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Abstract
Objectives This study aims to analyse the association between clinical trial design and treatment effects for cancer drugs with US Food and Drug Administration (FDA) approval.
Design Cross-sectional study and meta-analysis.
Setting Data from Drugs@FDA, FDA labels, ClincialTrials.gov and the Global Burden of Disease study.
Participants Pivotal trials for 170 drugs with FDA approval across 437 cancer indications between 2000 and 2022.
Main outcome measures Treatment effects were measured in HRs for overall survival (OS) and progression-free survival (PFS), and in relative risk for tumour response. Random-effects meta-analyses and meta-regressions explored the association between treatment effect estimates and clinical trial design for randomised controlled trials (RCTs) and single-arm trials.
Results Across RCTs, greater effect estimates were observed in smaller trials for OS (ß=0.06, p<0.001), PFS (ß=0.15, p<0.001) and tumour response (ß=−3.61, p<0.001). Effect estimates were larger in shorter trials for OS (ß=0.08, p<0.001) and PFS (ß=0.09, p=0.002). OS (ß=0.04, p=0.006), PFS (ß=0.10, p<0.001) and tumour response (ß=−2.91, p=0.004) outcomes were greater in trials with fewer centres. HRs for PFS (0.54 vs 0.62, p=0.011) were lower in trials testing the new drug to an inactive (placebo/no treatment) rather than an active comparator. The analysed efficacy population (intention-to-treat, per-protocol, or as-treated) was not consistently associated with treatment effects. Results were consistent for single-arm trials and in multivariable analyses.
Conclusions Pivotal trial design is significantly associated with measured treatment effects. Particularly small, short, single-centre trials testing a new drug compared with an inactive rather than an active comparator could overstate treatment outcomes. Future studies should verify results in unsuccessful trials, adjust for further confounders and examine other therapeutic areas. The FDA, manufacturers and trialists must strive to conduct robust clinical trials with a low risk of bias.
- Medical Oncology
- Drug Development
- Policy
- Methods
- Neoplasms
Data availability statement
All data relevant to the study are included in the article or uploaded as online supplemental information. All data used in this study were in the public domain. All data relevant to the study are included in the article or uploaded as online supplemental information.
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Data availability statement
All data relevant to the study are included in the article or uploaded as online supplemental information. All data used in this study were in the public domain. All data relevant to the study are included in the article or uploaded as online supplemental information.
Footnotes
X @DTMichaeli
Contributors DTM and TM had full access to all the data in the study and took responsibility for the integrity of the data and the accuracy of the data analyses. Concept and design: all authors. Acquisition, analysis or interpretation of data: all authors. Drafting of the manuscript: DTM Critical revision of the manuscript for important intellectual content: all authors. Statistical analysis: DTM. Administrative, technical or material support: all authors. Study supervision: all authors. DTM is the guarantor. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Provenance and peer review Not commissioned; externally peer reviewed.
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