Inefficiencies and Patient Burdens in the Development of the Targeted Cancer Drug Sorafenib: A Systematic Review

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.Author Summary: Numerous research subjects are exposed to unsafe and/or ineffective treatments in unsuccessful drug development programs. Yet, even successful drug development programs can involve heavy burdens for research subjects. In this manuscript, we measure risks and benefits for research subjects participating in the successful development of the anticancer drug sorafenib (first approved by the United States Food and Drug Administration in 2005). After discovering the first two cancer types responding to sorafenib, drug developers and researchers tested sorafenib against many other cancer types and in combination with many other drugs. We find that researchers were able to discover the utility of sorafenib for the first two cancer types quickly and with very little patient burden. Thereafter, attempts to extend the clinical application of sorafenib to other cancers and drug combinations involved many patients and adverse events and were mostly fruitless. We also find that many studies pursued after the first approval of sorafenib returned limited scientific information because they were duplicative or insufficiently informative. Our findings suggest that even successful drug development programs can entail substantial patient burden; they also point to ways that regulators, researchers, and policymakers can improve the risk-benefit ratio for research subjects.