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. "3 Case Study of a Mitigation-Selection Decision." A Risk-Characterization Framework for Decision-Making at the Food and Drug Administration. Washington, DC: The National Academies Press, 2011.
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In three randomized prelicensure trials, the first available tetravalent rhesus-human reassortant rotavirus vaccine, RRV-TV (RotaShield, Wyeth Lederle Vaccines, Philadelphia), was shown to be highly effective (80-100%) for the prevention of severe rotavirus gastroenteritis in infants (Rennels et al. 1996; Perez-Schael et al. 1997; Santosham et al. 1997; Joensuu et al. 1998).1 In the conduct of 27 prelicensure trials of RRV-TV, five cases of intussusception—a rare form of bowel obstruction in which a portion of the bowel prolapses into a more distal portion—were reported in 10,054 infants who received the vaccine compared with only one case in 4,633 recipients of placebo; the rates were not statistically significantly different (p > 0.45) (Rennels et al. 1998). After much deliberation about the potential risk of intussusception after RRV-TV, FDA approved RRV-TV on August 31, 1998, for administration at the ages of 2, 4, and 6 months. Intussusception was listed as a possible adverse reaction in the manufacturer's product insert and in the published recommendations of the Advisory Committee on Immunization Practices (ACIP) of the Centers for Disease Control and Prevention (CDC) and the American Academy of Pediatrics (AAP 1998; CDC 1999a).
From September 1, 1998, to July 7, 1999, 15 cases of intussusception in infants who had received RRV-TV were reported to the Vaccine Adverse Event Reporting System (VAERS). There were no data on how many infants received RRV-TV; the manufacturer estimated that it had distributed 1.8 million doses and that about 1.5 million doses had been administered as of June 1, 1999 (CDC 1999b). Although some studies indicated that that number of cases would be expected by chance alone (CDC 1999b), the facts that vaccine-induced intussusception had been identified as a potential issue in prelicensure trials and that adverse events after vaccination are typically under-reported to the VAERS raised concerns that the actual number of intussusception cases in RRV-TV recipients might be substantially greater than the 15 reported. That concern led to the implementation of a multistate investigation to determine whether an association existed between administration of RRV-TV and intussusception in infants. Data from a postlicensure study at Northern California Kaiser Permanente were also quickly reviewed. The resulting data from both studies suggested that there was an increased risk of intussusception after receipt of RRV-TV. On July 16, 1999, CDC recommended suspension of the RRV-TV immunization programs until additional data could be analyzed (CDC 1999b; Alpert 1999).
After review of all available data, Wyeth voluntarily withdrew RRV-TV from the market on October 21, 1999. The next day, the ACIP withdrew its recommendation of infant vaccination with RRV-TV on the basis of the increased rate of intussusception after its administration (CDC 1999c). Considerable discussion followed the withdrawal of the RRV-TV vaccine and the implications
Severe rotavirus gastroenteritis is defined as diarrhea with or without vomiting that requires hospitalization or rehydration in a medical facility; stool-sample analysis confirms rotavirus infection (other than vaccine strain) (CDC 2009).