- Email: [email protected]
The WHO international drug monitoring programme
The WHO International Drug Monitoring Programme History The Programme was established in 1968 as a pilot project with the participation of 10 countries that had organized national pharmacovigilance systems at that time. The intent was to develop international collaboration to make it easier to detect rare adverse drug reactions not revealed during clinical trials. The international drug monitoring centre was moved from WHO headquarters in Geneva, Switzerland, to a WHO Collaborating Centre for International Drug Monitoring in Uppsala, Sweden, in 1978. This was the result of an agreement between WHO and the government of Sweden by which Sweden assumed the operational responsibility for the Programme. WHO headquarters, Geneva, retained the responsibility for policy matters.
Present programme structure At present 54 countries are active members of the WHO Programme. Additional nine countries have formally applied for membership and they are considered associated members while the issue of technical compatibility of their reports with the W H O requirements is established. Member countries and associated member countries are listed in the table below. In each country a national centre, designated by the competent health authority, is responsible for the collection, processing, and evaluation of adverse reaction case reports submitted by health professionals. Information obtained from these reports is passed back to the professionals on a national basis, but is also submitted to the WHO-centre for inclusion in the international database. Collectively the centres annually provide 150 000-200 000 individual reports to WHO of reactions suspected of being drug-induced. The cumulative database of the WHO Programme now comprises two million case reports. Case reports submitted to the WHO-centre according to an agreed format, are checked for technical correctness and then incorporated in the international database in a weekly routine. The material is screened at least four times a year for new and serious reactions as well as the reporting frequencies of associations of particular interest. Many additional examinations of the data are made on an ad hoc basis. The WHO centre in Uppsala presently has 18 staff members. Director is Professor I. Ralph Edwards, clinical toxicologist. This staff is supported by people from various national centres, about 50 consultants of various kinds, as well as companies that provide particular specialist services. The Centre's strategy is to create a global network to optimally tackle drug safety issues.
Signal generation A combination of automatic signalling devices and scanning by experienced medical personnel is considered most advantageous to successfully fulfil the original aim of the programme, i.e., the early identification of new adverse drug reactions. National centres are provided with a variety of signalling documents four times a year, automatically generated by the W H O 529
The WHO international drug monitoring programme
530 Country
Year of entry
Country
Year of entry
ARGENTINA AUSTRALIA AUSTRIA BELGIUM BULGARIA CANADA CHILE CHINA, PR COSTA RICA CROATIA CUBA CZECH REPUBLIC DENMARK ESTONIA FINLAND FRANCE GERMANY GREECE HUNGARY ICELAND INDIA INDONESIA IRAN IRELAND ISRAEL ITALY ZIMBABWE
1994 1968 1991 1977 1975 1968 1996 1998 1991 1992 1994 1992 1968 1998 1974 1986 1968 1990 1990 1990 1998 1990 1998 1968 1973 1975 1998
JAPAN K O R E A , REP OF MALAYSIA MOROCCO NETHERLANDS NEW Z E A L A N D NORWAY OMAN PHILIPPINES POLAND PORTUGAL ROMANIA RUSSIA SINGAPORE SLOVAK REPUBLIC SOUTH AFRICA SPAIN SWEDEN SWITZERLAND TANZANIA THAILAND TUNISIA TURKEY UNITED KINGDOM USA VENEZUELA
1972 1992 1990 1992 1968 1968 1971 1995 1995 1972 1993 1976 1998 1993 1993 1992 1984 1968 1991 1993 1984 1993 1987 1968 1968 1995
Associated member countries Armenia Cyprus Egypt Macedonia Mexico
Pakistan Sri Lanka Vietnam Yugoslavia
computer system. In addition a panel of experts has been established to analyse reactions pertaining to particular body systems. Short summaries of their findings are circulated to participating national centres in a memorandum called "Signal". A recent investigation has demonstrated that the WHO Programme is successful in finding new drug-adverse reaction associations at an early stage and in providing useful information about them to national centres (1). In 1998 a new methodology (2) developed at the Uppsala Monitoring Centre, using a Bayesian ConfidencePropagation Neural Network (BCPNN) in analysing the database, was put into routine use. Case reports are received within the WHO Programme, but the intention is that other sources of drug safety information should also be considered. When the new data has been processed and entered into the A D R database, a BCPNN scan is run to generate statistical measurements for each drug-ADR combination. The resulting Combinations database (Combination: Adverse drug reaction ( A D R ) data elements occuring
The WHO international drug monitoring programme
531
together in A D R reports) will be made available to national centres, and to pharmaceutical companies, in the latter case including only information on the company's own patented products. The database will be presented in a computerised form which facilitates searching and sorting of the information. A n associations database (Association: Combinations selected f r o m a database on a quantitative basis.) is generated by selecting those combinations that pass a pre-set threshold. Based on the results of the test runs of the BCPNN the threshold level for associations is that of the lower 95% confidence limit of the IC value crossing zero when a new batch of reports is added. All associations are followed automatically for two years, the data being checked at 6monthly intervals. After the final listing, an association may be reintroduced for another 2year follow-up. The associations are also copied to a cumulative log file (history file), which will serve as a filter to exclude combinations that have in previous quarters passed the threshold level. This will prevent drug-ADR combinations with a confidence limit fluctuating around zero from being fed into the review process repetitiously. The database is also sent to the expert review panel for evaluation as well as in the Collaborating Centre. Before distributing the database, associations are checked against standard reference sources (e.g. Physician's Desk Reference (PDR), Martindale), and the published literature (using e.g. Med-line and Reactions). This facilitates the review and identifies those associations that are, if not generally known, at least identified previously. Searching and sorting of the associations data can be done, not only on drug, A D R and the various statistical measurements, but also on System Organ Class and on therapeutic drug groups using the Anatomical-Therapeutic-Chemical (ATC) classification. To ensure that there are at least two reviewers per SOC, we intend to extend the panel of reviewers from today's 30 experts to around double over the next few years. To the Associations stage, the process is purely quantitative, but clinical knowledge and judgement is necessary for the evaluation of associations, and is provided by the national centres and expert reviewers. The signals that have been identified will be published as before in the Signal document and sent to national centres. Individualised sections of the Signal document will be provided to companies on a subscription basis (only on their patented products). To aid the expert reviewers, and also to facilitate interpretation of the information presented in the Signal document, a set of guidelines is being established. As with the associations, all signals will be automatically reassessed on a 6-monthly basis, for two years, with a possibility of re-introduction for follow-up, and also copied to a history file for easy tracking. With the new follow up procedures we have introduced a mechanism by which signals can be re-evaluated following new information. This enables, for example, renewed consideration of associations for which there initially was not enough information to merit signalling. Signals that are later supported by new evidence can also be highlighted. The nature of the signal will determine what measures need be taken in terms of follow up. A larger number of variables than the routine drug-ADR combinations can also be considered using the Bayesian approach, as described above. For example, a specific pair of adverse reactions can be highly associated with a specific drug, or the effects can be determined of any other report variable or combination of variables on the 'information component' values. Also the effects of including drugs reported as 'concomitant medication' can be studied using the BCPNN. One of the outcomes of these analyses may be to identify patient subgroups that may be at particularly high risk of getting a specific adverse reaction when they have taken a specific drug. Another possibility is to establish that a drug safety problem is related to a particular country, or region, or a certain time period. It should, however, be pointed out that, in order for these data to be useful, there needs to be a substantial number of cases reported.
532
The WHO international drug monitoring programme
Reference source The data base of the WHO Programme is a unique reference source used in many different situations. When a national centre receives the first report of an unfamiliar drug-reaction association the WHO data base is often consulted to find out whether a similar observation has been made elsewhere in the world. If so, the initial signal may be strengthened. National centres are provided with an annual reference document providing summary figures of suspected drug-reaction associations reported to WHO. On-line search facilities are also at the disposal of national centres for up-to-date checking of the reporting situation. From the data base cohorts of patients affected by similar kinds of drug associated reactions may be retrieved. By looking for common features in these reports, risk factors and hypothesis for underlying mechanisms may be revealed. Quantification There is a general need to quantify adverse reaction information. Under-reporting of adverse reactions in routine monitoring is the norm. However, the degree of under-reporting differ from time-to-time, place-to-place and between drugs. The WHO-centre is working jointly with IMS International, to analyse adverse reaction reports together with drug use data from different countries. This allows national differences in reporting rates to be further analysed for reasons that may be due to differences in indications for use, medical practice and demographics etc. (3), (4). It is hoped that this type of analysis of international data will serve as a guide to the need of more precise pharmacoepidemiologicat investigations. A clearing house for information The Uppsala Monitoring Centre has an important role to play as a communication centre-a clearing house for information on drug safety at the service of drug regulatory agencies, pharmaceutical industry, researchers and other groups in need of drug safety information. Requests for special data base searches and investigations are received from these parties at a rate of around 250 per year. In addition flexible on-line retrieval programmes are made available by which the data base users may perform a variety of standardized searches by themselves. Access for non-member parties is subjected to confidentiality restrictions agreed by Programme members. Some countries maintain the right to refuse the release of their own information if they so wish. Use of the information released is subject to a caveat document as to its proper use. Detailed manuals for the or-line service and the customized retrievals on request are available from the Uppsala centre. National centres are provided with an Adverse Reactions Newsletter on a three-monthly basis since 1982. The Newsletter contains reviews of national adverse reaction bulletins and news of drug problems being investigated in various countries, supplemented by figures from the WHO register. A new type of bulletin, freely available to all interested parties, was recently introduced under the name "Uppsala Reports". It provides an easy-to-read account of news about the WHO Programme, its members and services. Communications within the WHO Programme has improved with the increasing use of electronic communications media. In the 1980s an electronic mail and conferencing system, DISNET, was introduced for communications between national centres. Since Internet in the 1990s has become more widely spread, the DISNET system has been replaced by e-mail. The Uppsala Monitoring Centre is now maintaining an e-mail discussion group called 'Vigimed', which allows for rapid exchange of information around the world on drug safety matters. Membership is restricted to persons connected to national pharmacovigilance centres. The Internet home page of the WHO Programme (http://www.who-umc.org) was introduced in 1996. It is intended to be developed into a dynamic tool for communications with all clients of the Uppsala Monitoring Centre.
The WHO international drug monitoring programme
533
Terminologies and standards The W H O Programme has assumed responsibility for developing a standardized adverse reaction terminology ( W H O - A R T ) and a comprehensive index of reported drugs ( W H O - D D ) , both of which have a utility beyond their importance to the monitoring system. These tools are used in the pre-marketing safety area, as well as for post-marketing studies by many pharmaceutical companies. W H O - A R T has also been adopted by the International Programme on Chemical Safety as the medical terminology to describe poisoning incidents. The W H O Drug Dictionary is unique in its coverage of drugs marketed throughout the world. It is available in paper print, as computer files or on a diskette together with user friendly software. The Uppsala Centre is developing it further to incorporate more detailed information and make it compatible with the pre-standard proposed by the European Committee for Standardisation (CEN). The Centre is also working with XML standards for its terminologies and dictionaries, as well as supporting such work with ICD10. The use of XML versions of terminologies will greatly enhance their combined utility and availability, for example, by internet. Within the W H O Programme a number of definitions of commonly used terms like adverse reaction, side effect, adverse event, signal etc. have been worked out (5). These definitions contribute to a harmonized way of communicating both inside and outside the Programme.
Education In order to foster education and communication in pharmacovigilance, the W H O Centre offers every second year, a two week training course in Adverse Reactions and Adverse Reaction Monitoring in Uppsala to which 25 health care professionals are accepted. The course is in three consecutive modules. The first offers some insight into the clinical aspects and diagnosis of adverse drug reactions, the second is about spontaneous monitoring and the practicalities of managing a drug monitoring centre. This section also offers hands on experience in using the data base of the W H O Programme. The final module is an introduction to wider issues in pharmacoepidemiology. There is an increasing trend towards local and regional meetings and courses in pharmacovigilance. The W H O Programme often takes part in such meetings, particularly those organized in developing countries, to provide support and technical advise.
Annual meetings Every year representatives of national centres are invited to a meeting arranged jointly by W H O and one of the participating countries. At these meetings technical issues are being discussed, both in relation to how to improve global drug monitoring in general and concerning individual drug safety problems. Since the meetings have very high attendance rates they are important for the establishment and maintenance of personal relationships subsequently contributing to good communications.
Programme development The Uppsala Monitoring Centre is currently exploring a number of leads to further improve the use of the information collected and to develop the services of the Programme. 9 By further developing the methodology of Bayesian artificial neural networks (see above) for the analysis of the large amount of data in the W H O data base it is expected that hitherto unrevealed risk factors for the development of drug related ailments will be possible to detect. 9 In response to the challenge to safety monitoring offered by traditional herbal remedies the
534
The WHO international drug monitoring programme
WHO-centre has taken initiatives to improve the classification systems for such medicines. In a joint project with institutions in the UK and the Netherlands, a system compatible with the ATC-system used for modern, synthetic medicines is being developed. Input from experts from all parts of the world, representing different therapeutic traditions, will be indispensable for this project. 9 In collaboration with the computer service company PharmaSoft, assisting the Uppsala Monitoring Centre, a new, extended, adverse reaction data base is being developed based on the recommendations of the CIOMS 1A and the ICH E2B working parties. In this data model much more detailed information on each case may be stored and case reports may also, in principle, be received directly from drug companies. Other software to support the functions of national centres is also being developed. 9 With the aim of improving communications in pharmacovigilance initiatives have been taken to call together representatives of all major groups involved in the provision of drug safety information. The so called Erice declaration on communicating drug safety information sets out the basis for further development in this area (6). The Uppsala Monitoring Centre is collaborating with the Council for International Organizations of Medical Sciences (CIOMS) to work out detailed recommendations on good communication practices in pharmacovigilance.
Collaboration with other organizations Reports of patient injuries caused by drugs used in doses above "normal" are usually referred to poison control centres and not to A D R centres. Experience gained in the W H O Programme has been used to assist also the International Programme on Chemical Safety (IPCS) in the collection of information on poisoning cases from all over the world. A separate data base for severe drug intoxication cases is being maintained by the Uppsala centre on a pilot basis. Co-operation with organizations interested in developing early signals of significance is of importance to achieve a safer drug therapy. The International Society for Pharmacoepidemiology (ISPE) is specifically interested in the science of pharmacovigilance and the Council for International Organizations of Medical Sciences (CIOMS) is pivotal in bringing interested parties together to mount various collaborative projects. Much support has been given to the European Society of Pharmacovigilance (ESOP) which is gaining increasing international status. The Centre also supports the European Pharmacovigilance Research Group which has allowed regulators and drug safety specialists from a variety of European countries to come together to plan coordinated drug safety exercises. Initiatives like these may pave the way for a much more logical development and investigation of drug safety signals world wide.
Joining the WHO Programme Considering the sensitive nature of the data being collected within the Programme, countries contributing such data to the scheme have agreed on certain requirements that should be complied with by countries wishing to join. Collaborating with W H O , being an organization for cooperation between member states, also requires a certain administrative structure of the drug monitoring activity. The basic requirements are: 9 General acquaintance with the methodology of spontaneous monitoring. A country joining the W H O Programme must have a programme for collection of spontaneous adverse reaction reports in place. 9 A national centre for pharmacovigilance must be designated and recognized by Ministry of Health (or equivalent). 9 Technical competence to fulfill reporting requirements to W H O . Case reports collected in
The W H O international drug monitoring programme
535
the national drug monitoring p r o g r a m m e must be submitted to the W H O Programme in a defined format.
For further information please contact: World Health Organization Division of Drug Management and Policy CH-1211 G e n e v a 27 Switzerland telephone +41-22 7912111 telefax +41-22 7910746 e-mail [email protected]
W H O Collaborating Centre for International Drug Monitoring Stora Torget 3 S-753 20 Uppsala Sweden telephone +46-18 656060 telefax +46-18 656080 e-mail who. [email protected], se
References 1. Fucik H, Edwards IR. Impact and credibility of the WHO adverse reaction signals. Drug Information Journal 1996;30:461-464. 2. Bate A, Lindquist M, Edwards IR, Olsson S, Orre R, Lansner A, De Freitas RM. A Bayesian neural network method for adverse drug reaction signal detection. Eur J Clin Pharmacol 1998;54:315-21. 3. Lindquist M, Sanderson J, Claesson C, Imbs J-L, Rohan A, Edwards IR. New pharmacovigilance information on an old drug; an international study of spontaneous reports on digoxin. Drug Invest 1994;8:73-80. 4. Stahl MMS, Lindquist M, Pettersson M, Edwards IR, Sanderson JH, Taylor NFA, Fletcher AP, Schou J. Withdrawal reactions with selective serotonin re-uptake inhibitors as reported to the WHO system. Eur J Clin Pharmacol 1997;53:163-9. 5. Biriell C, Edwards IR. Harmonisation in pharmacovigilance. Drug Saf 1994;10:93-102. 6. Olsson S. The role of the WHO Programme on International Drug Monitoring in coordinating worldwide drug safety efforts. Drug Saf 1998;19:1-10.
Present programme structure At present 54 countries are active members of the WHO Programme. Additional nine countries have formally applied for membership and they are considered associated members while the issue of technical compatibility of their reports with the W H O requirements is established. Member countries and associated member countries are listed in the table below. In each country a national centre, designated by the competent health authority, is responsible for the collection, processing, and evaluation of adverse reaction case reports submitted by health professionals. Information obtained from these reports is passed back to the professionals on a national basis, but is also submitted to the WHO-centre for inclusion in the international database. Collectively the centres annually provide 150 000-200 000 individual reports to WHO of reactions suspected of being drug-induced. The cumulative database of the WHO Programme now comprises two million case reports. Case reports submitted to the WHO-centre according to an agreed format, are checked for technical correctness and then incorporated in the international database in a weekly routine. The material is screened at least four times a year for new and serious reactions as well as the reporting frequencies of associations of particular interest. Many additional examinations of the data are made on an ad hoc basis. The WHO centre in Uppsala presently has 18 staff members. Director is Professor I. Ralph Edwards, clinical toxicologist. This staff is supported by people from various national centres, about 50 consultants of various kinds, as well as companies that provide particular specialist services. The Centre's strategy is to create a global network to optimally tackle drug safety issues.
Signal generation A combination of automatic signalling devices and scanning by experienced medical personnel is considered most advantageous to successfully fulfil the original aim of the programme, i.e., the early identification of new adverse drug reactions. National centres are provided with a variety of signalling documents four times a year, automatically generated by the W H O 529
The WHO international drug monitoring programme
530 Country
Year of entry
Country
Year of entry
ARGENTINA AUSTRALIA AUSTRIA BELGIUM BULGARIA CANADA CHILE CHINA, PR COSTA RICA CROATIA CUBA CZECH REPUBLIC DENMARK ESTONIA FINLAND FRANCE GERMANY GREECE HUNGARY ICELAND INDIA INDONESIA IRAN IRELAND ISRAEL ITALY ZIMBABWE
1994 1968 1991 1977 1975 1968 1996 1998 1991 1992 1994 1992 1968 1998 1974 1986 1968 1990 1990 1990 1998 1990 1998 1968 1973 1975 1998
JAPAN K O R E A , REP OF MALAYSIA MOROCCO NETHERLANDS NEW Z E A L A N D NORWAY OMAN PHILIPPINES POLAND PORTUGAL ROMANIA RUSSIA SINGAPORE SLOVAK REPUBLIC SOUTH AFRICA SPAIN SWEDEN SWITZERLAND TANZANIA THAILAND TUNISIA TURKEY UNITED KINGDOM USA VENEZUELA
1972 1992 1990 1992 1968 1968 1971 1995 1995 1972 1993 1976 1998 1993 1993 1992 1984 1968 1991 1993 1984 1993 1987 1968 1968 1995
Associated member countries Armenia Cyprus Egypt Macedonia Mexico
Pakistan Sri Lanka Vietnam Yugoslavia
computer system. In addition a panel of experts has been established to analyse reactions pertaining to particular body systems. Short summaries of their findings are circulated to participating national centres in a memorandum called "Signal". A recent investigation has demonstrated that the WHO Programme is successful in finding new drug-adverse reaction associations at an early stage and in providing useful information about them to national centres (1). In 1998 a new methodology (2) developed at the Uppsala Monitoring Centre, using a Bayesian ConfidencePropagation Neural Network (BCPNN) in analysing the database, was put into routine use. Case reports are received within the WHO Programme, but the intention is that other sources of drug safety information should also be considered. When the new data has been processed and entered into the A D R database, a BCPNN scan is run to generate statistical measurements for each drug-ADR combination. The resulting Combinations database (Combination: Adverse drug reaction ( A D R ) data elements occuring
The WHO international drug monitoring programme
531
together in A D R reports) will be made available to national centres, and to pharmaceutical companies, in the latter case including only information on the company's own patented products. The database will be presented in a computerised form which facilitates searching and sorting of the information. A n associations database (Association: Combinations selected f r o m a database on a quantitative basis.) is generated by selecting those combinations that pass a pre-set threshold. Based on the results of the test runs of the BCPNN the threshold level for associations is that of the lower 95% confidence limit of the IC value crossing zero when a new batch of reports is added. All associations are followed automatically for two years, the data being checked at 6monthly intervals. After the final listing, an association may be reintroduced for another 2year follow-up. The associations are also copied to a cumulative log file (history file), which will serve as a filter to exclude combinations that have in previous quarters passed the threshold level. This will prevent drug-ADR combinations with a confidence limit fluctuating around zero from being fed into the review process repetitiously. The database is also sent to the expert review panel for evaluation as well as in the Collaborating Centre. Before distributing the database, associations are checked against standard reference sources (e.g. Physician's Desk Reference (PDR), Martindale), and the published literature (using e.g. Med-line and Reactions). This facilitates the review and identifies those associations that are, if not generally known, at least identified previously. Searching and sorting of the associations data can be done, not only on drug, A D R and the various statistical measurements, but also on System Organ Class and on therapeutic drug groups using the Anatomical-Therapeutic-Chemical (ATC) classification. To ensure that there are at least two reviewers per SOC, we intend to extend the panel of reviewers from today's 30 experts to around double over the next few years. To the Associations stage, the process is purely quantitative, but clinical knowledge and judgement is necessary for the evaluation of associations, and is provided by the national centres and expert reviewers. The signals that have been identified will be published as before in the Signal document and sent to national centres. Individualised sections of the Signal document will be provided to companies on a subscription basis (only on their patented products). To aid the expert reviewers, and also to facilitate interpretation of the information presented in the Signal document, a set of guidelines is being established. As with the associations, all signals will be automatically reassessed on a 6-monthly basis, for two years, with a possibility of re-introduction for follow-up, and also copied to a history file for easy tracking. With the new follow up procedures we have introduced a mechanism by which signals can be re-evaluated following new information. This enables, for example, renewed consideration of associations for which there initially was not enough information to merit signalling. Signals that are later supported by new evidence can also be highlighted. The nature of the signal will determine what measures need be taken in terms of follow up. A larger number of variables than the routine drug-ADR combinations can also be considered using the Bayesian approach, as described above. For example, a specific pair of adverse reactions can be highly associated with a specific drug, or the effects can be determined of any other report variable or combination of variables on the 'information component' values. Also the effects of including drugs reported as 'concomitant medication' can be studied using the BCPNN. One of the outcomes of these analyses may be to identify patient subgroups that may be at particularly high risk of getting a specific adverse reaction when they have taken a specific drug. Another possibility is to establish that a drug safety problem is related to a particular country, or region, or a certain time period. It should, however, be pointed out that, in order for these data to be useful, there needs to be a substantial number of cases reported.
532
The WHO international drug monitoring programme
Reference source The data base of the WHO Programme is a unique reference source used in many different situations. When a national centre receives the first report of an unfamiliar drug-reaction association the WHO data base is often consulted to find out whether a similar observation has been made elsewhere in the world. If so, the initial signal may be strengthened. National centres are provided with an annual reference document providing summary figures of suspected drug-reaction associations reported to WHO. On-line search facilities are also at the disposal of national centres for up-to-date checking of the reporting situation. From the data base cohorts of patients affected by similar kinds of drug associated reactions may be retrieved. By looking for common features in these reports, risk factors and hypothesis for underlying mechanisms may be revealed. Quantification There is a general need to quantify adverse reaction information. Under-reporting of adverse reactions in routine monitoring is the norm. However, the degree of under-reporting differ from time-to-time, place-to-place and between drugs. The WHO-centre is working jointly with IMS International, to analyse adverse reaction reports together with drug use data from different countries. This allows national differences in reporting rates to be further analysed for reasons that may be due to differences in indications for use, medical practice and demographics etc. (3), (4). It is hoped that this type of analysis of international data will serve as a guide to the need of more precise pharmacoepidemiologicat investigations. A clearing house for information The Uppsala Monitoring Centre has an important role to play as a communication centre-a clearing house for information on drug safety at the service of drug regulatory agencies, pharmaceutical industry, researchers and other groups in need of drug safety information. Requests for special data base searches and investigations are received from these parties at a rate of around 250 per year. In addition flexible on-line retrieval programmes are made available by which the data base users may perform a variety of standardized searches by themselves. Access for non-member parties is subjected to confidentiality restrictions agreed by Programme members. Some countries maintain the right to refuse the release of their own information if they so wish. Use of the information released is subject to a caveat document as to its proper use. Detailed manuals for the or-line service and the customized retrievals on request are available from the Uppsala centre. National centres are provided with an Adverse Reactions Newsletter on a three-monthly basis since 1982. The Newsletter contains reviews of national adverse reaction bulletins and news of drug problems being investigated in various countries, supplemented by figures from the WHO register. A new type of bulletin, freely available to all interested parties, was recently introduced under the name "Uppsala Reports". It provides an easy-to-read account of news about the WHO Programme, its members and services. Communications within the WHO Programme has improved with the increasing use of electronic communications media. In the 1980s an electronic mail and conferencing system, DISNET, was introduced for communications between national centres. Since Internet in the 1990s has become more widely spread, the DISNET system has been replaced by e-mail. The Uppsala Monitoring Centre is now maintaining an e-mail discussion group called 'Vigimed', which allows for rapid exchange of information around the world on drug safety matters. Membership is restricted to persons connected to national pharmacovigilance centres. The Internet home page of the WHO Programme (http://www.who-umc.org) was introduced in 1996. It is intended to be developed into a dynamic tool for communications with all clients of the Uppsala Monitoring Centre.
The WHO international drug monitoring programme
533
Terminologies and standards The W H O Programme has assumed responsibility for developing a standardized adverse reaction terminology ( W H O - A R T ) and a comprehensive index of reported drugs ( W H O - D D ) , both of which have a utility beyond their importance to the monitoring system. These tools are used in the pre-marketing safety area, as well as for post-marketing studies by many pharmaceutical companies. W H O - A R T has also been adopted by the International Programme on Chemical Safety as the medical terminology to describe poisoning incidents. The W H O Drug Dictionary is unique in its coverage of drugs marketed throughout the world. It is available in paper print, as computer files or on a diskette together with user friendly software. The Uppsala Centre is developing it further to incorporate more detailed information and make it compatible with the pre-standard proposed by the European Committee for Standardisation (CEN). The Centre is also working with XML standards for its terminologies and dictionaries, as well as supporting such work with ICD10. The use of XML versions of terminologies will greatly enhance their combined utility and availability, for example, by internet. Within the W H O Programme a number of definitions of commonly used terms like adverse reaction, side effect, adverse event, signal etc. have been worked out (5). These definitions contribute to a harmonized way of communicating both inside and outside the Programme.
Education In order to foster education and communication in pharmacovigilance, the W H O Centre offers every second year, a two week training course in Adverse Reactions and Adverse Reaction Monitoring in Uppsala to which 25 health care professionals are accepted. The course is in three consecutive modules. The first offers some insight into the clinical aspects and diagnosis of adverse drug reactions, the second is about spontaneous monitoring and the practicalities of managing a drug monitoring centre. This section also offers hands on experience in using the data base of the W H O Programme. The final module is an introduction to wider issues in pharmacoepidemiology. There is an increasing trend towards local and regional meetings and courses in pharmacovigilance. The W H O Programme often takes part in such meetings, particularly those organized in developing countries, to provide support and technical advise.
Annual meetings Every year representatives of national centres are invited to a meeting arranged jointly by W H O and one of the participating countries. At these meetings technical issues are being discussed, both in relation to how to improve global drug monitoring in general and concerning individual drug safety problems. Since the meetings have very high attendance rates they are important for the establishment and maintenance of personal relationships subsequently contributing to good communications.
Programme development The Uppsala Monitoring Centre is currently exploring a number of leads to further improve the use of the information collected and to develop the services of the Programme. 9 By further developing the methodology of Bayesian artificial neural networks (see above) for the analysis of the large amount of data in the W H O data base it is expected that hitherto unrevealed risk factors for the development of drug related ailments will be possible to detect. 9 In response to the challenge to safety monitoring offered by traditional herbal remedies the
534
The WHO international drug monitoring programme
WHO-centre has taken initiatives to improve the classification systems for such medicines. In a joint project with institutions in the UK and the Netherlands, a system compatible with the ATC-system used for modern, synthetic medicines is being developed. Input from experts from all parts of the world, representing different therapeutic traditions, will be indispensable for this project. 9 In collaboration with the computer service company PharmaSoft, assisting the Uppsala Monitoring Centre, a new, extended, adverse reaction data base is being developed based on the recommendations of the CIOMS 1A and the ICH E2B working parties. In this data model much more detailed information on each case may be stored and case reports may also, in principle, be received directly from drug companies. Other software to support the functions of national centres is also being developed. 9 With the aim of improving communications in pharmacovigilance initiatives have been taken to call together representatives of all major groups involved in the provision of drug safety information. The so called Erice declaration on communicating drug safety information sets out the basis for further development in this area (6). The Uppsala Monitoring Centre is collaborating with the Council for International Organizations of Medical Sciences (CIOMS) to work out detailed recommendations on good communication practices in pharmacovigilance.
Collaboration with other organizations Reports of patient injuries caused by drugs used in doses above "normal" are usually referred to poison control centres and not to A D R centres. Experience gained in the W H O Programme has been used to assist also the International Programme on Chemical Safety (IPCS) in the collection of information on poisoning cases from all over the world. A separate data base for severe drug intoxication cases is being maintained by the Uppsala centre on a pilot basis. Co-operation with organizations interested in developing early signals of significance is of importance to achieve a safer drug therapy. The International Society for Pharmacoepidemiology (ISPE) is specifically interested in the science of pharmacovigilance and the Council for International Organizations of Medical Sciences (CIOMS) is pivotal in bringing interested parties together to mount various collaborative projects. Much support has been given to the European Society of Pharmacovigilance (ESOP) which is gaining increasing international status. The Centre also supports the European Pharmacovigilance Research Group which has allowed regulators and drug safety specialists from a variety of European countries to come together to plan coordinated drug safety exercises. Initiatives like these may pave the way for a much more logical development and investigation of drug safety signals world wide.
Joining the WHO Programme Considering the sensitive nature of the data being collected within the Programme, countries contributing such data to the scheme have agreed on certain requirements that should be complied with by countries wishing to join. Collaborating with W H O , being an organization for cooperation between member states, also requires a certain administrative structure of the drug monitoring activity. The basic requirements are: 9 General acquaintance with the methodology of spontaneous monitoring. A country joining the W H O Programme must have a programme for collection of spontaneous adverse reaction reports in place. 9 A national centre for pharmacovigilance must be designated and recognized by Ministry of Health (or equivalent). 9 Technical competence to fulfill reporting requirements to W H O . Case reports collected in
The W H O international drug monitoring programme
535
the national drug monitoring p r o g r a m m e must be submitted to the W H O Programme in a defined format.
For further information please contact: World Health Organization Division of Drug Management and Policy CH-1211 G e n e v a 27 Switzerland telephone +41-22 7912111 telefax +41-22 7910746 e-mail [email protected]
W H O Collaborating Centre for International Drug Monitoring Stora Torget 3 S-753 20 Uppsala Sweden telephone +46-18 656060 telefax +46-18 656080 e-mail who. [email protected], se
References 1. Fucik H, Edwards IR. Impact and credibility of the WHO adverse reaction signals. Drug Information Journal 1996;30:461-464. 2. Bate A, Lindquist M, Edwards IR, Olsson S, Orre R, Lansner A, De Freitas RM. A Bayesian neural network method for adverse drug reaction signal detection. Eur J Clin Pharmacol 1998;54:315-21. 3. Lindquist M, Sanderson J, Claesson C, Imbs J-L, Rohan A, Edwards IR. New pharmacovigilance information on an old drug; an international study of spontaneous reports on digoxin. Drug Invest 1994;8:73-80. 4. Stahl MMS, Lindquist M, Pettersson M, Edwards IR, Sanderson JH, Taylor NFA, Fletcher AP, Schou J. Withdrawal reactions with selective serotonin re-uptake inhibitors as reported to the WHO system. Eur J Clin Pharmacol 1997;53:163-9. 5. Biriell C, Edwards IR. Harmonisation in pharmacovigilance. Drug Saf 1994;10:93-102. 6. Olsson S. The role of the WHO Programme on International Drug Monitoring in coordinating worldwide drug safety efforts. Drug Saf 1998;19:1-10.