Prospects of off-label (OL) drug use in oncology: Identifying predicting variables for registration and universal healthcare reimbursement.
Authors: Noa Gordon, Daniel A Goldstein, Boaz Tadmor, Salomon M. Stemmer, Dan Greenberg
Journal: Journal of Clinical Oncology (2021)

e18842 Background: Many cancer drugs used OL, eventually complete clinical development and are registered and reimbursed, while others are not. We aimed to describe OL indications' registration and reimbursement prospects in a universal healthcare system and identify groups of treatments that remain OL longer. Methods: We studied 612 OL oncology prescription requests for 115 unique indications and 29 drugs. All requests were approved by the Institutional Drug Committee in Rabin Medical Center, a tertiary center in Israel, between January 2016 and December 2018. OL indications were not registered by the Israeli Ministry of Health (MOH) and were not included in the Israeli National List of Health Services (NLHS) for reimbursement at the time of prescription. Additionally, 459 requests for 100 indications were not approved by the FDA at the time of prescription. We explored the subsequent regulatory and reimbursement milestones in the timeline following each prescription. We identified three temporal events: FDA indication approval, MOH indication registration, and NLHS indication inclusion of reimbursement. We then defined three time-to-event variables from the OL prescription to each of the three milestones. We applied Kaplan-Meier analysis and multivariable Cox regression to identify drug and indication properties, which are predictors for registration and reimbursement. Results: With a median follow-up of 34.5 months, 10.4% of indications were eventually registered in Israel, and 6% were included in the NLHS. 7% of non-FDA approved indications were subsequently approved. For MOH registration, positive predictors were immunotherapy, sufficient evidence (ESMO-MCBS A-B, 5-4), and a patient access program at the time of prescription (HR = 21.99; p&lt; .0005, HR = 3.4; p= .02 and HR = 2.73; p&lt; .0005, respectively). Negative predictors were metastatic setting and lung and gastrointestinal (GI) cancers (HR = 0.42; p= .002, HR = 0.17; p= .001, and HR = 0.24; p= .043, respectively). For NLHS inclusion, positive predictors were immunotherapy, sufficient evidence, and an access program (HR = 9.03, HR = 6.24, and HR = 2.56, respectively, all p&lt; .0005). Negative predictors were lung and GI cancers and orphan disease designation (HR = 0.07; p= .002, HR = 0.14; p= .021, and HR = 0.13; p= .009, respectively). For FDA approval, positive predictors were immunotherapy, sufficient evidence, and a patient access program (HR = 12.11; p&lt; .0005, HR = 4.34; p= .002, and HR = 2.25; p= .001, respectively). Negative predictors were metastatic setting, lung cancer, and orphan disease (HR = 0.43; p= .003, HR = 0.25; p= .006, and HR = 0.08; p= .018, respectively). Conclusions: Few OL indications are subsequently approved and reimbursed, usually due to clinical futility and insufficient evidence. However, we identified factors related to lack of initiative for further clinical development and registration.