PMID- 30458579
OWN - NLM
STAT- MEDLINE
DCOM- 20190417
LR  - 20231012
IS  - 1539-1612 (Electronic)
IS  - 1539-1604 (Print)
IS  - 1539-1604 (Linking)
VI  - 18
IP  - 2
DP  - 2019 Mar
TI  - On estimands and the analysis of adverse events in the presence of varying 
      follow-up times within the benefit assessment of therapies.
PG  - 166-183
LID - 10.1002/pst.1915 [doi]
AB  - The analysis of adverse events (AEs) is a key component in the assessment of a 
      drug's safety profile. Inappropriate analysis methods may result in misleading 
      conclusions about a therapy's safety and consequently its benefit-risk ratio. The 
      statistical analysis of AEs is complicated by the fact that the follow-up times 
      can vary between the patients included in a clinical trial. This paper takes as 
      its focus the analysis of AE data in the presence of varying follow-up times 
      within the benefit assessment of therapeutic interventions. Instead of 
      approaching this issue directly and solely from an analysis point of view, we 
      first discuss what should be estimated in the context of safety data, leading to 
      the concept of estimands. Although the current discussion on estimands is mainly 
      related to efficacy evaluation, the concept is applicable to safety endpoints as 
      well. Within the framework of estimands, we present statistical methods for 
      analysing AEs with the focus being on the time to the occurrence of the first AE 
      of a specific type. We give recommendations which estimators should be used for 
      the estimands described. Furthermore, we state practical implications of the 
      analysis of AEs in clinical trials and give an overview of examples across 
      different indications. We also provide a review of current practices of health 
      technology assessment (HTA) agencies with respect to the evaluation of safety 
      data. Finally, we describe problems with meta-analyses of AE data and sketch 
      possible solutions.
CI  - (c) 2018 The Authors. Pharmaceutical Statistics Published by John Wiley & Sons Ltd.
FAU - Unkel, Steffen
AU  - Unkel S
AUID- ORCID: 0000-0002-2083-0090
AD  - Department of Medical Statistics, University Medical Center Goettingen, 
      Goettingen, Germany.
FAU - Amiri, Marjan
AU  - Amiri M
AD  - Center for Clinical Trials, University Hospital Essen, Essen, Germany.
FAU - Benda, Norbert
AU  - Benda N
AUID- ORCID: 0000-0001-5605-2414
AD  - Biostatistics and Special Pharmacokinetics Unit, Federal Institute for Drugs and 
      Medical Devices, Bonn, Germany.
FAU - Beyersmann, Jan
AU  - Beyersmann J
AD  - Institute of Statistics, Ulm University, Germany.
FAU - Knoerzer, Dietrich
AU  - Knoerzer D
AD  - Roche Pharma AG, Grenzach, Germany.
FAU - Kupas, Katrin
AU  - Kupas K
AD  - Bristol-Myers Squibb GmbH & Co. KGaA, Munchen, Germany.
FAU - Langer, Frank
AU  - Langer F
AD  - Lilly Deutschland GmbH, Bad Homburg, Germany.
FAU - Leverkus, Friedhelm
AU  - Leverkus F
AD  - Pfizer Deutschland GmbH, Berlin, Germany.
FAU - Loos, Anja
AU  - Loos A
AD  - Merck KGaA, Darmstadt, Germany.
FAU - Ose, Claudia
AU  - Ose C
AD  - Center for Clinical Trials, University Hospital Essen, Essen, Germany.
FAU - Proctor, Tanja
AU  - Proctor T
AD  - Institute of Medical Biometry and Informatics, University of Heidelberg, 
      Heidelberg, Germany.
FAU - Schmoor, Claudia
AU  - Schmoor C
AD  - Clinical Trials Unit, Faculty of Medicine and Medical Center, University of 
      Freiburg, Freiburg im Breisgau, Germany.
FAU - Schwenke, Carsten
AU  - Schwenke C
AD  - Schwenke Consulting: Strategies and Solutions in Statistics (SCO:SSIS), Berlin, 
      Germany.
FAU - Skipka, Guido
AU  - Skipka G
AD  - Institute for Quality and Efficiency in Health Care, Cologne, Germany.
FAU - Unnebrink, Kristina
AU  - Unnebrink K
AD  - AbbVie Deutschland GmbH & Co. KG, Ludwigshafen, Germany.
FAU - Voss, Florian
AU  - Voss F
AD  - Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany.
FAU - Friede, Tim
AU  - Friede T
AUID- ORCID: 0000-0001-5347-7441
AD  - Department of Medical Statistics, University Medical Center Goettingen, 
      Goettingen, Germany.
LA  - eng
PT  - Journal Article
DEP - 20181120
PL  - England
TA  - Pharm Stat
JT  - Pharmaceutical statistics
JID - 101201192
SB  - IM
MH  - Clinical Trials as Topic/*methods/statistics & numerical data
MH  - *Data Interpretation, Statistical
MH  - Drug-Related Side Effects and Adverse Reactions/*diagnosis
MH  - Endpoint Determination
MH  - Follow-Up Studies
MH  - Humans
MH  - Research Design
MH  - Technology Assessment, Biomedical/methods
MH  - Time Factors
PMC - PMC6587465
OTO - NOTNLM
OT  - adverse events
OT  - benefit assessment
OT  - clinical trials
OT  - estimands
OT  - safety data
EDAT- 2018/11/21 06:00
MHDA- 2019/04/18 06:00
PMCR- 2019/06/21
CRDT- 2018/11/21 06:00
PHST- 2018/05/03 00:00 [received]
PHST- 2018/09/19 00:00 [revised]
PHST- 2018/10/23 00:00 [accepted]
PHST- 2018/11/21 06:00 [pubmed]
PHST- 2019/04/18 06:00 [medline]
PHST- 2018/11/21 06:00 [entrez]
PHST- 2019/06/21 00:00 [pmc-release]
AID - PST1915 [pii]
AID - 10.1002/pst.1915 [doi]
PST - ppublish
SO  - Pharm Stat. 2019 Mar;18(2):166-183. doi: 10.1002/pst.1915. Epub 2018 Nov 20.