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

Further, the concept of an agent that appears relatively nontoxic, that needs
to be administered infrequently, and has the theoretical potential to prolong
the symptom- and disease-free existence of infected but still healthy
individuals clearly has enormous appeal, from the public health viewpoint as
well as from the individual perspectives of those infected and at high risk,
and of their caregivers. It therefore appears essential to focus research
efforts on the very population in which it is most difficult to establish
clinical benefit.
II. THE TRADITIONAL DRUG DEVELOPMENT STRATEGY
The development of new therapeutic regimens classically proceeds through 3
distinct stages:
Phase I studies are designed to establish that the regimen can be delivered
safely, to begin to understand its in vivo pharmacologic properties, and
frequently to establish appropriate dose levels and schedules of
administration for further testing. These studies generally include small
numbers (20-80) of relatively homogeneous patients.
Phase II studies focus on specific biological and clinical effects that are
associated with and may be predictive of clinical efficacy. These studies
include larger numbers of patients, frequently several hundred, and may be
randomized and placebo-controlled. In some cases, the effects seen at this
stage are sufficiently large that a conclusive assessment of efficacy is
warranted.
Phase III trials are designed to obtain definitive information concerning the
safety and clinical efficacy of regimens for which suggestive but inconclusive
data exist from Phase II.
III. THE TRADITIONAL APPROACH APPLIED TO THE EVALUATION OF THERAPEUTIC
VACCINES FOR HIV
Because of greatly varying rates of disease progression among patients with
different baseline levels of CD4+ cells, different approaches need to be
considered for three separate patient categories: those with CD4 levels under
200 per cubic mm, those with cell counts of 200-500, and those with CD4 levels
above 500.
Phase I:
Determine safety and immunogenicity. Study effects in all CD4 categories,
with 20-80 patients in each study. Measure CD4 and viral load to determine if
major effects appear to be induced. Move to Phase II in a given category if
safety is demonstrated and immune responses are observed in a reasonable
proportion of patients, even if CD4 counts and virologic markers do not appear
to be affected.

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