pharmacoepidemiology and drug safety 2005; 14: 285–286Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/pds.1058

LETTER TO THE EDITOR

The history of disproportionality measures (reporting oddsratio, proportional reporting rates) in spontaneous reporting ofadverse drug reactions

Nicholas Moore MD, PhD, FRCPE, FISPE*, Frantz Thiessard MD and Bernard Begaud MD,PhD

Department of Pharmacology, Universite Victor Segalen, Bordeaux, France

Dear Sir

The recent discussion in PDS about the proper modelfor the analysis of disproportionality in spontaneousreporting databases is fascinating. Rothman et al.1

give a very convincing argument for the fundamen-tally case-control-like nature of the analysis, ratherthan the cohort concept defended by Waller et al.2

Though both rest upon fundamentally different theo-retical approaches, the final difference may be moreconceptual than practical.3

However, a wrong impression may have been given,that the use of reporting odds ratios and proportionalreporting rate ratios in databases of spontaneousreporting of adverse drug reactions is very recent.Reporting odds ratios were not invented in 2004 oreven 2001 and we thought it could be helpful to retraceearlier uses and previous discussions, for those who areinterested in the history of science.

Though Finney mentions it on a theoretical basis in19744 and the use of proportional mortality rates incancer for instance is even older, the first published useof disproportionality of reporting in drug safety, as faras we are aware, was by Bruno Stricker.5 Ed Napke inCanada earlier used a form of manual disproportion-ality measure using pigeonholes.6 Bengt-Eric Wiholmused a computerized disproportionality method in theSwedish regulatory agency in the eighties, but this wasnever published. Another paper that may be of interestis one by Pascale Tubert et al.,7 which though not

strictly about disproportionality is close enough, ifonly because its conclusion is quite close to that ofPuijenboek et al.3 Disproportionality was also used(using reporting odds ratio) in 1993 with cough to ACEinhibitors in the Lancet, but the OR part was deletedfrom the final paper,8 and again in 1997 withhypoglycaemia to angiotensin converting enzymeinhibitors.9 This paper also explored some confound-ing by indication, and reviewed the issues associatedwith measures of disproportionaity of spontaneousreports. The term case-not-case was thought to be amore effective representation than case-control: thecontrols are not really controls since they are allexposed to at least one drug, and have at least oneevent—there are no untreated ‘healthy’ controls. Theyare simply not cases of the event of interest: they arecases of something else. That concept was first putforward by Bernard Begaud in 1983 at a meeting of theFrench Pharmacovigilance System concerning possi-ble hepatotoxicity of benzodiazepines, but was neverpublished either.

Since then, many papers and groups have describedmore or less complex approaches to disproportionality,ranging from the U.S. Food and Drug AdministrationGamma Poisson Shrinker,10 to the U.K. Medicines andHealthcare Products Regulatory Agency (the Agencyformerly known as MCA) PRR,11 the World HealthOrganization Drug Monitoring Centre in Uppsalabayesian neural network,12 among other methods.3

Because these large spontaneous reports databasesare now easily available, and the computing of theseindices is relatively easy, there may be a strongtemptation to use them without restraint. Howeverone should never forget that these odds are those of the

Received 25 September 2004Revised 11 November 2004

Copyright # 2005 John Wiley & Sons, Ltd. Accepted 15 November 2004

*Correspondence to: Dr N. Moore, Department of Pharmacology,INSERM U657, Universite Victor Segalen, 33076 Bordeaux, France.E-mail: nicholas.moore@pharmaco.u-bordeaux2.fr

drug-event pair being reported, which may or may nothave to do with anything actually happening (concern-ing both the event and the drug it is attributed to).13 Acareful analysis of biases, and especially notoriety biasshould precede any use of disproportionality bywhatever method. Used with caution, these measuresof disproportionality may be useful to generatehypotheses concerning new drug safety alerts.

REFERENCES

1. Rothman KJ, Lanes S, Sacks ST. The reporting odds ratio andits advantages over the proportional reporting ratio. Pharma-coepidemiol Drug Safe 2004; 13: 519–523.

2. Waller P, Van Puijenbroek E, Egberts A, Evans S. The report-ing odds ratio versus the proportional reporting ratio: ‘deuce’.Pharmacoepidemiol Drug Safe 2004; 13: 525–526.

3. van Puijenbroek EP, Bate A, Leufkens HG, Lindquist M, OrreR, Egberts AC. A comparison of measures of disproportional-ity for signal detection in spontaneous reporting systems foradverse drug reactions. Pharmacoepidemiol Drug Safe 2002;11: 3–10.

4. Finney DJ. Systemic signalling of adverse reactions to drugs.Methods Inf Med 1974; 13: 1–10.

5. Stricker BH, Tijssen JG. Serum sickness-like reactions to cefa-clor. J Clin Epidemiol 1992; 45: 1177–1184.

6. Napke E. The Canadian drug adverse reaction reporting pro-gram. Drug Inf J 1975; 9: 224–232.

7. Tubert P, Begaud B, Haramburu F, Pere JC. Spontaneousreporting: how many cases are required to trigger a warning?Br J Clin Pharmacol 1991; 32: 407–408.

8. Moore N, Noblet C, Joannides R, Ollagnier M, Imbs JL,Lagier G. Cough and ACE inhibitors. Lancet 1993; 341: 61.

9. Moore N, Kreft-Jais C, Haramburu F, Noblet C, Andrejak M,Ollagnier M, et al. Reports of hypoglycaemia associated withthe use of ACE inhibitors and other drugs: a case/non-casestudy in the French pharmacovigilance system database. Br JClin Pharmacol 1997; 44: 513–518.

10. Szarfman A, Machado SG, O’Neill RT. Use of screeningalgorithms and computer systems to efficiently signal higher-than-expected combinations of drugs and events in the US FDA’sspontaneous reports database. Drug Saf 2002; 25: 381–392.

11. Evans SJ, Waller PC, Davis S. Use of proportional reportingratios (PRRs) for signal generation from spontaneous adversedrug reaction reports. Pharmacoepidemiol Drug Safe 2001;10: 483–486.

12. Bate A, Lindquist M, Edwards IR, Olsson S, Orre R, LansnerA, et al. A Bayesian neural network method for adverse drugreaction signal generation. Eur J Clin Pharmacol 1998; 54:315–321.

13. Moore N, Hall G, Sturkenboom M, Mann R, Lagnaoui R,Begaud B. Biases affecting the proportional reporting ratio(PPR) in spontaneous reports pharmacovigilance databases:the example of sertindole. Pharmacoepidemiol Drug Safe2003; 12: 271–281.

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Copyright # 2005 John Wiley & Sons, Ltd. Pharmacoepidemiology and Drug Safety, 2005; 14: 285–286