Fragility of randomized trials supporting cancer drug approvals stratified by approval pathway and review designations
Wilson, B.E. (University of New South Wales)
Desnoyers, A. (Princess Margaret Cancer Centre. Department of Medical Oncology. University of Toronto)
Nadler, M.B. (Princess Margaret Cancer Centre. Department of Medical Oncology. University of Toronto)
Tibau Martorell, Ariadna (Institut d'Investigació Biomèdica Sant Pau)
Amir, Eitan (Princess Margaret Cancer Centre. Department of Medical Oncology. University of Toronto)
Universitat Autònoma de Barcelona

Date:	2021
Abstract:	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.
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Accelerated approvals ; FDA approvals ; Fragility index ; Trial robustness
Published in:	Cancer Medicine, Vol. 10 Núm. 16 (august 2021) , p. 5405-5414, ISSN 2045-7634

DOI: 10.1002/cam4.4029
PMID: 34323019

10 p, 328.7 KB

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