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

Benjamin Gregory Carlisle, James Mattina, Tiger Zheng, Jonathan Kimmelman
2019 medRxiv   pre-print
OBJECTIVE: To 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 SOURCES: Trials were captured by searching Embase and MEDLINE on July 27, 2015. STUDY SELECTION: Inclusion: 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:
more » ... ) 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 SYNTHESIS: Data were independently double-extracted and differences between coders were reconciled by discussion. MAIN OUTCOMES AND MEASURES: We 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. RESULTS: We 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. DISCUSSION: Risk/benefit for patients who enrolled in trials of non-approved indications of ixabepilone did not improve over the course of the drug's development. Clinical value was discovered very quickly; however, a large fraction of trials were uninformative.
doi:10.1101/19003467 fatcat:r6rwzbfkq5eafnxrpqojecc3va