Magnitude of clinical benefit of cancer drugs approved based on single-arm trials (SAT) by the US Food and Drug Administration (FDA)
Bibliographic record
Abstract
Background: The European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS) is a validated and reproducible tool to assess the magnitude of clinical benefit from anti-cancer drugs. In contrast to version 1.0 (v1.0) of this tool, which could be used to assess randomized controlled trials (RCT) only, the updated version 1.1 (v1.1) allows scoring of drugs approved on the basis of single-arm trials (SAT). Here, we applied the updated ESMO-MCBS v1.1 to the assessment of trials supporting FDA approval including those based on SAT. Methods: We searched the [email protected] website for anticancer drug approvals from January 2006 to December 2016. Drug labels and reports of registration trials were reviewed and study characteristics, efficacy, toxicity, and quality of life outcomes as well as regulatory pathways were collected. For RCT, ESMO-MCBS v1.0 and v1.1 grades were applied; for SAT only v1.1 was used. Substantial benefit was defined as a grade of A or B for trials of curative intent and 4 or 5 for those of palliative intent. Agreement between v1.0 and v1.1 scores was assessed using Cohen’s κ statistic. Results: Of 134 studies supporting FDA approval, 4 reported preplanned analyses in multiple subgroups but in 5, ESMO-MCBS could not be applied. Therefore, analysis was based on 133 data points. Of these, only 45 (34%) met thresholds for substantial benefit using the ESMO-MCBS v1.1 framework. Version 1.1 of the scale facilitated grading of 27 SAT and 1 RCT which were ungradeable with v1.0. Among the 106 studies for which we could calculate scores using both v1.0 and v1.1 of the ESMO-MCBS scale, grades were identical in 96 cases (91%; κ = 0.86). In 10 trials, grades were discrepant, including 5 upgrades and 5 downgrades. We observed only one case of change in substantial benefit thresholds (1%; κ = 0.96). Only 2 SAT (7%) met the threshold for substantial clinical benefit using ESMO-MCBS v1.1. Conclusions: In patients with advanced solid tumors, approximately one third of trials supporting FDA approval meet the threshold for substantial clinical benefit using ESMO-MCBS v1.1. Drug approvals supported by RCT were more likely to result in substantial benefit compared to approvals supported by SAT. Legal entity responsible for the study: Hospital de la Santa Creu i Sant Pau. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.
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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 | 0.208 | 0.293 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.003 | 0.007 |
| Bibliometrics | 0.010 | 0.008 |
| Science and technology studies | 0.001 | 0.003 |
| Scholarly communication | 0.004 | 0.003 |
| Open science | 0.001 | 0.003 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.006 | 0.001 |
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; the direct Gemma label and the distilled Codex classifier agree on what is shown here.
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".