Procedures for Reporting Adverse Events

An accepted definition of a veterinary adverse event is any observation of an event in an animal or animals, regardless of whether it is considered to be a product-related event, that is unfavorable and unintended and that is detected after use of a veterinary medicinal product. An adverse event report is a direct communication from an identifiable firsthand reporter that includes (at the minimum) the following information: an identifiable reporter, an identifiable animal or animals, an identifiable veterinary medicinal product, and 1 or more adverse events.

Adverse event reports for all veterinary biologic products are submitted to the CVB on a voluntary basis from the public. Adverse event reports may be submitted to the CVB via a toll-free number (800-752-6255), the CVB Web site,¹ mail, or fax. Manufacturers may also submit adverse event reports that they have received; participation of the manufacturers may be voluntary or may be at the request of the CVB. Additionally, adverse event reports related to veterinary biologic products received by the FDA Center for Veterinary Medicine are forwarded to the CVB.

Each adverse event report received by the CVB is reviewed for accuracy and to ensure the information is complete. When additional information is required or deemed important, follow-up contacts are made with the reporter or associated health professional. Adverse events are classified by the reporter, who selects from a list of event categories that includes anaphylaxishypersensitivity, autoimmune, birth defect, lack of expected efficacy, local, neoplasia-cancer, reproductive, systemic, or other. Events included in the category “other” included descriptions of neurologic signs, behavior changes, dermatopathies, and various other ailments. Vaccine-associated sarcomas in cats were classified in the neoplasia-cancer category. The report may be reclassified by personnel at the CVB when warranted by analysis of the available information.

On the basis of the seriousness, expectedness, or frequency of the adverse event or events, the CVB may request investigation reports or summary reports from the manufacturer regarding the biologic product or vaccine serial in question. The CVB may also request repeat or additional testing by the manufacturer or the CVB laboratory. Additionally, epidemiologic investigations or additional safety studies may be performed. Although no formal causality assessment is applied to a particular report, each report is reviewed and evaluated by the CVB. If, on the basis of the available evidence, product-related safety or efficacy problems exist, regulatory actions may follow that could include additions or changes to the product label, notifications sent to users, and suspensions of product distribution.

Adverse Event Reports

The CVB received 5,470 adverse event reports during the period from January 1, 1999, through December 31, 2005. The number of reports for each year during this time period was calculated (Figure 1). These reports included 12,409 affected animals, including 343 reported deaths. Seventeen reports involved ³ 20 affected animals, which included 2 reports that involved an estimated combined total of 5,600 affected animals. Therefore, those 2 reports accounted for a large proportion of the affected animals. There were 6 reports that had deaths of 10 or more animals, with the highest number being 62 animals that died. For events in which the reporter's relationship to the animal or animals was known, 87% were submitted by veterinarians, veterinary staff, or other health professionals and 12% were submitted by animal owners.

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Number of adverse event reports received each year by the USDA Center for Veterinary Biologics (CVB) for the period 1999 through 2005.

Citation: Journal of the American Veterinary Medical Association 229, 7; 10.2460/javma.229.7.1100

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Reported adverse events were categorized as anaphylaxis-hypersensitivity (n = 2,884), local (1,368), systemic (821), other (231), neoplasia-cancer (85), reproductive (41), autoimmune (18), lack of efficacy (13), and birth defect (9). Reports involving canids (n = 2,365) constituted the largest animal group, followed by reports involving felids (2,349), mustelids (ferrets and mink; 382), equids (297), bovids (60), pigs (7), sheep and goats (6), birds (including poultry; 2), and exotic animals (2). The relative proportion of adverse event reports for canids, felids, mustelids, and equids was calculated for the time period (Figure 2). Reports involving canids and felids were nearly equal during the entire period (n = 2,365 [43.24%] and 2,349 [42.94%], respectively). However, since 2002, the number of reports for adverse events in canids has exceeded the number of reports for adverse events in felids. Mustelids, primarily ferrets, were the third most common animal group involved in the reports during this period (n = 382 [6.98%]), and the number of reports for mustelids was fairly uniform during the period, varying from 5.34% to 10.29% on a yearly basis. Reports involving equids accounted for 297 (5.43%) of the total and varied from 1.79% to 18.18% on a yearly basis. Reports involving bovids accounted for 60 (1.10%) of the total and varied from 0.74% to 2.85% on a yearly basis. There were 17 (0.31%) adverse event reports involving pigs, sheep, goats, birds (including poultry), and exotic animals during this period; none of these animal groups had > 3 reports for any given year.

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Percentage of total annual adverse event reports for canids (gray bars), felids (black bars), mustelids (white bars), and equids (diagonal-striped bars) received by the USDA CVB for each year of the period 1999 through 2005.

Citation: Journal of the American Veterinary Medical Association 229, 7; 10.2460/javma.229.7.1100

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Event categories for each animal group for which there were at least 50 reports were summarized(Table 1). In canids, adverse event reports predominantly involved acute anaphylaxis-hypersensitivity reactions (n = 1,564 [66.13%]). In felids, anaphylaxis-hypersensitivity and local reactions were nearly equal (n = 933 [39.72%] and 891 [37.93%], respectively). Mink and ferrets primarily had reports of acute anaphylaxis-hypersensitivity (n = 337 [88.22%]), whereas systemic events were the most common reports for equids and bovids (112 [37.71%] and 25 [41.67%], respectively).

Discussion

The CVB receives adverse event reports for veterinary biologic products from the public, which comprises consumers and veterinarians, veterinary staff, and other health professionals. For the period 1999 to 2005, the annual number of adverse event reports ranged from a high of 1,620 reports to a low of 262 reports. There were substantially more reports received by the CVB in the years 1999 through 2002, compared with the number of reports for the years 2003 through 2005. This is primarily attributable to the fact that the US Pharmacopeia Veterinary Practitioners' Reporting Program ceased its adverse event report program for veterinary medicinal products on April 30, 2003.² Since discontinuance of that reporting program, the CVB typically has received 25.6 reports/mo (approx 307 reports in any 12-month period).

In addition, adverse events for veterinary biologic products may have been reported only to the manufacturers of those products. The manufacturers of veterinary biologic products have not been required to routinely furnish reports they receive to the CVB. Thus, the information provided here consists primarily of adverse event reports made directly to the CVB and may not be representative of the number or type of events reported directly to biologics manufacturers.

Since 2002, the percentage of reports involving canids has been greater than the percentage of reports involving felids. The reason for this pattern is not clear because the number of cats in US households is greater than the number of dogs in US households, and the rate of increase in cat ownership has outpaced that for dog ownership.³ The highest numbers of adverse event reports for equids were in 2003 and 2004 and were primarily related to reports involving reproductive and birth defects after administration of a product that contained West Nile virus. A causal relationship was never established, and a subsequent study⁴ provided evidence that the product did not compromise pregnancy in horses.

Anaphylaxis-hypersensitivity reactions were the most numerous type of adverse event reported, comprising 2,884 (52.72%) of the reports received. However, this category of reports varied from 10.10% for equids to 88.22% for mustelids. Two studies^5,6 have revealed the predisposition of ferrets toward anaphylactic reactions. In the study reported here, adverse events for canids were predominantly acute hypersensitivity reactions (66.13%). This is comparable to results for a study⁷ in which investigators evaluated adverse events after vaccine administration in dogs. In that study, the predominant clinical signs in a sample of 400 affected dogs were facial or periorbital edema (30.8%), urticaria or wheals (20.8%), and generalized pruritis (15.3%). If these reports had been received by the CVB, they would have been classified as hypersensitivity events.

Adverse event reports for felids were nearly equally divided between anaphylaxis-hypersensitivity and local reactions (39.72% and 37.93%, respectively). There were 82 reports categorized as neoplasia-cancer for felids during this period, which ranged from no reports of this type for 1999 and 2000 to a high of 34 reports of this type in 2003. Nearly all of these events were described as fibrosarcomas or vaccine-associated sarcomas by the reporters.

Adverse event reports for equids were most likely to be classified as systemic (37.71%), which was followed by other (20.54%), local (16.50%), and anaphylaxishypersensitivity (10.10%). The 60 adverse events for bovids were classified as systemic (41.67%), anaphylaxis-hypersensitivity (26.67%), other (13.33%), reproductive (10.00%), local (6.67%), and lack of efficacy (1.67%). The classification of adverse event reports for other species groups was not provided here because of the low numbers of reports (ie, < 50 reports/species group) for each.

This summary reflects adverse events reported to the CVB for the period 1999 through 2005. The USDA–Animal and Plant Health Inspection Service is interested in all potential associations between vaccines and adverse events. Reports are evaluated to identify unexpected patterns in the number, type, or seriousness of events, but should not be considered as documentation that a vaccine caused the event. The information reported here highlights the role veterinarians have in postmarketing surveillance of veterinary biologic products and detection of adverse reactions that may not be discernable by other means.