Observer Bias in Acellular Pertussis Vaccine Trials

To the Editor. We wish to comment on the recently published article1 that evaluates the impact of observer bias on the estimate of clinical efficacy of one acellular pertussis vaccine. The authors report that, in the Erlangen trial, the observed incidence in unblinded unvaccinated children (DT) was only 13%, compared with an expected figure of approximately 40%. To determine potential observer bias, the authors analyzed the trial physicians' cough referral rates and used these rates to divide the physicians into three categories indicating their compliance to the trial protocol, which required referral of any cough lasting >7 days. Physicians who had reported an at least 20% incidence of cough were classified as “highly compliant.” The authors then recalculated vaccine efficacy for each compliance category and found that the estimated efficacy greatly varied among the categories and that it was inversely proportional to the physician's referral rate, concluding that a bias had occurred. Because no correlation was found between the cough referral rate and the proportion of unvaccinated (DT) children in each physician's study subject group, the authors concluded that the bias did not depend on unblinded conditions and that a similar bias was thus likely to have occurred in all of the recently conducted pertussis trials. Although the evidence for the Erlangen trial is convincing, extending the conclusions …