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Cited by 11,914Pharmacovigilance and Adverse Drug ReactionsReliability and Agreement in MeasurementPharmaceutical Practices and Patient Outcomes

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A method for estimating the probability of adverse drug reactions

Naranjo, C A, Busto, U, Sellers, E M, Sandor, P, Ruiz, I, Roberts, E A, Janecek, E, Domecq, C, Greenblatt, D J·1981·Clinical Pharmacology and Therapeutics
DOI 10.1038/clpt.1981.154
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Abstract

The estimation of the probability that a drug caused an adverse clinical event is usually based on clinical judgment. Lack of a method for establishing causality generates large between-raters and within-raters variability in assessment. Using the conventional categories and definitions of definite, probable, possible, and doubtful adverse drug reactions (ADRs), the between-raters agreement of two physicians and four pharmacists who independently assessed 63 randomly selected alleged ADRs was 38% to 63%, kappa (k, a chance-corrected index of agreement) varied from 0.21 to 0.40, and the intraclass correlation coefficient of reliability (R[est]) was 0.49. Six (testing) and 22 wk (retesting) later the same observers independently reanalyzed the 63 cases by assigning a weighted score (ADR probability scale) to each of the components that must be considered in establishing causal associations between drug(s) and adverse events (e.g., temporal sequence). The cases were randomized to minimize the influence of learning. The event was assigned a probability category from the total score. The between-raters reliability (range: percent agreement = 83% to 92%; κ = 0.69 to 0.86; r = 0.91 to 0.95; R(est) = 0.92) and within-raters reliability (range: percent agreement = 80% to 97%; κ = 0.64 to 0.95; r = 0.91 to 0.98) improved (p < 0.001). The between-raters reliability was maintained on retesting (range: r = 0.84 to 0.94; R(est) = 0.87). The between-raters reliability of three attending physicians who independently assessed 28 other prospectively collected cases of alleged ADRs was very high (range: r = 0.76 to 0.87; R(est) = 0.80). It was also shown that the ADR probability scale has consensual, content, and concurrent validity. This systematic method offers a sensitive way to monitor ADRs and may be applicable to postmarketing drug surveillance. Clinical Pharmacology and Therapeutics (1981) 30, 239–245; doi:10.1038/clpt.1981.154

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Metadata

Authors
Naranjo, C. A., Busto, U., Sellers, E. M., Sandor, P., Ruiz, I., Roberts, E. A., Janecek, E., Domecq, C., & Greenblatt, D. J.
Affiliations
University of Toronto (CA)
Corresponding author
Naranjo, C A
ORCID
Venue
Clinical Pharmacology and Therapeutics
Publisher
Wiley
Published
1981-08
Volume
30
Issue
2
Pages
239-245
ISSN
  • 0009-9236 (ISSN-L)
  • 1532-6535
DOI
10.1038/clpt.1981.154
OpenAlex
W2067978628
Cited by
11,914
References
0
Citations by year
2026: 650 · 2025: 601 · 2024: 583 · 2023: 592 · 2022: 750 · 2021: 699 · 2020: 645 · 2019: 564 · 2018: 577 · 2017: 591 · 2016: 516 · 2015: 509 · 2014: 485 · 2013: 473 · 2012: 430
FWCI
11.57
Type
journal article
Language
en
Open access
closed
Locations
  • Clinical Pharmacology & Therapeutics (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Pharmacovigilance and Adverse Drug Reactions
  • Social Sciences › Decision Sciences › Statistics, Probability and Uncertainty › Reliability and Agreement in Measurement
  • Health Sciences › Medicine › Geriatrics and Gerontology › Pharmaceutical Practices and Patient Outcomes
Keywords
adverse drug reactions, drug causality assessment, probability of causation, inter-rater reliability, temporal sequence, post-marketing surveillance, pharmacovigilance, content validity, concurrent validity
MeSH terms
Evaluation Studies as Topic, Humans, Methods, Pharmacists, Physicians, Probability, Random Allocation, Drug-Related Side Effects and Adverse Reactions

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