Observations from Working Group Exercises

The Twenty-eighth Annual Meeting of Representatives of the National Centres participating in the WHO Programme for International Drug Monitoring was held from 26 to 29 September 2005, in Geneva, Switzerland. In this meeting, working group exercises focused on several key issues in pharmacovigilance including:

• how pharmacovigilance centres react to high profile (drug) withdrawals
• pharmacovigilance in public health programmes
• reporting adverse events following immunization (AEFI)
• developing an international taxonomy for patient safety events
• reporting and learning from patient safety events
• the relevance of the International Classification of Diseases (ICD) in pharmacovigilance.

Below is a summary of key concepts and conclusions from three of the exercises:

1. Improving the effectiveness of pharmacovigilance centres' responses to high profile withdrawals

Regulatory authorities have the responsibility for undertaking several procedures prior to withdrawing a medicine from the market. They must collate and review available data and conduct a risk/benefit assessment. They must also communicate the risk that they identify to prescribers in an adequate manner and identify alternative product options. However, depending on the capacity of the agency, there is much divergence among regulatory agencies in carrying out one or more of these procedures. Well-resourced, and well-established regulatory bodies have access to and capacity to analyse company trial data, local adverse drug reactions (ADR) data, data from the global ADR database and medical literature. Countries with less-developed regulatory systems are restricted by resource and/or capacity constraints. They may be limited to reviewing local data, and although trials may be ongoing in their country they may not have access to the company trial data. They may therefore have to rely on communications from regulatory authorities in developed countries on regulatory actions taken.

In general, from a regulator's perspective, access to drug safety information is often compromised by artificial or inappropriate timelines for reporting, confidentiality requirements, media and government pressure and gaps in human resources and skills.

Inadequate information hampers appropriate and timely regulatory measures, which in turn often erode professional and public confidence in the regulator in particular, and in pharmacovigilance, in general.

Recommendations for improving global-regulatory efficiency should focus around:

• improving information-sharing and multilateral collaborations;

• strengthening regulatory capacity by releasing, in a timely fashion, ADR reports, their evaluation, and all risk-communication material even while still in development;

• promoting electronic exchange and discussion on safety issues of global concerns (eg through Vigimed, E-Drug) and

• undertaking literature review of high risk products and creating a data bank for such literature.

2. Pharmacovigilance in public health programmes

The group identified that there are compelling reasons for including pharmacovigilance into public health programmes including those designed to treat HIV/AIDS, malaria, TB and helminth infections: Many new drugs are used to treat HIV/AIDS, malaria, TB and helminth infections on the basis of efficacy-focused clinical trials of limited duration with little knowledge of their long-term adverse effects. Available data on drug toxicity are mainly from industrialized countries (e.g. in HIV/AIDS treatments), which have a different clinical and operational context in developing countries. Drugs are used in combinations not assessed in developed countries. Life threatening side effects, co-morbidities and co-treatments impact on selection of preferential and alternative drugs

At present few if any public health programmes include a pharmacovigilance component in their design. In several countries that run public health programmes, there are no pharmacovigilance centres and hence, there are no systematic methods for collecting ADR reports in these countries. In those countries where both systems exist, they often function in parallel, with little communication between the national pharmacovigilance centres and the public health programmes.

United Republic of Tanzania, a case example:

The Tanzanian drug monitoring programme was created as a result of the malaria treatment programme in the country. It started as a process of active collection of ADR reports in the malaria treatment programme, the country now has a fully-fledged pharmacovigilance system and was recognized as a full member of the WHO programme for

International Drug Monitoring in 1993.

Recommendations:

• All public health programmes should be required to build pharmacovigilance into their agenda.

• As a first step, the concepts in the ICH E2E guideline on Pharmacovigilance Planning should be used to develop a system for meeting the needs of specific infectious diseases and drug treatment related safety concerns in public health programmes. This guideline describes a method for summarizing the important identified risks of a drug, important potential risks, and important missing information, including the potentially at-risk populations and situations where the product is likely to be used that have not been studied. It proposes a structure for a Pharmacovigilance Plan and sets out principles of good practice for the design and conduct of observational studies.

• The spontaneous reporting system could be used for flagging-off initial concerns which could be further verified using targeted active-surveillance programmes for specific ADR issues. These may be further reinforced with randomized clinical trials, if warranted.

• Where pharmacovigilance centres exist, it is incumbent upon the staff of these centres to establish communications with the relevant staff in the public health programmes, to visit and instruct public health workers in the importance, benefits and methods of reporting an ADR.

3. Vaccines: How to improve AEFI reporting to the WHO global ADR database

There are many barriers to reporting adverse events following immunization programmes. These include: a split between ADR and AEFI pharmacovigilance groups, with the two systems developing as parallel fiefdoms; issues of data ownership; lack of communication between immunization programmes and pharmacovigilance centres; differing objectives (e.g. vaccines programmes may focus more on procurement and storage issues than on pharmacovigilance); lack of education on the importance and benefits of AEFI reporting; insufficient AEFI-oriented elements in current pharmacovigilance training programmes; current taxonomy and definitions of adverse events/ reactions being drug (ADR) based; and insufficient vaccine-centres' participation in WHO annual meeting of pharmacovigilance centres.

If this situation is to change there must be an improvement in the following areas:

1. Political will and commitment. Officials at higher levels of authority must be involved to introduce AEFIreporting into national health agendas and there must be active participation of regulators, with appropriate legislation to empower AEFI reporting.

2. Communication, media and visibility: There must be improved communication between all partners, across and within systems, nationally and internationally, linking vaccines programmes with pharmacovigilance centres. Vaccine-related topics should be included in popular and reader-friendly journals such as Viewpoint, for increasing awareness about AEFI-issues. Vaccines should be a topic in all WHO annual meetings of national pharmacovigilance centres.

3. Education and training: Elements of vaccine-safety and AEFI reporting should be included in the curriculum of undergraduate training of all health professionals. Additional vaccine-safety courses in French, English and in vernacular languages should be organized.

4. Terminology: A focus should be on specific AEFI needs and terms. The WHO Collaborating Centre for International Drug Monitoring should analyse the most frequent text terms focusing only on vaccines. The ATC classification system for vaccines should be improved.

5. Harmonization: A common reporting system should be developed while retaining a focus on country specific issues. AEFI terms relevant to patient safety should be harmonized. Lot numbers of biological products should be collected in the AEFI reports, as well as details such as private versus publicly provided vaccines for facilitating 'track and search' functions. Common elements and synergies between AEFI and ADR reporting systems should be explored and developed such that both systems benefit mutually.