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signal is evaluated and to determine the possibility that the ingredient caused the adverse effect noted (using the guiding principles outlined later in this chapter and discussed in detail in the chapters that follow).

What Constitutes a Signal?

FDA is likely to receive or become aware of a variety of signals suggesting potential risks to human health with the use of a dietary supplement ingredient. Signals may come to FDA’s attention and thus be “detected” through notice of regulatory action taken by other countries regarding a specific dietary supplement, through routine monitoring of medical and scientific literature, directly through it’s own Special Nutrition/Adverse Event Monitoring System, or through consultation with experts. FDA may also become aware of signals indirectly through reports in the media, through new data from animal experiments suggesting a specific risk, or through information provided by consumer protection advocacy groups. Signals can thus come from many sources and originate from many different types of scientific data. Given the significant number of dietary supplement ingredients, FDA’s attention should focus on signals that indicate a serious3health problem may result from ingestion of a dietary supplement ingredient.

Quality of the Signal

In this first component little is done to evaluate the quality of the data because the focus is simply on signal detection. While some signals may result from concerns expressed by other expert bodies, such as those described in Chapter 2, or by case reports of adverse effects, the quality of the signal is not reviewed until the second component of the process (initial review of available information). The quality of the information behind the signals detected will be highly variable and in some cases may provide only weak evidence or be of little use or credence. Nonetheless, detecting these signals requires the attention of qualified professional staff at FDA and will result in a reaction by FDA (even if the reaction is only to consider the signal of little importance, as described in the next component).


“Serious” is defined as 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 [2002] and 21 C.F.R. § 314.80 [2002]).

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