Fragility of randomized trials supporting cancer drug approvals stratified by approval pathway and review designations

• Published in: Cancer medicine (Malden, MA) MA), 2021-08, Vol.10 (16), p.5405-5414
• Main Authors: Wilson, Brooke E., Desnoyers, Alexandra, Nadler, Michelle B., Tibau, Ariadna, Amir, Eitan
• Format: Article
• Language: English
• Subjects: accelerated approvals; Antineoplastic Agents - therapeutic use; Biological products; Clinical Cancer Research; Clinical trials; Consent Forms - statistics & numerical data; Disease-Free Survival; Drug Approval - statistics & numerical data; Drugs; FDA approval; FDA approvals; fragility index; Humans; Kaplan-Meier Estimate; Lost to Follow-Up; Neoplasm Recurrence, Local - epidemiology; Neoplasm Recurrence, Local - prevention & control; Neoplasms - drug therapy; Neoplasms - mortality; Progression-Free Survival; Randomized Controlled Trials as Topic - standards; Randomized Controlled Trials as Topic - statistics & numerical data; Regulatory approval; Sample Size; Sensitivity analysis; Solid tumors; Time Factors; trial robustness; United States; United States Food and Drug Administration - standards
• ISSN: 2045-7634; 2045-7634
• DOI: 10.1002/cam4.4029

Background It has been suggested that the results from fragile trials are less likely to translate into benefit in routine clinical practice. Methods We searched the Food and Drug Administration (FDA) archives to identify drug approvals for solid organ malignancies between 2010 and 2019. We calculated the Fragility Index (FI) supporting each approval, using methods to account for time‐to‐event. We compared FI and trial and approval characteristics using Mann‐Whitney U and Kruskal‐Wallis test. Using logistic regression, we examined study characteristics associated with withdrawal of consent or lost to follow‐up (WCLFU) exceeding the calculated FI. Results The median FI among 125 included studies was 23 (range 1–322). The FI was ≤10 in 35 studies (28%), 11–20 in 21 (17%), and >20 in 69 (55%). The median FI/Nexp was 7.7% (range 0.1–51.7%). The median FI was significantly lower among approvals processed through the accelerated vs regular pathway (5.5 vs 25, p = 0.001), but there was no difference in median FI/Nexp. The WCLFU exceeded FI in 42% of studies. Overall survival endpoints were more likely to have a WCLFU exceeding FI (OR 3.16, p = 0.003). WCLFU exceeding FI was also associated with a lesser magnitude of effect (median HR 0.69 vs 0.55, p FI. Conclusion The median FI among all trials was 23, and WCLFU exceeded FI in 42%. Comparative trials in solid tumors supporting approval through the accelerated pathway are more fragile compared to trials approved through the regular pathway, an observation likely explained by a lower sample size in the experimental arm. Trials in solid tumors supporting accelerated approval are more fragile compared to regular approvals. This finding supports the need for post‐marketing trials or real‐world analyses to ensure the benefit observed in clinical trials is robust and reproducible.