The Pharmacovigilance-Related ICH Topics

THE PHARMACOVIGILANCE-RELATED ICH TOPICS

So far, pharmacovigilance-related topics entered the ICH process in two waves. The first wave resulted in adoption of the ICH Topic ICH-E2A in 1994 with an extension to this work in the form of E2B and E2C, finalised between 1996 and 1997. The second wave started in 2002 with three further ICH topics, E2D, E2C Addendum and E2E, finalised between 2003 and 2004 (Table 5.1).

Drug Monitoring Programme established by WHO for pharmacovigilance of marketed medicinal products.

TOPIC ICH-E2A (STEP 5): CLINICAL SAFETY DATA MANAGEMENT – DEFINITIONS AND STANDARDS FOR EXPEDITED REPORTING

This ICH guideline, adopted at ICH Step 4 in 1994, represents the first one with relevance to pharmacovigilance. It forms part of Good Clinical Practice (GCP), and although it deals with expedited reporting of cases of serious, unexpected adverse drug reactions (ADRs) occurring in clinical trials during the pre-authorisation phase, it has also been used in the post-authorisation environment (Table 5.2). Reasons for this may have been the absence of an ICH guideline for the post-authorisation phase, but more importantly the fact that the ICH-E2A guideline was based on the Council for International Organi-sations of Medical Sciences (CIOMS) I and CIOMS reports for marketed medicinal products (CIOMS, 1990, 1992).⁵ The guideline also incorporated defini-tions agreed within the framework of the International.

ICH-E2D TOPIC (STEP 5): POST-APPROVAL SAFETY MANAGEMENT – DEFINITIONS AND STANDARDS FOR EXPEDITED REPORTING

During the second wave of pharmacovigilance-related ICH topics, it was considered important to issue an ICH (2003a) guideline on ADR case reports specif-ically for the post-authorisation phase (Table 5.3). Therefore, the ICH-E2D guideline was finalised in 2003 at ICH Step 4, formalising the application of relevant elements of ICH-E2A in the post-authorisation phase and responding to further harmon-isation needs with regard to the definitions and management of case reports for expedited reporting in this phase. Such further harmonisation needs had previously been discussed in the CIOMS V Report (CIOMS, 2001), which therefore formed an important basis for ICH-E2D.

ICH-E2B(M) TOPIC (STEP 5): CLINICAL SAFETY DATA MANAGEMENT – DATA ELEMENTS FOR TRANSMISSION OF INDIVIDUAL CASE SAFETY REPORTS

More specifically to reporting cases of ADRs/adverse events (AEs), the ICH-E2B guideline (ICH, 1997b) was developed to define the data fields for electronic reporting between all stakeholders and adopted at Step 4 in 1997. Also this ICH guideline took into account the CIOMS I Report (CIOMS, 1990). In parallel, the M2 EWG developed the related ICH-M2 recommendations ICH-ICSR DTD (syn.: ICH-M2 E2B(M)), first also adopted at Step 4 in 1997, describing the document type definition (DTD) of the electronic transmission of individual case safety reports (ICSR, syn.: ADR case report). With the mandate to further improve the definitions and spec-ifications provided in both these documents, a Main-tenance EWG was established in 1999 and revised documents were adopted at Step 4 in 2000 (ICH, 2000, 2001) (Table 5.4). A related questions and answers document is being kept updated by the EWG, last revised and adopted at Step 4 in March 2005 (ICH, 2005b). To incorporate adjustments on the basis gained through the implementation in the ICH regions, a second revision process was initi-ated and the revised ICH-E2B(M), now called ICH-E2B(R3), was signed off at Step 2 in May 2005 (ICH, 2005a).

ICH-E2C TOPIC (STEP 5): CLINICAL SAFETY DATA MANAGEMENT – PERIODIC SAFETY UPDATE REPORTS FOR MARKETED DRUGS

Besides the reporting of ADR case reports in the so-called ‘expedited manner’, periodic reporting of ADRs and other safety information was also covered in the first wave of pharmacovigilance-related activi-ties at ICH level by adopting the ICH-E2C guideline at Step 4 in 1996. This guideline describes the spec-ifications for format and content of periodic safety update reports (PSURs) reflecting the safety profile based on worldwide data and concluding upon need for action (Table 5.5). Also ICH-E2C was based on the work achieved by CIOMS, i.e. the CIOMS II and CIOMS III reports (CIOMS, 1992, 1995).

ICH-E2C ADDENDUM TOPIC (STEP 5): ADDENDUM TO CLINICAL SAFETY DATA MANAGEMENT – PERIODIC SAFETY UPDATE REPORTS FOR MARKETED DRUGS

After 1996, good experience had been gained with the concept of the PSURs, in particular in the EU, and so it was agreed to promote the concept by providing clarification and flexibility for the application of ICH-E2C in different product types and different circum-stances (Table 5.6) (ICH, 2003b). The need for such clarification and flexibility had been discussed before in the CIOMS V Report (CIOMS, 2001), which was therefore used when drafting ICH-E2C Addendum. This guideline was adopted at Step 4 in 2003.

ICH-E2E TOPIC (STEP 5): PHARMACOVIGILANCE PLANNING

This guideline was the last one being developed during the second wave and was adopted at Step 4 in 2004. This ICH topic was inspired by the excel-lence model for pharmacovigilance developed in the United Kingdom with international colleagues’ input (Waller and Evans, 2003). Also, the Japanese concept of Early Post-Marketing Phase Vigilance (EPPV), published by the Japanese Health Ministry in 2000 as a programme of communication between market-ing authorisation holders and healthcare professionals on newly marketed medicinal products to ensure safe roll-out to the market and to strengthen the sponta-neous reporting system in the early phase of market-ing (MHW, 2000), was considered in this context. However, pharmacovigilance planning is a different concept; it is intended to aid marketing authorisa-tion holders and authorities in planning data collec-tion, especially, but not exclusively, during the early phase of marketing. Such planning is based on the so-called ‘safety specification’, summarising identi-fied, potential and unknown risks for the medicinal product. Various methods for data collection may be used, and ICH-E2E therefore provides, in addition to a format for pharmacovigilance plans, harmonised terminology for methods of active and passive surveillance as well as principles for the conduct of pharmacoepidemiological studies of non-experimental design (syn.: observational studies, non-interventional studies) (Table 5.7). ICH-E2E is a framework for the formal preparation of pharmacovig-ilance in the pre-authorisation assessment phase as well as for a continued proactive approach through-out the post-authorisation phase. Although ICH-E2E is not a summary of risk minimisation tools to be implemented for a particular product, the contents of a pharmacovigilance plan may refer to such tools, as the safety specification may depend on the risk minimisa-tion systems in place, in particular where prescribing, dispensing and other health services come into play. Likewise, the planned data collection methods will depend on the health service systems and linked risk minimisation tools.