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Safety Observer Issue N°119 - January 2016

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Clinical Safety & Pharmacovigilance Regulatory Intelligence Review

Issue N°119 - January 2016

HIGHLIGHTS

The EMA has now released the final GVP document on Educational Materials, which is provided as an addendum to the GVP Module XVI on Risk minimisation measures.

The EMA has released for consultation a draft revision of the GVP Module XV and associated templates to cover Safety Communication. The changes include a new concept of core EU DHPCs for the situation where a common DHPC is not suitable for all Member States, and the possibility for one MAH to act on behalf of other MAHs.

The EMA has also released for consultation the draft of a new Product-specific guideline for Biological Medicinal Products, which is intended to complement GVP Modules to ensure that challenges associated to biologicals and biosimilars are addressed, which include immunogenicity and manufacturing variability.

The EMA has confirmed that the Article 57 database can be relied upon to provide the contact details of the EU QPPV and the location of the PSMF. Companies will no longer be required to submit variations to update this information.

The EMA has clarified that the new EU Clinical Trial Regulation is not planned to become effective until October 2018, more than 2 years later than the initial planned date.

The FDA has issued a new draft guidance entitled “Safety Assessment for IND Safety Reporting” to complement existing guidance on various aspects, including the composition and role of a safety assessment committee, reporting thresholds for IND safety reporting, and the development of a safety surveillance plan.

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IN THIS ISSUE

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

1.1 Newly Applicable Standards .............................................................................................................................. 3 1.1.1 EMA issues final GVP Module XVI Addendum on Educational Materials ...................................................... 3 1.1.2 EMA updates guidance on safety variations for “non-innovator” MAHs ...................................................... 3 1.1.3 EMA confirms reliance on Article 57 database for key PV Information ........................................................ 3 1.1.4 ICH issues revised E14 Questions & Answers document............................................................................... 3 1.1.5 New ENCePP Guidance on meta-analyses of completed PE Studies ........................................................... 4 1.1.6 EMA issues updated EURD list ....................................................................................................................... 4 1.1.7 EMA updates Questions & Answers Document on Signal Management ...................................................... 4

1.2 Developments to Watch ..................................................................................................................................... 5 1.2.1 EMA provides update on development of GVP Documents .......................................................................... 5 1.2.2 EMA issues draft revisions of GVP Module XV on Safety Communication .................................................... 5 1.2.3 EMA issues new Biologicals-specific GVP guidance for consultation ........................................................... 5 1.2.4 Update from ICH December 2015 Meetings in Jacksonville FL, USA ............................................................ 6 1.2.5 FDA issues draft guidance on Safety Assessment for IND Safety Reporting ................................................ 6 1.2.6 ICH E18 on Genomic Sampling enters consultation period ......................................................................... 6 1.2.7 Update on the EU Clinical Trial Regulation ................................................................................................... 7 1.2.8 EMA Management Board adopts revised EudraVigilance Access Policy ...................................................... 7

1.3 Beyond the Scope of Safety Observer ............................................................................................................... 7 1.3.1 Swissmedic prepares switch to full electronic ICSR reporting ..................................................................... 7

1.4 The Safety Observer Tracker ............................................................................................................................. 8 2. Product Safety Announcements ............................................................................................................................ 9

2.1 Valproate ............................................................................................................................................................ 9 2.2 Rosiglitazone (Avandia®, combined products and generics) ........................................................................... 9 2.3 Fingolimod (Gilenya) .......................................................................................................................................... 9 2.4 Posaconazole (Noxafil) ...................................................................................................................................... 9

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

4. Other Publications by Regulatory Agencies ........................................................................................................ 11

4.1 US Food and Drug Administration (FDA) ......................................................................................................... 11 4.2 European Medicines Agency (EMA) .................................................................................................................. 12 4.3 UK Agency (MHRA) ........................................................................................................................................... 14 4.4 French Agency (ANSM) ..................................................................................................................................... 14

5. Quality Assurance, Inspections and Audits ......................................................................................................... 15

6. Drug Safety and Liability Risk .............................................................................................................................. 15

7. Other News and Resources .................................................................................................................................. 15

8. Conferences and Training Events ........................................................................................................................ 16

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1. REGULATIONS, GUIDELINES AND OTHER STANDARDS

1.1 Newly Applicable Standards

1.1.1 EMA issues final GVP Module XVI Addendum on Educational Materials (15-Dec-2015) Following the consultation launched in April 2015, the EMA has now released the final Good Pharmacovigilance Practices (GVP) document on Educational Materials, which is provided as an addendum to the GVP Module XVI on “Risk minimisation measures - Selection of tools and effectiveness indicators”.

This document provides guidance for MAHs on the submission of draft educational materials to the competent authorities as well as guidance for these competent authorities on the assessment of such materials. This Addendum is applicable to both centrally and nationally authorised products, including those authorised through the mutual recognition and decentralised procedures.

The comments received during the consultation and a version with tracked changes are also available.

→ Link to EMA GVP Page → Direct link to GVP Module XVI Addendum → Direct link to GVP Module XVI Addendum (track-change version) → Link to Comments received on Draft GVP Module XVI Addendum

1.1.2 EMA updates guidance on safety variations for “non-innovator” MAHs (16-Dec-2015) The EMA has issued revised Questions and Answers for similar biological products (i.e. biosimilars) and generic/hybrid applications. The changes include revisions to the questions related to the timelines for submission of a safety variation/USR and subsequent implementation of the revised Product Information following changes to the innovator product (see Questions N°41.1, 41.3 & 42.1, 42.3).

→ Link to EMA Q&As for generic / hybrid applications → Link to EMA Q&As for biosimilars

1.1.3 EMA confirms reliance on Article 57 database for key PV Information (18-Dec-2015) Following earlier communication on this topic, the EMA has confirmed that the Article 57 database can now be relied upon to provide the contact details of the EU QPPV and the location of the PSMF. As of 01-Feb-2016, companies will no longer be required to submit type IA variations to update this information, which applies to both centrally and nationally authorised medicines. This brings significant simplification to the process for the notification of these changes for both companies and regulators.

→ Link to EMA News Release → Link to EMA Page on Data Reporting requirements for MAHs

1.1.4 ICH issues revised E14 Questions & Answers document (18-Dec-2015) ICH has published a revision to its E14 Questions-and-Answers document on the Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs. In this document, the E14 Q&A on Concentration-Response Modelling (# 5.1) was revised to generate harmonised guidance on how concentration response modelling could be used for regulatory decision making.

→ Link to ICH News Release → Link to ICH ICH E14 Q&As (R3)

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1.1.5 New ENCePP Guidance on meta-analyses of completed PE Studies (18-Dec-2015) The European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP) has published a new annex to its guide on methodological standards in pharmacoepidemiology. This new methodological guidance addresses the conduct of systematic reviews and meta-analyses of drug safety endpoints generated in completed comparative pharmacoepidemiological studies.

→ Link to ENCePP Page

1.1.6 EMA issues updated EURD list (21-Dec-2015) The EMA has published an updated EURD list, which provides the EU Reference Dates, frequencies for submission of PSURs and related data lock points for a list of active substances and combinations.

As communicated earlier, the EMA has started the single assessment of active substances contained exclusively in nationally authorised medicines, which are also included in the EURD list.

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)

1.1.7 EMA updates Questions & Answers Document on Signal Management (05-Jan-2016) The EMA has published a revised version of its Q&As on Signal Management. The revisions include the introduction of an advanced notification to MAHs of signals to be discussed by PRAC (Question 7). It also covers translations of PRAC recommendations for PI updates (Question 10) and includes clarification regarding the role of “non-innovator” MAHs (Question 12 & 18) and the clock start for submission of variations (Question 18).

It is specified that guidance on signal detection/validation by MAHs is being developed in the context of the revision of GVP Module IX, which will be the subject of public consultation in 2016.

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

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1.2 Developments to Watch

1.2.1 EMA provides update on development of GVP Documents (15-Dec-2015) The overall structure of GVP was reviewed by the Implementation Group and it was agreed that the development of the GVP modules is now concluded. GVP modules I to XVI cover major pharmacovigilance processes and module numbers XI, XII, XIII and XIV will stay void, as their planned topics have been addressed by other guidance documents. This concerns the planned Module XI on public participation, Module XII on safety-related action, Module XIII on incident management and exchange of information within the EU regulatory network, and Module XIV on international collaboration.

At this stage, there are two population-specific considerations chapters under development to cover Pregnancy and breast-feeding (Chapter P III) and Geriatric population (Chapter P IV), which are planned to be released for public consultation in the second quarter of 2016.

The Introductory cover note has been updated to reflect this revised GVP structure, the new release of final GVP Module XVI Addendum on Educational Materials and the concomitant launch of new consultations on the revised GVP Module XV and Biologicals-specific GVP guidance.

→ Link to EMA GVP Page → Direct link to GVP Introductory cover note

1.2.2 EMA issues draft revisions of GVP Module XV on Safety Communication (15-Dec-2015) The EMA has released for consultation a draft revision of the GVP Module XV, which covers Safety Communication (Rev. 1). The changes include a new concept of core EU DHPCs (Direct Healthcare Professional Communication) for the situation where a common DHPC prepared at EU level is not suitable for all Member States, in which case the PRAC/CHMP would agree on core messages only. It also brings the possibility for one MAH to act on behalf of other MAHs in situations where several MAHs are concerned.

Associated templates have also been released for consultation, including a revised DHPC template and a new template for the Communication Plan for Direct Healthcare Professional Communication (CP DHPC).

Comments on these documents are expected by 29-Feb-2016.

→ Link to EMA GVP Page → Link to draft GVP Module XV (Rev. 1) → Link to draft DHPC Template (Rev. 1) → Link to draft CP DHPC Template

1.2.3 EMA issues new Biologicals-specific GVP guidance for consultation (15-Dec-2015) The EMA has released a draft of a new Product or Population-specific considerations guidelines that are expected to provide additional guidance to the GVP Modules. This new document covers Biological Medicinal Products, which refer to 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.

This Product-Specific Considerations Chapter is intended to complement other GVP Modules and ensure that specific challenges associated to biologicals are addressed, which include immunogenicity, manufacturing variability, stability and product traceability.

With due consideration for these challenges, the document provides additional guidance for various Pharmacovigilance activities, including Management and reporting of adverse reactions, Risk Management, Periodic safety reporting, Signal Management and Safety communication.

Comments on this document are expected by 29-Feb-2016.

→ Link to EMA GVP Page → Link to new draft of Biologicals-specific GVP Guideline

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1.2.4 Update from ICH December 2015 Meetings in Jacksonville FL, USA (16-Dec-2015) The new International Council for Harmonisation (ICH) met in Jacksonville, USA, from 5 to 10-Dec-2015. In addition to its Expert Working Groups and Management Committee, the new ICH Assembly met in person for the first time and reviewed the application process for new Members and Observers with the view to increase the international outreach of ICH. The Assembly also finalised its rules of procedure, which reflect the new emphasis on clearer governance, transparency and openness in the operation of the reformed ICH.

Some of the key achievements at this meeting include progress made on a draft guideline for multi-regional clinical trials (ICH E17) and agreement on a draft guideline on genomic sampling data (ICH E18). A draft revision to the Questions and Answers document on clinical evaluation of QT prolongation (ICH E14 Q&A). Progress was also made on the draft addendum to the guideline on statistical principles for clinical trials (ICH E9) on providing a structured framework for improved clinical trial planning, conduct, analysis, and interpretation.

The ICH MedDRA Management Board confirmed the implementation of a 27th SOC in March 2016 for MedDRA Version 19.0 which will be called Product issues, to include terms related to product quality concepts. Four Standardised MedDRA Queries (SMQs) will also go into production in March 2016, which include 3 new topics (DRESS, Hypoglycaemia and Medication errors) and a revised SMQ (Pulmonary hypertension). In addition, the Board endorsed the second edition of the CIOMS SMQ IWG report, “Development and Rational Use of Standardised MedDRA Queries (SMQs): Retrieving Adverse Drug Reactions with MedDRA”, which is scheduled to be published in 2016 by CIOMS.

The next ICH meetings will be held from 11 to 16-Jun-2016 in Europe.

→ Link to ICH Press Release → Link to MedDRA Press Release

1.2.5 FDA issues draft guidance on Safety Assessment for IND Safety Reporting (17-Dec-2015) The FDA has issued a new draft guidance entitled “Safety Assessment for IND Safety Reporting”, which provides recommendations to sponsors on developing a systematic approach to investigational new drug application (IND) safety reporting for human drugs and biological products developed under an IND. More specifically, the draft guidance covers the composition and role of a safety assessment committee, aggregate analyses for comparison of adverse event rates across treatment groups, planned unblinding of safety data, reporting thresholds for IND safety reporting, and the development of a safety surveillance plan.

This draft guidance is a follow-on to the guidance for industry and investigators entitled “Safety Reporting Requirements for INDs and BA/BE Studies” that was issued in December 2012 to provide recommendations on how to identify and evaluate important safety information that must be submitted to FDA and all participating investigators, including a recommendation that sponsors develop a safety assessment committee.

Comments on the draft guidance are expected by 16-Feb-2016.

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

1.2.6 ICH E18 on Genomic Sampling enters consultation period (18-Dec-2015) The ICH E18 Guideline on Genomic Sampling and Management of Genomic Data reached Step 2b of the ICH Process in December 2015 and it has now entered the consultation period (Step 3). This new guideline is proposed to provide guidance on genomic sample collection to evaluate efficacy and safety of a drug for regulatory approval.

Stakeholders from EU, USA, Japan, Canada and Switzerland are encouraged to submit their comments to their respective Regulatory Authorities, who are expected to notify the consultation separately.

→ Link to ICH News Release → Link to ICH E18 Information

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1.2.7 Update on the EU Clinical Trial Regulation (18-Dec-2015) The EMA has published a new document entitled “Delivery time frame for the EU portal and EU database”, which provides updated information regarding the implementation of the new EU Clinical Trial Regulation and the associated timelines.

As a reminder, the new Clinical Trial Regulation (EU No 536/2014) will not apply until six months after these IT platforms have become fully functional. Although the Regulation specified that this would not happen before 28-May-2016, the new document clarifies that the implementation date is now planned in October 2018. A three-year transition period will then start until the EU Clinical Trials Directive 2001/20/EC is no longer applicable in October 2021.

The document however specifies that this is a maximum timeline and every effort will be made to bring the Regulation into application as soon as possible. Any adjustment to an earlier time will be agreed with the EMA Management Board and communicated by the Agency.

→ Link to EMA Delivery Timeframe Document

1.2.8 EMA Management Board adopts revised EudraVigilance Access Policy (18-Dec-2015) Following a broad public consultation, the EMA has now issued a revised version of the EudraVigilance Access policy, which will provide increased access to ADR reports.

The Agency has made data from EudraVigilance publically available since 2011 and the revised policy brings a series of changes, including access to more information for the public and academic researchers. New arrangements are also defined for the Uppsala Monitoring Centre (UMC) of the World Health Organization (WHO) and regulatory authorities in countries outside the EEA.

As described in the EudraVigilance Stakeholder Change Management Plan published in October 2015, MAHs will be granted enhanced access to the EudraVigilance in support of their signal detection and other pharmacovigilance legal obligations.

These changes will come into effect in the third quarter of 2017 in parallel with EMA implementing a series of technical improvements to the EudraVigilance system.

→ Link to EMA Press Release → Link to EMA Delivery Timeframe Document

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 Swissmedic prepares switch to full electronic ICSR reporting (16-Dec-2015) The Swiss Agency has issued a new announcement that provides the current status of ICSR electronic reporting. Both the E2B Gateway and ElViS have proved effective and although hard copy reports are still accepted, the Agency is evaluating the time point from which reports will be required to be submitted electronically. The intention is for companies with fairly low report volumes to report entirely via ElViS as of mid-2016 and from that date, Swissmedic will also forward reports from the regional pharmacovigilance centres to companies entirely electronically. It is also specified that from 2016, companies will be charged CHF 10’000 for each new activation to use the E2B Gateway.

Swissmedic has also released a revised version of its guidance for Industry on the electronic exchange of ICSRs through the Gateway.

→ Link to Swissmedic announcement → Link to guidance on Gateway

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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

31-Jan-2016 EMA Consultation on draft guideline for Post Authorisation Efficacy Studies (Link) 118

16-Feb-2016 FDA Consultation on draft guidance on Safety Assessment for IND Safety Reporting (Link)

119

29-Feb-2016 EMA Consultation on draft revisions of GVP Module XV on Safety Communication (Link)

119

29-Feb-2016 EMA Consultation on new Biologicals-specific GVP guidance (Link) 119

01-Mar-2016 Implementation of 27th SOC in MedDRA (Link) 112

01-Apr-2016 EMA guideline on use of Pharmacogenomics in Pharmacovigilance comes into effect (Link)

118

13-Jun-2016 European PSUR Repository will become mandatory to use (Link) 114

01-Jul-2016 Start of the transition phase for the implementation of international standards for the identification of medicinal products (IDMP) in Europe (Link)

118

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

117

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

119

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2. PRODUCT SAFETY ANNOUNCEMENTS

2.1 Valproate ANSM presents results of survey on new prescribing and delivery conditions (02-Dec-2015) Despite the Dear Doctor Letters sent since May 2015 to remind doctors about the new conditions of prescription and delivery for women of childbearing potential, these conditions appear insufficiently known. A phone survey was performed in October 2015: 77% of pharmacies were informed about the new measures but 62% of the patients were not or insufficiently informed. 94% of them have not signed the treatment agreement yet and 55% do not have a prescribing form from a specialist although the new requirements apply in January 2016 and Pharmacies would face difficulties to deliver Valproate after this date.

The results were presented during a press conference from ANSM.

→ Link to Le Quotidien du Médecin Article (in French)

2.2 Rosiglitazone (Avandia®, combined products and generics) FDA eliminates the Risk Evaluation and Mitigation Strategy (REMS) (16-Dec-2015) The FDA has announced that it is eliminating the Risk Evaluation and Mitigation Strategy (REMS) for rosiglitazone-containing type 2 diabetes medicines, as it is no longer necessary to ensure that the benefits of these medicines outweigh their risks.

This follows the 2013 decision to remove some restrictions after a review showed no elevated risk of heart attack or death with rosiglitazone compared to standard type 2 diabetes medicines. This review did not confirm the signal from a meta-analysis reported in 2007, which led the EMA to suspend the medicine in September 2010, while the FDA decided to impose severe restrictions at the time.

→ Link to FDA MedWatch alert

2.3 Fingolimod (Gilenya) EMA makes new recommendations to minimise risks of PML and skin cancer (18-Dec-2015) The EMA has issued new advice on the potential risks related to the immunosuppressive effect of the multiple sclerosis medicine Gilenya in order to minimise the risk of progressive multifocal leukoencephalopathy (PML) and basal cell carcinoma.

So far 3 confirmed cases of PML have been reported in patients who had not been previously treated with another immunosuppressive medicine, and 151 cases of basal cell carcinoma have been reported. The EMA recommends that patients should be evaluated before and during treatment with Gilenya to allow early identification of signs and symptoms. This includes a baseline MRI scan to serve as a reference to confirm any suspicion of PML, and a medical evaluation of the skin before and during treatment with Gilenya.

→ Link to EMA Press Release

2.4 Posaconazole (Noxafil) FDA approves changes to prevent additional dosing errors (04-Jan-2016) The FDA has issued a warning to alert that differences in dosing regimens between the two oral formulations of the antifungal Noxafil have resulted in dosing errors. Since November 2013, the FDA has received 11 reports of medication error, including one fatal case. The packaging and drug labels were revised to alert that the two oral formulations of Noxafil cannot be substituted for each other and prevent additional medication errors.

→ Link to FDA MedWatch alert

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3. DEAR DOCTOR LETTERS AND SAFETY NEWSLETTERS

3.1 ANSM Dear Doctor Letters Dear Doctor Letters sent in December 2015 are now available on the French Agency's website (all in French). Letters associated to safety concerns include the following:

• Viekirax (ombitasvir, paritaprévir, ritonavir) with or without Exviera (dasabuvir) : not recommended in patients with hepatic impairment

• Codeine: new restrictions in the treatment of cough • Nicorandil: new contraindications, new warnings • Midodrine: SmPC modifications

→ Link to ANSM Page

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 letters were issued in November 2015:

• Thalidomide: reduced starting dose in patients older than age 75 years • Mycophenolate mofetil (CellCept): pregnancy-prevention advice • Nicorandil (Ikorel): second-line treatment for angina; risk of progressive ulceration • Dimethyl fumarate (Tecfidera): new measures to minimise the risk of PML

→ Link to MHRA Page

3.3 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 eliminates the Risk Evaluation and Mitigation Strategy (REMS) for rosiglitazone-containing diabetes medicines

→ Link to FDA Page

3.4 New issue of MHRA “Drug Safety Update” The December issue of Drug Safety Update was published on 14-Dec-2015. It includes the following topics:

• Thalidomide: reduced starting dose in patients older than age 75 years • Mycophenolate mofetil (CellCept): new pregnancy-prevention advice for women and men • Bisphosphonates: very rare reports of osteonecrosis of the external auditory canal • Antiretroviral medicines: updated advice on body-fat changes and lactic acidosis

→ Link to Drug Safety Update (December)

3.5 New issues of Canadian “Health Product InfoWatch” The new issue of “Health Product InfoWatch” has been published, which provides an overview of health product advisories and safety reviews published in the previous month by Health Canada. The November issue was published on 17-Dec-2015 and includes a review of Finasteride and suicidality. The monthly recap covers several medicinal products including Abilify (aripiprazole), Avastin (bevacizumab) and Votrient (pazopanib).

→ Link to Newsletter

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3.6 New issue of WHO Pharmaceuticals Newsletter The latest edition of the WHO Pharmaceuticals Newsletter (N°6, 2015) 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 identified in the WHO VigiBase and the corresponding responses from MAHs:

• Atomoxetine – Neutropenia in paediatric patients • Deferasirox – Pancreatitis in paediatric patients • Desloratadine – Aggressive reaction

→ Link to WHO Pharmaceuticals Newsletter (N°6, 2015)

3.7 New issue of WHO Drug Information The latest edition of the WHO Drug Information, Vol. 29 No 4, is now available. The Safety news section provides the latest information on ADR reports, regulatory warnings and labelling changes. This issue also includes an article presenting the Council for International Organizations of Medical Sciences (CIOMS).

→ Link to WHO Drug Information

4. OTHER PUBLICATIONS BY REGULATORY AGENCIES

4.1 US Food and Drug Administration (FDA)

4.1.1 Drug Safety and Risk Management Advisory Committee: New material available The Drug Safety and Risk Management Advisory Committee met on 05-Nov-2015 in a Joint Meeting with the Antimicrobial Drugs Advisory Committee to discuss the Benefits and Risks of Systemic Fluoroquinolone Antibacterial Drugs in several indications. The Committees made several recommendations, which include strengthening boxed warnings, clarifying medication guides and implementing a Risk Evaluation and Mitigation Strategy (REMS). In addition to the material released earlier, the transcript of the meeting has now been published.

The Drug Safety and Risk Management Advisory Committee met again on 10-Dec-2015 in a Joint Meeting with the Pulmonary-Allergy Drugs Advisory Committee to discuss the safety of codeine in children 18 years of age and younger and considered that the use of codeine in children should be restricted further and should not remain available in OTC products. The slides and webcasts of the meeting are now available.

→ Link to FDA Page

4.1.2 New study explores impact of electronic prescribing on medication errors The FDA has released the report of a study that evaluated the impact of electronic prescribing — called computerized prescriber order entry (CPOE) — on the occurrence of medication errors. While these systems create opportunities to enhance patient safety, they also have potential for introducing new types of prescribing errors. The project investigates ways to better identify, understand, and prevent electronic ordering errors in the future.

→ Link to Study Report

4.1.3 New FAERS Quarterly Data Files available The FDA has made available the files with the extract from the FAERS database (FDA Adverse Event Reporting System) for the third quarter of 2015.

→ Link to FAERS Quarterly Data Files Page

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4.1.4 FDA announces 8th Annual Sentinel Initiative Public Workshop As already mentioned in our previous issue, the Eighth Annual Sentinel Initiative Public Workshop will take place on 03-Feb-2016 in Washington, DC and a live webcast is also available for those unable to attend in person. Presentations will include an update on the state of FDA’s Sentinel Initiative, overview of the transition from the Mini-Sentinel pilot to the full Sentinel System, and description of key activities and uses of the Sentinel System in 2015. In addition, panelists will discuss the future of the Sentinel System and opportunities to expand its capabilities.

→ Link to Sentinel Workshop Registration Page → Link to Federal Register Notice

4.2 European Medicines Agency (EMA)

4.2.1 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. Since January 2015, translations in all official EU languages as well as Norwegian and Icelandic are also made available.

The list of signals discussed at the December PRAC meeting was published on 06-Jan-2016 and includes recommendations to update the product information for the following combination of Product / Signal:

• Hormone replacement therapy (HRT) medicinal products – Increased risk of ovarian cancer • Human fibrinogen / human thrombin – Intestinal obstruction

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

4.2.2 EMA issues new CHMP Meeting Material The highlights of the December meeting of the CHMP have been published.

As communicated through Press Releases (see section 2), the CHMP provided new advice to minimise the risk of PML and basal cell carcinoma in patients treated with the multiple sclerosis medicine Gilenya (fingolimod).

The CHMP also provided an update on Xarelto (rivaroxaban), indicating that it is evaluating whether a defect with a test device used in a study of the anti-clotting medicine had an impact on the ROCKET-AF study results. The CHMP expects to conclude its assessment in the first quarter of 2016.

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 (14 to 17-Dec-2015)

4.2.3 EMA issues new Pharmacovigilance Programme Update The EMA has published a new issue of the Pharmacovigilance Programme Update (issue N°6), which is published quarterly to provide companies with information on the development of enhanced systems and help them prepare for business changes to come. It provides an update on the current status and timelines for a number of activities including the Medical Literature Monitoring (MLM) service, the Database of Medicinal Products (Article 57), the EudraVigilance System enhancements, and the PSUR repository.

→ Link to EMA Pharmacovigilance Programme Update (issue 6)

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4.2.4 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 7 new products have been added to the list in November 2015.

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

4.2.5 EMA issues new recommendations to prevent Medication Errors As introduced in November 2015, the EMA now systematically communicates on additional measures to prevent medication errors for specific medicines. A new webpage has been created to present such product-specific guidance to patients and healthcare professionals. The page has been updated to include guidance for the following products:

• Blincyto (blinatumomab) • Obizur (susoctocog alfa)

→ Link to EMA Recommendations on medication errors

4.2.6 EMA issues new information on outcome of PSUR assessment for NAPs Following the implementation of the single assessments 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 completed in September and October have been published and variations are required for the following substances:

• Hydrochlorothiazide / spironolactone • Amitriptyline / perphenazine

→ Link to PSUR Single Assessments Outcomes Page

4.2.7 CMDh issues new PSUR Assessment Reports for NAPs In line with the Best Practice Guide to facilitate European Work Sharing of PSURs for Nationally Authorised Products (NAPs) during the transition period, the conclusions of the Assessment Report are published on the CMDh website. Following the implementation of the Single Assessment Procedure for NAPs, this will be gradually replaced by the publication on the EMA website started in July 2015.

The MAHs of products for which there are no routine PSUR submission requirements have to take account of final assessment conclusions and submit a variation within 90 days, as necessary.

Summaries of PSUR Assessment Reports have been published for the following products on 06-Jan-2016: Didanosine, Epirubicin, Felbamate, Folinic acid / (di)sodium folinate / calcium folinate / calcium levofolinate, Gadopentetic acid dimeglumine, Imipenem/cilastatin, Labetalol, Macrogol 4000 and combinations, Mesalazine, Nedocromil, Paracetamol for infusion, Quetiapine fumarate, Ropinirole, Strontium (89Sr) Chloride, Tiagabine (hydrochloride), Tixocortol, Tixocortol/chlorhexidine.

→ Link to Summaries of Assessment Reports

4.2.8 EMA interactions with Patients’ and Healthcare Professionals’ Organisations The EMA has published the report 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 16-Sep-2015. This was a workshop on risk minimisation measures, which included an overview of the regulatory environment and current practices/experience in the implementation and evaluation of the effectiveness of additional risk minimisation.

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The minutes of the presentation of the joint meeting of 17-Sep-2015 have also been published. Participants were updated on a number of initiatives and ongoing activities including the new pharmacovigilance systems and services. Presentations also included the results of the survey to National Competent Authorities and the results from VISUALIZE research study (PROTECT project).

→ Link to EMA Meeting Page (16-Sep-2015) → Link to EMA Meeting Page (17-Sep-2015)

4.3 UK Agency (MHRA)

4.3.1 CPRD plans to redevelop its website The Clinical Practice Research Datalink (CPRD) is a service that provides access to high-quality anonymised NHS primary care and linked health care data for research in drug safety, amongst other topics. CPRD is planning to redevelop its website and is calling for feedback on how the current website is used to assist with the design of the new website.

→ Link to MHRA News Release

4.4 French Agency (ANSM)

4.4.1 ANSM provides update on PRAC/CHMP/CMDh meetings Following the PRAC meeting of December 2015, ANSM has issued a document on the ongoing evaluation of the risks of PML associated with natalisumab, ANSM recommends to strictly follow the SmPC and to monitor symptoms of PML.

→ Link to the ANSM release of December 2015 (in French)

Following the CMDh meeting of November 2015, ANSM has issued a document to summarise the decisions made. No specific French position or recommendation has been issued.

→ Link to the ANSM release of November 2015 (in French)

In the same way, following the CHMP meeting of December 2015, ANSM has issued documents to summarise the decisions made but no specific French position or recommendation has been issued.

→ Link to the ANSM release for December 2015 (in French)

4.4.2 Commissions / Committees in relation with Pharmacovigilance The commission in charge of the monitoring of the risk / benefit profile issued the minutes of the meeting of 24-Nov-2015. For the following items, the commission made the following advice:

• Zinc gluconate: the safety profile remains favourable and the commission recommends SmPC update • Estramustin: request of re-evaluation of the risks and benefits • Medroxyprogesterone: the safety profile remains favourable for certain cancers and recommendations of

SmPC modifications • Reserpine / bendroflumethiazide: absention • Flavoxate: the safety profile remains favourable and recommendations of SmPC modifications

→ Link to the Minutes of the Commission – 24-Nov-2015 (in French)

The pharmacovigilance committee issued the minutes of the meeting of 07-Jul-2015, where the following topics were discussed:

• HPV vaccines: results of the national monitoring, new synthesis awaited in November 2015 • Incretin mimetics (exenatide, iliraglutide, sitagliptine, vildagliptine, saxagliptine): national monitoring to

be continued and new analysis to be presented on associated risks, including pancreatitis, pancreatic cancer, etc.

→ Link to the Minutes of the Committee – 07-Jul-2015 (in French)

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5. QUALITY ASSURANCE, INSPECTIONS AND AUDITS

5.1 MHRA issues new set of Pharmacovigilance Inspection metrics As already announced in our previous issue, the MHRA has published a new Pharmacovigilance inspection metrics report on its website, which covers inspections conducted from April 2014 to March 2015. In addition, a summary of these metrics has now been published on the MHRA Inspectorate Blog.

The MHRA performed 47 Pharmacovigilance inspections of MAHs in the period, and one additional inspection was performed at a Pharmacovigilance Service Provider. The greatest part of critical findings concerned failures in relation to safety variations and their implementation. A significant increase of Critical Findings associated with signal management was identified.

→ Link to MHRA Blog Release → Link to MHRA Metrics Report

6. DRUG SAFETY AND LIABILITY RISK

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

7. OTHER NEWS AND RESOURCES

7.1 DSRU contributes to new book on safety of medicines in psychiatry The Drug Safety Research Unit (DSRU) has announced the release of a new book entitled “Pharmacovigilance in Psychiatry”. DSRU has contributed a chapter describing DSRU’s research on the safety of medicines in psychiatry and the use of Prescription-Based Event Monitoring Methods.

→ Link to DSRU Announcement

7.2 New issue of CIOMS Newsletter The December 2015 Newsletter (Issue 14) includes an obituary for Dr Juhana J. Idänpään-Heikkilä, who was Secretary-General of CIOMS from 2000 to 2006.

→ Link to CIOMS Newsletter

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8. CONFERENCES AND TRAINING EVENTS

DIA Events → Pharmacovigilance and Risk Management Strategies 2016

January 25 – 27 in Washington DC, USA → Pre-Marketing Clinical Safety

January 26 – 27 in London, UK → MHRA/DIA Excellence in Pharmacovigilance

February 01 – 05 in London, UK

→ Introduction to Signal Detection and Data Mining March 07 in Washington DC, USA

→ Benefit/Risk Management March 10 – 11 in Prague, Czech Republic

→ Premarketing Clinical Safety and Pharmacovigilance March 21 – 22 in Washington DC, USA

→ 28th Annual EuroMeeting April 06 – 08 in Hamburg, Germany

DSRU Events → Medical Aspects of Adverse Drug Reactions

January 20 – 22 in Southampton, UK → Monitoring Safety in Clinical Trials and Drug Development

February 03 – 04 in London, UK → Back to Basics in Pharmacovigilance

February 24 – 25 in Fareham, UK → EU Regulations and Guidelines for Pharmacovigilance

March 09 – 10 in London, UK

Other Events → Faculty of Pharmacy Paris V – Drug exposure and pregnancy (event in French)

January 18 in Paris, France → EGA – 9th Pharmacovigilance Conference

January 27 in London, UK → IFIS – Pharmacovigilance and Literature monitoring (event in French)

January 29 in Paris, France → IFIS – Pharmacovigilance Mission and Responsibilities of the Qualified Pharmacist (event in French)

February 08 in Paris, France → Virtue Insight – 10th Pharmacovigilance 2016

February 23 – 24 in London, UK → RQA – Practical Pharmacovigilance Auditing

March 08 – 10 in Cambridge, UK → IFIS – Pharmacovigilance Inspection (event in French)

March 10 in Paris, France → IFIS – Case Management (event in French)

March 11 in Paris, France → CBI – IDMP EU

March 16 – 17 in Barcelona, Spain → IFIS – Role, missions and responsibilities in Pharmacovigilance (event in French)

March 17-18 and April 08 in Paris, France