Download File - JOHN J. HADDAD, Ph.D.

Personalized Cancer Vaccines 79
impossible to precisely identify the target treatment group for any given vaccine
in any given indication without conducting a large randomized trial. Because the
patients’ immune response is part of his own treatment and must be intact for a
vaccine to work, the stage of the cancer as well as history of prior therapies are
much more important considerations for therapeutic vaccines than for conventional
cancer treatments. This makes the selection of a patient population
especially critical. Often a vaccine’s effect must be evaluated across a range of
disease stages to identify exactly which stages are most responsive to the
treatment. The target treatment population may vary by vaccine as well as by
cancer type; therefore, a large randomized trial must be conducted for each
vaccine in each indication for which it is to be developed.
According to current regulatory process, any benefit observed in a subgroup
of patients—even if statistically significant in predefined or post hoc
analyses—in most of the cases must be subsequently confirmed in a second
randomized trial involving this subgroup. Therefore, these large, late-stage trials
must be conducted sequentially, meaning that a late-stage development program
could last more than 10 years, which currently represents a significant impediment
to the success of the field of cancer vaccines.
Lack of Early Surrogate Markers
The lack of information with which to orient initial late-stage studies can be
attributed to the absence of a reliable early marker or critical event that indicates
that clinical benefit may be associated with the experimental treatment.
Newer therapies such as therapeutic cancer vaccines, EGFR/HER2/neu
inhibitors, and angiostatins tend to affect cancers in a different manner compared
with traditional cancer treatments. They appear to slow the course of
disease without causing earlier-measurable tumor shrinkage. Therefore, the
effect of treatment only becomes apparent later, when the growth of the tumor
lesions is retarded or absent, and the comparative time to progression is slowed.
Treatment effect in the earlier-stage disease or adjuvant treatment settings
can be even longer to ascertain, as the minimal tumor burden in these settings
makes quicker end points such as tumor response or time to progression
inapplicable. Therefore, identification of a surrogate marker or critical event
indicative of clinical benefit could provide earlier feedback to help identify the
group of patients most likely to benefit from treatment. This could help shorten
development timelines by making the newer adaptive trial designs feasible in
the earlier-disease/adjuvant treatment setting: By identifying patients that
seem to be benefiting most from treatment early in patient enrollment,
enrollment criteria could be tailored to focus on enrolling the optimal patient
population. This could potentially eliminate the need for a second trial to
confirm subset analysis findings, affording the opportunity for a single, latestage
clinical trial to establish all of the efficacy and safety information necessary
to support a treatment’s initial licensure.