Some observations on pharmacoepidemiology in Europe

The Netherlad

JOURNAL OF MEDICINE ELSEXIEK

Netherlands Journal of Medicine 51 (1997) 205-212

Original

article

Some observations on pharmacoepidemiology in Europe ’ C.J. van Boxtel a,* , G. Wang bye a Department

of Clinical

Pharmacology

and Pharmacotherapy, Academic Medical Centre, Meibergdreef I105 AZ Amsterdam, Netherlands b Depalrment of Medical Microbiology, Academic Medical Centre, Amsterdam, Netherlands ’ Department of Epidemiology, Hubei Medical University, Wuhan, China

9,

Received 3 December 1996; revised 20 May 1997; accepted 3 June 1997

Abstract The need for pharmacoepidemiology, defined as the study of the use of and the effects of drugs in large numbers of people, will increase exponentially in the next decade both in developed and in developing countries. Within Europe, a common market of over 350 million consumers, regulations and guidelines related to drug use were formulated, especially with respect to post-marketing surveillance and the detection, interpretation and management of rare but serious drug related adverse events. The activities of international organizations like the World Health Organization in this context are briefly addressed. In the European Union a choice has been made by the regulatory authorities for spontaneous reporting systems as a minimal requirement for post marketing surveillance in all member states. The French pharmacovigilance system has to some extend functioned as a blueprint for a common European post marketing surveillance system. Therefore the organization of this French system is explained in some detail. Also in this context the need for drug utilization studies to get quantitative information about drug use is stressed. For the creation of the databases needed for case control and cohort studies a variety of approaches is used in different countries, all with their own advantages and shortcomings. Some examples from England and the Netherlands are given. The efforts of the European Commission and various scientific organizations aiming to promote the harmonization of pharmacovigilance actions in Europe are discussed. Finally, some guidelines for good pharmacovigilance practice are suggested. 0 1997 Elsevier Science B.V. Keywords:

Pharmacoepidemiology; Regulations; Good post-marketing surveillance practice; European Union

1. Introduction

Although serious adverse drug reactions (ADRs) are very rare events, the occurrence of side-effects is * Corresponding author. Tel.: + 3 1 20 5665298. ’ This paper was originally written on invitation of the Chinese Society for Phannacoepidemiology, and in the fit half of 1997 a sliahtlv modified version will be uublished in Chinese in the Chinese Journal of Pharmacoepidemiology. ”

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not a rare phenomenon at all. Many studies during the last 2 decades in Europe and the United States have shown that 20-30% of in-patients experience unwanted effects of drugs and it seems that in ambulant patients this incidence is even higher. However, in the western world over-prescription of medicines is in the first place to blame for such high rates of adverse events. Recently, the Editor-in-Chief of the Journal of Clinical Epidemiology defined pharmacoepidemiol-

0 1997 Elsevier Science B.V. All rights reserved

ogy as a study of medicines as determinants 01 health and disease in populations [l]. He quite accurately observed that it is a new bridge-science, bringing together pharmacology, clinical specialties, epidemiology, biostatistics, demography and the social sciences, the two main bridgeheads being clinical pharmacology and epidemiology. He also predicts that the need for skilled practitioners of drug safety, of which pharmacoepidemiology is the basic science, will increase exponentially in the next decade. In his opinion this is the case in developed as well as developing countries and aggressive strategies in education are required to meet such needs. Also in Japan the same signals are voiced. Kusunoki [2] wrote that high-quality post-marketing surveillance (PMS) is an essential ingredient in the safe and beneficial use of drugs. In Japan increasingly more pharmaceutical companies and others concerned with drug safety are beginning to share this perception and a collaboration of the Japanese Ministry of Health and Welfare with the Japanese Pharmaceutical Manufacturers Association has successfully created an unique framework of PMS and guidelines for good post-marketing surveillance practice. PhillipsHoward [3], referring to the introduction of Artemisinin and its derivatives in some east Asian countries, concluded that regulatory mechanisms need to be strengthened in tropical countries to ensure the proper use of these valuable drugs and that post-registration surveillance is needed to monitor, at country level, drug quality, efficacy and safety. The Chinese Society of Pharmacoepidemiology and the South East Asian Clinical Epidemiology Network (SEACLEN) play an important role in promoting pharmacoepidemiology in these regions. So it is clear that there is an awareness of the need for pharmacoepidemiology also in non-western countries and although the conditions in different parts of the world are not the same, an exchange of experiences and knowledge can be fruitful. Several reasons for the need for pharmacoepidemiology can be perceived. The true incidence of less serious side-effects is often difficult to establish before marketing, serious events are rarely detected before marketing, comedications and comorbidities that are exclusion criteria for clinical trials can play an important role, risk groups for general use of the drug must be identified. Large numbers and its non-

interventional. observational nature are characteristic for pharmacoepidemiology and for its three most frequently used methodologies: the cohort study, the case-control study and the spontaneous report.

2. European regulations and guidelines The European Union now consists of 15 member-states and soon will be a common market of some 350 million consumers. It is obvious that within such a market some common rules and regulations are needed, especially with respect to post-marketing surveillance and the detection, interpretation and management of rare but serious drug related adverse events. However, apart from governmental guidelines two international organizations contributed considerably to a healthy post-marketing surveillance climate in Europe. Already in the late 1960s and early ’70s the World Health Organization (WHO) started to create a database of spontaneous reports, first on a small scale in Geneva and later in the WHO Collaborating Centre for International Drug Monitoring in Uppsala, Sweden [4]. Now the system is based on interchange of adverse reactions information between national drug monitoring centres in 45 countries. Together these centres annually provide more than 15 000-200 000 individual reports of suspected adverse drug events. The cumulative database that has been constructed from these reports now comprises over 1.4 million records [5]. The Centre is working in collaboration with Intercontinental Medical Statistics (IMS), a commercial organization which on an international scale collects drug utilization data and recently also outcome data for the pharmaceutical industry. This allows differences between countries to be analyzed for reasons that may be due to, among others, differences in indications, medical practice or demographics. Request for special database searches and investigations are accepted by the Centre under certain conditions. Probably the state of the art of international ADR reporting is reflected in a recent publication on digoxin from this WHO Centre [6]. Suspected ADRs for digoxin that were reported from Australia, France, Germany, Sweden, the UK and the US were examined. IMS data on drug utilization and demographic information were used to explain a much higher reporting of

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suspected reactions from Australia and a later peak of occurrence with age in France. Other activities of WHO include the Drug Utilization Research Group coordinated by WHO’s European Office in Copenhagen and the WHO Collaborating Centre for Drug Statistics Methodology in Oslo with its responsibilities for, among others, the determination and update of the most frequently used measure for the quantification of the use of various drugs, the defined daily doses (DDDs). The Council for International Organizations of Medical Sciences, CIOMS, which has its domicile in Geneva and often works in concert with WHO, should be acknowledged for its work on the standardization of the handling of safety issues by the pharmaceutical industry [7]. In 1986 it established a working group on International Reporting of Adverse Drug Reactions. This working group focused on safety monitoring by the pharmaceutical industry and it identified several urgent problems for each of which a subcommittee became active. In 1989 one of these sub-groups, CIOMS-I, came out with recommendations for the standardization of reporting of case histories by the industry. The standardization of safety updates for individual products of the pharmaceutical industry (CIOMS II) was published in 1992. Within the European Union the rules with regard to drugs are set by the European Commission via the Directives prepared by the CPMP, the Committee for Proprietary Medicinal Products. Although no direct quotation of ADR monitoring is found in these directives, pharmacovigilance is implicitly recognized by the ability to suspend or withdraw a drug from the market (Directive 65/65/EEC) when safety is implicated [8]. The criteria of Directive 65/65/EEC and the responsibilities given to the CPMP by the Directives 75/319/EEC and 87/22/EEC are the basis for the coordination of non-industry related pharmacovigilance activities within the Community. In 1992 Council Directive 89/341/EEC become operative. In article 33 of this Directive the obligations with respect to the marketing of medicinal products are regulated. Most important for the pharmaceutical industry in the EU are the CPMP guidelines 111/3174/93-EN, 111/3174/93-EN, 111/3174/93-EN and 111/3174/93-EN. In these guidelines rules concerning safety reporting and PMS or pharmacovigilance activities of marketing autho-

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rization holders are stipulated. These guidelines were implemented from January 1 of 1994. The Working Group of Pharmaco-Vigilance (WGPV), an official committee within the European Union which stems from the CPMP and in which at least one expert from each member state is active, was set up in February 1989. The WGPV formulated the following proposal: “Member States shall establish a pharmacovigilance system for collecting information about adverse reactions to medicinal products in human beings and for the scientific evaluation of such information”. Professor Royer formulated for the WGPV the primary strategy for post-marketing surveillance in the EC as follows: “The pharmacovigilance of the 12 Member States is based on spontaneous notification which aim to produce alert signals and to evaluate them” [9]. It is realized, especially in Europe, that standardization of terminology between different countries becomes of increasing importance [lo]. The Medical Dictionary for Drug Regulatory Affairs (MEDDRA) is a medical terminology being prepared for this purpose by an international working party for use by regulatory authorities, pharmaceutical companies and other relevant organizations. It incorporates terms relevant to all areas of drug regulation, including the marketing authorization (MA) process, MA maintenance/renewal and pharmacovigilance.

3. Spontaneous reporting It is clear that within the European Union a choice has been made by the regulatory authorities for spontaneous reporting systems as a minimal requirement for PMS in all member states. From what has been said above about regulations, guidelines and the decision making process within the European Union this was to be expected. During the deliberations of the WGPV the French pharmacovigilance system has functioned as a blueprint for a common European PMS system. Spontaneous reporting systems for hypothesis generation are now employed by all European governments. Also on the basis of the above mentioned European guidelines they are also operative within all innovative pharmaceutical industries in Europe. Most of these reports are ultimately sent to the WHO Centre in Uppsala. Among the advan-

tages of spontaneous reporting systems can be mentioned that they are inexpensive and relatively simple, that they cover in theory the whole patient population and can detect very rare events but also both early and late events. However it is recognized that these systems can only be used for hypothesis generation. For hypothesis testing other methodologies and especially access to databases are needed. Begaud and coworkers [ 1 I] recently gave an update of the extensive experience that exists in France. The French pharmacovigilance system was set up in 1973; reporting of ADRs was made mandatory in 1984 for prescribers. This system consists of a network of 30 regional centres under supervision of a coordinating committee at the French Drug Agency. The number of ADR cases received, assessed and recorded by the regional centres is around 10000 per year; a similar number of cases are reported to the Drug Agency by the pharmaceutical industry. Moreover, regional centres work as drug information centres answering more than 23 000 inquiries per year. It should thus be recognized that some very advantageous conditions exist in France. The system is regionalized and the various regions are run by pharmacologists and university departments which also have teaching obligations. The same rigid report validation criteria are used by the different departments and all validated reports ultimately go to a central database. The fact that the system in this way provides possibilities for a more easy follow-up and thus might overcome two of the major disadvantages of spontaneous reporting systems, namely the often limited clinical information that is provided and existing difficulties with respect to case evaluations. However other disadvantages such as selective reporting, underreporting and the inherent problems with respect to hypothesis testing remain also in the French situation. Since 1963 the Netherlands Centre for Monitoring of Adverse Drug Reactions (NARD), a national voluntary reporting system within the Ministry of Health, has been operative in the Netherlands. A regionalized system for the National Registration and Evaluation of Adverse Drug Reactions, the Foundation LAREB (which stands for Landelijke Registratie Evaluatie Bijwerkingen), has been functioning now for some years as a private initiative for the gathering of spontaneous reported reactions. Although ini-

tially LAREB showed an interest in all adverse events now. in analogy to the policy in France, the organization instructs physicians only to report unexpected and/or serious events. The forms on which those reactions should be reported are distributed together with the Dutch National Formulary and are also freely available in all pharmacies. Recently the Ministry entrusted the final responsibility for the Dutch National Voluntary Reporting System to the Dutch Medicines Control Agency and transferred the daily work obligations to LAREB. Thus a system was made official which shows similarities ,iith the situation in France, with comparable advantages and disadvantages as mentioned above. However, LAREB has no formal links to university departments, which is 1 of the hallmarks of the French system. Guidelines derived from the French experience and aimed at improving the quality of statistical calculations made on spontaneous reports were recently published [12]. The same authors observe in another publication that the possibility of receiving false-positive reports of coincidental drug-event associations has received little attention [ 131. In this paper they propose a method based on the Poisson distribution for computing the maximum number of reports of an ADR that could be expected to be reported coincidentally. Three parameters are required: (i> the background risk of the event in the reference population, (ii) the total number of patients treated with the drug considered and, (iii> the proportion of cases that have been reported to the pharmacovigilance system. For rare adverse events such as agranulocytosis or toxic epidermal necrolysis, coincidental associations are so unlikely that a number of reports greater than 3 constitutes a strong warning and requires further investigation. These findings suggest that for rare events, reports of coincidental drug-event associations are too unlikely to be considered as an important limitation of spontaneous reporting. The same causality assessment method is uniformly used in France. During a 2-month period, all physicians who reported ADRs to the centre had to express their opinions on the causal link by means of visual analogue scales and the reports were assessed with the French causality assessment method by a clinical pharmacologist who was blind to physicians’

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opinions [14]. The assessment by both physicians and the standardized method was performed for 75 ADR cases involving 120 drugs. Scores given by physicians were very high (causality considered very likely or 1ik:ely) in 60% of cases and very low (causality considered unlikely or dubious/possible) in 32% of cases, resulting in a U-shaped distribution. Scores obtained using the causality assessment method were low (causality dubious/possible) in 89% of cases and causality considered likely in only 11 cases, essentially in cases with positive rechallenge. Complete agreement between the assessment by physicians and the standardized method occurred in only 6% of cases. It should be realized that these French experiences do have consequences for the Dutch spontaneous reporting situation. For example, a more intense focusing by LAREB on rare but serious events is related to the above mentioned statistical considerations which indicate that coincidental associations are very unlikely for rare events. Especially for the interpretation of spontaneous reports information on drug utilization is extremely valuable. This is not only the case for prescription drugs, but also for over-the-counter preparations for which drug utilization data are scarce. Automated pharmacy services as they exist in several European countries, and also in the Netherlands, facilitate the study of drug use to a great extent. For example, in Denmark, pharmacy data are person-identifiable, making it possible to chart the population’s drug use from the perspective of individual users, and in a recent study the potential of this data source was explored, specifically with respect to heavy drug users [15]. Sorensen and Larsen [16] suggest that such a population-based Danish prescription data resource could be linked to information about adverse drug effects by cross-checking with the Danish Hospital Register and in some cases with the register of births and the register of congenital malformations with possible high validity in pharmacoepidemiological research.

4. Databases To create the large databases needed for case control and cohort studies a variety of approaches is used in different countries. The future of pharma-

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coepidemiology will to a large extent depend on the development of new databases and the improvement of existing ones. It is therefore not surprising that not many subjects have received as much attention from the pharmacoepidemiological community in the past few years as the generation, management and quality of large databases that can be used for drug epidemiology. Especially in the United Kingdom the whole hierarchy of the types of non-experimental or non-interventional strategies that can give information about the effects of medicines in certain settings, particularly the adverse effects of drugs, can be observed. Next to the yellow card system prescription event monitoring or PEM, and the VAMP (value added medical products) database were set up. As recordlinkage activities the Oxford Record Linkage Study and the Tayside Record Linkage Project can be mentioned. IMS has made arrangements, and not only in England, for doing cohort studies in Phase IV situations. Recently, Mann (who, as the former director of VAMP and at present responsible for the PEM system, gained a good insight into the pros and cons of such databases) reported about the present situation in the UK with a focus on PEM [17]. In this system the totally retrievable drug information about the individual patient is linked to the medical record and each case is studied as it was reported as an event. PEM can be used for prospective cohort studies. The terminology used in PEM for post-marketing surveillance is described by Kubota and Inman [ 181, the latter being the auctor intellectualis of the system. Currently, the events are arranged in 24 classes which include a total of 1306 terms, mainly used to code individual events reported by general practitioners, usually without an opinion about any possible causal relationship with a particular drug. The flexibility of PEM is limited by the fact that this system can only be used for prospective studies. Greater versatility is therefore offered by the VAMP health database [19]. Prescriptions for and all relevant medical information for several million patients are collected from automated practices of general practitioners in a standardized way, validated without infringing doctor-patient confidentiality and stored. Specific advantages of the availability of such computerized data include the possibility for rapid response and flexibility. Disease-oriented or drug-oriented problems can be solved and both prospective

and retrospective cohort or case control studies can be done. It is worth mentioning that VAMP has been taken over by the National Health Service and is now operating under the name of General Practice Research Database. PHARMO is a record linkage scheme in the Netherlands which links hospital morbidity data and drug use on an individual patient level using a probabilistic record-linkage method based on patient characteristics [20]. Studies which make use of such approaches can describe the epidemiology of adverse effects, but also the natural history of disease, outcomes after medical interventions and costs associated with all of these. Problems include the link the unique personal identifier in two types of record which links them. If use of this identifier allows recognition of the individual, privacy is jeopardized. The second related problem is validating the reality of the events which might also infringe upon privacy.

5. Organizations Collaboration in the field of pharmacovigilance is in the European Union considered to be of utmost importance. Interaction and communication are therefore stimulated by the European Commission and by the CPMP. However, in Europe the scientific community itself has also been active to establish international contacts and to organize itself. The first organization then to be mentioned is ESOP, the European Society of Pharmacovigilance. This society was launched in 1993 in Paris. Its fourth annual meeting was held last fall in Lisbon, Portugal, with an impressive number of attendees of over 300. In its introductory remarks Professor Royer, the President of ESOP, emphasized the close links the members of the society have with the daily practice of medicine and that its primary goal is the improvement of the safety of our pharmacotherapeutic armament. Much older are the European contacts between scientists active in the field of drug utilization studies. Already in 1968 a comparative study was completed on antibiotic sales in six different countries, with the Netherlands being one of them. It was this work which led WHO to have its Fist meeting on ‘Drug Consumption’ in Oslo in 1969 [21]. In the

early 1970s with the help and sponsorship of WHO, the formation of a Drug Utilization Research Group, EURO-DURG, was realized with members from all over Western Europe and later also from Eastern European countries. EURO-DURG has now an official status with regular international meetings, the next one being in September 1997 in Berlin, overlapping with meetings of ESOP and of the European Association of Clinical Pharmacology. The interest of the European Commission in pharmacovigilance is, among others, manifest from their funding of the European Pharmacovigilance Research Group. The purpose of this EPRG is to come to a concerted action for post-marketing surveillance in the EU. Since 1993 a collaborative effort is made by scientists, mostly in academia, from different Western and Eastern European countries to coordinate pharmacoepidemiological research in Europe. The two main activities of this concerted action are: the study of patterns of spontaneous ADR reporting in the member states to determine the optimal approach to signal recognition and the undertaking of transnational case-control studies. For such case control studies EURONET was created to study the occurrence of some rare but potentially very serious drug-induced diseases in a study population of over 18 million subjects. Also EURO-HEPATOX, an international effort to study the mechanisms and possible genetic or other predisposing factors that lead to drug induced liver disease, is financed by the European Commission. Finally, in this context EUROWATCH should be mentioned, a telematic communication system for the rapid transfer of drug safety data between member states which is also heavily sponsored by the European Commission.

6. Good pharmacovigilance

practice

Shortly after a consensus for good clinical practice was reached in the European Union discussions started about similar guidelines for good pharmacovigilance practice (GPP). In 1995 the European Society of Pharmacovigilance devoted its third annual meeting to discussions on this matter and in 1996 American guidelines for good epidemiology practices for drug, device, and vaccine research were published in the journal Pharmacoepidemiology and

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Drug Safety [22]. A necessity for GPP of spontaneous reporting systems is a high quality of the reports. This quality can be enhanced by, among others, the use of structured reporting forms which prompt the doctor to give appropriate information on the patient, the event and the drug or drugs involved. Regular feedback from the centre to the reporting doctors, which is much more easy in a regional organization, has been shown to improve the quality of reports. A prerequisite for good spontaneous reporting is adequate pharmacology training of medical doctors. Proper appraisal of the validity of each case and the use of a uniform and validated method for causality assessment are further crucial steps in the analysis of spontaneous reports. Although the true incidence or risk cannot be estimated from spontaneous reporting, research of the geographical distribution of reports and the link with information on drug utilization, e.g.. sales data, or with other variables can give indications about the seriousness of a signal. Good pharmacovigilance practice of case-control studies is in the first place a methodological issue with an emphasis on the prevention of bias and confounding. A rigorous description of the inclusion criteria for cases is essential. Also the number and the source of the controls should be considered very carefully. Whether hospital controls or population controls can be used depends strongly on the questions asked. Some very valuable information on GPP of case-control studies can be found in Brian Strom’s book on pharmacoepidemiology [23]. For drug risk assessment Hasford 1241 makes a case for large trials with lean protocols. Since large sample sizes are usually needed, the classic randomized trial, which collects large amounts of data per patient, seems to be impracticable. Using large trials with protocols requiring only minimal data collection to allow for recruitment of large sample sizes (> 1000) is thus suggested. The objectives of drug safety studies do not need the trial design used for large efficacy studies and therefore the large trial, lean protocol design is advocated. Its characteristics are that it is: multicentric, randomized, with no efficacy assessment, recording only baseline, followup and outcome data which are crucial to the primary objective of the trial; there is no ‘by tradition’ collection of data.

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Cohort studies in which pharmacovigilance plays an important role are and will be conducted and therefore recommendations for GPP for these trials have been formulated [23]. The general requirements for GPP in cohort studies probably will not differ substantially from those for good clinical practice and it is to be expected that especially the treatment target population will benefit from GPP. It is thus of major importance that the treatment distribution population and the population(s) of interest must be well defined. Also the differences between the various designs of cohort studies, e.g. the RCT, the pragmatic randomized trial and the controlled cohort trial need to be carefully addressed in the protocol as, among others, the generalizability of the trial depends on it. As it was shown that several idiosyncratic reactions have a genetic basis and since some of the interindividual variability of drug response is now predictable with molecular biological methods, the need for such additional laboratory studies should be discussed in the protocols for trials in which pharmacovigilance plays an important role. A fixed concentration approach is not to be chosen for trials in which pharmacovigilance plays an important role. During any informed consent procedure also privacy issues should be addressed. If no adverse events are observed the ‘rule of threes’ has to be taken into account. No events in x individuals means that P = 95% that the real risk I 3 + x. Thus the label ‘safety’ should not be used for small trials. Benefit/risk ratios should be quantified as much as possible and appropriate equations have to be developed for this purpose. And finally, also in cohort studies causality assessment should get proper attention.

7. Concluding remarks Also in Europe the attention for a critical appraisal of all aspects of drug treatment regimens and policies has intensified in recent years and consequently the number of studies concerning the objective evaluation of risks and/or the weighing of risk against benefit has been rising. It is increasingly realized that ideally all quantitative information on unwanted drug reactions should be weighed against valid information on drug use. The fact that the first

drug utilization studies were initiated in Europe some 30 years ago shows that pharmacoepidemiology has a long history in this part of the world. How to obtain information about the large numbers which are the subject of study in pharmacoepidemiology and the methods that can help the investigator to handle and especially to interpret them, got considerable attention, and in Europe this attention was focused on spontaneous reporting programs. Instead of using large health maintenance data bases, such as exist in the United States, in Europe an organized involvement of the patient as a direct source of information on ADRs could be a more direct approach. However, investigations with respect to the development and validation of new methods for causality assessment would then be urgently needed. How risks are assessed and the different ways in which risks are perceived by various groups within the community are subjects of extreme interest and importance. With respect to the risks of medicines this is the more so as pharmacoepidemiology ultimately will, and must lead to action and almost certainly also to legislative action. Drug legislation and regulatory actions with regard to drugs have in the past invariably led to increased costs while improved safety was never demonstrated. We can only hope that in the future scientifically sound and validated pharmacoepidemiological information will promote European legislation for efficacious, safe and affordable drug use.

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[9] [lo]

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[17] [18] [ 191

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