Discussion and Conclusions

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Chapter: Pharmacovigilance: Pharmacovigilance-Related Topics at the Level of the International Conference on Harmonisation

At the time of the first wave of pharmacovigilance-related ICH guidelines, the main focus was on gathering worldwide data in efficient manner for comprehensive assessment.


The ICH initiatives in the area of pharmacovigilance have to be seen not only given the background of general need for universal standards for the investigation on medicinal products, but moreover in the context of efforts in strengthening pharmacovigilance in the three ICH regions.

At the time of the first wave of pharmacovigilance-related ICH guidelines, the main focus was on gathering worldwide data in efficient manner for comprehensive assessment. Therefore, standards for electronic reporting of ADR case reports were intro-duced as well as the concept of the PSUR.

Latest technical developments offered new possi-bilities with regard to electronic reporting, which would reduce paper work and facilitate data sharing and database entries. Its implementation is still ongo-ing, given the major technical change it represents for marketing authorisation holders and authorities. However, the future possibilities of sharing detailed case data in structured data fields are considered of major benefit. With a view to signal identification and risk-factor identification, algorithms and statistical methods have already been applied to data available˝ in other electronic formats using efficient, automated analysis by computer (data mining) (Clark, 2002; Clark, Klincewicz and Stang, 2002; Evans, 2002; Edwards et al., 2002; van Puijenbroek, 2001). In accordance with EU legislation (Article 1(7), 2000; Article 51(c), 1993), the data processing network and management system EudraVigilance has been made available by the European Medicines Agency (EMEA) for expedited reporting and data stor-age in accordance with ICH-E2B(M) as well as MedDRA. Data mining tools for this system are under development. Electronic expedited reporting using EudraVigilance will become mandatory in the EU by legislation in November 2005. EudraVigilance allows networking and work sharing between the authori-ties in the EU, a necessity for the EU regulatory system. Aspects of ICH-E2A relevant to the post-authorisation phase have been implemented in the EU in Volume 9 of the Rules Governing Medicinal Prod-ucts in the EU since its first version of 1997 (Euro-pean Commission, 1997–2004), and ICH-E2D has been integrated in the revision of Volume 9A sched-uled for finalisation in 2006. In the United States, the FDA developed their Adverse Event Reporting System (AERS), likewise based on ICH-E2B(M) and MedDRA and enabling electronic reporting. ICH-E2A and ICH-E2D have been incorporated by the FDA in their Proposed Rule on Safety Reporting Require-ments (‘Tome’) (Raczkowski, 2003), and pharmaceu-tical industry hopes that current inconsistencies with regard to ICH-E2A, E2D and E2C will be cleared in the final rule (Khan, 2004). In Japan, electronic submission of ADR case reports, in accordance with ICH-E2B(M) and MedDRA/J (Japanese translation of MedDRA), was implemented in October 2003 and covered already after 6 months 55% of all submis-sions. Otherwise, ADR case reports are submitted on disks in accordance with ICH-E2B(M), so all ADR case reports are included in the database of the Japanese authorities on the basis of ICH stan-dards (K Tamiya, personal communication, 17 June 2004). The fact that marketing authorisation holders can submit ADR case reports to the authorities in the three ICH regions according to the same technical standards represents major work facilitation.

The PSUR had been implemented, immediately after the adoption of ICH-E2C, in the EU and in Japan, and this experience was judged very positively, so that the ICH parties agreed to develop ICH-E2C adden dum during the second wave of pharmacovigilance-related ICH guidelines. ICH-E2C Addendum opened further opportunities for the useful application of the PSUR. In the United States, both these ICH guide-lines were published in the Federal Register Notice, but the PSUR has not yet become the required format for periodic reporting. Since 2001, a waver request may be submitted by marketing authorisation holders who want to use the PSUR, and in 2003, the PSUR format was included by the FDA in their Proposed Rule on Safety Reporting Requirements (‘Tome’) (Chen, 2003; Khan, 2004). Again, the availability of an agreed stan-dard should allow marketing authorisation holders to submit the same PSUR in the three ICH regions at the same point in time and also promote co-operation between authorities. However, some legal issues in rela-tion to harmonisation of data lock points and submis-sion dates remain to be solved. On the other hand, the EU has successfully piloted work sharing and peer review between authorities in relation to PSUR assessment for products that otherwise fall outside the established structures of EU co-ordination (i.e. for purely nationally authorised products not subject to the centralised, mutual recognition or decentralised proce-dure) or for active substances subject to more than one authorisation procedure. This work sharing requires harmonisation of data lock points that go beyond the product, i.e. agreeing substance birth dates. This exam-ple shows how an ICH concept can be used for an even higher degree of harmonisation, as appropriate for a particular region. Moreover, from an EU perspec-tive, it has to be said that the pharmacovigilance-related ICH guidelines as a whole have formed the basis for the processes as they are in operation in the pharmacovigilance system of the EU today.

After the first wave of pharmacovigilance-related ICH guidelines was completed in 1997, the repre-sentatives from the authorities of the three ICH regions monitored the implementation of the guide-lines at their regular meetings from 1999 onwards and expressed interest in increased co-operation between the authorities on methods and product-related issues in pharmacovigilance. The ICH initiative has certainly been providing a framework for confidence building and formal co-operation beyond personal contact.

The second wave of pharmacovigilance-related ICH guidelines was then prepared by the Japanese Ministry in 2000, at the same time when they strengthened the Japanese pharmacovigilance system. The measures taken in Japan included the concept of EPPV described above.

In the United States, the FDA published their risk management strategy in 1999 and their Strategic Action Plan for Protecting and Advancing America’s Health in 2003, which included goals of risk manage-ment and patient safety (FDA, 2003). In accordance with the Prescription Drug User Fee Act (PDUFA) III authorised in 2002, the FDA finalised, following public consultation, three guidance papers in 2005 on risk assessment during the pre-authorisation phase, risk minimisation action plans as well as good phar-macovigilance practices and pharmacoepidemiologic assessment (FDA, 2005a–c).

In the EU, the European Commission initiated in early 2001 a stakeholders’ High Level Group on Innovation and the Provision of Medicines (2002, G10 Medicines), and one of their recommenda-tions was to optimise data collection processes in pharmacovigilance. Furthermore, welcoming proposals from the EMEA, the Heads of Medicines Agencies Ad Hoc Working Group (2003, 2005a,b) in the EU started developing a risk management strategy in 2002. More specifically with regard to products centrally authorised by the European Commission, the EMEA (2004b) established a procedure for assuring high-quality pharmacovigilance in both the pre-authorisation and the post-authorisation phase. Further initiatives are announced in the EMEA Road Map to 2010 (EMEA, 2004a), taking into account the revised legislation (Directive 2004/27/EC, 2004; Regulation (EC) No 726/2004, 2004) and the needs expressed by patients (EMEA/CHMP Working Group with Patient Organisations, 2005). The revised legislation introduces the concept of risk management systems to be put in place by marketing authorisation holders, and guidance has been included in the revised Volume 9A (European Commission, 2006). Needs expressed by patients include a proactive approach in pharmacovigilance.

All these activities in the three ICH regions reflect the high demand for strengthening pharmacovigilance from a public health, political as well as public point of view. Consequently, the limited available resources have to be used efficiently, and the ICH guidelines are important for global industry as well as the authorities in the three ICH regions.

A possible third wave of pharmacovigilance-related ICH guidelines is therefore currently under considera-tion. In October 2006, the ICHSC adopted a new ICH topic on safety update reports for the development phase of medicinal products (E2F).

Looking furthermore at the importance of phar-macovigilance and drug safety beyond the three ICH regions, one needs to note the work of the Uppsala Monitoring Centre (UMC): With the aim to support world health in the field of drug safety, the UMC manages the WHO’s Programme for Interna-tional Drug Monitoring and provides an international networking structure as well as many services for their 81 member countries. Amongst those, Vigibase is the database where the ADR case reports submitted by each member country are stored for retrieval by any member country and automated signal identifica-tion from worldwide data at the level of the UMC. Vigibase is compliant with the ICH-E2B guideline, and although it uses the ADR terminology WHO-ART, it also accepts cases coded in MedDRA (UMC).

Looking at drug safety from a global perspective and in particular not neglecting the needs of develop-ing countries, the following needs to be considered.

Efficacious and safe use of a medicinal product depends on the product, the patient with his/her genetic, acquired and culture-related factors, the health services and the regulatory control. Countries where new medicinal products are marketed first need strong pharmacovigilance systems. Countries with weak regulatory control, pharmacovigilance and health services need reliable information on efficacious and safe use of medicinal product from elsewhere while making all efforts to improve their systems and taking into account local public health needs. In such circumstances, priority in data collection and pharmacovigilance planning should be given to local specificities and investigations if data from other populations and/or from other health service/regulatory/cultural environments can be extrapolated. Extrapolation of safety data from clinical trials to an ethnic population other than the trial population is addressed in the ICH-E5 guideline with regard to intrinsic as well as extrinsic factors (ICH, 1998), and data justifying extrapolation of the clinical trial data may be used also for the interpreta-tion of data emerging in the post-authorisation phase.

However, there is more work to be done in this respect, such as epidemiological, health priority, health service, pharmacogenetic, drug utilisation and medical–anthropological research. This will be a major future challenge for risk minimisation and its evaluation, when working towards worldwide access to medicines and providing medicines to multiethnic populations. In any case, co-operating within regional and international structures is of key importance for all countries with the aim of high-quality risk assess-ment and minimisation as well as efficient use of resources.

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