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Safety Observer Issue N°126 - September 2016

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Clinical Safety & Pharmacovigilance Regulatory Intelligence Review

Issue N°126 - September 2016

HIGHLIGHTS

CIOMS has announced the publication of two new documents, including the Second Edition of their guidebook on Standardised MedDRA Queries (SMQs) and the Report of CIOMS Working Group X on Safety Meta-Analyses.

The FDA has published the final guidance documents related to the use of PBRER (Periodic Benefit Risk Evaluation Report), including both the ICH E2C(R2) guideline and the associated Questions and Answers document.

The EMA has published new final GVP documents, including the revised GVP Module VIII on Post-Authorisation Safety Studies (PASS) and its associated addendum. The final version of the Product-specific considerations guidelines for Biological medicinal products has also been released.

Other GVP documents have been published for comments by the EMA, including the draft of a major revision for GVP Module IX on Signal Management. A draft revision of the GVP Module VI on Management and Reporting of ICSRs has also been released, which sets the scene for the new EudraVigilance System and ICH-E2B(R3).

The EMA has also released for consultation a concept paper that outlines proposed changes to current guidance on first-in-human clinical trials in order to better identify and mitigate risks to trial participants, which takes into account the lessons learnt from the tragic death of a patient in January 2016 during a Phase I trial in France.

New material has been published in relation to inspections, including a new injunction by the French Agency following an inspection of Septodont. The MHRA has published new Pharmacovigilance inspection metrics and announced that it no longer requires compliance reports to be submitted routinely.

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IN THIS ISSUE

1. Regulations, Guidelines and Other Standards ...................................................................................................... 3

1.1 Newly Applicable Standards .............................................................................................................................. 3 1.1.1 ENCePP updates Guidance for pharmacoepidemiology studies ............................................................... 3 1.1.2 France updates and simplifies PV regulatory framework .......................................................................... 3 1.1.3 FDA issues ICH E2C(R2) PBRER guidance documents ................................................................................ 3 1.1.4 New release of the EU PSUR Repository now in production ...................................................................... 3 1.1.5 ENCePP issues updated information on the EU PAS Register ................................................................... 3 1.1.6 EMA issues revised GVP Module VIII and addendum I on PASS .................................................................. 4 1.1.7 EMA issues final Biologicals-specific GVP guidance ................................................................................... 4 1.1.8 EMA issues corrected Questions and Answers on Signal Management ..................................................... 4 1.1.9 CIOMS issues new Drug Safety guidance documents ................................................................................ 5 1.1.10 English MedDRA Version 19.1 now available .............................................................................................. 5 1.1.11 EMA releases new Important Medical Event Terms list .............................................................................. 5

1.2 Developments to Watch ..................................................................................................................................... 5 1.2.1 FDA issues draft guidance on updating Labeling for generics with no RLD .............................................. 5 1.2.2 ICH M4E(R2) on Benefit-Risk information enters implementation period ................................................ 6 1.2.3 Update from MedDRA June 2016 Meetings in Lisbon, Portugal ................................................................ 6 1.2.4 EMA consults on Proposals for first-in-human clinical trials ..................................................................... 6 1.2.5 Update on ICH E2B(R3) on Transmission of ICSRs ..................................................................................... 6 1.2.6 EMA issues draft revision of GVP Module IX on Signal Management ......................................................... 6 1.2.7 EMA issues draft revision of GVP Module VI on Management of ICSRs ...................................................... 7 1.2.8 EMA updates information on ISO IDMP implementation ........................................................................... 7 1.2.9 EMA updates documents on implementation of the new EudraVigilance ................................................ 8 1.2.10 US and Canada invite joint Public Meeting to prepare next ICH discussions ............................................ 8

1.3 Beyond the Scope of Safety Observer ............................................................................................................... 8 1.4 The Safety Observer Tracker ............................................................................................................................. 9

2. Product Safety Announcements ............................................................................................................................ 9

2.1 Meningitec (Meningitis C vaccine) ..................................................................................................................... 9 2.2 Idelalisib (Zydelig) .............................................................................................................................................. 9 2.3 Fluoroquinolone antibiotics ............................................................................................................................ 10 2.4 Opioid Medicines combined with Benzodiazepines ....................................................................................... 10

3. Dear Doctor Letters and Safety Newsletters ....................................................................................................... 10

4. Other Publications by Regulatory Agencies ........................................................................................................ 12

4.1 US Food and Drug Administration (FDA) ......................................................................................................... 12 4.2 European Medicines Agency (EMA) .................................................................................................................. 13 4.3 UK Agency (MHRA) ........................................................................................................................................... 17 4.4 French Agency (ANSM) ..................................................................................................................................... 17

5. Quality Assurance, Inspections and Audits ......................................................................................................... 18

6. Drug Safety and Liability Risk .............................................................................................................................. 19

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1. REGULATIONS, GUIDELINES AND OTHER STANDARDS

1.1 Newly Applicable Standards

1.1.1 ENCePP updates Guidance for pharmacoepidemiology studies (12-Jul-2016) The European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP) has issued the fifth revision of its guide on methodological standards in Pharmacoepidemiology. This guide was first issued in June 2011 and is updated annually to ensure that all developments in the field are incorporated. This latest version also includes a new chapter on using data from social media and electronic devices. ENCePP has also issued a revision of its Checklist for Study Protocols.

→ Link to ENCePP News Page

1.1.2 France updates and simplifies PV regulatory framework (15-Jul-2016) The order 2016-966 dated 15-Jul-2016 modifies ANSM procedures. French GVPs will now be published following a decision of ANSM, as opposed to a ministerial order previously. Another measure is that drug advertisement is not allowed if a Risk/Benefit reevaluation is ongoing.

→ Link to order 2016-966 (in French)

1.1.3 FDA issues ICH E2C(R2) PBRER guidance documents (19-Jul-2016) The FDA has now issued the final guidance documents related to the use of PBRER (Periodic Benefit Risk Evaluation Report), including both the ICH E2C(R2) guideline and the associated Questions and Answers document. The FDA had initially published the ICH PBRER guideline for consultation in April and May 2012 whereas the associated Questions and Answers document was released by ICH in April 2014.

As a reminder, the FDA released for consultation another guidance in April 2013, which was entitled “Providing Postmarket Periodic Safety Reports in the ICH E2C(R2) Format (Periodic Benefit-Risk Evaluation Report)”. The purpose of this guidance is to specify the conditions under which FDA will permit applicants to submit an ICH E2C(R2) PBRER to satisfy FDA requirements. This document is however still in draft at this point.

→ Link to Federal Register Notice → Link to FDA E2C(R2) PBRER Guidance → Link to FDA E2C(R2) Q&As

1.1.4 New release of the EU PSUR Repository now in production (25-Jul-2016) As communicated previously, the use of the EU PSUR Repository has become mandatory for all authorised medicines on 13-Jun-2016 and MAHs should no longer submit their PSURs to National Competent Authorities.

An updated version of the PSUR Repository was released on 25-Jul-2016 and the guidance available has been revised accordingly, including the PSUR Repository User Guidance documents for both MAHs and NCAs. Release Notes and a multimedia webinar are available to provide information on the new functionalities. A new version of the “Mandatory use Q&As” has also been published.

→ Link to PSUR Repository Page

1.1.5 ENCePP issues updated information on the EU PAS Register (02-Aug-2016) The European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP) has published new information regarding the EU Register of Post-Authorisation Studies (EU PAS Register), which is required to be used for both non-interventional post-authorisation safety studies (PASS) and post-authorisation efficacy studies (PAES).

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The newly released information includes a short presentation of the changes brought by the EU PAS Register upgrade of July 2016, which include a new data field for the RMP study category. A revised version of the “Frequently Asked Questions” and a new EU PAS Register Guide have also been published.

→ Link to EU PAS Register Page

1.1.6 EMA issues revised GVP Module VIII and addendum I on PASS (08-Aug-2016) The EMA has now published the revised GVP Module VIII on Post-Authorisation Safety Studies (PASS - Rev. 2), together with the associated addendum I entitled: “Requirements and recommendations for the submission of information on non-interventional Post-Authorisation Safety Studies” (Rev. 2). The corresponding draft documents were subject of a public consultation between August and October 2015.

The changes to Module VIII include clarifications on the link between the legislation on non-interventional PASS and categories 1-3 of non-interventional PASS described in GVP Module V on Risk Management Systems. In line with GVP Module VI Rev. 1, new text has been added to cover adverse events that will not be collected or reported. Some aspects have been transferred to Addendum I, which covers the registration in the EU PAS Register and the notification of study information to the Agency (substantial amendments to PASS protocols, progress reports and final reports).

In addition to the final documents, the comments received during the consultation and the versions with tracked changes are also available in the GVP Development section of the EMA website.

→ Link to EMA GVP Page → Link to draft GVP Module VIII (Rev. 2) → Link to draft GVP Module VIII Addendum I (Rev. 2) → Link to EMA GVP Development Page

1.1.7 EMA issues final Biologicals-specific GVP guidance (15-Aug-2016) The EMA has now published the final version of the Product-specific considerations guidelines for Biological medicinal products, which complements the GVP Modules for those active substances produced by or extracted from a biological source. This includes so-called “biosimilars” but the document does not apply to vaccines and advanced therapy medicinal products (ATMPs), which are covered by separate guidance. The corresponding draft document was under consultation between December 2015 and February 2016.

This Product-Specific Considerations Chapter brings additional guidance to other GVP Modules to ensure that specific challenges associated to biologicals are addressed, including immunogenicity, manufacturing variability, stability and product traceability. With due consideration for these challenges, the document provides guidance for various Pharmacovigilance activities, including ICSR Management, Risk Management, Periodic Safety Reporting, Signal Management and Safety Communication.

In addition to the final document, the comments received during the consultation and the version with tracked changes are also available in the GVP Development section of the EMA website.

→ Link to EMA News Release → Link to EMA GVP Page → Link to Biologicals-specific GVP Guideline → Link to EMA GVP Development Page

1.1.8 EMA issues corrected Questions and Answers on Signal Management (24-Aug-2016) The EMA has released a corrected version of its Questions & Answers Document on Signal Management, which includes minor procedural clarifications for a few questions, as detailed within the document.

→ Link to EMA Signal Management Page → Direct link to Q&As on Signal Management

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1.1.9 CIOMS issues new Drug Safety guidance documents (30-Aug-2016) The Council for International Organizations of Medical Sciences (CIOMS) has announced the publication of two new documents in their library of documents now available for purchase.

This includes the Second Edition of “Development and Rational Use of Standardised MedDRA Queries (SMQs): Retrieving Adverse Drug Reactions with MedDRA”, which covers the purpose and appropriate use of SMQs in safety surveillance activities.

The Report of CIOMS Working Group X has also been published, which covers “Evidence Synthesis and Meta-Analysis for Drug Safety”. It describes the rationale for meta-analyses and provides guidance on their conduct in the context of regulatory decision-making.

CIOMS is announcing that a new Guide for Active Vaccine Safety Surveillance is due to be released shortly.

→ Link to CIOMS Announcement

1.1.10 English MedDRA Version 19.1 now available (01-Sep-2016) The English release of MedDRA Version 19.1 is now available to subscribers. The two “Points to Consider” (PTC) documents have also been updated to address MedDRA Term Selection (MTS:PTC) and MedDRA Data Retrieval and Presentation (DRP:PTC), together with the redlined copies that identify all changes. The MTS:PTC document includes a new concept description and examples for intercepted medication errors, as well as revised concept descriptions for misuse, abuse, addiction, and off label use.

Additional MedDRA Guides are available on the MedDRA website, including Introductory Guides and a presentation of the changes introduced with Version 19.1.

→ Link to MedDRA release announcement → Link to MedDRA Page

1.1.11 EMA releases new Important Medical Event Terms list (05-Sep-2016) The EudraVigilance Expert Working Group (EV-EWG) coordinates the development of the Important Medical Event Terms (IME) list, which purpose is to facilitate the classification of suspected adverse reactions as well as aggregated data analysis and case assessment. The IME list was first made available in 2009 for guidance purposes only and a new update is released with each new version of the MedDRA dictionary.

The new version of the IME list has been published, which is based on MedDRA version 19.1. In addition, the EMA has published a document describing the inclusion/exclusion criteria for terms in the list, which are based on the official ICH definition of seriousness and of an “important medical event”.

Please note that the public pages of the EudraVigilance website have been decommissioned and the information has been transferred on the EMA corporate website, including the IME list.

→ Link to EMA EudraVigilance Overview Page → Direct link to IME list → Direct link to inclusion/exclusion criteria

1.2 Developments to Watch

1.2.1 FDA issues draft guidance on updating Labeling for generics with no RLD (11-Jul-2016) The FDA has issued a new draft guidance entitled “Updating ANDA Labeling After the Marketing Application for the Reference Listed Drug Has Been Withdrawn”, which describes the process for updating labeling for abbreviated new drug applications (ANDAs) in the specific cases where the approval of the reference listed drug (RLD) has been withdrawn. Comments on the draft guidance are expected by 09-Sep-2016.

→ Link to Federal Register Notice → Link to FDA Draft Guidance

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1.2.2 ICH M4E(R2) on Benefit-Risk information enters implementation period (14-Jul-2016) The International Council for Harmonisation (ICH) has announced that the revised version of the ICH M4E Guideline on “Enhancing the Format and Structure of Benefit-Risk Information in ICH” has reached Step 4 of the ICH Process in June 2016 and entered the implementation period (Step 5). This new version of the guideline includes greater specificity on the format and structure of benefit-risk information, harmonising the presentation of this information in regulatory submissions through the Common Technical Document (CTD). It is intended to better support regulatory decision-making through a more consistent description of information coming from clinical trial data, as well as other factors such as disease severity and availability of other treatment options.

→ Link to ICH News Release → Link to ICH M4E(R2) guideline

1.2.3 Update from MedDRA June 2016 Meetings in Lisbon, Portugal (20-Jul-2016) As reported in our previous issue, the International Council for Harmonisation (ICH) met in Lisbon, Portugal, from 11 to 16-Jun-2016. The MedDRA Management Board also met in Lisbon on 11 and 12-Jun-2016, where it awarded a new 7-year contract to Northrop Grumman for the MedDRA Maintenance and Support Services Organization (MSSO), which followed the call for tender launched by ICH in August 2014.

The ICH M1 Points to Consider (PtC) Working Group discussed the development of condensed versions of the PtC documents for translation into all MedDRA languages in complement to the full versions available in English and Japanese to support the implementation and use of MedDRA worldwide.

The next rounds of ICH meetings will be held from 05 to 10-Nov-2016 in Osaka, Japan.

→ Link to MedDRA Press Release

1.2.4 EMA consults on Proposals for first-in-human clinical trials (21-Jul-2016) The EMA has released for consultation a concept paper that outlines proposed changes to current guidance on first-in-human (FIH) clinical trials in order to better identify and mitigate risks to trial participants.

The release of the concept paper is part of a review of the EMA guideline published in 2007 to take into account the evolution of practices in the conduct of these studies. The review also takes into account the lessons learnt from the tragic death of a patient in January 2016 during a Phase I trial in France.

This concept paper will form the basis for an update of the guideline. Comments are requested by 30-Sep-2016 and a draft revised guideline is expected to be published for consultation before the end of 2016.

→ Link to EMA Press Release → Link to EMA Concept Paper

1.2.5 Update on ICH E2B(R3) on Transmission of ICSRs (25-Jul-2016) A new version of the ICH E2B(R3) Questions & Answers (Q&As) Document has been published by ICH, which includes a revision to Q&A 23 and a series of new Q&As (28 to 38).

The EMA has also published this updated document on its website.

→ Link to ICH E2B(R3) Page → Link to EMA ICH E2B(R3) Q&As

1.2.6 EMA issues draft revision of GVP Module IX on Signal Management (08-Aug-2016) The EMA has released for consultation a draft revision of the GVP Module IX, which covers Signal Management (Rev. 1). This represents a major revision based on the experience gained over the past 4 years. The new guidance includes procedural options for signals validated by MAHs and the definition and process for emerging safety issues, which was previously addressed in GVP Module VI on ICSR Management. Significant revisions have also been made regarding the periodicity of monitoring of EudraVigilance data.

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Streamlined information on scientific aspects of signal management is provided and methodological aspects are now addressed separately in a new Addendum, which is also available for comments. This document introduces the concept of Designated Medical Events (DMEs) to identify reports of suspected ADRs that deserve special attention to ensure that signals are not missed due to statistical criteria.

The list of DMEs used by the EMA has also been made available, which contains 62 MedDRA Preferred Terms corresponding to serious medical concepts often causally associated with drugs across multiple classes.

Comments on the draft GVP Module IX and Addendum I are expected by 14-Oct-2016.

The GVP Introductory cover note has been updated to reflect this consultation and other GVP updates reflected in this issue.

→ Link to EMA GVP Page → Link to draft GVP Module IX (Rev. 1) → Link to draft GVP Module IX Addendum 1 → Link to EMA Signal Management Page (DME List)

1.2.7 EMA issues draft revision of GVP Module VI on Management of ICSRs (08-Aug-2016) The EMA has released for consultation a draft revision of the GVP Module VI on Management and Reporting of Adverse Reactions to Medicinal Products (Rev. 2).

In addition to the transfer of the guidance on Emerging Safety Issue to GVP Module IX (see 1.2.6 in this issue), the revisions bring important changes that are all highlighted in “track changes” mode.

This includes various updates to prepare for the implementation of ICH-E2B(R3) format and of the new EudraVigilance System with centralised reporting. The definition of Spontaneous reports has been revised to include reports received through Medical Information enquiries, but also reports from non-interventional studies or compassionate use programs where there is no active safety data collection in place. The changes also impact case validity criteria based on patients and reporters identifiability, and the associated requirements for case follow-up, which is the subject of several new appendices.

Comments on the draft GVP Module VI are expected by 14-Oct-2016. The GVP Introductory cover note has been updated to reflect this consultation and other GVP updates reflected in this issue.

→ Link to EMA GVP Page → Link to draft GVP Module VI (Rev. 2)

1.2.8 EMA updates information on ISO IDMP implementation (16-Aug-2016) The EMA has updated its information page on the implementation of the ISO IDMP standards, which is due to replace the current eXtended EudraVigilance Medicinal Product Dictionary (XEVMPD). The page includes a high level timetable showing that the legal deadline of 01-Jul-2016 specified in the Implementing Regulation N°520/2012 will see the start of a transition phase. The MAHs will be required to align their systems and submit additional data during this transition phase until Q3/Q4 2018 when the maintenance phase will start.

The EMA has published the minutes and presentation material of the fifth meeting (30-Jun and 01-Jul-2016) of the task force for the implementation of IDMP, which was appointed to deliver an EU implementation guide to support the implementation of IDMP in Europe.

The EMA has also made available the video recording of the 04-Aug-2016 webinar to present the Substance, Product, Organisational and Referential (SPOR) data services and related impacts to the Industry, including the benefits and high level changes, implementation timelines and engagement approach.

→ Link to EMA Page on IDMP

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1.2.9 EMA updates documents on implementation of the new EudraVigilance (17-Aug-2016) As reported in our previous issue, the EMA Management Board has approved a revised schedule for the implementation of the new EudraVigilance System at its June 2016 meeting.

The system is now expected to go live in November 2017, which will include simplified centralised ICSR reporting and the mandatory reporting of non-serious cases in EudraVigilance. As a reminder, the new system will also support the use of the ISO ICSR (E2B(R3)) format and MAHs will be granted access to the database for Signal Detection purposes through the EudraVigilance Data Analysis System (EVDAS).

In relation to the schedule update, the EMA has published revised versions of the EudraVigilance Stakeholder Change Management Plan and of the associated “Key project milestones”. In addition, the EudraVigilance Training Plan and the Training Module entitled “Introduction to EMA’s training offering” (PhV-M0) have also been updated accordingly.

→ Link to EudraVigilance Change Management Page → Direct link to “Key project milestones and summary of associated communication activities” → Link to EudraVigilance Training Page

1.2.10 US and Canada invite joint Public Meeting to prepare next ICH discussions (29-Aug-2016) Under the Regulatory Cooperation Council (RCC) initiative, Health Canada and the FDA are holding a joint public consultation meeting on ICH guidelines currently under development, which will take place on 24-Oct-2016 in Ottawa, Canada. Interested persons may also submit comments prior to this date.

The purpose of this initiative is to seek input from stakeholders in preparation for the next ICH face-to-face meeting, which will take place in November 2016 in Osaka, Japan.

→ Link to Health Canada Page

1.3 Beyond the Scope of Safety Observer This section includes announcements collected through our secondary sources, which originate from authorities that we do not monitor systematically. For more information, please check our Q&As.

1.3.1 Spain announces changes to electronic transmission of ICSRs (15-Jul-2016) The Spanish Agency has issued a notice to MAHs to announce that from 01-Mar-2017 it will no longer accept ICSR submission by Data Entry into the national database FEDRA and no new applications to use this system will be accepted from 01-Dec-2016.

All submissions will be required to use the possibilities available through EudraVigilance (i.e. ESTRI gateway or EVWEB). The AEMPS also pointed that testing for the transmission of XML files is no longer necessary.

→ Link to AEMPS Page (in Spanish) → Direct link to AEMPS Notice to MAHs (in Spanish)

1.3.2 South Africa issues draft Clinical Trial Safety Reporting guideline (20-Aug-2016) The South African Medicines Control Council (MCC) has published a draft revision of its guideline on “Safety Reporting during Clinical Trials in South Africa”. Comments are expected by 28-Oct-2016.

→ Link to draft MCC guideline

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1.4 The Safety Observer Tracker This section includes a cumulative list of the future implementation and consultation deadlines. For your convenience, a link is provided and we also specify the issue where the corresponding article can be found.

By When? What? Issue

30-Sep-2016 EMA Consultation on Concept Paper on the revision of the Guideline on first-in-human clinical trials (Link)

126

14-Oct-2016 EMA Consultation on draft GVP Module IX (Rev.1) and Addendum I (Link) 126

14-Oct-2016 EMA Consultation on draft GVP Module VI (Rev.2) (Link) 126

Nov-2017 Implementation of the new EudraVigilance system in Europe (includes centralised reporting, E2B(R3), MAH obligation to monitor EudraVigilance for safety signals) (Link)

125

Q3/Q4-2018 Implementation of the ISO IDMP standards in Europe (Link) 126

Oct-2018 Planned date for implementation of Clinical Trials Regulation (EU) No 536/2014 (Link)

119

2. PRODUCT SAFETY ANNOUNCEMENTS

2.1 Meningitec (Meningitis C vaccine) ANSM concludes there is no risks for vaccinated people (18-Jul-2016) Meningitec was withdrawn in September 2014 due to the presence of iron and steel particles. Following contradictory study results, the French Agency has conducted new investigations and the expert committee concluded that there is no risk for vaccinated people in relation to the quality defect.

→ Link to ANSM website (in French)

2.2 Idelalisib (Zydelig) EMA confirms new Risk Minimisation Measures (22-Jul-2016) The CHMP has endorsed the PRAC recommendations following its review of Zydelig, which confirmed that the medicine’s benefits outweigh its risks in the treatment of two types of blood cancers, chronic lymphocytic leukaemia (CLL) and follicular lymphoma. Revised recommendations have however been issued to manage the risk of serious infections, including Pneumocystis jirovecii pneumonia. The new treatment advice includes concomitant antibiotic treatment and close monitoring for signs of infection.

This review was started in March 2016 at the request of the European Commission following an increased rate of serious adverse events in clinical trials including deaths, mostly due to infections.

→ Link to EMA Press Release

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2.3 Fluoroquinolone antibiotics FDA updates warnings due to disabling side effects (26-Jul-2016) The FDA has announced that it approved changes to the labels of FDA updates warnings for oral and injectable fluoroquinolone antibiotics, which are associated with disabling and potentially permanent side effects of the tendons, muscles, joints, nerves, and central nervous system. The existing Boxed Warning has been revised to address these serious safety issues, together with other parts of the label including the Warnings and Precautions and Medication Guide sections.

Fluoroquinolones should now be used only in patients who have no other treatment options for acute bacterial sinusitis, acute exacerbation of chronic bronchitis, and uncomplicated urinary tract infections where the risks generally outweighs the benefits.

→ Link to FDA MedWatch alert → Link to FDA News Release

2.4 Opioid Medicines combined with Benzodiazepines FDA requires Boxed Warnings about serious risks including death (31-Aug-2016) A FDA review has found that the growing combined use of opioid medicines with benzodiazepines or other drugs that depress the central nervous system (CNS) has resulted in serious side effects, including slowed or difficult breathing and deaths. In an effort to decrease this risk, the FDA is requiring several label changes, including new Boxed Warnings for both prescription opioid medicines and benzodiazepines.

This follows the review of several studies showing that serious risks are associated with the combined use of opioids and benzodiazepines, other drugs that depress the CNS, or alcohol.

The FDA is evaluating whether labeling changes are also needed for other CNS depressants, and the Agency is continuing to evaluate the evidence regarding combined use of benzodiazepines or other CNS depressants with drugs used to treat opioid addiction and dependence.

→ Link to FDA MedWatch alert → Link to FDA News Release

3. DEAR DOCTOR LETTERS AND SAFETY NEWSLETTERS

3.1 ANSM Dear Doctor Letters Dear Doctor Letters sent in July and August 2016 are now available on the French Agency's website (all in French). Letters associated to safety concerns include the following:

• Eligard (Leuprorelin): update of the recommendations for prescription and administration • Zydelig (Idelalisib): update of the recommendations following European re-evaluation • Hemolevel (Factor XI): measures to limit the risks of thrombosis • Ketoprofene topic: reminder on the risks of photosensibility • Noxafil (Posoconazole): pills and oral solution are not interchangeable • Colchicine: reminder on recommendations to limit the risks of overdosage

→ Link to ANSM Page (in French)

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3.2 MHRA Dear Doctor Letters The letters sent to Healthcare Professionals are routinely posted on the Agency’s website. The letters sent by the MHRA are presented in the subsequent issue of the MHRA “Drug Safety Update” bulletin. The following letter was issued in June 2016:

• Thalidomide Celgene: risks of viral reactivation and pulmonary hypertension

→ Link to MHRA Page (June)

The following letters were issued in July 2016:

• Riociguat (Adempas): not for use in patients with pulmonary hypertension associated with idiopathic interstitial pneumonias

• Posaconazole (Noxafil): tablets and oral suspension are not interchangeable

→ Link to MHRA Page (July)

3.3 New issue of MHRA “Drug Safety Update” The July issue of Drug Safety Update was published on 18-Jul-2016. It includes the following topics:

• Warfarin: reports of calciphylaxis • Citalopram: suspected drug interaction with cocaine • N-acetylcysteine: risk of false-low biochemistry test results due to interference with Siemens assays

→ Link to Drug Safety Update (July)

The August issue of Drug Safety Update was published on 08-Aug-2016. It includes the following topic:

• Riociguat (Adempas): not for use in patients with pulmonary hypertension associated with idiopathic interstitial pneumonias

→ Link to Drug Safety Update (August)

3.4 New issues of Canadian “Health Product InfoWatch” New issues of “Health Product InfoWatch” have been published, which provide an overview of health product advisories and safety reviews published in the previous month by Health Canada.

The July issue was published on 28-Jul-2016 and includes a Safety Brief on Truvada for pre-exposure prophylaxis to reduce the risk of HIV-1 infection in adults at high risk. The monthly recap covers several medicinal products including Atarax and generics (hydroxyzine), Avonex (interferon beta-1a), Tysabri (natalizumab), Uloric (febuxostat) and Lamisil (terbinafine).

→ Link to Newsletter (July)

The August issue was published on 25-Aug-2016 and includes the Vaccine Safety summary for Q4 2015. The monthly recap covers several medicinal products including Blincyto (blinatumomab), Codeine-containing products, Hydrocodone-containing products, Kogenate FS and Helixate FS (Antihemophilic Factor [Recombinant]) and Adalat XL (nifedipine extended-release tablets).

→ Link to Newsletter (August)

3.5 New issue of WHO Pharmaceuticals Newsletter The latest edition of the WHO Pharmaceuticals Newsletter (N°4, 2016) is now available. Prepared in collaboration with the Uppsala Monitoring Center, it includes a section on Regulatory Matters and Safety of Medicines. This issue includes a brief report from the Thirteenth Meeting of the WHO Advisory Committee on Safety of Medicinal Products (ACSoMP). As usual, the newsletter includes signals identified in the WHO VigiBase and the corresponding responses from MAHs, where available:

• Thiamazole and rhabdomyolysis

→ Link to WHO Pharmaceuticals Newsletter (N°4, 2016)

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3.6 New issue of Australian “Medicine Safety Update” The Australian Therapeutic Goods Administration (TGA) has issued the new edition of Medicines Safety Update (Volume 7, Number 4, August 2016). The contents include:

• Bcr-Abl tyrosine kinase inhibitors and hepatitis B virus reactivation • Denosumab and QT prolongation • Isotretinoin and psychiatric adverse events

→ Link to Medicines Safety Update

3.7 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 updates warnings for oral and injectable fluoroquinolone antibiotics due to disabling side effects • FDA warns about serious risks and death when combining opioid pain or cough medicines with

benzodiazepines; requires its strongest warning

→ Link to FDA Page

3.8 New Issue of the French Bulletin "Vigilances" The new French "Vigilances" Bulletin, number 70, has now been issued. It includes a summary of recent pharmacovigilance news. As usual it also includes statistics on ADR notifications received during in the first quarter of 2016, which show similar figures to the previous period.

→ Link to the ANSM Bulletin "Vigilances" (in French)

4. OTHER PUBLICATIONS BY REGULATORY AGENCIES

4.1 US Food and Drug Administration (FDA)

4.1.1 FDA implements real-time access to safety labeling change data The FDA has announced that safety labeling change (SLC) data will now be available in real time on the Web for health care providers, health information technology vendors, and the public to view, search, and download. Until now, the FDA MedWatch program posted these changes monthly to the FDA MedWatch web site. The SLC database provides approved safety labeling changes from January 2016 forward. Data prior to July 2016 will continue to be available on the MedWatch website. Ultimately, the FDA expects that prompt access to this information will promote public health.

→ Link to FDA SLC Page

4.1.2 FDA announces workshop on the Sentinel PRISM Program The FDA has announced that a public workshop entitled “The Sentinel Post-Licensure Rapid Immunization Safety Monitoring (PRISM) Program” will be held in Bethesda, MD on 07-Dec-2016. The purpose of this workshop is to describe the Sentinel Initiative and PRISM program, which is used in the evaluation of vaccine adverse events. The workshop will present how PRISM is used by the FDA with case examples. Discussions should also cover the future direction of PRISM in terms of expansion and further integration into the regulatory review process. Registration is open until 23-Nov-2016.

→ Link to Federal Register Notice → Link to FDA Event Page

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4.1.3 Commissioner gives speech on FDA actions to address the Opioid Crisis The FDA has published the material used by Dr. Robert M. Califf’s, Commissioner during his presentation of the FDA charge to the National Academy of Science, Engineering and Medicine’s Committee on Pain Management and Regulatory Strategies to Address Prescription Opioid Abuse, which took place at the Keck Center in Washington, DC on 06-Jul-2016. The presentation covers the FDA action plan in response to the opioid crisis and the plan to incorporate the Public Health Impact into the Risk-Benefit Assessment for Opioids.

→ Link to FDA Page

4.1.4 Drug Safety and Risk Management Advisory Committee: New material available The Drug Safety and Risk Management Advisory Committee met on 04-Aug-2016 in a Joint Meeting with the Anesthetic and Analgesic Drug Products Advisory Committee Meeting to discuss the NDA for morphine sulfate extended-release tablets submitted by Egalet U.S., which has been formulated with the intent to provide abuse-deterrent properties.

The webcasts of the meeting is now available on the FDA website in addition to other meeting material, including slides and final questions.

In addition, new material has been published in relation to previous meetings of the same committees, including the minutes of the meeting from 03 and 04-May-2016, and of the meetings from 07 and 08-Jun-2016. The transcripts of the meeting from 05-May-2016 and 07-Jun-2016 have also been published.

→ Link to FDA Page

4.2 European Medicines Agency (EMA)

4.2.1 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 were published on 26-Aug-2016. The PRAC did not initiate or conclude a safety referral at this meeting. The following new Safety Signals were considered:

• Dasabuvir – depression and suicidal ideation • Dasabuvir – risk of drug interaction with fluindione leading to a reduced INR • Riociguat – increased mortality and serious adverse events (SAEs) in patients with pulmonary

hypertension (PH) associated with idiopathic interstitial pneumonias (IIP) in a single clinical trial • Olanzapine – restless leg syndrome (RLS) • Pazopanib – polycythaemia

→ Direct link to PRAC Meeting Minutes (06 to 09-Jun-2016)

The agenda and highlights of the September PRAC meeting were published on 02-Sep-2016. The PRAC did not initiate or conclude a safety referral at this meeting. According to the agenda, the following new Safety Signals have been identified and considered:

• Azacitidine – pericarditis and pericardial effusion • Esomeprazole – gastric polyps • Lenalidomide – hemophagocytic lymphohistiocytosis (HLH) • Ritonavir – retinal pigment epitheliopathy • Darbepoetin alfa – incorrect use of device associated with adverse reactions including underdose, drug

dose omission, accidental exposure to product and injection site reactions • Propofol / valproate – pharmacokinetic drug interaction leading to an increased propofol exposure • Proton pump inhibitors (PPIs) – incident chronic kidney disease (CKD) and progression to end stage renal

disease (ESRD)

→ Direct link to PRAC Meeting Highlights (30-Aug to 02-Sep-2016)

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4.2.2 PRAC recommendations on Safety Signals The EMA routinely issues the PRAC recommendations resulting from the assessment of safety signals. MAHs are legally obliged to monitor this information to keep informed about the PRAC recommendations concerning their products, which may require the submission of a Safety Variation.

The list of signals discussed at the July PRAC meeting was published on 02-Aug-2016 and includes recommendations to update the product information for the following combination of Product / Signal:

• Ferrous sulfate – Mouth ulceration • Proton pump inhibitors (PPIs) – Elevated circulating levels of Chromogranin A

In complement, the EMA has published the corresponding document entitled: “New product information wording – Extracts from PRAC recommendations on signals”, which is available in all EU languages.

The list of all safety signals discussed at the PRAC since September 2012 has been updated accordingly. It includes links to the corresponding PRAC minutes and specifies whether a variation was recommended.

→ Link to EMA Page

4.2.3 EMA issues “Meeting Highlights” of last CHMP Meeting The highlights of the July meeting of the CHMP have been published. As communicated separately (see Section 2), the Committee CHMP confirmed the PRAC recommendations to minimise the risk of serious infections in patients treated with Zydelig (idelalisib). The CHMP also recommended the suspension of medicines over flawed bioequivalence studies conducted at Semler Research Centre in Bangalore, India.

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/PSURs.

→ Link to CHMP Meeting Highlights (18 to 21-Jul-2016)

4.2.4 EMA responds to Nordic Cochrane Centre on the safety review of HPV vaccines The EMA has published the two letters it sent in response to a complaint received from the Nordic Cochrane Centre regarding the safety review of human papillomavirus (HPV) vaccines, which highlighted a list of concerns in the way the EMA handled the issue including possible conflicts of interests and maladministration. The letter of complaint is also available through links in the EMA response letters.

→ Link to EMA “Open Letters” Page

4.2.5 Industry stakeholder platform on the operation of EU PV legislation The EMA hosted the eighth industry stakeholder platform on the operation of European Union pharmacovigilance legislation on 01-Jul-2016.

Presentations included updates on the Medical Literature Monitoring (MLM) service, the ISO IDMP and EudraVigilance. Discussions also concerned the Reference Safety Information (RSI) in Clinical Trials, which the industry blames for delays in product development.

→ Link to EMA Meeting Page

4.2.6 EMA to hold workshop on measuring the impact of pharmacovigilance activities As reported in previous issues, the PRAC committee adopted a strategy for measuring the impact of pharmacovigilance activities and the EMA is calling for expressions of interest in an associated workshop, which is scheduled on 05 and 06-Dec-2016. Requests to participate should be communicated to the Agency by 30-Sep-2016. The draft agenda for the workshop has now been published.

→ Link to EMA Event Page → Link to PRAC Strategy Document

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4.2.7 EMA to hold Medical Literature Monitoring (MLM) workshop The EMA has announced that it will hold a MLM workshop on 13-Sep-2016 to provide an opportunity for Marketing Authorisation Holders (MAHs) to discuss possible future changes to improve the service.

→ Link to EMA Event Page

4.2.8 EMA schedules Patient Registries workshop The EMA has announced that it will hold a Patient registries workshop on 28-Oct-2016. Through the Patient Registry Initiative launched in September 2015, the EMA aims to facilitate interactions between registry co-ordinators and potential users of registry data. This workshop is designed to bring together multiple stakeholders to discuss the challenges and barriers to collaboration and identify solutions.

→ Link to EMA Event Page → Link to EMA “Patient Registries” Page

4.2.9 European Commission issues Report on new EU Pharmacovigilance System The European Commission has published a new report on the pharmacovigilance activities of the EMA and Member States where the main activities of the collaborative EU PV System are reviewed in the period since the new legislation came into effect in 2012.

The EMA also published a Press Release to highlight that the PRAC and the regulatory tools brought by the new legislation allow for a more proactive approach to ensuring medicine safety. The new EU system has been successful at quickly detecting safety issues and is effectively engaging patients and healthcare professionals.

→ Link to EMA Press Release → Link to European Commission News Release

4.2.10 EMA issues new information on outcome of PSUR assessment for NAPs Following the implementation of the single assessment of PSURs for active substances contained only in Nationally Authorised Products (NAPs), the EMA is routinely publishing the results of these procedures, which may lead to a variation of the marketing authorisations. In such case, the information published includes the scientific conclusions, a timetable for implementation, and the wording of the product information.

Pharmaceutical companies are advised to regularly monitor this information to check for outcomes relevant to their products in order to submit the corresponding variations.

The outcomes of new PSUR single assessments have been published or updated since our previous issue and variations are required for the following substances:

• Metoclopramide • Perindopril • Acitretin • Ivermectin (topical use) • Furosemide / spironolactone • Dextromethorphan • Benazepril • Apomorphine • Minoxidil (topical formulation)

→ Link to PSUR Single Assessments Outcomes Page

4.2.11 EMA updates the list of Black Triangle Products As described in GVP Module X, the EMA is publishing the list of medicines under additional monitoring, which must be identified by a Black Triangle (▼) throughout Europe. The list specifies the reason for a product to be subject to additional monitoring and 11 new products have been added to the list in July 2016, whereas 2 products have been removed, as identified in the Summary of Changes presented on the EMA webpage.

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

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4.2.12 EMA issues updated EURD list The EMA has published an updated EURD list, which was last revised on 28-Jul-2016. It provides the EU Reference Dates, frequencies for submission of PSURs and related data lock points for a list of active substances and combinations including those contained exclusively in nationally authorised medicines.

The changes to the EURD list are highlighted. Please note that as specified in the cover note, the “Publication Date” is not revised for all types of amendments and this column cannot be used to filter all amended substances in Excel.

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

4.2.13 CMDh updates PSUR Work Sharing List 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 until they follow the EU single assessment procedure of PSURs, which should eventually apply to all products. The list is provided in pdf and Excel format, where all changes since the previous publication are highlighted, with most changes corresponding to the transfer of products to the EURD list.

→ Link to HMA Page → Direct link to list (pdf)

4.2.14 EMA issues updated list of substances subject to worksharing for signal management The legislation foresees that a lead Member State is appointed to monitor data in EudraVigilance and to validate and confirm signals for substances contained in products where at least one marketing authorisation was obtained through a national procedure. The first list of active substances with appointed Lead Member States was published in October 2012 after adoption by the CMDh and an updated list has just been published to align the Lead Member State for signal management with the Lead Member State for the PSUR single assessment procedure. Changes to the list are highlighted.

→ Link to signal management worksharing list

4.2.15 EMA provides update on submission of medicines information The EMA has issued updated material related to the electronic submission of information on authorised medicines, as required under Article 57(2) of the 2010 pharmacovigilance legislation.

New versions of the Controlled Vocabulary for several datapoints have also been released, including for substances, organisations, and pharmaceutical dose forms.

→ Link to EMA Page on Data Reporting requirements for MAHs → Link to Data Submission Guidance Page

4.2.16 CMDh updates list of safety concerns described in approved RMPs The European CMDh (Co-ordination Group for Mutual Recognition and Decentralised Procedures – Human) has published an update to the list that presents safety concerns of approved Risk Management Plans (RMPs) per product/active substance, which was first published in April 2015. The lack of publicly available information on approved RMPs is a significant challenge for generic products if no information is available on the safety concerns for the reference product and this has resulted in inconsistencies between separate RMPs for the same active substance.

The purpose of this list is to support the harmonisation of RMPs for the same active substances. The list is provided in Excel format and includes a “products overview”, which lists all products and indicates whether an RMP has been approved, and links to separate sheets where the safety concerns are specified.

→ Link to CMDh Page

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4.3 UK Agency (MHRA)

No relevant announcement was identified in the period covered by this issue.

4.4 French Agency (ANSM)

4.4.1 ANSM provides update on PRAC/CHMP/CMDh meetings Following the PRAC meeting of July 2016, the ANSM has issued a document to summarise the PRAC decisions.

→ Link to ANSM release – July 2016 PRAC (in French)

Following the CHMP meeting of July 2016, the ANSM has issued a document to summarise the CHMP decisions. The document does not include any ANSM recommendation.

→ Link to ANSM release – July 2016 CHMP (in French)

Following the CMDh meeting of July 2016, the ANSM has issued a document to summarise the CMDh decisions. The document does not include any ANSM recommendation.

→ Link to ANSM release – July 2016 CMDh (in French)

4.4.2 ANSM issues its 2015 annual report The ANSM has issued its 2015 Annual Report which provide a number of metrics:

• 7 in-depth pharmacovigilance inspections (18 in 2015) with 3 inspections leading to injunctions • 115 active substances to be re-evaluated, 52 already evaluated, with 22 drugs removed from the market,

25 restrictions of indications or modifications of the drug monitoring • Over 47,000 ADR reports received through Regional Centers of Pharmacovigilance (over 46,400 in 2015) • Over 29,400 serious ADR reports received from pharmaceutical companies (over 26,400 in 2015) • 17% of notifications from EU in EudraVigilance are French (16% in 2015) • 11 pharmacoepidemiology studies were conducted • 18 Authorisation of Temporary use – cohort and 8 Recommendations for Temporary Use authorised

→ Link to the ANSM 2015 Annual Report (in French) → Link to the ANSM 2015 Annual Report Synthesis (in French)

4.4.3 French Health Authority issues its 2015 annual report The HAS (Haute Autorité de Santé) has issued its 2015 Annual Report which provide a number of metrics on post-marketing studies:

• 97 on-going studies (128 in 2015) • 20 new studies requested (8 in 2015).

→ Link to the HAS 2015 Annual Report (in French) → Link to the HAS 2015 Annual Report Synthesis (in French)

4.4.4 ANSM suspends 11 Marketing Authorisations following CHMP recommendations Pending for the results of the European procedure, the ANSM has suspended 11 MA following the CHMP recommendations concerning the studies conducted by the Selmer Research Center in Bangalore, India.

This follows inspections by the FDA and the World Health Organization which raised serious concerns over data generated at Semler’s sites. The concerned products are generics of Atovaquone/Proguanil, Ebastine, and Eletriptan.

→ Link to the ANSM press release (in French)

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4.4.5 ANSM issues a new version of the thesaurus of Drug Interactions ANSM has issued the new version of the thesaurus of Drug Interactions (previous version issued in January 2016). It includes the Thesaurus itself, the substance index and a document that describes the changes from the previous version.

→ Link to the ANSM webpage (in French)

5. QUALITY ASSURANCE, INSPECTIONS AND AUDITS

5.1 EMA issues Annual Reports of PhV & GCP Inspections Working Group The EMA has published the Annual Report 2015 of the Pharmacovigilance Inspectors Working Group (PhV IWG), which outlines the activities carried out by the PhV IWG and specifies that 7 inspections were requested in 2015 by the CHMP, in addition to 36 inspections of companies with CAPs that were already considered in National Inspection Programmes. The document includes an overview of the categorisation of findings for CHMP requested inspections conducted in 2015.

The Annual Report also described the activities of the PhV IWG in various areas, including harmonisation, joint inspections and training activities.

The EMA has also published the 2015 Annual Report of the GCP IWG which shows that the CHMP requested 78 inspections in 2015 whereas 396 inspections were performed under national programmes. The report provides details regarding the number and type of findings and includes an overview of the other activities of the group.

→ Link to EMA PhV IWG 2015 Annual Report → Link to EMA GCP IWG 2015 Annual Report

5.2 New ANSM injunction letter published Injunctions are new administrative measures taken by ANSM after inspections in case of deficiencies that should be solved within a set timeframe. A new injunction for pharmacovigilance deficiencies has been issued for Septodont.

During the inspection at Septodont, deficiencies were identified in relation to control of pharmacovigilance activities performed by affiliates and maintenance of Product Information.

→ Link to Septodont injunction (in French)

5.3 MHRA issues new set of Pharmacovigilance Inspection metrics The MHRA has published a new Pharmacovigilance inspection metrics report on its website, which covers inspections conducted from April 2015 to March 2016. The metrics provide information on the number and type of MAHs inspected, the areas associated with common inspection findings, as well as the number of critical, major and other findings.

The MHRA performed 34 Pharmacovigilance inspections of MAHs in the period (compared with 47 the previous year), and one additional inspection was performed at a Pharmacovigilance Service Provider.

The average number of both Critical and Major Findings has decreased significantly compared to the previous year. The greatest part of Critical Findings concerned supervision and oversight of the Pharmacovigilance System whereas the Quality Management System was the main area for Major Findings.

→ Link to MHRA Metrics Page

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5.4 MHRA no longer requires GPvP compliance reports to be completed Over the last seven years the MHRA GPvP Inspectorate has requested MAHs in the UK to periodically complete and submit GPvP compliance reports (also known as Risk-Based Inspection questionnaires), which were mainly used to support inspection planning activities. The MHRA has now access to other information sources and will no longer require compliance reports to be submitted routinely.

→ Link to MHRA GPvP Page

5.5 MHRA provides update on GPvP inspections of service providers As communicated earlier, the MHRA started an initiative to evaluate the feasibility of conducting stand-alone inspections of pharmacovigilance service providers and two volunteers were inspected as part of a pilot phase to assess whether such inspections could reduce repetition of inspections at an organisation level.

The inspections conducted as part of this pilot show that client-specific processes and interfaces are often established and a single inspection of the general system and procedures at a service provider may be insufficient to confirm compliance across a number of MAHs.

In light of all challenges, the MHRA concluded that a routine programme of stand-alone inspections of service providers does not bring sufficient benefit and the activities performed by service providers will continue to be assessed in the context of MAH inspections. Where issues are identified, inspectors will request the service providers to conduct impact assessments and remediation across all its clients.

→ Link to MHRA Blog Post

5.6 MHRA issues new data integrity guidance for comments The MHRA has published a new draft GxP data integrity guidance, which is intended to be a useful resource on the core elements of a compliant data governance system across all GxP sectors, including pharmacovigilance. Comments are expected by 31-Oct-2016.

It should be highlighted that other publications have been issued in relation to Data Integrity, even though they do not mention Pharmacovigilance. This includes a new set of GMP Q&As published by the EMA and a draft guidance published by PIC/S on “Good Practices for Data Management and Integrity in Regulated GMP/GDP Environments”.

→ Link to MHRA News Release → Link to EMA Q&As → Link to PIC/S News Page

6. DRUG SAFETY AND LIABILITY RISK

6.1 GSK, MSD and HPV Vaccines $9 million lawsuit filed in Japan over safety of Cervical Cancer Vaccines Sixty-three young Japanese women are seeking a combined 945 million yen ($9 million) in compensation in a mass lawsuit concerning side effects from HPV vaccines, which has been brought against GSK and MSD. The plaintiffs argue the central government also bears responsibility for approving the vaccines and recommending their use without adequately looking into safety concerns.

→ Link to The Asahi Shimbun Article

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6.2 France and Depakine France announces compensation funds to indemnify the patients In relation to the issue of birth defects and developmental disorders caused by pregnancy exposure to the anti-epileptic drug valproate, France will set up an indemnity fund. Other measures such as screening of children etc. have also been presented.

This follows the publication of the results of a study conducted by ANSM and by the French Social Security which indicates that between 2007 and 2014, more than 14.000 exposed pregnancies occurred.

→ Link to French Health Minister press release (in French) → Link to ANSM press release (in French)

7. OTHER NEWS AND RESOURCES

7.1 Investigation of death during Phase 1 Clinical Trial in France The FDA has issued an update on its investigation of drugs in the same class as Portuguese company Bial's BIA 10-2474, which caused one death and five hospitalizations in a French trial. The Agency concluded that the products do not have the same safety risk as Bial’s FAAH inhibitor, which was found to have a unique toxicity not shared by other drugs in the same class.

→ Link to FDA Page

7.2 Update on WEB-RADR: mobile technologies and social media as PV tools The Innovative Medicines Initiative (IMI) WEB-RADR project aims to explore the use of mobile technologies and social media to further improve the collection and analysis of information on suspected ADRs. This includes the use of mobile apps to report adverse reactions and the possibility to identify potential safety issues from user comments on social media.

The EMA has announced the second WEB-RADR workshop on 19-Oct-2016 to engage with consumers, patients, healthcare professionals and regulatory authorities and maximise the benefits of the project.

The project has also launched a pair of surveys for healthcare professionals and patients to gather opinions on an app that people can use to report ADRs and receive safety information about medicines in order to improve the app already available and raise awareness.

→ Link to EMA Event Page → Link to WEB-RADR News Release

7.3 Update from the PROTECT project Although the PROTECT project terminated in February 2015, an update to the ADR database has just been published, which is intended to support signal detection and research activities. The PROTECT ADR database is a downloadable Excel file listing all ADRs listed in the SmPC of medicinal products authorised in the EU according to the centralised procedure, based on MedDRA terminology.

Two new publications have also been made available through the PROTECT website, namely: Afonso A et al: "A methodological comparison of two European primary care databases and replication in a US claims database: inhaled long-acting beta-2-agonists and the risk of acute myocardial infarction" and Schmield S. et al: "Response to Wise et al. (Tiotropium safety in real life populations)".

→ Link to PROTECT ADR Database Page → Link to PROTECT Publications Page

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7.4 New issue of MedDRA Messenger The MSSO (Maintenance and Support Services Organization) has published a new “Messenger” Newsletter, which highlights the main changes introduced with MedDRA Version 19.1 together with the MedDRA training offer, including revised webinars. It also presents the new edition of the CIOMS guide on how to use SMQs and the EVERREST International Adverse Event Consensus Group to develop standard maternal and fetal AE severity grading criteria.

→ Link to MedDRA Messenger

8. CONFERENCES AND TRAINING EVENTS

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

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

2 day-training course (see agenda for venues and dates) → Introduction to Pharmacovigilance and Rules for Expedited Reporting of ICSRs in Europe

October 04 in Paris, France (Event in French)

→ Information Day on Medication Errors October 20 in London, UK

→ PSUR Information Day October 28 in London, UK

→ Information Day on Risk Management Planning and Post-Authorisation Studies November 07 in London, UK

→ EudraVigilance Information Day November 08 in London, UK

DIA Events → 10th Annual Forum for Qualified Persons in Pharmacovigilance (QPPV)

October 05 – 06 in London, UK → Risk Management and Safety Communication Strategies

October 17 – 18 in Washington DC, USA → DIA Annual Canadian Meeting 2016

October 18 – 19 in Ottawa, Canada → Postmarketing Drug Safety & Pharmacovigilance

October 24 – 25 in Philadelphia PA, USA → 6th DIA Cardiac Safety Workshop in Japan

October 27 – 28 in Tokyo, Japan

DSRU Events → Reviewing and Understanding Clinical Papers

September 21 – 22 in Southampton, UK → Pharmacovigilance Planning and Risk Management

September 28 – 29 in Fareham, UK → Assessment and Medical Evaluation of Individual Case Safety Reports

October 12 – 13 in Fareham, UK → Risk Benefit Assessment in Pharmacovigilance

October 19 – 20 in Fareham, UK

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Other Events → Healthnetwork – World Drug Safety Congress Europe 2016

September 14 – 15 in Munich, Germany → IFIS – Quality in Pharmacovigilance (event in French)

September 19 in Paris, France → PIPA – First Steps in Pharmacovigilance

September 20 in London, UK → IFIS – Writing in English in Pharmacovigilance

September 20 – 21, October 14 in Paris, France → MHRA GCP symposium

September 20 – 21 in Birmingham, UK → RQA – Systems Approach to Good Pharmacovigilance Practice (GPvP)

September 20 – 22 in Cambridge, UK → Allan Lloyds – 3rd Annual Pharmacovigilance Summit

September 27 – 29 in Vienna, Austria → GLC – 4th Annual Pharmacovigilance Forum

September 29 – 30 in Berlin, Germany → PIPA – Annual Conference 2016

October 05 – 06 in Weybridge, UK → IFIS – Pharmacovigilance: role, missions and responsibilities (event in French)

October 06, 07 – November 04 in Paris, France → IFIS – Missions and Responsibilities in PV for the Qualified Pharmacist (event in French)

October 13 in Paris, France → IFIS – PV Case Management (event in French)

October 14 in Paris, France → ISoP – 16th Annual Meting: Pharmacovigilance For Safer Tomorrow

October 16 – 19 in Agra, India → RQA –PV QA: Interactions With and Auditing the Qualified Person Pharmacovigilance

October 17 in New York City, USA → Allan Lloyds – Risk Management and Pharmacovigilance America Summit

October 18 – 20 in Boston, USA → Corvus – European Pharmacovigilance and Clinical Trials 2016

October 25 – 26 in London, UK → RQA – Practical Pharmacovigilance Auditing

October 25 – 27 in Ascot, UK → RQA – 2016 Annual Conference

November 09 – 11 in Brighton, UK

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