Serious Adverse Events: Are SAEs as underreported as GAO suggests? (Part I)
In Part I of this two-part series, background will be provided regarding the origin and reason for the reporting system that is currently in place for serious adverse events (SAEs) associated with dietary supplements: the reason an investigation by the Government Accountability Office (GAO) was initiated and its reported findings, a brief description of the American Association of Poison Control Centers (AAPCC), the pertinent points of its reporting system, and an initial look at what the AAPCC appears to report as adverse events due to dietary supplements.
The 2006 Dietary Supplement and Nonprescription Drug Consumer Protection Act went into effect on December 22, 2007. The 2006 act amended the Federal Food, Drug, and Cosmetic Act by mandating that firms (i.e., manufacturers, packers or distributors whose names appear on the label) provide adverse event reports (AERs) of SAEs[1] associated with the ingestion of dietary supplements to the U.S. Federal Drug Administration (FDA) within 15 business days of receiving a complaint from consumers, health care professionals, or others.
The requirement for mandatory reporting of SAEs has its roots in the banning of botanical ephedrine alkaloids from use in dietary supplements. FDA banned the substances in 2004 due to numerous SAEs, including several deaths attributed to ingestion of the herbal ingredients in weight loss supplements. The 2006 act was created in partial response to the nearly ten years it took FDA to progress from speculation regarding the ephedrine alkaloids to FDA’s concluding that the alkaloid ingredients presented a significant or unreasonable risk of illness or injury when used as directed to the final action by rule-making that removed the ingredients from the market (GAO-03-1042T).[2]
On November 8, 2011, a congressional request was initiated by Representative Henry Waxman (D-CA) and Senator Richard Durbin (D-IL) that tasked the GAO with evaluating and reporting on the FDA’s use of AERs in its regulatory oversight of the dietary supplement industry. The GAO investigation began in December of that year, covered calendar years 2008 through 2011, and ended with a report (GAO-13-244) released in March 2013, “Dietary Supplements: FDA may have opportunities to expand its use of reported health problems to oversee products.” In this report the GAO suggests that SAEs are underreported by consumers and medical professionals who may not contact the manufacturer or FDA when ingestion of a dietary supplement is implicated in an SAE:
“From 2008 through 2011, the Department of Health and Human Services’ Food and Drug Administration (FDA) received 6,307 reports of health problems—adverse event reports (AER)—for dietary supplements; 71 percent [4478] came from industry as serious adverse events as required by law, and most of these AERs were linked with supplements containing a combination of ingredients, such as vitamins and minerals or were otherwise not classified within FDA’s product categories. However, FDA may not be receiving information on all adverse events because consumers and others may not be voluntarily reporting these events to FDA, although they may be contacting poison centers about some of these events. From 2008 to 2010, these centers received over 1,000 more reports of adverse events linked to dietary supplements than did FDA for the same period.”[3]
To evaluate whether or not SAEs are as under-reported as suggested by the GAO, the annual reports for years 2008 – 2011 of the AAPCC National Poison Data System (NPDS) were identified and for this article, reviewed in light of the GAO report and the view most readers of the collected reports would likely take. The remainder of this article will provide background explanation for context and a summary of initial findings presented via text and figures.
During the period of interest (2008 – 2011) the AAPCC NPDS began with 61 regional Poison Centers (PCs) consolidated down to 57 PCs and covered the entire populations of the 50 United States, American Samoa, District of Columbia, Federated States of Micronesia, Guam, Puerto Rico, and the US Virgin Islands. In 2011, the total number of individuals served by the AAPCC was 315,726,607. On average, the AAPCC logged and closed 4,047,560 calls each year from 2008 through 2011. Of the logged calls, 60% addressed a confirmed human exposure of some kind. The other 40% were calls related to confirmed human nonexposures, confirmed animal exposures and nonexposures, and calls requesting information not related to an exposure event.
A confirmed human exposure case falls into one of five major categories; in order of decreasing frequency: “Unintentional” (81.72% of human exposure calls from 2008 – 2011), “Intentional” (14.46%), “Adverse reaction”[4] (2.55%), “Other” (0.66%), and “Unknown” (0.61%). In the NPDS, the major category of “Adverse reaction” includes subcategories of “Drugs” (i.e., legitimate, prescription drugs), “Food,” and “Other.” Dietary supplements fall into the subcategory of “Other.” Regarding the other major categories and their subcategories, “Unintentional” exposures include “General,” “Therapeutic error,” “Misuse,” “ Bite/sting,” “Environmental,” “Food poisoning,” “Occupational,” and “Unknown” and not suspicious, while “Intentional” exposures include the subcategories “Suspected suicide,” “Misuse,” “Abuse,” and “Unknown” and suspicious and “Other” exposures include three subcategories, “Malicious,” “Contamination/tampering,” “Withdrawal,’’ and the “Unknown” category, which has only one subcategory, “Unknown reason,” for those exposures that are not understood or explained sufficiently well for any other classification.
Figure 1. Average percentage of adverse reaction cases attributed to dietary supplements, food, and prescription drugs compared with the other major causes of human exposure cases logged by AAPCC, 2008 – 2011.
By year, unintentional exposures accounted for 80-83% of all confirmed human exposures with 10-12% of exposures due to therapeutic error (e.g., inadvertent double-dosing, taking/giving the wrong medication or amount, breast milk exposures) and ~5% due to accidental misuse. Intentional exposures during this same period accounted for ~14.5% of human exposures each year, with more than half due to suspected suicide (9% of all human exposures). In comparison, adverse reactions accounted for an average of 2.6% of human exposures each year and were primarily due to prescription drugs (1.8% of all exposures), but also included food (0.2% of all exposures) and other (0.5% of all exposures). An estimated one-third of “other” adverse reaction exposures were linked to dietary supplements.
In the GAO investigation of the AAPCC NPDS annual reports, dietary supplements were limited to products intended for human consumption as defined by the Dietary Supplement Health and Education Act of 1994 (DSHEA). Dietary supplements that met the definition of DSHEA, but were available to consumers only by prescription, or were intended for veterinary use, were excluded from consideration. Products that had been deliberately adulterated (with prescription drugs or drug analogs), however, were included in the GAO definition of “dietary supplement” because the illicit products were marketed as dietary supplements to consumers, who had no means of realizing the materials were not legal dietary supplements. To approximate what would reasonably be considered dietary supplements as an initial assessment under these conditions, the following NPDS categories and subcategories were teased from the annual report data for our evaluation:
(1) “Dietary Supplements/Herbals/Homeopathic” category, including subcategories “Amino Acids,” “Botanical Products,” “Cultural Medicines,” “Energy Products,” “Hormonal Products,” “Miscellaneous Dietary Supplements/Herbals/Homeopathic,” and “Other Dietary Supplements;”
(2) “Electrolytes and Minerals” category (no subcategories);
(3) “Stimulants and Street Drugs” subcategories under “Diet Aids”:[5] “Other Types of Diet Aid, Over the Counter Only;”
(4) “Stimulants and Street Drugs” subcategories under “Miscellaneous Stimulants and Street Drugs”:[6]”Caffeine,” and “Ephedrine;” and
(5) “Vitamins” category, including subcategories “Miscellaneous Vitamins,” “Multiple Vitamin Liquids: Adult Formulations,” “Multiple Vitamin Liquids: Pediatric Formulations,” “Multiple Vitamin Tablets: Adult Formulations,” “Multiple Vitamin Tablets: Pediatric Formulations,” “Multiple Vitamins, Unspecified Adult Formulations,” “Multiple Vitamins, Unspecified Pediatric Formulations,” and “Other Vitamins” (single vitamins).
As mentioned previously, logged AAPCC calls for confirmed human exposures are sifted to separately report cases addressing the misuse, abuse, or accidental ingestion of a substance, such as a dietary supplement, from cases associated with adverse reaction to that substance. Although logged calls are also sorted regarding outcome (which can range from no outcome to death), the AAPCC reporting system provides no means of linking the exposure type to outcome, a limitation which will be further explored in Part II. The reported adverse reaction exposures in Figure 1, therefore, include those which were determined to have no outcome, minor and moderate outcomes, as well as those resulting in a serious outcome or death. Only dietary supplements included in the categories and subcategories provided above were included for consideration in the figure and then only when product being used as directed.
Initial examination of the NPDS data, yielded an average of 4,219 adverse reaction exposure cases associated with dietary supplements (4,055 in 2008; 4,104 in 2009; 4,295 in 2010; 4,422 in 2011). Figure 1 depicts the relationship of dietary supplement-related adverse reactions (no matter the outcome) to the adverse reactions associated with the ingestion of foods, prescription drugs taken in accordance with label directions and to all human exposure incidents logged by the AAPCC from 2008 – 2011. In Figure 2, the relationships are described pictorially by year from the total number of cases logged to adverse reaction cases associated with dietary supplements.
So far this isn’t looking so good for dietary supplements. It even appears that the GAO may have had a point. With the background now set, in the next quarter we’ll see what these numbers actually mean with regard to the product types involved and outcomes that affected consumers to at least a moderate degree.
Figure 2. Outcomes for all dietary supplement exposures (2008-2011) including intentional, unintentional, other, and adverse reaction).
Approximately 3% of each outcome could be associated with an adverse reaction exposure.
Continue to Serious Adverse Events: Part II
References
Bronstein, A.C., Spyker, D.A., Cantilena, Jr., L.R., Green, J.L., Rumack, B.H., and Giffen, S.L. (2009) 2008 Annual report of the American Association of Poison Control Centers’ National Poison Data System (NPDS): 26th Annual report. Clinical Toxicology, 47: 911-1084.
Bronstein, A.C., Spyker, D.A., Cantilena, Jr., L.R., Green, J.L., Rumack, B.H., and Giffen, S.L. (2009) 2009 Annual report of the American Association of Poison Control Centers’ National Poison Data System (NPDS): 27th Annual report. Clinical Toxicology, 48: 979-1178.
Bronstein, A.C., Spyker, D.A., Cantilena, Jr., L.R., Green, J.L., Rumack, B.H., and Dart, R.C. (2011) 2010 Annual report of the American Association of Poison Control Centers’ National Poison Data System (NPDS): 28th Annual report. Clinical Toxicology, 49: 910-941 with on-line appendix materials (tabulated data) pp. 1-171.
Bronstein, A.C., Spyker, D.A., Cantilena, Jr., L.R., Green, J.L., Rumack, B.H., and Dart, R.C. (2012) 2011 Annual report of the American Association of Poison Control Centers’ National Poison Data System (NPDS): 29th Annual report. Clinical Toxicology, 50: 911-1164.
[1] As defined by FFDCA amended by the 2006 act, SAEs are “any health-related events that result in, for example, a death, life-threatening experience, inpatient hospitalization, or birth defect or that require, based on reasonable medical judgment, a medical or surgical intervention to prevent these serious outcomes.”
[2] GAO, “Dietary Supplements Containing Ephedra: Health Risks and FDA’s Oversight”, GAO-03-1042T (Washington, D.C.: July 23, 2003).
[3] Although the GAO compared in its summary the number of adverse event reports received by poison centers with those received by FDA for the period of 2008 – 2010, the actual GAO report included an analysis of adverse event reports for the period of 2008 – 2011.
[4] “Adverse reaction” exposures are differentiated from “Intentional” and “Unintentional” exposures in that adverse reaction exposures are neither intentional nor accidental (unintentional) and are limited to exposures in which a drug, food, dietary supplement, or other material is given to/taken by the correct party with administration provided in adherence to label directions or convention, but in which an adverse reaction occurs or is suspected of occurring.
[5] “Diet Aids: Phenylpropanolamine Only,” “Diet Aids: Phenylpropanolamine and Caffeine Combinations,” “Other Types of Diet Aid, Prescription Only” and “Unknown Types of Diet Aid” were not included.
[6] The other subcategories, which largely consisted of illicit substances, were not included.