9.best Practice in Reporting of ICSRs

Best Practice In Reporting Of Individual Case Safety Reports (ICSRs)
Compiled by the Medicines and Healthcare products Regulatory Agency, the Association of the British Pharmaceutical Industry, the Proprietary Association of Great Britain, the British Association of Research Quality Assurance and the British Generic Manufacturers Association as part of a BROMI initiative
February 2011
MedDRA is a registered trademark of the International Federation of Pharmaceutical Manufacturers and Associations (IFPMA) Crown Copyright 2011 Published by the Medicines and Healthcare products Regulatory Agency Guidance on reproducing and re-using MHRA Crown copyright material can be found on our website at: http://www.mhra.gov.uk/CrownCopyright/index.htm An application for permission to reproduce MHRA material, available from our website, should be sent to the MHRA at the address below: Medicines and Healthcare products Regulatory Agency Information Services 4th Floor 151 Buckingham Palace Road London SW1W 9SZ E-mail: info@mhra.gsi.gov.uk
As of Feb 2011 / Ver: 1.0
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Crown copyright 2011
CONTENTS
1. CHAPTER 1 - INTRODUCTION .................................................................................................... 5 1.1 1.2 1.3 1.4 2. INTRODUCTION ........................................................................................................................ 5 BACKGROUND .......................................................................................................................... 5 REFERENCES........................................................................................................................... 6 FEEDBACK ............................................................................................................................... 6
CHAPTER 2 - VALID ADVERSE DRUG REACTION................................................................... 7 2.1 INFORMATION TO VALIDATE A CASE FOR EXPEDITED REPORTING ................................................. 7
3.
CHAPTER 3 - REPORTING REQUIREMENTS ............................................................................ 8 3.1 3.2 3.3 3.4 3.5 EXPEDITED REPORTING REQUIREMENTS .................................................................................... 8 REPORTING OVERDOSE, ABUSE AND MISUSE ............................................................................. 8 REPORTING OF MEDICATION ERRORS ........................................................................................ 9 REPORTS OF LACK OF EFFICACY ............................................................................................... 9 PRODUCT COMPLAINTS .......................................................................................................... 10
4.
CHAPTER 4 - ICSR SUBMISSIONS BASED ON MHRA ASPRS ............................................. 11 4.1 ICSR SUBMISSIONS BASED ON MHRA ASPRS ....................................................................... 11
5.
CHAPTER 5 - GENERAL DATA ENTRY GUIDANCE ............................................................... 13 5.1 GENERAL DATA ENTRY GUIDANCE ........................................................................................... 13
6.
CHAPTER 6 - PATIENT CHARACTERISTICS........................................................................... 14 6.1 PATIENT CHARACTERISTICS .................................................................................................... 14
7.
CHAPTER 7 - DRUG INFORMATION......................................................................................... 15 7.1 DRUG INFORMATION ............................................................................................................... 15 7.2 ADDITIONAL DRUG INFORMATION............................................................................................. 16 7.2.1 Drug dosage.................................................................................................................... 17 7.2.2 Pharmaceutical form ....................................................................................................... 17 7.2.3 Route of administration ................................................................................................... 18 7.2.4 Indication ......................................................................................................................... 18 7.2.5 Dates ............................................................................................................................... 18 7.2.6 Action taken with drug ..................................................................................................... 18
8.
CHAPTER 8 - REACTION INFORMATION ................................................................................ 20 8.1 8.2 8.3 8.4 8.5 8.6 8.7 8.8 8.9 8.10 8.11 8.12 MEDDRA .............................................................................................................................. 20 REACTION OUTCOMES ............................................................................................................ 23 ADVERSE DRUG REACTIONS VERSUS ADVERSE EVENTS ............................................................ 23 WITHDRAWAL REACTION CLASSIFICATION ................................................................................ 25 REACTION OCCURRING AT MULTIPLE BODY SITES ..................................................................... 25 DUPLICATION OF REACTION TERMS ......................................................................................... 26 DRUG INTERACTION ............................................................................................................... 26 DEFINITIVE AND PROVISIONAL DIAGNOSES WITH SIGNS AND SYMPTOMS ..................................... 26 OTHER PATIENT OUTCOMES.................................................................................................... 27 NO ADVERSE EFFECT ............................................................................................................. 27 PRODUCT SUBSTITUTION ........................................................................................................ 27 UNEXPECTED BENEFIT............................................................................................................ 27
9.
CHAPTER 9 - CASE NARRATIVE.............................................................................................. 28 9.1 CASE NARRATIVE ................................................................................................................... 28 CHAPTER 10 TEST RESULTS ........................................................................................... 29 TEST RESULTS ....................................................................................................................... 29
10. 10.1
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11. 11.1 11.2 12. 12.1 12.2 12.3 13. 13.1 14. 14.1 15. 15.1 15.2 15.3 15.4 15.5 15.6 15.7 16.
CHAPTER 11 FATAL REACTIONS .................................................................................... 31 REPORTS OF DEATH ............................................................................................................... 31 PATIENT DEATH DETAILS ......................................................................................................... 32 CHAPTER 12 - REPORTS OF DRUG EXPOSURE DURING PREGNANCY........................ 33 REPORTS OF DRUG EXPOSURE DURING PREGNANCY ................................................................ 33 PARENT - CHILD REPORTS ...................................................................................................... 33 PREGNANCY WITH CONTRACEPTIVE MEDICINES ....................................................................... 35 CHAPTER 13 - LITERATURE REPORTS .............................................................................. 36 LITERATURE REPORTS ............................................................................................................ 36 CHAPTER 14 - REPORTER DETAILS................................................................................... 38 REPORTER DETAILS ............................................................................................................... 38 CHAPTER 15 - ADMINISTRATIVE INFORMATION .............................................................. 39 WORLDWIDE UNIQUE CASE IDENTIFICATION NUMBER AND SAFETY REPORT ID............................ 39 REPORT TYPE ........................................................................................................................ 39 SERIOUSNESS CRITERIA AND MEDICALLY CONFIRMED SELECTION ............................................. 41 DUPLICATES AND NULLIFICATIONS ........................................................................................... 41 DATES ................................................................................................................................... 45 FOLLOW-UP REPORTS ............................................................................................................ 45 SENDER AND RECEIVER DETAILS ............................................................................................. 45 APPENDIX 1 ABBREVIATIONS.......................................................................................... 47
17. APPENDIX 2 ELECTRONIC TRANSMISSION OF INDIVIDUAL CASE SAFETY REPORTS MESSAGE SPECIFICATION (ICH ICSR DTD VERSION 2.1) ............................................................ 48 18. 19. 20. 21. 22. APPENDIX 3 MHRA VALIDATION RULES ........................................................................ 49 APPENDIX 4 PHARMACEUTICAL FORMS ....................................................................... 50 APPENDIX 5 ROUTE OF ADMINISTRATION..................................................................... 51 APPENDIX 6 USEFUL WEBSITES ..................................................................................... 52 APPENDIX 7 GLOSSARY ................................................................................................... 53
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1.
1.1
Chapter 1 - Introduction
Introduction
Spontaneous adverse drug reaction (ADR) reporting is fundamental in the post-marketing surveillance of medicines. It is therefore important to capture information on ADRs in a structured manner and to the highest possible quality standards to support accurate detection and analysis of drug safety signals. With the recent move to electronic reporting, maintaining quality for electronic reports received from industry is a major challenge as reports are no longer subject to the regulators internal review or manual intervention. It is therefore essential that a common understanding and methodology for best practice in coding and data classification is implemented. Through rigorous internal monitoring the MHRA has identified a need to develop a Best Practice guide in reporting of Individual Case Safety Reports (ICSRs) using the E2B standard. This guide aims to remove the various differences that occur in reporting through differing classification and coding practices across companies, a key problem highlighted through the MHRA audit process. The audit process involves reviewing a random sample of 50 UK E2B reports for four Marketing Authorisation Holders (MAHs) each month. The selection for audit may be based upon concerns raised through review of reports at signal assessment, compliance data or intelligence gathered from pharmacovigilance inspections. This guide combines ideas from both industry trade associations and the MHRA as part of a Better Regulation of Medicines Initiative (BROMI). It is hoped the guide will contribute to delivering high standards in classification by highlighting common findings from audits of ICSRs and providing specific examples of good practice.
1.2
Background
Electronic exchange of information on suspected adverse reaction reports between regulators and industry allows the data to be made immediately available for qualitative signal detection and evaluation. The E2B standard ensures that this information is easily transferred and therefore facilitates uniformity and high quality with regard to the content and format of ICSRs. At the MHRA the procedure for paper reports involves internal coding and quality review in the workflow to ensure data are correctly coded before they are committed to the database and made available in outputs such as ICSRs, Drug Analysis Prints (DAPs), Anonymised Single Patient Reports (ASPRs) and signal detection outputs. However, usually electronic reports received from industry are automatically committed to the database without manual intervention. This means that E2B reports are available in the public domain as initially coded by the MAH. Validation rules have been built to ensure basic quality standards are met. The full list of these rules can be found in Appendix 3. Nevertheless, the MHRAs audit of reports submitted from industry demonstrates a significant difference in classification and coding practices across companies. 5/55
Errors in the database could have serious consequences such as missing signals or creating false signals where ADRs are duplicated. Furthermore, such errors also generate a large volume of enquiries. This results in further work to update the case and/or contact the originator company to request an update to their case. Each enquiry that requires a case update will generate an updated version of the ASPR which is a significant administrative burden for both industry and the MHRA. The MHRA and industry trade associations have agreed to issue guidance on best practice to support consistent coding practices to satisfy all stakeholders.
1.3
References
It is intended that this guide will complement current EU legislation and guidance and provide practical advice to key stakeholders on the classification of ICSRs. It is important to note that the guide is not intended to replace the existing legislation and guidance. A list of the abbreviations referred to within the guide is provided in Appendix 1. This guide has been based on the current pharmacovigilance framework. New legislation for pharmacovigilance in the EU will have an impact on the guidance provided. References for this guide include: Electronic Transmission of Individual Case Safety Reports Message Specification (ICH ICSR DTD version 2.1). This document provides information on the E2B fields (see Appendix 2). Volume 9A of The Rules Governing Medicinal Products in the European Union Guidelines on Pharmacovigilance for Medicinal Products for Human Use (available from the European Commission website) http://ec.europa.eu/health/documents/eudralex/vol-9/index_en.htm Volume 10 ENTR/CT3 Detailed guidance on the collection, verification and presentation of adverse reaction reports arising from clinical trials on medicinal products for human use Volume 10 ENTR/CT4 Detailed guidance on the European database of Suspected Unexpected Serious Adverse Reactions (Eudravigilance - Clinical Trial Module) MedDRA Term Selection: Points to Consider (MTS: PTC) Note for guidance EudraVigilance Human Processing of safety messages and individual case safety reports (ICSRs)
The MHRA has also published a Good Pharmacovigilance Practice Guide which gives guidance on developing effective pharmacovigilance systems.
1.4
Feedback
For general enquiries about pharmacovigilance, the MHRAs Pharmacovigilance Service Desk can be contacted by e-mail at: pharmacovigilanceservice@mhra.gsi.gov.uk.
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2.
2.1
Chapter 2 - Valid Adverse Drug Reaction

Information to validate a case for expedited reporting
The minimum criteria for a valid case with regards to expedited reporting are: an identifiable patient (anonymised) a suspect drug a suspect reaction an identifiable healthcare professional reporter (should be anonymised to avoid data protection issues but reporter qualification must be available).
Further guidance on the four minimum criteria can be found in the relevant chapters (chapters 6, 7, 8 and 14). When one or more of these criteria are missing, it is expected that the MAH should follow up the case in order to validate the report. For consumer reports, it is expected that the MAH should seek the consumers consent to contact their healthcare professional to obtain medical confirmation. Medical notes relating to the reaction and the specific patient can be accepted as healthcare professional confirmation of a report from a consumer. Volume 9A states that if ICSRs, which do not qualify for expedited reporting provide information that may lead to a change in the known risk-benefit balance for the product, this possible change should be notified to the Competent Authorities without delay. If reports are received that provide details of a drug and a reaction term but not an identifiable patient and/or reporter, MAHs should enter these cases on their safety database and expedite if validating information is received. Invalid reports should be regularly reviewed to consider how these reports might provide information on the known risk-benefit balance for the product. MAHs should also take appropriate action to investigate the possibility of an emerging pattern e.g. reports from the same source or a cluster of similar adverse events. There is a need for further guidance to be developed on how to handle invalid reports and for reports identified through social networking websites, web blogs and other such sources of data. A valid ADR for expedited reporting must include an identifiable patient, a suspect drug, a suspect reaction, an identifiable healthcare professional reporter.
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3.
3.1
CHAPTER 3 - Reporting Requirements

Expedited reporting requirements
European expedited reporting requirements are covered in Volume 9A, with additional details of specific requirements for Member States provided in Annex 6. The following cases should be expedited to the MHRA: a) Spontaneous All UK serious. (The MHRA forwards all serious UK reports to the EMA and therefore companies must not expedite these cases to the EMA). All serious EU cases for centralised and MR products where the UK is the RMS or Rapporteur (including EU competent authority cases where applicable) All serious worldwide cases * All serious Black Triangle EU cases. **
It is important to note that reports derived from post-marketing studies are subject to the same reporting requirements as spontaneous reports. b) Clinical Trials reporting requirements for trial sponsors All UK SUSARs Any non-UK SUSAR that is related to an IMP under investigation by the sponsor in the UK.
It should be noted that although some reports may not meet the expedited reporting requirements, they should be recorded in the MAHs pharmacovigilance system as they may provide useful information on the overall risk-benefit balance of the medicinal product. These reports should be included for risk-benefit evaluation during signal detection and PSUR preparation e.g. reports of overdose, abuse and misuse that are not associated with a serious adverse drug reaction (see section 3.2).
3.2
Reporting overdose, abuse and misuse
In line with Volume 9A the MAH should continuously monitor and evaluate the potential impact of overdose, abuse and misuse on the overall risk-benefit balance of the medicinal product.
*
In addition to the legal requirement for reporting unexpected serious cases, MAHs are also encouraged to report electronically all expected serious adverse reactions occurring outside the EU on an expedited basis, regardless of the authorisation procedure.
In the UK, additional voluntary requirements are in place for products that are subject to intensive monitoring, also known as black triangle products to report all serious reactions that originate from within the EU to the MHRA.
**
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Only cases of overdose, abuse and misuse that lead to serious adverse reactions should be expedited to the MHRA. Reports should be routinely followed up to ensure that information is as complete as possible with regard to early symptoms, treatment and outcome. This includes cases of intended suicide. Reports of overdose, abuse and misuse that are not associated with a serious adverse drug reaction should be recorded in the MAHs pharmacovigilance system as they provide useful information on the overall risk-benefit balance of the medicinal product and should be included for risk-benefit evaluation during signal detection and PSUR preparation. If an overdose is reported and it was specifically stated that there were no clinical consequences, it is acceptable to code the LLT Overdose and the additional LLT No adverse effect on the MAHs database in line with the guidance in the MedDRA Term Selection: Points to Consider (MTS: PTC) document, however these reports should not be expedited as ICSRs to the MHRA. The most appropriate MedDRA term to describe the overdose should be selected e.g. whether the overdose is accidental or intentional or involves a multiple drug overdose. Reports that indicate that the taking of the suspect drug led to a suicidal intention and subsequent overdose of the suspect drug or other medication should also be expedited. Example 1: In the following example the patient was hospitalised following an overdose, however this case should not be expedited as there was no reaction associated with the overdose. The MAH should consider whether or not the drug may have contributed to the overdose and the report should be followed up for further information. <narrativeincludeclinical>Spontaneous report, reported by a nurse, received on 06OCT2009. A 21 year old female patient has taken an overdose of XXXXXX of 40 mg on 24SEP2009 at 11am. She also took an overdose of 20 mg XXXXXXX. The patient rang the hospital at 6pm and discharged herself at 3 am. No side effects were experienced by the patient. The reporting nurse did not provide a causality assessment and outcome.</narrativeincludeclinical>
3.3
Reporting of medication errors
Reports of medication errors such as wrong route of administration or wrong drug administered - should only be expedited to the MHRA if they are accompanied by a serious ADR.
3.4
Reports of lack of efficacy
Volume 9A states that reports of lack of efficacy should not normally be reported on an expedited basis, but should be recorded in the MAHs pharmacovigilance system and discussed in the relevant PSUR. However, in certain circumstances reports of lack of efficacy should be treated as expedited cases for reporting purpose. Medicinal products used for the treatment of life-threatening diseases, vaccines and contraceptives are examples of classes of medicinal products where lack of efficacy should be considered as cases requiring expedited reporting. It is important to provide batch numbers for vaccines.
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Judgement should be used in reporting, considering if other cases qualify for reporting. For example, antibiotics used in life-threatening situations where the medicinal product was not in fact appropriate for the infective agent should not be reported. However, a life-threatening infection where the lack of efficacy seems to be due to the development of a newly resistant strain of a bacterium previously regarded as susceptible should be reported on an expedited basis. Companies should apply judgment on a case by case basis to decide if the reports raise a concern about lack of efficacy. If in doubt, please contact us through the Pharmacovigilance Service Desk (pharmacovigilanceservice@mhra.gsi.gov.uk).
3.5
Product complaints
Product complaints should be reviewed for efficacy-related issues or problems with the manufacturing process in accordance with good manufacturing practice requirements. Reports of product technical complaints should also be reviewed on an ongoing basis to ensure that any reports associated with an ADR are recorded on the MAHs database so that they are included for risk-benefit evaluation during signal detection and PSUR preparation. Any reports that fulfil the requirements for expedited reporting should be submitted within the regulatory timeframes.
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4. Chapter 4 - ICSR Submissions Based On MHRA ASPRs

4.1 ICSR submissions based on MHRA ASPRs
Expedited reporting of ICSRs also applies to EU Competent Authorities. EU Competent Authorities are required to provide reports within 15 days of receipt of all serious adverse reactions occurring in their country to relevant MAHs and to the EMA. The MHRA provides this information to MAHs in the form of ASPRs (this includes ICSRs generated at the MHRA). The date the ASPR is made available to the MAH should be considered day 0. ICSRs based on MHRA ASPRs should not be reported back to the MHRA as this will generate duplicate cases in the MHRAs database and result in further duplicate ASPRs. It should be noted that EU competent authority cases should be expedited in line with reporting requirements. The Pharmacovigilance Service Desk (pharmacovigilanceservice@mhra.gsi.gov.uk.) should be contacted if an MAH has obtained significant follow-up information for a case received from the MHRA. The MHRA will provide advice on whether the case should be expedited. If it is deemed necessary to expedite an update to an ICSR originating from the MHRA, it is essential to use the correct format of the World Wide Reference Number (WWRN) in order to prevent the generation of duplicates: GB-MHRA-ADR XXXXXXXX
Do not send ICSRs based on MHRA ASPRs back to us.
The following are examples which should not have been reported to the MHRA as they are based on ASPRs. Example 1: This report has a case assigned company reference number which is reported as the WWR number. The MHRA reference number has been entered in the duplicate number field and the MHRA is listed as a reporter in the narrative. <reportduplicate> <duplicatesource>GBR-MHRA</duplicatesource> <duplicatenumb>ADR 10910173</duplicatenumb> </reportduplicate> <narrativeincludeclinical>Serious spontaneous case received on 20Jan-2010 from the U.K. Health Authorities MHRA (ADR 10910173)</narrativeincludeclinical>
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Example 2: This is an example where the ICSR maintains the MHRA assigned WWR number. An update case was created on the MHRA database, with no additional information reported. <authoritynumb>GB-MHRA-ADR 20226863</authoritynumb > <narrativeincludeclinical>This literature report was received via authority and originated in the United Kingdom...</narrativeincludeclinical>
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5.
5.1
Chapter 5 - General Data Entry Guidance

General data entry guidance
The guidance in this chapter is based on the most common findings from audits of E2B reports (further information and examples can be found in the following chapters). One of the most common findings from audit of E2B reports is that key information present in the case narrative is often missing from the structured fields. For example some reports may include information on the age or dose of the medicine in the case narrative but not in the structured E2B age or dose fields. This could affect signal analysis processes for example when reviewing ADRs in paediatric or elderly populations or for dose related affects. All information in the narrative should be correctly coded in the relevant structured fields to assess the cases quickly and facilitate consistent data retrieval. It should be noted that including the patient or reporter details in the case narrative may break confidentiality data protection rules. It is important to select the most appropriate MedDRA terms to describe the reaction and to ensure the correct coding of drug names in the suspected medicines field. Only reports of adverse drug reactions should be expedited, not adverse events (see section 8.3 on Adverse drug reaction versus adverse events).
All information in the narrative should be correctly coded in the relevant structured fields.
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6.
6.1
Chapter 6 - Patient Characteristics

Patient characteristics
For a report to be considered valid it must contain at least one of the following criteria: age, age group, sex, initials, date of birth, gestation period or identification number.
The <patientinitial> tag can be populated with the patients initials, UNKNOWN or PRIVACY. Entries such as XXX, N/A and --- are not acceptable. If the <patientinitial> tag is populated as UNKNOWN, then one of the other criteria for patient characteristics should be populated in order for the report to be considered valid e.g. date of birth. Entries such as Patient 1 should not be entered in the patient initials. Entries such as this should be captured in the patient investigation number field (B.1.1.1d). The following examples are accepted: <patientinitial>PRIVACY</patientinitial> or <patientinitial>KC</patientinitial>
Entries such as XXX, N/A and --- are not accepted: <patientinitial>XXX</patientinitial> or <patientinitial>---</patientinitial>
The information provided should be as complete as possible, taking into account EU legislation on data protection and relevant national legislation. Including patient details in the case narrative may break confidentiality data protection rules.
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7.
7.1
Chapter 7 - Drug Information

Drug information
This section covers coding on suspect drugs, vaccines and concomitant medication. It is important to ensure that drug information is correctly coded to ensure that ADR data can be aggregated at substance level. The drug characterisation indicates whether a drug is classified as suspect, concomitant or interacting. Interacting may be used when an interaction LLT is selected e.g. Drug interaction, Food interaction or Alcohol interaction. Suspect drug(s) The drug(s) suspected of causing the reaction should be listed as the suspect drug(s). Concomitant medication Any drug(s) that are not suspected of causing the reaction and that are administered to the patient at the time the case is reported should be listed as concomitant medication. If a drug has been recently discontinued prior to the reaction, the MAH should consider whether the drug should be coded as concomitant medication or medical history and document their working practices. For example the MHRA codes all drugs discontinued within 3 months prior to the reaction as concomitant medication. Patient Past Drug Therapy All drugs that were completed/discontinued before the start of the treatment with the suspect(ed) drugs should be included in the relevant section, Patient Past Drug Therapy (unless it was recently discontinued prior to the reaction and therefore coded as concomitant medication). It is important to note that any medication given as treatment for the ADR should not be classified as concomitant medication. The MHRA requires either the medicinal product or active substance name to be completed. Any information regarding the formulation and route of administration should be captured in the relevant tags (<drugdosageform> (B.4.k.7) and <routeadministration> (B.4.k.8)). It is important to note that the strength and dosage should not be captured in the drug name fields. Example 1: For example paracetamol 20 mg capsules contains drug name (substance or product) dosage and pharmaceutical form; however there are structured fields available in E2B for the dose and pharmaceutical form. The following is an example with correct coding: <drug> <drugcharacterization>1</drugcharacterization> <medicinalproduct>PANADOL</medicinalproduct>

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<drugstructuredosagenumb>500</drugstructuredosagenumb> <drugstructuredosageunit>003</drugstructuredosageunit> <drugadministrationroute>048</drugadministrationroute> <drugdosageform>045</drugdosageform> <activesubstance> <activesubstancename>PARACETAMOL</activesubstancename> </activesubstance> </drug> The following is an example of incorrect coding:
<drug> <drugcharacterization>1</drugcharacterization> <medicinalproduct>PANADOL 500mg tablets</medicinalproduct> <drugstructuredosagenumb></drugstructuredosagenumb> <drugstructuredosageunit></drugstructuredosageunit> <drugadministrationroute></drugadministrationroute> <drugdosageform></drugdosageform> <activesubstance> <activesubstancename>PARACETAMOL</activesubstancename> </activesubstance> </drug>
There should be no prefixes or suffixes used in the classification of these drugs unless they are part of the specific product (SP) name. Below is an example of how the MHRA requires drug names to be classified: Brand Name: to be entered in the <medicinalproduct>: NASONEX Active Substance to be entered in <activesubstance>: MOMETASONE FUROATE MONOHYDRATE In summary only the brand name and active substances should be classified in the <medicinalproduct> and <activesubstance> tags. Any additional information should be captured in the relevant structured fields and not included as prefixes and suffixes in the drug name tags.
7.2
Additional drug information
All details regarding the suspect and concomitant drugs should be captured in the structured fields. For example the dosage information should be captured as shown below: <drugstructuredosagenumb>200</drugstructuredosagenumb> <drugstructuredosageunit>21</drugstructuredosageunit>
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When the <drugstructuredosagenumb> is populated it is mandatory that the <drugstructuredosageunit> is also provided. Failure to do so will result in a case failure. This rule applies to other fields within the drug information. As a general rule, when a number is provided the corresponding unit also needs to be populated. Conversely if a unit is provided then a corresponding number needs to be populated. If this information is not known e.g. there is no information on units (simvastatin 20) then this information should be captured in the <drugdosagetext> field (see 7.2.1.).
Some correctly coded examples are shown below:
<drugseparatedosagenumb>200</ drugseparatedosagenumb> <drugstructuredosageunit>21</ drugstructuredosageunit> <drugcumulativedosagenumb>500</drugcumulativedosagenumb> <drugcumulativedosageunit>3</drugcumulativedosageunit>

The following examples would cause reports to be rejected:
<drugtreatmentduration></drugtreatmentduration> <drugtreatmentdurationunit>804</drugtreatmentdurationunit> <drugstartperiod>5</drugstartperiod> <drugstartperiodunit></drugstartperiodunit>
7.2.1 Drug dosage

All the drug dosage information should be captured in the structured fields. The <drugdosagetext> field can be used to supplement the dosage data; however whenever possible the information should be structured.
7.2.2 Pharmaceutical form

The pharmaceutical form of the drug should be entered in the <drugdosageform> field and the route of administration route should always be captured in the <drugadministrationroute> field. It is important to note that the pharmaceutical form should not be captured in the drug name fields. The pharmaceutical form xml tag can be populated with either a code or a text term the list of accepted terms has been adopted from the European Pharmacopoeia (see Appendix 4). <drugdosageform>65</drugdosageform> or <drugdosageform>capsules</drugdosageform>
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7.2.3 Route of administration

The route of administration should be populated as a code in the xml file using the predefined list in the E2B standard (see Appendix 5). Text terms are not accepted in this field. <drugadministrationroute>048</drugadministrationroute>
7.2.4 Indication
The indication of the drug should be captured in the <drugindication> field. If a drug has more than one indication, then the drug entry should be repeated for the second indication to be entered. The MedDRA LLT ill-defined disorder should not be coded as an indication. If the indication of the drug is unknown this field can be left blank or populated with LLT Drug use for unknown indication.
7.2.5 Dates
The start and stop dates should all be captured in the structured date fields within the drug tags. Please note that the MHRA accepts all formats of dates in these fields including full and partial dates. <drugstartdateformat>610</drugstartdateformat> <drugstartdate>200905</drugstartdate> <drugenddateformat>102</drugenddateformat> <drugenddate>20090603<drugenddate>
The MHRA has a validation in place so that the start date of the suspect drug cannot be later than the end date of the drug. Instances where the suspect drug end date is earlier than the start date will result in case failure.
The MHRA has a validation so that reactions that are reported to have started before the suspect drug was administered are rejected.
7.2.6 Action taken with drug

The action taken with the drug as a result of the reaction should be captured in the <actiondrug> field. This field should be populated with unknown rather than left blank if the action taken is unknown. A separate drug entry should not be entered for any changes to the dosage as a result of the reaction.
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Example 2: 50mg of the suspect drug was taken before the reaction and as a result of the reaction it was decreased to 25mg. The information regarding the reduced dose of 25mg should not be captured as a separate suspect drug entry as this did not contribute to the reaction. Instead the action drug field (B.4.k.16) of the 50mg entry should state dose decreased and the specific reduced dose (25mg) captured in the case narrative. The rechallenge fields should be used when identical symptoms are experienced on both exposures to the suspect drug. Any rechallenge information should be captured in the <drugrecurreadministration> and <drugrecuraction> fields. A separate drug entry should not be populated for the rechallenge information. Example 3: The patient was taking suspect drug Y and developed an itchy rash. Suspect drug Y was withdrawn on 01/01/2010 and the patient recovered. Suspect drug Y was re-introduced on 01/02/2010 and the patient developed an itchy rash again. Only the first drug date should be entered with the action taken with drug set as drug withdrawn. Only the first instance of the itchy rash should be captured as a reaction term. The <drugrecurreadministration> and <drugrecuraction> fields should be completed with the itchy rash that occurred on rechallenge.
If the patient experiences a different reaction on rechallenge or a more serious reaction then this should be recorded as a reaction term and not a rechallenge. Example 4: The patient was taking suspect drug X and experienced increased liver function tests. The drug was withdrawn on 01/01/2010 and the patient recovered. Drug X was re-introduced on 20/01/2010 and the patient experienced jaundice and acute liver failure. Both suspect drug dates should be separate entries Increased liver function tests, jaundice and acute liver failure should be classified as reaction terms with appropriate dates.
In this example the patient experienced a more serious reaction (jaundice and acute liver failure) when the drug was reintroduced and therefore this should be recorded as a separate entry.
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8.
8.1
Chapter 8 - Reaction Information

MedDRA
MAHs are required to code reports using the Medical Dictionary for Regulatory Activities (MedDRA) terminology. For further information on coding, please refer to the MedDRA Term Selection: Points to Consider (MTS: PTC) document. This is an ICH-endorsed guide for MedDRA users promoting accurate and consistent MedDRA term selection, which is available from the Maintenance and Support Services Organization (MSSO) website (see Appendix 6) and the ICH Web site: http://www.ich.org/cache/compo/276-254-1.html. In line with the guidance from the EMA and MSSO, the MHRA will implement new MedDRA versions on the first Monday of the second month after release (http://meddramsso.com/files_acrobat/VCGuidesemiannual.pdf). Any cases submitted with the new version of MedDRA prior this date will be rejected. On implementation the MHRA will continue to support the current and the previous version of MedDRA. Reaction terms should be classified using the LLT available to accurately reflect the reporters wording of the reaction. This is important to allow consistent and accurate classification of ICSRs. Medical judgement should be used if an exact match cannot be found and the most appropriate existing term should be selected. Terms should be selected for every ADR reported. Only current MedDRA LLTs should be selected. Non-current LLTs should not be used for term selection. The following are examples of where more specific reaction terms should have been selected.
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Example 1: In this example the MAH should have coded loss of vision in his left eye as LLT Unilateral vision loss rather than LLT Visual acuity reduced. <reaction> <primarysourcereaction>Loss of vision in his left eye</primarysourcereaction> <reactionmeddraversionllt>12.1</reactionmeddraversionllt> <reactionmeddrallt>10047531</reactionmeddrallt> <termhighlighted>3</termhighlighted> <reactionstartdateformat>102</reactionstartdateformat> <reactionstartdate>20100129</reactionstartdate> <reactionenddateformat>102</reactionenddateformat> <reactionenddate>20100129</reactionenddate> <reactionduration>1</reactionduration> <reactiondurationunit>804</reactiondurationunit> <reactionfirsttime>1</reactionfirsttime> <reactionfirsttimeunit>804</reactionfirsttimeunit> <reactionoutcome>1</reactionoutcome> </reaction> Coded to MedDRA LLT Visual acuity reduced Example 2: In this example the MAH should have coded drug interaction with pomegranate juice as LLT Food interaction rather than LLT Drug interaction. <reaction> <primarysourcereaction lang="en">DRUG INTERACTION WITH POMEGRANATE JUICE</primarysourcereaction> <reactionmeddraversionllt>12.1</reactionmeddraversionllt> <reactionmeddrallt>10013710</reactionmeddrallt> <reactionmeddraversionpt>12.1</reactionmeddraversionpt> <reactionmeddrapt>10013710</reactionmeddrapt> <termhighlighted>3</termhighlighted> <reactionoutcome>2</reactionoutcome> </reaction> Coded to MedDRA LLT Drug Interaction Reports that are ambiguous or confusing should be followed up for clarification. Terms such as LLT Ill-defined disorder and LLT Adverse drug reaction should not be expedited to the MHRA. There is also an option in addition to the LLT - to select the corresponding MedDRA preferred term (PT); however the MHRA does not require both of these to be completed. For any MedDRA term that is provided a corresponding MedDRA version is required. Failure to provide the MedDRA version will result in rejection of the report. For any MedDRA term that is provided a corresponding MedDRA version is also required. Failure to do so will result in case rejection.
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The exact wording used by the reporter should be captured in the <primarysourcereaction> field. This is a free text option and does not require a MedDRA term to be used. Example 3: This example demonstrates the use of the <primarysourcereaction>. In this example the verbatim term has been selected as increase in bladder muscle spasms and the LLT selected (10048994) bladder spasm. <reaction> <primarysourcereaction>INCREASE IN BLADDER MUSCLE SPASMS</primarysourcereaction> <reactionmeddraversionllt>12.0</reactionmeddraversionllt> <reactionmeddrallt>10048994</reactionmeddrallt> <reactionmeddraversionpt>12.0</reactionmeddraversionpt> <reactionmeddrapt>10048994</reactionmeddrapt> <termhighlighted>4</termhighlighted> <reactionstartdateformat>102</reactionstartdateformat> <reactionstartdate>20090302</reactionstartdate> <reactionenddateformat>102</reactionenddateformat> <reactionenddate>20090302</reactionenddate> <reactionduration>1</ reactionduration> <reactiondurationunit>804</ reactiondurationunit> <reactionfirsttime></reactionfirsttime> <reactionfirsttimeunit></reactionfirsttimeunit> <reactionlasttime></reactionlasttime> <reactionlasttimeunit></reactionlasttimeunit> <reactionoutcome>1</reactionoutcome> </reaction> Example 4: It is important to pay particular attention to avoid potential coding of past medical history or treatment procedures as suspected ADRs. The following is an example where deep vein thrombosis was incorrectly coded in the structured reaction fields. Swollen ankles should be coded as the reaction. <narrativeincludeclinical>Initial report received from a physician. The reporter stated that the patient had mild heart disease with symptoms of swollen ankles etc, believed to be linked to her old age. In the past the patient had also suffered from deep vein thrombosis.The patient received XXXXXX 12.5 mg in Feb 2010. Other suspect drug included XXXXXXX for depression. The patient developed swollen ankles on 04 Mar (exact date unspecified)The outcome and causality details for the other events were not provided at the time of this report.</narrativeincludeclinical> Pre-existing medical conditions that have not changed should generally be classified as medical history. Pre-existing medical conditions that have changed should be classified 22/55
using the most specific term e.g. if exacerbation of myasthenia gravis is reported, Myasthenia gravis aggravated should be selected. In the absence of such a term, the MHRAs internal practice is to select a term for the condition and an additional term to describe the modification of the condition, e.g., Condition aggravated, Disease progression. For example, if progression of Addisons disease is reported, Addisons disease and Disease progression should be selected. The MHRAs internal practice is not mandatory and each organisation should document their preference in their working practices. The MTS: PTC also provides guidance on term selection for these reports.
8.2
Reaction outcomes
It is important to ensure that the reaction outcomes are consistent with the information in the case narrative. For example coding the outcome field as not known is incorrect if the reaction has been coded as Death unexplained. The MHRA requires all reactions to have an outcome populated. If the outcome is unknown then the outcome field should be populated with unknown and not left blank. Also reaction outcomes should be consistent with the dates provided (e.g. if a stop date is provided then the outcome field must be populated as Recovered/resolved). The MHRA has a validation in place so that reactions that are reported to have started before the suspect drug was administered are rejected.
8.3
Adverse drug reactions versus adverse events
All reaction terms classified in a case report must be suspected to have a causal relationship to the drug. An adverse event is an undesirable experience that occurs during or after treatment with a medicine but is not necessarily caused by the medicine. Volume 9A provides definitions on adverse drug reactions and adverse events (see Appendix 7). It is important to apply judgement when reporting adverse drug reactions. Common errors include reporting surgical procedures, treatments or outcomes such as hospitalisation as the reaction. Cases should be assessed individually and followed up for further information e.g. to confirm whether the surgery was a result of the ADR or is unrelated to the reaction. If a report contains a reaction and an event, the reaction should be reported and the event captured in the case narrative (see the following example).
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Example 5: In this report the patient suffered from constipation after taking medication and was given an enema as treatment for this. The MAH has incorrectly coded Enema administration as the reaction. The only reaction term to be captured should be Constipation and the subsequent treatment with an enema should be stated in the case narrative. <reaction> <primarysourcereaction>Enema</primarysourcereaction> <reactionmeddraversionllt>11.1</reactionmeddraversionllt> <reactionmeddrallt>10050314</reactionmeddrallt> <termhighlighted>3</termhighlighted> <reactionoutcome>6</reactionoutcome> </reaction>
The following are some examples of adverse events which should not be expedited to the MHRA. Example 6: <reaction> <primarysourcereaction>Knee surgery</primarysourcereaction> <reactionmeddraversionllt>12.1</reactionmeddraversionllt> <reactionmeddrallt>10049662</reactionmeddrallt> <termhighlighted>3</termhighlighted> <reactionoutcome>6</reactionoutcome> </reaction> <narrativeincludeclinical>Initial report received from the nurse on xxxxxx :This patient was treated with xxxxxx for an unspecified indication since an unknown date. The patient underwent knee surgery on an unknown date and suffered cardiac arrest, according to his wife the patient 'almost died'. Following this incident, the patient suffered severe bradycardia and xxxxx was discontinued. The outcome of the event was not reported.</narrativeincludeclinical> In this example, the LLTs Bradycardia & Cardiac arrest should be selected, not Knee surgery.
Example 7: <reaction> <primarysourcereaction>Cataract operation</primarysourcereaction> <reactionmeddraversionllt>12.1</reactionmeddraversionllt> <reactionmeddrallt>10063797</reactionmeddrallt> <reactionmeddraversionpt>12.1</reactionmeddraversionpt> <reactionmeddrapt>Cataract operation</reactionmeddrapt> <reactionoutcome>6</reactionoutcome> </reaction>
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<narrativeincludeclinical>Information was received from a healthcare professional regarding a 64-year-old female patient who received xxxxxxx therapy and experienced right cataract operation. MEDICAL HISTORY: The patient's concurrent illness includes hormone replacement therapy. PRODUCT DETAILS: Indication for xxxxxx was rheumatoid arthritis. The dose regimen was 50 mg 1 time per day from an unspecified date to an unspecified date and then was unknown from an unspecified date to Feb-2009. Therapy was permanently discontinued. CONCOMITANT THERAPY: Concomitant therapy included xxxxxx. EVENT DETAILS: The patient experienced right cataract operation (cataract operation) in Apr-2008. OUTCOME: At the time of report the outcome of the operation was unknown. RELATED CASE(S): See related case(s): xxxxxxxxx. No additional information was available at the time of this report. </narrativeincludeclinical> In this example, the report of Cataract operation can be recorded on the MAHs database but should not be expedited.
8.4
Withdrawal reaction classification
Drug withdrawal reactions are reports where the reporter describes reactions which occur after withdrawal of the suspect drug. The MedDRA LLT Withdrawal reaction should only be used to classify a reaction when the reporter has stated this. In addition to this all the symptoms associated with the withdrawal should also be classified and coded as reactions. In instances where the reporter states Withdrawal reaction as the only reaction and gives no detail on the reactions suffered, these cases are still considered valid and should be expedited if they meet the minimum criteria for expediting reporting. However these cases should also be followed up for symptoms of the withdrawal reaction.
8.5
Reaction occurring at multiple body sites
The MTS: PTC suggests that if a reaction is reported to occur at more than one body site, and if all of those LLTs link to the same PT, then a single LLT that most accurately reflects the reaction should be selected. For example, if the reaction is described as Skin rash on face and neck, then the LLT Skin rash should be selected (rather than Rash on face and Neck rash as both of these LLTs link to the PT Rash).
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8.6
Duplication of reaction terms
MedDRA terms should not be duplicated unless the dates indicate two separate events. Multiple entries of the same reaction will be returned for reclassification i.e. cases where there is no evidence that two separate distinct events occurred. A separate case should be created if a patient experienced the same reaction on different dates. This is not a positive rechallenge as the patient did not stop taking the suspect drug.
8.7
Drug interaction
At least two suspect drugs should be classified for reports involving a drug interaction. When the reporter specifically states that an interaction occurred, an appropriate interaction term should be selected in addition to term(s) for any reaction(s) described.
8.8
Definitive and provisional diagnoses with signs and symptoms
If a definitive diagnosis and a set of symptoms are given, the MHRAs internal practice is to code the diagnosis and signs/symptoms to ensure that the most detailed information is available for signal detection. It should be noted that the MHRAs internal practice is not mandatory and each organisation should document their preference in their working practices. Example 8: If rhabdomyolysis with myalgia and acute Renal Failure is reported, the LLTs Rhabdomyolysis, Myalgia and Acute Renal Failure should be selected. A provisional diagnosis may be described as suspicion of, probable, presumed, likely, rule out, questionable, differential, etc. If a provisional diagnosis and a set of symptoms are given, the MHRAs internal practice is to code the signs/symptoms only. This is because the diagnosis is provisional and subject to change; however the signs and symptoms are not. It should be noted that the MHRAs internal practice is not mandatory and each organisation should document their preference in their working practices. Example 9: If Shortness of breath, with chest pain and coughing up blood, most likely pulmonary embolism? is reported, the LLTs Shortness of breath, Chest pain and Coughing blood should be selected. Follow-up should be requested to confirm the diagnosis and on receipt of this information the case should be updated as necessary. The MTS: PTC provides guidance on term selection and examples on options for definitive and provisional diagnoses with or without sign/symptoms.
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8.9
Other patient outcomes
Consequences of a reaction such as hospitalisation and disability are generally not considered to be ADRs and should not be expedited. Reports that only state an outcome e.g., hospitalisation but do not describe an ADR should be followed up for further information.
8.10 No adverse effect

The LLT No adverse effect may be used to maintain records for administrative purposes in the MAHs pharmacovigilance database, e.g. for pregnancy registries, overdoses, and medication errors; however such cases would not normally be expedited as there is no reaction.
8.11 Product substitution

If a report states that the reaction occurred after the patient switched to taking a different product, having previously been taking a different product containing the same active, it may be useful to code this by using an appropriate MedDRA term such as Product substitution issue, Product substitution issue brand to brand, Product substitution issue brand to generic, Product substitution issue generic to brand or Product substitution issue generic to generic.
8.12 Unexpected benefit

MAHs should record reports of unexpected therapeutic effects in their pharmacovigilance database for risk-benefit evaluation during PSUR preparation; however these reports do not need to be expedited. These reports may describe a beneficial effect of a drug aside from the use for which it had been given. Example: If a bald patient was pleased that he grew hair while using a product is reported, the term Hair growth increased can be selected. In addition, Unexpected therapeutic effect can be selected.
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9.
9.1
Chapter 9 - Case Narrative

Case narrative
In accordance with Volume 9A the case narrative should be a medical report containing all known relevant clinical and related information, including patient characteristics, therapy details, medical history, clinical course of the event(s), diagnosis, adverse reactions including the outcome, relevant laboratory evidence (including normal ranges) and any other information that supports or refutes an adverse reaction. The narrative should serve as a comprehensive, stand-alone medical report. The information should be presented in a logical time sequence; ideally with the source of the report and presented in the chronology of the patients experience. The information in the case narrative should also be captured in the relevant structured fields. The correct coding of this information has a significant impact on the ability to perform qualitative signal detection and evaluation. It is also important to ensure that the case narrative contains no information that could be used to identify a patient or reporter. All ICSRs should be anonymised in the narrative for both the patient and reporter. CIOMS V provides an example of a standard narrative template. Example 1: The following is an example of a clearly presented case narrative for an initial case: <narrativeincludeclinical>This case was considered medically important. Information was received from a healthcare professional regarding a 29-year-old male patient who received xxxxx and experienced hypertension. MEDICAL HISTORY: Relevant medical history was xxxxx. PRODUCT DETAILS: Indication for xxxxx was rheumatoid arthritis. Therapy began in Oct-2009 and was permanently discontinued in Apr-2010. Dose regimen was 50 mg, frequency unknown. CONCOMITANT THERAPY: Concomitant medications included xxxxx. EVENT DETAILS: The patient had been experiencing hypertension since he started the xxxxx therapy in Oct-2009. The decision was made to change his therapy to xxxxx. OUTCOME: The patient recovered from the events. RELATEDNESS ASSESSMENT: The reporter suspected that the adverse events were related to the suspect drug. No additional information was available at the time of this report. </narrativeincludeclinical>
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10. Chapter 10 Test Results

10.1 Test results
All tests relevant to the ADR should be captured in the structured test fields. <test> <testdateformat>102</testdateformat> <testdate>20090503</testdate> <testname>White blood cell count</testname> <testresult>4.2</testresult> <testunit>mmol/L</testunit> <lowtestrange>4</lowtestrange> <hightestrange>10</hightestrange> <moreinformation>2</moreinformation> </test> The MHRA only accepts MedDRA LLTs in the <testname> field. Any cases which have non-MedDRA terms in this field will be rejected. Any additional test information which uses more than 50 characters (e.g. scan or X-ray results) and therefore cannot be captured in the structured test fields should be captured in the free text <testresultsprocedures> tag. If the dates of the test are unknown but their chronology is known this information should be captured in the <testresult> field as shown below: <test> <testdateformat>102</testdateformat> <testdate>20090503</testdate> <testname>White blood cell count</testname> <testresult>On admission: 4.2</testresult> <testunit>mmol/L</testunit> <lowtestrange>4</lowtestrange> <hightestrange>10</hightestrange> <moreinformation>2</moreinformation> </test> For ICSRs derived from literature articles containing large amounts of laboratory data, judgement should be used to determine the level of test information entered into the structured fields. This can include limiting test data entered to only tests related to the reaction experienced, only tests with abnormal results or limiting test data to a three month period before and after the reaction was experienced. However where possible it is preferable for all test data to be entered into the structured fields. Please note that under no circumstances should individual test results all be entered in the free text field when the structured fields are available. Such reports will be returned for reclassification to ensure that this information is correctly coded. A test result without a unit
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should be coded in the testname and testresult fields e.g. Creatine kinase increased should be coded as <testname> Creatine kinase and<testresult> increased. The MHRA only accepts MedDRA LLTs in the <testname> field.
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11. Chapter 11 Fatal Reactions

11.1 Reports of death
If a reaction is fatal then the following practices should be followed: For reactions that occur over a period of time and which result in an outcome of death, the stop date should be classified as the date of death. A start date may be classified if this has been stated by the reporter. For Death unexplained cases, the date of death can be used as the start and stop date (with the same being applied for completed suicides). Reports of death e.g. Death unexplained, Sudden death, Sudden death unexplained, Sudden unexplained death in epilepsy and Completed suicide can only have a reaction outcome of fatal. Under no circumstances should these reaction terms be classified with any other outcome. If a reaction term has been coded with a fatal outcome then it is not correct to also include Death unexplained as a reaction term.
If the only information reported is death, then the most specific term available should be selected and the report followed up for further information. Reports of disease progression should only be coded as a reaction if the reporter suspects a causal relationship with the suspect drug. If the patient experiences a non fatal ADR, however later dies of an unrelated cause, then the cause of death should be coded in the <patientdeathreport> or <patientdetermineautopsy> fields only. Example 1: A patient with a history of bowel cancer received drug X for the treatment of nausea. Following the administration of drug X the patient experienced a rash. The patient recovered from the rash the next day, however died 4 weeks later from progression of the underlying bowel cancer. The reporter did not consider the death to be related to treatment with drug X. In this example, the report should be coded as: LLT coded: Rash with a reaction outcome of 'recovered' Seriousness flags: 'Patient died' should be flagged as 'no' as the patient did not die as a result of the reaction Reported cause of death field: Populated with Bowel cancer All information in <patientdeath> tabs should be completed when available. Also, Bowel cancer should be coded as medical history.
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11.2 Patient death details

The patient death fields should be used to capture information regarding the patients cause of death. If a patient death date is provided then the corresponding date format also needs to be populated. The patients cause of death should be recorded in the reported cause of death and autopsydetermined cause of death as appropriate. Reported cause of death (<patientdeathreport>): If Post-Mortem or Death Certificate details are not available, but information on the report suggests a likely cause(s) of death, this should be entered in the reported cause of death field. Autopsy-determined cause of death (<patientdetermineautopsy>): The cause(s) of death identified in an autopsy should be entered here. For each MedDRA term provided the corresponding MedDRA version must also be populated.
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12. Chapter 12 - Reports Of Drug Exposure During Pregnancy

12.1 Reports of drug exposure during pregnancy
Volume 9A states that the MAH should follow up all reports relating to pregnancies where the foetus may have been exposed to one of its medicinal products. This may include, but not be limited to, maternal exposure or transmission of a medical product via semen following paternal exposure. The MAH should gather information on both normal and abnormal outcomes. Individual cases with an abnormal outcome in association with a medicinal product should be reported on an expedited basis. This refers especially to: Reports of congenital anomalies in the foetus/child; Reports of foetal death and spontaneous abortion; and Reports of adverse reactions in the neonate that are classified as serious. Other cases, e.g. reports of termination of pregnancy without information on congenital malformation (including reports of elective termination) and reports of pregnancy exposure without outcome data, should not normally be reported on an expedited basis. In certain circumstances, the MAH may be requested to treat any reports of pregnancy exposure as cases requiring expedited reporting, e.g. pregnancy exposure to products contraindicated in pregnancy because of a high teratogenic potential should be expedited even without a known outcome. This may be a requirement of either a Pregnancy Prevention Program or Risk Management Plan. Expedited reports together with other reports on outcome of exposure during pregnancy should also be included in the PSUR together with aggregated data on the overall exposure and details of normal/abnormal outcomes. Reports from prospective registries should also be included and evaluated in the PSUR. If the MAH identifies, or becomes aware of, a signal of a possible teratogenic effect (e.g. through a cluster of similar abnormal outcomes) all Competent Authorities where a marketing authorisation is held, and also the European Medicines Agency (EMA) in the case of centrally authorised medicinal products, should be informed on an expedited basis. This also applies to possible signals arising from consumer reports for which medical confirmation has not been obtained.
12.2 Parent - child reports

Reports where a foetus/neonate/child suffers an ADR as a result of a medication that was taken by the parent should be classified as parent-child reports. In these cases the patient is classified as the foetus/neonate/child and the parent details captured in the parent fields. A separate case for the parent should only be generated if the parent also suffered adverse events (e.g. the foetus developed tachycardia and a heart 33/55
defect and the mother suffered heavy bleeding and high blood pressure). These reports should then be linked using the linked reports option. The ICH E2B(M) field A.1.12 Identification number of the report which is linked to this report can be used to link these reports or other report such as multiple reports resulting a literature article. The guideline EMEA/CHMP/313666/2005, Guideline on the exposure to medicinal products during pregnancy: need for post-authorisation data states that foetal death without information on malformation should be entered as one case for the mother. Early foetal death (before 22 completed weeks of gestation) comprises ectopic pregnancy and miscarriage and late foetal death (after 22 completed weeks of gestation) is known as stillbirth. Drug exposure during pregnancy should be recorded in the MAHs pharmacovigilance system; however these reports should not be expedited if there is no ADR. The MAH should follow up all reports relating to pregnancies at the expected due date where the foetus may have been exposed to one of its medicinal products. Other events relating to pregnancy such as Elective termination should also not be expedited in a parent-child report.
Example 1:
This report should not have been expedited as pregnancy is not normally considered an ADR; however MAHs may wish to record this information in their databases e.g. to facilitate discussion of pregnancy in PSURs. <reaction> <primarysourcereaction>Live birth</primarysourcereaction> <Reactionmeddraversionllt>12.1</reactionmeddraversionllt> <reactionmeddrallt>10049550</reactionmeddrallt> <reactionmeddraversionpt>12.1</reactionmeddraversionpt> <reactionmeddrapt>10049550</reactionmeddrapt> <reactionoutcome>6</reactionoutcome> </reaction> <narrativeincludeclinical>This prospective pregnancy case was reported by a pharmacist and described the occurrence of drug exposure during pregnancy in a female patient who received xxxxxxxx. The patient became pregnant. On an unknown date, approximately in her 12th week of pregnancy the patient started xxxxxxxx. At an unknown time after starting xxxxxxxx, the patient experienced drug exposure during pregnancy. At the time of reporting, the outcome of the event was unknown. LMP and EDD were not reported. Verbatim text: Medicines Information Pharmacist has reported that a female patient who is currently estimated to be 26 weeks pregnant has been receiving xxxxxxxxx since her 12 week pregnancy. Patient has been using xxxxxx at home. No adverse events have been observed at time of reporting. Follow up information received 19 June 2008 from patient's physician: The physician reported that the 35 year old pregnant patient's waters broke on 13 June 2008 at a gestational age of 31 weeks. Her estimated date of delivery was 14 August 2008. At an unknown time later the patient gave birth to a healthy baby via caesarean section. </narrativeincludeclinical>
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Information regarding the route of administration of the drug to the foetus should be captured in the <drugadministrationroute> field and the parent route in the corresponding <drugparadministration> field. The most common routes of administration include transplacental, transmammary and other (for father child cases). For father-child cases an appropriate term such as Paternal drug exposure may be coded to aid identification of these cases on an MAHs pharmacovigilance system. For cases where a patient experienced an ADR as a result of a medicine taken by their male partner the reaction term Transmission via semen may be coded. Please note that the indication of the suspect and concomitant drugs should be classified as that of the parent and not as Drug exposure during pregnancy.
12.3 Pregnancy with contraceptive medicines

The MHRA receives a large number of reports regarding ineffective contraceptive medicines resulting in unintended pregnancies. Whenever possible the most appropriate and accurate MedDRA terms should be coded rather than Drug ineffective or Lack of efficacy. The following reaction terms should be considered: Contraceptive failure with injectable contraceptive Pregnancy on contraceptive Pregnancy on oral contraceptive Pregnancy with injectable contraceptive Pregnancy with contraceptive device Pregnancy with contraceptive patch Pregnancy with implant contraceptive Pregnancy with vaginal contraceptive device.
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13. Chapter 13 - Literature Reports

13.1 Literature reports
Adverse reactions which appear in the published literature should be expedited in line with the reporting requirements. Further guidance is provided in Volume 9A and the MHRAs Good Pharmacovigilance Practice Guide. When reports from the world-wide literature are submitted as ICSRs, the literature references should be provided in the Vancouver Convention (known as Vancouver style) as developed by the International Committee of Medical Journal Editors in the field ICH E2B(M) A.2.2 Literature reference(s).
All Literature references should be provided in Vancouver style. Author. Title of journal article. Title of journal (this should be in italics); Year of publication: Volume number (Issue number); Page numbers of the article (use p. before a single page number and pp. where there are multiple pages). <literaturereference>Al-Aloul M, Miller H, Stockton P, Ledson M, Walshaw M. Acute renal failure in cystic fibrosis patients chronically infected by the Liverpool epidemic Pseudomonas aeruginosa strain (LES). Journal of cystic fibrosis 2005; 4: pp197201.</literaturereference>
All corresponding literature articles should be emailed as pdf documents to literature@mhra.gsi.gov.uk clearly stating the safetyreportid of the case that it refers to. Whenever possible, each patient included in a multiple patient report should be identified by at least one of the usual criteria (age, sex, etc.) and a report must be submitted for each patient separately. The details of these should not be amalgamated i.e. with an average age and unknown sex and the same report submitted for each patient - this does not meet the requirements of individual patient identifiers required for expedited reporting. Cases which do not contain individual patient identifiers do not meet the criteria for expedited reporting of ICSRs. Literature articles such as these when identified during routine literature searches should be assessed and included in the PSURs for relevant products and not submitted as expedited ICSRs. The MHRA have introduced an initiative to reduce the number of duplicate ADRs derived from the scientific literature. A list of UK literature cases received by the MHRA each day is published on the website. MAHs are advised to check this list before expediting a literature report to see if it has been reported previously. If the literature article and patient details can be identified in the list, the company report should not be forwarded to the MHRA. This list can be found at http://www.mhra.gov.uk/literatureadrs.
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Screenshot of Literature ADR list from MHRA website:
This process is designed to reduce the amount of duplicate reporting to the MHRA of ADR reports identified in the scientific literature. It is still expected that MAHs undertake literature searching activities for the purpose of identifying ICSRs and safety information relevant for ongoing safety monitoring activities and PSUR production. When receiving an ASPR for an ICSR derived from a literature article, MAHs are not required to submit follow-up information for that case based upon additional information included in the literature article if it is missing from the ASPR. If significant information relating to the suspect drug and reaction is missing, the MHRA should be contacted who will in turn request the MAH who submitted the original ICSR to submit an update ICSR with the necessary information.
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14. Chapter 14 - Reporter Details

14.1 Reporter details
For a report to be considered valid for expedited reporting it must contain an identifiable healthcare professional reporter. Volume 9A states that the reporter may be identified by name or initials, address or qualification (e.g. physician, dentist, pharmacist,), taking into account EU legislation on data protection and relevant national legislation. Contact details for a Healthcare Professional should be available for the reporter to be considered as identifiable. Healthcare professionals are defined as medically qualified persons, such as physicians, dentists, pharmacists, nurses and coroners. E2B qualifications include physician, pharmacist, other health professional, lawyer and consumer or other non health professional. Consumer and lawyer reports can be expedited when there is medical confirmation. Examples of other health professionals include radiographers, nurses, chiropodists, pharmacy assistants and healthcare assistants. The MHRA requires at least one reporter qualification per case. Cases with no reporter qualification will be rejected.
<reportertitle>Dr</reportertitle> <reportergivename>A</reportergivename> <reportermiddlename></reportermiddlename> <reporterfamilyname>Nother</reporterfamilyname> <reporterorganization></reporterorganization> <reporterdepartment>GP Surgery</reporterdepartment> <reporterstreet>High Street</reporterstreet> <reportercity>London</reportercity> <reporterstate>London</reporterstate> <reporterpostcode>SW8 5NQ</reporterpostcode> <reportercountry>GB</reportercountry> <qualification>1</qualification> Special characters (e.g. %$*#@) in these fields should be avoided. If there are any special characters in these fields the case will be rejected. The reporter needs to be contactable for acknowledgement and follow up. A case from the internet with a user name/ screen name would be considered valid for processing and entering on a safety database if an email address is available to gain validating information. A report is not valid if it is not possible to get back to the source of the report.
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15. Chapter 15 - Administrative Information

15.1 Worldwide unique case identification number and safety report ID
The Worldwide unique case identification number and the Safety report ID are numbers that are used to identify a case. The Worldwide unique case identification number is determined by the originator of the case and should be maintained through all future transmissions (including maintaining upper/lower case). The safety report ID is used by any organisation transmitting the case to record their reference number. If the originator and transmitter are the same organisation, then these values can be the same. The safety report ID should remain constant in subsequent transmissions of the case by the same sender. The safety report ID should be unique to a single ICSR. The prefix of the number should represent the country from which the report originated. The rest of the number should contain reference to the originating MAH followed by a series of digits unique to the case. For example a report transmitted by a company to a regulatory authority concerning a case from the UK would populate A.1.0.1 with GB-companyname-12345 where 12345 is a companys unique case report number. The reference number should not exceed the field length of 100 characters. Reference numbers greater than 100AN will result in the case being rejected. In instances where the report has been received from another Market Authorisation Holder (MAH) or Regulatory Authority then the <safetyreportid> should be maintained. Reports derived from MHRA ASPRs should not be reported back to the MHRA as this causes duplication. Such cases will be nullified and a notification sent back to the reporting MAH. Submission of cases received from licence partners may result in duplication of reports. It should be noted that the ICSR should be expedited to the MHRA from the MAH who has responsibility for reporting based upon the licensing agreement. If follow-up is received by a MAH that was not the original sender the follow-up information should be submitted using the <safetyreportid> assigned by the originating MAH.
15.2 Report type

All cases require a report type to be populated. Spontaneous cases <reporttype>1</reporttype> Reports from studies <reporttype>2</reporttype>
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A report type of spontaneous should be selected for any ADR reported to an MAH via a healthcare professional or patient. Reports from studies should be selected for any ADRs experienced in a clinical trial or postmarketing study. In order to further clarify which type of study the <observestudytype> field must be completed. Clinical trial <observestudytype>1</observestudytype> This should be selected for studies carried out with investigational drugs (e.g. in phase I to III of clinical trials) and interventional Phase IV clinical trials. Other studies <observestudytype>3</observestudytype> Study/Other Studies reports should be selected for post-marketing studies and clinical trials carried out with marketed drugs (e.g.non-interventional phase IV clinical trials). These reports may also have a EudraCT number in addition to the study/clinical trial numbers or names. Further to selecting the <observestudytype> field for all study cases the <studyname> and <sponsorstudynumb> are also mandatory. In clinical trial cases the<studyname> tag should be populated with the EudraCT number followed by # and the short name of the study. The <sponsorstudynumb> tag should be populated using the protocol number. <studyname>2009-123456-01#Short name of study</studyname> <sponsorstudynumb>123456789</sponsorstudynumb> If the study name exceeds 100 characters then the name should be truncated and entered in this field. Any study cases that do not have the <observestudytype>, <studyname> and <sponsorstudynumb> will be rejected. The field length for the <studyname> tag is 100 characters. On occasions where this field exceeds the character limit the file will be rejected. Please note that the MHRA does not accept clinical trial cases that have not been unblinded. Any SUSARs received that contain blinded study medications will be nullified and a notification sent. This includes instances where there is a known comparator listed as a cosuspect medication. These cases should not be expedited until the study medication has been unblinded so that a thorough causality assessment can be made. Other <reporttype>3</reporttype> On rare occasions where the source of spontaneous or study cannot be determined (usually as a result of a literature article) then the report type 'other' can be selected. This report type should only be used in exceptional circumstances.
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For the purpose of safety reporting, reports from registries are classified as solicited reports and, where possible should have an appropriate causality assessment by a Healthcare Professional or the MAH. Reports from registries should be coded as: <reporttype>2</reporttype> and <observestudytype>3</observestudytype>
A number of literature articles have been reported with a report type of other when it is clear that the source is spontaneous or from a study. Please ensure that the most appropriate report type is selected at all times.
15.3 Seriousness criteria and medically confirmed selection

All cases expedited to the MHRA must meet one of the seriousness criteria. Non-serious reports should not be reported to the MHRA. The seriousness criteria are (more than one can be selected): Results in death Is life-threatening Requires hospitalisation or prolongation or existing hospitalisation Results in persistent or significant disability/incapacity Is a congenital anomaly/birth defect Other medically important condition.
The terms life-threatening and other medically important conditions are defined in the ICH E2A guideline. <serious>1</serious> <seriousnessdeath>2</seriousnessdeath> <seriousnesslifethreatening>2</seriousnesslifethreatening> <seriousnesshospitalization>2</seriousnesshospitalization> <seriousnessdisabling>2</seriousnessdisabling> <seriousnesscongenitalanomali>2</seriousnesscongenitalanomali> <seriousnessother>1</seriousnessother> Only medically confirmed cases should be expedited to the MHRA. Consumer or other nonhealthcare professional reports should not be submitted to the MHRA. <medicallyconfirm>1</medicallyconfirm>
15.4 Duplicates and nullifications

The nullification of an ICSR indicates that the report should be considered void (nullified), for example, when the case is found to be erroneous or in the case of duplicate reports. Individual cases that have been nullified should not be used for scientific evaluation; however they should remain in the database for audit purposes.
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All previous versions or identified duplicates should be captured in the duplicate fields. <reportduplicate> <duplicatesource>Other MAH</duplicatesource> <duplicatenumb>123456789</duplicatenumb> </reportduplicate> Please note that both the <duplicatesource> and <duplicatenumb> fields need to be completed for each duplicate entry. Failure to do so will result in case failure. An individual case can only be nullified by the sending organisation. Do not submit nullifications to the MHRA for cases that have been sent from the MHRA as this will remove the case from the MHRAs database. It should be noted that an update cannot be submitted for a nullified case. The nullification reason should be clear and concise to explain why the report is no longer considered to be a valid report. For example a nullification reason stating, the report no longer meets the reporting criteria or report sent previously in error are not detailed enough explanations. <casenullification>Other MAH</casenullification> <nullificationreason>Valid reason to be entered here</nullificationreason> On submission of nullification the 'master' <safetyreportid> and the MHRA reference number should be entered in the <nullificationreason> field. All cases with nullification requests are checked before the nullification is complete. Cases which have been nullified with no reason given or with an incorrect reason will be returned.
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Cases can be nullified if when on receipt of follow-up the case is no longer valid. The table below outlines the scenarios of when cases can be nullified (see Volume 9A Table III.6.A): Scenario An individual case has been identified as a duplicate of another individual case previously submitted. An incorrect Worldwide unique case identification number was accidently used. This wrong Worldwide unique case did not refer to any existing case. On receipt of further information it is confirmed that the ADR occurred before the suspect drug was taken. On receipt of further information it was confirmed that the patient did not receive the suspect drug. On receipt of further information it was confirmed that the ADR did not occur. On receipt of further information it is confirmed that there are no valid patient identifiers. Action to be taken One of the cases should be nullified. The remaining valid case should be updated with any additional information and the duplicate fields completed with the details of the nullified case. Nullification should be submitted and a new case should be created with the correct worldwide unique case identification number. Nullification should be submitted.
Nullification should be submitted.
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The table below outlines scenarios where a case SHOULD NOT be nullified: Scenario An incorrect Worldwide unique case identification number was accidently used. This wrong Worldwide unique case refers to an existing case. On receipt of further information, it is confirmed that the patient did not receive the MAH's suspect drug. However the patient received other suspect drugs. On receipt of further information, it is confirmed that the case is not medically confirmed. On receipt of further information, the reporter confirmed that the ADR is no longer considered to be related to the suspect drug. Downgrading of case from serious to nonserious. On receipt of further information the primary source country has changed. The drug taken by the patient belongs to another MAH (e.g. a product with the same active substance but marketed under a different name). The suspect drug taken does not belong to the MAH (same active substance, the invented name is unknown and the report originates from a country, where the MAH has no marketing authorisation for the medicinal product in question). Action to be taken The report with the wrong Worldwide unique case identification number should not be nullified. A follow-up report should be created to correct the information previously submitted. A new ICSR should be created and submitted with the correct Worldwide unique case identification number. The case should not be nullified. Follow-up should be submitted updating the reporter qualification and medically confirmed fields. The case should not be nullified. The case should not be nullified. Follow up report should be submitted with the updated information. The case should not be nullified. Follow-up should be submitted with updates to the seriousness flags. The case should not be nullified. Follow-up should be submitted with updates made to the primary source country. The case should not be nullified. The sender should inform the other MAH about this case. The other concerned MAH should create a new case and reference the case number and name of the initial sending MAH. The case should not be nullified. The MAH should submit a follow-up report with this information. The case should not be nullified. An explanation should be sent by MAH A to the co-marketer MAH B that the case has already been reported. MAH B should provide any additional information as a follow-up report with the same Worldwide unique case identification number.
The case is mistakenly reported by MAH A although MAH B as co-marketer is responsible for reporting the case.
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15.5 Dates
The receive date is the date the report was first received from the primary source fulfilling the four minimum criteria for expedited reporting as described in section 2.1. The receipt date is the date of receipt of the most recent information for the report. Both of these fields are mandatory. The receive and receipt dates should be the same in all initial cases. <receivedateformat>102</receivedateformat> <receivedate>20090430</receivedate> <receiptdateformat>102</receiptdateformat> <receiptdate>20090430</receiptdate> <fulfillexpeditecriteria>1</fulfillexpeditecriteria> <companynumb>GB-MHRA-ADR12345678</companynumb> For any dates provided throughout the file a corresponding date format must be provided. Failure to do so will result in case rejection. It is important to ensure that the receipt date is correctly entered as the MHRA uses this date to measure MAH compliance.
15.6 Follow-up reports

When submitting follow-up information the company number must be the same as that in the initial case. In addition in follow-up cases the receive date should refer to the date where the initial information was received. The receipt date should then be updated to the date where the most recent information has been received. <receivedateformat>102</receivedateformat> <receivedate>20090430</receivedate> <receiptdateformat>102</receiptdateformat> <receiptdate>20090829</receiptdate> <fulfillexpeditecriteria>1</fulfillexpeditecriteria> <companynumb>GB-MHRA-ADR12345678</companynumb> Updates to MHRA cases should only be submitted when further information has been received from the original reporter and should be confirmed as a follow-up report with the MHRA before sending the update. Follow-up should not be sent to the MHRA where the updated information is from a third party and is not medically confirmed (e.g. media sources).
15.7 Sender and receiver details

The senders information should be completed as fully as possible with a full contact name and postal address as it is used for correspondence regarding the case. The sender type must always be populated with pharmaceutical company.
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<sender> <sendertype>1</sendertype> <senderorganization>MAH</senderorganization> <senderdepartment>Pharmacovigilance/Regulatory Affairs </senderdepartment> <sendertitle>Dr.</sendertitle> <sendergivename>A</sendergivename> <senderfamilyname>Nother</senderfamilyname> <senderstreetaddress>1 London Street</senderstreetaddress> <sendercity>London</sendercity> <senderpostcode>MH12 3RA</senderpostcode> <sendercountrycode>GB</sendercountrycode> <sendertel>123456</sendertel> <sendertelextension>7891</sendertelextension> <sendertelcountrycode>+44</sendertelcountrycode> <senderfax>4321</senderfax> <senderfaxextension>5678910</senderfaxextension> <senderfaxcountrycode>+44</senderfaxcountrycode> <senderemailaddress>someone@MAH.com</senderemailaddress> </sender> The information provided in the senders details is used for notification of duplicate identification and requests for further information letters. It is therefore essential that this information is complete. The MHRA receiver details are as follows: <receiver> <receivertype>2</receivertype> <receiverorganization>MHRAUK</receiverorganization> <receiverdepartment>Pharmacovigilance Signal Management</receiverdepartment> <receivergivename>Mick</receivergivename> <receiverfamilyname>Foy</receiverfamilyname> <receiverstreetaddress>3.M 151 Buckingham Palace Road</receiverstreetaddress> <receivercity>London</receivercity> <receiverpostcode>SW1W 9SZ</receiverpostcode> <receivercountrycode>GB</receivercountrycode> <receivertel>2070306550</receivertel> <receivertelcountrycode>44</receivertelcountrycode> <receiveremailaddress>pharmacovigilanceservice@mhra.gsi.gov.u k</receiveremailaddress> </receiver> MHRA <receiverorganization> MHRAUK - All post-marketing and clinical trial data should be sent here.
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16. Appendix 1 Abbreviations

ADR AE ASPR BROMI CHMP CIOMS DAP EMA EU ICH ICSR LLT MAH MedDRA MTS: PTC MHRA MR MSSO PT PSUR RMP RMS SUSAR Adverse drug reaction Adverse event Anonymised Single Patient Report Better Regulation of Medicines Initiative Committee for Medicinal Products for Human Use Council for International Organizations of Medical Sciences Drug Analysis Print European Medicines Agency European Union International Conference on Harmonisation Individual Case Safety Report Lowest Level Term (MedDRA) Marketing Authorisation Holder Medical Dictionary for Regulatory Activities MedDRA Term Selection: Points to Consider Medicines and Healthcare products Regulatory Agency Mutual Recognition Maintenance and Support Services Organization Preferred Term (MedDRA) Periodic Safety Update Report Risk Management Plan Reference Member State Suspected Unexpected Serious Adverse Reaction
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17. Appendix 2 Electronic Transmission of Individual Case Safety Reports Message Specification (ICH ICSR DTD version 2.1)
The Electronic Transmission of Individual Case Safety Reports Message Specification (ICH ICSR DTD version 2.1) provides information on the E2B fields (see attached link). http://estri.ich.org/icsr/ICH_ICSR_Specification_V2-3.pdf.
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18. Appendix 3 MHRA validation rules

Information on the MHRA validation rules (see attached link). http://www.mhra.gov.uk/Safetyinformation/Reportingsafetyproblems/Reportingsuspectedadv ersedrugreactions/InformationforthePharmaceuticalIndustry/E2BreportingwiththeMHRA/inde x.htm#2
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19. Appendix 4 Pharmaceutical Forms

The pharmaceutical form can be reported using both the text and code format. However, the terms / codes will need to be selected from the following table (see attached link). http://www.mhra.gov.uk/home/groups/pl-p/documents/websiteresources/con2033795.pdf
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20. Appendix 5 Route of Administration

The terms / codes for route of administration are available in the Electronic Transmission of Individual Case Safety Reports Message Specification (ICH ICSR DTD version 2.1) (see attached link). http://estri.ich.org/icsr/ICH_ICSR_Specification_V2-3.pdf
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21. Appendix 6 Useful Websites

The following is a list of useful websites. The content of external websites referenced in this guide is not the responsibility of the MHRA. Association of the British Pharmaceutical Industry (ABPI) - http://www.abpi.org.uk/ ABPI is the trade association representing UK companies engaged in research, development, manufacturing and marketing prescription medicines. British Association of Research Quality Assurance (BARQA) - http://www.barqa.com/ BARQA provides status and visibility for individuals concerned with the quality of research in pharmaceutical, agrochemical and chemical industry sectors. British Generic Manufacturers Association (BGMA) - http://www.britishgenerics.co.uk/ The British Generic Manufacturers Association (BGMA) represents the interests of UK-based manufacturers and suppliers of generic medicines and promotes the development and understanding of the generic medicines industry in the United Kingdom. EU Commission - http://ec.europa.eu/ Official website of the EU Commission. European Medicines Agency (EMA) - http://www.ema.europa.eu/ The European Medicines Agency is a decentralised agency of the European Union, responsible for the scientific evaluation of medicines developed by pharmaceutical companies for use in the European Union. International Conference on Harmonisation (ICH) - http://www.ich.org/home.html The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) is unique in bringing together the regulatory authorities and pharmaceutical industry of Europe, Japan and the US to discuss scientific and technical aspects of drug registration. Medicines and Healthcare products Regulatory Agency (MHRA) http://www.mhra.gov.uk The MHRA is the UK government agency which is responsible for ensuring that medicines and medical devices work, and are acceptably safe. MedDRA Maintenance and Support Services Organization (MSSO) http://www.meddramsso.com/ The MSSO serves as the repository, maintainer, and distributor of MedDRA as well as the source for the most up-to-date information regarding MedDRA and its application within the biopharmaceutical industry and regulators. Proprietary Association of Great Britain (PAGB) - http://www.pagb.co.uk/ This is the website of the Proprietary Association of Great Britain which represents the manufacturers of over-the-counter medicines and food supplements in the United Kingdom.
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22. Appendix 7 Glossary

Further information can be found in Eudralex Volume 9A. Abuse of a medicinal product, synonym: Drug abuse Persistent or sporadic, intentional excessive use of medicinal products which is accompanied by harmful physical or psychological effects. Adverse event Any untoward medical occurrence in a patient or clinical-trial subject administered a medicinal product and which does not necessarily have to have a causal relationship with this treatment. An adverse event can therefore be any unfavourable and unintended sign (e.g. an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Adverse reaction, synonym: Adverse drug reaction (ADR), suspected adverse (drug) reaction A response to a medicinal product which is noxious and unintended and which occurs at doses normally used in man for the prophylaxis, diagnosis or therapy of disease or for the restoration, correction or modification of physiological function. Response in this context means that a causal relationship between a medicinal product and an adverse event is at least a reasonable possibility. Adverse reaction also includes adverse clinical consequences associated with use of the product outside the terms of the Summary of Product Characteristics or other conditions laid down for the marketing and use of the product (including prescribed doses higher than those recommended, overdoses or abuse). Anonymised Single Patient Report (ASPR) Anonymised report of an ADR reported to the MHRA and sent to MAHs who hold the marketing authorisation for the suspected medicinal product (or substance where the product has not been specified) for reports meeting expedited reporting requirements. BROMI The Better Regulation of Medicines Initiative (BROMI) led by the MHRA, is a broad ranging UK strategy group, which includes representatives from the Proprietary Association of Great Britain (PAGB), the non-proprietary sector, the National Pharmacy Association (NPA), the Department of Health and the Cabinet Office. The aim of the initiative is to develop regulation that is accountable, proportionate, targeted, consistent and transparent. Clinical trial Any investigation in human subjects intended to discover or verify the clinical, pharmacological and/or other pharmacodynamic effects of one or more investigational medicinal product(s), and/or to identify any adverse reactions to one or more investigational medicinal product(s) and/or to study absorption, distribution, metabolism and excretion of one or more investigational medicinal product(s) with the objective of ascertaining its (their) safety and/or efficacy. Coding/Classification Transposition of ADR data from source documents into an XML file for submission as an ICSR.
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Consumer A person who is not a Healthcare Professional such as a patient, lawyer, friend or relative/parents/children of a patient. Drug Analysis Print (DAP) A DAP contains a complete listings of all UK spontaneous ADRs reported by health professionals, MAHs and patients to the MHRA. Each DAP lists all of the reactions reported for a particular medicine, which are listed by the name of the active ingredient. DAPs are available from the MHRA website and regularly updated. The website also includes an interpretation note explaining the limitations of the data. Healthcare Professional For the purposes of reporting suspected adverse reactions, Healthcare Professionals are defined as medically qualified persons, such as physicians, dentists, pharmacists, nurses and coroners. Individual Case Safety Report (ICSR), synonym: Safety report A document providing the most complete information related to an individual case at a certain point of time. An individual case is the information provided by a primary source to describe suspected adverse reaction(s) related to the administration of one or more medicinal products to an individual patient at a particular point of time. Medicinal product Any substance or combination of substances presented as having properties for treating or preventing disease in human beings; or Any substance or combination of substances which may be used in or administered to human beings either with a view to restoring, correcting or modifying physiological functions by exerting a pharmacological, immunological or metabolic action, or to making a medical diagnosis. Non-interventional trial A study where the medicinal product(s) is (are) prescribed in the usual manner in accordance with the terms of the marketing authorisation. The assignment of the patient to a particular therapeutic strategy is not decided in advance by a trial protocol but falls within the current practice and the prescription of the medicine is clearly separated from the decision to include the patient in the study. No additional diagnostic or monitoring procedures shall be applied to the patients and epidemiological methods shall be used for the analysis of the collected data. Post-authorisation study Any study conducted within the conditions laid down in the Summary of Product Characteristics and other conditions laid down for the marketing of the product or under normal conditions of use. A post-authorisation study falls either within the definitions of a clinical trial or a non-interventional study and may also fall within the definition of a postauthorisation safety study. Post-authorisation safety study (PASS) A pharmacoepidemiological study or a clinical trial carried out in accordance with the terms of the marketing authorisation, conducted with the aim of identifying or quantifying a safety hazard relating to an authorised medicinal product.
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Risk-benefit balance An evaluation of the positive therapeutic effects of the medicinal product in relation to the risks (any risk relating to the quality, safety or efficacy of the medicinal product as regards patients health or public health). Serious adverse reaction Serious adverse reaction means an adverse reaction which results in death, is lifethreatening, requires in-patient hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability or incapacity, or is a congenital anomaly/birth defect. Life-threatening in this context refers to a reaction in which the patient was at risk of death at the time of the reaction; it does not refer to a reaction that hypothetically might have caused death if more severe. Medical and scientific judgement should be exercised in deciding whether other situations should be considered serious reactions, such as important medical events that might not be immediately life-threatening or result in death or hospitalisation but might jeopardise the patient or might require intervention to prevent one of the other outcomes listed above. Examples of such events are intensive treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalisation or development of dependency or abuse. Any suspected transmission via a medicinal product of an infectious agent is also considered a serious adverse reaction. Solicited sources of Individual Case Safety Reports Organised data collection schemes which include clinical trials, registries, named-patients use programmes, other patient support and disease management programmes, surveys of patients or healthcare providers or information gathering on efficacy or patient compliance. For the purpose of safety reporting, solicited reports should be classified as Individual Case Safety Reports from studies and therefore should have an appropriate causality assessment by a Healthcare Professional or the Marketing Authorisation Holder. Spontaneous report, synonym: Spontaneous notification An unsolicited communication by a Healthcare Professional or consumer to a company, regulatory authority or other organisation (e.g. WHO, a regional centre, a poison control centre) which fulfils the following three conditions: It describes one or more suspected adverse reactions in a patient The patient was given one or more medicinal products It does not derive from a study or any organised data collection scheme. Healthcare Professionals or consumers may be stimulated to report a suspected adverse reaction by several situations including: A Direct Healthcare Professional Communication Early Post-Marketing Phase Vigilance (EPPV), e.g. in Japan A report in the press Direct questioning of Healthcare Professionals by company representatives. In these circumstances, provided the report meets the three conditions above, it should be considered a spontaneous report.
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9.best Practice in Reporting of ICSRs

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Best Practice In Reporting Of Individual Case Safety Reports (ICSRs)

Best Practice In Reporting Of Individual Case Safety Reports (ICSRs)

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Best Practice In Reporting Of Individual Case Safety Reports (ICSRs)

CHAPTER 6 - PATIENT CHARACTERISTICS........................................................................... 14 6.1 PATIENT CHARACTERISTICS .................................................................................................... 14

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Chapter 2 - Valid Adverse Drug Reaction

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CHAPTER 3 - Reporting Requirements

Reporting overdose, abuse and misuse

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Reporting of medication errors

Reports of lack of efficacy

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4. Chapter 4 - ICSR Submissions Based On MHRA ASPRs

Do not send ICSRs based on MHRA ASPRs back to us.

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Chapter 5 - General Data Entry Guidance

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Chapter 6 - Patient Characteristics

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Chapter 7 - Drug Information

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Additional drug information

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Some correctly coded examples are shown below:

<drugseparatedosagenumb>200</ drugseparatedosagenumb> <drugstructuredosageunit>21</ drugstructuredosageunit> <drugcumulativedosagenumb>500</drugcumulativedosagenumb> <drugcumulativedosageunit>3</drugcumulativedosageunit>

The following examples would cause reports to be rejected:

<drugtreatmentduration></drugtreatmentduration> <drugtreatmentdurationunit>804</drugtreatmentdurationunit> <drugstartperiod>5</drugstartperiod> <drugstartperiodunit></drugstartperiodunit>

7.2.1 Drug dosage

7.2.2 Pharmaceutical form

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