ICH E2B (R3) EudraVigilance

ICH E2B (R3) EudraVigilance – Impact, Challenges and the Importance of Ensuring Readiness

Dr. Prashant Dhanavade, Subject Matter Expert Medical Safety and Risk Management at Sciformix Corporation

While the EMA has done much to improve the EudraVigilance (EV) system, there have been some technical challenges which have resulted in increased effort, time, and cost to marketing authorization holders (MAHs). The main benefit of E2B(R3) over E2B(R2) is capturing of detailed data, and it provides options for inclusiveness, standardization of data, and collaboration with other stakeholders. It also focuses on the implementation of software and tools for creating, editing, sending, and receiving electronic Individual Case Safety Reports (ICSR) messages.

Background

On November 22, 2017, the EMA went live with a new and improved EV database, which was accompanied by updates to GVP Module VI (ICSR and Safety Reporting) and Module IX (Safety Signal Management).¹ Prior to November 2017, the EMA announced and published a checklist to help MAHs and sponsors prepare for the technical changes required for the launch of the new EV adverse event (AE) system.² The update to the EV database includes support for the exchange of ICSRs in E2B (R3) format.³

The ISO ICSR standard, International Council on Harmonisation (ICH) E2B (R3) specifications and the EU ICSR Implementation Guide (IG) work together to provide insight into the requirements of E2B (R3). The ISO ICSR standard provides the schema files (technical structure) to be used to create ICSR messages. The ICH E2B (R3) specifications are contained in a consensus document, which provides the data elements for the contents of ICSRs-which will vary in usage across the ICH regions. Not all data elements and requirements from ISO ICSR were used; the EU ICSR IG supplements the ICH E2B (R3) specifications with additional EU-specific requirements to support implementation of the ISO ICSR standard in accordance with ICH E2B (R3) in EU.⁴

Through the development of guidance from the ICH E2B(R3) Implementation Working Group on how to convert between the E2B(R2) and E2B(R3) ICSR formats, the ICH Backward Forward Compliance (BFC) tool was created as an option. This is one example of a possible solution that has created both an impact but also a challenge for MAHs and sponsors.

ICH E2B (R3)-how has it evolved?

While ICH E2B (R3) is applicable to ICSRs, it has been developed alongside new standards for the Identification of Medicinal Products (IDMP). IDMP standards aim to facilitate the reliable exchange of medicinal product information in a smooth and consistent manner, across all stakeholders. The development of E2B (R3) and IDMP includes the use of International Organization for Standardization (ISO) specifications which will help integrate IDMP standards with ICSR reporting. This will help improve patient safety by allowing more consistent identification of the medicinal products associated with adverse reaction reports across different geographies.

How E2B (R3) has impacted the industry?

The changes of E2B (R3) impact the way MAHs capture and report information in Drug Safety databases, meaning MAHs now have to upgrade their processes and technology or use the BFC tool the EMA has provided.

The real benefit of E2B (R3) is its interoperability, as a variety of clinical systems are able to use it to exchange data with each other. With this new structure, more data can be passed to regulatory authorities or MAHs, making the information much more valuable to all parties involved, ultimately leading to better patient outcomes.

The structure of E2B (R3) compliant safety systems is different to the earlier E2B (R2) compliant systems. E2B (R3) presents new fields, removed and/or modified fields, and some data elements which have been moved from the case level to the event level. These changes affect the look of the safety systems and the way that an adverse reaction is captured. In addition, the EU ICSR IG points out some additional requirements that should be used when submitting to EudraVigilance.

EudraVigilance has been upgraded to incorporate these functions while also offering better scalability, enhanced search capability, and more efficient data analysis. Essentially, E2B (R3) will help improve quality and completeness of ICSR data.

The key changes in EudraVigilance are outlined in Table 1.

Table 1: Key changes in EudraVigilance, post E2B (R3) and supplemented by EU ICSR IG

Change

Detail

Data Structure

E.g. Date format “Date of Creation” is replacing the safety report version number and provides a timestamp with date and time to the second ‘CCYYMMDDhhmmss[+/‐ZZzz]’

Additional data fields and/or codes

Removal or Deletion of data fields

Codes

The code “Drug Not Administered” can be used for submitting events in clinical trials and for medication error cases.

Field length

The field length of the case narrative has been extended five-fold from 20000 AN to 100000 AN (AN alphanumeric characters).

Attachments

A key requirement, it is now possible to include attachments like pdf, jpeg and other file types. (e.g. autopsy reports, copies of lab results) in the ICSR xml file. Per the guidance, this feature needs to be restricted to those documents that add value to the report.

Concept of null flavors

For specific reasons, information on mandatory data elements might be lacking for an ICSR that is still considered valid. Null flavor flags give a reason why this information is lacking (e.g. unknown, not provided). The ICH ICSR IG indicates where null flavors should be used and which types are allowed to be used.

While ICSRs can be submitted in either E2B (R2) or (R3) format, ICSRs can now only be downloaded from EudraVigilance in (R3) format. In order to be compliant to E2B (R3), all life science companies, their licensing partners, and service providers must have implemented the necessary process and technology changes so that they are able to accept cases in E2B (R3) format.

Challenges facing the industry since E2B (R3) go-live

Since the database went live the EMA has had to solve a number of teething problems. Some functionality of the platform has not worked as expected. For example, when MAHs started receiving files in the R3 format many faced challenges with conversion, meaning that the BFC tool became critical. There were also some initial software issues preventing the platform from accepting R2 files directly, resulting in increased workload for MAHs. For those who had already implemented an (R3) compliant system, the process has been smooth; however, other users have encountered teething problems with the system and have had to learn from experience. Furthermore, it is expected there will be new updates until (R3) is fully implemented by MAHs and tested with EMA and other agencies. It is recommended that MAHs keep strong vigilance on what is coming up and make use of the EMA website and training support available.⁶

Immediate requirements

Some of the immediate requirements facing life science companies include upgrading technology, updating/creating processes to collect, capture, and report data elements, performing compatibility testing, updating SOPs (standard operating procedures), and the training of staff due to increase in data fields. This would mean increase resourcing for departments.

Key considerations which should be noted by companies when looking to be R3 compliant include:

• If companies have products in EU, their system should be able to import both R2 and R3 files and export ICSR in both formats. 

• The new system alters the fields available, which should be kept in mind when converting files. It is useful to have a checklist of these fields and sufficient training of the teams using the system.

• Review and decide the codelists to be used, for example, UCUM for route of admin / form of admin.

• Data migration for those where a complete new (R3) system is required to be implemented.

• Updating SDEAs (Safety Data Exchange Agreements) with the marketing partner/business partners.

For large companies with disparate teams working on EV and case processing, cross functional working groups need to be formed to ensure that decisions are made centrally, and efforts aren’t duplicated.

For the smaller companies, the challenges are in the scale of the required changes and completing those within the time constraints. The EMA has provided guidance through an EV stakeholder change management plan to assist the industry in these challenges.⁵

Looking ahead, MAHs who don’t have an R3 compliant system, need to start planning for this. It can take between six months to a year for the MAH to move to an R3 compliant system. Therefore, a skilled technology and safety team along with a program management offfice is highly recommended.  

Summary

While the EMA has done much to improve the EudraVigilance system, there have been some technical challenges, which have resulted in increased effort, time, and cost to MAHs. Companies can appreciate and understand the impact of E2B (R3) by ensuring that they are equipped with the relevant subject matter expertise to prepare for the E2B (R3) requirements. The key to succes is to plan and be ready before it is mandated by agencies within the next three years.

References

• European Medicines Agency, 2017. EudraVigilance change management

• European Medicines Agency, 2017. EudraVigilance checklist and technical (internet) http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/q_and_a/q_and_a_detail_000165.jsp [Accessed 20/03/2018]support plan for Marketing Authorisation Holders and Sponsors of Clinical Trials in the EEA (internet) http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2017/06/WC500229797.pdf  [Accessed 20/03/2018]

• Implementing ISO ICSR/ICH E2B(R3): Key changes for pharmacovigilance Training Module PhV-M2a (Internet) http://www.ema.europa.eu/docs/en_GB/document_library/Presentation/2016/06/WC500208960.pdf [Accessed 20/03/2018]

• European Union individual case safety report (ICSR) implementation guide (Internet) http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2014/04/WC500165979.pdf [Accessed 20/03/2018]

• European Medicines Agency, 2017. EudraVigilance stakeholder change management plan (Internet) http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2015/10/WC500196029.pdf [Accessed 20/03/2018]

• EudraVigilance Training and Support- (Internet) http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/q_and_a/q_and_a_detail_000162.jsp#face%20to%20face%20training [Accessed 20/03/2018]

Dr. Prashant Dhanavade  is Subject Matter Expert of Medical Safety Operations at Sciformix Corporation. You can email him at prashant.dhanavade@sciformix.com