Skip to main content
SpringerLink
Log in

A Comprehensive Methodology to Systematically Identify Drug Hypersensitivity and Anaphylactic Reactions in Clinical Trial Databases

  • Original Research Article
  • Published:
Pharmaceutical Medicine Aims and scope Submit manuscript

Abstract

Background

The incidence of drug hypersensitivity or anaphylactic reactions in clinical trial databases is thought to be underestimated due to variable clinical presentations and lack of clear definitions.

Objective

Our objective was to develop a more comprehensive, systematic methodology for retrospectively identifying potential hypersensitivity or anaphylactic reactions reported in patients treated with investigational drugs in clinical trials and to accurately assess and characterise the risk.

Methods

A three-step approach was developed to identify hypersensitivity or anaphylactic reactions: clinical trial database search, medical review, and adjudication to confirm or rule out cases. The database search strategy consisted of the narrow search for Standardized MedDRA Query (SMQ) Hypersensitivity, a modified MedDRA query based on SMQ Anaphylactic reaction, and pyrexia-related MedDRA Preferred Terms. The cases identified from the search were further medically reviewed taking into consideration the temporal relationship, seriousness, severity, course, and management of the events, action taken, and outcomes of adverse events. Those cases deemed to have potentially drug-related hypersensitivity were then adjudicated to be confirmed or ruled out.

Results

The method was applied to a clinical trial database containing safety data for 421 patients treated with an investigational drug. Application of the methodology led to 19 hypersensitivity cases being identified. Of these, 12 were classified as immediate reactions and 7 as non-immediate reactions.

Conclusion

This three-step method provided a thorough and robust way to identify hypersensitivity reactions, including anaphylaxis, in a clinical trial database. This method could be applied to investigational drugs to improve early detection and monitoring of potential safety concerns, subsequent patient safety management strategies, and potentially programme-wide drug development decisions. Algorithmic tools and narrow and/or broad SMQs should be considered when evaluating safety concerns. The authors also recommend a revision of the MedDRA SMQ of Anaphylactic reaction.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Pilcher WJ. Drug hypersensitivity reactions: classification and relationship to T-cell activation. Drug hypersensitivity. Basel: Karger; 2007. p. 168–189.

    Google Scholar 

  2. Warrington R, Silviu-Dan F, Wong T. Drug allergy. Allergy Asthma Clin Immunol Off J Can Soc Allergy Clin Immunol. 2018;14(Suppl 2):60.

    Article  Google Scholar 

  3. Gell PGH, Coombs RRA. The classification of allergic reactions underlying disease. In: Coombs RRA, Gell PGH, editors. Clinical aspects of immunology. Oxford: Blackwell Scientific Publications; 1963.

    Google Scholar 

  4. Johansson SG, Bieber T, Dahl R, Friedmann PS, Lanier BQ, Lockey RF, et al. Revised nomenclature for allergy for global use: Report of the Nomenclature Review Committee of the World Allergy Organization, October 2003. J Allergy Clin Immunol. 2004;113(5):832–6.

    Article  CAS  Google Scholar 

  5. Sampson HA, Munoz-Furlong A, Campbell RL, Adkinson NF Jr, Bock SA, Branum A, et al. Second symposium on the definition and management of anaphylaxis: summary report-Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium. J Allergy Clin Immunol. 2006;117(2):391–7.

    Article  Google Scholar 

  6. Montañez MI, Mayorga C, Bogas G, Barrionuevo E, Fernandez-Santamaria R, Martin-Serrano A, et al. Epidemiology, mechanisms, and diagnosis of drug-induced anaphylaxis. Front Immunol. 2017;8:614.

    Article  Google Scholar 

  7. Reber LL, Hernandez JD, Galli SJ. The pathophysiology of anaphylaxis. J Allergy Clin Immunol. 2017;140(2):335–48.

    Article  CAS  Google Scholar 

  8. Simons FE, Ardusso LR, Bilo MB, Cardona V, Ebisawa M, El-Gamal YM, et al. International consensus on (ICON) anaphylaxis. World Allergy Organ J. 2014;7(1):9.

    Article  Google Scholar 

  9. Riedl MA, Casillas AM. Adverse drug reactions: types and treatment options. Am Fam Physician. 2003;68(9):1781–90.

    PubMed  Google Scholar 

  10. Demoly P, Adkinson NF, Brockow K, Castells M, Chiriac AM, Greenberger PA, et al. International Consensus on drug allergy. Allergy. 2014;69(4):420–37.

    Article  CAS  Google Scholar 

  11. Wang F, Weng Z, Li C, Peng G. A reliable method for the evaluation of the anaphylactoid reaction caused by injectable drugs. Molecules (Basel, Switzerland). 2016;21:10.

    CAS  Google Scholar 

  12. Roselló S, Blasco I, García Fabregat L, Cervantes A, Jordan K. Management of infusion reactions to systemic anticancer therapy: ESMO Clinical Practice Guidelines. Ann Oncol. 2017;28(suppl_4):100–18.

    Article  Google Scholar 

  13. Shimabukuro-Vornhagen A, Gödel P, Subklewe M, Stemmler HJ, Schlößer HA, Schlaak M, et al. Cytokine release syndrome. J Immunother Cancer. 2018;6(1):56.

    Article  Google Scholar 

  14. Chen CB, Abe R, Pan RY, Wang CW, Hung SI, Tsai YG, et al. An updated review of the molecular mechanisms in drug hypersensitivity. J Immunol Res. 2018;2018:6431694.

    PubMed  PubMed Central  Google Scholar 

  15. Macy E, Vyles D. Who needs penicillin allergy testing? Ann Allergy Asthma Immunol. 2018;121(5):523–9.

    Article  Google Scholar 

  16. Joint Task Force on Practice Parameters representing the American Academy of Allergy AaI, the American College of Allergy, Asthma and Immunology, and the Joint Council of Allergy, Asthma and Immunology. Drug Allergy: an updated practice parameter. Ann Allergy Asthma Immunol. 2010;105(4):259–73.

    Article  Google Scholar 

  17. Gomes ER, Kuyucu S. Epidemiology and risk factors in drug hypersensitivity reactions. Curr Treat Opt Allergy. 2017;4(2):239–57.

    Article  Google Scholar 

  18. Bailey C, Peddie D, Wickham ME, Badke K, Small SS, Doyle-Waters MM, et al. Adverse drug event reporting systems: a systematic review. Br J Clin Pharmacol. 2016;82(1):17–29.

    Article  Google Scholar 

  19. Cutroneo PM, Giardina C, Ientile V, Potenza S, Sottosanti L, Ferrajolo C, et al. Overview of the safety of anti-VEGF drugs: analysis of the Italian Spontaneous Reporting System. Drug Saf. 2017;40(11):1131–40.

    Article  CAS  Google Scholar 

  20. Tourillon C, Mahe J, Baron A, Lambert A, Yélehé-Okouma M, Veyrac G, et al. Immediate-type hypersensitivity cross-reactions to proton pump inhibitors: a descriptive study of data from the french national pharmacovigilance database. Int Arch Allergy Immunol. 2019;178(2):159–66.

    Article  CAS  Google Scholar 

  21. Chang LC, Mahmood R, Qureshi S, Breder CD. Patterns of use and impact of standardised MedDRA query analyses on the safety evaluation and review of new drug and biologics license applications. PLoS ONE. 2017;12(6):e0178104.

    Article  Google Scholar 

  22. Brown EG. Methods and pitfalls in searching drug safety databases utilising the medical dictionary for regulatory activities (MedDRA)1. Drug Saf. 2003;26(3):145–58.

    Article  Google Scholar 

  23. MedDRA. Introductory Guide for Standardised MedDRA Queries (SMQs) Version 20.1: MedDRA; 2017.

  24. Walsh KE, Cutrona SL, Foy S, Baker MA, Forrow S, Shoaibi A, et al. Validation of anaphylaxis in the Food and Drug Administration's Mini-Sentinel. Pharmacoepidemiol Drug Saf. 2013;22(11):1205–13.

    Article  Google Scholar 

  25. Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther. 1981;30(2):239–45.

    Article  CAS  Google Scholar 

  26. Demoly P, Kropf R, Bircher A, Pichler WJ. Drug hypersensitivity: questionnaire. EAACI interest group on drug hypersensitivity. Allergy. 1999;54(9):999–1003.

    Article  CAS  Google Scholar 

  27. Fischer M, Schmutzhard E. Posterior reversible encephalopathy syndrome. J Neurol. 2017;264(8):1608–16.

    Article  Google Scholar 

  28. Scully M, Hunt BJ, Benjamin S, Liesner R, Rose P, Peyvandi F, et al. Guidelines on the diagnosis and management of thrombotic thrombocytopenic purpura and other thrombotic microangiopathies. Br J Haematol. 2012;158(3):323–35.

    Article  Google Scholar 

  29. Salvadori M, Bertoni E. Update on hemolytic uremic syndrome: diagnostic and therapeutic recommendations. World J Nephrol. 2013;2(3):56–76.

    Article  Google Scholar 

Download references

Acknowledgements

The authors would like to acknowledge Alison Lee and Isobel Anderson for their contribution to programming support. The authors would like to acknowledge Bernadette Tynan, MSc, of Ashfield Healthcare communications, Macclesfield, UK, part of UDG Healthcare plc, for medical writing support that was funded by AstraZeneca in accordance with Good Publications Practice (GPP3) guidelines (https://www.ismpp.org/gpp3).

Author information

Authors and Affiliations

  1. Research and Development, AstraZeneca, Cambridge, UK

    Hugo Xavier, Lone H. Ottesen, Remy B. Verheijen & Dana Ghiorghiu

  2. Patient Safety, Medimmune-AstraZeneca, Cambridge, UK

    Indira Hara

  3. Global Patient Safety, AstraZeneca, One Medimmune Way, Gaithersburg, MD, 20878, USA

    Claire Morgan

Authors
  1. Hugo Xavier
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Indira Hara
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lone H. Ottesen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Remy B. Verheijen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Dana Ghiorghiu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Claire Morgan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Claire Morgan.

Ethics declarations

Funding

This study was funded by AstraZeneca.

Conflict of interest

Hugo Xavier, Indira Hara, Lone H. Ottesen, Remy B. Verheijen, Dana Ghiorghiu and Claire Morgan are AstraZeneca employees and shareholders.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent for publication

Not applicable.

Availability of data and material

Data was obtained from clinical trial database in an excel spreadsheet (data on file). Data underlying the findings described in this manuscript may be obtained in accordance with AstraZeneca’s data sharing policy described at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

Code availability

Not applicable.

Author contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by all authors. The first draft of the manuscript was written by Hugo Xavier, Indira Hara, and Claire Morgan and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Xavier, H., Hara, I., Ottesen, L.H. et al. A Comprehensive Methodology to Systematically Identify Drug Hypersensitivity and Anaphylactic Reactions in Clinical Trial Databases. Pharm Med 34, 335–345 (2020). https://doi.org/10.1007/s40290-020-00350-z

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40290-020-00350-z

Search

Navigation