Fragility of randomized trials supporting cancer drug approvals stratified by approval pathway and review designations
Por:
Wilson, BE, Desnoyers, A, Nadler, MB, Tibau, A, Amir, E
Publicada:
1 ago 2021
Ahead of Print:
1 jul 2021
Resumen:
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 < 0.001). In a sensitivity analysis including only studies with 1:1 randomization, 51% of studies had WCLFU >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.
Filiaciones:
Wilson, BE:
Univ Toronto, Princess Margaret Canc Ctr, Dept Med Oncol, Toronto, ON, Canada
Univ New South Wales, Kensington, NSW, Australia
Desnoyers, A:
Univ Toronto, Princess Margaret Canc Ctr, Dept Med Oncol, Toronto, ON, Canada
Nadler, MB:
Univ Toronto, Princess Margaret Canc Ctr, Dept Med Oncol, Toronto, ON, Canada
Tibau, A:
Hosp Santa Creu & Sant Pau, Inst dInvest Biomed Sant Pau, Oncol Dept, Barcelona, Catalonia, Spain
Univ Autonoma Barcelona, Barcelona, Catalonia, Spain
Amir, E:
Univ Toronto, Princess Margaret Canc Ctr, Dept Med Oncol, Toronto, ON, Canada
gold, Green Published
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