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Influence of drug safety advisories on drug utilisation: an international interrupted time series and meta-analysis
  1. Richard L Morrow1,
  2. Barbara Mintzes2,
  3. Patrick C Souverein3,
  4. Marie L De Bruin3,
  5. Elizabeth Ellen Roughead4,
  6. Joel Lexchin5,
  7. Anna Kemp-Casey4,
  8. Lorri Puil6,
  9. Ingrid Sketris7,
  10. Dee Mangin8,
  11. Christine E Hallgreen9,
  12. Sallie-Anne Pearson10,
  13. Ruth Lopert11,
  14. Lisa Bero12,
  15. Richard Ofori-Asenso9,
  16. Danijela Gnjidic2,
  17. Ameet Sarpatwari13,
  18. Lucy T Perry2,
  19. Colin R Dormuth1
  1. 1 Department of Anesthesiology, Pharmacology and Therapeutics, The University of British Columbia, Vancouver, British Columbia, Canada
  2. 2 School of Pharmacy, Faculty of Medicine and Health, and Charles Perkins Centre, University of Sydney, Sydney, New South Wales, Australia
  3. 3 Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University Faculty of Science, Utrecht, The Netherlands
  4. 4 Clinical and Health Sciences, University of South Australia, Adelaide, South Australia, Australia
  5. 5 School of Health Policy & Management, York University, Toronto, Ontario, Canada
  6. 6 School of Population and Public Health, The University of British Columbia Faculty of Medicine, Vancouver, British Columbia, Canada
  7. 7 Dalhousie University, College of Pharmacy, Halifax, Nova Scotia, Canada
  8. 8 Department of Family Medicine, McMaster University, Hamilton, Ontario, Canada
  9. 9 Copenhagen Centre for Regulatory Science, Department of Pharmacy, University of Copenhagen Faculty of Health and Medical Sciences, Copenhagen, Denmark
  10. 10 Centre for Big Data Research in Health, UNSW Sydney, Sydney, New South Wales, Australia
  11. 11 Department of Health Policy and Management, George Washington University, Washington, District of Columbia, USA
  12. 12 School of Medicine and Colorado School of Public Health, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
  13. 13 Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
  1. Correspondence to Mr Richard L Morrow, Department of Anethesiology, Pharmacology and Therapeutics, The University of British Columbia, Vancouver, BC V6T 1Z3, Canada; richard.morrow{at}


Objective To evaluate the association between regulatory drug safety advisories and changes in drug utilisation.

Design We conducted controlled, interrupted times series analyses with administrative prescription claims data to estimate changes in drug utilisation following advisories. We used random-effects meta-analysis with inverse-variance weighting to estimate the average postadvisory change in drug utilisation across advisories.

Study population We included advisories issued in Canada, Denmark, the UK and the USA during 2009–2015, mainly concerning drugs in common use in primary care. We excluded advisories related to over-the-counter drugs, drug-drug interactions, vaccines, drugs used primarily in hospital and advisories with co-interventions within ±6 months.

Main outcome measures Change in drug utilisation, defined as actual versus predicted percentage change in the number of prescriptions (for advisories without dose-related advice), or in the number of defined daily doses (for dose-related advisories), per 100 000 population.

Results Among advisories without dose-related advice (n=20), the average change in drug utilisation was −5.83% (95% CI −10.93 to –0.73; p=0.03). Advisories with dose-related advice (n=4) were not associated with a statistically significant change in drug utilisation (−1.93%; 95% CI −17.10 to 13.23; p=0.80). In a post hoc subgroup analysis of advisories without dose-related advice, we observed no statistically significant difference between the change in drug utilisation following advisories with explicit prescribing advice, such as a recommendation to consider the risk of a drug when prescribing, and the change in drug utilisation following advisories without such advice.

Conclusions Among safety advisories issued on a wide range of drugs during 2009–2015 in 4 countries (Canada, Denmark, the UK and the USA), the association of advisories with changes in drug utilisation was variable, and the average association was modest.

  • health policy
  • health services research
  • medication safety
  • pharmacoepidemiology

Data availability statement

No data are available. We are unable to share data used for this study due to a lack of data permissions for this purpose.

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See:

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Data availability statement

No data are available. We are unable to share data used for this study due to a lack of data permissions for this purpose.

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  • Contributors CD and RLM take responsibility for the integrity of the data and the accuracy of the data analysis. RLM is the guarantor, accepts full responsibility for the finished work, had access to the data, and controlled the decision to publish. Conception and design: CD, S-AP, BM, AK-C, RL, DM, CH, MLDB, LP, ER, RLM, IS, JL, LB and PCS. Acquisition, analysis or interpretation of data: CD, S-AP, BM, AK-C, RL, DM, CH, MLDB, LP, ER, RLM, IS, JL, LB, PCS, AS, DG, RO-A and LTP. Drafting of the manuscript: RLM. Critical revision of the manuscript: CD, S-AP, BM, AK-C, RL, DM, CH, MLDB, LP, ER, RLM, IS, JL, LB, PCS, AS, DG, RO-A and LTP. Statistical analysis: CD and RLM. Obtaining funding: CD, S-AP, BM, AK, RL, DM, CH, MLDB, LP, ER, IS, JL, LB, PCS, AS and DG. Supervision: CD and BM. Final approval of version to be published: CD, S-AP, BM, AK-C, RL, DM, CH, MLDB, LP, ER, RLM, IS, JL, LB, PCS, AS, DG, RO-A and LPT. All authors agreed to be accountable to all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

  • Funding This work was funded by grants from the Canadian Institutes of Health Research (PJT-153275) and the Australian Government National Health and Medical Research Council (1122332).

  • Competing interests MLDB declares PhD grants from Novo Nordisk, Lundbeck, Ferring Pharmaceuticals and LEO Pharma to the Copenhagen Centre for Regulatory Science; CH declares grants or contracts from Novo Nordisk A/S and H. Lundbeck A/S paid to her institution; BM is acting as an expert witness for Health Canada on a legal case and anticipates future payment for doing so; S-AP declares the Centre for Big Data Research in Health received funding for postmarket surveillance research, unrelated to the current study; LP has received a Michael Smith Foundation for Health Research Reach Grant; AS declares grants or contracts from Arnold Ventures and the FDA paid to his institution, consulting fees from West Health and payment for expert testimony from the ACLU; IS has received a CIHR Canadian Network for Observational Drug Effect Studies grant and a Drug Evaluation Alliance of Nova Scotia grant, and payment for serving as a member of the Patented Medicine Prices Review Board.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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