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

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.

Trials.csv

This CSV includes the per-trial data set, where every row describes one distinct clinical trial.

Column definitions:

g34: Grade 3-4 adverse events

g5: Grade 5 adverse events

total_n: Total patient enrolment

toxicity: Author-reported evaluation of toxicity

primary: Primary endpoint attainment

sponsor: Grouped into: industry; some/all non-industry; not stated

date_of_enrolment and date_of_closure: Refers to trial enrolment period

solid_or_not: Is the indication in question a solid or non-solid tumour?

Trajectories.csv

This CSV describes the same set of trials as Trials.csv, but with data grouped into "trajectories" defined by the drug and indication being studied. Each row represents one such trajectory.

Column definitions:

solid_or_not: Is the indication in question a solid or non-solid tumour?

patients: Total number of patients in the trajectory

Trials: Number of trials in the trajectory

Approved: Whether the drug was approved for that indication by the FDA within our follow-up timeframe

Reccomendation: Whether the drug was recommended for that indication explicitly by the NCCN within our follow-up timeframe

Indication number: The number of the indication explored within that drug's development (e.g. the first indication explored in that drug's development would be given a 1)

first_enrol: The enrolment date of the first trial in this trajectory

industry_trials: The number of trials sponsored by industry

non_industry_trials: The number of trials sponsored by all or some non-industry sources

ns_sponsor: Sponsor not stated

highest_phase: The number of the trial with the highest phase in this trajectory

k_positive_trials: The number of trials within this trajectory that had a positive primary outcome

g34: Grade 3-4 adverse events

g5: Grade 5 adverse events

g35: Grade 3-5 adverse events

rct_w_survival: The date of enrolment for an RCT with a survival endpoint in the same trajectory registered on ClinicalTrials.gov, if it exists, NA otherwise

nccn_uptake: The date of the NCCN recommendation, if any, NA otherwise