Safety Observer N°93 – September 2013 page 1/26

Safety Observer Clinical Safety & Pharmacovigilance Intelligence Review

Issue N°93 – September 2013 Highlights The FDA has issued two new Guidance Documents, which cover the electronic submission of Non-Expedited ICSRs and Safety Labeling Changes. In Europe, several documents describing transitional arrangements for the PV Legislation have been updated, including the interim ICSRs reporting requirements. The EMA has issued revised templates for Non-Interventional PASS Study Reports. Changes have also been introduced to the EU Risk Management Plans requirements, as there is no longer a requirement to update RMPs on a fixed-time basis. The new EU Variations Guidelines came into force on 04-Aug-2013, which implies a number of changes for the Regulatory Affairs activities related to Pharmacovigilance. A number of Product-Specific announcements were made over the summer. The European Commission has adopted the recommendation of the PRAC for Diane 35, and France has announced that the MA suspension will be lifted as a result. The EMA has concluded that available data does not confirm pancreas concerns for GLP-1-based diabetes therapies (Incretin Mimetics). The EMA has also recommended the suspension of oral ketoconazole antifungals, whereas the FDA decided on restrictions. In other news, the MHRA has announced that the next session for their popular Pharmacovigilance Inspections Symposium will take place on 14-Mar-2014. The EMA has issued the 2012 EudraVigilance Annual Report and ENCePP has published the results of a survey on the EU Member States requirements for data protection.

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In this issue

1. Regulatory Update .................................................................................................................... 3 1.1. Applicable Regulations, Guidelines and other Standards ............................................................ 3 1.1.1. ANSM updates its template for DHCP Letters .............................................................................. 3 1.1.2. New FDA Guidance on Non-Expedited ICSRs electronically Submissions ........................................ 3 1.1.3. FDA issues Final Guidance on Safety Labeling Changes ............................................................... 3 1.1.4. EMA issues updated interim ICSRs reporting requirements .......................................................... 3 1.1.5. Updated EU-RMP Annex I: Interface between EU-RMP and EudraVigilance ...................................... 4 1.1.6. EMA waives fees for some Pharmacovigilance-related variations ................................................... 4 1.1.7. CMDh updates information on PSUR Submission for NAPs ........................................................... 4 1.1.8. CMDh updates Q&As on transitional arrangements for the PV legislation ....................................... 4 1.1.9. EMA issues revised template for non-interventional PASS Study Reports ....................................... 5 1.1.10. New EU Variations Guidelines come into force ............................................................................. 5 1.1.11. EMA updates EURD list and interim PSUR submission requirements ............................................. 6 1.1.12. EMA introduces changes to EU Risk Management Plans requirements .......................................... 6 1.1.13. English MedDRA Version 16.1 now available ............................................................................... 6 1.2. Developments to watch ............................................................................................................ 7 1.2.1. Update on ICH E2B(R3) on Transmission of ICSRs ....................................................................... 7 1.3. Beyond the borders of Safety Observer ...................................................................................... 7 1.4. The Safety Observer Tracker ..................................................................................................... 8

2. Safety Update .......................................................................................................................... 8 2.1. Olmesartan Medoxomil (Alteis®, Axeler®, Olmetec®, Sevikar®) ................................................ 8 2.2. Methylphenidate (Ritaline®, Concerta®, Quasym®) ................................................................... 8 2.3. Lenalidomide (Revlimid®) ......................................................................................................... 8 2.4. Hydroxyethyl starch (HES) ........................................................................................................ 9 2.5. Bromocriptine (Parlodel® and generics) .................................................................................... 9 2.6. Ethinylestradiol/cyproterone acetate (Diane 35® and generics) ................................................ 9 2.7. Incretin Mimetic Drugs (GLP-1-based therapies) ........................................................................ 9 2.8. Oral ketoconazole-containing medicines .................................................................................. 10 2.9. Metoclopramide-containing medicines ..................................................................................... 10 2.10. Mefloquine (Lariam® and generics) ......................................................................................... 10 2.11. Acetaminophen (Paracetamol) ................................................................................................ 11 2.12. Fluoroquinolone Antibacterial Drugs ........................................................................................ 11 2.13. Fingolimod (Gilenya®) ............................................................................................................ 11

3. Quality Assurance, Inspections and Audits .............................................................................. 11

4. Drug Safety and Business Risk................................................................................................ 12

5. Other relevant Information and Resources ............................................................................... 12 5.1. US Food and Drug Administration (FDA) .................................................................................. 12 5.2. European Medicines Agency (EMA) ......................................................................................... 14 5.3. UK Agency (MHRA) ................................................................................................................ 17 5.4. French Agency (ANSM)........................................................................................................... 18 5.5. Other Sources ........................................................................................................................ 20

6. Time to Register ..................................................................................................................... 23

7. About the Authors .................................................................................................................. 26

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1. Regulatory Update

1.1. Applicable Regulations, Guidelines and other Standards

1.1.1. ANSM updates its template for DHCP Letters (23-Jul-2013) The French Agency updated the template for DHCP Letters featuring the new visual identity which was initially issued in June 2013.

Link to the template (in French)

1.1.2. New FDA Guidance on Non-Expedited ICSRs electronically Submissions (24-Jul-2013) The FDA has issued a new guidance to industry entitled “Providing Submissions in Electronic Format – Postmarket Non-Expedited ICSRs; Technical Questions and Answers”, which provides information on the file format to use for these submissions. FDA regulations require applicants to submit postmarket periodic safety reports at prescribed intervals, and corresponding Non-expedited ICSRs can be submitted on paper or electronically in XML format. Some companies have submitted non-expedited ICSRs to the eCTD in a pdf format and the guidance explains that these ICSRs should be resubmitted in the correct format.

Link to Federal Register Notice

Link to FDA Guidance Document

1.1.3. FDA issues Final Guidance on Safety Labeling Changes (30-Jul-2013) The FDA has now issued the final guidance entitled “Safety Labeling Changes – Implementation of Section 505(o)(4) of the FD&C Act”, which was previously published as a draft for consultation in April 2011. The Food and Drug Administration Amendments Act of 2007 (FDAAA) added new provisions authorizing FDA to require safety-related labeling changes based upon new safety information. This guidance defines what constitutes new safety information and describes the types of safety labeling changes that can be requested by FDA as a result. It also described the process and enforcement measures.

Link to Federal Register Notice

Link to FDA Guidance Document

1.1.4. EMA issues updated interim ICSRs reporting requirements (30-Jul-2013) The Agency has updated the document describing the transitional reporting requirements for individual case safety reports (ICSRs) applicable to MAHs during the interim period. The current revision (Rev. 7) includes changes to the requirements for the reporting of non-serious EU ICSRs within 90 days: This reporting is now required in Italy, whereas Austria now restricts this requirement to cases associated to vaccines or plasma preparations, and to products subject to additional monitoring.

Link to EMA Page

Direct Link to ICSRs Reporting Requirements (EMA/321386/2012 Rev. 7)

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1.1.5. Updated EU-RMP Annex I: Interface between EU-RMP and EudraVigilance (30-Jul-2013) The EU-RMP Annex 1 is the structured electronic representation of the EU Risk Management Plan as referred to in GVP Module V. The purpose of the EU-RMP Annex 1 is to allow for the monitoring of identified and potential risks and missing information in relation to suspected adverse reactions reported to EudraVigilance for centrally authorized medicinal products. The content of the template of the EU-RMP Annex 1 has been simplified and improved to capture the core elements of the RMP.

Link to EudraVigilance Page

1.1.6. EMA waives fees for some Pharmacovigilance-related variations (31-Jul-2013) The EMA has revised the rules on fees payable to the Agency, which came into force on 04-Aug-2013 and provide a total exemption from the payment of the fees for specific pharmacovigilance-related variations to the terms of marketing authorisations. The scope of this waiver includes: The introduction of, or changes to, a summary of pharmacovigilance system Changes in the frequency or date of submission of PSURs Inclusion or deletion of the black symbol and explanatory statements, as applicable Inclusion of the statements of adverse-drug-reaction reporting.

Link to EMA Press Release

1.1.7. CMDh updates information on PSUR Submission for NAPs (Jul-2013) The European CMDh (Co-ordination Group for Mutual Recognition and Decentralised Procedures – Human) has issued an updated “List of substances under PSUR Work Sharing scheme and other substances contained in Nationally Authorised Products with DLP synchronised”. This list contains substances and combinations that have been removed from the EURD list until they follow the EU single assessment procedure of PSURs. The list is provided in pdf and Excel format, where all changes since the previous publication are highlighted. The Best Practice Guide for PSUR Work Sharing during the transition period has also been updated, which describes the Assessment Procedure and includes the associated templates.

Link to HMA Page

Direct link to list (pdf)

Direct link to Best Practice Guide

1.1.8. CMDh updates Q&As on transitional arrangements for the PV legislation (02-Aug-2013) The CMDh has also issued an updated Q&A document to address the situation where the summary of the RMP is missing in the application. It clarifies that there is no need to submit a variation and the summary can be added during the procedure.

Link to CMDh Q&As (Rev.7 – July 2013)

Link to CMDh Q&As (track changes)

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1.1.9. EMA issues revised template for non-interventional PASS Study Reports (02-Aug-2013) The EMA has published a revised guidance for the format and content of the final study report for non-interventional post-authorisation safety studies (PASS). The revised template includes changes in section 11 (Discussion) and 13 (Conclusion) in order to highlight the need to discuss the impact of the study results on the benefit-risk balance of the concerned product(s) and to remove redundancies.

Link to EMA Guidance Page

Direct link to PASS Study Report Template: Word – pdf

1.1.10. New EU Variations Guidelines come into force (04-Aug-2013) As announced in May, the European Commission adopted new Guidelines on the details of the various categories of variations, and the corresponding requirements came into force on 04-Aug-2013. The guideline was published in the Official Journal on 02-Aug-2013, which corrects a clerical error to clarify that the PSMF number should be provided for a variation C.I.8, as opposed to the full PSMF (Please note that the version of the guideline published in Eudralex Volume 2 is not corrected at this time). The EMA has issued a Practical Questions and Answers Document to support the implementation of the new requirements with regards to new classification categories. These cover the obligations and conditions of a MA (including the RMP), the submission of studies, and the impact on post-authorisation measure (PAM) submissions. It also highlights that changes in EU QPPV still require a Type IAIN Variation at this time, as the Article 57 database is not fully functional yet. The EMA has also updated the separate “Questions and Answers” Document on variations to an existing Pharmacovigilance system as described in the DDPS (Detailed Description of the Pharmacovigilance System). It clarifies how changes to an existing Pharmacovigilance System should be processed, including changes in QPPV or deputy. Finally, the new variation guidelines brings changes to multiple procedures, which relate to PSURs, Post-authorisation measures, Post-authorisation safety studies (PASS), grouping of variations, etc. These changes have been reflected in the comprehensive EMA Q&A Documents providing pre- and post-authorisation procedural advice for users of the centralised procedure.

Link to Guideline (EU Official Journal C223)

Link to EMA Practical Q&A Document

Link to EMA Q&As on DDPS-related variations

Link to EMA pre-authorisation procedural advice Document

Link to EMA post-authorisation procedural advice Document

The European CMDh (Co-ordination Group for Mutual Recognition and Decentralised Procedures – Human) has updated its Q&A document on variations accordingly.

Link to CMDh Q&As (Rev.21 – July 2013)

Link to CMDh Q&As (tracked)

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1.1.11. EMA updates EURD list and interim PSUR submission requirements (06-Aug-2013) A new update of the EURD list was published on 01-Aug-2013, which provides the European Union Reference Dates, frequencies for submission of PSURs and related data lock points for a list of active substances and combinations. The changes to the EURD list are highlighted and concern 10 products. The introductory cover note has been updated to include a new annex “Summary of PSUR submission requirements for single assessment procedures”, which provides an overview of the corresponding guidance. The aforementioned guidance document describing National Competent Authorities (NCAs) and European Medicines Agency (EMA) requirements for PSUR submission during the transitional period has also been revised to include the requirements for Croatia, who joined the European Union on 01-Jul-2013.

Link to EMA Guidance Page (EURD list and PSUR Submission)

1.1.12. EMA introduces changes to EU Risk Management Plans requirements (21-Aug-2013) The EMA has announced that there is no longer a requirement to update RMPs on a fixed-time basis and an updated RMP should now be submitted only on request or whenever the risk-management system is modified (e.g. new information with impact on the benefit-risk profile). The authorities may however specify a date for submission of the next RMP as a condition of the marketing authorisation in exceptional cases. A new version of the templates for the EU Risk Management Plans (RMPs) has been released where the word “important” has been removed from the term “important missing information” to define this category of safety concerns. This change was introduced to avoid misunderstanding with regard to Regulation (EC) No 726/2004, which states that a marketing authorisation should be refused if the applicant has not properly or sufficiently demonstrated the quality, safety or efficacy of its product. Updates to GVP guideline module V and annex 1 are scheduled for update later in 2013, which could reflect additional revisions to the RMP formats.

Link to EMA RMP Page

1.1.13. English MedDRA Version 16.1 now available (01-Sep-2013) The release of English MedDRA Version 16.1 is now available to subscribers. The availability of translations is announced for 15-Sep-2013. Additional MedDRA Guides are available on the MedDRA website, including Introductory Guides and a presentation of the changes introduced with Version 16.1, which is also the subject of a Webinar scheduled on 12-Sep-2013.

Link to MedDRA announcement

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1.2. Developments to watch

1.2.1. Update on ICH E2B(R3) on Transmission of ICSRs (27-Aug-2013) As announced in July, ICH has made available the Implementation Guide package for the E2B(R3) Guideline on “Electronic Transmission of Individual Case Safety Reports (ICSR)”, which reached Step 4 of the ICH process in November 2012. The EMA has now announced that this deliverable has been adopted to Step 5 in Europe.

Link to EMA Announcement

Further to the endorsement by the ICH Steering Committee in June 2013, ICH has also published the Concept Paper for the E2B(R3) Implementation Working Group, which provides details on the deliverables and priorities for the group.

Link to E2B(R3) IWG Concept Paper

1.3. Beyond the borders of Safety Observer

1.3.1. Belgium clarifies new local Pharmacovigilance requirements (15-Jul-2013) The Belgian Agency (famhp: federal agency for medicines and health products) has issued a couple of Circular letters to MAHs, which are available in French and Dutch. Circular Letter N°599 describes the local arrangements associated to the implementation of the EU Pharmacovigilance Legislation in Belgium, which covers several topics including expedited and periodic reporting, RMPs, PASSs, etc. Circular Letter N°600 describes the requirements applicable to the Local Contact Person for Pharmacovigilance, which comes in replacement of the former Local Qualified Person. The qualification and registration requirements have been simplified and the Agency requires all MAHs to submit two notifications containing respectively details about the Local Contact Person and Pharmacovigilance System. Corresponding templates are available and notifications are required within 3 months of publication.

Link to Circular Letters Page (in French)

Link to Circular Letters Page (in Dutch)

1.3.2. Austria updates Guidance on Non-Interventional Studies (30-Jul-2013) The Austrian AGES has updated its “Scientific Guidance for the Conduct of Non-Interventional Studies (NIS) in Austria”, which purpose is to aid in the planning, reporting and conduct of this type of trials. This document is available in both English and German, and includes a section on Collection and Reporting of Adverse Events.

Link to AGES Page

1.3.3. German BfArM updates guidance on PSUR submission (13-Aug-2013) The BfArM has revised its FAQ on the submission of PSURs according to the new Pharmacovigilance legislation and the template for PSUR submission has also been updated.

Link to BfArM Page (in German)

Link to BfArM Page (in English)

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1.4. The Safety Observer Tracker This section includes a cumulative list of the future deadlines for implementation and end of consultation periods, which are associated to the most important announcements made in the current and previous issues of Safety Observer. For your convenience, a link to the main sources is provided and we also specify the issue where the corresponding article can be found.

By When ? What ? Issue 28-Oct-2013 Deadline for national transposition of Directive

2012/26/EU (amending Directive 2001/83/EC) (Link) 85

31-Dec-2013 Deadline to implement inverted equilateral triangle (▼) for products subject to additional monitoring approved in the EU before 01-Sep-2013 (Link)

89

2. Safety Update

2.1. Olmesartan Medoxomil (Alteis®, Axeler®, Olmetec®, Sevikar®) ANSM recommends caution in case of intestinal problems (12-Jul-2013) Following the announcement by the FDA of the Label Changes for the blood pressure drug Olmesartan Medoxomil to include Intestinal Problems, the French Agency recommends that Patients consult a gastro-enterologist for advice in case of severe diarrhea and significant weight loss. If no reason is found for the enteropathy, the drug should be stopped and replaced by another blood pressure drug.

Link to ANSM Press release (in French)

2.2. Methylphenidate (Ritaline®, Concerta®, Quasym®) ANSM confirms limited cases of misuse and positive risk/benefit profile (17-Jul-2013) The French Agency has issued a synthesis on the use of the drug used in children suffering from attention-deficit hyperactivity disorder (ADHD). The synthesis shows that existing risk minimisation measures have been successful to limit misuse and the risk-benefit assessment remains positive. A patient brochure has also been issued.

Link to ANSM Press release (in French)

2.3. Lenalidomide (Revlimid®) FDA halts clinical trial because of significant safety concerns (18-Jul-2013) The FDA has issued a statement to explain that it halted a clinical trial of the anti-cancer drug Revlimid to evaluate a new use for chronic lymphocytic leukemia (CLL), which is not an approved indication. The trial showed higher rates of death in patients treated with Revlimid while the trial is unlikely to show a benefit in the CLL indication.

Link to FDA MedWatch alert

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2.4. Hydroxyethyl starch (HES) ANSM recommends to consider the risks of these products (18-Jul-2013) The French Agency has issued an update to inform that following the June PRAC recommendation to suspend this product used to treat hypovolemia, a re-examination procedure has been initiated after the MAHs appealed the decision. Meanwhile ANSM recommends to avoid prescribing these products, as recommended by the PRAC.

Link to ANSM Press release (in French)

2.5. Bromocriptine (Parlodel® and generics) ANSM considers that risks outweigh benefits in lactation suppression (25-Jul-2013) Following cardiovascular and neuropsychiatric side-effects, the French Agency re-evaluated risks and benefits for this product in lactation suppression and concluded that it is no longer favourable. While other indications are not impacted, ANSM will now refer this to EMA for a European re-evaluation. A Q&A has been issued for patients.

Link to ANSM Press release (in French)

2.6. Ethinylestradiol/cyproterone acetate (Diane 35® and generics) European Commission makes PRAC recommendations legally binding (25-Jul-2013) Following the majority endorsement by the CMDh (Coordination Group for Mutual Recognition and Decentralised Procedures – Human) in May, the European Commission has now adopted the recommendation of the PRAC. This is a legally binding decision to maintain the marketing authorisation in the treatment of moderate to severe acne with specific measures to minimise the risk of thromboembolism.

Link to EMA Referral Page

ANSM announces that MA suspension will be lifted (02-Aug-2013) The French Agency has issued a statement to announce that the suspension decided in February 2013 and implemented in May despite the PRAC recommendation will be lifted to allow the product back onto the market with agreed restrictions.

Link to ANSM Release (in French)

2.7. Incretin Mimetic Drugs (GLP-1-based therapies) EMA concludes that available data does not confirm pancreas concerns (26-Jul-2013) The EMA has finalised its review of GLP-1-based diabetes therapies, which was initiated in March 2013 after a published study suggested an increased risk of pancreatitis and pancreatic duct metaplasia. The Agency has concluded that available data do not confirm these concerns. All concerned medicines already carry warnings related to the risk of pancreatitis, which the EMA recommends to harmonise. The data available regarding pancreatic cancer is too limited to draw conclusions on the long-term effect of these medicines and several studies are planned or ongoing to address this gap, which will be reflected in the Risk Management Plans of the products concerned. Two large independent studies are also on-going to study the risk profile of diabetes treatments in general, and the first results are expected in the spring of 2014.

Link to EMA Press Release

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2.8. Oral ketoconazole-containing medicines EMA recommends suspension due to risk of liver injury (26-Jul-2013) The review was triggered by the suspension of the medicine in France and showed that the incidence and seriousness of liver injury with oral ketoconazole were higher than with other antifungals. The EMA could not identify measures to adequately reduce this risk while the clinical benefit of oral ketoconazole is uncertain. Considering the availability of alternative antifungal treatments, the EMA concluded that the benefits did not outweigh the risks and recommended that the marketing authorisations of oral ketoconazole-containing medicines should be suspended throughout Europe. Topical formulations of ketoconazole can continue to be used and national authorities may make oral ketoconazole-containing medicines available under controlled conditions for treating patients with Cushing’s syndrome, which is an off-label use.

Link to EMA Press Release

The MHRA has issued a corresponding Press Release.

Link to MHRA Press Release

FDA decides to limit the use due to several safety concerns (26-Jul-2013) The FDA has issued a Drug Safety Communication to announce that Nizoral oral tablets should not be used as a first-line treatment for any fungal infection. The FDA has approved label changes and a new Medication Guide to include a revised warning on the risk of severe liver injuries and adrenal gland problems, and to advise that it can lead to harmful drug interactions.

Link to FDA MedWatch alert

2.9. Metoclopramide-containing medicines EMA recommends changes to reduce the risk of neurological side effects (26-Jul-2013) Metoclopramide-containing medicines have been authorised separately in individual Member States with differing indications such as nausea and vomiting of various causes and gastrointestinal motility disorders. The review was performed at the request of the French Agency (ANSM) and confirmed the well-known risks of neurological effects such as short-term extrapyramidal disorders and tardive dyskinesia, which increase at high doses or with long-term treatment while the risk of acute neurological effects is higher in children. The EMA therefore recommended that metoclopramide should only be prescribed for short-term use (up to five days) in a reduced set of indications, that it should not be used in children below one year of age and only as a second-choice treatment in other children. In addition, the maximum recommended doses in adults and children should be restricted, and higher strength formulations removed from the market.

Link to EMA Press Release

2.10. Mefloquine (Lariam® and generics) FDA warns about risk of serious psychiatric and neurologic side effects (29-Jul-2013) The FDA has issued a Drug Safety Communication to announce strengthened and updated warnings regarding neurologic and psychiatric side effects associated with the antimalarial drug mefloquine hydrochloride. A boxed warning has been added to the label and the Medication Guide has been revised to include that the neurologic side effects may persist or become permanent.

Link to FDA MedWatch alert

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2.11. Acetaminophen (Paracetamol) FDA warns about risk of serious skin reactions, including SJS & TEN (01-Aug-2013) The FDA has issued a Drug Safety Communication to announce that Acetaminophen has been associated with a risk of rare but serious skin reactions, including Stevens - Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and acute generalized exanthematous pustulosis (AGEP), which can be fatal. Other drugs used to treat fever and pain (e.g. NSAIDS) also carry this risk, which is already described in their label.

Link to FDA MedWatch alert

2.12. Fluoroquinolone Antibacterial Drugs FDA warns about risk of permanent nerve damage (15-Aug-2013) The FDA has issued a Drug Safety Communication to announce that it has required the drug labels and Medication Guides for all Fluoroquinolone antibacterial drugs to better describe the serious side effect of peripheral neuropathy, which may be permanent.

Link to FDA MedWatch alert

2.13. Fingolimod (Gilenya®) FDA investigating first PML case reported after Gilenya treatment (29-Aug-2013) The FDA has alerted the public that a patient in Europe diagnosed with possible multiple sclerosis (MS) has developed progressive multifocal leukoencephalopathy (PML) following the administration of Gilenya.

Link to FDA MedWatch alert

3. Quality Assurance, Inspections and Audits

3.1. MHRA 2014 Pharmacovigilance Inspections Symposium announced The MHRA has published preliminary information about the next Pharmacovigilance Inspections Symposium, which will take place on 14-Mar-2014 in London, UK. This event is a popular opportunity to gain a greater understanding of the MHRA Inspectors’ expectations for Pharmacovigilance Systems. Registration will open later in the autumn when further information about the event will be available.

Link to MHRA Event Page

3.2. Austria provides updated advice on Pharmacovigilance Inspections The Austrian Agency has published an updated version of the questionnaire that should be submitted to the Agency prior to the Pharmacovigilance Inspections. The AGES has also issued a Questions & Answers document to address practical points regarding Pharmacovigilance inspections in Austria.

Link to AGES PhV Inspection Page (in German)

Link to AGES FAQ Page (in German)

3.3. Germany updates information on Pharmacovigilance Inspections The German BfArM has published updated information about the performance of Pharmacovigilance Inspections in German. The information available provides some details about the process and the documentation that should be prepared to facilitate the conduct of inspections.

Link to BfArM PhV Inspection Page (in German)

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3.4. EMA issues new PhV Inspections Working Group documents The EMA has published the Annual Report 2012 of the Pharmacovigilance Inspectors Working Group (PhV IWG). The document outlines the activities carried out by the PhV IWG and specifies that 9 inspections were requested in 2012 by the CHMP, in addition to 26 inspections of companies with CAPs that were already considered in National Inspection Programmes. The Annual Report also described the activities of the PhV IWG in various areas, including harmonisation through the production of guidance, training and joint inspections. The EMA has also issued a revised version of the “Mandate, objectives and rules of procedure for the PhV IWG”, which specifies how the group operates in order to promote an effective management of Pharmacovigilance inspections in Europe. Finally, the EMA has issued a revised “Pharmacovigilance Inspection Policy for Centralised Procedures”, which provides the framework for PhV inspections to be requested.

Link to EMA PhV IWG Page

3.5. EMA issues revised SOP for Reporting of GCP Inspections The GCP Inspectors Working Group has issued a revised SOP for the reporting of GCP inspections, which will be used for a 12-month pilot phase. The SOP describes the process for reporting and follow-up, including the production of the “Post-Inspection Preliminary Outcome Report”, and provides links to the associated report templates.

Link to EMA INS-GCP-4 procedure for reporting of GCP inspections

4. Drug Safety and Business Risk

4.1. Takeda and Actos® Lawyer argues that company gave priority to sales over consumer safety The second of about 3,000 lawsuits related to Actos is going to trial in the USA and a lawyer argues that the company knew by 2005 about a link between Actos and cancer, but failed to issue a warning until six years later.

Link to Bloomberg News article

5. Other relevant Information and Resources

5.1. US Food and Drug Administration (FDA)

5.1.1. FDA public meeting discussed Standardisation and Evaluation of REMS As announced prior to the meeting, the FDA held a 2-day workshop to obtain input on issues and challenges associated with the standardization and assessment of risk evaluation and mitigation strategies (REMS), which took place on 25 and 26-Jul-2013. The material from this workshop is now available on the FDA website, including slides and meeting transcripts.

Link to FDA Event Page

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5.1.2. FDA Mini-Sentinel Webinar on Rotavirus Vaccines and Risk of Intussusception On 23-Jul-2013, the Engelberg Center for Health Care Reform at Brookings held a roundtable webinar, “Findings from a Mini-Sentinel Assessment: Rotavirus Vaccines and Risk of Intussusception”. This webinar highlighted a recent study which examined this association, including an overview of study methods, analysis, results and how the FDA responded to the study findings. The audio recording of this webinar has been made publically available.

Link to Brookings Event Page

5.1.3. FDA to hold Mini-Sentinel Webinar on Active Medical Product Surveillance The FDA has announced that a Brookings Roundtable Webinar will take place on 16-Sep-2013 to provide an overview of the design and implementation of FDA's Prospective Routine Observational Monitoring Program Tools (PROMPT). The goal of this Mini-Sentinel pilot program is to examine several new products simultaneously and identify excess risk in relation to health outcomes of interest.

Link to FDA Page

5.1.4. New FAERS Quarterly Data Files available The FDA has now made available for download the files with the extract from the FAERS database (FDA Adverse Event Reporting System) for the period from Sep-2012 to Dec-2012.

Link to FAERS Quarterly Data Files Page

5.1.5. New Public Summary of Drug Safety Oversight Board meeting The public summary for the last meeting of the FDA Drug Safety Oversight Board (DSOB) has been posted. The Board met on 16-May-2013 and heard presentations on the FDA Drug Safety Communication (DSC) Program. It also heard an update on REMS activities, which introduced the discussion of REMS experience.

Link to DSOB Public Summary

5.1.6. Drug Safety and Risk Management Advisory Committee: New material available The Drug Safety and Risk Management Advisory Committee met on 10-Jul-2013 to discuss the risk management of Lotronex (Alosetron hydrochloride), which is approved for the treatment of women with severe diarrhea predominant irritable bowel syndrome. The material of this meeting has now been published, including the slides, transcript and a recording of the webcast.

Link to FDA Page

5.1.7. FDA updates Drug Code Lists The FDA is now updating the National Drug Code Directory on a weekly basis, and it can be downloaded from their website.

Link to National Drug Code Directory Page

The “Drugs@FDA” Downloadable Data Files were last updated on 04-Sep-2013.

Link to Drugs@FDA Page

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5.1.8. New FDA Drug Safety Podcasts The FDA Drug Safety Podcasts provide emerging safety information about drugs in conjunction with the release of Public Health Advisories and other drug safety issues. Both Podcasts and Transcripts are posted on the FDA website and the following communications have been recently added: FDA limits usage of Nizoral (Ketoconazole) oral tablets due to potentially fatal liver

injury and risk of drug interactions and adrenal gland problems FDA approves label changes for antimalarial drug Mefloquine hydrochloride due to

risk of serious psychiatric and nerve side effects FDA warns of rare but serious skin reactions with the pain reliever/fever reducer

Acetaminophen FDA requires label changes to warn of risk for possibly permanent nerve damage

from antibacterial Fluoroquinolone drugs taken by mouth or by injection FDA investigating rare brain infection in patient taking Gilenya (Fingolimod)

Link to FDA Page

5.2. European Medicines Agency (EMA)

5.2.1. EMA issues 2012 EudraVigilance Annual Report The EMA has now published the 2012 EudraVigilance Human annual report, which provides a summary for a range of activities including the development of new functionalities and data analysis. By 31-Dec-2012, the EudraVigilance database held a total of 3,867,243 adverse reaction reports and 2,213 potential safety issues were detected in 2012 (1,586 in 2011), which led to 52 validated signals. Although this is the 3rd Annual Report, it is the first time that this report has been published for submission to the European Parliament, the Council and the European Commission under a provision of the new Pharmacovigilance legislation.

Link to EMA Press Release

Link to 2012 EudraVigilance Human annual report

5.2.2. EMA reviews first year of PRAC operations The PRAC was established under the new Pharmacovigilance legislation in July 2012 for the assessment and monitoring of safety issues for human medicines. Over its first year of operation, the PRAC has made a number of milestone recommendations on the safe and effective use of some widely used medicines. The PRAC’s full range of work includes pre-authorisation activities, such as the assessment of RMPs for medicines under evaluation, as well as post-authorisation activities, such as the evaluation of PSURs and the evaluation of safety signals. In the past year, the PRAC has looked at a total of 92 signals. For 37 of these, the PRAC made recommendation for changes and 8 signals led to referral procedures. The PRAC was also involved in 21 EU referral procedures triggered by Member States or the European Commission. The PRAC involves patient and healthcare representatives and also engaged the general public to contribute in one review of medicine, and the next step will be to open up the discussion on safety issues, which could include public hearings.

Link to EMA Press Release

Safety Observer N°93 – September 2013 page 15/26

5.2.3. EMA issues new Pharmacovigilance Risk Assessment Committee (PRAC) material The EMA routinely makes available the agendas, minutes and highlights of the Pharmacovigilance Risk Assessment Committee (PRAC).

Link to EMA PRAC Page

The minutes of the June PRAC meeting have now been published, which provides a summary of the discussions related to safety signals, RMPs, PSURs, etc. The PRAC has made recommendations regarding Codeine, Diclofenac, Hydroxyethyl-starch-containing solutions, and Flupirtine. The PRAC has also started a new referral procedure for the intravenous nutrition preparations Numeta G13%E and G16%E following reports of hypermagnesaemia in premature babies. The products concerned by new Safety Signals included Adalimumab, Capecitabine, Infliximab, Lenograstim, and Orlistat. The PRAC followed up on previously identified signals for Etanercept, Exenatide & liraglutide, Leflunomide, Pandemic influenza vaccine (H1N1), Somatropin, Tiotropium bromide, Tramadol, and Zolpidem.

Direct link to PRAC Meeting Minutes (10 to 13-Jun-2013)

The agenda and highlights of the July PRAC meeting have been published. Some MAHs of Hydroxyethyl-starch (HES)-containing solutions for infusion have requested the PRAC to re-examine its June 2013 recommendation to suspend these medicines. The implementation of the PRAC’s recommendation has been put on hold and a review procedure requested by the UK will run in parallel with the re-examination of the PRAC recommendation. The PRAC started a new referral procedure for Zolpidem and the risk of next-morning impairment. The review of Combined Hormonal Contraceptives (CHCs) continues and a recommendation from the PRAC is expected in October 2013. A specific webpage has been created which provides key messages regarding the safety of CHCs, together with information on the current and previous review procedures. According to the agenda, new Safety Signals have been identified for the following products: Fondaparinux, Lopinavir/Ritonavir, Sitagliptin, Tamsulosin, Thiopental, and Human papillomavirus vaccines.

Direct link to PRAC Meeting Highlights (08 to 11-Jul-2013)

Direct link to EMA CHC Page

The agenda and highlights of the September PRAC meeting have just been published. The PRAC has recommended restrictions to the use of short-acting beta-agonists in obstetric indications. It also recommended the suspension and reformulation for Numeta G13%E and risk minimisation measures for Numeta G16%E. The PRAC also started a new review procedure for Bromocriptine-containing medicines when used orally for preventing or suppressing lactation. According to the agenda, new Safety Signals have been identified for the following products: Chloroquine & Hydroxychloroquine, Denosumab, Dexmedetomidine, Fingolimod, Interferon beta 1a & 1b, Triamcinolone acetonide, Ustekinumab, and Vemurafenib.

Direct link to PRAC Meeting Highlights (02 to 05-Sep-2013)

Safety Observer N°93 – September 2013 page 16/26

5.2.4. EMA issues new CHMP Monthly Meeting Highlights The highlights for the July meeting of the Committee for Medicinal Products for Human Use (CHMP) have now been published. The CHMP has finalised a review of glucagon-like-peptide-1 (GLP-1)-based diabetes therapies (Incretin Mimetics) and concluded that available data do not confirm recent concerns over an increased pancreatic cancer risk. The Committee also issued recommendations on Ketoconazole-containing medicines for oral use and Metoclopramide-containing medicines. The “Meeting Highlights” are presented in a tabular format, which allows users to view the main opinions adopted at the meeting, including on safety variations and community reviews initiated.

Link to CHMP Meeting Highlights (22 to 25-Jul-2013)

5.2.5. EMA updates list of Black Triangle Products As described in GVP Module X, the EMA is publishing the list of medicines under additional monitoring, which will be identified by a Black Triangle (▼) throughout Europe. First published in April 2013, the list has been updated and now includes 119 products. The list specifies the reason for a product to be subject to additional monitoring and is routinely reviewed by the PRAC. The list now refers to an annex, which identifies all Cyproterone-acetate / Ethinylestradiol-containing products.

Link to EMA Page: Pharmacovigilance / List of Black Triangle Products

5.2.6. EMA provides update on reorganisation The management team has now transitioned to a new organisational structure designed to better support the activities of the Agency. The complete new structure and revised operating processes should be implemented in 2014. Details of the new organisational structure, together with the confirmed leadership team, will be announced in September.

Link to EMA News Release

5.2.7. EMA updates information on submission of medicines information The EMA has published revised versions for several Extended EudraVigilance product report message (XEVMPD) controlled vocabularies, which support compliance with Article 57(2) of new EU Pharmacovigilance legislation whereby MAHs are required to perform electronic submission of medicinal product information. The controlled vocabularies are updated regularly to improve the standardisation of the terminology used. MAHs are however not required to resubmit if medicine information has already been submitted using a previous version of the controlled vocabularies.

Link to EMA Page: Electronic submission of information on medicines

Some important changes the business rules of XEVMPD have also been implemented on 02-Aug-2013, and all operations related to approved substances will be rejected until further notice. The EMA has provided an alternate procedure for these operations.

Link to EMA Announcement

Safety Observer N°93 – September 2013 page 17/26

5.2.8. EMA interactions with Patients’ and Healthcare Professionals’ Organisations As announced earlier, the EMA has now established a formal Healthcare Professionals’ Working Party (HCPWP). The minutes of meeting of 05 & 06-Jun-2013 have now been published, which focused on the establishment of the HCPWP, including the mandate and rules of procedures, roles and responsibilities.

Link to EMA Meeting Page

The EMA has published material of the meeting of the Working Party with Patients' and Consumers' Organisations (PCWP) that took place on 06-Jun-2013. The agenda included a presentation about the workshop on the management of safety data from Patient Support Programmes (PSPs) and Market Research Programmes (MRPs).

Link to PCWP Meeting Page

The EMA has published the minutes and presentations of the joint meeting of the Working Party with Patients’ and Consumers’ Organisations (PCWP) and the Healthcare Professionals’ Working Party (HCPWP), which took place on 05-Jun-2013. In the area of Pharmacovigilance, the topics discussed included the Agency workshop on medication errors, benefit-risk-assessment visualisation tools and the communication strategy on additional monitoring.

Link to EMA Meeting Page

5.3. UK Agency (MHRA)

5.3.1. New issues of MHRA “Drug Safety Update” Bulletin The July issue of Drug Safety Update (Volume 6, Issue 12, July 2013) was published on 11-Jul-2013. It includes the following topics: Codeine for analgesia: restricted use in children due to morphine toxicity Retigabine (Trobalt): restrictions and new monitoring requirements after reports of

pigment changes in ocular tissue, skin, lips, or nails Ondansetron I.V.: new posology due to dose-dependent QT interval prolongation

Link to MHRA Newsletter (pdf)

The latest issue of Drug Safety Update (Volume 7, Issue 1, August 2013) was published on 07-Aug-2013. It includes the following topics: Intravenous iron: serious hypersensitivity reactions Nitrofurantoin: precautions for use, especially renal impairment in (elderly) patients Oral Ketoconazole: do not prescribe or use for fungal infections - risk of liver injury Metoclopramide: restrictions due to risk of neurological adverse effects

Drug Safety Update is available as a fully searchable online resource.

Link to MHRA Newsletter Page

5.3.2. MHRA issues Pharmacovigilance Expert Advisory Group summary minutes The MHRA has published the summary minutes for the June meeting of the Pharmacovigilance Expert Advisory Group. The topics discussed: The role of Paracetamol in the management of pain in mild osteoarthritis Managing oral Diclofenac as a pharmacy medicine

Link to Summary Minutes

Safety Observer N°93 – September 2013 page 18/26

5.3.3. MHRA Dear Doctor Letters The letters sent to Healthcare Professionals are routinely posted on the Agency’s website. The letters from July are related to the following safety information: Numeta nutrition preparation: Risk of hypermagnesaemia Zofran (ondansetron): Change in dose to avoid QT interval prolongation Durogesic DTrans transdermal patch (fentanyl): Warning of serotonin syndrome

when product received with serotonergic drugs Votrient (pazopanib): Change to liver test monitoring for hepatotoxicity

Link to MHRA Page (July)

The letters from August are related to the following safety information: Diclofenac: contraindicated in patients with established congestive heart failure,

ischaemic heart disease, peripheral arterial disease or cerebrovascular disease Neupogen (filgrastim) and Neulasta (pegfilgrastim): risk of capillary leak syndrome

Link to MHRA Page (August)

5.4. French Agency (ANSM)

5.4.1. ANSM 2012 Annual Report The ANSM has issued its 2012 Annual Report, which provides a number of metrics: 9 in-depth pharmacovigilance inspections (17 in 2011) including 1 inspection

conducted in a foreign country and 1 inspection leading to regulatory action Over 38,000 adverse reactions received through Regional Centers of

Pharmacovigilance (CRPV) (over 36,000 in 2011) Over 23,900 notifications of serious adverse reactions (initial and follow up)

received from pharmaceutical companies (over 23,000 notifications in 2011) 20.5 % of notifications from EU in Eudravigilance are French (French people

represents 13% of the European population) 67 RMP reviewed with 32 initial RMP and 35 RMP updates (62 in 2011) 49 protocols/reports of epidemiological studies reviewed (included in a RMP or in

addition to a European RMP) (46 in 2011) 110 national re-evaluations in the last two years with 11 MA suspensions, 24

unfavorable advices transmitted for European referral.

Link to ANSM Annual Report (in French)

5.4.2. New Issue of the French Bulletin " Vigilances" The new French " Vigilances" Bulletin, Number 58, has now been issued. The bulletin includes a description of the " solicited notifications" of pulmonary hypertension associated with Dasatinib and a summary on the risks of overdose with Colchicine. The main safety issues from recent Press Releases and Dear Doctors Letters are summarized. It also includes information on ADR notifications received during the first quarter of 2013 by the regional centers of pharmacovigilance (CRPV): 74% are from Physicians, 17% from Pharmacists, 5% from patients and 64% of them are serious.

Link to Bulletin (in French)

Safety Observer N°93 – September 2013 page 19/26

5.4.3. ANSM Dear Doctor Letters Dear Doctor Letters sent in July and August 2013 are now available on the French Agency' s website (all in French). Letter due to safety concerns include the following: Diclofenac (Voltarene® and generics): new contra-indications Bevacizumab (Avastin®): risks of necroziting fasciitis Almitrine (Vectarion®): MA withdrawn for unfavourable risk /benefit Mefloquine (Lariam®): update of the safety profile with neurologic effects Lenalidomide (Revlimid®): new indication and risk minimisation measures Tetrazepam (Myolastan®): MA suspension Retigabine (Trobalt®): restrictions of use due to pigmentation

Link to ANSM Webpage

5.4.4. ANSM provides update on PRAC and CHMP activities Following the issuance of PRAC minutes, ANSM issued a document in French which summarises the discussions and decisions taken by the PRAC, together with ANSM positions and recommendations for the Healthcare Professionals.

Link to ANSM synthesis for the PRAC meeting of July 2103 (in French)

In the same way, ANSM issued a summary of the discussions and decisions taken by the CHMP on Metoclopramide, oral Ketoconazole and incretin mimetic drugs.

Link to ANSM synthesis for the CHMP meeting of July 2103 (in French)

5.4.5. ANSM issues syntheses on the safe use of various products ANSM has issued the following two syntheses:

Link to ANSM Synthesis on Coxibs

Link to ANSM Synthesis on NSAIs

5.4.6. ANSM to finance selected safety projects ANSM has issued the list of the projects chosen after a call for research projects launched in January 2013. 17 projects (all from public research organizations or foundations) were selected with a total financial commitment of 5.7 million Euros. The projects will start in 2014 and cover various themes including " strengthening monitoring of health products" , " off-label use analysis and risks" and " risk/benefit in specific populations" .

Link to ANSM Press Release (in French)

5.4.7. France revises thesaurus of Drug Interactions (31-Jul-2013) The ANSM has issued an updated and consolidated version of the Thesaurus. A document showing the differences with the previous version from December 2012 is also available.

Link to ANSM Webpage (in French)

Safety Observer N°93 – September 2013 page 20/26

5.4.8. Commissions / Committees in relation with Pharmacovigilance The Commission for the initial benefit-risk assessment of new products had meetings on 30-Apr-2013, 16-May-2013 and 28-May-2013 and the minutes are now available. 30-Apr-2013: Opinion was given on Bromocriptine: negative R/B ratio in its

indications of lactation inhibition / prevention 16-May-2013: The commission recommends the setup of a national RMP, in

addition to the European RMP for Nalmefene (Selincro®) 28-May-2013: Opinion was given on Carpipramine (Prazinil®): negative R/B ratio

Link to Minutes of the Commission – 30-Apr-2013 (in French)

Link to Minutes of the Commission – 16-May-2013 (in French)

Link to Minutes of the Commission – 28-May-2013 (in French)

The Pharmacovigilance Committee issued minutes of the meetings on 18-Mar-2013, 16-Apr-2013 and 21-May-2013. The discussion concerned the following products: 18-Mar-2013: Paracetamol/Opium, Prasugrel, COLOKIT® 16-Apr-2013: Paracetamol/Opium, Nefopam, Fentanyl, Baclofene 21-May-2013: Curare, Misoprostol, Atazanavir, Vit D

Link to the minutes of the Committee – 18-Mar-2013 (in French)

Link to the minutes of the Committee – 16-Apr-2013 (in French)

Link to the minutes of the Committee – 21-May-2013 (in French)

The Committee in charge of the interfaces with the Industry issued the minutes of its meeting of 20-Jun-2013. The results of a survey performed by the LEEM (the French organisation of pharmaceutical industries) were presented, which covered the regulatory and scientific activities of ANSM (number of submissions, timelines, etc.). 625 Safety Variations were submitted since January 2012, and only 4% have been processed with a 220-day median time.

Link to the minutes of the Committee – 21-Jun-2013 (in French)

5.5. Other Sources

5.5.1. UMC Research Team refines automatic screening of data The Uppsala Monitoring Centre (UMC) has published an article describing a recent project to establish a new way of unmasking information that can otherwise remain hidden in enormous data-sets. This new algorithm excludes outlier reports that can distort analysis and mask other possible problems of interest.

Link to UMC Release

5.5.2. Study finds no link between faster drug approvals and safety issues A new research published by the Canadian Health Policy Institute concluded that there is no link between faster drug approvals and regulatory safety warnings and drug withdrawals in Canada and the USA.

Link to PharmaLive article

Safety Observer N°93 – September 2013 page 21/26

5.5.3. ICH announces Launch of New MedDRA Website The new MedDRA website introduces a new visual identity for MedDRA, with a logo that reflects the global harmonisation which MedDRA supports. The new site replaces the former MedDRA MSSO website and includes all MedDRA files and documentation, and new automated features for subscriptions and event registration (e.g. training).

Link to ICH News Release

Link to MedDRA Website

5.5.4. ENCePP issues survey results on EU Member States requirements for data protection ENCePP (European Network of Centres for Pharmacoepidemiology and Pharmacovigilance) has published the results of a survey conducted among EU Member States on national requirements on data privacy in the conduct of pharmacoepidemiology research. Responses were received from 13 European Union Member States and the compiled responses are published as they were submitted in full, including links to additional resources.

Link to ENCePP Survey Report

5.5.5. ENCePP meets with Pharmaceutical Industry A meeting between industry associations and ENCePP (European Network of Centres for Pharmacoepidemiology and Pharmacovigilance) took place on 22-May-2013, and the corresponding report is now available. The objective of the meeting was to stimulate further collaboration between ENCePP and the industry in the conduct of robust post-authorisation studies in a transparent and scientifically independent manner. A specific proposal to be further considered was for the formation of a joint ENCePP-industry working group. The meeting report includes links to the presentation material used at the meeting.

Link to Meeting Report

5.5.6. IMI launches new Call for Proposals As announced previously through its Newsletter, IMI (Innovative Medicines Initiative) has now officially launched its 9th Call for Proposals. One of the topics is “WEBAE – Leveraging emerging technologies for Pharmacovigilance”. The deadline for submitting Expressions of Interest is 09-Oct-2013.

Link to IMI Page

5.5.7. New issues of PRM Newsletter Two new issues of the PharmacoEpi and Risk Management (PRM) Newsletter, which has been created by the MAPI Research Trust have now been published. The July issue includes an article on the new European requirements for safety reporting in post-authorisation non-interventional studies (NIS).

Link to PRM Newsletter N°15 (July 2013)

The August issue includes articles on the progress of the new EU Pharmacovigilance Legislation and the new PASS requirements, and a review of Regulatory Requirements for Benefit-Risk Assessment.

Link to PRM Newsletter N°16 (August 2013)

Safety Observer N°93 – September 2013 page 22/26

5.5.8. New issue of WHO Pharmaceuticals Newsletter The last edition of the WHO Pharmaceuticals Newsletter (N°3, 2013) is now available. Prepared in collaboration with the Uppsala Monitoring Center, it includes a section on Regulatory Matters and Safety of Medicines. The newsletter also includes signals based on the information available in the WHO Global database VigiBase and responses from MAHs: Fluoxetine and Deafness.

Link to WHO Pharmaceuticals Newsletter (N°3, 2013)

The newsletter N°4, 2013 has also been published, which includes a summary of discussions from the tenth meeting of the WHO Advisory Committee on Safety of Medicinal Products (ACSoMP). The following signals are presented: Agomelatine and QT prolonged, and Response from Servier Tapentadol and Aggressive reaction, and Response from Grünenthal and Janssen.

Link to WHO Pharmaceuticals Newsletter (N°4, 2013)

5.5.9. Health Canada provides updated Adverse Reaction Online Database The Canada Vigilance Adverse Reaction Online Database contains information about suspected adverse reactions reports submitted to Health Canada. The accessible database now includes data from 1965 to 31-Mar-2013.

Link to Health Canada Page

5.5.10. UMC Newsletter The Uppsala Monitoring Center has published its Newsletter Issue N°3, September 2013. It highlights the release of the September 2013 version of the WHO Drug Dictionaries and of the version 2.0 of the WHO Drug Dictionaries Best Practices. It also calls for users to join one of the existing Working Groups and provides the schedule of webinars for the User Group Community.

Link to UMC Newsletter

5.5.11. New issue of Uppsala Reports Uppsala Reports 62 – July 2013 is now available. It provides a report from the 10th meeting of the WHO Advisory Committee on Safety of Medicinal Products (ACSoMP). It also highlights the introduction of electronic reporting forms in Kenya and provides an overview of VigiLyze, the powerful tool designed to search and analyse VigiBase.

Link to Uppsala Reports

5.5.12. New issue of Australian “Medicine Safety Update” The new edition of Medicines Safety Update (Volume 4, Number 4, August 2013) is now available. The contents include: Vancomycin and nephrotoxicity Dapagliflozin - new chemical entity Dexmedetomidine hydrochloride and cardiovascular events Bevacizumab and necrotising fasciitis

Link to Medicines Safety Update

Safety Observer N°93 – September 2013 page 23/26

5.5.13. New issue of IMB Drug Safety Newsletter The last edition of the Ireland Medicine Board Drug Safety Newsletter (Issue N°55) was made available on 15-Jul-2013. The contents include: Diclofenac: same cardiovascular precautions as for selective COX-2 inhibitors Codeine: restricted use as an analgesic in children and adolescents Dianette (cyproterone acetate /ethinylestradiol): New risk minimisation measures to

prevent thromboembolism Lariam (mefloquine): updated product information and new guidelines Hydroxyethylstarch (HES) Infusion Solutions: PRAC recommends suspension

Link to Newsletter

5.5.14. New issue of Japanese PMDSI Newsletter The Pharmaceuticals and Medical Devices Safety Information (PMDSI) Newsletter is issued based on safety information collected by the Japanese Ministry of Health, Labour and Welfare (MHLW) and is intended to promote safer use of pharmaceuticals and medical devices by healthcare providers. The English Summaries of the latest editions of the Newsletter (Issue N°303 & 304) are now available and include: Tolvaptan and Hepatic Dysfunction Revision of Precautions: Loxoprophen sodium hydrate (oral), Paliperidone Important Safety Information and Products Subject to Early Post-marketing Vigilance

Link to PMDA Page

5.5.15. Japanese PMDA provides updated list of drugs under review The Pharmaceuticals and Medical Devices Agency (PMDA) has updated its webpage where it provides information on drug risks under review by the PMDA/MHLW, which can be based on safety information submitted to the Japanese Agency or due to communication from foreign drug agencies.

Link to PMDA Page

6. Time to Register

Barnett Events Webinar – Drug Safety and Pharmacovigilance

September 11, 01:OO PM to 02:30 PM Eastern Adverse Events: Managing and Reporting for Pharmaceuticals

September 11 – 12 in San Diego CA, USA Webinar – Quality Risk Management in Clinical Trials and Pharmacovigilance

October 08, 09:OO AM to 10:30 AM Eastern Webinar – Introduction to Signal Detection and Data Mining

October 09, 01:OO PM to 02:30 PM Eastern Pharmacovigilance in Europe

October 16 – 17 in Philadelphia PA, USA Webinar – Adverse Event Monitoring for CRAs

October 25, 12:OO PM to 02:00 PM Eastern Webinar – Final FDA Guidance: Reporting of Safety Information from Clinical Trials to IRBs

November 04, 12:0O PM to 01:30 PM Eastern Webinar – The European Pharmacovigilance Legislation

November 05, 01:OO PM to 02:30 PM Eastern Signal Detection and Pharmacovigilance

November 07 in Philadelphia PA, USA

Safety Observer N°93 – September 2013 page 24/26

EMA/DIA Events EudraVigilance and Electronic Reporting of ICSRs in the EEA

3 day-training course (see schedule for venues and dates) Extended EudraVigilance Medicinal Product Dictionary (XEVMPD) Training Course

2 day-training course (see schedule for venues and dates) Introduction to Pharmacovigilance and Electronic Transmission of ICSRs

October 08 in London, UK 1st Information Day on the use of MedDRA including Medication Errors

October 22 in London, UK Introduction to Pharmacovigilance and Electronic Transmission of ICSRs

November 12 in London, UK Excellence in Pharmacovigilance: Clinical Trials and Post-Marketing

November 18 – 22 in London, UK

DIA Events Webinar: Safety and Social Media – Is this The Question or The Answer?

September 12, 11:00AM - 12:30PM Webinar: Risk Management of Medicinal Products: REMS and RMP - Need for Harmonization?

September 18, 10:00AM - 11:30AM Diagnosis and Management of Drug-Induced Liver Injury (DILI)

September 19 – 20 in Paris, France ICH Endorsed Pharmacovigilance

September 22 – 23 in Muscat, Oman Online Training Course : Introduction to Signal Detection and Data Mining

September 24 – October 03, 12:00PM - 1:30PM 10th Middle East Regulatory Conference (MERC) 2013

September 24 – 25 in Muscat, Oman Benefit / Risk Management

September 26 – 27 in Prague, Czech Republic 7th DIA Annual Clinical Forum

October 08 – 09 in Dublin, Ireland Drug-Induced Injury of Liver, Heart, Kidney, and Skin

October 15 – 17 in North Bethesda MD, USA Postmarketing Drug Safety & Pharmacovigilance

October 21 – 22 in Horsham PA, USA Signal Detection and Data Mining

October 22 – 24 in Beijing, China DIA’s Annual Canadian Meeting

October 29 – 30 in Ottawa, Canada Webinar: CDER Town Meeting: Safety Hot Topics

October 30, 2:30PM - 4:00PM EDT Risk Management and Safety Communication Strategies

November 04 – 05 in Horsham PA, USA

Signal Management in Pharmacovigilance November 06 – 07 in Paris, France

10th DIA Japan Annual Meeting November 06 – 08 in Tokyo, Japan

How to Prepare for Pharmacovigilance Audits and Inspections November 07 – 08 in Paris, France

Global AE Reporting: Drug Safety Requirements in the US and EU November 12 in Bethesda MD, USA

ICH Endorsed Pharmacovigilance November 28 – 29 in Zagreb, Croatia

Safety Observer N°93 – September 2013 page 25/26

DSRU Events Critical Appraisal of Medical and Scientific Papers: How to read between the lines

October 09 – 10 in Fareham, UK Risk Benefit Assessment in Pharmacovigilance

October 16 – 17 in Fareham, UK Case Narrative Writing for Reporting Adverse Events

October 30 – 31 in Winchester, UK Pharmacovigilance in Products Subject to Licensing Agreements

November 13 – 14 in London, UK Pharmacovigilance Planning and Risk Management

November 27 – 28 in Fareham, UK

Other Events TOPRA/ISOP – Practical Application of Benefit-Risk Assessment

September 23 in Brussels, Belgium PTI – Signal Detection Strategies

September 25 – 26 in London, UK PIPA Forum: PV & QPPV for Small and Medium Sized Companies

September 26 in London, UK IFIS – Medical writing for drug safety

September 26 – 27, and October 11 in Paris, France RQA – Good Vigilance Practice

September 30 – October 02 in Cambridge, UK Management Forum – Advanced Pharmacovigilance

September 30 – October 02 in London, UK ISOP – 2013 Annual Meeting

October 01 – 04 in Pisa, Italy PTI – Intermediate Pharmacovigilance and Adverse Event Reporting

October 10 – 11 in London, UK Management Forum – New Pharmacovigilance legislation – The Complete Picture

October 14 – 15 in London, UK IFIS – Pharmacovigilance: roles, missions and responsibilities (event in French)

October 21 – 22, November 15 in Paris, France ISPE – 8th Asian Conference on Pharmacoepidemiology

October 25 – 27 in Hong Kong Management Forum – PSURs/PBRERs

October 31 in London, UK RQA – New EU PV Legislation Challenges with Implications

November 06 in Solihull, UK RQA – Safety Reporting in Clinical Trials

November 06 in Solihull, UK Informa – 7th Annual Pharmacovigilance and Risk Management

November 06 – 07 in Berlin, Germany IFIS – Risk Management Plan (event in French)

November 21 in Paris, France IFIS – Clinical Trials Safety (event in French)

November 22 in Paris, France RQA – Practical Pharmacovigilance Auditing

November 25 – 27 in Cambridge, UK IFIS –Writing periodic reports in Drug safety

November 28 – 29 in Paris, France Management Forum – Latest developments in Pharmacovigilance

November 28 – 29 in London, UK

Safety Observer N°93 – September 2013 page 26/26

7. About the Authors

SUNNIKAN Consulting is offering a wide range of services related to Risk, Quality and Process Management Systems for Pharmaceutical Industry since 1996. SUNNIKAN Consulting’s areas of expertise cover Clinical Research, Regulatory Affairs, Pharmacovigilance, Computerized Systems, and more. For more information please visit SUNNIKAN Consulting’s website at: www.sunnikan.com

PV Focus is a small specialty company established since December 2004. Based in France, PV Focus has successfully centered its business on the provision of Pharmacovigilance Audits and related services to the Pharmaceutical Industry. Due to its experience of both Audits and Regulatory Inspections at a global level, PV Focus is a partner of choice to assist with the performance of Pharmacovigilance System Audits and can also support the preparation of Regulatory Inspections. For more information please visit www.pvfocus.com

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