Fragility index of positive phase II and III randomised clinical trials of treatments for hepatocellular carcinoma (2002–2022)
Sabrina Sidali,
Nanthara Sritharan,
Claudia Campani,
Jules Gregory,
François Durand,
Nathalie Ganne-Carrié,
Maxime Ronot,
Vincent Lévy,
Jean-Charles Nault
Affiliations
Sabrina Sidali
Université de Paris, Service d’Hépatologie, DMU DIGEST, Hôpital Beaujon, APHP Nord, Clichy, France; Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris, Team ‘Functional Genomics of Solid Tumors’, Equipe Labellisée Ligue Nationale Contre le Cancer, Labex OncoImmunology, Paris, France
Nanthara Sritharan
Department of Clinical Research, Paris Seine Saint Denis Hospital, Sorbonne Paris University, APHP, Bobigny, France
Claudia Campani
Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris, Team ‘Functional Genomics of Solid Tumors’, Equipe Labellisée Ligue Nationale Contre le Cancer, Labex OncoImmunology, Paris, France
Jules Gregory
Department of Radiology, FHU MOSAIC, Hôpital Beaujon APHP Nord, Clichy, France; Université de Paris, INSERM, UMR1153, Epidemiology and Biostatistics Sorbonne Paris Cité Center (CRESS), METHODS Team, Paris, France
François Durand
Université de Paris, Service d’Hépatologie, DMU DIGEST, Hôpital Beaujon, APHP Nord, Clichy, France
Nathalie Ganne-Carrié
Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris, Team ‘Functional Genomics of Solid Tumors’, Equipe Labellisée Ligue Nationale Contre le Cancer, Labex OncoImmunology, Paris, France; Liver Unit, Hôpital Avicenne, Hôpitaux Universitaires Paris-Seine-Saint-Denis, Assistance-Publique Hôpitaux de Paris, Bobigny, France; Unité de Formation et de Recherche Santé Médecine et Biologie Humaine, Université Sorbonne Paris Nord, Bobigny, France
Maxime Ronot
Department of Radiology, FHU MOSAIC, Hôpital Beaujon APHP Nord, Clichy, France; Université de Paris, INSERM U1149 ‘Centre de Recherche sur L'inflammation’, CRI, Paris, France
Vincent Lévy
Department of Clinical Research, Paris Seine Saint Denis Hospital, Sorbonne Paris University, APHP, Bobigny, France; ECSTRRA Team, CRESS UMR 1153, Hôpital Saint-Louis, APHP, Paris, France
Jean-Charles Nault
Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris, Team ‘Functional Genomics of Solid Tumors’, Equipe Labellisée Ligue Nationale Contre le Cancer, Labex OncoImmunology, Paris, France; Liver Unit, Hôpital Avicenne, Hôpitaux Universitaires Paris-Seine-Saint-Denis, Assistance-Publique Hôpitaux de Paris, Bobigny, France; Unité de Formation et de Recherche Santé Médecine et Biologie Humaine, Université Sorbonne Paris Nord, Bobigny, France; Corresponding author. Address: AP-HP, Hôpital Avicenne, Service d’Hépatologie, 125 rue de Stalingrad 93000 Bobigny, France.
Background & Aims: The fragility index (FI), i.e., theminimum number of best survivors reassigned to the control group required to revert the statistically significant result of a clinical trial to non-significant, is a metric to evaluate the robustness of randomized controlled trials (RCTs). We aimed to assess the FI in the field of HCC. Methods: This is a retrospective analysis of phase 2 and 3 RCTs for the treatment of HCC published between 2002 and 2022. We included two-arm studies with 1:1 randomization and significant positive results for a primary time-to-event endpoint for the FI calculation, which involves the iterative addition of a best survivor from the experimental group to the control group, until positive significance (p <0,05, Log-rank test) is lost. Results: We identified 51 phase 2 and 3 positive RCTs, of which 29 (57%) were eligible for fragility index calculation. After reconstruction of the Kaplan-Meier curves, 25/29 studies remained significant, among which the analysis was performed. The median (interquartile range (IQR)) FI was 5 (2-10) and Fragility Quotient (FQ) was 3% (1%-6%). Ten trials (40%) had a FI of 2 or less. FI was positively correlated to the blind assessment of the primary endpoint (median FI 9 with blind assessment versus 2 without, p = 0.01), the number of reported events in the control arm (RS = 0.45, p = 0.02) and to impact factor (RS = 0.58, p = 0.003). Conclusions: Several phases 2 and 3 RCTs in HCC have a low fragility index, underlying the limited robustness on the conclusion of their superiority over control treatments. The fragility index might provide an additional tool to assess the robustness of clinical trial data in HCC. Impact and implications: The fragility index is a method to assess robustness of a clinical trial and is defined the minimum number of best survivors reassigned to the control group required to revert the statistically significant result of a clinical trial to non-significant. Among 25 randomised controlled trials in HCC, the median fragility index was 5, and 10 trials among 25 (40%) had a fragility index of 2 or less, indicating an important fragility.
