Metabolife 356, which claims to raise the body’s metabolism and help dieters lose weight while maintaining high energy levels, contains 32 ingredients, including ephedra, guarana (an herbal source of caffeine), bee pollen, and caffeine. The product label recommends that adults take one to two caplets two to three times per day or every 4 hours, not to exceed eight caplets per day. Warnings on the product label suggest that a health care professional be consulted by individuals who are using any other dietary supplement, prescription drug, or over-the-counter drug containing ephedrine alkaloids or who have, or have a family history of, any of 11 health conditions, including heart disease, high blood pressure, diabetes, recurrent headaches, and depression. The label also recommends that persons should not use the product for more than 12 weeks and that exceeding the recommended amount may cause serious adverse health effects including heart attack or stroke. Other possible side effects mentioned on the label include rapid heartbeat, dizziness, severe headache, and shortness of breath. The complete product label is in appendix II. The Dietary Supplement Health and Education Act of 1994 created a framework for FDA’s regulation of dietary supplements as part of its oversight of food safety. Dietary supplements are generally marketed without prior FDA review of their safety and effectiveness. Manufacturers of dietary supplements are responsible for ensuring the safety of the dietary supplements they sell. Therefore, FDA relies on voluntary reports of adverse events from consumers, health professionals, and others in its effort to oversee the safety of marketed dietary supplements. Although there are no adverse event reporting requirements for manufacturers of dietary supplements, there are such requirements for many other products regulated by FDA. Various types of adverse events associated with the use of human drugs and biologics, animal drugs, animal feeds containing animal drugs, medical devices, infant formulas, and radiation-emitting devices must be reported to FDA. In addition to dietary supplements, other products regulated by FDA that do not require adverse event reporting are foods, cosmetics, and color additives. (See app. III for details about adverse event reporting requirements.) Voluntary adverse event reporting systems can be valuable tools for identifying potentially serious health issues that may be associated with the use of a product and for maintaining ongoing surveillance. FDA has used adverse event reports to identify issues for further investigation and, as we previously reported, it has used adverse event reports to help identify dietary supplements for which evidence of harm existed, and has issued warnings and alerts for dietary supplements. However, by themselves, adverse event reporting systems generally are not sufficient to establish that a product caused the reported health problem. As we noted in 1999, all voluntary surveillance systems, including FDA’s adverse event reporting system, have certain weaknesses. These include underreporting, reporting biases, difficulties estimating population exposure, and poor report quality. For example, the Department of Health and Human Services (HHS) Inspector General reported that a study commissioned by FDA estimated that FDA receives reports for less than 1 percent of adverse events associated with dietary supplements. In addition, it is often difficult to rule out other possible explanations for the event; for example, the event may have been caused by preexisting medical conditions, or by the concurrent use of prescription drugs, over- the-counter drugs, or other supplements. For these reasons, data from adverse event reports alone cannot be used to determine if the occurrence of a symptom among product users is unusually high. Between August and December 2002, Metabolife International released copies of 15,948 pages of documents that it said contained call records that reported adverse events associated with Metabolife 356 that the company had received from May 1997 through July 2002. Some pages of call records contained information about more than one call while others did not contain reports of adverse events. Some pages were photocopies or duplicates of other pages. The information about reported adverse events in the 14,684 health-related call records we examined was limited. Most of the call records we reviewed did not completely record demographic or medical history information about the consumer. Information about age, sex, weight, height, the amount of product used, and the duration of use was frequently not recorded. Handwritten call records were difficult to read and interpret. Information was often inconsistent across different versions of the same call record. The call records contained limited information about reported adverse events and consumers. In some cases the evidence for a report of an adverse event was a single health-related word on the call record, such as “seizure” or “stroke.” In addition, demographic and medical history information was not consistently recorded in the call records. Most of the call records we reviewed did not record information about the consumers’ sex, age, weight, or height. Eighty-eight percent of the call records did not record at least one of these variables. In addition, information about the amount of Metabolife 356 used and the duration of use was not recorded in 27 and 33 percent of the call records, respectively. (See table 1.) The absence of this information makes it difficult to assess whether the call records represent a signal of health concerns related to the consumption of Metabolife 356. Both the amount of product used and duration of use were recorded for 60 percent of the calls reporting adverse events. Relatively few of these records involved consumers who reported taking too much Metabolife 356 or using it for too long a period. Specifically, among call records containing information on the amount of product used or duration of use, 99 and 91 percent of consumers, respectively, reported using the product within the guidelines recommended on the label. The format of the call records varied from brief handwritten notes to typed notations to printed versions of a form used by Metabolife International. In general, less information was recorded for the one-third of call records that were handwritten than all other types of records. For example, calls recorded on a typed form more frequently recorded additional information such as recommendations by Metabolife International to discontinue Metabolife 356 (62 percent) or contact a doctor (54 percent) than did those on handwritten forms (13 percent and 8 percent, respectively). Further, it was often difficult to read handwritten call records. We could not always determine how many calls were reported on a single page since there was rarely a clear delineation of events. Because handwritten call records did not follow a template, we were unable to determine if some information was medical history or symptom information, or if a number was a weight, heart rate, or blood pressure. Information in call records was sometimes inconsistent. Where duplicate call records were available, information about consumers and their usage of Metabolife 356 was sometimes presented differently in the different records of the same consumer call. In addition, Metabolife International officials told us that its nurses sometimes used several different terms to document the same type of adverse event. We found that 14,684 of the Metabolife International call records reported at least one adverse event. Ninety-two of these were for the serious adverse events identified in the proposed label warning for dietary supplements containing ephedra that FDA announced on February 28, 2003. Other adverse events reported included significant elevation of blood pressure, abnormal heart rhythm, loss of consciousness, and systemic rash. We cannot establish that any of the reported adverse events were caused by the use of Metabolife 356. We counted 92 reports of heart attack, seizure, stroke, or death—the serious adverse events identified in FDA’s proposed label warning for dietary supplements containing ephedra (see table 2). In its 1997 proposed rule on dietary supplements, FDA also identified other types of adverse events as serious or potentially serious. Table 3 shows our counts for almost all such events. The serious and potentially serious types of adverse events described in FDA’s June 4, 1997, proposed rule were reported to the agency prior to June 7, 1996. FDA officials report that some other types of adverse events not included in the table may be considered serious or potentially serious but had not been reported to FDA during the time period considered by its proposed rule. In addition, the 14,684 call records with health-related reports presented a broad range of types of adverse events. Many of the call records contained reports of jitters, insomnia, hair loss, bruising, menstrual irregularities, and sexual dysfunction, as well as vague references to events such as “side effect” or “felt sick.” Some reported blood in stool, blood in urine, or blood clots. There were also some reports of visits to emergency departments and hospital admissions. Some call records contained reports of diseases such as pulmonary embolus (a blockage of an artery in the lungs), multiple myeloma, and inflammation of heart tissue. We cannot establish that any of the adverse events reported in the Metabolife International call records were caused by the use of Metabolife 356. As we noted earlier, adverse event reports by themselves are generally not sufficient to establish that a health problem was caused by the use of a particular product. For example, for many adverse event reports it is difficult to rule out other possible explanations for the event— the event may have been caused by preexisting medical conditions, or by the concurrent use of prescription drugs, over-the-counter drugs, or other dietary supplements. In addition, the limited information available in the Metabolife International call records means that we cannot confirm that a particular adverse event occurred, much less identify a specific cause for it. All the reviews of the Metabolife International call records, including ours, counted reports of serious adverse events. None of the reviews reported identical tabulations of these events. For the set of adverse events that Metabolife International counted—heart attack, stroke, seizure, death, and cardiac arrest—our counts are similar to those of the other reviews (see table 4). In total, we counted 96 such events, Metabolife International counted 78, and the counts of the other reviews ranged from 65 to 107. There are several possible reasons for the slightly different counts of serious adverse events in the different reviews.