The Subtle Horror of Package Inserts

If you want to scare yourself about vaccine safety, just read the package insert.

Package inserts are not medical communication documents; they’re legal communication documents. Vaccine side effects that occur during clinical trials will often appear in the package insert even when those side effects occur at the same rate in those who received placebo. In other words, the vaccine didn’t cause the problem. The rotavirus vaccine provides a perfect example.

The rotavirus vaccine, RotaTeq, was tested in about 72,000 infants in a prospective, placebo-controlled trial. Rotaviruses are a common cause of fever, vomiting, diarrhea, and dehydration in infants and young children. Before the vaccine was licensed in the U.S. in 2006, every year about 55,000 to 70,000 children would be hospitalized with severe dehydration caused by rotavirus. The rotavirus vaccine was shown to be about 95% effective at preventing hospitalization. Seizures occurred in 27 of 36,150 (0.07%) vaccine recipients and 18 of 35,536 (0.05%) placebo recipients. These differences were not statistically significant. Nonetheless, seizures are listed in the rotavirus vaccine package insert. Ironically, after the rotavirus vaccine was licensed, large post-licensure studies showed that the vaccine actually decreased the risk of seizures. Because natural rotavirus infection can cause seizures with or without fever, and the rotavirus vaccine prevented natural infection, this wasn’t surprising.

Similarly, some children in the large clinical trial of RotaTeq suffered from Kawasaki disease, which causes inflammation of the blood vessels primarily in children less than 5 years old. Symptoms of Kawasaki disease include high fever, rash, conjunctivitis, a reddening of the tongue, swollen hands and feet, and occasionally severe damage to the arteries that supply the heart. During the rotavirus clinical trial, Kawasaki disease occurred in 5 of 36,160 (0.01%) vaccine recipients and 1 of 35,536 (0.003%) placebo recipients. This difference was not statistically significant but appears in the package insert. Subsequent studies of larger numbers of children did not show an increased risk of Kawasaki disease in children receiving the rotavirus vaccine.

Of interest, during the clinical trial of the rotavirus vaccine, 5 cases of arm and leg fractures occurred in the placebo group and none in the vaccine group. This was a statistically significant difference. In other words, the rotavirus vaccine prevented arm and leg fractures. Not surprisingly, this finding doesn’t appear in the package insert because it doesn’t make biological sense. If you are worried that the rotavirus vaccine might cause seizures or Kawasaki disease, then you should be reassured that it might also prevent arm and leg fractures. Such is the problem with small numbers in large databases.