PMID- 38172810
OWN - NLM
STAT- MEDLINE
DCOM- 20240118
LR  - 20240118
IS  - 1471-2288 (Electronic)
IS  - 1471-2288 (Linking)
VI  - 24
IP  - 1
DP  - 2024 Jan 3
TI  - Adverse events in single-arm clinical trials with non-fatal time-to-event 
      efficacy endpoint: from clinical questions to methods for statistical analysis.
PG  - 3
LID - 10.1186/s12874-023-02123-z [doi]
LID - 3
AB  - BACKGROUND: In any single-arm trial on novel treatments, assessment of toxicity 
      plays an important role as occurrence of adverse events (AEs) is relevant for 
      application in clinical practice. In the presence of a non-fatal time-to-event(s) 
      efficacy endpoint, the analysis should be broadened to consider AEs occurrence in 
      time. The AEs analysis could be tackled with two approaches, depending on the 
      clinical question of interest. Approach 1 focuses on the occurrence of AE as 
      first event. Treatment ability to protect from the efficacy endpoint event(s) has 
      an impact on the chance of observing AEs due to competing risks action. Approach 
      2 considers how treatment affects the occurrence of AEs in the potential 
      framework where the efficacy endpoint event(s) could not occur. METHODS: In the 
      first part of the work we review the strategy of analysis for these two 
      approaches. We identify theoretical quantities and estimators consistent with the 
      following features: (a) estimators should address for the presence of right 
      censoring; (b) theoretical quantities and estimators should be functions of time. 
      In the second part of the work we propose the use of alternative methods 
      (regression models, stratified Kaplan-Meier curves, inverse probability of 
      censoring weighting) to relax the assumption of independence between the 
      potential times to AE and to event(s) in the efficacy endpoint for addressing 
      Approach 2. RESULTS: We show through simulations that the proposed methods 
      overcome the bias due to the dependence between the two potential times and 
      related to the use of standard estimators. CONCLUSIONS: We demonstrated through 
      simulations that one can handle patients selection in the risk sets due to the 
      competing event, and thus obtain conditional independence between the two 
      potential times, adjusting for all the observed covariates that induce 
      dependence.
CI  - (c) 2023. The Author(s).
FAU - Tassistro, Elena
AU  - Tassistro E
AD  - Bicocca Center of Bioinformatics, Biostatistics and Bioimaging (B4 centre), 
      School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy. 
      elena.tassistro@unimib.it.
FAU - Bernasconi, Davide Paolo
AU  - Bernasconi DP
AD  - Bicocca Center of Bioinformatics, Biostatistics and Bioimaging (B4 centre), 
      School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.
FAU - Valsecchi, Maria Grazia
AU  - Valsecchi MG
AD  - Bicocca Center of Bioinformatics, Biostatistics and Bioimaging (B4 centre), 
      School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.
AD  - Biostatistics and Clinical Epidemiology, Fondazione IRCCS San Gerardo dei 
      Tintori, Monza, Italy.
FAU - Antolini, Laura
AU  - Antolini L
AD  - Bicocca Center of Bioinformatics, Biostatistics and Bioimaging (B4 centre), 
      School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.
LA  - eng
GR  - 20178S4EK9/Grant PRIN project/
GR  - 20178S4EK9/Grant PRIN project/
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Review
DEP - 20240103
PL  - England
TA  - BMC Med Res Methodol
JT  - BMC medical research methodology
JID - 100968545
SB  - IM
MH  - Humans
MH  - Bias
MH  - *Models, Statistical
MH  - Probability
MH  - *Research Design
MH  - Clinical Trials as Topic
PMC - PMC10765745
OTO - NOTNLM
OT  - Adverse events
OT  - Competing risks
OT  - Dependent censoring
OT  - IPCW
OT  - Survival analysis
COIS- The authors declare no competing interests.
EDAT- 2024/01/04 11:44
MHDA- 2024/01/05 06:42
PMCR- 2024/01/03
CRDT- 2024/01/03 23:51
PHST- 2023/05/19 00:00 [received]
PHST- 2023/12/07 00:00 [accepted]
PHST- 2024/01/05 06:42 [medline]
PHST- 2024/01/04 11:44 [pubmed]
PHST- 2024/01/03 23:51 [entrez]
PHST- 2024/01/03 00:00 [pmc-release]
AID - 10.1186/s12874-023-02123-z [pii]
AID - 2123 [pii]
AID - 10.1186/s12874-023-02123-z [doi]
PST - epublish
SO  - BMC Med Res Methodol. 2024 Jan 3;24(1):3. doi: 10.1186/s12874-023-02123-z.