Clinical Evaluation of Therapeutic Vaccines for HIV Seropositives: Approaches to the Design of Efficacy Trials

consensus of both researchers and the communities at risk that speeding up the
process is worth some increased risk of errors in establishing efficacy or
even lack of harm.
In this light, another approach to testing a new modality such as therapeutic
vaccines could be the implementation of a large trial in which clinical
benefit could be addressed in all CD4 categories, immediately following the
completion of Phase I. The goals of such a trial would be twofold:
1. To detect reliably a clinically meaningful effect of the treatment;
2. To study possible correlations of effects on intermediate outcomes (e.g.,
immune responses, immunologic and virologic markers) with clinical outcomes,
so that future vaccine trials could be based on these earlier outcomes.
Thus, this approach essentially nests the Phase II study within the Phase III
study. An outline of such a trial is as follows:
o Fundamental design: -Randomized, double-blind placebo-controlled trial
with broad eligibility criteria and clinical endpoints
o Patient population: HIV-infected individuals at any stage of disease
with no contraindication to any of the trial products
o Products to be tested: Multiple products, preferably providing a broad
range of product types, with a placebo control.
o Limitations on concomitant medication: None (except for other
therapeutic vaccines). No restriction on participation in other clinical
trials.
o Primary endpoint: First AIDS-defining event or death, depending on
prior history
o Time frame: One year of patient accrual; 3-4 years of followup.
o Stratification: Three strata, according to entry CD4 level (under 200;
200-500; and over 500) per cubic mm.
o Data to be collected: Baseline data (demographics, CD4 count, current
therapies, prior AIDS-defining events) collected by telephone at time of
randomization; minimal followup data focusing on toxic reactions and
clinical outcomes requested semiannually on paper form. More detailed
data collected from selected sites to develop fuller understanding of
vaccine-induced immune responses and associations with changes in
immunologic and virologic markers.
o Sample size: Sufficient to detect a one-third reduction in risk in each
stratum, and a 25% reduction overall. Actual numbers will depend on
number of products to be tested, and duration of followup. With 3

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