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An Empirical Approach to Explore the Relationship Between Measures of Disproportionate Reporting and Relative Risks from Analytical Studies

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Abstract

Introduction

Although it seems reasonable to suppose that a drug that increases the risk of an adverse event might tend to show increased disproportionality statistics in spontaneous reporting databases, that relationship is not clear. Therefore, an empirical approach was taken to investigate the relationship between proportional reporting ratios (PRRs) and relative risk (RR) estimates from formal studies in a set of known adverse drug reactions (ADRs).

Methods

Drug-event pairs that were the subject of pharmacovigilance-driven European regulatory actions from 2007 to 2010 were selected. Only pairs having RR derived from formal studies and where it was considered that there was well-established evidence supporting the actions were included. A best estimate of the RR for each ADR was chosen based on pre-specified rules. PRRs were then calculated in Eudravigilance using only those cases reported before the date of first recognition of the ADR in the medical community. An additional analysis was carried out in FEDRA, the Spanish spontaneous reports database. A descriptive analysis and an orthogonal regression model were performed.

Results

From an initial dataset of 78 drug-event pairs, 15 were selected. The regression model (ln RR = 0.203 + 0.463 × ln PRR) showed a significant (p < 0.001) correlation between RR and PRR in Eudravigilance. None of the ADR-related variables analysed modified the relationship. Exploratory results in FEDRA went in the same direction.

Conclusions

Disproportionality measures should not replace formal studies but could provide an initial indication of the likely clinical importance of an ADR, should the signal be confirmed subsequently. Whether the same conclusions can be applied to other datasets should be further studied.

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Notes

  1. In 2012, this became the Pharmacovigilance Risk Assessment Committee.

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Acknowledgments

The views expressed in this paper are those of the authors only and do not reflect the official policy or position of the IMI JU (Innovative Medicines Initiative Joint Undertaking), the European Union, AEMPS (Spanish Agency for Medicines and Medical Devices), or the European Federation of Pharmaceutical Industries and Associations.

The authors would like to thank Pilar Vicente, previously a trainee at the AEMPS, for contributions to the early phases of this project.

Author information

Authors and Affiliations

  1. AEMPS (Spanish Agency for Medicines and Medical Devices), Campezo, 1 Ed-8, 28221, Madrid, Spain

    Miguel-Angel Maciá-Martínez

  2. Pharmacology Unit, Department of Biomedical Sciences, School of Medicine, University of Alcalá, Madrid, Spain

    Francisco J. de Abajo

  3. Clinical Pharmacology Unit, University Hospital Príncipe de Asturias, Madrid, Spain

    Francisco J. de Abajo

  4. Global Clinical Safety and Pharmacovigilance, GlaxoSmithKline, Middlesex, UK

    Gilly Roberts

  5. European Medicines Agency, 30 Churchill Place, Canary Wharf, London, E14 5EU, UK

    Jim Slattery

  6. Roche, Basel, Switzerland

    Bharat Thakrar

  7. Global Regulatory Affairs, Patient Safety, AstraZeneca, Mill Court, Silk Road Business Park, Macclesfield, Cheshire, SK10 2NA, UK

    Antoni F. Z. Wisniewski

Authors
  1. Miguel-Angel Maciá-Martínez
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  2. Francisco J. de Abajo
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  6. Antoni F. Z. Wisniewski
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Corresponding author

Correspondence to Miguel-Angel Maciá-Martínez.

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Funding

The research leading to these results was conducted as part of the PROTECT consortium (Pharmacoepidemiological Research on Outcomes of Therapeutics by a European ConsorTium, http://www.imiprotect.eu), which is a public-private partnership coordinated by the European Medicines Agency. The PROTECT project has received support from the Innovative Medicine Initiative Joint Undertaking (http://www.imi.europa.eu) under Grant Agreement No. 115004, resources of which are composed of financial contribution from the European Union’s Seventh Framework Program (FP7/2007–2013) and companies of the European Federation of Pharmaceutical Industries and Associations in-kind contribution.

Conflicts of interest

Miguel-Angel Maciá-Martínez, Francisco J. de Abajo and Jim Slattery have no conflicts of interest that are directly relevant to the content of this study. Gilly Roberts is an employee of GlaxoSmithKline and has shareholdings in GlaxoSmithKline and Astra Zeneca. Bharat Thakrar is an employee of Roche. Antoni F. Z. Wisniewski is a full-time employee of Astra Zeneca. Products from these companies were among those used to test the methodologies in this research.

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Maciá-Martínez, MA., de Abajo, F.J., Roberts, G. et al. An Empirical Approach to Explore the Relationship Between Measures of Disproportionate Reporting and Relative Risks from Analytical Studies. Drug Saf 39, 29–43 (2016). https://doi.org/10.1007/s40264-015-0351-3

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