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Improving pharmacovigilance and the role of the pharmacistGrootheest, Adrianus Cornelis van

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3The role of thepharmacist

Abstract

IntroductionThe participation of the pharmacist in national spontaneous reporting systems foradverse drug reactions (ADRs) has not always been a matter of course. Even today,there are a number of countries, in particular the Scandinavian countries, wherepharmacists are not authorised to report ADRs. In those countries in which they areallowed to report they do not always use this opportunity.

MethodsWe have conducted a review of the literature to investigate the involvement ofpharmacists in ADR reporting. In addition, we evaluated the pharmacists’ actualcontributions in 2001 by means of an international questionnaire-based surveyamong those countries participating in the WHO Drug Monitoring Programme inSeptember 2002. Apart from the numbers of pharmacists’ reports, respondents wereasked to indicate their assessment of both the quality and the significance of thecontribution. Of the 68 participating countries 41 responded by returning thequestionnaire.

Results and conclusionsThe appreciation of pharmacists’ ADR reports is high in those countries that hadmore experience with greater numbers of pharmacists' reports. The countries thatreceived fewer reports from pharmacists gave lower scores to their contribution. Ifthe specific contribution pharmacists can make to the quantity and quality of ADRreports were to be exploited to a greater extent, this could lead to a substantialimprovement of the international adverse drug reactions reporting system.

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3.1.1 IntroductionPharmacists play an important role in the field of medicinal drugs including in thescientific field dealing with the safety of drugs - pharmacovigilance. This seems amatter of course. Whereas for doctors pharmacotherapy and the knowledge ofdrugs form only a minor component of their training, the study of pharmacyfocuses almost exclusively on drugs. With respect to pharmacovigilance, bothsound clinical judgement of the adverse drug reaction (ADR) and insight into theeffects of the drug are required to allow a conclusion to be drawn as to therelationship between the adverse event and the drug involved. Currently the role of the pharmacist in the reporting of adverse drug reactions isnot appreciated everywhere. In the Scandinavian countries, for instance,pharmacists are not authorised to report ADRs.(1,2) and in the United Kingdomthey have only recently been allowed to report independently.(3) By contrast, in theNetherlands 40% of the reports on ADRs are submitted by pharmacists and,moreover, their role in the maintenance of pharmacovigilance is substantial.(4)

A retrospective analysis of the pharmacist’s role in ADR reporting The initiative of an international reporting system for adverse drug reactions camein the wake of the thalidomide tragedy in the early 1960s. Although the Food andDrug Administration in the United States had been established some yearspreviously, this disaster was the catalyst for the initiation of systematic collection ofdata on ADRs primarily through the Hospital Reporting Program. In 1968 tencountries operating a national reporting system decided to collaborate under theauspices of the World Health Organization (WHO) and initiated the WHO PilotResearch Project for International Drug Monitoring.(5) In 1971 a resolution of theTwentieth World Health Assembly laid the foundation for the WHO Programmefor International Drug Monitoring.(6) In 1972 a report was published that wouldgive rise to the current international monitoring system of national centrescollaborating in the WHO Programme.(7,8) In 1973 a resolution by the WorldHealth Assembly supporting the report underlined the importance of exchange ofinformation on adverse drug reactions.(9) In the report, whose content is mainlystill relevant today, no mention is made of the pharmacist as a reporter of ADRs,although an Annex does refer to a study from 1965 that made use of dataoriginating from pharmacies.(10,11) In a recent WHO publication entitled TheImportance of Pharmacovigilance there is a passage that reads ‘inviting reports fromall professionals’, but the pharmacist as an independent reporter is notmentioned.(12) The Guidelines for setting up and running a PharmacovigilanceCentre, issued in 2000 by the WHO, does refer to the pharmacist.(13) Here,pharmacists are mentioned on a par with family practitioners and medicalspecialists. Pharmacists, nurses and dentists are also specifically mentioned in the

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WHO-publication Safety of Medicines. A guide to detecting and reporting adversedrug reactions.(14)

The different roles of the pharmacistThe role of the pharmacist differs between countries but common factors in allcountries are that the knowledge of drugs defines the profession and that qualitycontrol and dispensing are the key tasks since the preparation of drugs nowconstitutes only a minor part of the pharmacist’s responsibility. Increasingly, careaspects and clinical knowledge are becoming essential to the study of pharmacy.However, the contribution pharmacists can make using the model of‘pharmaceutical care’ is not always exploited to its full extent and judgements oftheir contributions in this respect are not always favourable.(15)The various roles of the pharmacist can be categorised as follows:

1. The pharmacist as a dispenser of drugs This is the pharmacist’s traditional role and characteristically defines the imageof the profession. Many practitioners view this as the role befitting thepharmacist. The pharmacist delivers the medication as prescribed by thephysician and monitors its quality. In general and if requested, the pharmacist isexpected to provide information about the drug he or she dispenses althoughthis is often not seen as an integral part of his or her duties.(16) In addition tothe pharmacist’s growing (clinical) expertise, the advanced computerisation ofpharmacies in many countries has led to the awareness that the above is toolimited a role.(17)

2. The pharmacist as a drug consultantThis is the function the hospital pharmacist fulfils in most countries, albeit thathis or her contribution in the pharmacotherapeutic care of patients may varyacross countries. The pharmacist is recognised as an expert on drugs and has aconsultative role in pharmacotherapy. They may help to draft a formulary orassist in the treatment of individual patients undergoing complicated drugtherapies. Much of the literature on pharmacists relates to this function ofhospital pharmacists. In the USA the hospital pharmacist has an explicitcoordinating role when hospitals wish to report adverse events.(18) In theNetherlands legislation is being drafted that will give the pharmacist the statusof co-consultant. Pharmacotherapeutic discussion groups (FTOs), in whichgeneral practitioners and community pharmacists participate, have helpedchange the way general practitioners view the pharmacist.(19) In these FTOs thepharmacotherapy is discussed systematically and, as a rule, decisions concerningthe pharmacotherapeutic policy to be adopted are made by mutual agreement.

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Few other countries have awarded the status of consultant to the communitypharmacist although in several countries there have been developments in thisdirection.

3. The pharmacist as a ‘substitute doctor’ In many parts of the world there is a shortage of doctors and pharmacists maybe the only providers of medical care available to people. The high costsassociated with health care may be the reason for this deficiency, but also thelarge distances to be travelled may play a role. This implies that patients willconsult the nearest pharmacy and ask for therapy they can afford, without priormedical consultation. It needs to be noted that usually pharmacists or pharmacyassistants who are acting as ‘substitute doctors’ are inadequately trained. Insome African countries, for instance, a registered nurse is qualified to set up andrun a pharmacy. Although this practice mainly occurs in low-income countries,the increasing use of over-the-counter (OTC) medication may also be relevantin this model.

It is clear that the involvement of the pharmacist in the practice of reporting ADRsis closely related to the function in society the profession is given.

What is known? There is relatively little quantitative and qualitative information available about thecontribution of pharmacists in ADR reporting. In an international review, Griffinnotes that in 1986 many countries have accepted pharmacists’ reporting ADRs asstandard practice.(20) In 1989 Fincham comments: ‘Exclusion of pharmacistssimply does not make sense’.(21) In their 1993 article on the differences betweenEuropean countries Lindquist and Edwards remark: ‘Pharmacists who advisepatients directly….are the most likely to detect adverse reactions’.(22) Roberts et al.conclude in 1994: ‘It is hoped that pharmacists in other countries will also beencouraged to participate in ADR reporting, a procedure that could only lead tobetter patient care’. The Uppsala Monitoring Centre (UMC) regularly publishes anoverview of the ways the national reporting systems in the various countries areoperated, in which the volume of pharmacist reports are also listed.(1) Theliterature on the actual contribution of pharmacists in ADR reporting often relatesto the hospital pharmacist in the USA, Canada and the UK.(22-25) The majority of publications concern the ongoing debate in the UK where, for the pastten years, the desirability of direct reporting by pharmacists has been discussed.(26,27)In the various textbooks on pharmacoepidemiology and pharmacovigilance thepharmacist receives little attention, with the exception of Inman who, as early as1986, devoted a chapter to the role of the pharmacist.(28) The authors examine their

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Panel 1Questionnaire send to 68 National Centres participating in de WHO DrugMonitoring Programme

Questionnairesent back - by email: ac.vangrootheest@lareb.nl

- by fax: + 31 73 642 61 36

You can also contact me for more information

Country :Your name :Organisation :Your email address :

1. Are pharmacists officially permitted to report to the national centre?in your country? yes / no

2. If they are permitted, are they also encourage to report yes / no

3. How many report did you receive in 2001?- total number of reports :- are these reports direct reports from health care professionals

or also reports from pharmaceutical industry?direct from health professionals / industry / both

- origin of the reports to the National Centre: - physicians :- pharmacists :- pharmaceutical industry :- patients/consumers :- other :

4. About pharmacist reports:- how many reports did you receive from hospital pharmacists? :- how many reports did you receive from dispensing or community pharmacists?:

+--------- total number of reports from pharmacist did you receive in 2001? :

5. How do you consider the quality of pharmacists reports compared with those from physicians?- specificity of clinical information: bad/ moderate/ good/ excellent- completeness of case details: bad/ moderate/ good/ excellent- completeness of medication history bad/ moderate/ good/ excellent

6. How do you consider the contribution of pharmacist’s reports to your national centre?non valuable/ moderate valuable / very valuable

7. If you don’t accept pharmacist’s reports: - Are there any plans for the future?- Why are the pharmacists reports not accepted?

8. Do you have any suggestion or comments?

contribution in relation to non-prescription drugs. They also point to the value ofthe medication history that pharmacies keep and the advantage pharmacists havethrough the use of computer technology. They conclude by stating: ‘It is to behoped that protection of professional territories will not prejudice such acontribution’.

3.1.2 An international surveyTo gain insight into the current contribution of pharmacists in ADR reporting, wehave conducted an exploratory survey among countries participating in the WHODrug Monitoring Programme. The aim of our study was to:1. investigate in which countries pharmacists are authorised to report2. determine the proportion of ADR reports submitted by pharmacists3. evaluate per country how the pharmacists’ contributions are valued

MethodsThe survey included countries participating in the WHO Drug MonitoringProgramme. The WHO Programme for International Drug Monitoring iscoordinated from Geneva by the Quality Assurance and Safety of Medicines Team,which is part of the Department of Essential Drugs and Medicines Policy. TheUppsala Monitoring Centre (UMC) has the operational responsibility for theWHO Programme and maintains the international database of the ADRs it receivesfrom the national centres.In September 2002, we sent all invited countries a questionnaire by e-mail (see Panel1) in which they were requested to list their data on the reports that had beensubmitted by pharmacists in the year 2001. After three months, the countries thathad not responded received a reminder. The questionnaire made a distinctionbetween the total number of reports each country had received and the directreports the national centres had received via the spontaneous reporting systemduring that period, which is after subtraction of the reports submitted by thepharmaceutical industry sector (marketing authorisation holders). A furtherdistinction was made between reports originating from hospital pharmacists andthose stemming from community pharmacists.In addition, the respondents were asked to indicate their assessment of the qualityof the reports. If pharmacists did not participate in the national reporting system,the countries were requested to state the reason why they were not included and toprovide any future plans in this respect.

ResultsAt the time of the survey 68 countries participated in the WHO Programme and 41completed forms were returned, two of which (i.e. from Brunei and Suriname)

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Table 1Countries included in our study, year of participation in WHO Drug Monitoring Programme,pharmacists permitted to report, total number of all reports in 2001 and percentage frompharmacists , number of reports direct from health professionals and percentage frompharmacists , total number of reports from hospital pharmacists and community pharmacists.

per- total % % country since mitted number pharm1 direct pharm1 hosp comm

1. Australia 1968 yes 11,118 30.0 8,289 40.3 2,768 5722. Belgium 1977 yes 2,161 3.7 548 14.4 ? most3. Brazil 2001 yes 175 53 4 84. Bulgaria 1975 yes 80 84 - 95. Canada 1968 yes 7,389 28.4 2,375 88.3 2,0971 -6. Chile 1996 yes 771 528 215 407. China 1998 yes 7,718 7,718 >50% few8. Croatia 1992 yes ±1,200 ±50 - 129. Czech Republic 1992 yes 721 - 2 -10. Egypt 2001 yes 210 - ? 1411. Finland 1974 no 7133 ? - -12. France 1986 yes 33,406 4.0 18,690 7.3 683 67313. Germany 1968 yes 11,124 6.0 3,257 20.6 6702 -14. Ghana 2001 yes 8 - 4 -15. Greece 1990 yes 497 297 - 2016. Hungary 1990 yes 97 61 2 -17. Ireland 1968 yes 2,282 3.4 738 10.6 29 4918. Italy 1975 yes 7,043 1.1 1,008 7.7 - 7819. Japan 1972 yes 26,545 6.0 4,094 39.0 ? ±160020. Latvia 2002 yes 29 16 - 121. Malaysia 1990 yes 813 746 >50% <2022. Morocco 1992 yes 1,100 4.3 1,036 4.5 - 4723. The Netherlands 1968 yes 4,139 29.3 3,018 40.2 16 1,19824. New Zealand 1968 yes 2,871 10.0 2,492 11.5 60 22625. Norway 1971 no 1,248 1,061 - 226. Oman 1995 yes 401 - 15 -27. Portugal 1993 yes 1,342 14.6 837 23.4 33 16328. Singapore 1992 yes 561 528 104 629. South Africa 1992 yes 1,094 2.8 591 5.3 312 -30. Spain 1984 yes 8,071 24.5 7,494 25.9 556 136631. Sweden 1968 no 3,3194 3,3194 - -32. Switzerland 1991 yes 2,361 1,277 ? <3033. Tanzania 1993 yes 38 38 ±15 -34. Thailand 1984 yes ±180 ±180 ±702 -35. Tunisia 1993 yes 780 776 2 236. United Kingdom 1968 yes 19,505 11.9 ? 1,779 53537. Uruguay 2001 yes 174 166 10 438. USA 1968 yes 281,761 ? 19,3325 18 ±18%6 -39. Zimbabwe 1998 Yes 72 5.6 71 5.6 1 31. Percentages of reports from pharmacists are only calculated if there were more as thousand

reports in total and more as hundred pharmacist’s reports in a country.2. Total number of pharmacist’s reports; no distinction could be made between hospital

pharmacists and community pharmacists.3. Number for 2000 according to Saarinen.(2)4. Including about 500 reports from nurses5. Including reports direct from patients6. For the USA the percentage of pharmacist report of those who could be identified of the total

number of reports. Kennedy et al. give higher figures for the number of direct reports.(44)

stemmed from countries that did not participate in the programme, but have astatus as observer. Eight countries were associate members meaning that they donot yet meet the criteria for full membership mainly because theirpharmacovigilance systems have only recently become operational, which mayprevent them from being able to submit their reports on a regular basis. Eight of the 41 questionnaires were returned in response to our reminder, makingthe total response of member states of the WHO Programme 57.4% (39/68). Mostof the countries that had participated in the programme for more than ten yearsreturned the questionnaire. Only in three of the 41 responding countries thepharmacist was not authorised to report, i.e. Finland, Norway and Sweden. Of the 68 countries participating in the WHO Programme for International DrugMonitoring in October 2002, a few had only recently joined the programme, as canbe seen in Table 1. Table 1 lists the total number of ADR reports per country for 2001, the number ofreports per profession and the number of reports submitted by pharmacists dividedinto the categories hospital pharmacists and community pharmacists. Fourcountries, Australia, Canada, The Netherlands and Spain, have a considerablecontribution from pharmacists, both in percentage (>20%) and number of reports(>100 reports). This is also the case in Chile and the USA, but a percentage couldnot be calculated. In Table 2 the assessments of the clinical information are presented, as well as theratings of the quality of content and medication history, both per report. Inaddition, the subjective general judgment of the quality of the contributions of thepharmacists to the national reporting systems is provided. The countries that havethe highest score of this subjective general judgment were Australia, Canada,Ireland, Japan, Tanzania and the USA.

3.1.3 DiscussionAlthough in most countries pharmacists are allowed to report ADRs to theirnational reporting systems, only a limited number of countries indicate that thesecontributions are of major significance to the system and quality ratings vary.

Differences per member stateWhat stands out is the fact that in the Nordic countries mentioned (i.e. Finland,Norway and Sweden) pharmacists do not participate in the nationalpharmacovigilance system. This is also the case in countries such as Denmark,Iceland and Estonia. Indonesia, Vietnam, Oman, the Czech Republic, Rumania andSlovakia stated that they do not receive any reports from pharmacists according aWHO survey of 1999.(1) Italy, the United Kingdom and Oman do acceptpharmacist reports. In several countries, such as France, Italy and Spain, the

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Table 2Subjective judgment of specificity of clinical information, completeness of casedetails, completeness of medication history and appreciation of the contribution ofpharmacists’ reports to the National Centre1.

clinical completeness drug history appreciationAustralia + ++ ++ ++Belgium + + + +Brazil - + + +Bulgaria + + + +Canada ++ ++ ++ +Chile + + + +China + + + +Croatia + + +Egypt ++ + ++France + + + ++Germany + - - +Ghana + + + ++Greece + + + +Hungary + + + +Ireland + + + +Italy + + + -Japan + + + +Latvia + + + -Malaysia + + + +Morocco + + + +Nederland + + + +New Zealand + + + +Oman ++ + + +Portugal +Singapore + ++ + +South Africa +Spain + + + +Switzerland + + + +Tanzania + + + +Thailand + + + +Tunisia + + + +United Kingdom + + + +Uruguay - + +USA + + + +Zimbabwe + + + +

1. Only these countries are included in this figure that accept pharmacist’s ADR reports andanswered the involved questions.

reporting of ADRs is mandatory, including that of pharmacists. It is notable that inSweden nursing staff are authorised to report, whereas pharmacists are not. Ingeneral, only those authorised to prescribe medication are allowed to report ADRs.We did not find a clear relationship between the level of training and theinterpretation of the profession of pharmacist and the fact whether or notpharmacists are allowed to report. In Sweden an extensive study on thecontribution pharmacists can make with respect to the detection of drug-relatedproblems was published recently.(29) In Finland pharmacists are highly trained andthere is an extensive network of pharmacies. Not authorising pharmacists to reporthere is justified as follows: ‘It is thought that limited resources would be used morecost effectively when the reporting is focused on medically confirmed seriousADRs from physicians’.(2) In Norway plans have been developed to involve thepharmacist more closely in the process of ADR reporting, with an emphasis onOTC medication. It must be noted that pharmacist’s reports are accepted whensubmitted in this country, although this occurs only sporadically. Other countries, such as Cuba, Ireland, the Netherlands and Singapore, havelaunched programmes to promote the participation of pharmacists.(30,31)

The quantitative contribution of the pharmacistThe total number of pharmacist reports per country for the year 2001 is presentedin Table 1. In Australia, Canada, France, Japan, the Netherlands, Spain, the UK andthe USA pharmacists submitted more than 1000 ADR reports. All of thesecountries have at least a twenty-year tradition in the systematic collection of ADRs.Chile also received a relatively high volume of pharmacists' reports.The proportional contribution of the pharmacist needs to be taken into accountwhen analysing the number of reports each country has indicated since the reportsare either received directly from health professionals or have been submitted by thepharmaceutical industry. In the latter case, the background of those responsible forthe report is not always known, so the number of pharmacists’ reports could beunderestimated. Some countries could not make this distinction for their direct,spontaneous reports. For these countries the highest percentages of pharmacists'reports received via the spontaneous reporting systems were recorded by Canada(88.3%), Australia (40.3%), the Netherlands (40.2%), Japan (39%), Spain (25.9) andPortugal (23.4%). The actual numbers are represented in Table 1. Percentages ofreports from pharmacists are only calculated if there were more than one thousandreports in total and more than one hundred pharmacists reports in a country.

The qualitative contribution of the pharmacistTable 2 presents the quality assessments of pharmacists' reports as indicated inresponse to the relevant question of the questionnaire. All the countries that had

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received large quantities of pharmacist reports also awarded high ratings to thecontributions and regarded them as valuable. This also applies to those countries inwhich the proportion of the reports by pharmacists in the total volume received ishigh. It is important to take into consideration that both the quality and significanceratings were subjective. It was also of interest to determine whether, in those countries in which thepharmacists’ contribution was substantial, the reports had predominantly been sentin by hospital pharmacists or mainly by community pharmacists. In Japan, theNetherlands and Portugal community pharmacists submit the bulk of reports; in allother countries most reports stem from hospital pharmacists. In an earlierpublication the contribution of the Dutch pharmacists- community pharmacists inparticular- has been described in more detail.(4) In the Netherlands pharmacistshave played a significant role in the formation of the national reportingsystem.(31,32)The contribution of the hospital pharmacist varies per country. In the USA andCanada this group is instrumental in the ADR reporting by hospitals.(18,33-35)

The pharmacist as an ADR reporterAs has been mentioned above, the pharmacist is appreciated in his or her role ofreporter in countries in which pharmacists have long been closely involved in thenational reporting systems. A review of the literature showed that the quality of thereports of both the hospital pharmacist and the community pharmacist is sufficientto contribute to the systems’ success.(4,25,36) Yet, direct reporting by thepharmacist has not been accepted in all countries. Notable in this respect is that inseveral of the Nordic countries the pharmacist is mainly restricted to the role ofdispensing pharmacist and is not considered sufficiently qualified to report onADRs. Furthermore, in many of the countries in which pharmacists are authorisedto report, their contribution to the system is negligible or non-existent. Although there are differences both with respect to the attitude of the variousnational spontaneous reporting systems towards the pharmacist and to theperception of the function of the profession in society, it is clear that the role of thepharmacist is changing. Fundamental to the pharmacist’s role is to ensure thatmedicines are used safely.(37) The standard practice of preparing and dispensingdrugs is increasingly shifting towards pharmaceutical care. The pharmacist’soriginal field of expertise, primarily in the domains of chemistry and formulae, isevolving into more pharmacotherapy-related clinical knowledge. Several countriesare considering the possibility of authorising the pharmacist to write certainprescriptions such as repeat prescriptions. In the Netherlands steps have been takento award the pharmacist the official status of co-consultant. This will allow thepharmacist access to patient files, which will afford him or her the opportunity to

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become more actively involved in patient treatment and pharmacovigilance.There is ample evidence that shows that the pharmacist is both willing and capableto adequately fulfil the role of a reporter of ADRs.(25,26,37-41) In addition to thisdirect role, the pharmacist can also play a coordinating role, both in general practiceand in a hospital setting. The fact that in many countries most pharmacies are highlycomputerised is important in this context. The argument against direct reporting by pharmacists is that their clinicalknowledge is limited. On the other hand, one could also argue that the knowledgedoctors have about drugs is often limited since this aspect is not given sufficientattention during their training.(42) The contribution the pharmacist can make willvary per country and will depend on the expertise and the status the profession isgiven within the different health care systems. Cooperation between doctors andpharmacists appears to be of vital importance, with each of the two professionalgroups contributing their respective expertise and experience to promote therational and safe use of medicinal drugs.

3.1.4 ConclusionIn several countries the pharmacist plays a prominent role in ADR reporting.Particularly in those countries that have participated in the WHO Drug MonitoringProgramme longer and accept pharmacists’ reports, the number of pharmacistreports is substantial and the reports are generally highly valued. In a large numberof countries the pharmacist’s contribution is small and in some countries,specifically the Nordic countries, the pharmacist is not authorised to report ADRsindependently to the national reporting system. The aim of a comparison of the various practices and experiences of differentcountries is to learn from the differences.(5,43) With respect to the potentialcontribution pharmacists can make to the national reporting systems, the practicalexperience of countries such as Australia, Canada, the Netherlands and the USAmay significantly improve both the quantity and the quality of the reports onADRs worldwide.

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References

1. Olsson S. National Pharmacovigilance Systems – Country Profiles and Overview (secondedition). Uppsala Monitoring Centre. Uppsala 1999.

2. Saarinen S. Adverse drug reaction reporting – comparison between Finland and TheNetherlands. Master’s thesis. University of Kuopio. Kuopio 2002.

3. Major E. The yellow card scheme and the role of pharmacists as reporters. Pharm J; 269:25-6.

4. Grootheest AC van, Puijenbroek EP van, Jong – van den Berg LTW de. Contribution ofpharmacists to the reporting of adverse drug reactions. Pharmacoepeidemiol Drug Saf,2002;11:205-10.

5. Lindquist A.M. Seeing and Observing in International Pharmacovigilance. Thesis. KatholiekeUniversiteit Nijmegen. Nijmegen 2003.

6. WHO. Handbook of resolutions and decisions of the World Health Assembly and ExecutiveBoard, 11th ed. World Health Organization. Geneva 1972. (WHA 20.51).

7. WHO. International Drug Monitoring: The Role of National Centres. Technical ReportSeries. WHO. Geneva 1972.

8. Olsson S. The Role of the WHO Programme on International Drug Monitoring inCoordinating Worldwide Drug Safety Efforts. Drug Saf 1998;19:1-10.

9. WHO. Handbook of resolutions and decisions of the World Health Assembly and ExecutiveBoard, Vol 11948-1972. Geneva, World Health Organization, 1973. WHA 16.36 Clinical andpharmacological evaluation of drugs.

10. Esch AF. The planning of a national drug monitoring system. In: International Drug Monitoring:The Role of National Centres. Technical Report Series. WHO Geneva 1972. Annex 3:44-47.

11. Friedman GD, Collen MF, Harris LE, Van Brunt EF, Davis LF. Experience in monitoring drugreactions in outpatiens. JAMA 1971;217:567.

12. WHO. The Importance of pharmacovigilance. Safety Monitoring of medical products. WHO.Geneva 2002.

13. UMC. Guidelines for setting up and running a Pharmacovigilance Centre. UMC. Uppsala 2000.

14. WHO. Safety of Medicines – A guide to detecting and reporting adverse drug reactions.Geneva 2002. (www.WHO/EDM/QSM)

15. Strom BL, Hennessy S. Pharmacists Care and Clinical Outcomes for Patients With ReactiveAirways Disease. JAMA 2002;288:1642-3.

96

16. Moss RL, Garnett WR, Steiner KC. Physician attitudes towards pharmacists counselingpatients on adverse drug reactions. Am J Hosp Pharm 1980;37:243-7.

17. Tilson HH, Hartzema AG, Porta M. Pharmacoepidemiology: The Future. In:Pharmacoepidemiology, an Introduction. Hartzema AG, Tilson HH, Porta M, editors.Harvey Whitney Books Company Cincinnati 1998.

18. FDA. Guideline for Postmarketing Reporting of Adverse Drug Experiences. Department ofHealth and Human Services (85D-0249). FDA 1992.

19. Reebye RN, Avery AJ. Bosch WJHM van den, Aslam M, Nijholt A, Bij A van der. Exploringcommunity pharmacists’ perception of their professional relationship with physicians inCanada and the Netherlands. Int J Pharm Pract 1999;7:149-58.

20. Griffin JP. Survey of the spontaneous adverse drug reactions reporting schemes in fifteencountries. Br J Clin Pharmacol 1986;12:243-7.

21. Fincham JE. Adverse Drug Reaction Reporting and Pharmacists. J Clin Pharm Therapeutics1989;14:79-81.

22. Lindquist M, Edwards IR. Adverse drug reactions reporting in Europe: some problems ofcomparison. Int J Risk Saf Med 1993;4:35-46.

23. Leape LL, Cullen DJ, Dempsey Clapp M, Burdick E, Demonaco HJ, Erickson JI, Bates DW.Pharmacist Participation on Physician Rounds and Adverse Drug Events in the Intensive CareUnit. JAMA 1999;282:267-70.

24. Wistanley PA, Irvin LE, Smith JC, Orme ML’E, Breckenridge AM. Adverse Drug Reactions:a hospital pharmacy-based reporting scheme. Br J Clin Pharmacol 1989;28:113-6.

25. Ahmad SR, Freiman JP, Graham DJ, Nelson RC. Quality of Adverse Drug ExperienceReports Submitted by Pharmacists and Physicians to the FDA. Pharmacoepidem Drug Saf1996;5:1-7.

26. Roberts PI, Wolfson DJ, Booth TG. The Role Of Pharmacists in Adverse Drug ReactionReporting. Drug Saf 1994:11:7-11.

27. Beard K. Introduction. In: Adverse Drug Reactions. A Lee, editor. Pharmaceutical Press,London 2001.

28. Poston J, Parish P. The pharmacist. In: Monitoring for drug safety. WHW Inman, editor. MTPPress. Lancanster 1986.

29. Westerland T. Drug-related problems, indentification, characteristics and pharmacyinterventions. Thesis. Göteborg University 2002.

30. Debesa F, Jiménez G, Figueras A, Diogène E, Peña JP, Avila J, Laporte J-R. Spontaneousreporting of adverse drug reaction in Cuba: integrating continuous education, training andresearch in network approach. Br J Clin Pharmacol 2002;54:334-5.

97

31. Grootheest AC van, Puijenbroek EP van. Pharmacovigilance in the Netherlands. In:Pharmacovigilance. Mann R, Andrew E, editors. John Wiley and Sons. Chichester 2002.

32. Koning GPH. A regionalized spontaneous surveillance programme for adverse drug reactionsas a tool to improve pharmacotherapy. Thesis. Utrecht University 1994.

33. Accreditation Manual for Hospitals 1993. Joint Commission on Accreditation of HealthcareOrganizations, Oakbrook Terrace, Ill, 1993.

34. ASHP guidelines on adverse drug reaction monitoring and reporting. Practice Standards ofASHP 1992-93. American Society of Hospital Pharmacists, Bethesda MD, 1992.

35. Standards of Practice. Canadian Society of Hospital Pharmacists. 1990.

36. Lee A, Bateman DN, Edwards C, Smith JM, Rawlins MD. Reporting of adverse drugreactions by hospital pharmacists: pilot scheme. BMJ;315:519.

37. Grootheest AC van, Mes K, Jong – van den Berg LTW de. Attitudes of communitypharmacists in the Netherlands towards adverse drug reactions reporting. In J Pharm Pract2002;10:167-72.

38. Emerson AE, Martin RM, Tomlin M, Mann RD. Prospective cohort study of adverse eventsmonitored by hospital pharmacists. Pharmacoepidemiol Drug Saf 2001;10:95-103.

39. Green CF, Mottram DR, Raval D, Proudlove C, Randall C. Community pharmacists’ attitudeto adverse drug reaction reporting. Int J Pharm Pract 1999;7:92-9.

40. Sweis D, Wong ICK. A survey on factors that could affect adverse drug reaction reportingaccording to hospital pharmacists in Great Britain. Drug Saf 2000;2:165-72.

41. Green FG, Mottram DR, Rowe PH, Pirmohamed M. Attitudes and knowledge of hospitalpharmacists to adverse drug reaction reporting. Br J Clin Pharmacol 2001;51:81-6.

42. Grootheest AC van, Edwards IR. Labelling and ‘Dear Doctor’ Letters, Are TheyNoncommittal? Drug Saf 2002;25:1051-1055.

43. Hughes ML, Whittlesea CMC, Luscombe DK. Review of National Spontaneous ReportingSchemes, Strengths and Weaknesses. Adv Drug React Toxicol Rev 2002;21:231-41.

44. Kennedy DL, Goldman SA, Lillie RB. Spontaneous Reporting in the United States. In:Pharmacoepidemiology. WHW Strom, editor. John Wiley and Sons. Chichester 2000.

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Chapter 3.1

Pharmacists’ role in reporting adverse drug reactions in an international perspective

Pharmacoepidemiol Drug Saf 2003 (in press)

Kees van Grootheest, MD1

Sten Olsson, MSc Pharm2

Mary Couper, MD3

Lolkje T.W. de Jong – van den Berg, PhD, PharmD4

1. Netherlands Pharmacovigilance Centre Lareb, ‘s-Hertogenbosch, The Netherlands

2. WHO Collaborating Centre for International DrugMonitoring, Uppsala, Sweden

3. WHO Programme for International Drug Monitoring, Geneva, Switzerland

4. Department of Social Pharmacy and Pharmacoepidemiology,GUIDE, Groningen, the Netherlands

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Chapter 3.2Attitudes of community pharmacists in the Netherlands towards adverse drug reaction reporting

Int J Pharm Pr 2002;10:267-72.

Kees van Grootheest, MD1

Kyros Mes, PharmD2

Lolkje T.W. de Jong-van den Berg, PharmD, PhD2

1. Netherlands Pharmacovigilance Centre Lareb,’s-Hertogenbosch, the Netherlands.

2. Department of Social Pharmacy and Pharmacoepidemiology, GUIDE, Groningen, the Netherlands

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Abstract

ObjectiveAim of the study is to gain insight into the attitude and behaviour of communitypharmacists in the Netherlands with respect to the reporting of adverse drugreactions.

MethodsA questionnaire survey conducted among 200 community pharmacists at randomselected from the membership list of the Royal Dutch Society for the Advancementof Pharmacy.

ResultsResponse was 73% (n=147). Community pharmacists in the Netherlands regard thereporting of adverse drug reactions (ADRs) as an integral part of their professionalduties (100%) and they do not experience any major impediments in this respect.This is reflected in the frequency and number of reported ADRs the nationalpharmacovigilance centre receives. The following impediments for reporting werementioned most frequently: the adverse effect is assumed to be already known(32%), the reporting procedure is too time-consuming (25%), and there isuncertainty concerning the causal relationship between ADR and drug (25%). Feedback is mentioned most as the chief impetus for reporting, both with respect tothe actual report submitted and general feedback as provided in publications.Although consultation with the attending clinician is not compulsory in theNetherlands, 55% of the pharmacists deem this an important aspect in the reportingprocess.

ConclusionCommunity pharmacists in the Netherlands are knowledgeable about reportingADRs and highly motivated to do so. This positive attitude towards reportingadverse events is based on the established tradition of pharmacists reporting in theNetherlands.

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3.2.1 IntroductionPharmacists can play an important role in the detection and reporting of suspectedadverse drug reactions (ADRs). Greater participation by pharmacists in ADRreporting could be an important tool to counter under-reporting of ADRs. Thepharmacist’s role in pharmacovigilance varies from country to country. In themajority of countries participating in the WHO Programme for International DrugMonitoring, pharmacists can report independently, but in the UK for instance theright to report direct has only been achieved in recent years.(1,2) The WHOProgramme is co-ordinated by the Uppsala Monitoring Centre, which maintains aglobal ADR database. The Netherlands has a long history of pharmacists reportingsuspected ADRs. Pharmacists were allowed to submit reports from the beginningof ADR reporting schemes in the Netherlands in 1963, but were boosted with thestart of Lareb’s regional activities in 1986.(3) The contribution of pharmacist ADRreports is substantial in the Netherlands, in terms of both quality and quantity: 40per cent of spontaneous reports to Lareb originate from pharmacists, almost all ofwhom are community pharmacists.(4) Earlier research showed that nearly all Dutch pharmacists were aware of theexistence of the reporting system and familiar with the reporting procedure.Awareness was considerably lower for general practitioners and medical specialists,at 82 per cent and 45 per cent, respectively.(5)However, little was known about pharmacists’ attitude towards their perceived rolein the reporting of ADRs, the factors that encourage or discourage the actualsubmission of reports, and the pharmacists’ behaviour in relation to ADRs. A smallstudy conducted by Green et al. among community pharmacists in the UK is theonly published study of community pharmacists and ADRs.(6) The contribution ofhospital pharmacists has been more extensively investigated.(7,8) However mostpublications on ADR reporting concern the attitude and behaviour of medicalpractitioners.(9,10) Thus, the aim of the present survey was to gain insight into the attitudes and reportingbehaviour of community pharmacists in the Netherlands to ADR reporting.

3.2.2 MethodsA structured, 39-item questionnaire was sent to a stratified random sample of 200community pharmacies in the Netherlands at the end of 2000 with a request for oneof the practising pharmacists to complete it. There were 2,636 practisingcommunity pharmacists working in 1,602 pharmacies in the Netherlands in 2000.A reminder was sent after six weeks. The forms could be returned anonymously.The membership list of the Royal Dutch Society for the Advancement of Pharmacy(KNMP) was consulted to select all registered community pharmacists.Subsequently, from each of the 23 districts into which the KNMP members are

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Table 1Statements given in the questionnaire – pharmacist could give their (dis)agreementin a scale 1 – 4.

1. Reporting ADRs is part of the profession of a pharmacist.2. I feel pharmacovigilance is important.3. I want to be sure the ADR is related to the drug before reporting.4. I do not report ADRs of OTC products delivered by my pharmacy.5. I report an ADR that causes:

a. hospitalisationb. a life threatening situationc. a congenital anomalyd. persistent disability or incapacitye. death of the patient.

6. I report to get more insight about ADR questions at hand.7. I report to show the patient that his concern is taken seriously.8. I always report ADRs because it is part of pharmaceutical care.9. Consulting the physician is important before reporting an ADR.10. I discuss ADRs at the Pharmacotherapy Consultation Group.11. I don’t report because reporting forms are not available.12. I don’t report because I don’t know the address where these reports should be sent.13. The reporting form is to complicated to fill in.14. Reporting ADRs is time consuming.15. All serious ADRs are detected before registration.16. I don’t report ADRs because I want to publish about it myself.17. I don’t report because I am not convinced about the confidential handling of the

report.18. I don’t report ADRs because I fear to harm the confidence of my patients.19. I don’t report because I find it difficult to admit that the patient has got harmed.20. I don’t report because reporting may give the impression that I am ignorant

concerning ADRs.21. I don’t report because I fear legal liability for the reported ADR.22. I am not motivated to report.23. I don’t report because I have insufficient clinical knowledge.24. I don’t report because I don’t know how to report an ADR.25. I don’t report because I am not convinced the ADR is caused by the drug.26. I would report more if:

a. there is an obligation to do sob. there is a feec. I see my colleagues are doing sod. my attention is drawn to it by a publication, for instance the Drug

Bulletine. I received more feedback by mailings.

organised, pharmacists were randomly selected in proportion to the district’s totalnumber of community pharmacists. The questionnaire items were formulated usinga modified version of the Fishbein and Azjen model defining the relationship betweenknowledge, attitude and behaviour, the influence of the social norm and the impedingand facilitating factors involved.(11) The first four questions covered the details andcharacteristics of the participating pharmacist. Pharmacists were asked which school ofpharmacy they had attended and which year they had qualified. The next four itemsconsisted of general questions aimed at establishing the extent of the respondent’sknowledge about the Dutch ADR reporting system. Twenty-six items explored thepharmacist’s attitude to reporting and the factors that either positively or negativelyaffect his or her attitude. These items were worded as a series of statements and thepharmacist was asked to indicate their agreement or disagreement on a Likert scalefrom 1 to 4 (Table 1). One of the statements gave the criteria for serious ADRs set bythe Council for International Organisations of Medical Sciences (CIOMS) and wasintended to assess pharmacists’ knowledge of the criteria.(12) Four questionsinvestigated pharmacists’ behaviour. A final open-ended question invited therespondents to suggest possible ways to increase pharmacists’ motivation to reportADRs. Prior to the survey, the questionnaire was piloted with eight pharmacists,which resulted in adaptation of the phrasing of several of the questions.

3.2.3 ResultsThe first mailing resulted in 120 questionnaires being returned. After the reminder,another 27 responses were received. Thus, a total of 147 of the original 200 formswere returned, a response rate of 73.5%. Of the respondents 56.2% were male and43.8% female; 71.3% indicated being first pharmacist (owner or manager) and28.1% second pharmacist (pharmacist working in a partnership). The distributionof the universities where the pharmacists had trained and the years in which theyqualified were similar to the expected distribution. The data thus indicated that therespondents could be regarded as a representative sample of the total population ofDutch community pharmacists.

- Familiarity with the reporting system All but one respondent indicated being familiar with the way in which ADRreporting is organised in the Netherlands. Almost three-quarters (73%) knew thatthe Netherlands Pharmacovigilance Centre Lareb was an independent foundationof medical practitioners and pharmacists. 27% thought Lareb was an officialgovernment body. This is not surprising since Lareb receives government fundingand reports to the Medicines Evaluation Board. Overall, 68% of respondentsdisagreed with the statement that ‘all serious ADRs are detected beforeregistration.’ Just over three-quarters (76%) said that they used the reporting forms

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provided in the Farmacotherapeutisch Kompas (the main drug desk reference bookin the Netherlands) and 24% used the forms from the Dutch Drug Bulletin(Geneesmiddelenbulletin). 7% indicated they sometimes also reported electronically.

- Attitude All respondents considered the reporting of ADRs to be integral to theirprofessional duties and, with the exception of one pharmacist, they all acknowledgedthe importance of reporting, although 3.5% said that they were not motivated toreport. 82% saw reporting as an inherent part of pharmaceutical care and the samepercentage said that ADR reporting was an indication of taking patients’ complaintsseriously. More than two-thirds (68%) of the respondents were of the opinion thatreporting adverse effects helped them to gain more insight into the problemsassociated with side effects. A majority (55%) said that, before reporting, theyneeded to be convinced of the causality between the drug and adverse reaction. Inthe Netherlands pharmacists can report independently. However, 55% ofrespondents felt the need to discuss their proposed report with the medicalpractitioner involved before submitting it. Almost half (47%) said that theydiscussed reports with the GPs and pharmacists who participated in their localpharmacotherapy consultation group, a regular forum in which communitypharmacists meet with general practitioners.(13)

- BehaviourOf the pharmacists surveyed, 53% indicated that they had reported more than oneadverse event in the previous year. Although it was not possible to identify individualpharmacists’ reports to Lareb, a comparison could be made with the reports submittedover that period. The results of that comparison suggested that pharmacists’ self-reports overestimated those submitted by a factor of almost three. The majority of pharmacists completed the reporting procedure themselves, with apharmacy assistant doing so in less than 3% of cases. In 96% of cases, the report wassubmitted to the Lareb Centre. Of these reports, 40% were also sent to otherinstitutions: the marketing authorisation holder (MAH) or the pharmacist’s ownprofessional society. Four pharmacists said that they reported solely to the MAH.Adverse reactions to over-the-counter (OTC) products were said to be reported by84% of pharmacists. Over 95% of the respondents indicated that they were aware thatparticularly serious side effects needed to be reported as well as unusual adversereactions and adverse events relating to a newly marketed drug.The survey investigated whether pharmacists recognised adverse events that aredenoted as serious according to the criteria set by the CIOMS as significant eventsto be reported. This proved to be the case for 97% of respondents.

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- Barriers Pharmacists were asked which factors negatively affected their willingness to report. Aquarter of respondents indicated that reporting ADRs was too time-consuming, and asimilar number mentioned uncertainty concerning the causal relationship betweenADR and drug. The fact that the adverse effect was assumed to be already known wasan obstacle for 32%. An intention to publish their own report on the adverse reactionwas the reason stated for not reporting the ADR for only 3% of the pharmacists. Asingle pharmacist mentioned doubts about the confidentiality of the information as thereason for not reporting and in one other case the pharmacist indicated that they foundit difficult to report that a drug had caused harm to a patient and stated fear of liabilityclaims as the reason for not reporting. Unavailability of the reporting forms and other practical barriers played minorroles: 1.4% and 2%, respectively. Finally, 9% of the respondents thought the formis too complicated. An overview of the scores of the possible barriers to reportingis provided in Table 2.

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Table 2Impeding factorsLevel of agreement in percentages (n=147)

strongly agree disagree stronglyagree disagree

- no reporting forms available 0 1 33 66- reporting address unknown 0 2 33 65- reporting form too complicated 1 8 40 51- too time-consuming 3 22 40 35- all adverse reactions are known 8 24 46 22- want to publish myself 1.5 1.5 29 68- confidentiality 0 1 38 61- patient confidentiality 0 0 37 63- difficult to admit harm to patient 0 1 38 61- reporting could show ignorance 0 0 41 59- fear of liability 0 1 41 58- no motivation 0 4 44 52- insufficient clinical knowledge 0 2 49 49- do not know how to report 0 2 39 59- causality uncertain 4 21 47 28

- Facilitating factors To investigate which factors might motivate pharmacists to report suspected ADRs,the questionnaire explored their views on a number of factors mentioned in theliterature. In addition, an open-ended question invited them to state their ownsuggestions. Table 3 provides an overview of the suggestions made in response tothe open-ended question.

Of the total sample of pharmacists, 53% mentioned more or improved feedback astheir prime motivator, and 39% indicated that publication on adverse effects injournals like the Geneesmiddelenbulletin was the most important stimulus toreporting. Respondents were asked whether making ADR reporting compulsorywould motivate them to report: 30% answered in the affirmative. Only 18%indicated that receiving financial compensation for reports submitted wouldmotivate them to report more readily. Peer reporting was an important incentive for12% of the respondents.

3.2.4 DiscussionThis is the first published study of Dutch community pharmacists’ familiarity withand attitudes towards ADR reporting, their self-reported behaviour and factorsinfluencing their attitudes. The response rate was good, at over 70%, and analysis

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Table 3Suggestions to encourage reporting adverse drug reactions, as mentioned by therespondents (open question)

Suggestions are ordered in frequency of occurrence expressed by the number ofrespondents who proposed them.1. feedback 292. publications 263. information about the national centre 174. simplification of reporting procedure 145. promoting reporting as part of professional duty 136. encouraging patients to report adverse drug reactions to the pharmacist 77. financial compensation 78. more attention to ADR reporting in university curriculum 69. database of national centre available on the Internet 610. compulsory reporting 2

of respondents’ demographics indicated that they were representative of the totalpopulation of Dutch community pharmacists. Our findings show that communitypharmacists in the Netherlands have a positive attitude towards reporting ADRs.For pharmacists to report ADRs several practical requirements need to be fulfilled,which are listed in Table 4. In many countries these criteria are not being met. Therehas been little in the published literature about the attitude and behaviour ofcommunity pharmacists in relation to ADR reporting. Green et al described theattitude of community pharmacists in the UK.6 Their study was conducted in 1999,two years after pharmacists in the UK were officially granted the right to reportdirect to the Committee on Safety of Medicines (CSM), following years ofdebate.(14) We compared the results from our survey with the data available in the literature oncommunity pharmacists, hospital pharmacists and medical practitioners.

- Familiarity with the reporting systemAn earlier study of ours had already shown that the familiarity of pharmacists in theNetherlands with the existing ADR reporting system was high.(4) This finding wasconfirmed in the present study: 99% of our respondents indicated being familiarwith the reporting system. Green et al found a comparable percentage forcommunity pharmacists in the UK (93%) and this was even higher for hospitalpharmacists: 97%.(6,8) For medical practitioners in the Netherlands the level ofknowledge about the system was lower, particularly among doctors working inhospitals.(5)

- Attitude Pharmacists are directly involved in pharmacotherapy and consequently might beexpected to regard reporting suspected adverse events as an integral part of theirprofessional duties and this was the case in our study. Our respondents also saw

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Table 4Practical requirements enabling pharmacist’s ADR reporting

1. Formal access to the national pharmacovigilance system2. Knowledge about the reporting system3. Availability of the reporting form (paper or electronic)4. Simple and user-friendly reporting form5. Feedback

reporting ADRs as a vital part of pharmaceutical care. The notion that theindividual pharmacist carries professional responsibility within the context ofpharmaceutical care is well developed in the Netherlands.(15) In the UK, Green etal found that 77% of community pharmacists considered ADR reporting aprofessional obligation, and the figure was 86 % for hospital pharmacists.(6,8) Sincethe latter are part of a larger organisation, their contribution could also involvefacilitating, maintaining and supporting a reporting system in their ownhospitals.(16,17)In the Netherlands, pharmacists are not legally bound to consult the patient’sdoctor prior to reporting. Nevertheless, 55% of respondents saw this as animportant element of the reporting process. In Reebye et al’s study, two-thirds ofDutch community pharmacists reported regularly conferring with the GP onmatters of pharmacotherapy, specifically within the framework of thepharmacotherapy consultation group. In these local discussion groups, communitypharmacists and general practitioners meet each other approximately every twomonths.(18) In our survey, 47% of the respondents stated that these were used fordiscussions on ADRs. In the UK, consultation with the GP is part of thepharmacist’s reporting protocol and may be an important barrier, particularly whenthe relationship between pharmacist and doctor is poor or where pharmacists lackconfidence about their knowledge level or skills.(5)

- Behaviour Our study did not investigate the actual behaviour of pharmacists, but did ask fortheir self-reported behaviour. Actual ADR reporting during the years 1995-2000 wasstudied previously.(4) Pharmacists’ own ideas about the number of reports wereoptimistic: they overestimated their actual reporting by a factor of almost three.One explanation for this discrepancy could be that there was confusion betweennumbers of reports and numbers of ADRs: an average pharmacist report containstwo ADRs. Almost all the pharmacists reported to Lareb, but some also sent a duplicate to themarketing authorisation holder. The reason for the high percentage of reports toLareb could be that Lareb is considered by pharmacists to be their organisation.Pharmacists’ high awareness of which ADRs should be considered to be seriousaccording to the CIOMS criteria is in line with the results of the earlier study of thequality of pharmacists’ reports.(4) We found no studies in the literature on thistopic relating to community pharmacists.

- Barriers Our survey did not reveal any major barriers preventing pharmacists fromreporting ADRs. The issues mentioned most frequently were considering reporting

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too time-consuming and assuming that serious ADRs were known beforemarketing. Uncertainty about causality was also mentioned relatively frequently.Practical obstacles, such as the unavailability of forms or unfamiliarity with thereporting procedure, were not found to be significant factors. The same applied toconcerns about liability and possible lack of clinical expertise. Our analysis investigated whether experiencing barriers was related to reportingbehaviour and no such association was found. However, the number of barriersmentioned was small. It is striking that our findings strongly differ from results obtained among hospitalpharmacists in the UK in whom time required to report, insecurity about theirability to recognise possible adverse events, patient confidentiality and the absenceof electronic patient records were mentioned most frequently as barriers.(7,8) Asurvey among GPs revealed that, apart from considerations concerning the natureof the adverse reactions (too well known or too insignificant), the time factor anduncertainty about the causality between ADR and drug were seen as the mainobstacles to reporting.(9,10)Green et al. found that 70% of the community pharmacists in their study said theydid not report side effects of an OTC product they themselves had dispensed. Thiswas not confirmed in our survey: 84% of the respondents said they reported ADRsto OTC products. This is an important finding because pharmacists increasinglyplay a pivotal role in this context.(19)Uncertainty about the causality between a suspected ADR and the drug used ismentioned by both physicians and pharmacists as a barrier to the submission ofreports. This is perhaps unsurprising, and signifies a scientific way of thinking thatrequires certainty for action. However, it is unfortunate that this mind-set preventssome from reporting. After all, pharmacovigilance concerns the gathering of dataon suspected adverse events. It is the task of the national reporting centres to try toestablish the causality between the reported suspected ADRs and the drugs used byelimination of as many uncertainties as possible by means of causality assessmentand statistical methods.(20)

- Facilitating factors Feedback was mentioned most frequently as a factor that would facilitate reporting,both in response to the questionnaire items and as suggestions elicited by the open-ended question. This relates to specific feedback on reports submitted as well asgeneral feedback in terms of publications from the reporting centre. Surprisingly,feedback did not emerge as a facilitating factor in any of the earlier surveys ofcommunity pharmacists, hospital pharmacists or physicians. In the Netherlands,Lareb provides those who submit a report with customised feedback. Pharmacistsin the Netherlands appear to highly appreciate this and see it, together with Lareb’s

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regular publications, as an important incentive to report. We therefore recommendthat this practice of providing report-related feedback should be more widelyadopted. Pharmacists in the UK predominantly mentioned education and training asimportant motivating factors.(6,7,8) Receiving a fee for reports submitted wasmentioned by just 18% of the Dutch respondents as an incentive, whereas in thestudy by Green et al6 one-third of the pharmacists mentioned financialcompensation. This seems to show that while in the Netherlands ADR reporting ismore generally perceived as inherent to pharmacists’ existing and usual professionalresponsibilities, in the UK it may be seen as a new and additional role. Hospitalpharmacists also indicated the presence of a ‘written hospital policy’ as a motivatingfactor.(7)

3.2.5 ConclusionCommunity pharmacists in the Netherlands were found to have a positive attitudeto ADR reporting. They considered reporting integral to their professionalresponsibilities and reported relatively frequently. Based on the findings available inthe literature, they appear to be ahead of their colleagues in other countries.

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References

1. Olsson S. National Pharmacovigilance Systems, country profiles and overview. 2nd ed. WHOUppsala Monitoring Centre. Uppsala 1999.

2. Pharmacy ADR reporting now official. Pharm J 1997;258:582.

3. Koning GPH de. A regionalized spontaneous surveillance program for adverse drug reactionsas a tool to improve pharmacotherapy. Thesis. Utrecht University, 1994.

4. Grootheest AC van, Puijenbroek EP van, Jong-van de Berg LTW de. Contribution ofpharmacists to the reporting of adverse drug reactions. Pharmacoepidemiol Drug Saf2002;11:205-10.

5. Grootheest AC van, Puijenbroek EP van. Artsen en apothekers kennen Lareb - is dat zo?[Physicians and Pharmacists know Lareb – is that true?]. Pharm Weekbl 2000;135:489-91.

6. Green CF, Mottram DR, Raval D, Proudlove C, Randall C. Community pharmacists’ attitudeto adverse drug reaction reporting. Int J Pharm Pract 1999;7:92-9.

7. Sweis D, Wong ICK. A survey on factors that could affect adverse drug reaction reportingaccording to hospital pharmacists in Great Britain. Drug Saf 2000;2:165-72.

8. Green FG, Mottram DR, Rowe PH, Pirmohamed M. Attitudes and knowledge of hospitalpharmacists to adverse drug reaction reporting. Br J Clin Pharmacol 2001;51:81-6.

9. Belton KJ, Lewis SC, Payne S, Rawlings MD, Wood SM. Attitudinal survey of adverse drugreaction reporting by medical practitioners in the United Kingdom. Br J Clin Pharmacol1995;39:223-6.

10. Eland EA, Belton KJ, Grootheest AC van, Meiners AP, Rawlins MD, Stricker BHCh.Attitudinal survey of voluntary reporting of drug reactions. Br J Clin Pharmacol 1999;48:623-7.

11. Fishbein M, Azjen I. Belief, attitude, intention and behavior: an introduction to theory andresearch. Reading 1975.

12. CIOMS Working Group IV. Benefit-risk balance for marketing drugs: safety signals. CIOMS.Geneve 1998.

13. Vries CS de. Collaboration in healthcare, the tango to drug safety. Thesis. Groningen 1998.

14. Whittlesea CMC, Walker R. An adverse drug reaction reporting scheme for communitypharmacists. Int J Pharm Pract 1996;4:228-34.

15. Mill JWF van. Pharmaceutical Care, the future in pharmacy. Thesis: Groningen, 1999.

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16. Emerson AE, Martin RM, Tomlin M, Mann RD. Prospective cohort study of adverse eventsmonitored by hospital pharmacists. Pharmacoepidemiol Drug Saf 2001;10:95-103.

17. Lareb/NVZA. Het melden van bijwerkingen, de rol van de ziekenhuisapotheker. Lareb. ’s-Hertogenbosch 2001.

18. Reebye RN, Avery AJ, Bosch WJHM van den, Aslam M, Nijholt A, Bij A van der. Exploringcommunity pharmacists’ perception of their professional relationship with physicians, inCanada and the Netherlands. Int J Pharm Pract 1999;7:149-58.

19. Sinclair HK, Bond CM, Hannaford PC. Pharmacovigilance of Over-the-Counter Productsbased in community pharmacy; a feasible option? Pharmacoepidemiol Drug Saf 1999;8;479-91.

20. Meyboom RHB. Causal or casual? The role of causality assessment in pharmacovigilance.Drug Saf 1997;16:374-89.

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Chapter 3.3Contribution of pharmacists to the reporting ofadverse drug reactions

Pharmacoepidemiol Drug Saf 2002;11:205-10.

Kees van Grootheest MD1

Eugène.P. van Puijenbroek MD, PhD1

Lolkje.T.W. de Jong – van den Berg PharmD, PhD2

1. Netherlands Pharmacovigilance Centre Lareb, ’s-Hertogenbosch, the Netherlands.

2. Department of Social Pharmacy and Pharmacoepidemiology,GUIDE, Groningen, the Netherlands.

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Abstract

AimAim of the study is to get a better view about the possible contribution of pharmacistsreports to the quantity and the quality of reports and in this way to the quality of avoluntary reporting system of adverse drug reactions.

Methods15,293 reports, send to the Netherlands Pharmacovigilance Centre, then namedNetherlands Pharmacovigilance Centre Lareb between 1995 and 2000 wereanalysed for the characteristics of pharmacist’s reports and the differences withreports of physicians, dispersion of adverse drug reaction in relation to the differentSystem and Organ Classes, the seriousness of the reports according to the CIOMS-criteria and the documentation grade of the reports.Two hundred reports were ad random selected and their quality assessed for thequality of the reports.

ResultsPharmacists are responsible for 40% of the reports sent in to Lareb during thisperiod. Their report more frequently concern adverse effects in relation to skin andthe eyes.The seriousness of pharmacist’s report is less as with physician’s reports as is the casewith the documentation grade of reports. Also the quality of the clinical informationof physician’s reports is higher.

ConclusionThe contribution of pharmacists in the voluntary reporting system in theNetherlands is of great importance, both for the number of reports and the qualityof reports.

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3.3.1 IntroductionReports of suspected adverse drug reactions (ADRs) form the basis of the surveillanceof drugs after marketing. The occurrence of phocomelia in association withthalidomide in the 1960s brought an increasing awareness of the necessity to detectpossible but as yet unknown effects of marketed drugs at an early stage.A voluntary reporting system is an important tool in the detection of signalsindicating a possible relationship between an adverse drug reactions and a particulardrug.(1) A signal can be defined as a set of data constituting a hypothesis relevant tothe rational and safe use of a drug in humans.(2) It is inherent to a spontaneousreporting system that solid conclusions cannot be drawn.(3) To strengthen a signal, asufficient number of reports of suspected ADRs is required and these need to be welldocumented and of good quality. To confirm the suspicion raised by a spontaneousreporting system often analytical studies such as pharmacoepidemiological researchare needed.Regulatory bodies often cannot afford to wait for the results ofpharmacoepidemiological studies to become available.(4) For public health reasonsregulators have to make decisions as soon as the possible relationship between adrug and a serious ADR is sufficiently strong. Due to today’s rapid disseminationof information via the media and the Internet public concern is easily raised,increasing the demand for decisions at an early stage. This has created an urgentneed for reliable information and clear decisions.(5) Since decisions may affect theconditions of registration, the content of the Summary of Product Characteristics(SPC), and may possibly even result in the withdrawal of the product concerned, itis vital that the methodology and results of a reporting system meet the higheststandards. Meyboom has postulated standards reporting systems need tomaintain.(6) These standards not only pertain to the number and quality of reports,but also to the care paid to and the accuracy of the collection process and analysisof the reports received.In a number of countries the pharmacist plays an important role in the reporting ofsuspected ADRs. This is also the case in The Netherlands, where pharmacists havethe possibility to derive crucial information about their clients’ medication historiesfrom the data stored in their computer system. Patients in The Netherlands have ingeneral only one pharmacist where they obtain their medicaments.The Netherlands Pharmacovigilance Centre Lareb maintains a voluntary ADRreporting system for physicians and pharmacists in the Netherlands since 1984 andwas officially appointed as the national reporting centre in 1995.(7) Lareb is fundedby and reports to the Dutch Medicines Evaluation Board. Since its establishment,pharmacists have played an important role in the Lareb pharmacovigilance system,both as reporters and as intermediaries in promoting physicians to participate.Given their substantial role in the reporting and collection of ADRs in the

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Netherlands, and because in a number of countries pharmacists have also expresseda growing interest in voluntary reporting systems, we have studied the significanceof pharmacists’ reports to Lareb during the period between 1995 and 1999. The aimof the study was to gain a deeper insight into the contribution their reports maketo both the quantity and the quality of the reports and thus into the quality of avoluntary reporting system.

3.3.2 MethodsVarious characteristics of the pharmacists’ reports in the Lareb database betweenJanuary 1, 1995 and January 1, 2000 were analysed and compared with those of thereports originating from physicians. The following characteristics were studied: thedistribution of the ADRs in relation to the different organ systems, the seriousnessof the ADRs reported, and the quality of the reports. In addition to objective

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Figure 1Grading scheme for the quality of documentation

information about these characteristics, a subjective analysis was conducted inorder to get a more detailed picture of the quality of the information about thesuspected ADR provided in the report.To analyse the distribution of reports in relation to the different organ systems inthe Lareb database, ADRs were first coded according to the WHO AdverseReaction Terminology (WHO-ART).(8) For each report the suspected drug ordrugs were assessed and each ADR was coded with a so-called WHO-preferredterm. Subsequently, each preferred term was attributed to a specific System andOrgan Class (SOC), i.e. a group of preferred terms pertaining to the same organsystem. In order to determine the SOC distribution differences in the reports ofpharmacists and physicians, odds ratios (OR) were calculated for the differentSOCs with corresponding 95% confidence intervals. The odds ratio is defined asthe odds of the number of reports on a specific SOC by pharmacists as comparedto physicians, divided by the odds of the number of all other SOCs reported bypharmacists as compared to physicians. The OR was adjusted for age, gender andyear of reporting. Criteria formulated by the Council for International Organizations of MedicalSciences (CIOMS) were used in order to rate the seriousness of the reports. Thesecriteria were first published in the 1995 Guideline on expedited reporting of ADRsof the International Conference on Harmonization of Technical Requirements forRegistration of Pharmaceuticals for Human Use (ICH) and were subsequentlyadopted by Working Group IV of the CIOMS.(9) The criteria for a serious reportare: death, life threatening, hospitalisation or prolongation of hospitalisation,persistent or significant disability/incapacity and a congenital anomaly/birth defect. In order to assess the quality, we compared reports submitted by pharmacists tothose sent in by doctors using two different methods. Firstly, an automated analysiswas carried out of all reports received during the period under investigation bymeans of the documentation grading scheme as developed by the WHO - seeFigure 1.(10) This so-called documentation grade gives an indication of the qualityof the information provided. However, it does not allow a subjective judgement ofthe information, nor does it take into account any additional information the reportmay contain.Therefore, to evaluate the quality of the reports in a wider perspective, a secondanalysis was carried out. Two hundred reports were additionally judged withrespect to completeness of information and quality of the clinical information. Thereports were blinded for source (physician or pharmacist) and randomly selectedfrom the database. Completeness of information was subjectively scored for sixaspects, each of which was awarded one point (1 means good, 0 means insufficient).The aspects assessed included: basic information about the patient (age and gender),date of onset of the ADR, information about the drug and concomitant medication,

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Table 1Differences in System Organ Classes for pharmacists and physicians

System and Organ Class Odds ratio Number of reported (95% CI) ADRs

skin and appendages disorders 0.8 (0.7-0.9) 3385musculo-skeletal system disorders 0.9 (0.7-1.0) 893collagen disorders 2.4 (0.9-6.0) 25central & peripheral nervous system disorders 1.0 (0.9-1.0) 3227autonomic nervous system disorders 1.0 (0.7-1.5) 93vision disorders 0.6 (0.5-0.7) 735hearing and vestibular disorders 0.8 (0.6-1.0) 171special senses, other disorders 0.5 (0.4-0.7) 404psychiatric disorders 1.8 (1.6-1.9) 2925gastro-intestinal system disorders 0.9 (0.9-1.0) 4069livers and biliary system disorders 5.0 (3.6-7.0) 307metabolic and nutritional disorders 0.9 (0.7-1.2) 261endocrine disorders 1.6 (1.1-2.5) 104cardiovascular disorders, general 1.3 (0.9-1.7) 175myo-, endo-, pericardial & valve disorders 4.1 (1.8-9.1) 46heart rate and rhythm disorders 1.2 (1.0-1.5) 515vascular (extracardiac) disorders 0.9 (0.7-1.2) 229respiratory system disorders 0.8 (0.7-0.9) 871red blood cell disorders 2.2 (1.0-4.6) 36white cell and res disorders 5.7 (3.0-11.1) 87platelet, bleeding & clotting disorders 0.8 (0.6-0.9) 407urinary system disorders 0.8 (0.7-1.0) 322reproductive disorders, male 2.2 (1.6-3.1) 192reproductive disorders, female 1.0 (0.8-1.2) 450foetal disorders 4.3 (1.3-14.4) 23neonatal and infancy disorders 2.5 (0.8-7.7) 17neoplasms 1.2 (0.4-4.3) 11body as a whole-general disorders 1.0 (0.9-1.1) 2645application site disorders 1.2 (0.9-1.7) 186resistance mechanism diorders 0.6 (0.3-1.0) 50secondary terms-events 0.6 (0.2-1.5) 18

95%CI: 95% confidence intervall

information about the period the suspected drug was used and the outcome. Thequality of the clinical information and the quality of the follow-up information wasjudged using a Visual Analogue Scale ranging from 1 to 5. The first 30 reports,selected at random, were rated by four experienced assessors. Differences betweenthese assessors were determined using Cronbach’s alpha. Since no significantdifferences were found, the other 170 reports were assessed by the first author.

3.3.3 ResultsBetween January 1995 and January 2000 Lareb received 15,293 reports covering25,183 ADRs. About 40% of the reports were sent in by pharmacists with themajority of reports submitted by community pharmacists; the contribution ofhospital pharmacists was less than 1%. The differences in system organ classes for which ADRs were reported are depictedin Table 1. Compared to pharmacists, physicians reported statistically significantlymore ADRs related to the cardiovascular system, malfunctions of the liver andpsychiatric disorders, whereas pharmacists reported a significant greater number ofpresumed ADRs of ‘external’ organ systems such as disorders of the skin and eyes. The seriousness ratings of the reports are shown in Figure 2. The percentage ofreports that was coded as serious was twice as high for physicians as it was forpharmacists. The number of serious reports submitted by physicians increasedmore during the period investigated than that of pharmacists. As regards the quality of documentation we found that for both groups the proportionof reports providing more adequate documentation had gradually risen. However, thiseffect was more pronounced for the physicians’ reports, of which about 60% receiveda grade 2 or higher, than for the reports submitted by the pharmacists, of which lessthan 40% were graded as such. The documentation of hospital specialists was of ahigher quality than that of general practitioners (see Table 2)The subjective quality assessment of the 200 investigated reports did not reveal astatistically significant difference regarding the completeness of the informationprovided by pharmacists and physicians (5.39 and 5.35, respectively; p > 0.05).However, for the quality of the clinical information we did find a significantdifference (pharmacists: 3.24, physicians: 3.85; p < 0.001).

3.3.4 DiscussionThe findings of the present study indicate that the contribution pharmacists maketo the voluntary ADR reporting system in the Netherlands is considerable, both interms of quantity and quality of the reports.Our study clearly showed that the pharmacists’ share in the number of reports onADRs submitted to the spontaneous reporting system is substantial. In his thesisDe Koning already reported on their sizeable contribution to Lareb.(11)

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In the period covered by this study roughly 40% of the reports received annuallyoriginated from pharmacists.In contrast to the Netherlands, in the United Kingdom the number of reportssubmitted by pharmacists is low. Green et al. described the first experiences withreporting by community pharmacists in the UK.(12) Although 93% of the

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Figure 2Grades of documentation quality of pharmacists, general practitioners and consultants.

Table 2Percentages of serious reports from pharmacists and physicians

Year of Number of serious reports Number of serious reports Odds ratioreporting by physicians by pharmacists (95% CI)

1995 26 13 1.2 (0.6-2.3)1996 88 21 3.7 (2.3-6.1)1997 124 30 3.4 (2.3-5.2)1998 255 55 4.2 (3.1-5.2)1999 327 59 4.6 (3.5-6.1)

Differences between serious and non-serious reports by physicians and pharmacists:Odds ratio is defined as the odds among the serious cases divided by the odds of thenon-serious cases. 95%CI: 95% confidence interval.

pharmacists indicated to have been aware of the fact that they could report, onlyfew actually did. They were also found to be aware of the importance of reportingADRs and the significant role they could play in their reporting. Green andcolleagues concluded that more research into which factors induce and whichinhibit pharmacists to report is needed.In the United States Syed Rizwanuddin Ahmad et al studied the contribution ofpharmacists to the serious reports received by the FDA.(13) From all seriousreports from health professionals 68% originated from pharmacists. Theyconcluded that the quality of the reports by pharmacists and physicians was equal.The criteria on which the quality assessment was based consisted of, among otheraspects, the presence of a good description of the side effects, medical history,relevant laboratory results and, if possible, a report of a biopsy or autopsy.Physicians reported death resulting from an ADR more frequently. Pharmacistsreported 95% of the hospital admissions due to an adverse drug reaction. It needsto be noted that the majority (85%) of reports submitted to the FDA stem frompharmaceutical companies. This is due to the fact that the sector is obliged by lawto forward all the information it receives from health professionals, which, in theAmerican situation, are predominately physicians. The serious reports the FDAreceives from pharmacists are in general reports from hospital pharmacists. This ismainly accounted for by the fact that also hospitals in the USA are obliged tomaintain a reporting system for ADRs. Sometimes the validity of pharmacists’ reporting is questioned because they cannotprovide clinical information. To compensate for this lack, in the UK a pharmacistcan only report after consultation of the physician treating the patient.(12) In theNetherlands such consultation is not compulsory. Hospital pharmacists, however,are in a good position to include the necessary clinical information in their reports.Since in the Netherlands hospital pharmacists are increasingly actively involved inthe integrated treatment of patients, this will better enable them to submit well-documented reports of suspected ADRs.In the present study we investigated multiple parameters to ensure that we obtainedan accurate picture of the quality of the reports sent in by pharmacists in theNetherlands. The number of ADRs specified per report was not significantlydifferent for pharmacists and doctors. In this context it needs to be noted that a highnumber of adverse reactions per report may indicate that, rather than cleardiagnoses related to ADRs, symptoms are being reported. To assess the seriousness of the reports, we analysed the number of reports rated asserious in concordance with the CIOMS criteria. We found the share of seriousreports from physicians to be twice as high as those from pharmacists. This is notsurprising since the former are more likely to encounter a serious ADR in theircapacity as medical doctors.

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Regarding the dispersion of reports in relation to the different organ systems, wefound that pharmacists report relatively more on eye and skin diseases and othermore common complaints. This can be explained by the fact that since thesedisorders are more likely to be observed by the patients themselves and they tendto prefer to discuss these effects with a pharmacist. Moreover, such symptoms canbe more easily attributed to the involved organ system. For more seriouscomplaints, however, patients will prefer a medical consultation. Although the quality assessment of 200 randomly selected reports did show a small,though not statistically significant difference in documentation grades (i.e. moredoctors’ reports received a higher grade), overall the completeness of the reportsand the quality of the information was similar for the two professional groups.Pharmacists take up a special position in the reporting of suspected adversereactions of over-the-counter products and especially alternative medicines.Hannaford et al. found that pharmacists are motivated for this role.(14) Theseaspects were not investigated in this study, since the Lareb database contains littleinformation about over-the-counter products and alternative medicines such asherbal products. Research into this aspect of the role of pharmacists in theNetherlands is recommended.

3.3.5 ConclusionOur analysis of the reports the Lareb Centre received between 1995 and 2000revealed that the contribution of pharmacists to the Dutch spontaneous reportingsystem is substantial. Despite the finding that the quality of their reports was, ingeneral, slightly lower than that of those sent in by physicians, as was their share inthe number of serious reports, apart from their considerable quantitativecontribution, pharmacists also provided information that was complementary tothe physicians’ reports. The present findings based on the experiences in the Netherlands show thatpharmacists can indeed play an important role in the reporting of adverse drugreactions.

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References 1. Edwards IR, Lindquist M, Wiholm BE, Napke E. Quality criteria for early signals of possible

adverse drug reactions. Lancet 1990;336:156-8.

2. Meyboom RH, Egberts AC, Edward IR, Hekster YA, Koning FH de, Gribnau FW. Principlesof signal detection in pharmacovigilance. Drug Saf 1997;16:355-65.

3. Abenhaim L, Moore N, Bégaud B. The role of pharmacoepidemiology in pharmacovigilance.Pharmacoepidemiol Drug Saf 1999;8:S1-7.

4. Rawlin MD. The challenge to pharmacoepidemiology. Pharmacoepidemiol Drug Saf 1995;4:5-9.

5. Effective communications in pharmacovigilance, the Erice report. WHO Uppsala MonitoringCentre. 1998.

6. Meyboom RHB. Good practice in the postmarketing surveillance of medicines. PharmacyWorld Science 1997;19:186-90.

7. Broekmans AW, Lekkerkerker JFF, Koning GHP de, Vree PH. Nieuwe regels voor het meldenvan bijwerkingen na 1995. Ned Tijdschr Geneeskd 1996;140:1166-7.

8. Anonymous. WHO Adverse Drug Reaction Dictionary. WHO Centre for International DrugMonitoring, Uppsala, 1995.

9. CIOMS Working Group IV. Benefit-Risk Balance for Marketing Drugs: Safety Signals.CIOMS, Geneva, 1998.

10. WHO Adverse Reaction Database users’ manual. Uppsala Monitoring Centre. 1996.

11. Koning GPH de. A regionalized spontaneous surveillance program for adverse drug reactionsas a tool to improve pharmacotherapy. Thesis. Utrecht University, 1994.

12. Green CG, Mottram DR, Raval D, Proudlove C, Randall C. Community pharmacists’attitudes to adverse drug reaction reporting. Int J Pharm Pract 1999;7:92-9.

13. Ahmad SR, Freiman JP, Graham DJ, Nelson RC. Quality of adverse drug experience reportssubmitted by pharmacists and physicians to the FDA. Pharmacoepidemiol Drug Saf 1996;5:1-7.

14. Hannaford PC, Bond CM, Sinclair HK. Supporting the safe use of over-the counter medicinesin the UK – a pilot pharmacovigilance study of OTC ibuprofen. Pharmacoepidemiol Drug Saf2000;9:S73.

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Chapter 3.4Thromboembolism associated with the new contraceptive Yasmin®

BMJ 2003;326:257.

Kees van Grootheest, MDTom Vrieling, PharmD

Netherlands Pharmacovigilance Centre Lareb,’s-Hertogenbosch, the Netherlands.

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3.4.1 CasesThe Netherlands Pharmacovigilance Centre Lareb, the Dutch spontaneousreporting system for adverse drug reactions, recently received five reports ofthromboembolism as a suspected adverse drug reaction to the new oralcontraceptive ethinylestradiol and drospirenone (Yasmin®)

A 17 year-old woman suddenly collapsed and died after taking the contraceptiveethinylestradiol with drospirenone for a period of six months. Autopsy showed thatshe had a massive pulmonary embolism. No obvious risk factors forthromboembolism, such as smoking, period of long immobilisation, air flights, orconcomitant medication, were evident.(1) Because she died suddenly no bloodsample was taken. Blood taken from her parents did not test positive for any of theknown risk factors: concentrations of proteïne C and antithrombin III were normal.The activated partial thromboplastin time (APTT) and partial thromboplastin time(PTT) were normal, and the existence of factor V Leiden mutation was excluded.

A 28 year old woman changed her oral contraceptive from ethinylestradiol withdesogestrel (Marvelon®) to ethinylestradiol with drospirenone. Four months latershe had thrombosis in one leg and was treated with acenocoumarol. Risk factors orconcomitant drugs were unknown.

Another patient, a 45 year old woman, had deep vein thrombosis in one leg aftertaking ethinylestradiol with drospirenone for two month, as did a 50 year oldwoman who took the contraceptive for three months.

A 35 year old woman had pulmonary thrombosis 17 days after she started takingthe contraceptive. She had given birth four months earlier.

3.4.2 DiscussionEthinylestradiol with drospirenone has been approved as an oral contraceptive inall European Union countries since 2000 and has recently been launched in theUnited Kingdom.(2) The public assessment rapport of the contraceptive gives onlyone suspected case of pulmonary embolism but also says that the number of casesin the preregistration studies are too low for a reliable conclusion on this matter.(3) The risk of thromboembolism for women using the third generation (combined)pill has long been debated. Physicians therefore may prefer a new type of combinedpill, like ethinylestradiol with drospirenone, assuming that these are safer.However, an association of these drugs with a lower risk of thromboembolism hadnot been proved by research.

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3.4.3 ConclusionOur cases show that also newer contraceptive pills may have a risk ofthromboembolism. At present, insufficient data on the superiority ofethinylestradiol with drospirenone are available.Reporting of adverse drug reactions is important in order to get an insight in thesekind of events.

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References

1. Winkler UH. Oral contraception in woman at risk of venous disease. Gynaecology Forum2001;6:23-8.

2. Sheldon T. Dutch GPs warned against new contraceptive pill. BMJ 2002;324:869.

3. Official site of the Dutch Medicines Evaluation Board. www.cbg.-meb.nl/nl/docs/gnsmiddl/par-yasmin.pdf (accessed 21 October 2002).

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