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

CLINICAL EVALUATION OF THERAPEUTIC VACCINES FOR HIV SEROPOSITIVES
Approaches to the Design of Efficacy Trials
I. BACKGROUND
HIV infection has presented unique and difficult challenges to the scientific
community. Unlike most infections, it causes a chronic disease; the virus
progressively destroys the immune system over a period of years, resulting in
increasing vulnerability to a variety of potentially fatal pathogens. Average
time from infection to occurrence of one of these serious opportunistic
diseases is 10-11 years; for a large proportion of these years the individual
may be completely asymptomatic (although capable of transmitting the virus to
others).
Clinical trials of potentially therapeutic agents have been performed
primarily in populations whose immune systems have already become moderately
to severely depressed. Drug development and evaluation proceeds in an
atmosphere of intense urgency, due to the life-threatening nature of the
disease and the paucity (and limited efficacy) of available treatments.
Investigators are increasingly looking to earlier indicators of efficacy on
which to base evaluations of new agents, hoping to speed the process of
identifying new effective treatment regimens; conventional regulatory
standards have been modified to permit widespread availability of agents that
appear promising, even without traditionally definitive evidence of clinical
efficacy. Expanded access, or parallel track, programs have been established
to provide an unprecedented degree of access to investigational drugs well
before they are even considered for marketing approval.
Therapeutic vaccines present a new approach to the treatment of HIV infection.
The fundamental rationale for this approach, as well as early data from Phase
I trials, suggests that it may be most successful in those individuals at the
earliest stages of infection, when the immune system is still relatively
intact. To establish clinical benefit in this population (as evidenced by
delaying occurrence of serious opportunistic diseases) would require many
years of patient followup because of the extended latency period described
above. The use of laboratory measurements of immune system status (CD4+ cell
counts) as trial endpoints has been proposed; in November 1991, however, an
expert advisory panel convened by the Food and Drug Administration concluded
that there was insufficient rationale, and no data, to support the use of CD4
counts as the sole basis for evaluating therapeutic vaccines.
This situation poses a difficult conundrum for the clinical research
community. Ordinarily, one would study a new agent first in those with
advanced disease, since this population will have the highest rate of adverse
outcomes and thereby provide the fastest means of establishing clinical
benefit. This approach has been taken for the 3 nucleoside analogs currently
approved for use in HIV-infected individuals. For vaccines, however, this
approach may not be suitable since patients with severely depressed immune
systems are thought to be least likely to experience clinical benefit.