PMID- 31756032
OWN - NLM
STAT- MEDLINE
DCOM- 20210601
LR  - 20210601
IS  - 1521-4036 (Electronic)
IS  - 0323-3847 (Linking)
VI  - 62
IP  - 3
DP  - 2020 May
TI  - Quantitative assessment of adverse events in clinical trials: Comparison of 
      methods at an interim and the final analysis.
PG  - 658-669
LID - 10.1002/bimj.201800234 [doi]
AB  - In clinical study reports (CSRs), adverse events (AEs) are commonly summarized 
      using the incidence proportion (IP). IPs can be calculated for all types of AEs 
      and are often interpreted as the probability that a treated patient experiences 
      specific AEs. Exposure time can be taken into account with time-to-event methods. 
      Using one minus Kaplan-Meier (1-KM) is known to overestimate the AE probability 
      in the presence of competing events (CEs). The use of a nonparametric estimator 
      of the cumulative incidence function (CIF) has therefore been advocated as more 
      appropriate. In this paper, we compare different methods to estimate the 
      probability of one selected AE. In particular, we investigate whether the 
      proposed methods provide a reasonable estimate of the AE probability at an 
      interim analysis (IA). The characteristics of the methods in the presence of a CE 
      are illustrated using data from a breast cancer study and we quantify the 
      potential bias in a simulation study. At the final analysis performed for the 
      CSR, 1-KM systematically overestimates and in most cases IP slightly 
      underestimates the given AE probability. CIF has the lowest bias in most 
      simulation scenarios. All methods might lead to biased estimates at the IA except 
      for AEs with early onset. The magnitude of the bias varies with the time-to-AE 
      and/or CE occurrence, the selection of event-specific hazards and the amount of 
      censoring. In general, reporting AE probabilities for prespecified fixed time 
      points is recommended.
CI  - (c) 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
FAU - Hollaender, Norbert
AU  - Hollaender N
AUID- ORCID: 0000-0003-1031-7397
AD  - Novartis Pharma AG, Basel, Switzerland.
FAU - Gonzalez-Maffe, Juan
AU  - Gonzalez-Maffe J
AD  - Novartis Pharma AG, Basel, Switzerland.
FAU - Jehl, Valentine
AU  - Jehl V
AD  - Novartis Pharma AG, Basel, Switzerland.
LA  - eng
PT  - Comparative Study
PT  - Journal Article
DEP - 20191122
PL  - Germany
TA  - Biom J
JT  - Biometrical journal. Biometrische Zeitschrift
JID - 7708048
RN  - 0 (Antineoplastic Agents)
SB  - IM
MH  - Antineoplastic Agents/adverse effects/therapeutic use
MH  - Biometry/*methods
MH  - Breast Neoplasms/drug therapy
MH  - *Clinical Trials as Topic
MH  - Humans
MH  - Sampling Studies
MH  - Statistics, Nonparametric
OTO - NOTNLM
OT  - adverse events
OT  - clinical study
OT  - competing event
OT  - interim analysis
OT  - simulations
EDAT- 2019/11/23 06:00
MHDA- 2021/06/02 06:00
CRDT- 2019/11/23 06:00
PHST- 2018/08/09 00:00 [received]
PHST- 2019/11/06 00:00 [revised]
PHST- 2019/11/11 00:00 [accepted]
PHST- 2019/11/23 06:00 [pubmed]
PHST- 2021/06/02 06:00 [medline]
PHST- 2019/11/23 06:00 [entrez]
AID - 10.1002/bimj.201800234 [doi]
PST - ppublish
SO  - Biom J. 2020 May;62(3):658-669. doi: 10.1002/bimj.201800234. Epub 2019 Nov 22.