Guidance for Industry Appendix I (B) to the ICH E2B(R3) ICSRs Implementation Guide Backwards and Forwards Compatibility U. S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER) April 2022 ICH Revision 1 Guidance for Industry Appendix I (B) to the ICH E2B(R3) ICSRs Implementation Guide Backwards and Forwards Compatibility Additional copies are available from: Office of Communications, Division of Drug Information Center for Drug Evaluation and Research Food and Drug Administration 10001 New Hampshire Ave., Hillandale Bldg., 4th Floor Silver Spring, MD 20993-0002 Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353 Email: druginfo@fda.hhs.gov https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs and/or Office of Communication, Outreach and Development Center for Biologics Evaluation and Research Food and Drug Administration 10903 New Hampshire Ave., Bldg. 71, Room 3128 Silver Spring, MD 20993-0002 Phone: 800-835-4709 or 240-402-8010 Email: ocod@fda.hhs.gov https://www.fda.gov/vaccines-blood-biologics/guidance-compliance-regulatory-information-biologics/biologics-guidances U. S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER) April 2022 ICH Revision 1 Contains Nonbinding Recommendations This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on this topic. It does not establish any rights for any person and is not binding on FDA or the public. You can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations. To discuss an alternative approach, contact the FDA office responsible for this guidance as listed on the title page. Note 1: This guidance was jointly developed by the E2B(R3) and M2 Expert Working Groups of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) and has been subject to consultation by the regulatory parties, in accordance with the ICH process. This document has been endorsed by the ICH Steering Committee at Step 4 of the ICH process, November 2012. At Step 4 of the process, the final draft is recommended for adoption to the regulatory bodies of the European Union, Japan, and the United States. Note 2: FDA has added title pages and front matter to meet the requirements of the Agency's good guidance practices. FDA has maintained all other elements of the original implementation guidance, including pagination and heading numbers. The heading numbers are consistent with the structure and format of the ICH E2B(R3) Implementation Guide. * * This guidance was updated to incorporate technical updates made to the ICH Appendix I (B) to the Implementation Guide for Electronic Transmission of Individual Case Safety Reports - Backwards and Forwards Compatibility Recommendations in 2022. You may submit comments on the guidance at any time. Submit comments to Docket No. FDA-2011-D-0720 (available at https://www.regulations.gov/search?filter=FDA-2011-D- 0720). Contains Nonbinding Recommendations Document History Date of Title of Document Version Published for WG Finalisation April Appendix I (B) to the Implementation Guide for 2.00 Step 4 document E2B EWG Electronic Transmission of Individual Case Safety 2013 Reports (ICSRs) Backwards and Forwards Compatibility Recommendations November Editorial corrections made – the accompanying 2.01 Step 4 document E2B history spreadsheet should be consulted for details of 2014 IWG changes November Change reference from M5 to ISO IDMP 2.02 Step 4 document E2B IWG 2016 March 2022 Editorial corrections made 2.03 Step 4 document E2B(R3) Update scenarios and examples of 5.2.6 EWG/IWG Legal notice: This document is protected by copyright and may, with the exception of the ICH logo, be used, reproduced, incorporated into other works, adapted, modified, translated or distributed under a public license provided that ICH's copyright in the document is acknowledged at all times. 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Contains Nonbinding Recommendations TABLE OF CONTENTS 1.0 PURPOSE…………………………………………………………………………………... 4 2.0 BACKGROUND……………………………………………………………………............. 4 3.0 COMPATIBILITY……………………………………………………………………......... 5 3.1 Definitions…………………………………………………………………………………... 5 3.1.1 Compatibility 5 3.1.2 Backwards Compatibility 5 3.1.3 Forwards Compatibility 5 3.2 Compatibility Use Cases…………………………………………………………………….5 3.2.1 Assumptions 5 3.2.2 Exchange Use Case 6 3.2.3 Retransmission Use Case 7 3.3 Ensuring Data Integrity During E2B(R2) and E2B(R3) Conversions………………….. 8 4.0 APPROACH FOLLOWED BY THIS APPENDIX……………………………………… 8 5.0 GUIDANCE FOR CONVERSION………………………………………………………. 10 5.1 Date Format……………………………………………………………………………….. 10 5.1.1 Same Precision 10 5.1.2 Less Precision in E2B(R3) 11 5.1.3 More Precision in E2B(R3) 11 5.1.4 Date of this Transmission 12 5.1.5 Time Zones 13 5.2 Code Mapping…………………………………………………………………………….. 13 5.2.1 Coded value set 13 5.2.2 Report Nullification / Amendment 15 5.2.3 Sender Type 16 5.2.4 Age Group 17 -1- Contains Nonbinding Recommendations 5.2.5 Drug Characterization 18 5.2.6 Free Text and Codes for Route of Administration 18 5.2.7 Time Interval 21 5.2.8 MedDRA Codes 23 5.2.9 Code Lists and UCUM Codes 24 5.2.10 Free Text and UCUM Codes 25 5.2.11 Re-administration and Recurrence of Reaction on Re-administration 25 5.2.12 Patient and Parent Sex 26 5.2.13 Acknowledgement Codes 27 5.3 Deletion…………………………………………………………………………………….. 28 5.3.1 Fields to Ignore 28 5.3.2 Fields with Default Value 28 5.3.3 Safety Report Version Number 29 5.3.4 Number of Separate Dosages 29 5.4 Addition……………………………………………………………………………………. 30 5.4.1 Fields with No Mapping 30 5.4.2 Study Registration 31 5.4.3 ISO IDMP identifiers 32 5.4.4 Investigational Product Blinded 33 5.4.5 Case Narrative in Native Language 33 5.4.6 Reaction as Reported and Translated 34 5.4.7 Reported cause(s) of death 34 5.4.8 Autopsy-determined Cause(s) of Death 35 5.5 Field Length……………………………………………………………………………….. 36 5.5.1 Extended Fields to Truncate 36 5.5.2 Extended Fields to Keep 37 5.5.3 Length of Numeric Fields (Extended) 38 5.6 Null Flavour……………………………………………………………………………… 39 5.6.1 Null Flavour for Optional Free Text Fields 39 5.6.2 Null Flavour for Fields Required in E2B(R3) 40 5.6.3 Null Flavour for Optional Codes and Dates 41 5.7 Structure…………………………………………………………………………………… 42 -2- Contains Nonbinding Recommendations 5.7.1 Country of Primary Source 42 5.7.2 Country of Event/Reaction 43 5.7.3 Unique Case Number 43 5.7.4 Sender's Telephone and Fax 44 5.7.5 Literature References 45 5.7.6 Seriousness and Seriousness Criteria 45 5.7.7 Results of Tests 49 5.7.8 Drug and Dosage Information 50 5.7.9 Substance Strength 52 5.7.10 Indication 53 5.7.11 Drug-Reaction / Event Matrix 54 5.7.12 Additional Information on Drug 57 5.7.13 Additional Sender Diagnosis 58 5.7.14 Batch and Message Wrappers 59 5.7.15 ICSR Message Sender and Receiver in ACK 60 -3- Contains Nonbinding Recommendations 1.0 PURPOSE This document is an appendix to the Implementation Guide (IG) for the 'International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) Electronic Transmission of Individual Case Safety Reports (ICSRs)'. This Appendix is intended to assist reporters and recipients (including pharmaceutical companies, authorities and non-commercial sponsors) in implementing systems with special focus on the recommendations for conversion back and forth between the previous standard, i.e., E2B(R2) and this standard, i.e., E2B(R3). The evolution of the guideline, from E2B(R2) to E2B(R3), has the consequence that ICSRs cannot be perfectly converted from one standard version to the other (either backwards or forwards). Repeated conversion could result in transformation or loss of information. Therefore receivers need to evaluate contents carefully. This document presents the recommendations for conversion agreed within ICH so as to provide a reference to system providers, and a common understanding on the way to convert ICSRs and ICSR acknowledgments (ICSR ACKs) between E2B(R2) and E2B(R3). 2.0 BACKGROUND The current pharmacovigilance databases are operating largely on the basis of the ICH E2B(R2) guideline and the DTD version 2.1. Whilst it is envisaged that ICH E2B(R3) will improve the current standards, it is obvious that there will be a time of transition until all stakeholders (regulators, pharmaceutical industry and other parties in the pharmaceutical business sector) have implemented the new guideline and have their pharmacovigilance databases adapted to these new standards. This implies that pharmacovigilance databases operating ICH E2B(R2) and / or ICH E2B(R3) standards will have to coexist and mapping procedures must be in place to ensure a coherent and harmonized exchange of ICSRs among all stakeholders at the international level. This is even more important since the exchange of ICSRs takes place between multiple senders and receivers and therefore depends on the implementation status (E2B(R2) or E2B(R3)) of each party in each transmission. As a result, it is of major importance to address the compatibility between the two guidelines and the relevant message specifications and to provide a mapping standard that will ensure a smooth transition phase. The present appendix intends to • describe the need for a harmonized and documented backwards and forwards compatibility • define the method to address compatibility issues -4- Contains Nonbinding Recommendations • categorize the compatibility issues • define the mapping recommendations for the ICH E2B(R2) and the ICH E2B(R3) 3.0 COMPATIBILITY 3.1 Definitions 3.1.1 Compatibility Different systems (e.g., programs, file formats, protocols, programming languages) that can work together or exchange data are said to be compatible. For ICH E2B, compatibility refers to different pharmacovigilance systems (e.g., programs, file formats, protocols, programming languages) that can interact to support the electronic exchange of pharmacovigilance data on the basis of the ICH E2B(R2) and ICH E2B(R3) and applicable message specifications. 3.1.2 Backwards Compatibility Backwards compatibility in the context of this appendix covers the capability to map the data elements of the ICH E2B(R3) guideline to the previous version, i.e., the ICH E2B(R2) guideline dated February 2001. The backwards compatibility should ensure that the integrity of the data is maintained and that limitations are fully described and supported by the E2B community (e.g., in case some data is lost during the conversion). 3.1.3 Forwards Compatibility Forwards compatibility in the context of this appendix covers the capability to map the data elements of the ICH E2B(R2) guideline dated February 2001 to the new version i.e., ICH E2B(R3). The forwards compatibility should ensure that the integrity of the data is maintained and that limitations are fully described and supported by the E2B community (e.g., in case some data is lost during the conversion). 3.2 Compatibility Use Cases 3.2.1 Assumptions Compatibility applies to pharmacovigilance systems and their capability to handle the message specifications in ICH E2B(R2) and ICH E2B(R3) formats. It is assumed that the stakeholders will always send the reports in the format supported by their own pharmacovigilance system. The receiver of a case safety report is the only one who might be called upon to perform a conversion (either backwards or forwards) in order to load the report into his / her system. -5- Contains Nonbinding Recommendations Here is the list of assumptions made in the context of the present appendix: • Pharmacovigilance systems that currently support the E2B(R2) format will continue to receive E2B(R2)- compliant messages, and there is no guarantee that these systems will immediately evolve to directly support E2B(R3)-compliant messages. • Pharmacovigilance systems that are developed to support the E2B(R3) format will support E2B(R3) compliant messages and there is no guarantee that these systems will also be developed to support E2B(R2) messages. However, system developers are encouraged to provide backwards compatibility support. • Pharmacovigilance systems should be built to process ICH message specifications. This implies that the underlying information model (usually the database) should be compatible with the ICH information model of the safety and acknowledgment messages. However, it is expected that national or regional requirements that govern system development might be outside the scope of the ICH information model, and therefore these recommendations for conversion might be extended to cover such additional requirements. • Pharmacovigilance systems should be fully validated to ensure that the information exchanged in the ICH message format can be appropriately processed and stored in computer and human readable format. 3.2.2 Exchange Use Case When exchanging ICH E2B messages between a sender and a receiver, the message can be created and processed by systems running either the ICH E2B(R2) or the ICH E2B(R3) specifications. In such situation, there is a need to convert the file from E2B(R3) to E2B(R2) or vice versa. The conversion will always occur on the receiver side, i.e., just before loading the case into the pharmacovigilance system. Sender Conversion Receiver E2B(R3) E2B(R2) to E2B(R2) E2B(R3) E2B(R2) Sender Conversion Receiver E2B(R2) E2B(R3) to E2B(R3) E2B(R2) E2B(R3) Sender Receiver Figure 1: Use Case for Exchange -6- Contains Nonbinding Recommendations In order to properly be treated by the receiver's system, the message should be converted from the format used by the sender to the one in use by the receiver. The objective of this conversion is to retrieve all the relevant information at the receiver's side: • Conversion from E2B(R3) to E2B(R2) calls for the retrieval of all the relevant E2B(R2) data elements and their content from the E2B(R3) format and mapping them to the E2B(R2) message format to generate an E2B(R2)-compliant message. • Conversion from E2B(R2) to E2B(R3) calls for the generation of a new message format. This is accomplished by mapping the E2B(R2) data elements and their content to the E2B(R3) format. Note that some E2B(R2) information might not be available to map to E2B(R3) and therefore the new E2B(R3) formatted message should support the absence of information. 3.2.3 Retransmission Use Case Based upon pharmacovigilance reporting requirements, E2B messages can be retransmitted between different senders and receivers. During this retransmission process, information previously submitted about the case should not be omitted or changed if no new information is available for retransmission. Recommended exceptions are listed in the E2B(R3) Specifications; these exceptions concern information available in both E2B(R2) and E2B(R3) information models. The retransmission use case is described in the diagram below. Figure 2: Use Case for Retransmission In such case, the conversions should ensure data integrity as much as possible, i.e., with limited loss of information. Ideally, the initial and retransmitted messages should be identical from a content perspective except for the information updated by the re-transmitter. This appendix intends to provide the recommended rules to follow regarding the conversion of E2B messages (backwards and forwards) including the capabilities regarding the retransmission use case, and known limitations. -7- Contains Nonbinding Recommendations 3.3 Ensuring Data Integrity During E2B(R2) and E2B(R3) Conversions The conversion use cases call for limiting the amount of data lost during the conversion process. Conversion from E2B(R2) to E2B(R3) might result in some information being absent from the E2B(R3) formatted message because some of the data elements in E2B(R2) are no longer supported in E2B(R3), e.g., information on the receiver. Conversion from E2B(R3) to E2B(R2) should provide an abbreviated version of the data content because some data elements in E2B(R3) have been modified to increase the size of the text field, e.g., the sender's comments. To minimize data lost during conversions, the following principles have been taken into account: • If a data element in E2B(R2) is not present in E2B(R3), this implies that related information might not be considered required and therefore this information can be omitted. For example, the information about the receiver in E2B(R2) has been removed in E2B(R3). • If a data element has been added in E2B(R3), this does not imply that current E2B(R2)-compliant systems would support the new information and therefore it is not always called for to convert the data to E2B(R2). However, the most important information will be converted to E2B(R2) as part of the case narrative section. • For the retransmission use case where re-transmitters manage several conversions between E2B(R2) and E2B(R3), re-transmitters parse the content of the case narrative section of E2B(R2) in order to reconstruct the E2B(R3) message as close as possible to the original message. The case narrative section of E2B has originally a limited size (20,000 characters). It is recommended to amend E2B(R2) system and design E2B(R3) systems so as to support the case narrative section with no size limitation. This would allow the use of the case narrative placeholder to store the fields that cannot be converted directly, i.e., at the location where the fields appear in E2B. If the E2B(R2) system cannot be amended to remove the size limitation on the case narrative field, it is then recommended to extract the information out of the case narrative field into an external file, for the information part coming from the conversion process. 4.0 APPROACH FOLLOWED BY THIS APPENDIX The Implementation Guide for the E2B(R3) message provides technical recommendations on the way to encode the new E2B information model using the XML Schema of the ICH ICSR message. Therefore, the information fields that have not been amended in the new specification can be converted by following the same recommendations as the one provided in the Implementation Guide. The present appendix focuses on -8- Contains Nonbinding Recommendations changes provided by E2B(R3), and for each change, or change type, guidance is provided regarding the way to convert the information backwards and forwards. Changes provided by E2B(R3) can be categorized as follows: • Date format: the E2B(R2) guideline supports dates with 2 separate fields, one for the date itself and one for the date format. The implementation of the E2B(R3) message has taken another approach by supporting the date data type, i.e., with both date value and date format in the same field. Guidance is provided on the conversion of dates. • Code mapping: E2B(R2) and E2B(R3) provide sets of codes for several fields. In some case, one format has additional code values than the other. Guidance is provided on the conversion of codes. • Deletion: some fields of E2B(R2) have been deleted in E2B(R3). Guidance is provided on the way to handle such fields. • Addition: some fields have been added in E2B(R3). Guidance is provided on the way to handle such fields. • Field length: some fields have been extended (i.e., increased field length) in E2B(R3). Guidance is provided on the conversion of such fields. • Masking: E2B(R3) provides another way to mask information, for privacy purposes, or because information is unknown. Guidance is provided on the way to pass from one encoding to the other, and vice versa. • Structure: E2B(R3) provides another way to structure the information that was available in E2B(R2) guideline. Guidance is provided on the way to pass from one structure to the other, and vice versa. The next section provides the guidance for conversion. The section has been organized per type of change, as to provide generic guidance before instructions specific per field, for both the ICSR and the ICSR Acknowledgement messages. -9- Contains Nonbinding Recommendations 5.0 GUIDANCE FOR CONVERSION 5.1 Date Format The E2B(R2) guideline supports dates with 2 separate fields, one for the date itself and one for the date format. For each field, the list of supported formats is specified in the guideline. The implementation of the E2B(R3) message has taken another approach in supporting the date type, i.e., with both date value and date format in the same field. E2B(R3) only defines a minimal precision, and dates should be reported with the appropriate precision. In E2B(R3), dates can be reported with a time zone. Guidance is provided on the conversion of dates, which depend on whether E2B(R3) supports the same date precision as E2B(R2), or whether additional formats are supported, with more or less precision. 5.1.1 Same Precision All the date fields, except E2B(R2) A.1.3 / E2B(R3) C.1.2 (see section 5.1.4), can be expressed in a format that is appropriate for E2B(R2) and E2B(R3). In such case, the following conversion recommendation should apply: • To upgrade to E2B(R3), the date value should be copied from the date field of E2B(R2) into the field of E2B(R3). The date format field of E2B(R2) should be ignored. Example: Input in E2B(R2): date value: 20081025; date format: CCYYMMDD Output in E2B(R3): date field: 20081025 • To downgrade to E2B(R2), the date value should be copied from the field of E2B(R3) into the date field of E2B(R2), and, based on the number of characters, the date format should be detected and pasted into the date format field. Example: Input in E2B(R3): date value: 20081025 Output in E2B(R2): date field: 20081025; date format: CCYYMMDD -10- Contains Nonbinding Recommendations 5.1.2 Less Precision in E2B(R3) For several date fields, E2B(R3) supports the same or lower precision than in the E2B(R2) guideline. Conversion guidance is only called for when a date is encoded with low precision in E2B(R3). The following fields can be encoded in E2B(R3) with precision to the year, while the E2B(R2) guideline expects a precision to the month or the day: E2B(R2) E2B(R3) Description Field Format Field Format Date of birth (patient) B.1.2.1 CCYYMMDD D.2.1 at least to the day Last menstruation period date B.1.6 CCYYMM D.6 at least to the year (patient) CCYYMMDD Date of birth (parent) B.1.10.2.1 CCYYMMDD D.10.2.1 at least to the year Last menstrual period date B.1.6 CCYYMMDD D.10.3 at least to the year (parent) In such a case, the following conversion recommendation should apply: • To upgrade to E2B(R3), the date value should be copied from the date field of E2B(R2) into the field of E2B(R3). The date format field of E2B(R2) should be ignored. Example: Input in E2B(R2): date value: 20081025; date format: CCYYMMDD Output in E2B(R3): date field: 20081025 • To downgrade to E2B(R2), the closest date format available in E2B(R2) should be selected, i.e., the lowest possible date precision of E2B(R2) for the field. The date value should be copied from the E2B(R3) field and completed with the additional digits set to default values, i.e., 01 for months and days, and 00 for hours, minutes and seconds. Example: Input in E2B(R3): date value: 2008 Output in E2B(R2): date field: 2008; date format: CCYY 5.1.3 More Precision in E2B(R3) For all the date fields, E2B(R3) supports the same or higher precision than in the E2B(R2) guideline. All the date fields can be encoded in E2B(R3) with a precision below the second (format CCYYMMDDhhmmss.uuuu), while the E2B(R2) guideline expects a precision to the year, the month, the day, the minute or the second (formats CCYY, CCYYMM, CCYYMMDD, CCYYMMDDhhmm or CCYYMMDDhhmmss). In such case, the following recommendation applies: • To upgrade to E2B(R3), the date value should be copied from the date field of E2B(R2) into the field of E2B(R3). The date format field of E2B(R2) should be ignored. Example: Input in E2B(R2): date value: 20081025; date format: CCYYMMDD -11- Contains Nonbinding Recommendations Output in E2B(R3): date field: 20081025 • To downgrade to E2B(R2), the following cases can occur: 1) If the date format used in E2B(R3) exists in E2B(R2), see section 5.1.1. 2) If the date format used in E2B(R3) does not exist in E2B(R2), the closest date format available in E2B(R2) should be selected, i.e., the highest possible date precision of E2B(R2) for the field. The date value should be copied from the E2B(R3) field and truncated to fit the date format of E2B(R2). Example: Input in E2B(R3): date value: 20081025093512.1234 Output in E2B(R2): date field: 20081025; date format: CCYYMMDD 5.1.4 Date of this Transmission In the context of the backwards and forwards compatibility, the field C.1.2 (i.e., the date of this transmission) is also used to carry information on the safety report version number (which is only available in the E2B(R2) message format). E2B(R2) E2B(R3) Description Field Format Field Format Safety report version number 2AN - - Date of this transmission A.1.3 CCYYMMDD C.1.2 CCYYMMDDhhmmss In E2B(R2), the safety report version number may be used to distinguish the evolution of the same safety report over time. In E2B(R3), this distinction is supported with the field C.1.2 which timestamps the case safety report down to the second. In E2B(R2), the field A.1.3 has precision to the day only. To retain the versioning of case safety report, the following recommendation applies: • To upgrade to E2B(R3), the date value of C.1.2 should be copied from the date field of E2B(R2) into the field of E2B(R3). The safety report version number, which is a number assumed to always remain below 60, should be appended to the field C.1.2 as seconds. Example: Input in E2B(R2): date value of A.1.3: 20081025 safety report version number: 3 Output in E2B(R3): date value of C.1.2: 20081025000003 • To downgrade to E2B(R2), the date value of C.1.2 should be truncated to the day (see section 5.1.3) and the safety report version number should not be set. If the safety report version number is to be populated, the downgrade recommendations should be extended so as to support the batch conversion of ICSR messages, taking into account the sequence of safety reports. Whether this is to be provided depends on the -12- Contains Nonbinding Recommendations national / regional pharmacovigilance systems, and the related mechanisms are not described in this document. 5.1.5 Time Zones For all the date fields, E2B(R3) supports the provision of a time zone at the end of the date format (CCYYMMDDhhmmss.uuuu±ZZzz). The E2B(R2) guideline does not support time zones. In such case, the following recommendation applies: • To upgrade to E2B(R3), the date value should be copied from the date field of E2B(R2) into the field of E2B(R3). The date format field of E2B(R2) should be ignored. No time zone should be defined when copying the date to E2B(R3): Example: Input in E2B(R2): date value: 200810250935; date format: CCYYMMDDHHMM Output in E2B(R3): date field: 200810250935 • To downgrade to E2B(R2), the time zone should be ignored: Example: Input in E2B(R3): date value: 200810250935+06 Output in E2B(R2): date field: 200810250935; date format: CCYYMMDDHHMM If, in addition to a time zone, the date has less or more precision in E2B(R3), then the recommendations defined in sections 5.1.2 and 5.1.3 also apply. 5.2 Code Mapping E2B(R2) and E2B(R3) provide sets of codes for several fields. In some case, one version of the standard has more code values than the other. Guidance is provided on the conversion of codes, which depend on whether E2B(R3) supports the same codes or whether additional code values have been introduced. 5.2.1 Coded value set -13- Contains Nonbinding Recommendations A. E2B(R2) and E2B(R3) expect the same set of codes for the following fields: E2B(R2) E2B(R3) Description Field Code List Field Code List Type of report A.1.4 4 possible values C.1.3 4 possible values Are additional documents A.1.8.1 yes / no C.1.6.1 true / false (+) available? Does this case fulfil the local A.1.9 yes / no C.1.7 true / false (*)(+) criteria for an expedited report? Other case identifiers in A.1.11 yes C.1.9.1 true (*)(+) previous transmissions Qualification A.2.1.4 5 possible values C.2.r.4 5 possible values (*) (primary source) Study type in which the A.2.3.3 3 possible values C.5.4 3 possible values reaction(s) / event(s) were observed Continuing B.1.7.1d 3 possible values D.7.1.r.3 3 possible values (*) (patient medical history) Was autopsy done? B.1.9.3 3 possible values D.9.3 3 possible values (*) Continuing B.1.10.7.1d 3 possible values D.10.7.1.r.3 3 possible values (*) (parent medical history) More information available B.3.1.3 yes / no F.r.7 true / false (tests) In such case, the following recommendation applies: • To upgrade to E2B(R3), the field value should be copied from the E2B(R2) field into the E2B(R3) field. The effective encoding of the code value should follow the guidance set in the related Implementation Guide. • To downgrade to E2B(R2), the field value should be copied from the E2B(R3) field into the E2B(R2) field. The effective encoding of the code value should follow the guidance set in the related Implementation Guide. B. E2B(R2) and E2B(R3) expect the same terms, however the codes may differ. E2B(R2) E2B(R3) Description Field Code List Field Code List Outcome of reaction / event B.2.i.8 6 possible values E.i.7 6 possible values at the time of last observation Action taken with the drug B.4.k.16 6 possible values G.k.8 6 possible values The fields that are marked with an asterisk (*) represent fields that can be nullified in E2B(R3). In such cases, the following downgrade recommendations apply: -14- Contains Nonbinding Recommendations • If the field is nullified as 'unknown' and an 'unknown' code is available in the code list of E2B(R2) for that field, the E2B(R2) field should be set to the code corresponding to 'unknown'. • If the field is nullified as 'unknown' but no 'unknown' code is available in the code list of E2B(R2) for that field, the E2B(R2) field should not be set. • If the field is nullified as another way (e.g., 'masked'), the E2B(R2) field should not be set. The fields that are marked with a plus sign (+) represent fields that are required in E2B(R3) and optional in E2B(R2). In such case, the following upgrade recommendations apply: • If the E2B(R2) field is set, the mapping should apply as described above. • If the E2B(R2) field is not set, the E2B(R3) field should beset as follows: 1) Field C.1.6.1 should be set to 'false'. 2) Field C.1.7 should be set with a null flavour of type 'NI'. 3) Field C.1.9.1 should be set with a null flavour of type 'NI'. 5.2.2 Report Nullification / Amendment E2B(R2) and E2B(R3) expect different codes for the report nullification / amendment: E2B(R2) E2B(R3) Description Field Code List Field Code List Report nullification / A.1.13  Yes C.1.11.1  nullification amendment  amendment The following recommendation applies: • To upgrade to E2B(R3), the following cases can occur: 1) If the field value of E2B(R2) is set to 'yes', the field of E2B(R3) should be set to the code 'nullification'. The effective encoding of the code value should follow the guidance set in the related Implementation Guide. 2) If the field value of E2B(R2) is not present, the field of E2B(R3) should not be provided in the upgraded message. • To downgrade to E2B(R2), the following cases can occur: 1) If the field value of E2B(R3) is set to 'nullification', the field of E2B(R2) should be set to the code 'yes'. 2) If the field value of E2B(R3) is set to 'amendment', the field of E2B(R2) should not be provided and the following information should be appended to the case narrative section (B.5.1): -15- Contains Nonbinding Recommendations NULLIFICATION / AMENDMENT: Amendment: <content of field C.1.11.2: reason for nullification / amendment> 3) If the field value of E2B(R3) is not present, the field of E2B(R2) should not be provided in the downgraded message. 5.2.3 Sender Type E2B(R2) and E2B(R3) expect different codes for the sender type: E2B(R2) E2B(R3) Description Field Code List Field Code List Sender type A.3.1.1  pharmaceutical C.3.1  pharmaceutical company company  regulatory authority  regulatory authority  health professional  health professional  regional pharmacovigilance  regional centre pharmacovigilance  WHO collaborating center centres…  WHO collaborating  other center…  patient / consumer  other The following recommendation applies: • To upgrade to E2B(R3), the field value should be copied from the E2B(R2) field into the E2B(R3) field. The effective encoding of the code value should follow the guidance set in the related Implementation Guide. • To downgrade to E2B(R2), the following cases can occur: 1) If the field value of E2B(R3) is not 'patient / consumer', the field value should be copied to the field of E2B(R2). 2) If the field value of E2B(R3) is 'patient / consumer', the field value of E2B(R2) should be set to the code 'other'. -16- Contains Nonbinding Recommendations 5.2.4 Age Group E2B(R2) and E2B(R3) expect different codes for the age group: E2B(R2) E2B(R3) Description Field Code List Field Code List Age group B.1.2.3  neonate D.2.3  foetus  infant  neonate  child  infant  adolescent  child  adult  adolescent  elderly  adult  elderly The following recommendation applies: • To upgrade to E2B(R3), the field value should be copied from the E2B(R2) field into the E2B(R3) field. The effective encoding of the code value should follow the guidance set in the Implementation Guide. • To downgrade to E2B(R2), the following cases can occur: 1) If the field value of E2B(R3) is not 'foetus', the field value should be copied to the field of E2B(R2). 2) If the field value of E2B(R3) is 'foetus', no information should be provided in the E2B(R2) field B.1.2.3. Instead, the E2B(R2) field for patient name and initials (i.e., B.1.1 according the E2B(R2) numbering), should be set with the term 'FOETUS'. -17- Contains Nonbinding Recommendations 5.2.5 Drug Characterization E2B(R2) and E2B(R3) expect different codes for the characterization of the drug role: E2B(R2) E2B(R3) Description Field Code List Field Code List Characterization B.4.k.1  suspect G.k.1  suspect of drug role  concomitant  concomitant  interacting  interacting  drug not administered The following recommendation applies: • To upgrade to E2B(R3), the field value should be copied from the E2B(R2) field into the E2B(R3) field. • To downgrade to E2B(R2), the following cases can occur: 1) If the field value of E2B(R3) is not set to 'drug not administered', the field value should be copied to the E2B(R2) field. 2) If the field value of E2B(R3) is set to 'drug not administered', the corresponding E2B(R2) field should be set to 'suspect' and text 'drug not administered' should be appended to the E2B(R2) field on Additional information on drug (i.e., B.4.k.19 according to the E2B(R2) numbering): 'DRUG NOT ADMINISTERED' 5.2.6 Free Text and Codes for Route of Administration For the following fields, one guideline expects a code while the other expects a free text value: E2B(R2) E2B(R3) Description Field Code List Field Code List Route of administration B.4.k.8 67 possible codes G.k.4.r.10.1 free text (patient) G.k.4.r.10.2a Term ID G.k.4.r.10.2b Term ID Version Route of administration B.4.k.9 67 possible codes G.k.4.r.11.1 free text (parent) G.k.4.r.11.2a Term ID G.k.4.r.11.2b Term ID Version In E2B(R2), the fields above contain codes as they are defined in the Appendix of the E2B(R2) guideline. In E2B(R3), the same E2B(R2) codes can be used or they can be converted to the codes of EDQM Standard Terms (see USER GUIDE: Use of EDQM terminologies for Dose Forms and Routes of Administration for Individual Case Safety Reports in E2B(R3) message). If standard terms are not available, free text values can be provided as appropriate free text values. Therefore, the following recommendation applies when E2B(R2) codes are used: -18- Contains Nonbinding Recommendations • To upgrade to E2B(R3), there are three possible scenarios: 1) An E2B(R2) code (i.e., the numeric value) should be copied to the corresponding E2B(R3) code with reference to the E2B(R2) vocabulary: Example: Input in E2B(R2): code value: 030 Output in E2B(R3): Term ID version (field 2a): E2B / R2 Term ID (field 2b): 030 2) If an E2B(R2) RoA term has mapped with an EDQM Standard Term by the EDQM User Guide, the E2B(R2) code (i.e., the numeric value) should be converted to the mapped EDQM RoA Concept Class-Concept Code (i.e., alphabetic numeric value): Example: Input in E2B(R2): code value: 030 Output in E2B(R3): Term ID version (field 2a): Corresponding Version Number of EDQM RoA Concept Code Term ID (field 2b): ROA-20035000 3) If an E2B(R2) RoA term has NOT mapped with an EDQM Standard Term by the EDQM User Guide, the E2B(R2) term should be copied or an appropriate term should be entered in the free text field: Example: Input in E2B(R2): code value: 025 Output in E2B(R3): Free text: Intrahepatic Term ID version (field 2a): blank Term ID (field 2b): blank • To downgrade to E2B(R2), there are three possible scenarios: 1) If a code is provided in E2B(R3) with reference to the code system / version E2B / R2, the code field (i.e., the field 2a) should be copied as is to the E2B(R2) field: Example: Input in E2B(R3): Term ID version (field 2a): E2B / R2 Term ID (field 2b): 030 Output in E2B(R2): Code value: 030 -19- Contains Nonbinding Recommendations 2) If a code is provided in E2B(R3) with an EDQM RoA Concept Class-Concept Code (i.e., alphabetic numeric value) and its corresponding term has mapped with an E2B(R2) RoA term, the corresponding E2B(R2) code should be entered in the E2B(R2) field. Example: Input in E2B(R3): Term ID version (field 2a): Corresponding Version Number of EDQM RoA Concept Code Term ID (field 2b): ROA-20035000 Output in E2B(R2): Code value: 030 3) If a code is provided in E2B(R3) with an EDQM RoA Concept Class-Concept Code (i.e., alphabetic numeric value) and its corresponding term has NOT mapped with an E2B(R2) RoA term, or if a free text field is used in E2B(R3), the code value should be set to '050' (i.e., Other) in the E2B(R2) field, and the information should be copied to the E2B(R2) field B.4.k.19 according to the following examples (with header 'ROUTE' or 'PARENT ROUTE'): Example Input in E2B(R3): Term ID version (field 2a): 1 (patient Corresponding Version Number of EDQM RoA route): Concept Code Term ID (field 2b): ROA-20013500 Or Free text: XYZ Output in E2B(R2): Code value: 050 B.4.k.19 ROUTE: ROA-20013500 (Corresponding Version Number of EDQM RoA Concept Code) Or B.4.k.19 ROUTE: XYZ Example Input in E2B(R3): Term ID version (field 2a): 2 (parent Corresponding Version Number of EDQM RoA route): Concept Code Term ID (field 2b): ROA-20013500 Or Free text: XYZ Output in E2B(R2): Code value: 050 B.4.k.19 PARENT ROUTE: ROA-20013500 (Corresponding Version Number of EDQM RoA Concept Code) -20- Contains Nonbinding Recommendations Or B.4.k.19 PARENT ROUTE: XYZ Once Term IDs are identified, the recommendations should rely on a mapping between the list of values possible in E2B(R2) and the ones possible in E2B(R3). 5.2.7 Time Interval E2B(R2) and E2B(R3) expect different codes for the time interval unit: E2B(R2) E2B(R3) Description Field Code List Field Code List Number of units in interval B.4.k.5.4 3N G.k.4.r.2 4N Time interval unit B.4.k.5.5  Year G.k.4.r.3  UCUM Code  Month  {cyclical}  Week  {asnecessary}  Day  {total}  Hour  Minute The following recommendation applies: • To upgrade to E2B(R3), the field value should be copied from the E2B(R2) field into the E2B(R3) field. The effective encoding of the code value should follow the guidance set in the related Implementation Guide. • To downgrade to E2B(R2), the following cases can occur: 1) If the unit value of E2B(R3) is supported in E2B(R2) and if the number of units is not too long, the fields (number and unit) should be copied to the corresponding fields of E2B(R2). 2) If the number of units is too long (i.e., using 4 digits), the E2B(R2) field should be not provided in field G.k.4.r.2. Instead, the information should be appended to the E2B(R2) field on dosage text (i.e., B.4.k.6), along with the unit: Example Input in E2B(R3): number: 0.25 ; unit: h Output in E2B(R2): B.4.k.6: Time Interval: <number><unit> 3) If the unit value of E2B(R3) is not supported in E2B(R2), the E2B(R2) field should not be provided in field G.k.4.r.2. Instead, the information should be appended to the E2B(R2) field on dosage text (i.e., B.4.k.6): -21- Contains Nonbinding Recommendations  When the code is set to 'Cyclical', the dose quantity (value and unit, i.e., G.k.4.r.1a and G.k.4.r.1b) should be copied, followed by the corresponding term : <dose-value><dose-unit> CYCLICAL <dose-value><dose-unit> AS NECESSARY <dose-value><dose-unit> IN TOTAL 4) It should be noted that the conversion of this particular field should be seen in light of the structural changes provided by E2B(R3) on the dosage information (see more information under section 5.7.8). 5) If the field value of E2B(R3) is not present, the field of E2B(R2) should not be provided in the downgraded message. -22- Contains Nonbinding Recommendations 5.2.8 MedDRA Codes E2B(R2) and E2B(R3) expect different ways to encode MedDRA codes: E2B(R2) E2B(R3) Description Field Format Field Format Structured information for B.1.7.1a.2 250AN D.7.1.r.1b 8N disease, surgical procedure… Indication B.1.8f.2 250AN D.8.r.6b 8N Reaction B.1.8g.2 250AN D.8.r.7b 8N Reported cause of death B.1.9.2.b 250AN D.9.2.r.1b 8N (*) Autopsy-determined cause of B.1.9.4b 250AN D.9.4.r.1b 8N (*) death Structured information for B.1.10.7.1a.2 250AN D.10.7.1.r.1b 8N disease, surgical procedure… Indication B.1.10.8f.2 250AN D.10.8.r.6b 8N Reaction B.1.10.8g.2 250AN D.10.8.r.7b 8N Reaction / event in MedDRA B.2.i.1b 250AN E.i.2.1b 8N terminology Test name B.3.1c 100AN F.r.2.2b 8N (*) Sender's diagnosis / B.5.3b 250AN H.3.r.1b 8N syndrome and / or reclassification of reaction / event Although the format defined for MedDRA codes in E2B(R2) is alpha-numeric and composed of 250 characters, the requested information in E2B(R3) is a MedDRA code, composed of 8 digits. Therefore, the following recommendation applies: • To upgrade to E2B(R3), the following cases can occur: 1) If the field value of E2B(R2) consists of 8 digits, it should be copied as is to the corresponding E2B(R3) field. For the MedDRA code fields, the corresponding field for the MedDRA version is identical in both messages, and should be copied as is. 2) If the field value of E2B(R2) does not consist of 8 digits, the field should be ignored unless the E2B(R3) message format foresees a free text field (i.e., see fields flagged with an asterisk). For these fields, the value of E2B(R2) should be copied as is in the free text field of E2B(R3), extended with the MedDRA version field. Example: Input in E2B(R2): code value: free-text Output in E2B(R3): free text: free-text • To downgrade to E2B(R2), the MedDRA code value of E2B(R3) should be copied as is into the free text field of E2B(R2). If there is no MedDRA code value, but a free text field, then the free text field should be -23- Contains Nonbinding Recommendations copied instead. If both code and free text fields are present, the coded field should be copied along with the MedDRA version field. 5.2.9 Code Lists and UCUM Codes E2B(R2) and E2B(R3) expect different codes for the following fields: E2B(R2) E2B(R3) Description Field Code List Field Code List Age unit (patient) B.1.2.2b 6 possible codes D.2.2b  UCUM Code (incl. decade)  Decade Gestation period unit B.1.2.2.1b 4 possible codes D.2.2.1b  UCUM Code (patient) (incl. trimester)  Trimester Age unit (parent) B.1.10.2.2b 1 possible code D.10.2.2b  UCUM Code  Decade Duration unit B.2.i.6b 7 possible codes E.i.6b  UCUM Code Dose unit B.4.k.5.2 32 possible codes G.k.4.r.1b  UCUM Code Cumulative dose unit B.4.k.5.7 32 possible codes G.k.5b  UCUM Code Duration of drug B.4.k.15b 6 possible codes G.k.4.r.6b  UCUM Code administration (unit) Gestation period (unit) B.4.k.10b 4 possible codes G.k.6b  UCUM Code (incl. trimester)  Trimester Time interval (unit) B.4.k.13.1b 7 possible codes G.k.9.i.3.1b  UCUM Code B.4.k.13.2b G.k.9.i.3.2b The following recommendation applies: • To upgrade to E2B(R3), the following cases can occur: 1) If the E2B(R2) unit is 'decade' or 'trimester' (values 800 and 810, respectively), the UCUM unit code should be defined within curly braces. Example: Input in E2B(R2): value 1 ; unit code: 810 Output in E2B(R3): value 1 ; unit: {trimester} 2) In the other case, the corresponding UCUM unit code should be used. Example: Input in E2B(R2): value 10 ; unit code: 003 Output in E2B(R3): value 10 ; unit: mg • To downgrade to E2B(R2), the following cases can occur: 1) The UCUM unit code used in E2B(R3) should be mapped to a unit of the E2B(R2) guidance. In such case, the corresponding coded value should be copied into the E2B(R2) field. The effective encoding of the unit should follow the guidance set in the related Implementation Guide. -24- Contains Nonbinding Recommendations Note that the present specification for backwards and forwards compatibility assumes that the UCUM unit codes used for E2B(R3) messages are the same as the unit codes supported in E2B(R2). 5.2.10 Free Text and UCUM Codes E2B(R2) and E2B(R3) expect different ways to encode units for: E2B(R2) E2B(R3) Description Field Format Field Code List Test unit B.3.1e 35AN F.r.3.3 UCUM Code Although the format defined for the test unit in E2B(R2) is alpha-numeric and composed of 35 characters, it is expected to consist of a UCUM code. Therefore, the following recommendation applies: • To upgrade to E2B(R3), the E2B(R2) field should be mapped to the list of UCUM codes, and the mapped code should be copied as is to the E2B(R3) field. • To downgrade to E2B(R2), the UCUM code value of E2B(R3) should be copied as is into the free text field of E2B(R2). 5.2.11 Re-administration and Recurrence of Reaction on Re-administration E2B(R2) and E2B(R3) expect different information for the re-administration and the recurrence of reaction on re- administration: E2B(R2) E2B(R3) Description Field Format Field Code List Did reaction recur on re- B.4.k.17.1  Yes administration?  No  Unknown Did re-administration G.k.9.i.4  Re-challenge was take place? done, reaction recurred (yes-yes)  Re-challenge was done, reaction did not recur (yes-no)  Re-challenge was done, outcome unknown (yes)  No re-challenge was done (no) -25- Contains Nonbinding Recommendations Only one reaction is a subject for B.4.k.17.1 in E2B(R2) while multiple reactions can be subjects for G.k.9.i.4 in E2B(R3): • To upgrade to E2B(R3), the following mapping applies, for all the reactions identified to recur within the E2B(R2) field B.4.k.17.2: 1) If the E2B(R2) value is set to 'Yes', the E2B(R3) value should be set to 'Re-challenge was done, reaction recurred (yes-yes)'. 2) If the E2B(R2) value is set to 'No', the E2B(R3) value should be set to 'Re-challenge was done, reaction did not recur (yes-no)'. 3) If the E2B(R2) value is set to 'Unknown', the E2B(R3) value should not beset. • To downgrade to E2B(R2), the following mapping applies: 1) If the E2B(R3) value is set to 'Re-challenge was done, reaction recurred (yes-yes)', the E2B(R2) value should be set to 'Yes'.  All reactions that recurred on re-administration should be copied in E2B(R2) field B.4.k.17.2 (see section 4.7.11). 2) If the E2B(R3) value is set to 'Re-challenge was done, reaction did not recur (yes-no)', the E2B(R2) value should be set to 'No'. 3) If the E2B(R3) value is set to any other value, the E2B(R2) value should be set to 'Unknown'. 5.2.12 Patient and Parent Sex E2B(R2) and E2B(R3) expect different ways to encode units for: E2B(R2) E2B(R3) Description Field Format Field Code List Sex (patient) B.1.5  Male D.5  Male  Female  Female  Null Flavour: UNK, MSK, ASKU, NASK Sex (parent) B.1.10.6  Male D.10.6  Male  Female  Female  Null Flavour: UNK, MSK, ASKU, NASK In both formats, these fields are optional. Therefore, the following recommendation applies: • To upgrade to E2B(R3), the E2B(R2) field should be mapped to the list of codes available in E2B(R3). If the field is not set in E2B(R2), the corresponding field should not be set in E2B(R3). -26- Contains Nonbinding Recommendations • To downgrade to E2B(R2), the E2B(R3) field should be mapped to the list of codes available in E2B(R2). If the field is not set in E2B(R3), or if the field is set to 'Unknown', or if the field is attached to a null flavour, the corresponding field should not be set in E2B(R2). 5.2.13 Acknowledgement Codes E2B(R2) and E2B(R3) expect different ways to encode codes for: E2B(R2) E2B(R3) Description Field Format Field Code List ACK Transmission ACK: A.1.6  01 (All Reports ACK: ACK.A.4  AA (Application code loaded into Acknowledgement database) Accept)  02 (ICSR Error,  AE (Application not all reports Acknowledgment Error) loaded into the  AR (Application database) Acknowledgment  03 (SGML parsing Reject) error, no data extracted) ACK Code for ACK: B.1.8  01 (Report loaded ACK:  CA (Commit Accept) report successfully) ACK.B.r.6  CR (Commit Reject)  02 (Report not loaded) The following recommendation applies: • To upgrade to E2B(R3), the field A.1.6 of the E2B(R2) ACK should be mapped as follows: 1) E2B(R2) code '01'should be converted to E2B(R3) code 'AA'. 2) E2B(R2) code '02'should be converted to E2B(R3) code 'AE'. 3) E2B(R2) code '03'should be converted to E2B(R3) code 'AR'. • To upgrade to E2B(R3), the field B.1.8 of the E2B(R2) ACK should be mapped as follows: 1) E2B(R2) code '01'should be converted to E2B(R3) code 'CA'. 2) E2B(R2) code '02'should be converted to E2B(R3) code 'CR'. • To downgrade to E2B(R2), the E2B(R3) field should be mapped as follows: 1) E2B(R3) code 'AA' should be converted to E2B(R2) code '01'. 2) E2B(R3) code 'AE' should be converted to E2B(R2) code '02'. 3) E2B(R3) code 'AR' should be converted to E2B(R2) code '03'. 4) E2B(R3) code 'CA' should be converted to E2B(R2) code '01'. 5) E2B(R3) code 'CR' should be converted to E2B(R2) code '02'. -27- Contains Nonbinding Recommendations 5.3 Deletion Some fields of E2B(R2) have been deleted in E2B(R3). Guidance is provided on the way to handle such fields. 5.3.1 Fields to Ignore The following fields have been deleted in E2B(R3) as they are no longer useful anymore for handling case safety reports: E2B(R2) E2B(R3) Description Field Format Field Format Was the case medically A.1.14 1N - - confirmed? MedDRA version for B.2.i.2 8AN / 250AN - - reaction / event term PT ACK Safety report version ACK: B.1.2 2AN - - ACK Authority number ACK: B.1.4 100AN - - ACK Company number ACK: B.1.5 100AN ACK Date of receipt of the ACK: B.1.7b 8N - - most recent information The following recommendation applies: • To upgrade to E2B(R3), the E2B(R2) field should be ignored as there is no counterpart element in E2B(R3). • To downgrade to E2B(R2), the field should not be provided in E2B(R2), as the related field is optional in E2B(R2). 5.3.2 Fields with Default Value The following fields have been deleted in E2B(R3) but should receive a default value when converted back to E2B(R2), as they are required in E2B(R2): E2B(R2) E2B(R3) Description Field Default Value Field Format ACK: Message type ACK: M.1.1 ichicsrack - - Message format version (ACK) M.1.2 2.1 - - Message format release (ACK) M.1.3 1.0 - - Information on receiver of A.3.2 empty root element - - case safety report The following recommendation applies: -28- Contains Nonbinding Recommendations • To upgrade to E2B(R3), the fields of E2B(R2) should be ignored, as there is no counterpart element in E2B(R3). • To downgrade to E2B(R2), the following cases occur: 1) Field M.1.1 should receive the default value 'ichicsrack' (in ICSR ACK). 2) Field M.1.2 should receive the default value '2.1' (in ICSR and ICSR ACK). 3) Field M.1.3 should receive the default value '1.0' (in ICSR and ICSR ACK). 4) Field A.3.2 should be created with the empty root element 'receiver'. 5.3.3 Safety Report Version Number This E2B(R2) field does not exist in E2B(R3) but the related treatment is covered in section 5.1.4. 5.3.4 Number of Separate Dosages E2B(R3) has reviewed the structure of information regarding dosage, and the field related to the number of separate dosages (i.e., B.4.k.5.3 according to the E2B(R2) field numbering) has been deleted. The recommendations regarding this element should be retrieved from the section dedicated to the dosage information, section 5.7.8. -29- Contains Nonbinding Recommendations 5.4 Addition Some fields have been added in E2B(R3). Guidance is provided on the way to handle such fields, depending on whether the E2B(R3) field has a counterpart in E2B(R2), or whether some mapping can be defined. 5.4.1 Fields with No Mapping The following fields have been added in E2B(R3), with no counterpart in E2B(R2): E2B(R2) E2B(R3) Description Field Format Field Format Included documents - - C.1.6.1.r.2 File (held by the sender) Primary source telephone - - C.2.r.2.7 33AN Included documents - - C.4.r.2 File (literature references) Family history (patient) - - D.7.1.r.6 Boolean Concomitant therapies - - D.7.3 Boolean Medical confirmation by - - E.i.8 Boolean health professional MedDRA code for Test F.r.2.2b 8N Name The following recommendation applies: • To upgrade to E2B(R3), the E2B(R3) field should not be provided, as there is no counterpart element in the E2B(R2) guideline. • To downgrade to E2B(R2), the value of the E2B(R3) field should be captured in narrative field (B.5.1). E2B(R2) E2B(R3) Description Field Format Field Format ACK Date of transmission - - ACK: ACK.B.r.5 Date • To upgrade to E2B(R3), the E2B(R3) field should not be provided, as there is no counterpart element in the E2B(R2) guideline. • To downgrade to E2B(R2), ACK.B.r.5 field should be blank. -30- Contains Nonbinding Recommendations 5.4.2 Study Registration In E2B(R3), the study registration number and the study registration country have been added: E2B(R2) E2B(R3) Description Field Format Field Format Study registration number - - C.5.1.r.1 50AN ASKU, NASK Study registration country - - C.5.1.r.2 2A ASKU, NASK The following recommendation applies: • To upgrade to E2B(R3), these two fields should not be provided, as there is no counterpart in the E2B(R2) guideline, and therefore no value in the E2B(R2) message. • To downgrade to E2B(R2), the study registration number(s) and country(ies) should be copied to the E2B(R2) message as a prefix for the study name field, i.e., A.2.3.1 according to the E2B(R2) field numbering. The study registration number can repeat in E2B(R3), and when copied back into E2B(R2), repeated fields should appear separated by a comma. If one of these fields is nullified, the term 'UNKNOWN' should be used instead. Example: Input in E2B(R3): Study #1: registration number(s): 111 for UK, 222 for BE Study #2: registration number(s): 333 for FR, ASKU for IT Output in E2B(R2): study name: Study #1: 111 (UK),222 (BE):<study-name-1> Study #2: 333 (FR), UNKNOWN (IT): <study-name-2> -31- Contains Nonbinding Recommendations 5.4.3 ISO IDMP identifiers M5 identifiers have been renamed to ISO IDMP terms and identifiers. E2B(R3) supports the concepts of MPID and PhPID for the following fields: E2B(R2) E2B(R3) Description Field Format Field Format MPID and MPID version - - D.8.r.2a AN for patient drug history D.8.r.2b AN PhPID and PhPID version - - D.8.r.3a AN for patient drug history D.8.r.3b AN MPID and MPID version - - D.10.8.r.2a AN for parent drug history D.10.8.r.2b AN PhPID and PhPID version - - D.10.8.r.3a AN for parent drug history D.10.8.r.3b AN MPID and MPID version - - G.k.2.1.1a AN for drug identification G.k.2.1.1b AN PhPID and PhPID version - - G.k.2.1.2a AN for drug identification G.k.2.1.2b AN Substance TermID - - G.k.2.3.r.2a AN and version G.k.2.3.r.2b AN Dose Form TermID G.k.4.r.9.2a AN and version G.k.4.r.9.2b AN The following recommendation applies: • To upgrade to E2B(R3), the field should not be provided, as there is no counterpart to this field in the E2B(R2) guideline. • To downgrade to E2B(R2), the drug identification should be copied to the E2B(R2) message as a prefix for the related drug name field (see the mapping below). For each drug, the following fields should be copied: MPID and MPID version date / number, or PhPID and PhPID version date / number. Information should be preceded by the prefix 'MPID' or 'PhPID'. The version dates should display between parentheses. MPID or PhPID and the drug name should repeat, if appropriate, separated by a semi-colon. The correspondence between the identification and name fields is as follows: 1) D.8.r.2a-2b-3a-3b should be copied as prefix of the field B.1.8aof E2B(R2). 2) D.10.8.r.2a-2b-3a-3b should be copied as prefix of the field B.1.10.8a of E2B(R2). 3) G.k.2.1.1a-1b-2a-2b should be copied as prefix of the field B.4.k.2.1 of E2B(R2). Example: Input in E2B(R3): MPID: abcdef ; version date / number: 20080925 or PhPID: ghijkl ; version date / number: 20081028 -32- Contains Nonbinding Recommendations Output in E2B(R2): MPID: abcdef (20080925): <drug name> or PhPID: ghijkl (20081028): <drug name> 5.4.4 Investigational Product Blinded E2B(R3) supports the concepts of investigational product blinded: E2B(R2) E2B(R3) Description Field Format Field Format Investigational product - - G.k.2.5 Boolean blinded The following recommendation applies: • To upgrade to E2B(R3), the field should not be set. • To downgrade to E2B(R2), if the field is set to 'true', the term 'INVESTIGATIONAL' should be added to the E2B(R2) field B.4.k.19 (additional information on the drug). 5.4.5 Case Narrative in Native Language The case narrative field in native language has been added in E2B(R3): E2B(R2) E2B(R3) Description Field Format Field Format Case summary and reporter's - - H.5.r.1a 100000 AN comment text / language H.5.r.1b 3A The following recommendation applies: • To upgrade to E2B(R3), the E2B(R3) field should not be provided, as there is no counterpart element in the E2B(R2) guideline. • To downgrade to E2B(R2), the fields H.5.r.1a and H.5.r.1b of E2B(R3) should be appended to the case narrative section, i.e., B.5.1 of E2B(R2). The information should be preceded by the prefix 'CASE SUMMARY', extended with the identification of the language between parentheses. -33- Contains Nonbinding Recommendations Example: Input in E2B(R3): Reporter's comments text: abcdefghikjkl Reporter's comments language: jap Output in E2B(R2): <content of case narrative> CASE SUMMARY (jap): abcdefghikjkl 5.4.6 Reaction as Reported and Translated The following field has been added in E2B(R3), with no counterpart in E2B(R2): E2B(R2) E2B(R3) Description Field Format Field Format Reaction / event as reported B.2.i.0 200AN E.i.1.1a 250AN by primary source Reaction / event as reported - - E.i.1.2 250AN by primary source (translation) The following recommendation applies: • To upgrade to E2B(R3), the E2B(R3) field should not be provided, as there is no counterpart element in the E2B(R2) guideline. • To downgrade to E2B(R2), the following cases occur: 1) If the E2B(R3) field E.i.1.2 is set, it should be copied into the E2B(R2) field B.2.i.0, truncated if appropriate, as described in section 5.5.2. 2) If the E2B(R3) field E.i.1.2 is not set, the E2B(R3) field E.i.1.1a should be copied with the E2B(R3) field E.i.1.1b (language code) into the E2B(R2) field B.2.i.0, truncated if appropriate, as described in section 5.5.2. 5.4.7 Reported cause(s) of death The following field in E2B(R2) is split into two field in E2B(R3): E2B(R2) E2B(R3) Description Field Format Field Format Reported cause(s) of death B.1.9.2b 250AN D.9.2.r.1b 8N Reported Cause(s) of Death - - D.9.2.r.2 250AN (Free text) -34- Contains Nonbinding Recommendations The E2B(R2) Guideline recommends 'MedDRA if applicable' for this data element, the following recommendation applies: • To upgrade to E2B(R3): 1) Populate E2B(R3) D.9.2.r.1b field with E2B(R2) B.1.9.2b data if MedDRA code is used in the report. 2) Populate E2B(R3) D.9.2.r.2 field with E2B(R2) B.1.9.2b data if it is free text in the report. • To downgrade to E2B(R2), the following cases occur: 1) If only the E2B(R3) D.9.2.r.1bfield is set, it should be copied into the E2B(R2) field B.1.9.2b. 2) If only the E2B(R3) D.9.2.r.2 field is set, it should be copied into the E2B(R2) field B.1.9.2b. 3) If both E2B(R3) D.9.2.r.1b and E2B(R3) D.9.2.r.2 fields are set:  Copy only the E2B(R3) D.9.2.r.1b field into the E2B(R2) field B.1.9.2b.  Copy the E2B(R3) B.1.9.2.r.b2 field into narrative field. 5.4.8 Autopsy-determined Cause(s) of Death The following field in E2B(R2) is split into two field in E2B(R3): E2B(R2) E2B(R3) Description Field Format Field Format Autopsy-determined Cause(s) B.1.9.4b 250AN D.9.4.r.1b 8N of Death Autopsy-determined Cause(s) - - D.9.4.r.2 250AN of Death (Free text) The E2B(R2) Guideline recommends 'MedDRA if applicable' for this data element, the following recommendation applies: • To upgrade to E2B(R3): 1) Populate E2B(R3) D.9.4.r.1b field with E2B(R2) B.1.9.4.b data if MedDRA code is used in the report. 2) Populate E2B(R3) D.9.4.r.2 field with E2B(R2) B.1.9.4b data if it is free text in the report. • To downgrade to E2B(R2), the following cases occur: 1) If only the E2B(R3) D.9.4.r.1b field is set, it should be copied into the E2B(R2) field B.1.9.4b. 2) If only the E2B(R3) D.9.4.r.2 field is set, it should be copied into the E2B(R2) field B.1.9.4b. 3) If both E2B(R3) D.9.4.r.1b and E2B(R3) D.9.4.r.2 fields are set:  Copy only the E2B(R3) D.9.4.r.1b field into the E2B(R2) field B.1.9.4b. -35- Contains Nonbinding Recommendations  Copy the E2B(R3) B.1.9.4.r.b2 field into narrative field. 5.5 Field Length For some fields, the length has been extended in E2B(R3). Guidance is provided on the conversion of such fields, depending on whether truncation is appropriate or not. 5.5.1 Extended Fields to Truncate The following fields have been extended in E2B(R3), and the effective size can be found in the Implementation Guide of E2B(R3). These fields should be truncated when converted back to E2B(R2): E2B(R2) E2B(R3) Description Field Field Size Field Field Size Reporter given name, middle A.2.1.1b 35 C.2.r.1.2 60 (*) name and family name A.2.1.1c 15 C.2.r.1.3 60 (*) A.2.1.1d 50 C.2.r.1.4 60 (*) Sender organization A.3.1.2 60 C.3.2 100 Sender title, given name, A.3.1.3b 10 C.3.3.2 50 middle name and family A.3.1.3c 35 C.3.3.3 60 name A.3.1.3d 15 C.3.3.4 60 A.3.1.3e 35 C.3.3.5 60 Patient / parent initials B.1.1 10 D.1 60 (*) B.1.10.1 10 D.10.1 60 (*) Test name (free text) B.3.1c 100 F.r.2.1 250 Dosage text B.4.k.6 100 G.k.4.r.8 2000 Pharmaceutical dose form B.4.k.7 50 G.k.4.r.9.1 60 (*) text Method and result of B.4.k.18.3 35 G.k.9.i.2.r.2 60 assessment B.4.k.18.4 35 G.k.9.i.2.r.3 60 The following recommendation applies: • To upgrade to E2B(R3), the E2B(R2) field should be copied into the field of E2B(R3). • To downgrade to E2B(R2), the following cases occur: 1) If the field value does not exceed the size limitation set by the E2B(R2) guideline, the field value should be copied to the element of E2B(R2). 2) If the field value exceeds the size limitation set by the E2B(R2) guideline, the field value should be truncated to the size limitation set by the E2B(R2) guideline, less 3 characters, which are replaced by '…' so as to highlight that truncation has been applied. Example: Input in E2B(R3): Field with size of 20 characters: 123456789012345 -36- Contains Nonbinding Recommendations Output in E2B(R2): Field with size of 10 characters: 1234567… Fields with an asterisk (*) can be masked (for privacy or because information is unknown). The conversion of such fields is described in section 5.6. 5.5.2 Extended Fields to Keep The following fields have been extended in E2B(R3), and the effective size can be found in the Implementation Guide of E2B(R3). These fields should be truncated when converted back to E2B(R2), but the full value should be copied to the narrative section of E2B(R2): E2B(R2) E2B(R3) Description Field Field Size Field Field Size List of documents held by the A.1.8.2 100 C.1.6.1.r.1 2000 sender Source of the case identifier A.1.11.1 50 C.1.9.1.r.1 100 Reason for Nullification / A.1.13.1 200 C.1.11.2 2000 Amendment Study name A.2.3.1 100 C.5.2 2000 Sponsor study name A.2.3.2 35 C.5.3 50 Medical history B.1.7.1g 100 D.7.1.r.5 2000 (patient and parent) B.1.10.7.1g D.10.7.1.r.5 Name of the drug as reported B.1.8a 100 D.8.r.1 250 (patient and parent) B.1.10.8a 100 D.10.8.r.1 250 Reaction / event as reported B.2.i.0 200 E.i.1.1a 250 by the primary source Medicinal product as B.4.k.2.1 70 G.k.2.2 250 reported by primary source Substance name B.4.k.2.2 100 G.k.2.3.r.1 250 Additional information on B.4.k.19 100 G.k.11 2000 drug (free text) Reporter's comments B.5.2 500 H.2 20000 Sender's Comments B.5.4 2000 H.4 20000 The following recommendation applies: • To upgrade to E2B(R3), the E2B(R2)field should be copied into the field of E2B(R3). • To downgrade to E2B(R2), the following cases occur: 1) If the field value does not exceed the size limitation set by the E2B(R2) guideline, the field value should be copied to the element of E2B(R2). -37- Contains Nonbinding Recommendations 2) If the field value exceeds the size limitation set by the E2B(R2) guideline, the field value should be truncated to the size limitation set by the E2B(R2) guideline, less 3 characters, which are replaced by '…' so as to highlight that truncation has been applied. In addition, the field of E2B(R3) should be completely copied into the narrative section of E2B(R2), i.e., B.5.1 of E2B(R2). The information should be preceded by a prefix depending on the field to be copied:  A.1.8.2 / C.1.6.1.r.1 ADDITIONAL DOCUMENTS  A.1.11.1 / C.1.9.1.r.1 CASE IDENTIFIER  A.1.13.1 / C.1.11.2 NULLIFICATION / AMENDMENT REASON  A.2.3.1 / C.5.2 STUDY NAME  A.2.3.2 / C.5.3 SPONSOR STUDY NUMBER  B.1.7.1g / D.7.1.r.5 MEDICAL HISTORY  B.1.8a / D.8.r.1 DRUG HISTORY  B.1.10.7.1g / D.10.7.1.r.5 PARENT MEDICAL HISTORY  B.1.10.8a / D.10.8.r.1 PARENT DRUG HISTORY  B.2.i.0 / E.i.1.1a REACTION / EVENT  B.4.k.2.1 / G.k.2.2 DRUG  B.4.k.2.2 / G.k.2.3.r.1 ACTIVE INGREDIENT  B.4.k.19 / G.k.11 ADDITIONAL INFORMATION ON DRUG  B.5.2 / H.2 REPORTER COMMENTS  B.5.4 / H.4 SENDER COMMENTS Example: Input in E2B(R3): Field with size of 120 characters: 123456789012345 Output in E2B(R2): Field with size of 100 characters: 1234567… Case narrative section (for the study name part): <case narrative section> STUDY NAME: 123456789012345 5.5.3 Length of Numeric Fields (Extended) The size of the following numeric field has been extended in E2B(R3): E2B(R2) E2B(R3) Description Field Field Size Field Field Size Age (parent) B.1.10.2.2a 2 D.10.2.2a 3 -38- Contains Nonbinding Recommendations The following recommendation applies: • To upgrade to E2B(R3), the E2B(R2) field should be copied into the field of E2B(R3). • To downgrade to E2B(R2), the following cases occur: 1) If 2 digits are used, the field of E2B(R3) should be copied into the field of E2B(R2). 2) If 3 digits are used, the field of E2B(R2) should be set to '99'. 5.6 Null Flavour For several fields, E2B(R3) provides null flavoured information, for privacy purposes or because information is unknown. Guidance is provided on the way to pass from one encoding to the other, and vice versa. 5.6.1 Null Flavour for Optional Free Text Fields In E2B(R3), the following optional text fields can be encoded with a null flavour: E2B(R2) E2B(R3) Description Field Supported Field Supported Masks Masks Reporter's title A.2.1.1a - C.2.r.1.1 MSK, ASKU, NASK, UNK Reporter's given, middle A.2.1.1b - C.2.r.1.2 MSK, ASKU, NASK and family name A.2.1.1c C.2.r.1.3 A.2.1.1d C.2.r.1.4 Reporter's organization A.2.1.2a - C.2.r.2.1 MSK, ASKU, NASK and department A.2.1.2b C.2.r.2.2 Reporter's street, city, A.2.1.2c - C.2.r.2.3 MSK, ASKU, NASK state or province and post A.2.1.2d C.2.r.2.4 code A.2.1.2e C.2.r.2.5 A.2.1.2f C.2.r.2.6 The following recommendation applies: • To upgrade to E2B(R3), the following cases occur: 1) If the E2B(R2) field is not set, the E2B(R3) field should not be provided (as it is optional). 2) If the E2B(R2) field is set to 'UNKNOWN'  If supported, the E2B(R3) field should be provided with the unknown null flavour (UNK).  If not supported, the E2B(R3) field should not be provided. 3) If the E2B(R2) field is set to 'PRIVACY'  If supported, the E2B(R3) field should be provided with the mask null flavour (MSK).  If not supported, the E2B(R3) field should not be provided. -39- Contains Nonbinding Recommendations 4) In any other case, the field should be copied according to recommendations defined in the other sections of this document, if applicable. • To downgrade to E2B(R2), the E2B(R3) field should be copied into the field of E2B(R2). 1) If the E2B(R3) field is not set, the E2B(R2) field should not be provided (as it is optional). 2) If the E2B(R3) field is provided with an unknown null flavour (UNK, ASKU, NASK), the E2B(R2) field should be provided with the default term 'UNKNOWN'. 3) If the E2B(R3) field is provided with the mask null flavour (MSK), the E2B(R2) field should be provided with the default term 'PRIVACY'. 4) In any other case, the field should be copied according to recommendations defined in the other sections of this document, if applicable. The other E2B(R3) fields that can receive a null flavour (UNK, ASKU, NASK, NI, MSK…) should be ignored when converted back to E2B(R2), i.e., the related E2B(R2) field should not be set. 5.6.2 Null Flavour for Fields Required in E2B(R3) In E2B(R3), the following required fields can be encoded with a null flavour: E2B(R2) E2B(R3) Description Field Supported Field Supported Masks Masks Patient (name or initials) B.1.1 - D.1 MSK, ASKU, NASK, UNK The following recommendation applies: • To upgrade to E2B(R3), the following cases occur: 1) If the E2B(R2) field is not provided, the corresponding E2B(R3) field should be provided with the null flavour set to 'unknown' (UNK). 2) If the E2B(R2) field 'Initials' (i.e., B.1.1) is provided with the value 'UNKNOWN', the corresponding E2B(R3) field should be provided with the null flavour set to 'unknown' (UNK). 3) If the E2B(R2) field 'Initials' (i.e., B.1.1) is provided with the value 'PRIVACY', the corresponding E2B(R3) field should be provided with the null flavour set to 'mask' (MSK). • To downgrade to E2B(R2), the following cases occur: 1) If the E2B(R3) field 'Initials' (i.e., D.1) is provided with the null flavour set to 'unknown' (UNK, NASK or ASKU), the corresponding E2B(R2) field should be provided with the default value 'UNKNOWN'. -40- Contains Nonbinding Recommendations 2) If the E2B(R3) field 'Initials' (i.e., D.1) is provided with the null flavour set to 'mask' (MSK), the corresponding E2B(R2) field should be provided with the default value 'PRIVACY'. 5.6.3 Null Flavour for Optional Codes and Dates In E2B(R3), the following code and date fields can be encoded with a null flavour: E2B(R2) E2B(R3) Description Field Supported Field Supported Masks Masks Reporter's country code A.2.1.3 - C.2.r.3 MSK, ASKU, NASK, UNK Qualification A.2.1.4 - C.2.r.4 UNK Date of birth B.1.2.1b - D.2.1 MSK (patient) Was Autopsy Done? B.1.9.3 3=Unknown D.9.3 ASKU, NASK,UNK Date of birth B.1.10.2.1b - D.10.2.1 MSK, ASKU, NASK (parent) Continuing B.1.7.1d 3=Unknown D.7.1.r.3 MSK, ASKU, NASK, UNK (patient or parent B.1.10.7.1d D.10.7.1.r.3 medical history) The following recommendation applies: • To upgrade to E2B(R3), the following cases occur: 1) If the field 'Was Autopsy Done' (i.e., B.1.9.3) or 'Continuing (patient or parent medical history)' (i.e., B.1.7.1d or B.1.10.7.1d) is provided with value '3' (unknown) in E2B(R2), the corresponding field should be provided in E2B(R3) with the null flavour (UNK). 2) If any of the other fields are not provided in E2B(R2), the corresponding fields in E2B(R3) should not be provided. • To downgrade to E2B(R2), the following cases occur: 1) If the field 'Was Autopsy Done' (i.e., D.9.3) or 'Continuing (patient or parent medical history)' (i.e., D.7.1.r.3 or D.10.7.1.r.3) has null flavour (UNK) in E2B(R3), the corresponding field in E2B(R2) should be provided with value '3' (unknown). 2) If any of the other fields has a null flavour in E2B(R3), the corresponding field in E2B(R2) should not be provided. -41- Contains Nonbinding Recommendations 5.7 Structure For several fields, E2B(R3) provides a new way to structure the information on case safety reports. Guidance is provided on the way to pass from one structure to the other, and vice versa. 5.7.1 Country of Primary Source In E2B(R3), the primary source entity can repeat, with one primary source selected for regulatory purposes. The structural change impacts the following fields: E2B(R2) E2B(R3) Description Field Format Field Format Identification of the country of A.1.1 2A - - the primary source Reporter country code A.2.1.3 2A C.2.r.3 2A Primary source for regulatory - - C.2.r.5 1N purposes The following recommendation applies: • To upgrade to E2B(R3): 1) The E2B(R2) field A.1.1 should be ignored. 2) Each E2B(R2) entity A.2.1 (Primary Source) should be mapped to an entity C.2.r.1 in E2B(R3). 3) For each Primary Source, the E2B(R2) field A.2.1.3 should be copied to the E2B(R3) field C.2.r.3. 4) The field C.2.r.5 of E2B(R3) should be set to '1' for the first occurrence of the Primary Source available in the E2B(R2) message. The other Primary Source occurrences should not have the field C.2.r.5set. • To downgrade to E2B(R2): 1) The E2B(R2) field A.1.1 should be filled with the country value (i.e., the E2B(R3) field C.2.r.3) of the Primary Source that was set for regulatory purposes (i.e., with E2B(R3) field C.2.r.5 set to '1'). 2) Each E2B(R3) entity C.2.r.1 (Primary Source) should be mapped to an entity A.2.1 in E2B(R2). 3) For each Primary Source, the E2B(R3) field C.2.r.3 should be copied to the E2B(R2) field A.2.1.3. 4) The field C.2.r.5 of E2B(R3) should be ignored. -42- Contains Nonbinding Recommendations 5.7.2 Country of Reaction / Event E2B(R3) provides a different approach for the country of reaction / event, as it is stored at the level of the case, i.e., unique, in E2B(R2) and at the level of the reaction, i.e., repeatable, in E2B(R3). The structural change impacts the following fields: E2B(R2) E2B(R3) Description Field Format Field Format Country where the reaction / A.1.2 2A - - event occurred unique Country where the reaction / - - E.i.9 2A event occurred repeatable The following recommendation applies: • To upgrade to E2B(R3), the E2B(R2) field A.1.2 should be copied into all the occurrences of the E2B(R3) field E.i.9, i.e., with the same value for all the reactions / events. • To downgrade to E2B(R2), the E2B(R3) field E.i.9 of the first occurrence of the reaction / event having a E.i.9 field set, should be copied into the E2B(R2) field A.1.2, i.e., at the case report level. The other country fields in the reaction / event section should be ignored. 5.7.3 Unique Case Number E2B(R3) provides a different approach for the unique case number. The structural change impacts the following fields: E2B(R2) E2B(R3) Description Field Format Field Format Regulatory authority's A.1.10.1 100AN - - case report number Worldwide unique - - C.1.8.1 100AN case identifier Other sender's A.1.10.2 100AN - - case report number First sender of this case - - C.1.8.2  regulator  other The following recommendation applies: • To upgrade to E2B(R3), the following cases can occur: 1) If the E2B(R2) field A.1.10.1 for the regulatory authority's number is provided, the field value should be copied into the E2B(R3) field C.1.8.1, and field C.1.8.2 should be set to 'regulator'. -43- Contains Nonbinding Recommendations 2) If the E2B(R2) field A.1.10.2 for the other sender's number is provided, the field value should be copied into the E2B(R3) field C.1.8.1, and field C.1.8.2 should be set to 'other'. 3) If both fields are provided in the E2B(R2) message, only the regulatory authority's number should be converted. • To downgrade to E2B(R2), the following cases can occur: 1) If the E2B(R3) field C.1.8.2 is set to 'regulator', the E2B(R3) field C.1.8.1 should be copied into the E2B(R2) field A.1.10.1 (i.e., regulatory authority's number). 2) If the E2B(R3) field C.1.8.2 is set to 'other', the E2B(R3) field C.1.8.1 should be copied into the E2B(R2) field A.1.10.2 (i.e., other sender's number). 5.7.4 Sender's Telephone and Fax E2B(R3) provides a different approach for the sender's telephone and fax. The structural change impacts the following fields: E2B(R2) E2B(R3) Description Field Format Field Format Sender's telephone A.3.1.4f 10AN C.3.4.6 33AN Sender's telephone extension A.3.1.4g 5AN - - Sender's telephone A.3.1.4h 3AN - - country code Sender's fax A.3.1.4i 10AN C.3.4.7 33AN Sender's fax extension A.3.1.4j 5AN - - Sender's fax A.3.1.4k 3AN - - country code The following recommendation applies: • To upgrade to E2B(R3), the three E2B(R2) fields should be merged, along with the prefix 'tel' or 'fax', and copied into the single E2B(R3) field. There is no limitation in the field size. Example: Input in E2B(R2): phone: 12345678 phone extension: 123 phone country code: +44 Output in E2B(R3): phone: tel: +44 12345678 123 -44- Contains Nonbinding Recommendations • To downgrade to E2B(R2), the single E2B(R3) field should be copied, without the prefix 'tel' or 'fax', into the corresponding E2B(R2) field (i.e., the longest field). If the value to be copied is too long, the value should be truncated. Example 1: Input in E2B(R3): phone: tel: +44 123456 Output in E2B(R2): phone: +44 123456 Example 2: Input in E2B(R3): phone: tel: +44 12345678 123 Output in E2B(R2): phone: +44 123… 5.7.5 Literature References E2B(R3) provides a different approach for the literature references. The structural change impacts the following fields: E2B(R2) E2B(R3) Description Field Format Field Format Literature references A.2.2 500AN C.4.r.1 500AN in primary source in safety report ASKU, NASK The following recommendation applies: • To upgrade to E2B(R3), the E2B(R2) field A.2.2 from all the primary sources should be copied, and these values should be copied into E2B(R3) field C.4.r.1 so as to have one entry per primary source. • To downgrade to E2B(R2), all the not-nullified E2B(R3) fields C.4.r.1 should be copied, and these values should be copied into the E2B(R2) field A.2.2 of the primary source for regulatory purposes. Fields should be separated with a semi-colon. If the value to be copied extends the field size limit, the information should be truncated. 5.7.6 Seriousness and Seriousness Criteria E2B(R3) provides a different approach for the seriousness criteria. In E2B(R3), such information is stored in the reaction / event section, and could therefore be provided for each reaction / event. The structural change impacts the following fields: -45- Contains Nonbinding Recommendations E2B(R2) E2B(R3) Description Field Format Field Format Seriousness A.1.5.1  Yes - - report level  No Seriousness criteria A.1.5.2  Yes E.i.3.2  true (6 different criteria) report level  No reaction level  Null Flavour (NI) Term highlighted B.2.i.3  yes, highlighted by E.i.3.1  Yes, highlighted by by the reporter reaction level the reporter, NOT reaction level the reporter, NOT serious serious  no, not highlighted  No, not highlighted by the reporter, by the reporter, NOT NOT serious serious  yes, highlighted by  Yes, highlighted by the reporter, the reporter, SERIOUS SERIOUS  no, not highlighted  No, not highlighted by the reporter, by the reporter, SERIOUS SERIOUS The following recommendation applies: • To upgrade to E2B(R3): 1) The E2B(R2) field B.2.i.3 (term highlighted by the reporter) should be mapped to the E2B(R3) field E.i.3.1 (same values). 2) The E2B(R2) fields for seriousness criteria, stored at the safety report level, i.e., A.1.5.2, should be copied to the E2B(R3) field E.i.3.2 of each reaction / event if the E2B(R2) field B.2.i.3 is set to 'serious'. The E2B(R3) field E.i.3.2 should be set to 'NI' for each reaction / event if the E2B(R2) field B.2.i.3 is set to 'not serious'. 3) The E2B(R2) fields for seriousness criteria, stored at the safety report level, i.e., A.1.5.2 should be copied to the E2B(R3) field E.i.3.2 of each reaction / event if the E2B(R2) field B.2.i.3 is not provided. 4) Example 1: Input in E2B(R2): Seriousness criteria (A.1.5.2): death: yes; disabling: no Reaction 1 (B.2.i.3): yes, highlighted, serious Reaction 2 (B.2.i.3): no, not highlighted, not serious Output in E2B(R3): Reaction 1: Term highlighted by reporter (E.i.3.1): yes, highlighted, serious Seriousness criteria (E.i.3.2): death: true; life threatening: NI; -46- Contains Nonbinding Recommendations Hospitalisation: NI; disabling: NI; Birth defect: NI; Other: NI Reaction 2: Term highlighted by reporter (E.i.3.1): no, not highlighted, not serious Seriousness criteria (E.i.3.2): death: NI; life threatening: NI; Hospitalisation: NI; disabling: NI; Birth defect: NI; Other: NI Example 2: Input in E2B(R2): Seriousness criteria (A.1.5.2): death: yes; disabling: no Reaction 1 (B.2.i.3): yes, highlighted, serious Reaction 2 (B.2.i.3): blank Output in E2B(R3): Reaction 1: Term highlighted by reporter (E.i.3.1): yes, highlighted, serious Seriousness criteria (E.i.3.2): death: yes; life threatening: NI; Hospitalisation: NI; disabling: NI; Birth defect: NI; Other: NI Reaction 2: Term highlighted by reporter (E.i.3.1): blank Seriousness criteria (E.i.3.2): death: yes; life threatening: NI; Hospitalisation: NI; disabling: NI; Birth defect: NI; Other: NI • To downgrade to E2B(R2): 1) The E2B(R3) field E.i.3.1 (term highlighted by the reporter) should be mapped to the E2B(R2) field B.2.i.3 (same values). 2) The E2B(R2) field A.1.5.1 should be set to 'Yes' if there is at least one reaction / event with the corresponding seriousness criteria set to 'true' (i.e., E2B(R3) field E.i.3.2). 3) Each seriousness criteria (i.e., E2B(R2) fields A.1.5.2) should be set to 'Yes' if there is at least one reaction / event, highlighted as serious, with the corresponding criteria set to 'true' (i.e., E2B(R3) field E.i.3.2). Example: Input in E2B(R3): -47- Contains Nonbinding Recommendations Reaction 1: Term highlighted by reporter (E.i.3.1): yes, serious Seriousness criteria (E.i.3.2): death: yes; disabling: no Reaction 2: Term highlighted by reporter (E.i.3.1): no, serious Seriousness criteria (E.i.3.2): death: no; disabling: yes Output in E2B(R2): Serious (A.1.5.1): yes Seriousness criteria (A.1.5.2): death: yes; disabling: yes Reaction 1 (B.2.i.3): Yes, highlighted, serious Reaction 2 (B.2.i.3): No, not highlighted, serious -48- Contains Nonbinding Recommendations 5.7.7 Results of Tests E2B(R3) provides a different approach for the results of tests. In E2B(R3), the test result can be expressed as a value, with or without a qualifier, or coded. Additionally, the E2B(R3) field on the results can repeat for each test. The structural change impacts the following fields: E2B(R2) E2B(R3) Description Field Format Field Format Test result B.3.1d 50AN F.r.3.1 as code (1N) F.r.3.2 as value (50N) F.r.3.4 free text (2000AN) Results of tests B.3.2 2000AN F.r.3.4 2000AN unique The following recommendation applies: • To upgrade to E2B(R3), the following recommendations apply: 1) The upgrade of the E2B(R2) field B.3.1.d depends on its content:  If the E2B(R2) field B.3.1.d is numeric, the content should be copied as is to the E2B(R3) field F.r.3.2 (as value).  If the E2B(R2) field B.3.1.d is not numeric (e.g., because of the presence of a qualifier), the content should be copied as is to the E2B(R3) field F.r.3.4. 2) The unique E2B(R2) field B.3.2 should be copied into the E2B(R3) field F.r.3.4. • To downgrade to E2B(R2), the following recommendations apply: 1) The downgrade of the E2B(R3) fields F.r.3 depends on their content:  If the E2B(R3) field F.r.3.1 is set (coded value), it should be copied to the E2B(R2) field B.3.1.d.  If the E2B(R3) field F.r.3.1 is not set, the field F.r.3.2 (numeric value) should be copied instead.  If the E2B(R3) fields F.r.3.2 (numeric value) is qualified (e.g., as 'greater than'), the information that is copied to the E2B(R2) field B.3.1.d should be made up of the qualifier followed by the numeric value.  If the E2B(R3) fields F.r.3.1 and F.r.3.2 are not set, the free text field F.r.3.4 should be copied, truncated if appropriate.  If both coded (F.r.3.1) and numeric (F.r.3.2) fields are set, the coded value should be copied to the E2B(R2) field B.3.1.d, and the numeric value (with qualifier and unit, if set) should be copied to the E2B(R2) field B.3.2 in the form of -49- Contains Nonbinding Recommendations TEST <test name> (<date>) [RESULT: <result>]: <unstructured test results> 2) The test result fields of E2B(R3), i.e., F.r.2.1 (test name), F.r.1 (date) and F.r.6 (comments), should be concatenated into the E2B(R2) field B.3.2 (see pattern above).  If there is not enough space in the E2B(R2) field B.3.2, it should be truncated (see section 5.5 for instructions on the way to truncate fields) and the complete field value should be appended to the E2B(R2) case narrative field, i.e., B.5.1. The information should be preceded by the prefix 'TEST RESULTS'. 5.7.8 Drug and Dosage Information E2B(R3) provides a different approach for the dosage information, which repeats for a given drug in E2B(R3). The structural change impacts the following fields: E2B(R2) E2B(R3) Description Field Format Field Format Dosage information B.4.k.5 unique per drug G.k.4.r repeatable per drug The general principle to support multiple dosage information in E2B(R2) is to repeat the drug section for each dosage, which implies repeating the drug section for each dosage information of the same drug. The upgrade to E2B(R3), however, should not try to further structure the information, e.g., by grouping the dosage information for the same drug under a unique drug section. The dosage information should be upgraded to E2B(R3) as is. The following recommendation applies: • To upgrade to E2B(R3), the unique set of dosage information fields in E2B(R2) (fields B.4.k.3, B.4.k.5.1 to B.4.k.5.5, B.4.k.6, B.4.k.7, B.4.k.8, B.4.k.9, B.4.k.12, B.4.k.14 and B.4.k.15) should be copied into the dosage information in E2B(R3) of the corresponding drug section. There should be no attempt to recombine the dosages below the same 'drug' element even if the constituents of the drug are the same. • To downgrade to E2B(R2), a separate drug section (i.e., B.4.k) should be created for each dosage information of the same drug. For each drug section created during the conversion, the fields not related to dosage information should be filled with the same content. Example: Input in E2B(R3): Drug 1: Dosage Information: dosage A Dosage Information: dosage B -50- Contains Nonbinding Recommendations Drug 2: Dosage Information: dosage C Dosage Information: dosage D Output in E2B(R2): Drug 1A: information on drug 1 and dosage A Drug 1B: information on drug 1 and dosage B Drug 2C: information on drug 2 and dosage C Drug 2D: information on drug 2 and dosage D In addition, the E2B(R3) takes another approach regarding separate dosages. The E2B(R2) field for the number of separate dosages, i.e., B.4.k.5.3, has been deleted in E2B(R3). This calls for a set of conventions when converting dosage information between the two message formats. The following recommendation applies: • To upgrade to E2B(R3), the following cases can occur: 1) The dose value and the number of separate doses are provided. In such case, the dose value in E2B(R3) should be multiplied by the number of separated doses. In addition, the number of separated doses should be appended to the E2B(R3) field G.k.4.r.8 (dosage text). Example: Input in E2B(R2): Dose: 2 mg Number of separated doses: 3 Output in E2B(R3): Dose: 6 mg Dosage text: 3 separated doses Formula: Dose (E2B(R3)) = Dose (E2B(R2)) x Number of separated doses 2) The dose value is provided but not the number of separated doses. In such case, the dose value in E2B(R3) should be the same as in E2B(R2). Example: Input in E2B(R2): Dose: 2 mg -51- Contains Nonbinding Recommendations Number of separated doses: <not provided> Output in E2B(R3): Dose: 2 mg Formula: Dose (E2B(R3)) = Dose (E2B(R2)) x 1 • To downgrade to E2B(R2), if the dose value is provided in E2B(R3), the same value should be used in E2B(R2), accompanied by a number of separated doses set to 1. Example: Input in E2B(R3): Dose: 2 mg Output in E2B(R2): Dose: 2 mg Number of separated doses: 1 5.7.9 Substance Strength E2B(R3) supports the strength for the drug substance, which does not exist in E2B(R2). The structural change impacts the following fields: E2B(R2) E2B(R3) Description Field Format Field Format Strength - - G.k.2.3.r.3a 10N Strength unit - - G.k.2.3.r.3b UCUM Code Additional information B.4.k.19 100AN G.k.11 2000AN on drug (free text) The following recommendation applies: • To upgrade to E2B(R3), the fields should not be set, as they do not exist in E2B(R2). • To downgrade to E2B(R2), the E2B(R3) fields for substance strength and strength unit should be concatenated and copied to the E2B(R2) field for additional information on drug, i.e., B.4.k.19. If the value to copy exceeds the size limit of the field, truncation should apply as described in section 5.5. Example: Input in E2B(R3): Substance #1: Name: substance-1-name -52- Contains Nonbinding Recommendations Strength and strength unit: 1 mg Substance #2: TermID: substance-2-term-id TermID version date / number: substance-2-version Strength and strength unit: 2 mg Output in E2B(R2): Additional information on drug (free text): substance-1-name: 1 mg; substance-2-term-id (substance-2-version): 2 mg 5.7.10 Indication E2B(R3) provides a different approach for the indication information, which repeats in E2B(R3). The structural change impacts the following fields: E2B(R2) E2B(R3) Description Field Format Field Format Indication B.4.k.11 unique per drug G.k.7.r repeatable per drug The general principle, when converting the information back to E2B(R2), is to focus on the first indication only. Each additional indication should be copied to the narrative section. The following recommendation applies: • To upgrade to E2B(R3), the unique indication for the drug should be copied to the indication section of the E2B(R3) message. If the E2B(R2) message contains multiple drug sections, for the same drug information but different indications, the information should be copied as in E2B(R2) without any attempt to recombine the indication information under the same drug section. • To downgrade to E2B(R2), the drug section should not be duplicated to support multiple indications. Instead, only the first indication should be copied from E2B(R3) back to E2B(R2). The other indications should then be copied into the narrative section, under the prefix 'INDICATION', extended with the name of the drug between parentheses. The content of the indication field should be composed of the drug indication as reported by the primary source (i.e., G.k.7.r.1), and the indication in MedDRA terminology along with the MedDRA version (i.e., G.k.7.r.2a and G.k.7.r.2b). Example: Input in E2B(R3): Drug 1: drug-1 -53- Contains Nonbinding Recommendations 2 Indications: indication-1a, indication-1b Drug 2: drug-2 3 Indications: indication-2a, indication-2b, indication-2c Output in E2B(R2): Drug 1: drug-1 Indication: indication-1a Drug 2: drug-2 Indication: indication-2a <content of case narrative> INDICATION drug-1: indication-1b (MedDRA code; MedDRA version) INDICATION drug-2: indication-2b (MedDRA code; MedDRA version) INDICATION drug-2: indication-2c (MedDRA code; MedDRA version) 5.7.11 Drug-Reaction / Event Matrix E2B(R3) provides a different approach for the drug-reaction / event matrix. The structural change impacts the following fields: E2B(R2) E2B(R3) Description Field Format Field Format Time interval B.2.i.7 4 fields G.k.9.i.3 - (start – last) B.4.k.13 Drug recurrence B.4.k.17 - G.k.9.i.4 - (See section 4.2.12) Drug reaction relatedness B.4.k.18 - G.k.9.i.1 - G.k.9.i.2.r The general principle of the upgrade to E2B(R3) is to combine the E2B(R2) fields for drug recurrence (i.e., B.4.k.17) and for drug-reaction relatedness (i.e., B.4.k.18) into the E2B(R3) field for drug-reaction matrix (i.e., G.k.9.i). The downgrade to E2B(R2) should focus on a single value for the time interval between drug administration and start of reaction / event (field B.4.k.13) in E2B(R2). The following recommendation applies: • To upgrade to E2B(R3), the approach is as follows: 1) All the information related to the drug-reaction / event matrix should be listed in a unique table, ordered per reaction / event. -54- Contains Nonbinding Recommendations 2) An entry in the matrix for each reaction / event occurrence should be created. 3) The time interval value from the first occurrence of the reaction / event in B.2.i should be retrieved. 4) The recurrence flag for that particular reaction / event (see section 5.2.11) should be set. 5) The assessment fields for that reaction / event should be iterated. Example: Input in E2B(R2): Drug: Time interval (start – last): 10 days - 2 days Recurrent administration: Yes Drug recurrence: Event 1 Drug relatedness: Event 1: Source: reporter Method: global introspection Result: related Event 1: Source: company Method: algorithm Result: possibly related Event 2: Source: reporter Method: global introspection Result: not related Event 2: Source: company Method: algorithm Result: possibly related Input in E2B(R3): Drug matrix for Event 1: Time interval (start – last): 10 days - 2 days Recurrent administration: Re-challenge was done, reaction recurred Relatedness A: Source: reporter Method: global introspection Result: related -55- Contains Nonbinding Recommendations Relatedness B: Source: company Method: algorithm Result: possibly related Drug matrix for Event 2: Time interval (start – last): 10 days - 2 days Relatedness A: Source: reporter Method: global introspection Result: not related Relatedness B: Source: company Method: algorithm Result: possibly related • To downgrade to E2B(R2), the approach is as follows: 1) The time interval for the first reaction / event listed in B.2.i should be retrieved. 2) For each reaction / event:  The time interval for the first reaction to the drug section should be copied.  The drug recurrence as in the matrix section (see section 5.2.11) should be set.  If it recurs, i.e., when E2B(R3) field G.k.9.i.4 is set to 'Re-challenge was done, reaction recurred (yes-yes)', the corresponding reaction(s) / event(s) should be copied into the recurrence section.  The assessment fields for that reaction / event should be iterated. Example: see above -56- Contains Nonbinding Recommendations 5.7.12 Additional Information on Drug E2B(R3) provides a different approach for the additional information on the drug, which consists of repeatable coded values in E2B(R3) instead of a single free text field in E2B(R2). The structural change impacts the following fields: E2B(R2) E2B(R3) Description Field Format Field Format Additional information - - G.k.10.r 11possible values on drug (coded) Additional information B.4.k.19 100AN G.k.11 2000AN on drug (free text) The following recommendation applies: • To upgrade to E2B(R3), the E2B(R2) field B.4.k.19 should be copied into the E2B(R3) field G.k.11. • To downgrade to E2B(R2), the E2B(R3) fields G.k.10.r, i.e., the meaning of the coded values, should be copied into the E2B(R2) field B.4.k.19, separated by commas. The field should be extended with the content of the field G.k.11, if any. If there is not enough space in E2B(R2) field B.4.k.19, the information should be truncated (see section 5.5) and the full information should be stored in the narrative section, under the prefix 'ADDITIONAL INFO ON DRUG'. The heading should be extended with the name of the drug between parentheses. Example (with enough space in B.4.k.19): Input in E2B(R3): Drug: drug-1 Codes: code-1, code-2 Other info: other-information Output in E2B(R2): Additional info: meaning-code-1, meaning-code-2, other-information Example (with not enough space in B.4.k.19): Input in E2B(R3): Drug: drug-1 Codes: code-1, code-2, code-3, code-4, code-5 Other info: other-information Output in E2B(R2): Additional info: meaning-code-1, meaning-code-2, meaning-code-3… -57- Contains Nonbinding Recommendations Narrative section: ADDITIONAL INFO ON DRUG (drug-1): meaning-code-1, meaning-code-2, meaning-code-3, meaning-code-4, meaning-code-5, other-information 5.7.13 Additional Sender Diagnosis E2B(R3) provides a different approach for the additional sender diagnosis, which repeats in E2B(R3). The structural change impacts the following fields: E2B(R2) E2B(R3) Description Field Format Field Format Sender diagnosis B.5.3 unique H.3.r repeatable The following recommendation applies: • To upgrade to E2B(R3), the field B.5.3 should be copied to the field H.3.r of E2B(R3). • To downgrade to E2B(R2), the first occurrence of E2B(R3) field H.3.rshould be copied into the E2B(R2) field B.5.3. The other fields, if any, should be copied into the narrative section under the heading 'ADDITIONAL SENDER DIAGNOSIS'. Example: Input in E2B(R3): Sender diagnosis #1: diagnosis-1, diagnosis-version-1 Sender diagnosis #2: diagnosis-2, diagnosis-version-2 Sender diagnosis #3: diagnosis-3, diagnosis-version-3 Output in E2B(R2): Sender diagnosis: diagnosis-1, diagnosis-version-1 Narrative section: ADDITIONAL SENDER DIAGNOSIS: diagnosis-2 (diagnosis-version-2), diagnosis-3 (diagnosis-version-3) -58- Contains Nonbinding Recommendations 5.7.14 Batch and Message Wrappers E2B(R3) provides a unique batch wrapper and a repeatable message wrapper, while the E2B(R2) guideline only provides a unique message wrapper. E2B(R2) E2B(R3) Description Section Characteristic Section Characteristic Batch wrapper M.1 unique N.1 unique Message wrapper - - N.2.r repeatable Although the E2B(R2) section M.1 is named 'message wrapper', it corresponds to a batch wrapper as it covers all the safety reports the message contains. Therefore, the following recommendations apply: • To upgrade to E2B(R3), the following recommendations apply: 1) The E2B(R2) section M.1 should be mapped to the E2B(R3) section N.1, with a one-to-one relationship (see related implementation guides), except for the elements covered in sections 5.2.2 (codes for the type of message), 5.3.2 (format version and release), and 5.1.3 (date of transmission). 2) The E2B(R3) section N.2.rshould be filled with the following contents:  E2B(R3) field N.2.r.1 (message ID) with E2B(R2) field A.1.0.1  E2B(R3) field N.2.r.2 (message sender ID) with E2B(R2) field M.1.5  E2B(R3) field N.2.r.3 (message receiver ID) with E2B(R2) field M.1.6  E2B(R3) field N.2.r.4 (date of message creation) with E2B(R2) field A.1.3 • To downgrade to E2B(R2), the following recommendations apply: 1) The E2B(R2) section M.1 should be mapped to the E2B(R3) section N.1, with a one-to-one relationship (see related implementation guides), except for the elements covered in sections 5.2.2 (codes for the type of message), 5.3.2 (format version and release), and 5.1.3 (date of transmission). 2) The E2B(R3) section N.2.rshould be ignored. -59- Contains Nonbinding Recommendations 5.7.15 ICSR Message Sender and Receiver in ACK E2B(R3) provides a different way to exchange ICSR message sender and receiver in the Acknowledgement message. E2B(R2) E2B(R3) Description Section Characteristic Section Characteristic ICSR Message Receiver ACK: A.1.4 unique ICSR Message ACK Sender ACK: ACK.B.r.4 repeatable ICSR Message Sender ACK: A.1.3 unique ICSR Message ACK ACK: ACK.B.r.3 repeatable Receiver Given that the ICSR message ACK follows the opposite route than the ICSR message itself, the identification of sender and receiver should be swapped. Therefore, the following recommendations apply: • To upgrade to E2B(R3), the E2B(R2) fields for ICSR message sender should be copied to each occurrence of the ICSR message ACK receiver in E2B(R3). Similarly, the E2B(R2) fields for ICSR message receiver should be copied to each occurrence of the ICSR message ACK sender in E2B(R3). • To downgrade to E2B(R2), the E2B(R3) fields for ICSR message ACK sender and receiver should be copied from the first occurrence of the message acknowledgement to the ICSR message receiver and sender fields in E2B(R2), respectively. -60-