The third step of the framework process is conducting an integrative evaluation of those dietary supplements that are deemed to warrant further investigation.
A key point of the report is that FDA does not have to find direct evidence of actual harm from use of a supplement ingredient to determine that the product poses an unreasonable risk to consumers’ health. According to DSHEA, the agency can act to protect the public’s health when an ingredient poses a significant or unreasonable risk. Determining whether an ingredient carries unreasonable risks does not require the same level of definitive proof that would be needed to document actual harm.
The report describes the different kinds of data the agency can use in its safety evaluation. Often, useful information on an ingredient’s effects in people is lacking because the supplement manufacturers are not required to conduct pre-market testing or report evidence of adverse experiences. Moreover, historical use of an ingredient often is not sufficient to demonstrate that an ingredient does not cause harm. The report discusses the significance of the kinds of information available, such as data from animal studies, tests done in laboratories, or toxicity of similar or related substances. Some of these types of data may be sufficient by themselves for the FDA to determine that a supplement ingredient poses an unreasonable risk. The report classifies scientific information into four broad categories for use in determining the potential for serious harm for a specific dietary supplement ingredient—human data, animal data, related substances, and in vitro data. Guiding principles for evaluation of data to determine unreasonable risk are shown in Attachment 1 to this statement. They are also found in Box ES-3 of the report.
With the approach recommended in the report, it is possible for the FDA to conduct effective safety evaluations within the current regulatory framework established by DSHEA. However, in the process of developing the approach and reviewing the science, the committee noted that the constraints imposed by aspects of DSHEA limit the agency’s ability to conduct these evaluations as effectively and efficiently as possible. Therefore, the report recommends some changes that could mitigate these constraints and make the law more effective in meeting the goal of protecting public health. For example, reports of adverse events associated with the use of a product can be an important way by which the FDA becomes aware of potential health risks. Currently, supplement manufacturers and distributors are not required to notify the agency about health problems that they discover related to the use of their products. The law should be modified to require such reporting. But other parties also bear responsibility for ensuring that health problems related to use are brought to the FDA’s attention. Health professionals should be educated about ways to report health concerns and encouraged to use them. Likewise, the toll-free number for the FDA’s MedWatch should be printed on all supplements’ packaging so that consumers have a clear way to relay any health concerns. More detail on these recommendations is in Attachment 2.
While the committee was not formed to do a cost analysis of implementing the framework, implementing any framework to systematically evaluate the safety of dietary supplement ingredients will require additional resources. Thus, the report recommends that Congress provide the FDA additional funding so that it can more effectively protect the public's health.
Barriers to Evaluating the Safety of Dietary Supplements
Through the process of developing the framework, the committee identified a number of legal and regulatory barriers to evaluating the safety of dietary supplements that hamper FDA’s ability to protect the public health. The FDA currently has no authority to require the collection or reporting of specific safety data from dietary supplement manufacturers or distributors after their products are made available for sale to the public.
In line with these findings, 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 DHSEA, be revised. The constraints imposed on the FDA with regard to ensuring the absence of unreasonable risk associated with the use of dietary supplements make it difficult for the health of the American public to be adequately protected.
Thank you for the opportunity to address you on this important topic. I would be pleased to answer your questions.
1. The use of the term “concern” denotes a need for further investigation and inquiry by the FDA based on a relative level of interest arising from initial information.
2. Serious—any experience resulting in any of the following outcomes: Death, a life-threatening adverse experience, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant disability/incapacity, or a congenital anomaly/birth defect. Important medical events that may not result in death, be life-threatening, or require hospitalization may be considered serious when, based upon appropriate medical judgment, they may jeopardize the individual and may require medical or surgical intervention to prevent one of the outcomes previously listed (in accordance with 21 C.F.R. 600.80  and 21 C.F.R. 314.80 .
Please Note: Attachment 1 can be found via a link to the Report which has been posted to the Web site of the National Academies Press.
The following recommendations, while not part of the Framework itself, are designed to enhance the utility of the Framework and enhance the ability of the FDA to protect consumers from unreasonable risk of illness or injury resulting from use of dietary supplements.
Ø Prospective systematic monitoring and tracking mechanism for dietary supplement ingredients should be maintained and refined.
A prospective, systematic method for recording and monitoring the history of safety issues with specific dietary supplements is necessary to implement the Framework for FDA to evaluate the safety of dietary supplement ingredients. During the period of this study, the FDA has developed a new method of monitoring and tracking dietary supplement adverse event reports. However, a prospective system is required that enables tracking of information leading to all levels of concern.
The system should be open, transparent, and useful for establishing varying levels of concern related to dietary supplements as outlined in the Framework. Resources to support these activities should be provided to the FDA.
Ø Adequate resources to protect the consumer under DSHEA must be provided.
While the committee did not conduct an analysis of the cost of implementing this Framework, implementation of any framework for comprehensive safety evaluation will generate 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.
Ø Adverse Event Reporting:
- DSHEA should be amended to require that a manufacturer and distributor report to the FDA, in a timely manner, any serious adverse event associated with use of its marketed product of which the manufacturer or distributor is aware.
- The 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.
- The 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 supplement ingredients.
- The FDA MedWatch toll-free telephone number should be provided on product labels to facilitate reporting of adverse events.
Reports of adverse events are an important source of information by which the FDA becomes aware of potential risks to public health from exposure to dietary supplement ingredients. It has been estimated that the FDA receives reports of less than one percent of all adverse events associated with dietary supplements. While spontaneous adverse event reports have recognized limitations, they have considerable strength as potential warning signals of problems requiring attention, making monitoring by the FDA crucial.
Ø To initiate the 75-day premarketing review period, the distributor and manufacturer should be required to provide the FDA with all available data, both favorable and unfavorable, regarding the safety of the product.
Ø 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.
Many dietary supplement ingredients on the market today have new formulations and are produced through very different processes than related dietary supplement ingredients in traditional usage, or even other dietary supplement ingredients bearing the same name. This may result in markedly different bioactive substances of potential harm, and very different kinetics (e.g., absorption, distribution in the body, metabolism, and excretion).
Ø 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.
While the focus of this report is on developing a framework and not on safety issues related to good manufacturing practices, these are inseparable because variability in content hampers the evaluation of safety.
Ø Adoption of the labeling changes recommended in Inspector General Report: Dietary Supplement Labels: Key Elements is urged.
Required labeling information that would be of use to the consumer in making informed decisions about safety is limited. Current regulations related to source of a product only require the name and place of business of the manufacturer, packer, or distributor to be on the label. There are usually few manufacturers of a product, but many distributors or packers. Thus both sources need to be on the label.
Ø Additional Research on the Potential to Cause Harm:
- The continued development of effective working relationships and partnerships between FDA and the National Institutes of Health is encouraged.
- The 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 when research is needed to further evaluate concerns.
- All federally supported research on dietary supplements conducted to assess efficacy should be required to include the collection and reporting of all data on the safety of the ingredient under study.
There is no legal or regulatory requirement that dietary supplement ingredient manufacturers conduct toxicology or safety pharmacology studies on their products or ingredients. Thus, experiments and studies to address safety issues will, in most cases, be initiated by the FDA or other federal agencies.
SOURCE: IOM 2004. Dietary Supplements: A Framework for Evaluating Safety. Washington, DC: National Academies Press. Prepublication Version. Pages ES-12 –ES-13.