Patient burden and clinical advances associated with post-approval monotherapy cancer drug trials: a systematic review

Objectives: After regulatory approval, drug companies, public funding agencies and academic researchers often pursue trials aimed at extending the uses of a new drug by testing it in new non-approved indications. Patient burden and clinical impact of such research is not well understood.

Design/setting: We conducted a retrospective cohort study of post-approval clinical trials launched within five years after the drug's first approval, testing anticancer drugs in monotherapy in indications that were first pursued after a drug's first FDA license, for all 12 anticancer drugs approved 2005-2007. (Search date: 2019-02-12.)

Primary and secondary outcome measures: Our primary objective was to measure burden and clinical impact for patients enrolling in these trials. Each trial was sorted into a “trajectory” defined by the drug and cancer indication. Risk was operationalized by proportions of grade 3-4 severe adverse events and deaths. Clinical impact was measured by estimating the proportion of patients participating in trajectories that resulted in FDA approval, uptake into National Comprehensive Cancer Network (NCCN) clinical practice guidelines or advancement to randomized controlled trials (RCT) within eight years.

Results: Our search captured 104 published trials exploring monotherapy, including 69 unique trajectories. In total, trials in our sample enrolled 4699 patients. Grade 3-4 adverse events were experienced by 19.6% of patients; grade 5 events were experienced by 2.8% of patients. None of the trajectories launched after initial drug approval received FDA approval. Five trajectories were recommended by the NCCN within eight years of the first trial within that trajectory. Eleven trajectories were advanced to randomized controlled testing.

Conclusions: The challenges associated with unlocking new applications for drugs that first received approval 2005-2007 were similar to those for developing new drugs altogether. Our findings can help inform priority setting in research, and provide a basis for calibrating expectations when considering enrollment in label-extending trials

Methods
Monotherapy clinical trials aimed at extending the label of the 12 novel anti-cancer drugs that received first FDA approval between 2005 and 2007 inclusive.