title: Control of type 1 error in a hybrid complete two-period vaccine efficacy trial.
abstract: A complete two-period experimental design has been defined as one in which subjects are randomized to treatment, observed for the occurrence of an event of interest, re-randomized, and observed again for the event in a second period. A 4-year vaccine efficacy trial was planned to compare a high-dose vaccine with a standard dose vaccine. Subjects would be randomized each year, and subjects who had participated in a previous year would be allowed to re-enroll in a subsequent year and would be re-randomized. A question of interest is whether positive correlation between observations on subjects who re-enrolled would inflate the variance of test statistics. The effect of re-enrollment and correlation on type 1 error in a 4-year trial is investigated by simulation. As conducted, the trial met its power requirements after two years. Subjects therefore included some who participated for a single year and others who participated in both years. Those who participated in both years constituted a complete two-period design. An algebraic expression for the variance of the treatment difference in a complete two-period design is derived. It is shown that under a 'no difference' null, correlation does not result in variance inflation in this design. When there is a treatment difference, there is variance inflation but it is small. In the vaccine efficacy trial, the effect of correlation on the statistical inference was negligible.
authors.affiliation: Sanofi Pasteur, Swiftwater, Pennsylvania, USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Dunning
authors.forename: John
authors.initials: J
authors.lastname: Reeves
mesh_terms: D006801:Humans; D007252:Influenza Vaccines / Q000627:therapeutic use; D007251:Influenza, Human / Q000453:epidemiology / Q000517:prevention & control; D016032:Randomized Controlled Trials as Topic / Q000379:methods / Q000706:statistics & numerical data*; D012107:Research Design / Q000706:statistics & numerical data*; D016896:Treatment Outcome
chemical_list: D007252:Influenza Vaccines
keywords: complete two-period design; experimental design; multi-year trial; re-enrollment; re-randomization; repeated measures; two-period design; type 1 error control; vaccine efficacy trial