PHARMACOVIGILANCE AZANTA

Effective date: 15 November 2017 Page: 1 of 17 PHARMACOVIGILANCE AZANTA Table of Contents See next page 1 Purpose and Scope The purpose of this quality instruction is to describe pharmacovigilance procedures within A- consult specific to Azanta. 2 Responsibilities This instruction must be read and understood by: Literature Monitoring Assistant Case Processor Case Assessor Medical Writer Pharmacovigilance Responsible person (PVR) dqppv

Effective date: 15 November 2017 Page: 2 of 17 1 Purpose and Scope... 1 2 Responsibilities... 1 3 Definitions... 3 4 Procedure... 3 4.1 Single case handling... 3 4.1.1 Triage form and AE front page... 3 4.1.2 Follow-up procedure for Azanta clinical trial cases... 3 4.1.3 Upgrading and downgrading of cases... 4 4.1.4 Prioritisation of late cases... 4 4.1.5 Case handling of post-marketing ADR reports... 5 4.1.5.1 ADR reports received in EVWEB... 5 4.1.5.2 ADR reports received at A-Consult... 9 4.1.6 Case handling of Adverse Events from clinical studies... 11 4.2 Single Case Reporting... 11 4.3 Reconciliation... 11 Partner initiates the reconciliation process... 11 A-consult initiates the reconciliation process... 12 4.4 Pharmacovigilance Agreements with Azanta partners... 12 4.5 Periodic Safety Update Reports... 13 4.6 Risk Management Plans... 14 4.7 Company Core Safety Information (CCSI)... 14 4.8 Signal Detection... 14 4.9 Pharmacovigilance System Master File... 14 4.10 QPPV Periodic Report... 14 4.11 Periodic meetings... 14 5 Audits and inspections... 15 6 Archiving... 15 7 References... 15 8 Change Log... 15

Effective date: 15 November 2017 Page: 3 of 17 3 Definitions Please refer to QI02 for Definitions and Abbreviations used in this instruction. Azanta partners refer to companies which have signed a pharmacovigilance agreement with Azanta. 4 Procedure 4.1 Single case handling Azanta uses PV247 as pharmacovigilance database. All information pertaining to Azanta ICSRs must be entered in PV247 in English. Single case handling is performed as described in QI34 Case Handling Using PV247. Supplementary description is provided in sections 4.1.1 4.1.4. The tasks are matched in QI34AP01 (Triage Form /AE Front Page) and completion of a task requires signature in the matching field in QI34AP01. Narrative writing and case assessment is performed according to QI18 Case Narrative Writing and QI25 Case Assessment and Writing Sender s Comment, respectively. All reportable cases shall be approved within the timelines allowing timely submission to the authorities or partners, and the remaining cases shall be approved within 30 calendar days of receipt. 4.1.1 Triage form and AE front page A Case Processor performs triage as depicted below and completes the relevant fields of QI34AP01 (Triage Form / AE Front Page). During the triage phase of a potential adverse event report, the triager must determine: 1) whether the case is valid, i.e. the four elements of an AE case are present (an identifiable patient, an identifiable reporter, a suspect drug and an adverse event), or if immediate pre-evaluation follow-up is needed AND whether 2) the case is reportable according to the Reporting Matrix (QI24). The triager adds the case to the Azanta s reconciliation spreadsheet located on the K drive in the reconciliation folder of Azanta pharmacovigilance. The relevant fields of the AE front page (QI34AP01) are filled in by each role involved in the case handling process. 4.1.2 Follow-up procedure for Azanta clinical trial cases The responsibility for the follow-up procedure for Azanta clinical trial cases lies with the study Sponsor. If additional information is considered necessary, A-Consult is entitled to request the information through the Sponsor. For spontaneous cases, the procedure in QI20 is followed.

Effective date: 15 November 2017 Page: 4 of 17 4.1.3 Upgrading and downgrading of cases When a case is upgraded from non-serious to serious, the need for submitting an expedited report must be reconsidered. Day zero for expedited reporting is the day that the information used to upgrade the case was received and not just the date that the decision to upgrade the case was made. Note that if the non-serious case originates from the Danish Medicines Agency (DMA), and the MAH wants to upgrade the case to serious, an e-mail with clarification should be sent to ADR@dkma.dk. The Agency will, if appropriate, update the case and will distribute a new version. The mail submitted to ADR@dkma.dk must be filed with the case. The receipt date of the updated version of the case is the date of receipt of the mail from the DMA with the reasoning. Follow-up information may result in downgrading of a case. In relation to causality, only when the reporter explicitly states there is no longer a causal relationship and A-consult agrees should a case be downgraded. In either situation, the reason for upgrading or downgrading the case should be documented in Sender s Comment. This also applies to upgrading or downgrading following QC checks. The table below depicts when to change the date of receipt (= day 0) of the most recent information for the report. New information received? Change has impact on the evaluation of the case? Change the data element Date of receipt of the most recent information for this report (ICH-E2B(R2) A.1.7)? No No No Yes Yes or No Change to date of most recent information received No Yes Yes (change to the date when changes are made which impact on the interpretation of the case) (e.g. following QC of cases) If a case was initially submitted as an expedited report and upon receipt of follow-up information was downgraded, this should be notified to the Competent Authorities who received the initial report, on an expedited basis. 4.1.4 Prioritisation of late cases Reports received late from internal or external partners shall be prioritised and given special attention to assure timely reporting to Competent Authorities and other partners or to minimise the delay in reporting. 1. Case Processor Requests the sender to investigate the reason for Initiate investigation the late delivery and to send the result of the

Effective date: 15 November 2017 Page: 5 of 17 investigation to A-consult 2. Case Processor Archives the result of the investigation together with the case documentation Archiving 4.1.5 Case handling of post-marketing ADR reports ADR reports are received either through EVWEB or directly reported to A-Consult. Depending on the reporting route, there are different ways of case handling in PV247. 4.1.5.1 ADR reports received in EVWEB The flow for ADR reports received in EVWEB is depicted below. The flow concerns both serious and non-serious ADR reports. 1. Case processor When an ADR report is received in EVWEB ensure to: Add the case(s) to the reconciliation sheet(s) Fill a triage form (Perform Duplicate Check) Save the case in different formats as described in details in QI15 EVWEB Case Handling Process. Receipt of ADR report in EVWEB 2. Case processor 3. Case processor 4. Case processor For serious cases send CIOMS from EVWEB to Azantas QPPV for case assessment/medical assessment. For non-serious cases, the QPPV should confirm if the case should remain non-serious or if the case should be upgraded to serious. Archiving: Save e-mail containing CIOMS on the drive and in hard copy in folder of the version of the case. Name the file: CIOMS for review. Once the answer is received, it should be filed as: QPPV case assessment. Import the XML-file and contact Assured to upload the case to PV247 as described in QI34 Case Handling Using PV247. Archiving: All the correspondence with Assured regarding upload of XML-files must archived in accordance with QI34 Case Handling Using PV247. A) Cases from DKMA are translated to English by the case processor. B) If the case is received in another language than English or Danish, external translation of certain sections of the case is Send CIOMS from EVWEB to QPPV Archiving Import of XML file and upload to PV247 Archiving Translation to English

Effective date: 15 November 2017 Page: 6 of 17 needed 1. Make the case ready for translation: Mark the following sections of the RTF-file yellow: Case narrative Reporter s comment Adverse Reactions as reported Primary Source Information Test/Procedure Results or any other terms in original language which are to be entered in structured fields of the database. Delete patient identifiers as date of birth, initials and sex before sending the file for translation. Archiving: Save the RTF-file for translation in hard copy and on the drive in the folder Translation placed in the correct version of the case. Archiving 2. Send the case for translation: Find contact information and the language competencies of trusted translation bureaus in Translation Overview on the drive: I/Services/OKteam/Oversættelsesbureauer. Send the RTF-file with yellow marking of sections to be translated and without patient identifiers to a selected translation bureau asking for a price. If the offer is acceptable, proceed with translation process. Elucidate that the translation output should be placed below the original language in the RTF-file. Archiving: Save the e-mail Case for translation in hard copy and on the drive in the folder Translation under the correct version of the case. Archiving 3. Output of translation: Once a reply is received with the translated text, save the output of translation as Translation output in hard copy and on the drive in the folder Translation under the correct version of the case. 5. Case assessor If the case is in English or Danish, the case is ready for QC once it has been added to PV247. If the case is in other languages than Danish or English and translation is awaited, the QC should be postponed until translation output is received. Case processing - Case identification Case identification screen:

Effective date: 15 November 2017 Page: 7 of 17 Date first received (=Day 0) is the date that the case is transferred to EVWEB by the competent authority or other sender (i.e. not the date on the CIOMS or the date that we see it in EVWEB) Worldwide case number: If the safety report ID number is not the same as the authority number in the XML-file, write both numbers in Worldwide case number as presented in the below example for a case from DKMA: DK-WBS-XXXXXXX/DK-DKMA ADR-XXXXX It is important not to make space before and after the backslash in order to have the possibility to find the case in search duplicate using wildcards around one of the numbers e.g.*dk-wbs-xxxxxxx* Add company s local reference number to the Legacy case number field Ownership update to own name rather than HUMAN. Check if the Authority Number is imported automatically. Remember to write the case numbers in the top of the narrative as Other identifiers. Mother/child cases: link to each other on Case Identification screen. Note that it can be difficult to find the cases, thus try with different search criteria. 6. Case assessor Patient screen: Check all information against the material from the competent authority. Add omissions, if any. 7. Case assessor Adverse Event Screen: Verbatim: Insert English terms as provided in the translation form (keep the original term/original language term in parenthesis) Case processing - Patient Case processing - Adverse Event For Angusta cases add the respective MedDRA codes: Maternal exposure during delivery (not serious, unclassifiable) Fetal exposure during delivery (not serious, unclassifiable) Both codes classify as listed terms and should have causality Unassessable /Unclassifiable according to QI25 Case Assessment and Writing Sender s Comment. Check Reporter s Assessment : Tick the correct box for seriousness and fill the causality. 8. Case assessor Product Screen: Case

Effective date: 15 November 2017 Page: 8 of 17 Tick Company product and code Angusta or Diaphin in the Company Product Dictonary. Remember to add indication (= reason for use) Check or add Dose and Route of Administration processing Product 9. Case assessor Narrative screen: Insert the English narrative in the company narrative. Below the English narrative insert the original language wording with a headline: Original Language Remember to remove Note to MAH text 10. Case assessor Company comment: For all ADR reports for Angusta, copy the comment from QPPV to the screen for company comment. For Diaphin, only serious and unlisted ADR reports, should have a company comment. Case processing Narrative Writing of company comment and reporter s comment Reporter s comment: If there is any reporter s comment, copy the comment from the narrative and insert it to reporter s comment. 11. Case assessor Assessment screen: Perform Company assessment/reporter s assessment the English valid SmPC as reference document following A-Consults standards. 12. Reviewer Case approval: Approve the case Print CIOMS Archive CIOMS electronically and in hard copy 13. Follow-up questions to competent authorities should only be posed when a clarification is absolutely needed to make a proper assessment of the case. Case assessment in PV247 Case approval and archiving Follow-up request to CA Follow the A-Consults standards for follow-up request as described in QI20 Follow-up on Adverse Events. For submission of follow-up questions in Scandinavian Countries (DK, NO, SE and FI), the following addresses should be used: Denmark: Follow-up questions should be submitted through DKMAnet. The security administator uploads the questions to DKMAnet. The security administrator is an appointed employee at A-Consult. For mother/child report: State the number in the top field Report ID/ADR number. Add the other ADR number to the first question field of the form.

Effective date: 15 November 2017 Page: 9 of 17 Deadline for submission of follow-up request is maximum 3 weeks from the day the adverse reaction report was received. Norway: Only if the ADR is a potential/important risk or missing information in RMP, it is justified for the MAH to request followup information. Send follow-up questions to: adr@noma.no Sweden: Send follow-up questions to: adr-report@mpa.se Finland: Send follow-up questions to: FIMEA.EV@fimea.fi 4.1.5.2 ADR reports received at A-Consult ADR reports may be received at A-Consult by fax, e-mail or phone. A-Consult s fax number and the e-mail address: pharmacovigilance@a-consult.dk is provided at Azantas homepage as contact point for reporting of ADRs. In such case, the written documentation received at A-Consult should provide case source documentation. There is also a possibility of receiving of the information regarding ADR s by phone. In this case, the pharmacovigilance employee should follow A-Consults standards for receipt of ADR completing the Adverse Event Form as described in details in QI28 Handling of Adverse Reports in A-consult. The flow for ADR reports received in EVWEB is depicted below. The flow concerns both serious and non-serious ADR reports. 1. Case assessor A-consult may receive the ADR report as fax, e- mail or by phone. Once the ADR report is received ensure to: Add the case(s) to the reconciliation sheet(s) Fill a triage form (Perform Duplicate Check) Save the source documentation in Azanta folder as described in details in QI34 Case Handling Using PV247. Receipt of ADR report at A-Consult 2. Case assessor Place case source documentation in the tray for Data Entry. Enter the case in PV247 translating the text to English. Case processing - Data entry and QC in PV247 Perform QC according to the QI34 Case Handling using PV247.

Effective date: 15 November 2017 Page: 10 of 17 3. Case assessor Assessment screen: Perform Company assessment/reporter s assessment using the English valid SmPC as reference document. Case assessment in PV247 4. Case assessor Evaluate the need for follow-up questions. If relevant, draft the follow-up questions following the A-Consults standards for follow-up request as described in QI20 Follow-up on Adverse Events. 5. Case assessor Create draft CIOMS and send it to QPPV as soon as possible: State clearly in the subject line that the case is for submission and when the deadline is. If there is a need for discussion of FU questions with QPPV, the drafted questions can be sent with CIOMS form. For non-serious cases, the QPPV should confirm if the case should remain non-serious or if the case should be upgraded to serious. Follow-up request to reporter Send draft CIOMS for case assessment to QPPV before submission Archiving: Save e-mail containing CIOMS on the drive and in hard copy in folder of the version of the case. Name the file: Draft CIOMS for review. Once the answer is received, it should be filed as: QPPV assessment. 6. Case assessor Company comment: For all ADR reports for Angusta, copy the comment from QPPV to the screen for company comment. Writing of company comment and reporter s comment For Diaphin, only serious and unlisted ADR reports, should have a company comment. Reporter s comment: If there is any reporter s comment, copy the comment from the narrative and insert it to reporter s comment. 7. Case assessor When QPPVs case assessment has been copied into the case in PV247, final CIOMS should be created. Archiving: Archive the final CIOMS. Name the file according to AC standard for as CIOMS. 8. Case assessor Report the case within 15-days reporting obligation as described below. Creation of final CIOMS Archiving Case submission

Effective date: 15 November 2017 Page: 11 of 17 4.1.6 Case handling of Adverse Events from clinical studies Azanta A/S is not sponsor for any clinical study. Azanta A/S provides medicinal drug for some investigator initiated studies but is otherwise not involved in the initiation and conduct of these studies. Sponsors of clinical studies, where the sponsor is not Azanta A/S, are responsible for expedited reporting of Serious Adverse Events (SAEs) directly to Competent Authorities and send a copy to A-consult. SAE reports are entered centrally into A-consult s safety database (PV247). A-consult is responsible for performing quality control (QC), coding, causality and a suggested medical assessment. A detailed description of case handling is described in QI34 Case Handling in PV247. Archiving: All source documents and the confirmation of receipt e-mail are archived both electronically and in paper copy. For SAEs which are imported to PV247 as XML-files, all the correspondence with Assured regarding upload of XML-files must archived as well. The structure of the archiving of the correspondence with Assured is outlined in QI34 Case Handling in PV247. 4.2 Single Case Reporting Reporting to regulatory authorities and partners is performed according to: QI24 Reporting Matrix QI34 Case Handling Using PV247. QI15 EVWEB Case Handling Process QI19 Expedited Reporting in case of system failure Reporting shall be documented on page 2 of QI34AP01. 4.3 Reconciliation A-consult is responsible for reconciliation with Azanta and its partners. Reconciliation between A-consult and Azanta is performed biannually. The reconciliation frequency, who initiates the process etc., is specified in Pharmacovigilance Agreements (PV Agreements) between Azanta and Azanta partners. Reconciliation sheet(s) is located on the K drive in the reconciliation folder of Azanta pharmacovigilance. Partner initiates the reconciliation process 1. Case Sends a reminder to the partner if the reconciliation list isn t received no later than the 7 th calendar day Sending reminder to partner

Effective date: 15 November 2017 Page: 12 of 17 of the following month of the period. 2. Case Compares received reconciliation lists with A- consult s records Comparison of the lists 3. Case Confirm the correctness of the reconciliation list or advise the partner of any discrepancies.. Sending conclusion to partner 4. Case Provides missing documentation held by A-consult to the partner and receives missing documentation, Exchange of missing documentation held by the partner, from the partner. 5. Case Any new documentation is added to the case handling flow and distributed, if appropriate. Handling of new documentation 6. Case Documentation is archived in hard copy in the physical archive and electronically on the K drive. Archiving * Or other A-consult employees whose job description includes reconciliation. A-consult initiates the reconciliation process 1. Case Creates reconciliation list Creation of list 2. Case Sends the reconciliation list to the partner or Azanta no later than the 7 th calendar day of the Sending reconciliation list to 3. Case 4. Case following month of the period. Receives confirmation of the correctness of the reconciliation list or advice from the partner/azanta of any discrepancies. Provides missing documentation held by A-consult to the partner/azanta or receives missing documentation from the partner/azanta. partner or Azanta Receiving conclusion from partner/azanta Exchange of missing documentation 5. Case Any new documentation is added to the case handling flow and distributed, if appropriate. Handling of new documentation 6. Case Documentation is archived in hard copy in the physical archive and electronically on the K drive. Archiving * Or other A-consult employees whose job description includes reconciliation. 4.4 Pharmacovigilance Agreements with Azanta partners PV Agreements are reviewed (and updated if necessary) by A-consult every second year to assure compliance with current international guidelines for good pharmacovigilance practices. PV Agreements should be reviewed outside the 2-years cycle if current international guidelines for good pharmacovigilance practices changes. PV Agreements should be updated if these changes affect procedures described in the agreements. Amendments to PV Agreements are negotiated and agreed to independently of the licensing agreement. PV Agreements are signed by the QPPV, CEO for Azanta and the Partner, if applicable. 1. Case Assessor Submission of PV Agreement draft to Partner Submission of

Effective date: 15 November 2017 Page: 13 of 17 template to partner 2. Case Assessor The review and commenting phase includes A-consult and the partner. Azanta is copied on e-mails send to the partner as appropriate. Review and commenting phase 3. Case Assessor Issues not resolved during step 2 are escalated to the dqppv. 4. dqppv Contacts the partner for resolution of unresolved issues. 5. dqppv Issues not resolved during step 4 are escalated to the QPPV and Azanta. The dqppv and QPPV/Azanta agree on how to continue. 6. Case Assessor Send the final draft to Azanta and to QPPV for signatures. Escalation to QPPV Resolution of unresolved issues (QPPV) Escalation to Azanta Collection of signatures 7. QPPV and Azanta Signs the PV Agreement Signing PV 8. Case Assessor A copy of the signed PV Agreement is archived in hard copy in the physical archive and electronically on the K drive. Originals are sent to Azanta for archiving. 9. dqppv All A-consult pharmacovigilance employees are informed about the new Partner agreement. Internal pharmacovigilance procedures are updated. Agreement Archiving Informing pharmacovigilance employees Update of internal pharmacovigilance procedures 4.5 Periodic Safety Update Reports The process for writing Periodic Safety Update Reports (PSURs), as well as for preparing response documents to Assessment Reports, follows QI07 Preparation of Periodic Safety Update Reports (PSURs). The PSUR Data Lock Point (DLP) table is managed by A-consult. A Case Processor updates the DLP table according to new information regarding new products, new territories where Azanta is Marketing Authorisation Holder and with new changes in DLPs.

Effective date: 15 November 2017 Page: 14 of 17 4.6 Risk Management Plans The process and format for Risk Management Plans (RMPs) shall follow the GVP Guideline Module V and Guidance on format of the RMP in the EU in integrated format. 4.7 Company Core Safety Information (CCSI) A-consult is responsible for establishing and maintaining CCSI s on Azanta s products. New and updated CCSIs are sent to partners within two weeks or as specified in PV Agreements with the respective partners. The dqppv decides whether to define section 4.3 4.9 of a national SPC or EU SPC as the CCSI or to create a CCSI according to QI36 CCSIs 4.8 Signal Detection Signal detection is performed according to QI31 Signal Detection and Evaluation. A potential signal may arise from information from ICSR(s). Any A-consult pharmacovigilance staff member identifying a Potential Signal informs the dqppv and QPPV immediately (within 24 hours). In case of urgent safety measures in clinical trials (e.g. halt of a trial, substantial protocol amendment, restriction in distribution of study drug) or in case of emerging safety issues, the QPPV or Deputy QPPV shall inform the members of the Safety Management Team immediately (within 24 hours). Please refer to QI31 for further guidance. 4.9 Pharmacovigilance System Master File A-consult shall compile and maintain the Pharmacovigilance System Master File (PSMF). The PSMF shall be reviewed once a year to ensure correctness and completeness of the document. To ensure that Annexes are updated on a continuous basis, A-consult will ask Azanta at each Safety Management Team meeting whether there is new information relevant for PSMF Annexes. Annex F concerning compliance monitoring shall be updated and shared with Azanta on a quarterly basis. 4.10 QPPV Periodic Report A-consult shall prepare the QPPV Periodic Report on a quarterly basis in order to substantiate the data provided in Annex F. QI35 QPPV Periodic Report applies. 4.11 Periodic meetings The frequency of Safety Management Team (SMT) meetings follows that described in the SMT Guidelines. QI30 Safety Management Teams applies. The recommendations and actions are documented in the meeting minutes.

Effective date: 15 November 2017 Page: 15 of 17 5 Audits and inspections Audits and self-inspections will be performed according to the audit plan and QI09 (Inspections and Audits at A-consult). Azanta shall be informed about findings from audits/inspections that may affect Azanta s products/pharmacovigilance system. Critical and major findings shall be added to the PSMF. 6 Archiving All documents and emails are archived as original pharmacovigilance documents (see QI05 Archiving at A-consult a/s). 7 References QI05 Archiving at A-consult a/s QI07 Preparation of Periodic Safety Update Reports (PSURs) QI09 Inspections and Audits at A-consult QI16 EVWEB Surveillance QI15 EVWEB Case Handling Process QI18 Case Narrative Writing QI20 Request for Follow-Up QI21 Monitoring of Scientific Literature QI23 Deviations (pharmacovigilance) QI25 Case assessment and writing Sender s Comment QI30 Safety Management Teams QI31 Signal Detection and Evaluation QI34 Case handling using PV247 QI35 QPPV Periodic Report QI36 CCSIs Safety Management Team Guidelines Guideline on good pharmacovigilance practices: Module V Risk Management Systems (EMA) Guidance on format of the RMP in the EU in integrated format 8 Change Log Version Change description Effective date 8.0 Section 4.1: 15November 2017 o Updated to reflect that all Azanta ICSR information in PV247 must be entered in English. Section 4.1.5: o Section 4.1.5 Handling of cases received through EVWEB account is replaced by o Case handling of post-marketing ADR reports Section 2, 4.4, 4.7, 4.8: o Update of responsibilities of QPPV/dQPPV throughout the

Effective date: 15 November 2017 Page: 16 of 17 document as the responsibility of QPPV role is not in house at A-Consult Section 4.10: o Section about QPPV report reinserted 7.0 Appendix 01 outdated. Number of appendices changed to 0. 1 February 2017 6.0 Section 4.1: 15 September 2016 o o Updated to reflect new Triage form/ae Front page New section 4.1.2 describing follow-up procedure for clinical trial cases o Old Section 4.1.2 re-numbered to 4.1.3 o Old Section 4.1.3 re-numbered to 4.1.4 o Old Section 4.1.4 re-numbered to 4.1.5 Section 4.3: o Deleted that each Partner will have its own reconciliation sheet Section 4.4: o Added that Partner also signs PV-agreements Section 4.6 on RMPs added Section 4.8: o Specified that PSMF Annex F shall be updated on a quarterly basis Section 4.9 on QPPV Report deleted Section 4.10: o Frequency of SMT meetings deleted, and a reference added to SMT guidelines Section 5 (Audits and inspections) added References updated 5.0 Section 4.1 o Applicable QIs moved to References o Timelines for case handling changed o Added that PV247 is used and QI34 applies o PV case log replaced with PV247 database, and all actions related to PV case log deleted o Description of case handling process deleted and referenced to QI34 Section 4.3 o Process simplified and some of the timelines deleted Section 4.4 o Deleted that Azanta is responsible for signature collection Section 4.5 o Process description deleted and referenced to QI07 Section 4.6 o Process description deleted and referenced to QI36 Section 4.7 o Updated with emerging safety issues and urgent safety measures o Process description deleted and referenced to QI31 Section 4.8 o Frequency for PSMF updates added o Reference to QI38 deleted, as it no longer exists Section 4.10 o Frequency for periodic meetings changed from biannual to 15 May 2016

Effective date: 15 November 2017 Page: 17 of 17 quarterly o Text about SMT and SMT Guideline added o Process description deleted and referenced to QI30 Appendix 1 o Removed, and reference to QI34AP01 added 4.0 New templates for QIs and appendices in effect from 15 Jan 2015. New Section 4.2.1 Identification of a potential signal with reference to QI31. Section 4.2.2 o Create a Triage Form / AE front page for the case (Step 1) Section 4.2.3 o Added that external medical evaluation is required if the Case Assessor assesses the causal relationship between the event and the product as unrelated (Step 8) o Deadlines for case approval (Step 10) New Section 4.2.4: Triage (Description of Triage step). Archiving added (Section 5) List of appendices added (Section 6) References added (Section 7) 01 March 2015 Appendices now managed separately: Former Appendix 1 of created as an independent document named QP01. 3.0 Section 4.2.3 Upgrading of cases renamed 4.2.3 Upgrading and downgrading of cases and rewritten. 15 June 2014 Section 4.2.4 Delayed cases (late reports) renamed 4.2.4 Prioritisation of late cases and rewritten 2.0 New Appendix 1 added. 15 April 2014 Section 4.1.1 Database changed to 4.1 Database. Section 4.1 Single Case Handling is now 4.2 Single Case Handling. This section updated to align the process (task) with signature fields on the Appendix. New section 4.2.3 Upgrading of cases New section 4.2.4 Delayed cases (late reports). New section 4.3 Single case reporting added. Section 4.11 Periodic Meetings updated with standard agenda and process for writing and approval of meeting minutes. 1.0 New document 1 November 2013