A Global Outlook
In an increasingly globalised Pharmaceutical industry, harmonization is essential to assure the safety of patients. International cooperation between regulatory bodies for the conformance of regulatory requirements is key to support the effective development of medicines and ensuring sufficient safety oversight. A prominent change, which is sweeping across the global for drug safety, is the transition of technical transmission of Individual Case Safety Reports (ICSRs) from ICH E2B (R2) to ICH E2B (R3) format. ICH E2B (R3) format poses an opportunity to gain greater insights into case reports and the benefit-risk profile of medicines due to the improved granularity of the data and thereby the quality of ICSRs. The revision, however, also introduces the industry to technical challenges requiring detailed preparation and lengthy planning to maintain regulatory compliance, as increasing countries come onboard. EMA, Japan, China and FDA are well on their way to the implementation. At ICON our dedicated Intelligence and Regulatory Change Management groups are in touch with other ICH countries that through ICON’s careful analysis are showing signs of progressing to this electronic submission method. Countries such as South Korea have already mandated E2B(R2) xml submissions, movement to E2B(R3) submissions is not likely to be far off.
Implementation Map - ICH E2B (R3)
Clinical Safety Data Management
ICH E2B (R3) Clinical Safety Data Management: Data Elements for Transmission of Individual Case Safety Reports is now in Step 5 of the ICH processes; as such this signifies that the document is entering into regulatory implementation by all ICH regions. There is no specified timeframe for this implementation process, although some regions such as Europe (European Commission), Japan (MHLW/PMDA) and the USA (FDA) have already adopted this into national regulations. Other regions will need to follow suit.
Regions and countries also have the further option of adding data element requirements on top of the ICH E2B (R3) guidance covered in the original ISO standard ICH E2B (R3) - ‘ISO/HL7 Health informatics - Individual case safety reports (ICSRs) in pharmacovigilance - Part 2: Human pharmaceutical reporting requirements for ICSR’. With this in mind, therefore, regional implementation guidance is expected to facilitate industry in developing these region specific requirements, which again adds another layer to the complexity in assuring readiness and compliance with country specific submissions.
Constructing safety messages for exchanging pharmacovigilance information involves multiple levels of input*.
* see Figure.1
One element is that software tools need to align as appropriate to support creating, editing, sending and receiving electronic ICSR messages. For that reason, it is essential to understand the changes that ICH E2B (R3) bring. Some key changes include:
- Causality assessment – mandatory use, with controlled options
- Case to event level for the following data elements: seriousness, country of occurrence, medical confirmation
- Additional data fields and codes- fields for IDMP (when available), patient age group-foetus D.2.3, codes for special situations (useful for risk-benefit analysis or signal detection), batch number field for suspect biological drugs, Device fields: Device ID, Device name, device batch number
- H.1 Case narrative – increased size allowance (100000AN)
- Drug not administered –(rules to prevent cases not required or that contain data error(s)
- Amendment reports (for minor corrections)
- Attachment functionality (for example for literature articles)
- Concept of Null flavours (reasons as to why mandatory data elements are missing, i.e unknown, not provided)
- Merged fields (for example: worldwide unique country identification number (C.1.8.1)
- Updated fields: C.1.8.2 First Sender of this case (value regulator; other)
- Download functionality ( of note, companies using the conversion tool to send R2 reports in R3 may struggle to receive R3 format report for their own safety databases)
- National variances, e.g. language requirements.
Implementation Plan Map - ICH E2B (R3)
To help facilitate the transition from ICH E2B (R2) to ICH E2B (R3), ICON has developed an ICH E2B (R3) Implementation Map (see fig.2 below as an example of part of our map) alongside other tools to assure on-boarding and readiness. Additionally, we are in direct contact with National Competent Authorities to support our Regulatory teams in preparing for these ICH E2B (R3) milestones, as with all such legislative transformations, preparation involves cross-functional analysis and change across departments.
1. FDA, US (CDER & CBER)
- E2B (R3) implementation plan is in progress
- FDA plans to share its progress with implementation in 3 public meetings in 2019 and 2020.
- CT MP: N/A ( IND reports to be submitted in eCTD format via ESG)
- PM MP: Currently submission in ICH E2B(R3) format is mandatory for vaccine reports and only optional for drug and biologic reports.
Health Canada, E2B(R3)
- Please contact ICON for a full implementation map
2. ANVISA, Brazil
- Use WHO's VigiFlow for message exchange of E2B (R3). Project is being planned.
3. EC, Europe
- Started in November 2017
- A survey on readiness (readiness survey) was made on Q3- Q4
4. Swissmedic, Switzerland
- The database of adverse event reports is prepared for E2B (R3) to date E2B (R3)
- Implementation project planned in 2019
5. CFDA, China (Clinical trial)
- Started in May 2018
- Reporting by E2B (R3) is mandatory from May 2019
- The plan is to start accepting reports by E2B (R3) from July 2019
- Fully implemented in 2022
6. MHLW / PMDA, Japan
- Started in April 2016
- Reporting by E2B (R3) is mandatory from April 2019
7. TGA, Australia
- For details on Australia ‘s plans ,and other countries, please contact us for our full implementation map.
For further details on any of the above topic and to request a copy of our ICH E2B (R2/R3) implementation map, please contact our dedicated Pharmacovigilance Intelligence Group. https://www.iconplc.com/services/clinical-research-services/pharmacovigilance
- ISO/HL7 27953-1:2011 (HL7) Health informatics -- Individual case safety reports (ICSRs) in pharmacovigilance -- Part 1: Framework for adverse event reporting
- ISO 11239:2012 Health informatics -- Identification of medicinal products -- Data elements and structures for the unique identification and exchange of regulated information on pharmaceutical dose forms, units of presentation, routes of administration and packaging
- ICH E2B (R3) Clinical Safety Data Management: Data Elements for Transmission of Individual Case Safety Reports
- R2B (R3) IWG Implementation: Electronic Transmission of Individual Case Safety Reports (published in July 2013)
- E2B (R3) EDQM Dose Form and Route of Administration Term User Guide ICH Conference Notes released 18Jul2018