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

miocardico (GISSI) trials have clarified optimal treatment strategies
for patients suffering myocardial infarction. These trials operated on
the "uncertainty principle": eligibility for the trials was based
simply on whether the treating physician was uncertain as to the optimal
therapeutic approach for a particular patient. Ancillary treatments
were unrestricted.
While it is true that there had been substantially more prior experience
with the treatments used in these trials than there will have been for
therapeutic anti-HIV vaccines, several AIDS drugs (with much greater
potential for serious toxicity) have already been made widely available
through expanded access/parallel track programs after relatively small
numbers of patients had been treated with the drug.
o Why include patients at all stages of disease when it seems unlikely
that patients with severely depressed immune systems are unlikely to
benefit?
Since we do not know -that this approach will be ineffective in patients
with low counts, and such patients are at greatest risk of serious
illness and death, they should be permitted to try a new
approach with any hope of delaying an adverse outcome. It will take
no longer to complete the trial if such patients are included.
o Why would a placebo control be required?
Since there is no evidence as yet to suggest that these products are
clinically efficacious, and the possibility that one or more will prove
harmful cannot be ruled out, it would be unethical to proceed without a
placebo control. In addition, if there were no differences among the
products tested, it would be impossible without a placebo to know
whether the products were all effective, all ineffective or all harmful.
It should be noted that patients would be permitted to receive any
other treatment, including standard antiretroviral therapies and
prophylaxis for opportunistic infections, whether or not they were
assigned to receive a therapeutic vaccine or a placebo.
o What is the basis for specifying one year of accrual and 3-4 years of
followup?
The faster the patients can be accrued, the sooner the answer will be
available. With the intense community interest in these products, a one
year accrual interval appears feasible. The advantages of a shorter
followup period, in addition to getting an answer sooner, are fewer
losses to followup, less noncompliance and fewer potential effects of
new therapies becoming available during the course of the trial. The
major disadvantage is that the very earliest events may not give a true
picture of the relative efficacy of these agents.