* The database 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 database 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 database, 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 hypotheses for underlying mechanisms may be revealed.
* In 1998 a new methodology developed at the Uppsala Monitoring Centre (UMC) using a Bayesian Confidence Propagation Neural Network (BCPNN) in analysing the database, was put into routine use. The concept of data mining (not random data dredging!) is now operating to support all countries in their work. It is based on artificial intelligence using a Bayesian logic system. It has been fully validated and is under continuous development (Bate, 2000; Bate et al, 1998a, 1998b, 2000; Lindquist, 2000; Lindquist et al., 1999; Orre et al., 2000).
A combination of automatic signalling devices and scanning by experienced medical personnel is considered most advantageous to fulfil successfully the original aim of the programme, i.e. the early identification of new ADRs. This method provides a quantitative measure of the strength of association of a drug-reaction combination in the database. Combinations that occur more frequently than expected as compared with the generality of the database are highlighted.
When the new data has been processed and entered into the ADR database, a BCPNN scan is run to generate statistical measurements for each drug-ADR combination. The resulting Combinations database (Combination: ADR data elements occurring together in ADR reports) is 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 is presented in a computerised form which facilitates searching and sorting of the information.
An associations database (Association: Combinations selected from 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 Information Component (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 six-monthly intervals. After the final listing, an association may be reintroduced for another two-year 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.
A panel of experts has been established to analyse reactions pertaining to particular body systems. The associations database is sent to the expert review panel for evaluation. Before distributing the database, associations are checked against standard reference sources (e.g. Physician's Desk Reference (PDR), Martindale), and the published literature (using, for example, Medline and Reactions Weekly). 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, ADR and the various statistical measurements, but also on System Organ Class (SOC) 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. Short summaries of their findings are circulated to participating national centres in a memorandum called "Signal". An 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.
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 six-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 numbers of variables than the routine drug-ADR combinations can also be considered using the Bayesian approach, as described above. One of the advantages of a neural network, as used in the BCPNN, is that it can search for patterns of associations between fields that are not determined a priori: it can find novel complex relationships. 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. By further developing the BCPNN methodology for the analysis of the large amount of data in the WHO database, it is expected that hitherto unrevealed risk factors for the development of drug related ailments may be detected.
* The UMC 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 database searches and investigations are received from these parties at a rate of around 275 per year. In addition, flexible on-line retrieval programmes are made available by which the database users may perform a variety of standardised 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 online service and the customised retrievals on request are available from the Uppsala centre.
National centres were provided with an Adverse Reactions Newsletter on a three-monthly basis from 1982 to 1999. The Newsletter contained reviews of national adverse reaction bulletins and news of drug problems being investigated in various countries, supplemented by figures from the WHO register. It was recently decided to incorporate this information into the WHO Pharmaceuticals Newsletter, distributed by the Health Technology and Pharmaceuticals department of WHO headquarters, leading to a wider distribution of the information to all member countries of WHO.
Uppsala Reports is the name of a bulletin which is made freely available to all interested parties by the UMC. It provides an easy-to-read account of news about pharmacovigilance, the WHO Programme, its members and services.
Communications within the WHO Programme has improved with the increasing use of electronic communications media. The UMC is 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 UMC. Recently, internet-based seminars and training courses were introduced on the UMC web site.
* International comparisons of drug safety reporting have been made (Lindquist, 1990; Lindquist and Edwards, 1993). These comparisons have shown important differences in country profiles of reporting. The differences between countries may be due to a variety of factors. Some of the differences may be purely technical but others may relate to differences in medical practice, the use of medical terms, societal influences such as media interest (Mills and Edwards, 1999). Sometimes the indications, doses of medicines and/or the routes of administration may be significant ((Lindquist et al., 1996). It is sometimes alleged that these findings are not signals, but this is to take a narrow view of a "signal" as simply a previously unreported medicine/ADR association, rather than to consider that any significant new evidence on a medicine-related risk is a signal (see WHO definition-Edwards, 1997).
* Definitions for a variety of pharmacovigilance terms have been proposed and accepted widely (Edwards, 1997). Within the WHO Programme a number of definitions of commonly used terms, such as adverse reaction, side effect, adverse event, signal, have been worked out. These definitions contribute to a harmonised way of communicating both inside and outside the Programme (Edwards and Biriell, 1994).
* Guidelines for signal finding have been proposed and widely accepted (Edwards et al., 1990). It is an important concept that a medicine related signal from spontaneous reports should be considered starting with the seriousness of the apparent signal and then appraising both the quantity of reports as well as the strength/quality of the information in those reports. Because the quality of information on a report is limited does not necessarily mean that the observation underlying it is less valid: but it does mean that objective assessment may be difficult or impossible. Assessing the weight of reported evidence is a complex clinical decision, which has further been aided by definitions of "certain", "probable", "possible", etc. (Edwards, 1997).
• The idea of the possibility of an exhaustive data set being stored was initiated, and has become the ICH E2B project. A new WHO database containing all the fields is completed (see below) (CIOMS, 1995; Lindquist, 1998). First with CIOMS and then with ICH, we have developed a comprehensive set of data fields, which have been included in our new database, which is now undergoing acceptance tests. 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. Our new database has great complexity, and it seems unlikely that many of the available fields will be completed until a "paperless" system comes into operation in several countries. The new database is fully compatible with the old one, so that we can use them in a parallel fashion during an introductory period. To provide flexibility for users with varying requirements and sophistication is a great challenge, but we are hopeful that the new database will pave the way for the international availability of much more useful case data, without recourse to the original provider for more details. Along with the provision of the new database (which is offered as a single-stop repository for industry reports, rather than their sending them to each national centre), we are planning to give more active support to national centres over their IT development. Many delays in the transmission of reports to the WHO are secondary to a variety of technical issues, which must be minimised.
• Biennial Uppsala, and regional, training courses have been introduced.
To foster education and communication in phar-
macovigilance, the WHO Centre offers every second year, a two-week training course in
Adverse Reactions and Adverse Reaction Monitoring in Uppsala to which 25 healthcare professionals are accepted. The course is in two consecutive modules. The first is focused on spontaneous monitoring and the practicalities of managing a drug monitoring centre. This section also offers hands-on experience in using the database of the WHO 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 pharmacovigi-lance. The WHO Programme often takes part in such meetings, particularly those organised in developing countries, to provide support and technical advise. UMC staff are commonly invited all over the world to speak at professional meetings.
* Every year representatives of national centres are invited to a meeting arranged jointly by WHO 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.
* The requirements for a new ADR terminology were set out including the need for definitions (Edwards et al., 1993a, 1993b). The WHO Programme has developed a standardised adverse reaction terminology (WHO-ART) and a comprehensive index of reported drugs (WHO-DD), 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. WHO-ART has also been adopted by the International Programme on Chemical Safety as the medical terminology to describe poisoning incidents.
The WHO Drug Dictionary is unique in its coverage of drugs marketed throughout the world. It is available in paper print, as computer files or on CD. The UMC 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.
* The use of IMS drug-use denominator data was made possible for international pharmacovigi-lance (Lindquist and Edwards, 1997; Lindquist et al., 1994, 1996, 1997). There is a general need to quantify adverse reaction information. 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. It is hoped that this type of analysis of international data will serve as a guide to the need for more precise pharmaco-epidemiological investigations.
* The concept of benefit-risk analysis was refined for drug safety (Edwards et al., 1996). Benefit-risk analysis is more than the subjective opinion of a group of experts and is in its infancy for drug therapy. The needs of managed care and the adoption of guidelines for therapy in all therapeutic areas mean that there needs to be satisfactory methods for measuring benefits and risks in clinical practice for all major therapeutic interventions, so that they may be compared. They must be updated regularly.
Safety must be seen as relative: there is no absolute safety. The relativity is in the risk or harm that one medicine causes compared with another and in the risk or harm caused by a drug in relation to its benefits. Andrew Herxheimer (personal communication) has pointed out that there is a lack of symmetry in the expression "benefit-risk", since benefit is actuality, whereas risk is potentiality, harm being the corresponding symmetrical term for actual damage. The recognition of the balance between terms is important. Benefits of medicines are generally based on hard scientific evidence from clinical trials, and are taken as fact or a high probability of effectiveness (although the medicine may perform differently, usually less well than expected, in the uncontrolled patient population that makes up ordinary clinical practice. Even if the patient being treated is well represented by the trial population, it may be difficult to predict the outcome in that individual.) Harm, above a certain incidence, is measurable in clinical trials, but we have much less information on safety than we need, because clinical trials are not well designed to elicit information about adverse effects. Additional information comes from individual case reports of varying quality and quantity and from observational studies, which are not consistently performed with all drugs and all ADRs. Information on harm is therefore often based on uncontrolled material. The observational material, reports or studies, is susceptible to various biases to different degrees. It may therefore be more useful to use the potential term, because from the patient's point of view the usually single benefit can be explained in close-to-precise terms, but the negative side of the equation is at best made of probabilities and more often made up of unquan-tified evidence and opinion.
In the future, the Human Genome Project, and other investigations into genetic variance, must be linked to our knowledge of ADRs and, in particular, idiosyncratic ADRs so that we are able to be more predictive about issues of drug safety.
* The concept and needs for benefit-risk communication have been explored and developed. One of the widely quoted outcomes was the ''Erice Declaration'' which proposes principles for such communication (Bowdler, 1997; Edwards and Hugman, 1997; Edwards, 1999; Edwards et al., 2000). 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 Erice report on communicating drug safety information sets out the basis for further development in this area. The UMC is collaborating with the CIOMS to work out detailed recommendations on good communication practices in pharmacovigilance.
• National Pharmacovigilance Systems—Country Profiles and Overview (Olsson, 1999) is an important publication useful to many people who wish to know who's who and what's where in pharmacovigilance. We are also considering a web version of this as well as much more information and analysis of activity.
• The idea of monitoring herbal medicines and classifying them has been introduced and is operating (Farah, 1998; Farah et al., 2000a, 2000b; Lindquist et al., 2000). In response to the challenge to safety monitoring offered by traditional herbal remedies, the UMC has taken initiatives to improve the classification systems for such medicines. In a joint project with institutions in the United Kingdom 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, is indispensable for this project. The database is far enough advanced to be finding some herbal signals and allow us to respond to queries using an extensive literature resource as well as ADR reports. Collaboration is commencing with South Africa, the United States and Germany.
• The need for new pharmacovigilance approaches to deal with the aggressive global marketing of drugs has been identified: see below (Edwards, 2000).
• There have been 86 publications in 10 years actively involving UMC staff
• An Anniversary Symposium was held in 1998 to commemorate 20 years of the UMC in Sweden. It was attended by about two hundred delegates.
• Developments within WHO have led to a meeting of an expert group to produce an advocacy document for pharmacovigilance which has the tentative title of: "The value of pharmacovigilance" and subsidiary title of: "In public health and patient care''. The results of this meeting will be made available and will set the scene for much to be done in the future.
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