Evaluation of the value of attribution in the interpretation of adverse event data: a North Central Cancer Treatment Group and American College of Surgeons Oncology Group investigation.
OBJECTIVE
In March 1998, Common Toxicity Criteria (CTC) version 2.0 introduced the collection of attribution of adverse events (AEs) to study drug. We investigate whether attribution adds value to the interpretation of AE data.


METHODS
Patients in the placebo arm of two phase III trials-North Central Cancer Treatment Group Trial 97-24-51 (carboxyamino-triazole v placebo in advanced non-small-cell lung cancer) and American College of Surgeons Oncology Group Trial Z9001 (imatinib mesylate v placebo after resection of primary gastrointestinal stromal tumors)-were studied. Attribution was categorized as unrelated (not related or unlikely) and related (possible, probable, or definite).


RESULTS
In total, 398 patients (84 from Trial 97-24-51 and 314 from Trial Z9001) and 7,736 AEs were included; 47% and 50% of the placebo-arm AEs, respectively, were reported as related. When the same AE was reported in the same patient on multiple visits, the attribution category changed at least once 36% and 31% of the time. AE type and sex (Trial Z9001) and AE type and performance status (Trial 97-24-51) were associated with a higher likelihood of AEs being deemed related.


CONCLUSIONS
Nearly 50% of AEs were reported as attributed to study drug on the placebo arm of two randomized clinical trials. These data provide strong evidence that AE attribution is difficult to determine, unreliable, and of questionable value in interpreting AE data in randomized clinical trials.
Hillman
Shauna L
SL
Mayo Clinic, Rochester, MN 55905, USA. hillman.shauna@mayo.edu
Mandrekar
Sumithra J
SJ
Bot
Brian
B
DeMatteo
Ronald P
RP
Perez
Edith A
EA
Ballman
Karla V
KV
Nelson
Heidi
H
Buckner
Jan C
JC
Sargent
Daniel J
DJ
D000293:Adolescent; D000328:Adult; D016907:Adverse Drug Reaction Reporting Systems / Q000706:statistics & numerical data*; D000368:Aged; D000369:Aged, 80 and over; D001549:Benzamides; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D017326:Clinical Trials, Phase III as Topic; D004311:Double-Blind Method; D005260:Female; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D000068877:Imatinib Mesylate; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000627:therapeutic use*; D010919:Placebos; D011743:Pyrimidines / Q000627:therapeutic use*; D016032:Randomized Controlled Trials as Topic; D012189:Retrospective Studies; D015996:Survival Rate; D016896:Treatment Outcome; D014230:Triazoles / Q000627:therapeutic use*; D055815:Young Adult
D001549:Benzamides; D010879:Piperazines; D010919:Placebos; D011743:Pyrimidines; D014230:Triazoles; C062058:carboxyamido-triazole; D000068877:Imatinib Mesylate