A Method for Estimating the Probability of Adverse Drug Reactions

Clinical Pharmacology & TherapeuticsVolume 30, Issue 2 p. 239-245 Original Article A method for estimating the probability of adverse drug reactions C A Naranjo MD, Corresponding Author C A Naranjo MD Clinical Pharmacology Program, Addiction Research Foundation Clinical Institute Departments of Medicine and Pharmacology, University of TorontoC A Naranjo, MD, Clinical Pharmacology Program, Addiction Research Foundation Clinical Institute, 33 Russell St., Toronto, Ontario M5S 2S1, Canada.Search for more papers by this authorU Busto PharmD, U Busto PharmD Clinical Pharmacology Program, Addiction Research Foundation Clinical Institute Departments of Medicine and Pharmacology, University of TorontoSearch for more papers by this authorE M Sellers MD, PhD, E M Sellers MD, PhD Clinical Pharmacology Program, Addiction Research Foundation Clinical Institute Departments of Medicine and Pharmacology, University of TorontoSearch for more papers by this authorP Sandor MD, P Sandor MD Clinical Pharmacology Program, Addiction Research Foundation Clinical Institute Departments of Medicine and Pharmacology, University of TorontoSearch for more papers by this authorI Ruiz PharmD, I Ruiz PharmD Clinical Pharmacology Program, Addiction Research Foundation Clinical Institute Departments of Medicine and Pharmacology, University of TorontoSearch for more papers by this authorE A Roberts MD, E A Roberts MD Clinical Pharmacology Program, Addiction Research Foundation Clinical Institute Departments of Medicine and Pharmacology, University of TorontoSearch for more papers by this authorE Janecek BSc, Phm, E Janecek BSc, Phm Clinical Pharmacology Program, Addiction Research Foundation Clinical Institute Departments of Medicine and Pharmacology, University of TorontoSearch for more papers by this authorC Domecq PharmD, C Domecq PharmD Clinical Pharmacology Program, Addiction Research Foundation Clinical Institute Departments of Medicine and Pharmacology, University of TorontoClinical Pharmacy Group, Faculty of Chemical Sciences, Universidad de Chile, Santiago, Chile.Search for more papers by this authorD J Greenblatt MD, D J Greenblatt MD Clinical Pharmacology Program, Addiction Research Foundation Clinical Institute Departments of Medicine and Pharmacology, University of TorontoDivision of Clinical Pharmacology, New England Medical Centre Hospital, Boston, MA.Search for more papers by this author C A Naranjo MD, Corresponding Author C A Naranjo MD Clinical Pharmacology Program, Addiction Research Foundation Clinical Institute Departments of Medicine and Pharmacology, University of TorontoC A Naranjo, MD, Clinical Pharmacology Program, Addiction Research Foundation Clinical Institute, 33 Russell St., Toronto, Ontario M5S 2S1, Canada.Search for more papers by this authorU Busto PharmD, U Busto PharmD Clinical Pharmacology Program, Addiction Research Foundation Clinical Institute Departments of Medicine and Pharmacology, University of TorontoSearch for more papers by this authorE M Sellers MD, PhD, E M Sellers MD, PhD Clinical Pharmacology Program, Addiction Research Foundation Clinical Institute Departments of Medicine and Pharmacology, University of TorontoSearch for more papers by this authorP Sandor MD, P Sandor MD Clinical Pharmacology Program, Addiction Research Foundation Clinical Institute Departments of Medicine and Pharmacology, University of TorontoSearch for more papers by this authorI Ruiz PharmD, I Ruiz PharmD Clinical Pharmacology Program, Addiction Research Foundation Clinical Institute Departments of Medicine and Pharmacology, University of TorontoSearch for more papers by this authorE A Roberts MD, E A Roberts MD Clinical Pharmacology Program, Addiction Research Foundation Clinical Institute Departments of Medicine and Pharmacology, University of TorontoSearch for more papers by this authorE Janecek BSc, Phm, E Janecek BSc, Phm Clinical Pharmacology Program, Addiction Research Foundation Clinical Institute Departments of Medicine and Pharmacology, University of TorontoSearch for more papers by this authorC Domecq PharmD, C Domecq PharmD Clinical Pharmacology Program, Addiction Research Foundation Clinical Institute Departments of Medicine and Pharmacology, University of TorontoClinical Pharmacy Group, Faculty of Chemical Sciences, Universidad de Chile, Santiago, Chile.Search for more papers by this authorD J Greenblatt MD, D J Greenblatt MD Clinical Pharmacology Program, Addiction Research Foundation Clinical Institute Departments of Medicine and Pharmacology, University of TorontoDivision of Clinical Pharmacology, New England Medical Centre Hospital, Boston, MA.Search for more papers by this author First published: August 1981 https://doi.org/10.1038/clpt.1981.154Citations: 1,097 AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text 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Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat 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 Citing Literature Volume30, Issue2August 1981Pages 239-245 RelatedInformation