Abstract
Failure in cancer drug development exacts heavy burdens on patients and research systems. To investigate inefficiencies and burdens in targeted drug development in cancer, we conducted a systematic review of all prelicensure trials for the anticancer drug, sorafenib (Bayer/Onyx Pharmaceuticals). We searched Embase and MEDLINE databases on October 14, 2014, for prelicensure clinical trials testing sorafenib against cancers. We measured risk by serious adverse event rates, benefit by objective response rates and survival, and trial success by prespecified primary endpoint attainment with acceptable toxicity. The first two clinically useful applications of sorafenib were discovered in the first 2 efficacy trials, after five drug-related deaths (4.6% of 108 total) and 93 total patient-years of involvement (2.4% of 3,928 total). Thereafter, sorafenib was tested in 26 indications and 67 drug combinations, leading to one additional licensure. Drug developers tested 5 indications in over 5 trials each, comprising 56 drug-related deaths (51.8% of 108 total) and 1,155 patient-years (29.4% of 3,928 total) of burden in unsuccessful attempts to discover utility against these malignancies. Overall, 32 Phase II trials (26% of Phase II activity) were duplicative, lacked appropriate follow-up, or were uninformative because of accrual failure, constituting 1,773 patients (15.6% of 11,355 total) participating in prelicensure sorafenib trials. The clinical utility of sorafenib was established early in development, with low burden on patients and resources. However, these early successes were followed by rapid and exhaustive testing against various malignancies and combination regimens, leading to excess patient burden. Our evaluation of sorafenib development suggests many opportunities for reducing costs and unnecessary patient burden in cancer drug development.
Highlights
In cancer, only 1 in 20 new drugs introduced to clinical development receives approval from the United States Food and Drug Administration (FDA) [1]
11,355 patients were exposed to sorafenib in prelicensure trials in 26 malignancies, with an estimated 3,928 patient-years of involvement over a period of 13.2 y
Consistent with our earlier reports looking at the anticancer drug sunitinib [13], we find that drug developers identified useful dosing, scheduling, and responding indications in a short amount of time with only a minimal number of trials, adverse events, or patient years
Summary
Only 1 in 20 new drugs introduced to clinical development receives approval from the United States Food and Drug Administration (FDA) [1]. This high rate of attrition imposes burdens and opportunity costs on research subjects. Numerous studies have identified various sources of inefficiency in research, including poor priority setting, [2] biased study design, [3] underpowering, [4] and incomplete reporting [5]. Eliminating such inefficiencies holds promise for improving human protections and the social return on research investments. To quantify the patient burden and examine inefficiencies in cancer drug development, we undertook a systematic review of all published clinical trials for the drug sorafenib for which there was no FDA label at the time of trial launch (hereafter called “prelicensure trials”)
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
