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Safety Observer Issue N°125 - July 2016

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Clinical Safety & Pharmacovigilance Regulatory Intelligence Review

Issue N°125 - July 2016

HIGHLIGHTS

The use of the EU PSUR Repository has become mandatory for all authorised medicines on 13-Jun-2016 and PSURs should no longer be submitted to National Competent Authorities. The EMA has published revised guidance to accompany this important change.

The EMA has also implemented new functionalities in the EudraVigilance registration system, including the concept of a “regulatory contact point” within the EudraVigilance registration database.

The EMA Management Board has approved an updated schedule for the implementation of the new EudraVigilance System, which is now expected to go live in November 2017.

Also related to the new EudraVigilance System, the EMA has released a first batch of training modules, which cover the planned simplified ADR reporting and associated enhanced EudraVigilance functionalities, amongst other topics.

The FDA has issued the Regional Implementation Specifications for ICH E2B(R3), which is intended to support the electronic submission of ICSRs into FAERS for Medicinal and Biological Products (except Vaccines).

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IN THIS ISSUE

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

1.1 Newly Applicable Standards .............................................................................................................................. 3 1.1.1 New EU Guidance published on PSUR Submission ...................................................................................... 3 1.1.2 EMA issues revised EudraVigilance Registration guidance ........................................................................... 3 1.1.3 FDA issues ICH E2B(R3) Regional Specifications for Drugs and Biologics .................................................... 3 1.1.4 ANSM issues new guidance on submission of variations ............................................................................. 4 1.1.5 France updates requirements for immediate Clinical Trial Safety Reporting ............................................. 4

1.2 Developments to Watch ..................................................................................................................................... 4 1.2.1 EMA postpones implementation of the new EudraVigilance System .......................................................... 4 1.2.2 EMA issues Training Material related to new EudraVigilance System .......................................................... 4 1.2.3 EMA creates new webpage for the Clinical Trial Regulation EU No 536/2014 .............................................. 4 1.2.4 Update from ICH June 2016 Meetings in Lisbon, Portugal ........................................................................... 5 1.2.5 EMA communicates on results of Brexit referendum ................................................................................... 5

1.3 Beyond the Scope of Safety Observer ............................................................................................................... 5 1.4 The Safety Observer Tracker ............................................................................................................................. 6

2. Product Safety Announcements ............................................................................................................................ 6

2.1 OTC Antacids containing Aspirin ....................................................................................................................... 6 2.2 Loperamide (Imodium) ...................................................................................................................................... 6 2.3 Sumatriptan Patch (Zecuity) ............................................................................................................................. 6 2.4 Canagliflozin and Dapagliflozin ......................................................................................................................... 7 2.5 Tramadol ............................................................................................................................................................ 7 2.6 Riociguat (Adempas) .......................................................................................................................................... 7 2.7 Posaconazole (Noxafil) ...................................................................................................................................... 7 2.8 Pregabaline ........................................................................................................................................................ 7 2.9 Idelalisib (Zydelig) .............................................................................................................................................. 8

3. Dear Doctor Letters and Safety Newsletters ......................................................................................................... 8

4. Other Publications by Regulatory Agencies .......................................................................................................... 9

4.1 US Food and Drug Administration (FDA) ........................................................................................................... 9 4.2 European Medicines Agency (EMA) .................................................................................................................. 10 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 .............................................................................................................................. 16

7. Other News and Resources .................................................................................................................................. 16

8. Conferences and Training Events ........................................................................................................................ 17

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1. REGULATIONS, GUIDELINES AND OTHER STANDARDS

1.1 Newly Applicable Standards

1.1.1 New EU Guidance published on PSUR Submission (10-Jun-2016) As communicated previously, the use of the EU PSUR Repository has become mandatory for all authorised medicines on 13-Jun-2016 and MAHs should no longer submit their PSURs to National Competent Authorities. Several guidance documents have been published to accompany this change.

The EMA post-authorisation procedural advice for users of the centralised procedure has been updated with new and revised questions and answers regarding PSUR requirements. A specific “questions and answers” document has also been published regarding the PSUR repository mandatory use. Finally, new versions of the PSUR Repository User Guidance documents for both MAHs and NCAs have been released.

The CMDh (Co-ordination Group for Mutual Recognition and Decentralised Procedures – Human) has also published a revised version of its SOP on PSUR single assessment procedures (PSUSAs).

→ Link to EMA News Release → Link to EMA PSUR Page → Link to PSUR Repository Page → Link to CMDh SOP on Processing PSUSAs (track change version)

1.1.2 EMA issues revised EudraVigilance Registration guidance (17-Jun-2016) The EMA has implemented new functionalities in the EudraVigilance registration system with effect from 13-Jun-2016. This includes the concept of a “regulatory contact point” within the EudraVigilance registration database. The regulatory contact point is an individual or department authorised for communication with the EMA on behalf of the MAH. The registered EU QPPV or trusted deputy user is required to log in to the secure area of EudraVigilance and provide the regulatory contact point information.

The EMA has updated the guidance on the EudraVigilance registration accordingly, which includes a new Questions and Answers document and they are all available on new dedicated pages of the EMA website as the public pages of the current EudraVigilance website will be decommissioned in July 2016.

→ Link to EMA Notice on new functionalities → Link to EMA Notice regarding the “regulatory contact point” → Link to EMA EudraVigilance Registration Guidance Page → Link to EudraVigilance Registration Q&As → Link to EudraVigilance website announcement

1.1.3 FDA issues ICH E2B(R3) Regional Specifications for Drugs and Biologics (23-Jun-2016) The FDA has issued the Regional Implementation Specifications for ICH E2B(R3), which is intended to support the electronic submission of Individual Case Safety Reports (ICSRs) associated to Medicinal and Biological Products, except Vaccines that are covered by a separate set of specifications published in August 2015.

This document supplements the E2B(R3) Implementation Guide and describes FDA's technical approach for receiving ICSRs, for incorporating regionally controlled terminology, and for adding region-specific data elements when reporting to the FDA Adverse Event Reporting System (FAERS).

→ Link to Federal Register Notice → Link to FDA Regional Implementation Specifications

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1.1.4 ANSM issues new guidance on submission of variations (23-Jun-2016) The ANSM has issued several documents related to the quality of the variation translation, including national recommendations for translation and a template for a commitment on translation conformity.

The ANSM has also issued documents related to pending variations. The MAH can now submit a list of pending variations at the time of a new submission and obtain approval for all variations at once.

→ Link to ANSM webpage (in French)

1.1.5 France updates requirements for immediate Clinical Trial Safety Reporting (30-Jun-2016) The ANSM has issued a revised version of the document "immediate safety reporting", which was initially published in March 2016 to implement a priority processing of SUSAR for first-in-Man Studies.

The specific requirements are now applicable for all studies with healthy volunteers, whatever the clinical study phase. The ANSM has also updated the explanatory note for SUSAR reporting accordingly.

→ 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)

1.2 Developments to Watch

1.2.1 EMA postpones implementation of the new EudraVigilance System (17-Jun-2016) As communicated in the minutes of its June 2016 meeting, the EMA Management Board has approved an updated schedule for the implementation of the new EudraVigilance System, which is now expected to go live in November 2017 instead of the July 2017 timeline previously communicated.

The delay is reportedly due to the need to optimise the performance of the new system prior to its launch and the “Key Project Milestones” document has been revised accordingly.

As a reminder, the new system will offer enhanced functionalities for the reporting and analysis of suspected adverse drug reaction to all stakeholders, including simplified centralised reporting and use of the ISO ICSR (E2B(R3)) format for the submission of ICSRs. MAHs will also be granted access to the database for Signal Detection purposes through the EudraVigilance Data Analysis System (EVDAS).

→ Link to EMA Management Board: highlights of June 2016 meeting → Link to EudraVigilance Change Management Page → Direct link to “Key project milestones and summary of associated communication activities”

1.2.2 EMA issues Training Material related to new EudraVigilance System (17-Jun-2016) As reported when it was released in April 2016, the EMA has produced a document entitled: “EudraVigilance training plan”, which details the training curriculum to prepare all EudraVigilance Stakeholders on the changes to be introduced with the new EudraVigilance System expected to go live in November 2017.

In line with the plan, the Agency has now released the first batch of the planned training modules, which cover the planned simplified ADR reporting and associated enhanced EudraVigilance functionalities, the implementation of ISO ICSR/ICH E2B(R3), and the revised EudraVigilance access policy.

Both slide decks and video recordings of these training modules are made available.

→ Link to EudraVigilance Training Page

1.2.3 EMA creates new webpage for the Clinical Trial Regulation EU No 536/2014 (23-Jun-2016) The EMA has set up a new page on its website that is dedicated to the Clinical Trial Regulation EU No 536/2014. It presents all information on the activities and current status related to the implementation of this legislation, which currently expected to become applicable 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.

→ Link to EMA Page on EU Clinical Trial Regulation

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1.2.4 Update from ICH June 2016 Meetings in Lisbon, Portugal (27-Jun-2016) The International Council for Harmonisation (ICH) met in Lisbon, Portugal, from 11 to 16-Jun-2016. Building on the objective to establish itself as a truly global platform, ICH welcomed 2 new Members and 14 Observers representing regulatory authorities, regional health initiatives and pharmaceutical industry. A new Questions and Answers document on Membership and Observership has also been published.

Highlights of the meeting include the adoption of a final revised ICH guideline on format and structure of benefit-risk information in the common technical document (ICH M4E (R2)), which is expected to support regulatory decision-making through a more consistent description of information coming from clinical trial data, as well as other factors such as disease severity and availability of other treatment options.

The draft guideline on multi-regional clinical trials (ICH E17) was also endorsed and will now be released for stakeholder consultation, with adoption of the final guideline planned for 2017. Also relevant to Clinical Trials, the integrated addendum (ICH E6 (R2)) reached Step 3 of the ICH process and is now expected to be adopted later in 2016 to enable implementation of innovative approaches.

The next rounds of ICH meetings will be held from 05 to 10-Nov-2016 in Osaka, Japan, and in Spring 2017 in Montreal, Canada.

→ Link to ICH Press Release → Link to ICH Q&A document on Membership and Observership

1.2.5 EMA communicates on results of Brexit referendum (06-Jul-2016) The EMA has issued a statement to acknowledge the outcome of the referendum of 23-Jun-2016 where a majority voted against UK’s continued membership of the European Union. The EMA highlighted that its procedures and work streams are not affected by the outcome of the referendum at this time. However the future implications for the location and operations of the Agency and its 890 employees are unknown.

→ Link to EMA News Release

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 Switzerland issues revised instructions on Clinical Trial Safety Reporting (31-May-2016) The Swiss Agency has published updated instructions on the notification of safety measures and SUSARs in clinical trials. The revision brings clarification regarding the Reference Safety Information (RSI) and safety reporting modalities. The instructions and associated template are provided in English, but they are also available in German, Italian and French.

→ Link to SwissMedic Page

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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

29-Jul-2016 EMA Consultation on Draft Reflection Paper on collecting and reporting information on off-label use in pharmacovigilance (Link)

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02-Aug-2016 FDA Consultation on ICH E18 on genomic sampling and management of genomic data (Link)

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31-Aug-2016 Public Consultations on aspects of the EU Clinical Trial Regulation (Link) 123

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

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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 OTC Antacids containing Aspirin FDA to consider further action to address serious bleeding risk (06-Jun-2016) The FDA has issued a new warning about the risk of serious bleeding when using OTC aspirin-containing antacid products. Despite the existing label warnings, the FDA still receives reports of this serious safety issue and plans to convene an advisory committee to evaluate the need for additional FDA actions.

→ Link to FDA MedWatch alert

2.2 Loperamide (Imodium) FDA warns about risk of serious cardiac events due to overdose (07-Jun-2016) The FDA has issued a warning that taking higher than recommended doses of the diarrhea medicine loperamide can cause serious cardiac adverse events, including QT interval prolongation, Torsades de Pointes or other ventricular arrhythmias, syncope, and cardiac arrest. The risk may also be increased due to interacting medicines. The majority of reports concerned individuals who were intentionally misusing and abusing loperamide in attempts to self-treat opioid withdrawal symptoms or to achieve a feeling of euphoria.

→ Link to FDA MedWatch alert

2.3 Sumatriptan Patch (Zecuity) Teva decides to suspend marketing due to risks of burns scarring (13-Jun-2016) Following the June announcement that the FDA is investigating the risk of serious burns and permanent scarring with the use of Zecuity migraine patch, Teva has decided to suspend sales, marketing, and distribution. Health care professionals and patients are recommended to discontinue using the product.

→ Link to FDA MedWatch alert

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2.4 Canagliflozin and Dapagliflozin FDA strengthens Kidney Warnings and provides Risk Minimization advice (14-Jun-2016) The FDA has strengthened the existing warning about the risk of acute kidney injury for the type 2 diabetes medicines canagliflozin (Invokana, Invokamet) and dapagliflozin (Farxiga, Xigduo XR), which belong to the class of SGLT2 inhibitors. The warnings have been revised to include information about acute kidney injury and recommendations to minimize this risk, which include pre-treatment assessment and periodic monitoring of the kidney function.

→ Link to FDA MedWatch alert

2.5 Tramadol ANSM warns about the risks of medication errors in children (16-Jun-2016) Following several reports of serious side-effects associated to overdose, the French Agency stresses that clear instruction should be provided to parents by Healthcare Professionals and that the posology should be strictly followed. Symptoms of overdose and recommendations for the posology are also presented.

→ Link to ANSM website (in French)

2.6 Riociguat (Adempas) EMA recommends new contraindication following early termination of a clinical trial (24-Jun-2016) The EMA recommends that Adempas should not be used in patients with ‘symptomatic pulmonary hypertension associated with idiopathic interstitial pneumonia’ or PH-IIP, which is not an authorised use. This follows the early termination of a clinical trial after preliminary results showed an increased number of deaths and serious adverse events in this patient population. The product information for Adempas will be updated to add a contraindication for PH-IIP but the benefits continue to outweigh the risks in authorised uses, i.e. Chronic Thromboembolic Pulmonary Hypertension (CTEPH) and Pulmonary Arterial Hypertension (PAH).

→ Link to EMA Press Release

2.7 Posaconazole (Noxafil) EMA warns that tablets and oral suspension are not interchangeable (24-Jun-2016) The EMA has announced that the Product Information for Noxafil will be updated to strengthen warnings that the two oral forms cannot be interchanged at the same dose. This antifungal medicine is available as tablets and oral suspension but the recommended doses for the two forms are different and Medication Errors have caused lack of efficacy due to underdosing, and side effects due to overdose. The packaging will also be changed to prevent further dosing errors and a Dear Healthcare Professionals Letter will be issued.

→ Link to EMA Press Release

2.8 Pregabaline ANSM warns about the risks of abuse, misuse and drug addiction (30-Jun-2016) The French Agency has issued a warning about the prescription conditions of this product used to treat partial epilepsy, anxiety and neurological pain, mainly in patients suffering of addictions. Several cases of abuse have been reported and a national monitoring of addictions is in place.

→ Link to ANSM website (in French)

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2.9 Idelalisib (Zydelig) EMA issues revised Risk Minimisation Measures (08-Jul-2016) The EMA has now completed its review of Zydelig, which confirmed that the medicine’s benefits outweigh its risks in the treatment of two types of blood cancers, chronic lymphocytic leukaemia (CLL) and follicular lymphoma. The PRAC however confirmed that there is a risk of serious infections with Zydelig, including Pneumocystis jirovecii pneumonia and revised recommendations have been issued to manage this risk, including concomitant antibiotic treatment and close monitoring for signs of infection.

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

→ Link to EMA Press Release

3. DEAR DOCTOR LETTERS AND SAFETY NEWSLETTERS

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

• Thalidomide: risks of viral reactivation and pulmonary hypertension • Ifosfamide: modifications of expiry date due to increase of adverse events after this period • Tiapride: modifications of the indications and the posology • Riociguat (Adempas): contraindication in pulmonary hypertension with idiopathic interstitial pneumonia

→ 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 following letters were issued in May 2016:

• Erwinase: Vials from batch 174g should be used with a 5-micron filter needle

→ Link to MHRA Page

3.3 New issue of MHRA “Drug Safety Update” The May issue of Drug Safety Update was published on 15-Jun-2016. It includes the following topics:

• Canagliflozin (Invokana▼, Vokanamet▼): signal of increased risk of lower extremity amputations in trial in high cardiovascular risk patients

• Topical miconazole, including oral gel: reminder of potential for serious interaction with warfarin

→ Link to Drug Safety Update (June)

3.4 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 June issue was published on 30-Jun-2016 and includes a review article on Alpha-lipoic acid and serious hypoglycemic episodes. The monthly recap covers several medicinal products including BCR-ABL tyrosine kinase inhibitors, Eylea (aflibercept), Zydelig (idelalisib), proton pump inhibitors and SGLT2 inhibitors.

→ Link to Newsletter

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3.5 New issue of WHO Pharmaceuticals Newsletter The latest edition of the WHO Pharmaceuticals Newsletter (N°3, 2016) 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:

• Dabigatran and thromboembolism: analysis of case histories for risk factors • Febuxostat and allergic vasculitis

→ Link to WHO Pharmaceuticals Newsletter (N°3, 2016)

3.6 New issue of WHO Drug Information The latest edition of the WHO Drug Information, Vol. 30 No 2, is now available. The Safety news section provides the latest information on ADR reports, regulatory warnings and labelling changes.

→ Link to WHO Drug Information

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

• FDA evaluating the risk of burns and scars with Zecuity (sumatriptan) migraine patch • FDA warns about serious bleeding risk with over-the-counter antacid products containing aspirin • FDA warns about serious heart problems with high doses of the antidiarrheal medicine loperamide

(Imodium), including from abuse and misuse

→ Link to FDA Page

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 07 and 08-Jun-2016 in a Joint Meeting with the Anesthetic and Analgesic Drug Products Advisory Committee Meeting to discuss separate New Drug Applications (NDAs) for new opioid treatments, i.e. Teva’s Vantrela ER (hydrocodone bitartrate extended-release tablets) on 07-Jun-2016 and Pfizer’s Troxyca ER (oxycodone hydrochloride / naltrexone hydrochloride extended-release capsules) on 08-Jun-2016.

The webcasts of both meetings are now available on the FDA website in addition to other meeting material, including slides and final questions. Minutes are also available for the June 08 Meeting.

→ Link to FDA Page

4.1.2 REMS Integration Initiative : New Workshop material available The FDA has released new material in relation to the REMS Integration Initiative, which purpose includes the improved standardization and assessment of REMS. A Public Workshop was held on 07-Jun-2016 at Duke Universtity on “Building a Common REMS Platform”. The video recording of this event is now available.

→ Link to Workshop Video

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4.1.3 FDA updates information on Potential Safety Signals The FDA has updated the information posted on its website regarding drugs with potential safety signals, as required by the 2007 FDA Amendments Act. Drugs that appear on the list are identified based on reports from the FDA Adverse Event Reporting System (FAERS).

The new report covers the first quarter of 2016 and includes the following combinations of Product / Signal:

• Aripiprazole-containing drug products – Impulse-control disorders • Belviq (lorcaserin hydrochloride) – Hypersensitivity • Brilinta (ticagrelor) – Atrioventricular block • Cometriq (cabozantinib) – Drug interaction with warfarin • Diflucan (fluconazole) – Adverse pregnancy outcomes • Exparel (bupivacaine liposome) – Local Anesthetic Systemic Toxicity (LAST) • Kynamro (mipomersen sodium) – Ineffectiveness of the REMS • Metformin-containing drug products – Hepatitis • PDE-5 inhibitors – Skin melanomas • Ranexa (ranolazine) – Seizure • Vascepa (icosapent ethyl) – Liver injury • Velcade (bortezomib) – SJS and TEN

→ Link to FDA’s Potential Signals Page

4.1.4 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 first quarter of 2016.

→ Link to FAERS Quarterly Data Files Page

4.2 European Medicines Agency (EMA)

4.2.1 EMA to hold Introduction Webinar for SPOR data services The EMA has announced that a webinar will be held on 04-Aug-2016 to support industry in understanding the substance, product, organisational and referential (SPOR) data services and related impacts, which purpose is to facilitate the implementation of the ISO standards for the identification of medicinal products (IDMP). Following a phased implementation, pharmaceutical companies will be required to submit data on medicines to EMA in accordance with these formats and terminologies.

→ Link to EMA Event Page

4.2.2 EMA to hold workshop on measuring the impact of pharmacovigilance activities As reported in our previous issue, the PRAC committee adopted a strategy for measuring the impact of pharmacovigilance activities and the EMA is now calling for expressions of interest in an associated workshop. Requests to participate should be communicated to the Agency by 30-Sep-2016.

→ Link to call for expressions of interest → Link to PRAC Strategy Document

4.2.3 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 12 new products have been added to the list in June 2016, whereas 3 products have been removed, as identified in the Summary of Changes presented on the EMA webpage.

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

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4.2.4 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 May PRAC meeting were published on 01-Jul-2016. The PRAC did not initiate or conclude a safety referral at this meeting. The following new Safety Signals were discussed:

• Anakinra; canakinumab – weight increase • Metronidazole – severe hepatic and neurologic toxicity in patients with Cockayne syndrome • Regorafenib – angioedema • Vedolizumab – hepatotoxicity • Dexlansoprazole; lansoprazole – unexpected histopathological findings from a juvenile rat toxicity study • Fluconazole – spontaneous abortion and stillbirth • Fluoroquinolones – aortic aneurysm and dissection

→ Direct link to PRAC Meeting Minutes (10 to 13-May-2016)

The agenda and highlights of the June PRAC meeting were published on 10-Jun-2016. The PRAC did not initiate or conclude a safety referral at this meeting. According to the agenda, the following new Safety Signals have been identified and discussed:

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

hypertension (PH) associated with idiopathic interstitial pneumonias (IIP) in a single clinical trial

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

The agenda and highlights of the July PRAC meeting were published on 08-Jul-2016. As communicated separately (see Section 2), the PRAC concluded the review of Zydelig and issued updated risk minimisation recommendations. The PRAC also initiated several reviews :

• Modified- and prolonged-release paracetamol tablets and risk of overdose • Retinoid medicines, pregnancy prevention and possible risk of neuropsychiatric disorders • Factor VIII and risk of developing inhibitor proteins • SGLT2 inhibitors and risk of amputations (extension of the scope of the canagliflozin review to the class)

The EMA also conducted a practice run to test the process for public hearings, which enabled the EMA to ensure that all arrangements are now in place to implement public hearings, where necessary. According to the agenda, the following new Safety Signals have been identified and discussed:

• Acenocoumarol, fluindione, phenindione, phenprocoumon – calciphylaxis • Aripiprazole – compulsive shopping • Ceftriaxone – drug reaction with eosinophilia and systemic symptoms (DRESS) • Ipilimumab – type 1 diabetes mellitus • Loperamide – serious cardiac events with high doses of loperamide from abuse and misuse • Vildagliptin, vildagliptin / metformin – pemphigoid • Exenatide – incorrect use of device associated with ADRs including hyperglycaemia and hypoglycaemia • Fluoroquinolones – uveitis • Methylphenidate – priapism

→ Direct link to PRAC Meeting Highlights (04 to 08-Jul-2016)

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

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

• Natalizumab – Necrotising retinitis • Warfarin – Calciphylaxis

The list of signals discussed at the June PRAC meeting was published on 04-Jul-2016 and includes recommendations to update the product information for the following combination of Product / Signal:

• Riociguat – Increased mortality and serious adverse events (SAEs) in patients with pulmonary hypertension (PH) associated with idiopathic interstitial pneumonias (IIP) in a single clinical trial

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

4.2.6 EMA issues “Meeting Highlights” of last CHMP Meeting The highlights of the June meeting of the CHMP have been published. As communicated separately (see Section 2), the Committee recommended that Adempas (riociguat) should not be used in patients with symptomatic pulmonary hypertension associated with idiopathic interstitial pneumonia (PH-IIP). The CHMP also warned that Noxafil (posaconazole) tablets and oral suspension are not interchangeable and changes will be made to prevent Medication Errors.

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 (20 to 23-Jun-2016)

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

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

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

• Nifedipine • Meropenem • Rilmenidine • Asparaginase • Iodine (131i) iobenguane • Glycopyrronium / neostigmine • Glycopyrronium bromide (all indications except for chronic obstructive pulmonary disease) • Diclofenac (systemic formulations)

→ Link to PSUR Single Assessments Outcomes Page

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4.2.8 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 14-Jun-2016: Amlodipine/Atorvastatine, Paracetamol/Tramadol and Clarithromycin.

→ Link to Summaries of Assessment Reports

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

New versions of the Controlled Vocabulary for several datapoints have also been released, including for Substances and Organisations. The Q&As document has also been updated and includes a summary of changes, which are all highlighted in the document.

The XEVMPD training page has also been updated with a revised set of Frequently Asked Questions.

→ Link to EMA Page on Data Reporting requirements for MAHs → Link to Data Submission Guidance Page → Direct link to Article 57(2) Questions and Answers → Link to XEVMPD Training Page

4.2.10 EMA issues updated EudraVigilance support guide As reported at the time, the EMA launched an online EMA Service Desk portal in February 2016, which should be used to report an issue, request a service or ask a question about EMA systems in replacement of previously existing functional mailboxes.

First issued in May 2016, the EMA has published an update of its EudraVigilance support guide, which clarifies where queries should be directed depending on their nature. As mentioned previously, Pharmacovigilance questions should be directed to the “Ask EMA” service and EudraVigilance registration questions should go to the dedicated email address. Users should not use the EMA Service Desk portal for this type of enquiries.

→ Link to EMA EudraVigilance Page → Direct link to EudraVigilance support guide

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

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

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

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4.2.12 EMA provides updated information 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 guidance document that describes how “chargeable units” are derived from information held within the XEVMPD database. The Explanatory Note and the pharmacovigilance fees questions-and-answers (Q&As) have also been updated.

→ Link to EMA “Pharmacovigilance Fees” Page → Direct link to “Pharmacovigilance Fees” Q&As

4.3 UK Agency (MHRA)

4.3.1 MHRA issues new toolkit to minimise the risks of valproate during pregnancy The MHRA has published information about a new toolkit on the risks of valproate medicines in female patients. The Agency has worked with industry, healthcare professionals and patient groups on this toolkit to ensure female patients are better informed about the risks of the epilepsy medicine during pregnancy.

→ Link to MHRA Page

4.4 French Agency (ANSM)

4.4.1 ANSM provides update on PRAC/CHMP/CMDh meetings Following the CMDh meeting of May 2016, the ANSM has issued a document to summarise the CMDh decisions. The document does not include any ANSM recommendation.

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

Following the PRAC meeting of June 2016, the ANSM has issued a document to summarise the PRAC decisions. The document also gives recommendations for riociguat pending the EMA evaluation procedure. The product should not be prescribed in case of pulmonary hypertension associated with interstitial pneumonia.

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

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

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

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4.4.2 Commissions/Committees in relation with Pharmacovigilance The Commission in charge of the monitoring of risk / benefit issued the initial minutes of its meeting of 21-Jun-2016 where the following topics were discussed:

• Iproniazide: risk / benefit ratio remains favourable with SmPC updates and prescription conditions • Sodique Profimere: risk / benefit ratio unfavourable

→ Link to ANSM Commission initial minutes– 21-Jun-2016 (in French)

The Pharmacovigilance Committee has issued the minutes of the meeting of 19-Jan-2016 where the following topics were discussed:

• Macrogol: national monitoring to be continued for renal effects and colitis and national enquiry proposed for all preoperative bowel preparation

• Agomelatine: risk / benefit ratio to be re-evaluated • Teriflunomide: monitoring to be continued, focused on hepatitis effects • Nitrofurantoine: although several measures have been taken, 60% of the prescriptions are off label.

→ Link to ANSM PV Committee minutes – 19-Jan-2016 (in French)

The Pharmacovigilance Committee has issued the minutes of the meeting of 16-Feb-2016 where the following topics were discussed:

• Vedolizumab: national monitoring to be continued • Tramadol in pediatric use: SmPC to be modified • Vismodegib: national monitoring to be continued (and to be set up for Odomzo)

→ Link to ANSM PV Committee minutes – 16-Feb-2016 (in French)

The Committee in charge of the interfaces with Pharmaceutical Industries has issued the minutes of meeting of 17-Mar-2016 where the topic of the variations and their management by ANSM was discussed.

→ Link to ANSM PV Committee minutes – 17-Mar-2016 (in French)

5. QUALITY ASSURANCE, INSPECTIONS AND AUDITS

5.1 MHRA Pharmacovigilance Inspections Symposium 2016 announced ! The MHRA has announced that the 2016 Pharmacovigilance Inspections Symposium will take place on Friday 02-Sep-2016, as a repeat of the symposium of November 2015. This event is a popular opportunity to gain a greater understanding of the MHRA Inspectors’ expectations for Pharmacovigilance Systems. Registration is now open and interested people are encouraged to register early as the event usually fills up rapidly.

→ Link to MHRA Event Page

5.2 EMA issues Work Plan for Pharmacovigilance Inspectors The EMA has published the Work Plan 2016 for the Pharmacovigilance Inspectors Working Group (PhV IWG). The document includes a list of guidelines and training activities that the group is preparing to support Pharmacovigilance Inspections for both Human and Animal medicinal products. It also mentions the implementation of the common repository to facilitate sharing of information on planned and conducted pharmacovigilance inspections between Member States.

→ Link to EMA PhV IWG Work Plan 2016

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5.3 EMA provides update on infringement procedure against Roche The EMA has announced that it has now concluded its second inquiry within the framework of its infringement procedure against Roche, which was started at the request of the European Commission.

This followed an initial inquiry as part of the infringement procedure started by the EMA in October 2012 after a pharmacovigilance inspection by the MHRA, which suggested that 80,000 case reports, including more than 15,000 deaths had been collected through a Patient Support Programme in the USA but had not been evaluated to check if they qualified for reporting to EU authorities. The assessment of the additional data provided by Roche has not identified any important new safety concerns.

The EMA has now sent its final report to the European Commission for a decision on further action and financial penalties, which could reach up to 5 % of Roche’s annual EU turnover under applicable rules.

→ Link to EMA Press Release

6. DRUG SAFETY AND LIABILITY RISK

6.1 Sanofi and Depakine Sanofi wants the French office of medical accidents indemnification to indemnify the patients In relation to the issue of birth defects and developmental disorders caused by pregnancy exposure to the anti-epileptic drug valproate, Sanofi has informed patients and their family that in absence of clear responsibilities of the different stakeholders, Sanofi considers that the French Office for the indemnification in case of medical accidents (ONIAM) should indemnify them.

→ Link to le Figaro Article (in French)

6.2 France and Class Action Lawsuits France passes new legislation to allow class action lawsuits against drug manufacturers The article L.1143-1 of the Public Health Code authorizes authorized associations of patients to file class action lawsuit against Manufacturers / Services Providers of health products (including drugs) since 01-Jul-2016.

→ Link to Article L.1143-1 of Public Health Code (in French)

7. OTHER NEWS AND RESOURCES

7.1 Investigation of death during Phase 1 Clinical Trial in France Following the death of one volunteer and the hospitalisation of five others in a phase 1 clinical trial on an endogenous neurotransmitter (Fatty Acid Amide Hydrolase) sponsored by the Portuguese drugmaker Bial, a case has been filed for manslaughter by the Paris Public Prosecutor.

→ Link to an article of Le Monde (in French)

7.2 New TranScrip Commentary on DIA EuroMeeting The consultancy company has published a new report where it provides a summary of the key presentations their representatives attended during the 28th DIA Annual Euromeeting held by in Hamburg in April 2016. The topics presented include the New EU Clinical Trial Regulation, Medication Errors and the new GVP Module V.

→ Link to TranScrip Commentary

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7.3 New article explores possibilities to improve Pharmacovigilance A new article entitled “The Future of Pharmacovigilance: Proposals for More Efficient and Effective Systems-Based Approaches” and published in “Pharmaceutical Medicine” has been made available in open access. It includes the views of the authors, including Giovanni Furlan, EU QPPV at Helsinn Birex, who argue that pharmacovigilance should be better integrated in clinical research and development.

→ Link to Springer Page

7.4 New issue of QuarterWatch The Institute for Safe Medication Practices (ISMP) has issued a new issue of QuarterWatch, the independent publication that monitors adverse drug events reported to the FDA. This issue includes a review of the following topics:

• SGLT2 Inhibitors – a health gamble with a new class of drugs for diabetes • Oral anticoagulants linked to nearly 3,000 reported patient deaths, 16,000 hemorrhages • Overall opioid use drops, but oxycodone use grows

→ Link to QuarterWatch

7.5 New issue of CIOMS Newsletter The June 2016 Newsletter (Issue 15) includes a presentation of Dr Lembit Rägo, the new Secretary-General of CIOMS. It also describes that CIOMS aims to have closer working relations with ICH by becoming an ICH observer and includes an update on the status of current CIOMS Working Groups.

→ Link to CIOMS Newsletter

7.6 Health Canada provides updated Adverse Reaction Online Database The Canada Vigilance Adverse Reaction Online Database contains information about suspected ADRs submitted to Health Canada. The accessible database now includes data from 1965 to 31-Mar-2016.

→ Link to Health Canada Page

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) → Information Day on Medication Errors

October 20 in London, UK

→ PSUR Information Day October 28 in London, UK

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

October 05 – 06 in London, UK → DIA Annual Canadian Meeting 2016

October 18 – 19 in Ottawa, Canada

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DSRU Events → Back to Basics in Pharmacovigilance

September 07 – 08 in Fareham, UK → Reviewing and Understanding Clinical Papers

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

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

October 12 – 13 in Fareham, UK

Other Events → ISPE – 32nd International Conference on Pharmacoepidemiology & Therapeutic Risk Management

August 25 – 28 in Dublin, Ireland → MHRA GPvP symposium

September 02 in London, UK → ISoP / UMC Training Course

September 07 – 09 in Lima, Peru → Healthnetwork – World Drug Safety Congress Europe 2016

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

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

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

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

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

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

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

September 29 – 30 in Berlin, Germany → IFIS – Preparation of a Pharmacovigilance Inspection (event in French)

September 30 in Paris, France → PIPA – Annual Conference 2016

October 05 – 06 in Weybridge, UK

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