Patient burden and clinical advances associated with post-approval monotherapy cancer drug trials: a systematic review
Bibliographic record
Abstract
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
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.038 | 0.227 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.007 | 0.009 |
| Bibliometrics | 0.012 | 0.020 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.003 | 0.004 |
| Open science | 0.002 | 0.002 |
| Research integrity | 0.002 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".