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Current Drug Safety


ISSN (Print): 1574-8863
ISSN (Online): 2212-3911

The Role of Disproportionality Analysis of Pharmacovigilance Databases in Safety Regulatory Actions: a Systematic Review

Author(s): Patrícia Dias, Ana Penedones, Carlos Alves, Carlos F. Ribeiro and Francisco B. Marques

Volume 10, Issue 3, 2015

Page: [234 - 250] Pages: 17

DOI: 10.2174/1574886310666150729112903

Price: $65


Introduction: Disproportionality analysis (DA) of adverse drug reactions spontaneous reporting (SR) databases is used to identify signals of disproportionate reporting (SDR). The objective of this study was to identify the generation of SDR in the published literature and whether it led to regulatory action.

Methods: A systematic literature search in MEDLINE and Cochrane Central Register for Controlled Trials (CENTRAL) in a 10-year period, from 2005 to 2014, was conducted, to identify studies designed to detect drug safety signals through the use of disproportionality measures applied to spontaneous reporting databases of adverse drug reactions.

Results: Seventy three studies were included. The number of publications has been rising over the study time period. Forty nine studies focus on drug-event combinations. Large international and smaller national or regional databases were identified. The disproportionality measures applied included frequentist and Bayesian methods and some studies used more than one method. SDRs were identified in more than ninety percent of the studies. Ten studies were found to be confirmatory of previous regulatory decision.

Conclusion: It was not found any safety signal issued by drug regulatory agencies exclusively generated by DA. More research devoted to this issue is needed, since the value of these methods on drug safety signaling and their impact on drug regulation actions remains to be established.

Keywords: Adverse drug reactions, disproportionality analysis, safety signal generation, spontaneous reports, systematic review, regulatory actions.

Hammad TA, Pinheiro SP, Neyarapally GA. Secondary use of randomized controlled trials to evaluate drug safety: a review of methodological considerations. Clin Trials 2011; 8(5): 559-70.
Alves C, Macedo AF, Marques FB. Sources of information used by regulatory agencies on the generation of drug safety alerts. Eur J Clin Pharmacol 2013; 69(12): 2083-94.
Hauben M, Aronson JK. Defining “signal”and its subtypes in pharmacovigilance based on a systematic review of previous definitions. Drug Saf 2009; 32(2): 99-110.
CIOMS Working Group VIII. Practical Aspects of Signal Detection in Pharmacovigilance Geneva; 2010 Available from: http: // [cited: 06th April 2015].
Bate A, Evans SJW. Quantitative signal detection using spontaneous ADR reporting. Pharmacoepidemiol Drug Saf 2009; 18(6): 427-36.
Madigan D, Ryan P, Simpson S, Zorych I. Bayesian Methods in Pharmacovigilance. In: Bernardo JM, Bayarri M, Berger J, Dawid A, D.H. Smith, Eds. Bayesian Statistics 9. Oxford: Oxford University Press 2010.
Hauben M, Reich L. Communication of findings in pharmacovigilance: use of the term “signal” and the need for precision in its use. Eur J Clin Pharmacol 2005; 61(5-6): 479-80.
Moher D, Liberati A, Tetzlaff J, Altman DG. for the PRISMA Group. Preferred reporting items for systematic reviews and metaanalyses: The PRISMA statement. PLoS Med 2009; 151(4): 264-9. W64
Khadem TM, Manen RPvan, Brown J. How safe are recently FDA-approved antimicrobials? A review of the FDA Adverse Event Reporting System Database. Pharmacotherapy 2014; 34(12): 1324-9.
Gahr M, Zeiss R, Lang D, et al. Risk of bleeding related to selective and non-selective serotonergic antidepressants : a case / non-case approach using data from two pharmacovigilance databases. Pharmacopsychiatry 2015; 48: 19-24.
Mcdonald CJ, Kalisch LM, Barratt JD, Caughey GE. A cross-country comparison of rivaroxaban spontaneous adverse event reports and concomitant medicine use with the potential to increase the risk of harm. Drug Saf 2014; 37: 1029-35.
Haber P, Moro PL, Mcneil MM, et al. Post-licensure surveillance of trivalent live attenuated influenza vaccine in adults, United States, vaccine adverse event reporting system (VAERS), July 2005 – June 2013. Vaccine 2014; 32(48): 6499-504.
Biagi C, Conti V, Montanaro N, Melis M, Buccellato E. Comparative safety profiles of intravitreal bevacizumab, ranibizumab and pegaptanib : the analysis of the WHO database of adverse drug reactions. Eur J Clin Pharmacol 2014; 70: 1505-12.
Raschi E, Poluzzi E, Koci A, Caraceni P, Ponti FD. Assessing liver injury associated with antimycotics : Concise literature review and clues from data mining of the FAERS database. World J Hepatol 2014; 6(8): 601-12.
Napoli AA, Wood JJ, Coumbis JJ, Soitkar AM, Seekins DW, Tilson HH. No evident association between efavirenz use and suicidality was identified from a disproportionality analysis using the FAERS database. J Int AIDS Soc 2014; 17: 1-4.
Moulis G, Sommet A, Lapeyre-Mestre M, Montastruc J-L. for the Association Française des Centres Régionaux de PharmacoVigilance. Is the risk of tumour necrosis factor inhibitor-induced lupus or lupus-like syndrome the same with monoclonal antibodies and soluble receptor? A case/non-case study in a nationwide pharmacovigilance database. Rheumatology (Oxford) 2014; 53(10): 1864-71.
Viola E, Opri S, Moretti U, et al. α 1 -Adrenergic receptor antagonists and gynecomastia. A case series from the Italian spontaneous reporting system and VigiBaseTM. Eur J Clin Pharmacol 2014; 70: 1003-9.
Takada M, Fujimoto M, Yamazaki K, Takamoto M, Hosomi K. Association of statin use with sleep disturbances: Data mining of a spontaneous reporting database and a prescription database. Drug Saf 2014; 37: 421-31.
Béné J, Moulis G, Auffret M, et al. Alopecia induced by tumour necrosis factor-alpha antagonists: Description of 52 cases and disproportionality analysis in a nationwide pharmacovigilance database. Rheumatol (United Kingdom) 2014; 53(8): 1465-9.
Mendes D, Alves C, Batel-Marques F. Safety profiles of adalimumab, etanercept and infliximab: A pharmacovigilance study using a measure of disproportionality in a database of spontaneously reported adverse events. J Clin Pharm Ther 2014; 39(3): 307-13.
Fujimoto M, Hosomi K, Takada M. Statin-associated lower urinary tract symptoms: data mining of the public version of the FDA adverse event reporting system, FAERS. Int J Clin Pharmacol Ther 2014; 52(4): 259-66.
Ali AK. Peripheral neuropathy and Guillain-Barré syndrome risks associated with exposure to systemic fluoroquinolones: A pharmacovigilance analysis. Ann Epidemiol 2014; 24(4): 279-85.
Ali AK. Pharmacovigilance analysis of serious averse events reported for biologic response modifiers used as prophylaxis against transplant rejection: a real-world postmarketing experience from the US FDA adverse event reporting system (FAERS). Int J Organ Transplant Med 2013; 4(2): 62-71.
Brinker AD, Lyndly J, Tonning J, Moeny D, Levine JG, Avigan MI. Profiling cumulative proportional reporting ratios of drug-induced liver injury in the FDA Adverse Event Reporting System (FAERS) database. Drug Saf 2013; 36(12): 1169-78.
Raisch D, Garg V, Arabyat R. Anaphylaxis associated with gadolinium-based contrast agents: data from the Food and Drug Administration’s adverse event reporting system and review of case. Exp Opin Drug Saf 2014; 13(1): 15-23.
Moro PL, Harrington T, Shimabukuro T, et al. Adverse events after Fluzone ® Intradermal vaccine reported to the Vaccine Adverse Event Reporting System (VAERS), 2011-2013. Vaccine 2013; 31(43): 4984-7.
Roberto G, Piccinni C, D’Alessandro R, Poluzzi E. Triptans and serious adverse vascular events: data mining of the FDA Adverse Event Reporting System database. Cephalalgia 2014; 34(1): 5-13.
Hauben M, Hung EY. Pneumothorax as an adverse drug event: an exploratory aggregate analysis of the US FDA AERS database including a confounding by indication analysis inspired by Cornfield’s condition. Int J Med Sci 2013; 10(8): 965-73.
Yoshimura K, Kadoyama K, Sakaeda T, Sugino Y, Ogawa O, Okuno Y. A survey of the FAERS database concerning the adverse event profiles of α1-adrenoreceptor blockers for lower urinary tract symptoms. Int J Med Sci 2013; 10(7): 864-9.
Pugi A, Bonaiuti R, Maggini V, et al. Safety profile of antiviral medications: a pharmacovigilance study using the Italian spontaneous-reporting database. Am J Health Syst Pharm 2013; 70(12): 1039-46.
Buccellato E, Biagi C, Vaccheri A, Melis M, Montanaro N, Motola D. Possible occurrence of paraesthesia in patients taking norethisterone: an analysis on the WHO Global Individual Case Reports database (VigiBase). Expert Opin Drug Saf 2013; 12(5): 615-9.
Hauben M, Hung EY. A quantitative analysis of the spontaneous reporting of congestive heart failure-related adverse events with systemic anti-fungal drugs. J Clin Pharmacol 2013; 53(7): 762-72.
Martin D, Menschik D, Bryant-Genevier M, Ball R. Data mining for prospective early detection of safety signals in the Vaccine Adverse Event Reporting System (VAERS): a case study of febrile seizures after a 2010-2011 seasonal influenza virus vaccine. Drug Saf 2013; 36(7): 547-56.
Hoog SL, Cheng Y, Elpers J, Dowsett SA. Duloxetine and pregnancy outcomes: safety surveillance findings. Int J Med Sci 2013; 10(4): 413-9.
Okon E, Engell C, van Manen R, Brown J. Tigecycline-related pancreatitis: a review of spontaneous adverse event reports. Pharmacotherapy 2013; 33(1): 63-8.
Ali A and , Hartzema AG. Assessing the association between omalizumab and arteriothrombotic events through spontaneous adverse event reporting. J Asthma Allergy 2012; 5: 1-9.
Motola D, Biagi C, Leone R, et al. Ticlopidine safety profile: a case/non-case study on the basis of the spontaneous ADRs reporting in Italy. Curr Drug Saf 2012; 7(2): 99-105.
Schmedt N, Andersohn F, Garbe E. Signals of progressive multifocal leukoencephalopathy for immunosuppressants: a disproportionality analysis of spontaneous reports within the US Adverse Event Reporting System (AERS). Pharmacoepidemiol Drug Saf 2012; 21(11): 1216-20.
Tamura T, Sakaeda T, Kadoyama K, Okuno Y. Omeprazole- and esomeprazole-associated hypomagnesaemia: data mining of the public version of the FDA Adverse Event Reporting System. Int J Med Sci 2012; 9(5): 322-6.
Kadoyama K, Sakaeda T, Tamon A, Okuno Y. Adverse event profile of tigecycline: data mining of the public version of the U.S. Food and Drug Administration adverse event reporting system. Biol Pharm Bull 2012; 35(6): 967-70.
Shamloo BK, Chhabra P, Freedman AN, Potosky A, Malin J, Weiss Smith S. Novel adverse events of bevacizumab in the US FDA adverse event reporting system database: a disproportionality analysis. Drug Saf 2012; 35(6): 507-18.
Moro PL, Arana J, Cano M, et al. Postlicensure safety surveillance for high-dose trivalent inactivated influenza vaccine in the Vaccine Adverse Event Reporting System, 1 July 2010-31 December 2010. Clin Infect Dis 2012; 54(11): 1608-14.
Caillet C, Chauvelot-Moachon L, Montastruc J-L, Bagheri H. Safety profile of enantiomers vs racemic mixtures: it’s the same? Br J Clin Pharmacol 2012; 74(5): 886-9.
Motóla D, Piccinni C, Biagi C, et al. Cardiovascular, Ocular and Bone Adverse Reactions Associated with Thiazolidinediones. A disproportionality Analysis of the US FDA Adverse Event Reporting System Database. Drug Saf 2012; 35(4): 315-23.
Leroy Z, Broder K, Menschik D, Shimabukuro T, Martin D. Febrile seizures after 2010-2011 influenza vaccine in young children, United States: a vaccine safety signal from the vaccine adverse event reporting system. Vaccine 2012; 30(11): 2020-3.
Kadoyama K, Miki I, Tamura T, Brown JB, Sakaeda T, Okuno Y. Adverse event profiles of 5-fluorouracil and capecitabine: data mining of the public version of the FDA Adverse Event Reporting System, AERS, and reproducibility of clinical observations. Int J Med Sci 2012; 9(1): 33-9.
Sakaeda T, Kadoyama K, Okuno Y. Statin-associated muscular and renal adverse events: data mining of the public version of the FDA adverse event reporting system. PLoS One 2011; 6(12)e28124
Kadoyama K, Kuwahara A, Yamamori M, Brown JB, Sakaeda T, Okuno Y. Hypersensitivity reactions to anticancer agents: data mining of the public version of the FDA adverse event reporting system, AERS. J Exp Clin Cancer Res 2011; 30(1): 93.
Brown J, Aitken SL, van Manen RP. Potential for linezolid-related blindness: a review of spontaneous adverse event reports. Pharmacotherapy 2011; 31(6): 585-90.
Tuccori M, Lapi F, Testi A, Ruggiero E. Drug-Induced Taste and Smell Alterations. Drug Saf 2011; 34(10): 849-59.
Sakaeda T, Kadoyama K, Yabuuchi H, et al. Platinum agent-induced hypersensitivity reactions: data mining of the public version of the FDA adverse event reporting system, AERS. Int J Med Sci 2011; 8(4): 332-8.
Ben-Hamou M, Marshall NS, Grunstein RR, Saini B, Fois RA. Spontaneous adverse event reports associated with zolpidem in Australia 2001-2008. J Sleep Res 2011; 20(4): 559-68.
Willemen MJ, Mantel-Teeuwisse AK, Straus SM, Meyboom RH, Egberts TC, Leufkens HG. Use of dipeptidyl peptidase-4 inhibitors and the reporting of infections: a disproportionality analysis in the World Health Organization VigiBase. Diabetes Care 2011; 34(2): 369-74.
Muhammad RD, Haber P, Broder KR, et al. Adverse Events Following Trivalent Inactivated Influenza Vaccination in Children: Analysis of the Vaccine Adverse Event Reporting System. Pediatr Infect Dis J 2010; 30(1): 1-8.
Ferrajolo C, Capuano A, Verhamme KMC, et al. Drug-induced hepatic injury in children: a case/non-case study of suspected adverse drug reactions in VigiBase. Br J Clin Pharmacol 2010; 70(5): 721-8.
Giezen T, Mantel-Teeuwisse A. Mapping the Safety Profile of Biologicals. Drug Saf 2010; 33(10): 865-78.
Schwan S, Sundström A, Stjernberg E, Hallberg E, Hallberg P. A signal for an abuse liability for pregabalin--results from the Swedish spontaneous adverse drug reaction reporting system. Eur J Clin Pharmacol 2010; 66(9): 947-53.
Mannesse C, van Pijenbroek E, Jansen P, van Marum R, Souverein P, Egberts T. Hyponatraemia as an Adverse Drug Reaction of Antipsychotic Drugs. A Case-Control Study in VigiBase. Drug Saf 2010; 33(7): 569-78.
Rivkees SA, Szarfman A. Dissimilar hepatotoxicity profiles of propylthiouracil and methimazole in children. J Clin Endocrinol Metab 2010; 95(7): 3260-7.
Poluzzi E, Raschi E, Motola D, Moretti U, De Ponti F. Antimicrobials and the risk of torsades de pointes: the contribution from data mining of the US FDA Adverse Event Reporting System. Drug Saf 2010; 33(4): 303-14.
Strandell J, Bate A, Hägg S, Edwards IR. Rhabdomyolysis a result of azithromycin and statins: an unrecognized interaction. Br J Clin Pharmacol 2009; 68(3): 427-34.
Slade BA, Leidel L, Vellozzi C, et al. Postlicensure safety surveillance for quadrivalent human papillomavirus recombinant vaccine. JAMA 2009; 302(7): 750-7.
Do C, Huyghe E, Lapeyre-Mestre M, Montastruc J-L, Bagheri H. Statins and Erectile Dysfunction: Results of a Case/Non-Case Study Using the French Pharmacovigilance System Database. Drug Saf 2009; 32(7): 591-7.
Poluzzi E, Raschi E, Biolsc UM, Ponti F De. Drug‐induced torsades de pointes: data mining of the public version of the FDA Adverse Event Reporting System (AERS). Pharmacoepidemiol Drug Saf 2009; 18(l): 512-8.
Yang X, Brandenburg N. Venous Thromboembolism in Myelodysplastic Syndrome Patients Receiving Lenalidomide. Clin Drug Investig 2009; 29(3): 161-71.
Baker RA, Pikalov A, Tran Q-V, Kremenets T, Arani RB, Doraiswamy PM. Atypical antipsychotic drugs and diabetes mellitus in the US Food and Drug Administration Adverse Event database: a systematic Bayesian signal detection analysis. Psychopharmacol Bull 2008; 42(1): 11-31.
Andersohn F, Garbe E. Cardiac and noncardiac fibrotic reactions caused by ergot-and nonergot-derived dopamine agonists. Mov Disord 2009; 24(1): 129-33.
Chen Y, Guo JJ, Healy DP, Lin X, Patel NC. Risk of hepatotoxicity associated with the use of telithromycin: a signal detection using data mining algorithms. Ann Pharmacother 2008; 42(12): 1791-6.
Tuccori M, Moretti U, Lapi F. Statin-associated psychiatric adverse events: A case/non case evaluation of an Italian database of spontaneous reporting of adverse drug reactions. Drug Saf 2007; 31(12): 1115-24.
Knudsen JF, Sokol GH, Flowers CM. Adjunctive topiramate enhances the risk of hypothermia associated with valproic acid therapy. J Clin Pharm Ther 2008; 33(5): 513-9.
Salvo F, Polimeni G, Cutroneo PM, et al. Allergic reactions to oral drugs: A case/non-case study from an Italian spontaneous reporting database (GIF). Pharmacol Res 2008; 58(3-4): 202-7.
Hagg S, Bate A, Stahl M, Spigset O. Associations Between Venous Thromboembolism and Antipsychotics. A Study of the WHO Database of Adverse Drug Reactions. Drug Saf 2008; 31(8): 685-94.
Hauben M, Vegni F, Reich L, Younus M. Postmarketing hepatic adverse event experience with PEGylated/non-PEGylated drugs: a disproportionality analysis. Eur J Gastroenterol Hepatol 2007; 19(11): 934-41.
Carvajal A, Macias D, Gutiérrez A, et al. Gynaecomastia associated with proton pump inhibitors: a case series from the Spanish Pharmacovigilance System. Drug Saf 2007; 30(6): 527-31.
Salvo F, Polimeni G, Moretti U, et al. Adverse drug reactions related to amoxicillin alone and in association with clavulanic acid: data from spontaneous reporting in Italy. J Antimicrob Chemother 2007; 60(1): 121-6.
Hauben M, Horn S, Reich L, Younus M. Association between gastric acid suppressants and Clostridium difficile colitis and community-acquired pneumonia: analysis using pharmacovigilance tools. Int J Infect Dis 2007; 11(5): 417-22.
Motola D, Vargiu A, Leone R, et al. Hepatic adverse drug reactions: a case/non-case study in Italy. Eur J Clin Pharmacol 2007; 63(1): 73-9.
Szarfman A, Tonning JM, Levine JG, Doraiswamy PM. Atypical antipsychotics and pituitary tumors: a pharmacovigilance study. Pharmacotherapy 2006; 26(6): 748-58.
Polimeni G, Salvo F, Cutroneo P, Morreale I, Caputi A. Adverse reactions induced by NSAIDs and antibacterials. Drug Saf 2006; 29(5): 449-59.
Hauben M, Reich L, Gerrits C. Reports of hyperkalemia after publication of RALES—a pharmacovigilance study. Pharmacoepidemiol Drug Saf 2006; 15(11): 775-83.
Leone R, Conforti A, Venegoni M, et al. Drug-Induced Anaphylaxis Case / Non-Case Study Based on an Italian. Drug Saf 2005; 28(6): 547-56.
Xolair. Procedural steps taken and scientific information after the authorisation. Available from http: // GB/document_library/EPAR_-_Procedural_steps_taken_and_scie ntific_information_after_authorisation/human/000606/WC500057297.pdf [cited: 06th April 2015]
FDA Drug Safety Communication: FDA approves label changes for asthma drug Xolair (omalizumab), including describing slightly higher risk of heart and brain adverse events. Available from. http: // [cited: 06th April 2015].
Lyrica Procedural steps taken and scientific information after the authorisation. Available from http: // GB/document_library/EPAR_-_Procedural_steps_taken_and_scien tific_information_after_authorisation/human/000546/WC500046604.pdf [cited: 06th April 2015].
Guideline on good pharmacovigilance practices (GVP). Module IX - Signal management. European Medicines Agency, 2012. Available from http: // ry/Scientific_guideline/2012/02/WC500123209.pdf [cited: 06th April 2015].
Montrastruc JL, Sommet A, Bagheri H, Lapeyre-Mestre M. Benefits and strengths of the disproportionality analysis for the identification of adverse drug reactions in a pharmacovigilance database. Br J Clin Pharmacol 2011; 72(6): 905-8.

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