Patient Benefit and Risk in Anticancer Drug Development: A Systematic Review of the Ixabepilone Trial Portfolio

OBJECTIVETo describe the patient burden and benefit, and the dynamics of trial success in the development of ixabepilone--a drug that was approved in the US but not in Europe. DATA SOURCESTrials were captured by searching Embase and MEDLINE on July 27, 2015. STUDY SELECTIONInclusion: 1) primary trial reports, 2) interventional trials, 3) human subjects, 4) phase 1 to phase 3, 5) trials of ixabepilone in monotherapy or combination therapy of 6) pre-licensure cancer indications. Exclusion: 1) secondary reports, 2) interim results, 3) meta-analyses, 4) retrospective/observational studies, 5) laboratory analyses (ex vivo tissues), 6) reviews, 7) letters, editorials, guidelines, interviews, abstract-only and poster presentations. DATA EXTRACTION AND SYNTHESISData were independently double-extracted and differences between coders were reconciled by discussion. MAIN OUTCOMES AND MEASURESWe measured risk using the number of 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. RESULTSWe identified 39 publications of ixabepilone monotherapy and 23 primary publications of combination therapy, representing 5615 patients and 1598 patient-years of involvement over 11 years and involving 17 different malignancies. In total, 830 patients receiving ixabepilone experienced objective tumour response (16%, 95% CI 12.5%-20.1%), and 74 died from drug-related toxicites (2.2%, 95% CI 1.6%-2.9%). Responding indications and combinations were identified very quickly; thereafter, the search for additional responding indications or combinations did not lead to labelling additions. A total of 11 "uninformative" trials were found, representing 27% of studies testing efficacy, 208 grade 3-4 events and 226 patient-years of involvement (21% and 26% of the portfolio total, respectively). After the European Medicines Agency rejected ixabepilone for licensing, all further trial activity involving ixabepilone was pursued outside of Europe. DISCUSSIONRisk/benefit for patients who enrolled in trials of non-approved indications of ixabepilone did not improve over the course of the drugs development. Clinical value was discovered very quickly; however, a large fraction of trials were uninformative.