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

Personalized Cancer Vaccines 77
Compared with many other disease areas, prognosis for cancer patients
tends to be poorer and they generally have fewer treatment options. Therefore,
clinical development of a cancer treatment is often more condensed than the
typical phase 1/2/3 drug development model. In oncology, an investigational
agent is usually evaluated in one or more earlier-stage trials (phases 1 and 2,
involving about 20–80 patients) to determine dosing and evaluate for safety and
preliminary signals of efficacy, followed by one or more late-stage trials
(phases 2 and 3, involving about 40–>200 patients). The late-stage trials are
randomized, meaning that the experimental agent is being compared with a
“control” treatment (usually the current standard of care), and patients are randomly
assigned to receive one treatment or the other. In this way, the effect of the
investigational therapy can be compared with the effect of the control treatment.
To be approved for marketing, a clinical trial of an experimental treatment
typically must successfully meet its primary end point(s). Depending on the type of
end point used, the U.S. Food and Drug Administration (FDA) employs two
approval pathways for oncology treatments: regular approval and accelerated
approval. Regular approval is based on an end point that provides direct evidence of
clinical benefit (e.g., OS) or on a surrogate end point (e.g., PFS) that reliably
predicts clinical benefit. Accelerated approval, which is used for new treatments that
provide an advantage over currently available therapy, may be based on a less
established surrogate end point that is only reasonably likely to predict clinical
benefit (e.g., objective response rate to treatment). Under the terms of accelerated
approval, the drug manufacturer is required to conduct post-approval studies to
determine if the treatment provides direct clinical benefit (e.g., improvement in OS).
In cases in which a late-stage clinical trial fails to meet its primary end point,
subset analyses (either predefined or post hoc) may find evidence of benefit in a
subgroup of patients. According to conventional regulatory process, a second latestage
study conducted specifically in this patient subgroup is almost always necessary
to confirm the benefit observed in the first late-stage trial.
The conventional regulatory process for developing and assessing cancer
treatments is largely based on evaluation of traditional chemotherapeutics. The
earlier and now standard regulatory pathways have successfully introduced a
formidable arsenal of treatments against both new and recurrent cancers, but
have yet to license a single therapeutic cancer vaccine to date.
CHALLENGES IN CLINICAL DEVELOPMENT OF CANCER VACCINES
Longer Trials to Reach Evaluable Clinical End Points
Experimental cancer agents are often clinically evaluated in the metastatic or
advanced disease setting. For many reasons, this disease setting allows for more
rapid clinical development. Often this patient population has limited or no treatment
options, which provides clinical, regulatory, and financial incentive for working to
fill unmet medical needs. Also, patient prognosis is usually poor due to the advanced