An Empirical Approach to Explore the Relationship Between Measures of Disproportionate Reporting and Relative Risks from Analytical Studies.
BACKGROUND
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.
AEMPS (Spanish Agency for Medicines and Medical Devices), Campezo, 1 Ed-8, 28221, Madrid, Spain. mmacia@aemps.es.
Miguel-Angel
MA
Maciá-Martínez
Pharmacology Unit, Department of Biomedical Sciences, School of Medicine, University of Alcalá, Madrid, Spain.|Clinical Pharmacology Unit, University Hospital Príncipe de Asturias, Madrid, Spain.
Francisco J
FJ
de Abajo
Global Clinical Safety and Pharmacovigilance, GlaxoSmithKline, Middlesex, UK.
Gilly
G
Roberts
European Medicines Agency, 30 Churchill Place, Canary Wharf, London, E14 5EU, UK.
Jim
J
Slattery
Roche, Basel, Switzerland.
Bharat
B
Thakrar
Global Regulatory Affairs, Patient Safety, AstraZeneca, Mill Court, Silk Road Business Park, Macclesfield, Cheshire, SK10 2NA, UK.
Antoni F Z
AF
Wisniewski
D016907:Adverse Drug Reaction Reporting Systems / Q000706:statistics & numerical data*; D016208:Databases, Factual / Q000706:statistics & numerical data*; D064420:Drug-Related Side Effects and Adverse Reactions / Q000453:epidemiology*; D005260:Female; D006801:Humans; D008297:Male; D060735:Pharmacovigilance; D012044:Regression Analysis; D012306:Risk; D013030:Spain