HIV VACCINE TRIALS - SOME DESIGN ISSUES INCLUDING SAMPLE-SIZE CALCULATION

Anticipating the availability of one or more candidate HIV vaccines fo r efficacy testing in the next few years, public health agencies are n ow planning for the conduct of large-scale efficacy trials. We expect these trials to be randomized, double-blind, placebo-controlled studie s with prevention of infection as the primary goal. We discuss in deta il factors that influence sample size. Factors most influential are th e incidence rate of HIV infection in the study population and the mini mum efficacy at which a vaccine is still considered acceptable. The sm aller either of these factors is, the larger the sample size will be. The desire to complete trials quickly, the gradual accrual of benefit from vaccination, the inaccuracies of assays to detect infection, the need to counsel participants to avoid exposure to HIV, and loss to fol low-up all tend to drive up sample size. To illustrate, 83 subjects pe r study arm suffice to detect 90% efficacy in a population with a 7% a nnual risk of infection. This assumes a 3-year study with accrual comp leted in 1 year, no loss to follow-up, and Types I and II error rates of 5 and 10%, respectively. In contrast, 4,254 subjects per arm are re quired to identify a 60% effective vaccine in a population with a 1% a nnual risk. The study is also shortened to 2 years, assumes a 5% annua l loss to follow-up, and supposes that the full benefit of vaccination is achieved in 6 months. The most realistic assumptions indicate that trials are very likely to require several thousand participants. Limi tations of the proposed designs are also discussed.