Magnitude of Clinical Benefit of Cancer Drugs Approved by the US Food and Drug Administration
- Regulatory agencies assess drug safety and efficacy, but thresholds may differ from those accepted by clinicians .
- Only 43.8% of RCTs for FDA-approved drugs meet the ESMO-MCBS threshold for meaningful benefit, reflecting potential softening of FDA standards.
- Encouraging trends include an increasing number of trials meeting ESMO-MCBS thresholds over time, influenced by improved QoL and safety profiles.
- Trials for curative intent are more likely to meet ESMO-MCBS criteria than those for palliative intent.
- Drugs approved with companion diagnostic tests are more likely to meet ESMO-MCBS thresholds.
- ESMO-MCBS grades are similar for drugs approved through regular and accelerated pathways, but phase III trials and those with overall survival as the primary endpoint score higher.
- Orphan drug approvals are associated with smaller, single-arm trials and intermediate efficacy endpoints.
- The ESMO-MCBS system has limitations, including its non-universal acceptance and challenges in consistent grading due to data variability.
- A sensitivity analysis showed minimal changes in ESMO-MCBS scores when using hazard ratios instead of lower 95% confidence intervals.
- There are limitations in the study, including missing QoL data, variability in toxicity reporting, and applicability of ESMO-MCBS to single-arm studies.
- Overall, the oncology community should continue to prioritize high standards and clinically meaningful outcomes in cancer clinical trials.
The US Food and Drug Administration (FDA) criteria for drug approval require substantial evidence of clinical benefit from adequate and well-controlled trials (1). Efficacy should be demonstrated by either prolonging patient survival or improving quality of life (QoL), or both. There is ongoing controversy over the FDA’s current drug approval mechanisms. While the FDA’s statutory mandate does not provide a provision for the exception of drugs used by selected subgroups such as terminally ill patients, the last 40 years have shown a relative softening of rules for anticancer drugs, including the use of accelerated approvals. Additionally, regulations aimed at speeding up the review process (fast track, priority review, and breakthrough therapy designations), as well as orphan drug designations, have been promoted to improve access to therapeutics for life-threatening diseases, including cancer.
The benefits of the current system of rapid review and approval are uncertain. Shortened development and review times and earlier marketing of drugs have been associated with negative outcomes and have raised questions about the rigor and safety of data supporting regulatory approval..
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