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Abstract
Background: Little is known about the total patient burden associated with clinical development and where burdens fall most heavily during a drug development program. Our goal was to quantify the total patient burden/benefit in developing a new drug.
Methods: We measured
risk using drug-related adverse events that were grade 3 or higher,
benefit by objective response rate, and trial
outcomes by whether studies met their primary
endpoint with acceptable safety. The differences in risk (death rate)
and benefit
(overall response rate) between industry and
nonindustry trials were analyzed with an inverse-variance weighted fixed
effects
meta-analysis implemented as a weighted
regression analysis. All statistical tests were two-sided.
Results: We identified
103 primary publications of sunitinib monotherapy, representing 9092
patients and 3991 patient-years of involvement
over 10 years and 32 different malignancies. In
total, 1052 patients receiving sunitinib monotherapy experienced
objective
tumor response (15.7% of intent-to-treat
population, 95% confidence interval [CI] = 15.3% to 16.0%), 98 died from
drug-related
toxicities (1.08%, 95% CI = 1.02% to 1.14%), and
at least 1245 experienced grade 3–4 drug-related toxicities (13.7%, 95%
CI
= 13.3% to 14.1%). Risk/benefit worsened as the
development program matured, with several instances of replicated
negative
studies and almost no positive trials after the
first responding malignancies were discovered.
Conclusions: Even for a
successful drug, the risk/benefit balance of trials was similar to
phase I cancer trials in general. Sunitinib
monotherapy development showed worsening
risk/benefit, and the testing of new indications responded slowly to
evidence that
sunitinib monotherapy would not extend to new
malignancies. Research decision-making should draw on evidence from
whole research
programs rather than a narrow band of studies in
the same indication.
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