Fragility index of trials supporting approval of anti-cancer drugs in common solid tumours

Desnoyers, Alexandra; Wilson, Brooke E; Nadler, Michelle; Amir, Eitan

doi:10.1016/j.ctrv.2021.102167

Cited by 13 publications

(12 citation statements)

References 26 publications

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“…The median FI among the 125 included studies was 23 (range 1–322), meaning 23 additional events would result in a non‐significant effect for the trial endpoint supporting drug approval. This is slightly lower to prior data reported in oncology examining approvals for only a subset of tumors, 3 but higher than the median FI of 8 calculated by Walsh et al for the primary endpoint of high impact general medicine studies with dichotomous outcomes, 5 suggesting that outcomes for solid organ malignancies may be more robust. This may be a reflection of the higher statistical power that results from the use of time‐to‐event rather than dichotomous outcomes which form the majority of endpoints in general medicine 18 …”

Section: Discussioncontrasting

confidence: 72%

“…In cancer, where the benefit of a drug is often measured by its ability to prolong life and/or delay disease progression or relapse, ignoring the time‐to‐event occurrence can over‐estimate the fragility of trials, as demonstrated previously 13‐15 . We have previously developed alternative methods for calculating the FI 3 . Among a subset of tumor types, estimated median FI was 28 3 …”

Section: Introductionmentioning

confidence: 99%

“…The Fragility Index (FI) is a metric quantifying the statistical robustness of randomized controlled trials (RCTs) 3 . The FI quantifies the internal reliability of clinical trials by estimating the number of events needed to change a statistically significant result to non‐significant.…”

Section: Introductionmentioning

confidence: 99%

“…The Fragility Index (FI) is a metric quantifying the statistical robustness of randomized controlled trials (RCTs). 3 The FI quantifies the internal reliability of clinical trials by estimating the number of events needed to change a statistically significant result to non‐significant. In contrast to a p‐value which relates to the probability that the observed results are no different between comparison groups, the FI quantifies the difference in terms of the number of events required to change a trial from positive to negative.…”

Section: Introductionmentioning

confidence: 99%

“… 13 , 14 , 15 We have previously developed alternative methods for calculating the FI. 3 Among a subset of tumor types, estimated median FI was 28. 3 …”

Section: Introductionmentioning

confidence: 99%

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

et al. 2021

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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.

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Section: Discussioncontrasting

confidence: 72%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“… 13 , 14 , 15 We have previously developed alternative methods for calculating the FI. 3 Among a subset of tumor types, estimated median FI was 28. 3 …”

Section: Introductionmentioning

confidence: 99%

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

et al. 2021

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Clinical benefit and fragility evaluation of systemic therapy trials for advanced soft tissue sarcoma

Braik,

Lemieux,

Wilson

et al. 2024

Cancer

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BackgroundThe clinical benefit of systemic anticancer therapies can be unclear despite positive trials, and outcomes may not translate to real‐world practice. This study evaluated the benefit of soft tissue sarcoma (STS) treatments using the European Society of Medical Oncology Magnitude of Clinical Benefit Scale (MCBS) v1.1 and measured the robustness of STS trial results using Fragility Index (FI).MethodsDatabase searches for adult phase II or III trials in advanced STS (January 1998–December 2023) were performed. Therapies with trial outcomes that met the criteria for MCBS were scored 1–5 (≥4 represents substantial clinical benefit). For randomized clinical trials with positive time‐to‐event endpoints, the number of additional events that would render results nonsignificant, FI, was calculated and expressed as a proportion of the experimental arm size (fragility quotient [FQ]). Higher FI/FQ implies more robust results.ResultsAmong 194 trials, 19 (9.8%) were phase III. Most phase II trials (146/175; 83.4%) had single‐arm or non‐comparative design. Trials that were eligible for MCBS scoring (n = 78; 40.2%) evaluated 56 different agents/regimens. Median MCBS score was 2. Only three agents/regimens (all cytotoxic therapies) had an MCBS score ≥4. Among 47 randomized clinical trials, 16 (8 phase II; 8 phase III) trials had positive outcomes. Median FI was 7 (range, 2–52) and 10 trials (62.5%) had an FQ < 10%, with median of 7% (range, 1%–59%).ConclusionsMost systemic therapies in STS trials did not confer substantial clinical benefit per European Society of Medical Oncology‐MCBS. Additionally, positive randomized trials were often fragile. Novel STS therapy trials should use clinically meaningful endpoints and real‐world efficacy confirmation is essential, especially for less robust trials.

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The fragility index and reverse fragility index of FDA investigational device exemption trials in spinal fusion surgery: a systematic review

Proal,

Moon,

Kwon

2024

Eur Spine J

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Fragility index of trials supporting approval of anti-cancer drugs in common solid tumours

Cited by 13 publications

References 26 publications

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

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

Clinical benefit and fragility evaluation of systemic therapy trials for advanced soft tissue sarcoma

The fragility index and reverse fragility index of FDA investigational device exemption trials in spinal fusion surgery: a systematic review

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