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

Phase II:

CD4 < 200: Conduct randomized, placebo-controlled trial aimed at assessing
clinical benefit (prolongation of time to serious disease and death). Measure
immunologic and virologic markers for correlation with clinical outcomes.
Sample sizes would range from 300-800 per arm for trials with up to 5 years of
followup; trials of shorter duration will require patient numbers on the upper
end of this range. The expected event rate is sufficiently high in this
category that conclusive assessment of clinical efficacy may be made at this
stage.
CD4 200-500, CD4 > 500: Because clinical event rates are much lower in these
patients, the primary endpoints of randomized, placebo-controlled Phase II
trials in these patient categories would be effects on markers of immune
system status (CD4+ cell count) and viral load, with the goal of identifying
agents that should be definitively evaluated in Phase III. Minor clinical
symptoms would also be assessed, as well as any serious clinical events that
do occur during the trial. Sample sizes of 400-500 per arm would be needed to
evaluate CD4 declines overtime.
Phase III:
CD4 200-500, CD4 > 500: If Phase II marker effects are demonstrated, conduct
larger randomized placebo-controlled studies to assess clinical benefit.
These trials will need to be very large to ensure observation of sufficient
clinical events in a reasonable time frame. Sample sizes could range from
1000-2000 patients in the CD4 200-500 category, and 2500-5000 for patients
with CD4 > 500, depending again on the duration of followup (2-5 years). It
would not seem desirable to plan for durations of followup of longer than 5
years.
In addition to clinical effects, these trials would be designed to evaluate
the correlation between such effects and the earlier vaccine-induced effects
on markers. If strong correlations are observed, evaluation of future vaccine
candidates could be accelerated by relying on marker endpoints observed in
Phase II.
If no marker effects are seen in Phase II, no further studies of the product
would be performed. Thus, this approach depends strongly on the assumption
that clinical benefit will invariably be predicted by vaccine-induced changes
in surrogate markers.
IV. A MODIFICATION OF THE TRADITIONAL APPROACH
It has become almost commonplace for AIDS drug development to deviate in major
ways from the traditional path. The invariably fatal nature of the disease,
the relative youth of the populations at greatest risk, and the lack of any
cure or therapies with known long-term efficacy, have led AIDS clinical
researchers (with the approval and encouragement of the FDA) to accelerate the
drug development process wherever possible. There appears to be a general

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