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European Journal of Clinical Pharmacology

, Volume 75, Issue 8, pp 1135–1141 | Cite as

Adverse drug reaction causality assessment tools for drug-induced Stevens-Johnson syndrome and toxic epidermal necrolysis: room for improvement

  • Jennifer L. GoldmanEmail author
  • Wen-Hung Chung
  • Brian R. Lee
  • Chun-Bing Chen
  • Chun-Wei Lu
  • Wolfram Hoetzenecker
  • Robert Micheletti
  • Sally Usdin Yasuda
  • David J. Margolis
  • Neil H. Shear
  • Jeffery P Struewing
  • Munir Pirmohamed
Pharmacoepidemiology and Prescription

Abstract

Purpose

Establishment of causality between drug exposure and adverse drug reactions (ADR) is challenging even for serious ADRs such as Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). Several causality assessment tools (CAT) exist, but the reliability and validity of such tools is variable. The objective of this study was to compare the reliability and validity of existing ADR CATs on SJS/TEN cases.

Methods

Seven investigators completed three CAT (ALDEN, Naranjo, Liverpool) for 10 SJS/TEN cases. Each CAT categorized the causality of 30 potential drugs as definite/very probable, probable, possible, or doubtful/unlikely. An additional reviewer provided expert opinion by designating the implicated drug(s) for each case. A Kappa score was generated to compare CAT responses both by method (reliability of all 7 reviewers, by CATs) and by reviewer (reliability of the 3 CAT, by reviewer). A c statistic was calculated to assess validity.

Results

Inter-rater reliability by CAT was poor to fair: ALDEN 0.22, Naranjo 0.11, and Liverpool 0.12. Reliability was highest when causality classification was definite/very probable (0.16–0.41). Similarly, intra-rater reliability by reviewer was poor. When comparing the validity of the overall CAT to expert reviewer, area under the curve was highest for ALDEN (c statistic 0.65) as compared to Liverpool (0.55) or Naranjo (0.54).

Conclusion

Available CAT have poor reliability and validity for drug-induced SJS/TEN. Due to the importance of determining ADR causality for research, industry, and regulatory purposes, development of an enhanced tool that can incorporate data from immunological testing and pharmacogenetic results may strengthen CAT usefulness and applicability for drug-induced SJS/TEN.

Keywords

Causality assessment tool Adverse drug reactions Stevens-Johnson syndrome Toxic epidermal necrolysis 

Notes

Acknowledgements

The authors would like to thank Jyoti Gupta and Ceclia Dupecher for assistance with data collection and coordination. This study was performed by a NIH SJS/TEN Standardizing Case Definitions Working Group. MP thanks the MRC Centre for Drug Safety Science for the support.

Disclaimer

The views expressed are those of the authors

Authors’ contribution

Dr. Goldman contributed to the concept and design, analysis and interpretation of data, drafting, and revising of the manuscript.

Dr. Chung contributed to the concept and design, acquisition of data, analysis and interpretation of data, drafting, and revising of the manuscript.

Dr. Lee contributed to the concept and design, analysis and interpretation of data, drafting, and revising of the manuscript.

Dr. Chen contributed to the acquisition of data, drafting, and revising of the manuscript.

Dr. Lu contributed to the acquisition of data, drafting, and revising of the manuscript.

Dr. Hoetzenecker contributed to the concept and design, analysis and interpretation of data, drafting, and revising of the manuscript.

Dr. Micheletti contributed to the concept and design, analysis and interpretation of data, drafting, and revising the manuscript.

Dr. Yasuda contributed to the concept and design, analysis and interpretation of data, drafting, and revising the manuscript.

Dr. Margolis contributed to the concept and design, analysis and interpretation of data, drafting, and revising the manuscript.

Dr. Shear contributed to the concept and design, analysis and interpretation of data, drafting, and revising the manuscript.

Dr. Struewing contributed to the concept and design, analysis and interpretation of data, drafting, and revising the manuscript.

Dr. Pirmohamed contributed to the concept and design, analysis and interpretation of data, drafting, and revising the manuscript.

Funding

JLG received support by a CTSA grant from NCATS awarded to the University of Kansas Medical Center for Frontiers: The Heartland Institute for Clinical and Translational Research KL2TR000119. MP is a NIHR Senior Investigator, and is also supported by the NIHR North West Coast CLAHRC.

Compliance with ethical standards

Ethical statement

Since the data received by the SJS/TEN Standardizing Case Definitions Working Group was de-identified and no potentially identifiable variables were provided, no ethical approval was needed.

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

228_2019_2670_MOESM1_ESM.docx (13 kb)
ESM 1 (DOCX 12 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019
corrected publication June 2019

Authors and Affiliations

  • Jennifer L. Goldman
    • 1
    Email author
  • Wen-Hung Chung
    • 2
  • Brian R. Lee
    • 3
  • Chun-Bing Chen
    • 2
  • Chun-Wei Lu
    • 2
  • Wolfram Hoetzenecker
    • 4
  • Robert Micheletti
    • 5
  • Sally Usdin Yasuda
    • 6
  • David J. Margolis
    • 5
    • 7
  • Neil H. Shear
    • 8
  • Jeffery P Struewing
    • 9
  • Munir Pirmohamed
    • 10
  1. 1.Department of Pediatrics, Divisions of Pediatric Infectious Diseases & Clinical PharmacologyChildren’s Mercy Hospitals & ClinicKansas CityUSA
  2. 2.Department of Dermatology, Drug Hypersensitivity Clinical and Research CenterChang Gung Memorial Hospital, Keelung and Linkou Branches, College of Medicine, Chang Gung UniversityTaipeiTaiwan
  3. 3.Division of Health Services and Outcomes ResearchChildren’s Mercy Hospitals & ClinicsKansas CityUSA
  4. 4.Department of DermatologyUniversity Hospital LinzLinzAustria
  5. 5.Department of DermatologyUniversity of PennsylvaniaPhiladelphiaUSA
  6. 6.Food and Drug AdministrationSilver SpringUSA
  7. 7.Department of Biostatistics, Epidemiology and InformaticsUniversity of PennsylvaniaPhiladelphiaUSA
  8. 8.Division of DermatologyDepartment of Medicine, Sunnybrook Health Sciences Center and University of TorontoTorontoCanada
  9. 9.Division of Genomic MedicineNational Human Genome Research Institute, National Institutes of HealthBethesdaUSA
  10. 10.Department of Molecular and Clinical PharmacologyUniversity of LiverpoolLiverpoolUK

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