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Safety Observer Issue N°132 - March 2017

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Clinical Safety & Pharmacovigilance Regulatory Intelligence Review

Issue N°132 - March 2017

HIGHLIGHTS

CIOMS issues new Guide to Active Vaccine Safety Surveillance This new publication focuses on the needs of the country organizations responsible for developing vaccines safety surveillance strategies and implementing new vaccination programmes into resource-limited environments.

EMA clarifies PV requirements for herbal and homeopathic products The EMA has published a Note for Clarification regarding Pharmacovigilance requirements and EudraVigilance access applicable to herbal and homeopathic medicinal products, which depend on the registration procedure followed.

EFPIA issues Position Paper on Post-Approval Change Management The EFPIA has issued a new Position Paper that describes the challenges with the current landscape for managing variations, and presents opportunities and recommendations for global convergence and improvement to facilitate patients’ timely access to quality medicines and up-to-date safety information.

EFPIA welcomes publication of European Study on Off-Label Use The EFPIA has also commented the results of a European study on off-label use and calls for policy measures to prevent the promotion of off-label use for economic reasons.

EMA warns about risk of toe amputation with SGLT2 inhibitors Information about this risk will be included in the prescribing information for all products in the class, which are used in the treatment of type 2 diabetes.

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IN THIS ISSUE

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

1.1 Newly Applicable Standards .............................................................................................................................. 3 1.1.1 CIOMS issues new Guide to Active Vaccine Safety Surveillance ................................................................... 3 1.1.2 FDA extends validity of guidance on Dear Health Care Provider Letters ..................................................... 3 1.1.3 ENCePP issues updated EU PAS Register Guide ........................................................................................... 3 1.1.4 New release of the EU PSUR Repository now in production ........................................................................ 3 1.1.5 France updates requirements for Clinical Trial Safety Reporting ................................................................ 4 1.1.6 English MedDRA Version 20.0 now available ................................................................................................. 4 1.1.7 EMA clarifies PV requirements for herbal and homeopathic products ........................................................ 4

1.2 Developments to Watch ..................................................................................................................................... 5 1.2.1 EFPIA issues Position Paper on Post-Approval Change Management ......................................................... 5 1.2.2 ICH issues reports of November 2016 Meetings in Osaka, Japan ................................................................. 5 1.2.3 ICH issues presentation of reports of ICH E6 (R2) GCP Guideline ................................................................. 5 1.2.4 EMA launches consultation on revised policy on access to documents ...................................................... 5 1.2.5 EFPIA comments publication of European Study on Off-Label Use ............................................................. 6

1.3 Beyond the Scope of Safety Observer ............................................................................................................... 6 1.4 The Safety Observer Tracker ............................................................................................................................. 7

2. Product Safety Announcements ............................................................................................................................ 7

2.1 Fluoride-based medicinal products .................................................................................................................. 7 2.2 Selexipag (Uptravi) ............................................................................................................................................. 7 2.3 Docetaxel ............................................................................................................................................................ 8 2.4 SGLT2 inhibitors ................................................................................................................................................. 8 2.5 Valproate ............................................................................................................................................................ 8

3. Dear Doctor Letters and Safety Newsletters ......................................................................................................... 9

4. Other Publications by Regulatory Agencies ........................................................................................................ 10

4.1 US Food and Drug Administration (FDA) ......................................................................................................... 10 4.2 European Medicines Agency (EMA).................................................................................................................. 11 4.3 UK Agency (MHRA) ........................................................................................................................................... 14 4.4 French Agency (ANSM) ..................................................................................................................................... 14

5. Quality Assurance, Inspections and Audits ......................................................................................................... 14

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 CIOMS issues new Guide to Active Vaccine Safety Surveillance (Feb-2017) The Council for International Organizations of Medical Sciences (CIOMS) has announced the availability of the CIOMS Guide to Active Vaccine Safety Surveillance in its library of documents available for purchase. Please note that it is now possible to purchase publications online with a credit card through the CIOMS e-shop.

This CIOMS publication focuses on the special needs of the country level organizations responsible for developing vaccines safety surveillance strategies and implementing new vaccination programmes into resource-limited environments. It provides a structured process for evaluating whether significant knowledge gaps exist, whether passive safety surveillance is adequate, and if not, methods for and practical aspects of conducting active vaccine safety surveillance with associated case studies.

→ Link to CIOMS Page

1.1.2 FDA extends validity of guidance on Dear Health Care Provider Letters (08-Feb-2017) The FDA has re-issued the final guidance entitled “Dear Health Care Provider Letters: Improving Communication of Important Safety Information” in order to extend the expiration date to 31-Jan-2020.

This guidance published in January 2014 offers specific recommendations to industry on the content and format of Dear Health Care Provider (DHCP) letters. It provides recommendations on when to use a DHCP letter, the types of information to include and how to organize it, and formatting techniques to make the information more accessible.

→ Link to FDA Guidance

1.1.3 ENCePP issues updated EU PAS Register Guide (14-Feb-2017) 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).

A new version of the EU PAS Register Guide is available to replace the previous version issued in July 2016.

→ Link to EU PAS Register Page

1.1.4 New release of the EU PSUR Repository now in production (20-Feb-2017) The EU PSUR Repository has become mandatory to use for all authorised medicines since 13-Jun-2016 and MAHs should no longer submit their PSURs to National Competent Authorities.

An updated version of the PSUR Repository has just been released, which provides the ability to indicate if an RMP is included in the submission for Centrally Authorised Products. Defect fixes and improvements to the PSUR Repository notifications have also been implemented.

Details are available in updated Release Notes and the guidance available has been revised accordingly, including the PSUR Repository User Guidance documents for both MAHs and NCAs.

→ Link to PSUR Repository Page

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1.1.5 France updates requirements for Clinical Trial Safety Reporting (28-Feb-2017) The ANSM has issued a revised version of the document "immediate safety reporting", which takes into account decree 2016-1537 of 16-Nov-2016 and clarifies the requirements applicable to the Sponsor:

• The reporting to ANSM of SUSARs associated with death and life-threatening immediately (the principle of "no later than seven days" has been removed)

• Specifically for trials with healthy volunteers, the reporting to ANSM of all other Serious Adverse Events that occurred in France

• The modified definition of New Events The ANSM has also updated the explanatory note for SUSAR reporting accordingly as well as the corresponding page on its website.

→ Link to ANSM synthesis "immediate safety reporting" (in French) → Link to ANSM explanatory note for SUSAR (in French) → Link to ANSM explanatory note for SUSAR (in English) → Link to ANSM webpage on safety reporting (in French)

1.1.6 English MedDRA Version 20.0 now available (01-Mar-2017) The English release of MedDRA Version 20.0 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.

Additional MedDRA Guides are available on the MedDRA website, including Introductory Guides and a presentation of the changes introduced with Version 20.0. This includes revisions to Medication Errors and Product Use Issues Hierarchies and structural changes to existing SMQs.

→ Link to MedDRA release announcement → Link to MedDRA Page

1.1.7 EMA clarifies PV requirements for herbal and homeopathic products (02-Mar-2017) The EMA has published a Note for Clarification regarding Pharmacovigilance requirements and EudraVigilance access applicable to Traditional herbal medicinal products and simplified registrations for homeopathic medicinal products.

The document clarifies that Pharmacovigilance requirements do not apply to homeopathic medicinal products registered further to the special, simplified registration procedure under Article 14(1) of Directive 2001/83/EC. As a result, there are no routine ADR or PSUR reporting requirements for these products and there is no need to submit medicines information to the Article 57 database (XEVMPD).

On the other hand, Pharmacovigilance requirements apply to other homeopathic medicinal products and to herbal medicinal products. It is however specified that routine PSUR reporting requirements do not apply to those herbal products registered further to a simplified registration procedure (traditional use-registration). The holders of registration for these products should submit information to XEVMPD in order to gain access to EudraVigilance once the simplified reporting is implemented.

→ Link to EMA Note for Clarification

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1.2 Developments to Watch

1.2.1 EFPIA issues Position Paper on Post-Approval Change Management (16-Feb-2017) The EFPIA (European Federation of Pharmaceutical Industries and Associations) has issued a new Position Paper entitled “Optimising Post-Approval Change Management for Timely Access to Medicines Worldwide”, which describes the challenges with the current landscape for managing variations, and presents opportunities and recommendations for global convergence and improvement. The paper addresses both quality variations and safety label updates, and the recommendations aim to bring consistency and predictability to the global management of variations, whilst contributing to patients’ timely access to quality medicines and the latest safety information.

→ Link to EFPIA Announcement → Link to EFPIA Position Paper

1.2.2 ICH issues reports of November 2016 Meetings in Osaka, Japan (08-Feb-2017) As already reported previously, the ICH Assembly and Management Committee met in November 2016 and the corresponding reports are now available.

The Assembly report reflects the main decisions taken by the ICH Assembly and the MedDRA Management Board. Highlights include the adoption of ICH E6 (R2) to modernise the 1996 GCP Guideline and the agreement to renew the package of guidelines that relate to GCP and clinical trial design. It was also decided to begin work on the development of a new ICH E19 guideline to harmonise requirements on the collection of safety data during late stage pre-market and post-approval clinical studies. An updated implementation guide for the ICH E2B(R3) ICSR guideline and Q&A document have also been adopted and should be available shortly.

New MedDRA SMQs (Standardised MedDRA Queries) will go into production in March 2017 and condensed versions of the PtC documents for translation into all MedDRA languages will be made available to users.

A separate report reflects the main decisions taken at the ICH Management Committee meeting, which relate to its responsibilities for oversight of ICH operational aspects, including administrative and financial matters.

→ Link to ICH Assembly Page → Direct link to ICH Assembly Report → Link to ICH Management Committee Page

1.2.3 ICH issues presentation of reports of ICH E6 (R2) GCP Guideline (10-Feb-2017) As reported above, the integrated addendum ICH E6 (R2) has been adopted by the ICH Assembly to modernise the 1996 GCP Guideline and facilitate the implementation of innovative approaches in clinical trials. This amendment needs to be implemented by ICH members through national and regional guidance and it was already adopted in Europe on 15-Dec-2016.

An associated training presentation has been developed by the Expert Working Group, which is now available on the ICH website.

→ Link to ICH E6 (R2) Training Presentation

1.2.4 EMA launches consultation on revised policy on access to documents (17-Feb-2017) The EMA has launched a new consultation on the proposed revision to its policy on access to documents, which describes the rules to grant access to the documents held by the EMA.

The new version extends the scope of the policy to include both scientific and corporate documents. It also takes into account the Agency’s proactive approach to transparency.

The revisions are highlighted in the policy document and stakeholders can submit their comments on the proposed revisions until 18-May-2017.

→ Link to EMA News Release → Link to EMA Page on Access to Documents

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1.2.5 EFPIA comments publication of European Study on Off-Label Use (02-Mar-2017) The EFPIA (European Federation of Pharmaceutical Industries and Associations) has issued a joint statement with other Industry Associations to welcome the results of the European Commission’s study on off-label use.

The report highlights the negative impact of off-label use, which creates uncertainties regarding the liability of healthcare professionals, undermines the EU market authorisation process and discourages R&D. As already expressed, the Industry is strictly opposed to off-label use for economic reasons, which is promoted by some authorities, and calls for corresponding policy measures.

→ Link to EFPIA Joint Statement → Link to Report of EU Study on off-label use

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 India issues new Pharmacovigilance Guideline for Biological Products (Feb-2017) The Indian CDSCO (Central Drugs Standard Control Organization) has published a new guidance document entitled “Pharmacovigilance Requirements for Biological Products”, which finalizes a draft guidance published in July 2014. This document is intended to provide guidance for the MAH in the safety surveillance activities throughout the life cycle of biological products, including vaccines. It defines the roles and responsibilities of all stakeholders and covers Pharmacovigilance Planning and Risk Minimization Activities.

→ Link to CDSCO Guideline

1.3.2 Australia issues updated Guideline on Therapeutic Product Vigilance (16-Feb-2017) The Australian TGA (Therapeutic Goods Administration) has issued an updated version of its overarching document describing Australia’s therapeutic product vigilance processes, including the guiding principles and associated tools. This document does not provide details about the responsibilities of Marketing Authorisation Holders (i.e. Sponsors in Australia), which are described in separate Pharmacovigilance Guidelines.

→ Link to TGA Therapeutic Product Vigilance Guideline

1.3.3 Good Pharmacovigilance Practice of the Eurasian Economic Union It has come to our attention recently that new requirements are expected to come into force in the Eurasian Economic Union (EAEU), which includes Belarus, Kazakhstan, Russia, Armenia and Kyrgyzstan.

The EAEU was established as part of a treaty in 2014 and a number of documents were adopted in November 2016 to promote a common drug market, including Resolution № 87 “Concerning adoption of the Good Pharmacovigilance Practice of EAEU”.

The information we were able to collect does not allow to confirm the current status of this new set of requirements, which includes the nomination of a Qualified Person for Pharmacovigilance (QPPV). We will include this topic in our monitoring and report any new development in future issues of Safety Observer.

→ Link to Lidings Law Firm Legal Update → Link to EAEU Press Release

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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

18-May-2017 EMA Consultation on revised policy on access to documents (Link) 132

01-Jun-2017 EMA guideline on Post Authorisation Efficacy Studies comes into effect (Link) 130

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) 129

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

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2. PRODUCT SAFETY ANNOUNCEMENTS

2.1 Fluoride-based medicinal products ANSM restricts the indication to children above 6 months (13-Feb-2017) Following the recommendations of the French Health Authority HAS (Haute Autorité de Santé) which do not include oral fluoride supplementation in the prevention of dental cavities in children before 6 months, the ANSM has restricted the indication of Zymaduo, Fluorex and Fluosterol to children above 6 months. This restriction of indication took effect on 07-Feb-2017.

→ Link to ANSM Point of Information (in French)

2.2 Selexipag (Uptravi) EMA initiates review of French safety signal (14-Feb-2017) The EMA has announced that it is reviewing the safety of Uptravi, which is used to treat Pulmonary Arterial Hypertension. Based on a preliminary review of available data, the EMA advises that Uptravi may continue to be used in line with the current prescribing information, both in existing and new patients. The PRAC will further explore this issue and provide final conclusions once the review is completed.

This follows the January announcement by the French Medicines Agency, who raised a signal after the death of 5 patients were reported. The issue was brought to the attention of the PRAC for further assessment and in the meantime, the ANSM requested that the product should not be used in new patients in France.

→ Link to EMA Press Release

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2.3 Docetaxel ANSM and INCa advise against use in breast cancer (17-Feb-2017) Following 6 cases of enterocolitis in neutropenic female patients treated by docetaxel for breast cancer, 5 of which were fatal, the ANSM and the French National Cancer Institute INCa (Institut National du Cancer) recommend to temporarily avoid the use of docetaxel in localized, operable breast cancers. The ANSM will ensure the supply in paclitaxel, which can be prescribed in this indication. This recommendation does not concern other indications of docetaxel but healthcare professionals are invited to exercise caution.

The ASNM also specified that a pharmacovigilance enquiry started in September 2016 is being finalised. It will be presented at the Pharmacovigilance Committee scheduled on 28-Mar-2017.

→ Link to ANSM Point of Information of 15-Feb-2017 (in French) → Link to ANSM Point of Information of 17-Feb-2017 (in French)

2.4 SGLT2 inhibitors EMA requires label warning about the potential increased risk of toe amputation (24-Feb-2017) The EMA has issued a Press Release to warn about a potential increased risk of lower limb amputation in patients taking the SGLT2 inhibitors canagliflozin, dapagliflozin and empagliflozin used for type 2 diabetes.

The review of SGLT2 inhibitors was prompted by an increase in lower limb amputations, mostly affecting the toes, in patients taking canagliflozin in two clinical trials that are still ongoing. Although this has not been observed with other medicines of the same class, the data available are limited and the risk may also apply.

The mechanism by which canagliflozin may increase the risk of amputation is still unclear at this time but patients are reminded of the importance of preventative foot care and information about the potential increased risk of toe amputation will be included in the prescribing information for all SGLT2 inhibitors.

→ Link to EMA Press Release

2.5 Valproate ANSM strengthens information on risks during pregnancy (02-Mar-2017) As of 01-Mar-2017, a pictogram alerting on the risks of taking medicinal products containing valproate or a derivative during pregnancy (Depakine, Micropakine, Depamide, Depakote, and generics) is to be included on the outer packaging. Information letters were sent to healthcare professionals and patients with at least one valproate prescription in 2016. This measure is part of the actions taken by the French agency to reduce the risks of malformation and neurodevelopmental issues associated with the exposure to valproate or its derivatives during pregnancy.

A patient card was also sent to healthcare professionals, which must be given to female patients during their annual visit together with the care agreement form and the information leaflet already available.

→ Link to ANSM Point of Information (in French)

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3. DEAR DOCTOR LETTERS AND SAFETY NEWSLETTERS

3.1 ANSM Dear Doctor Letters Dear Doctor Letters sent in February 2017 are now available on the French Agency's website (all in French). Letters associated to safety concerns include the following:

• Valproate and derivatives: availability of a patient card • Docetaxel: fatal enterocolitis cases • Levothyroxine (Levothyrox): new formulation and follow-up of at risk patients • Zolpidem (Edluar, Stilnox and generics): new prescription and delivery conditions

→ Link to ANSM Page (in French)

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 letters issued in January 2017 include the following:

• Mirena (levonorgestrel intrauterine delivery system): batch insertion tube defect • Ulipristal acetate (ellaOne): pregnancy registry • ERWINASE: notice of special handling instructions

→ Link to MHRA Page

3.3 New issue of MHRA “Drug Safety Update” The February issue of Drug Safety Update was published on 20-Feb-2017. It includes the following topics:

• Hyoscine butylbromide (Buscopan) injection: risk of serious adverse effects in patients with underlying cardiac disease

• Yellow Card reporting added to second clinical software system

→ Link to Drug Safety Update

3.4 New issue of the French Bulletin "Vigilances" The new French "Vigilances" Bulletin, number 72, has now been issued. It includes a summary of recent pharmacovigilance news and presents statistics on ADR notifications received during the third quarter of 2016, which show similar figures to the previous period.

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

3.5 New issue of Australian “Medicine Safety Update” The Australian Therapeutic Goods Administration (TGA) has issued the new edition of Medicines Safety Update (Volume 8, Number 1, February 2017). The contents include:

• Certain medicines and Progressive Multifocal Leukoencephalopathy (PML) • Aripiprazole and impulse control disorders • Vemurafenib and risk of radiation injury

→ Link to Medicines Safety Update

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3.6 New issues of Canadian “Health Product InfoWatch” The new issue of “Health Product InfoWatch” has been published, which provides an overview of safety labelling updates and safety reviews from the previous month. The February issue was published by Health Canada on 23-Feb-2017 and includes a monthly recap of Safety Reviews, which covers several products including Amiodarone, Erwinase, Fluoroquinolones, Gadolinium-based contrast agents, oral retinoid products and Selective serotonin reuptake inhibitors (SSRIs).

This issue also includes the Vaccine safety quarterly summary for Q2 2016 and a review article on the risk of intestinal perforation with colorectal stents and bevacizumab.

→ Link to Newsletter

3.7 New issue of WHO Pharmaceuticals Newsletter The latest edition of the WHO Pharmaceuticals Newsletter (N°1, 2017) 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 feature articles reporting on recent meetings and describing the introduction of an electronic system for reporting ADRs in Tanzania. As usual, the newsletter includes signals identified in the WHO VigiBase and the corresponding responses from MAHs, where available:

• Chymotrypsin and anaphylactic shock • Ganciclovir and hypoglycaemia • Lamivudine and hearing decreased

→ Link to WHO Pharmaceuticals Newsletter (N°1, 2017)

3.8 New FDA Drug Safety Podcasts The FDA Drug Safety Podcasts provide emerging safety information about drugs in conjunction with the release of Public Health Advisories and other drug safety issues. Both Podcasts and Transcripts are posted on the FDA website and the following communication has been added:

• FDA warns about rare but serious allergic reactions with the skin antiseptic chlorhexidine gluconate

→ Link to FDA Page

4. OTHER PUBLICATIONS BY REGULATORY AGENCIES

4.1 US Food and Drug Administration (FDA)

4.1.1 FDA workshop on the Sentinel PRISM Program As announced prior to the event, the FDA held a public workshop entitled “The Sentinel Post-Licensure Rapid Immunization Safety Monitoring (PRISM) Program” on 07-Dec-2016. The purpose of this workshop was to describe the Sentinel Initiative and PRISM program, which is used in the evaluation of vaccine adverse events. The workshop presented how PRISM is used by the FDA with case examples. Discussions also covered the future direction of PRISM in terms of expansion and further integration into the regulatory review process. The transcript of this workshop is now available.

→ Link to FDA Event Page → Direct link to Workshop Transcript

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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 September 2016 PRAC meeting were published on 21-Feb-2017. The PRAC did not initiate or conclude a safety referral at this meeting. The following new Safety Signals were considered:

• Lenvatinib – cholecystitis • Nivolumab – pemphigoid

→ Direct link to PRAC Meeting Minutes (26 to 29-Sep-2016)

The minutes of the October 2016 PRAC meeting were also published on 22-Feb-2017. The PRAC did not initiate or conclude a safety referral at this meeting. The following new Safety Signals were considered:

• Nivolumab, pembrolizumab – transplant rejection • Flucloxacillin – acute generalised exanthematous pustulosis (AGEP) • Enzalutamide – hepatotoxicity

→ Direct link to PRAC Meeting Minutes (24 to 27-Oct-2016)

The agenda and highlights of the latest PRAC meeting were published on 10-Feb-2017. As communicated separately (see Section 2), the PRAC concluded that SGLT2 inhibitors diabetes medicines may contribute to the risk of toe amputation. The PRAC also started the review of Uptravi (selexipag) in the context of a safety signal and initiated a new safety referral to review systemic and inhaled quinolone and fluoroquinolone antibiotics in order to evaluate the persistence of serious side effects mainly affecting muscles, joints and the nervous system. According to the agenda, the following new Safety Signals have been identified and considered:

• Dabigatran – Major haemorrhage following dabigatran interaction with simvastatin or lovastatin • Darbepoetin & various forms of epoetin – Severe cutaneous adverse reactions (SCARs) including Stevens-

Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) • Levonorgestrel – Anxiety, panic attacks, mood changes, sleep disorders and restlessness • Tick-borne encephalitis vaccine (inactivated) – Potential vaccination failure in children

→ Direct link to PRAC Meeting Highlights (06 to 09-Feb-2017)

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.

A correction was published on 27-Feb-2017 for the list of signals discussed at the PRAC meeting of 04 to 08-Jul-2016, which concerned the signal of Mouth Ulceration associated to Ferrous sulfate.

→ Link to EMA Page

4.2.3 EMA issues “Meeting Highlights” of last CHMP Meeting The highlights of the February meeting of the CHMP have been published. As communicated separately (see Section 2), the Committee endorsed the PRAC proposal to include information on potential risk of toe amputation in the prescribing information of SGLT2 inhibitors.

As announced in October 2016, the Highlights no longer include the opinions on safety variations/PSURs, which are presented in the minutes of the CHMP meeting published one month after the meeting.

→ Link to CHMP Meeting Highlights (20 to 23-Feb-2017)

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4.2.4 WEB-RADR workshop on mobile technologies and social media as Pharmacovigilance 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.

As announced prior to the event, the EMA held its second WEB-RADR workshop on 19-Oct-2016 to engage with all stakeholders and maximise the benefits of the project. The workshop report is now available.

→ Link to EMA Event Page

4.2.5 EMA workshop on “Big Data” As reported earlier, the EMA held a workshop on 14 and 15-Nov-2016 to identify opportunities for big data in medicines development and regulation, and to address the challenges of their exploitation. The workshop reviewed the advances made in the field of big data and the opportunities for its application in medicine regulation, including how it can contribute to the benefit-risk assessment of medicines.

In addition to the presentation material and video recordings released earlier, the report of the workshop is now available on the EMA Event Page.

→ Link to EMA Event Page

4.2.6 EMA Patient Registries workshop As reported previously, the EMA held 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 was designed to bring together multiple stakeholders to discuss the challenges and barriers to collaboration and identify solutions. In addition to the video recordings released earlier such, the workshop report is now available.

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

4.2.7 EMA/DIA Information Day on Medication Errors As announced prior to the event, the EMA held its first Information Day on Medication Errors on 20-Oct-2016.

This information day was an opportunity to exchange experience on the new EU Good Practice Guide on medication errors published in 2015. The objective was to raise awareness of EU pharmacovigilance obligations for medication errors and to discuss operational aspects and good practice recommendations with regard to medication error reporting, evaluation and prevention.

The presentations used during the event are now available on the EMA Event Page.

→ Link to EMA Event Page

4.2.8 EU PAS Register reaches major milestone with 1,000 registered studies The EMA has announced that the 1,000th study has been uploaded in the EU electronic Register of Post-Authorisation Studies (EU PAS Register), which was developed through the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP).

The EU PAS Register is an openly accessible platform with information on post-authorisation research in medicines already marketed in Europe and includes study protocols, study results, related publications and other relevant information, as required by EU pharmacovigilance legislation.

→ Link to EMA News Release

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4.2.9 EMA issues Educational Video on Safety Referrals A new short video has been posted on the EMA YouTube channel to explain the process for the various European Safety Referral procedures, including Art. 31, Art. 107i and Art. 20.

→ Direct link to EMA Video (What is a European Safety Referral ?)

4.2.10 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 3 new products have been added to the list in February 2017, as identified in the Summary of Changes presented on the EMA webpage. The list of dexamfetamine sulphate-containing medicinal products first included in September 2014 has also been updated (Annex XII).

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

4.2.11 EMA issues updated EURD list The EMA has published an updated EURD list, which was last revised on 28-Feb-2017. 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 and the list should be filtered by cell colour to identify all revisions. Please note that as specified in the cover note, the “Publication Date” is not revised for all types of amendments and this date cannot be used to filter all amended substances in Excel.

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

4.2.12 EMA provides updated Q&As on Pharmacovigilance Fees As communicated at the time, the Agency has started to charge and collect annual fees for nationally authorised products (NAPs). This came into effect on 01-Jul-2015 and applies annually in addition to the fees for pharmacovigilance procedures, which started in August 2014.

The EMA has published an updated set of questions-and-answers (Q&As). There is however no information presented on the nature of the revisions made.

→ Direct link to “Pharmacovigilance Fees” Q&As

4.2.13 EMA issues outcomes of imposed non-interventional PASS for NAPs The EMA is publishing the regulatory outcomes following the assessment of final study results of imposed non-interventional post-authorisation safety studies (PASS). Whereas the outcomes associated to PASS for Centrally Authorised Products (CAPs) are published as part of the European Public Assessment Report (EPAR), the outcomes for active substances contained in Nationally Authorised Products (NAPs) are presented on a dedicated webpage.

Where required, MAHs for products containing the active substance concerned by the PASS final report should submit a variation to align their marketing authorisation with the adopted outcome. MAHs for products containing the same active substance but not concerned by the PASS should consider whether the proposed changes apply to their products.

The outcome of the assessment of new PASS final study results has been published and a variation is required for the following substance:

• Cyproterone/ethinylestradiol (Changes to the conditions of the marketing authorisations)

→ Link to EMA outcomes of imposed PASS

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4.2.14 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

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 February 2017, the ANSM has issued a document to summarise the PRAC decisions. The document reminds the precautionary measures taken by the ANSM pending the final PRAC recommendations regarding Selexipag (Uptravi).

→ Link to ANSM release – February 2017 PRAC (in French)

Following the CHMP meeting of January 2017, the ANSM issued a document to summarise the CHMP decisions. The document does not include any ANSM recommendation.

→ Link to ANSM release – January 2017 CHMP (in French)

5. QUALITY ASSURANCE, INSPECTIONS AND AUDITS

5.1 EMA issues 2017 Work Plan for GCP Inspectors Working Group The EMA has published the Work Plan for 2017 for its GCP Inspectors Working Group (GCP IWG). The document describes the priorities for the group to support the performance of GCP Inspections. These priorities include support for the upcoming implementation of the new Clinical Trials Regulation.

→ Link to EMA GCP IWG Work Plan 2017

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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 Australian TGA issues results of consultations The Australian TGA (Therapeutic Goods Administration) has published the submissions it received as well as the TGA response for three recent consultation related to safety:

→ Submissions and TGA response: NSAIDs – proposed additional advisory statement → Submissions and TGA response: paracetamol and ibuprofen – proposed additional advisory statement → Submissions received: Guidance on Risk Management Plans for medicines and biologicals

7.2 Eu2P Education & Training: Applications now open for 2017-2018 As part of the European Innovative Medicines Initiative (IMI), the Education & Training project Eu2P runs numerous courses covering various aspects of medicines research and development, including pharmacovigilance. The courses range from short online courses to full Master’s programmes.

Registration is now open for the Eu2P Master programme in pharmacovigilance and pharmacoepidemiology for the academic year 2017-2018. The deadline for applications is 25-Jun-2017.

→ Link to Eu2P Master Programme Overview

7.3 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 20.0. It also includes reports from recent User Group Meetings and the schedule of upcoming meetings.

→ Link to MedDRA Messenger

7.4 WHODrug Newsletter The Uppsala Monitoring Center has published the March 2017 edition of the WHODrug Newsletter, which highlights the important changes in WHO Drug Formats coming in 2017 (B3- and C3-formats).

→ Link to WHODrug Newsletter

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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)

DIA Events → Pragmatic Approaches to Drug Safety Across the Premarketing and Postmarketing Continuum

March 20 – 22 in San Diego CA, USA → 29th Annual EuroMeeting

March 29 – 31 in Glasgow, UK → Introduction to Signal Detection and Data Mining

April 07 in Washington DC, USA → Practical Guide for Pharmacovigilance: Clinical Trials and Post-Marketing

April 10 – 11 in Dubai, UAE → Benefit/Risk Management

April 24 – 25 in Berlin, Germany → Essentials and Overview of the Regulatory Framework in Europe

April 25 – 26 in Berlin, Germany → How to Prepare for Pharmacovigilance Audits and Inspections

April 26 – 27 in Berlin, Germany → Pharmacovigilance Conference

May 10 – 11 in London, UK → China Annual Meeting

May 21 – 24 in Shanghai, China

DSRU Events → EU Regulations and Guidelines for Pharmacovigilance

March 22 – 23 in London, UK → Introduction to Pharmacoepidemiology

April 05 – 06 in Fareham, UK → Forum on UK Pharmacovigilance post-Brexit

April 26 in London, UK → Medical Aspects of Adverse Drug Reactions

May 03 – 05 in Fareham, UK → Periodic Safety Reports: PSURs and PBRERs

May 17 – 18 in Fareham, UK → Global Pharmacovigilance Regulatory Requirements: What’s New?

May 31 – June 01 in London, UK → 9th Biennial Signal Detection Conference

June 06 – 08 in London, UK → Medication Errors course

July 05 – 06 in London, UK

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Other Events → IFIS – Responsibilities of the Responsible Pharmacist in Pharmacovigilance (event in French)

March 14 in Paris, France → IFIS – Clinical Trials Safety (event in French)

March 21 in Paris, France → IFIS – PV case management (event in French)

March 30 in Paris, France → ISPE – 2017 Mid-Year Meeting

April 01 – 04 in London, UK → RQA – Systems Approach to Good Pharmacovigilance Practice (GPvP)

May 09 – 11 in Cambridge, UK → 6th Bordeaux Pharmacoepi Festival

May 10 – 12 in Bordeaux, France → PIPA – Advanced Pharmacovigilance Skills

May 16 in London, UK → Faculté de Pharmacie – Paris V – Audit and Inspection in Pharmacovigilance (event in French)

May 18 – 19, France → 3rd Annual Pharmacovigilance Europe Congress 2017

May 24 – 25 in London, UK → ISoP – Mid Year Training Course

May 25 – 26 in Bangkok, Thailand → RQA – Practical Pharmacovigilance Auditing

June 06 – 08 in Cambridge, UK → PIPA – Pharmacovigilance System Master File (PSMF)

June 08 in London, UK