* Based on information circulated by the WHO Collaborating Centre for International Drug Monitoring during the session on Surveillance Monitoring at the International Conference on Harmonization meeting in Tokyo, 21 May 2001.

The foundations of international adverse drug reaction monitoring were established by WHO in 1968 and significant development has been achieved since then by the WHO International Drug Monitoring Programme. This achievement has been possible through work carried out by the National Centres participating in the Programme and by the WHO Collaborating Centre for International Drug Monitoring at the Uppsala Monitoring Centre (UMC) in collaboration with the Council for International Organizations of Medical Sciences (CIOMS), the International Conference on Harmonization (ICH), other professional groups, national regulatory authorities, academic institutions and industry.

Membership of the WHO International Drug Monitoring Programme is open to countries having established a national reporting centre. Each National Centre, of which there are now more than sixty, agrees to comply with standards established by the Programme, including submission of adverse drug reaction (ADR) data in reporting format to the WHO data base. This data base now holds 2.7 million reports and is used without restriction by the National Centres - some of whom have agreed to make their data available to outside parties. The data base has a multiple search facility and ad hoc searches are carried out by staff of the WHO Collaborating Centre on request. Data mining has now been added as a search possibility.

International harmonized standards, including definitions, caveat documents and procedures for confidentiality of data have been established. These definitions are agreed by all National Centres and changes and additions are made on request and by consensus. The Caveat document is binding on all outside parties using the WHO data, and outlines clearly the limits for use and interpretation.

The following outputs are currently produced by the Programme:

• Type A annual tabular listing of adverse drug reactions reported in the previous 3 years.

• A combinations data base (i.e. data underlying signal generation with Bayesian Confidence Propagation Neural Network (BCPNN) information components).

• Annual reporting statistics.

All output formats have been devised by the National Centres and are thoroughly tested and quality assured.

International expert review panel

Over 30 international experts assist the WHO Collaborating Centre in finding and evaluating new drug safety signals. In this work, a signal also includes clinically important information on a known drug/adverse drug reaction relationship. International standards for signal reviewers have also been developed.

Publications

The following publications are available from the WHO Collaborating Centre at the UMC on http://www.who-umc.org

WHO Drug Dictionary

This has become the standard drug reference for the data base accepted by all member countries, including the European Agency for the Evaluation of Medicines (EMEA), and the majority of pharmaceutical companies. It is published quarterly, but immediate ad hoc requests for updates can be carried out at a small charge

WHO Adverse Reaction Terminology (WHO-ART)

This is the standard drug safety and chemical safety dictionary of medical terms for the WHO Programme. Links with the International Classification of Diseases (ICD), Versions 9 and 10, are already in place and will be enhanced. Discussions are ongoing concerning the relationships between MedDRA, ICD and WHO-ART.

SIGNAL

For over a decade, this has been the vehicle for informing National Centres of evaluated signals from the international data base. It has recently been made available to single, international market authorization holders for their own products. SIGNAL also allows for follow-up commentary on signals reported in previous editions.

National Pharmacovigilance Systems

This is the only record of the detailed systems and processes of the National Centres who make up membership of the WHO Programme.

WHO Pharmaceuticals Newsletter

The Newsletter is a much valued information source on international regulatory action and safety updates and is produced by WHO for drug regulatory authorities.

Reactions Weekly (ADIS Press)

An agreement with the publisher has permitted availability to all National Centres of this important synopsis of drug safety issues in international and national medical journals.

Uppsala Reports

These quarterly reports are the ‘house magazine’ of the WHO Collaborating Centre and National Centres participating in the Programme. The reports serve as a general newsletter on a wide range of information on pharmacovigilance. It has a circulation of over 2000 and is free of charge.

Other ongoing activities

The ADR Signal Analysis Project (ASAP)

Collaboration is ongoing with the Intercontinental Marketing Services (IMS) using international spontaneous report rates in international signal analysis. This collaboration is currently operative for signals which are considered by the WHO Collaborating Centre and IMS as being of significant public health interest, and in which sales and drug use information will be an important contribution to understanding. Discussions are underway to extend this joint project.

Development of Bayesian Confidence Propagation Neural Network (BCPNN)

This is a data-mining process, capable of enhancing earlier and more sophisticated signal detection. The validation of this approach is now complete. It is not a replacement but a complement to other methods of signal detection. The method is being used experimentally for unsupervised and ab initio patter-recognition within data elements, with the aim of determining complex relationships

Communication in evaluating safety signals

The WHO Collaborating Centre, National Centres and many others from the various disciplines and interest groups linked to drug safety concerns have established effective communication skills as a legitimate and high priority issue in reassessing the established benefit-risk relationship of market drugs when a new safety problem arises. This activity was focalized at the Erice Meeting, and led to the Erice Declaration in 1997 (1). Collaboration with CIOMS has resulted in recommended approaches (2).

Training

Activities in pharmacovigilance theory and practice are provided by the WHO Collaborating Centre for international participants in Uppsala and also at other venues around the world. Annual international and regional training courses in pharmacoviglance are also undertaken either by the UMC alone or in cooperation with related institutions. Some training material is available on the UMC Website and teleconferencing is under consideration as an enhanced option.

Herbals

Research and development of single, worldwide herbals classification and preparation for integrating herbals into the global pharmacovigilance process is ongoing. The classification of all the herbal product/ADR information in the WHO database is now complete. A herbal ATC has been agreed with the WHO Collaborating Centre for Drug Statistics Methodology. The classification will continue to be maintained by the WHO Collaborating Centre.

Contribution to CIOMS initiatives

The WHO Collaborating Centre at the UMC has been an active contributor to the range of CIOMS publications on drug safety (except for the first). The UMC initiated and chaired the work on CIOMS 1a which was later the basis for the ICH E2B guideline on data transmission and storage. The conceptual work on benefit-risk was generated in the UMC with some outside collaborators prior to being used by CIOMS Working Group IV (2).

New WHO report data base

The above work has been used to develop an ICH E2B compatible data base for WHO Programme reports including the WHO historic data. The new data base also uses a drug file which was based upon the CEN pre-standard. This new Drug Dictionary contains the historic data from the previous WHO Drug Dictionary, and can store many more useful data fields as drug information is added.

Development of new drugs

In collaboration with industry partners, WHO develops drugs for diseases of public health significance. As part of the process, WHO has an obligation to collect and analyse drug safety information and many WHO programmes work closely with the WHO Collaborating Centre.

Conferencing

The ‘Vigimed’ e-mail conferencing system allows members of National Centres to discuss issues of interest. This is increasingly used by all counties and serves to reduce misunderstandings about regulatory activity and decisions in different countries

Conclusion

WHO is the only official body in the world having an independent and international perspective on drug safety, through its Collaborating Centre and National Centres. International harmonization, which permits understanding and variation when justified, or in situations of uncertainty, and standardization by applying agreed and optimal practices in the same way, without variation, are difficult to achieve without consensus. It is through WHO that this work can be achieved, and its record in this area is now recognized as substantial, authoritative and widely-accepted.

References

1. The Erice Declaration. WHO Drug Information, 12: 80 (1998).

2. Council of International Organizations of Medical Sciences. Benefit-risk balance for marketed drugs: evaluating safety signals. Geneva, 1998.