PMID- 28184420
OWN - NLM
STAT- MEDLINE
DCOM- 20180129
LR  - 20220408
IS  - 1569-8041 (Electronic)
IS  - 0923-7534 (Linking)
VI  - 28
IP  - 6
DP  - 2017 Jun 1
TI  - Statistical controversies in clinical research: Value of adverse events 
      relatedness to study treatment: analyses of data from randomized double-blind 
      placebo-controlled clinical trials.
PG  - 1183-1190
LID - 10.1093/annonc/mdx043 [doi]
AB  - BACKGROUND: Collection and reporting of adverse events (AEs) and their 
      relatedness to study treatment, known commonly as attribution, in clinical trials 
      is mandated by regulatory agencies (the National Cancer Institute and the Food 
      and Drug Administration). Attribution is assigned by the treating physician using 
      judgment based on various factors including patient's baseline status, disease 
      history, and comorbidity as well as knowledge about the safety profile of the 
      study treatments. We evaluate the patterns of AE attribution (unrelated, 
      unlikely, possibly, probably, and definitely related to the treatment) in 
      treatment, symptom intervention (cancer patients) and cancer prevention 
      (participants at high risk for cancer) setting. MATERIALS AND METHODS: Nine 
      multicenter placebo-controlled trials (two treatment, two symptom intervention, 
      and five cancer prevention) were analysed separately (2155 patients). Frequency 
      and severity of AEs were summarized by arm. Attribution and percentage of 
      repeated AEs whose attribution changed overtime were summarized for the placebo 
      arms. Percentage of physician over- or under-reporting of AE relatedness was 
      calculated for the treatment arms using the placebo arm as the reference. 
      RESULTS: Across all trials and settings, a very high proportion of AEs reported 
      as related to treatment were classified as possibly related, a significant 
      proportion of AEs in the placebo arm were incorrectly reported as related to 
      treatment, and clinician-reported attribution over-estimated the rate of AEs 
      related to treatment. Fatigue, nausea, vomiting, diarrhea, constipation, and 
      neurosensory were the common AEs that were over reported by clinician as related 
      to treatment. CONCLUSIONS: These analyses demonstrate that assigning causality to 
      AE is a complex and difficult process that produces unreliable and subjective 
      data. In randomized double-blind placebo-controlled trials where data are 
      available to objectively assess relatedness of AE to treatment, attribution 
      assignment should be eliminated.
CI  - (c) The Author 2017. Published by Oxford University Press on behalf of the European 
      Society for Medical Oncology. All rights reserved. For Permissions, please email: 
      journals.permissions@oup.com.
FAU - Le-Rademacher, J
AU  - Le-Rademacher J
AD  - Departments of Health Sciences Research.
FAU - Hillman, S L
AU  - Hillman SL
AD  - Departments of Health Sciences Research.
FAU - Meyers, J
AU  - Meyers J
AD  - Departments of Health Sciences Research.
FAU - Loprinzi, C L
AU  - Loprinzi CL
AD  - Medical Oncology.
FAU - Limburg, P J
AU  - Limburg PJ
AD  - Gastroenterology and Hepatology, Mayo Clinic, Rochester, USA.
FAU - Mandrekar, S J
AU  - Mandrekar SJ
AD  - Departments of Health Sciences Research.
LA  - eng
PT  - Journal Article
PL  - England
TA  - Ann Oncol
JT  - Annals of oncology : official journal of the European Society for Medical 
      Oncology
JID - 9007735
RN  - 0 (Placebos)
SB  - IM
MH  - Double-Blind Method
MH  - Female
MH  - Humans
MH  - Male
MH  - Neoplasms/physiopathology/prevention & control/*therapy
MH  - Placebos
MH  - *Randomized Controlled Trials as Topic
OTO - NOTNLM
OT  - adverse events
OT  - attribution
OT  - cancer prevention
OT  - clinical trials
OT  - symptom intervention
OT  - treatment trials
EDAT- 2017/02/12 06:00
MHDA- 2018/01/30 06:00
CRDT- 2017/02/11 06:00
PHST- 2017/02/12 06:00 [pubmed]
PHST- 2018/01/30 06:00 [medline]
PHST- 2017/02/11 06:00 [entrez]
AID - S0923-7534(19)32413-5 [pii]
AID - 10.1093/annonc/mdx043 [doi]
PST - ppublish
SO  - Ann Oncol. 2017 Jun 1;28(6):1183-1190. doi: 10.1093/annonc/mdx043.