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Safety Observer Issue N°118 - December 2015

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Clinical Safety & Pharmacovigilance Regulatory Intelligence Review

Issue N°118 - December 2015

HIGHLIGHTS

The EMA has published two final good practice guides to improve the reporting, evaluation and prevention of medication errors. The EMA has also started to communicate on additional measures to prevent medication errors for specific medicines on a new dedicated webpage.

The EMA has released a draft guideline that outlines how Post-Authorisation Efficacy Studies (PAES) should be designed. Both EMA and CMDh have issued a set of Q&As in relation to the submission of study protocols and their assessment, the assessment of results, and possible regulatory outcomes.

The EMA has released the final guideline on key aspects for the use of pharmacogenomics in pharmacovigilance.

In the USA, the consultation on a Notice of Proposed Rulemaking (NPRM) to revise the rules for Clinical Trial oversight has been extended until January 2016.

The MHRA has published a new Pharmacovigilance inspection metrics report on its website, while the FDA has issued a new Warning Letter for deviations to the Postmarketing ADE Reporting Requirements.

Amongst other product-specific announcements, the FDA has completed a review of Plavix which found that long-term treatment does not change the risk of death. The FDA has also required additional warnings to the labels of SGLT2 type 2 diabetes medicines.

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IN THIS ISSUE

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

1.1 Newly Applicable Standards .............................................................................................................................. 3 1.1.1 EMA updates Q&As on implementation of new PV legislation ..................................................................... 3 1.1.2 EMA updates information on Medical Literature Monitoring service ........................................................... 3 1.1.3 France updates guidance on notification of off-label prescriptions ............................................................ 3 1.1.4 CMDh updates Cover Note for list of safety concerns in approved RMPs .................................................... 3 1.1.5 EMA issues final good practice guides on medication errors ....................................................................... 4 1.1.6 EMA provides updated guidance on submission of medicines information ................................................ 4 1.1.7 EMA issues updated EURD list ....................................................................................................................... 4 1.1.8 EMA issues revised procedural advice for PSUR submission........................................................................ 5 1.1.9 EMA and CMDh provide guidance on Post Authorisation Efficacy Studies .................................................. 5

1.2 Developments to Watch ..................................................................................................................................... 5 1.2.1 EMA issues draft guideline on Post Authorisation Efficacy Studies ............................................................. 5 1.2.2 EMA updates information on ISO IDMP implementation ............................................................................. 5 1.2.3 EMA issues adopted Reflection Paper on safety of parabens as excipients ................................................. 6 1.2.4 EMA issues final guideline on Pharmacogenomics use in Pharmacovigilance ............................................ 6 1.2.5 New deadline for comments on US rules for oversight of Clinical Trials ..................................................... 6

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

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

2.1 Clopidogrel (Plavix) ............................................................................................................................................ 7 2.2 OTC Acetaminophen (Paracetamol) .................................................................................................................. 7 2.3 Iodine-containing contrast agents .................................................................................................................... 8 2.4 HPV vaccines (Gardasil, Cervarix) ...................................................................................................................... 8 2.5 Meningitec .......................................................................................................................................................... 8 2.6 SGLT2 Inhibitors ................................................................................................................................................. 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 ......................................................................................................... 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 EMA updates Q&As on implementation of new PV legislation (06-Nov-2015) The EMA has issued a revision of its list of questions and answers to clarify some practical considerations for the implementation of the new Pharmacovigilance legislation. No change has been made to the content but new text has been added to clarify that some questions are no longer relevant or have been integrated in the EMA post-authorisation guidance.

→ Link to EMA page on Implementation of the Pharmacovigilance legislation → Direct link to EMA Q&A Document

1.1.2 EMA updates information on Medical Literature Monitoring service (11-Nov-2015) The new information includes a revised version of the User Manual describing the new functionalities for MAHs to access and download the ICSRs from EudraVigilance, including the EV ICHISCR Export Manager, MLM EVWEB & tracking spreadsheets. This update is related to a new Cell highlighting function, which allows users to track how long a case is to remain in the ICSRs spreadsheet (see section 3.2.4 of the User Manual).

Following the publication of the Launch Phase Closure Report in October, the EMA has now published the first MLM Service Quarterly Report, which covers the period from August to October 2015. The document provides the latest results for the key performance indicators and describes some planned enhancements to the tracking sheets. It also presents upcoming milestones, including the independent Audit of the MLM service and a stakeholder satisfaction survey.

→ Link to EMA MLM Page → Direct link to MLM User Manual → Direct link to MLM Service Report

1.1.3 France updates guidance on notification of off-label prescriptions (13-Nov-2015) Following the publication of the guide in September 2015, ANSM has issued an update to clarify that individual notification of off-label prescription is not required, as opposed to an identified practice. The date of the document has not been changed (September 2015).

→ Link to the ANSM guidance (in French)

1.1.4 CMDh updates Cover Note for list of safety concerns in approved RMPs (27-Nov-2015) The European CMDh (Co-ordination Group for Mutual Recognition and Decentralised Procedures – Human) has issued an updated Cover Note for the list that presents safety concerns of approved Risk Management Plans (RMPs) per product/active substance. The revision includes a clarification that the Member State who has approved the RMP will request the MAH to send the list of safety concerns through the approval letter issued at the end of the regulatory procedure. The MAHs should only provide the list of safety concerns once they have been requested.

The lack of publicly available information on approved RMPs is a significant challenge for generic products if no information is available on the safety concerns for the reference product and this has resulted in inconsistencies between separate RMPs for the same active substance.

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

→ Link to CMDh Page

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1.1.5 EMA issues final good practice guides on medication errors (27-Nov-2015) Following the consultation conducted from April to June 2015, the EMA has now published two final good practice guides that aim to improve the reporting, evaluation and prevention of medication errors.

The first guide provides guidance on how suspected adverse reactions that are caused by medication errors should be recorded, coded, reported and assessed. It also includes recommendations on how to process information on medication errors that have not caused adverse reactions, as this information is required in PSURs and RMPs.

The other guide focuses on the prevention of medication errors and proposes measures to minimise the risk of medication errors throughout the life cycle of a medicine. The addendum to this guide has also been published, which covers the Risk Minimisation Strategy for high-strength insulin and fixed-combination insulin products. This document was developed by the PRAC over concerns that medication errors with these new medicines could harm patients through over- or under-dosing.

The overviews of comments received on the draft documents have also been published.

As described in the document entitled “Streamlining EMA public communication on medication errors”, the EMA will now systematically communicate on additional measures to prevent medication errors for specific medicines. A new webpage has been created to present such product-specific guidance to patients and healthcare professionals (Note: this will be covered in section 4.2 of Safety Observer).

→ Link to EMA News Release → Link to EMA Medication Errors Page → Direct link to “Streamlining EMA public communication on medication errors”

1.1.6 EMA provides updated guidance on submission of medicines information (01-Dec-2015) 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.

This includes a revised version of the Frequently Asked Questions and an update of the detailed XEVPRM user guidance (Chapter 3.II: Product Report Message). The changes are highlighted in the documents, some of which relate to the upcoming implementation of the notifications of changes to QPPV details/PSMF location via the Article 57 database, which the EMA Management Board will consider at its December meeting. Until a formal notification on this functionality is issued, MAHs should continue to notify these changes through a type IAIN variation.

In addition, a new document has been published on “Coding of Indications”, which is intended to promote Best Practices for the coding of indications based on section 4.1 of the SmPC using MedDRA terminology, with the view of facilitating future migration of data into the ISO IDMP format.

→ Link to EMA Data Submission Guidance Page → Direct link to Article 57(2) Q&As → Direct link to Coding of indications in XEVMPD

1.1.7 EMA issues updated EURD list (27-Nov-2015) The EMA has published an updated EURD list, which provides the EU Reference Dates, frequencies for submission of PSURs and related data lock points for a list of active substances and combinations.

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

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

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

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1.1.8 EMA issues revised procedural advice for PSUR submission (04-Dec-2015) The EMA has published a revised version of the “Post-authorisation procedural advice for users of the centralised procedure”, which includes updates to the PSUR section in relation to the PSUR submission process and the requirement for electronic submission (see section 15).

→ Link to EMA Procedural Advice (post-authorisation with track changes)

1.1.9 EMA and CMDh provide guidance on Post Authorisation Efficacy Studies (01-Dec-2015) The EMA has included a new Q&A section in the Post-Authorisation Procedural Advice for users of the centralised procedure (section 13), which clarifies aspects in relation to the imposition of PAES, including the submission of study protocols by companies and their assessment by EMA, the assessment of the study results, and the possible regulatory outcomes.

The CMDh (Co-ordination Group for Mutual Recognition and Decentralised Procedures – Human) has issued a mirror set of Q&As where the responses have been adapted for products approved under Mutual Recognition and Decentralised Procedures.

→ Direct link to EMA PAES Q&As (CAP) → Direct link to CMDh PAES Q&As (MRP/DCP)

1.2 Developments to Watch

1.2.1 EMA issues draft guideline on Post Authorisation Efficacy Studies (06-Nov-2015) The EMA has released a draft guideline that outlines how Post-Authorisation Efficacy Studies (PAES) should be designed by companies to support regulatory decision making.

These studies can be imposed by regulators or may be carried out voluntarily by companies. The situations where a PAES can be required by medicines regulatory authorities in the EU were specified by the European Commission in April 2014 (Commission Delegated Regulation (EU) No 357/2014), and PAES can be required for medicines with a standard marketing authorisation in specific situations.

Comments on the draft guideline are expected by 31-Jan-2016.

→ Link to EMA Press Release → Direct link to EMA Draft Guideline

1.2.2 EMA updates information on ISO IDMP implementation (13-Nov-2015) As described in the EudraVigilance Stakeholder Change Management Plan published in October 2015, the implementation of the new EudraVigilance system and centralised reporting is planned in July 2017 but the ISO IDMP set of standards and their resulting terminologies will not be fully available at that time.

The EMA has updated its information page on the implementation of the ISO IDMP standards, which includes a high level timetable showing that the legal deadline of 01-Jul-2016 specified in the Implementing Regulation N°520/2012 will be the beginning of a transition phase until Q2 2018 when the maintenance phase will start. The MAHs will be required to align their systems and submit additional data during this transition phase. The Agency will provide a detailed plan, including details of what data is to be submitted, and communicate when the new format will become mandatory well in advance of any change.

→ Link to EMA Page on IDMP

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1.2.3 EMA issues adopted Reflection Paper on safety of parabens as excipients (19-Nov-2015) Following the European Commission decision to revise the Annex of the guideline on “Excipients in the label and package leaflet of medicinal products for human use”, a multidisciplinary group of experts was created in 2011 to update the labelling of selected excipients based on a review of their safety.

Q&A documents on excipients have been progressively released for public consultation, which include proposals for new or updated information for the labelling and package leaflet. All final information will be grouped in a single document, which will be integrated in the updated Annex of the new revised EC guideline.

The EMA has just released the Reflection Paper that has been adopted for methyl- and propylparaben, together with an overview of the comments received during the consultation period.

→ Link to EMA Page on Excipients labelling → Link to Reflection Paper on the use of parabens as excipients → Link to Overview of Comments received on the Reflection Paper

1.2.4 EMA issues final guideline on Pharmacogenomics use in Pharmacovigilance (20-Nov-2015) Following the consultation conducted from February to July 2014, the EMA has now released the final guideline on key aspects for the use of pharmacogenomics in the pharmacovigilance of medicinal products, which will come into effect on 01-Apr-2016.

This document describes how pharmacogenomics can be used in Risk Management Plans, Risk Minimisation Measures, Signal Detection and Benefit-Risk evaluation by linking genetic features with efficacy and safety. The guideline describes different types of genomic biomarkers that can be relevant for Pharmacovigilance.

An overview of comments received during the consultation is also available on the EMA Pharmacogenomics Page, together with the initial Concept Paper and the 2014 draft guideline.

→ Link to EMA Pharmacogenomics Page → Direct link to guideline on Pharmacogenomics in PV

1.2.5 New deadline for comments on US rules for oversight of Clinical Trials (25-Nov-2015) As reported in previous issues, the U.S. Department of Health and Human Services (HHS) and fifteen other Federal Departments and Agencies have announced proposed revisions to the Federal Policy for the Protection of Human Subjects. A Notice of Proposed Rulemaking (NPRM) was published, which purpose is to improve the protection of human subjects involved in research, while facilitating research and reducing burden, delay, and ambiguity. The main changes proposed relate to the rules for informed consent and the level of review, which would be more proportional to risks.

The comment period has been extended by 30 days and comments are now expected by 06-Jan-2016.

→ Link to Federal Register Notice → Link to HHS page (includes summary of proposed changes)

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 Austria issues revised Q&As on Pharmacovigilance (03-Nov-2015) The Austrian Agency has issued a revised set of Questions and Answers, which provides guidance on a number of Pharmacovigilance requirements including PSURs, RMPs and E2B Reporting, amongst other topics. The page is available in both German and English language.

→ Link to BASG/AGES 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

06-Jan-2016 USA Consultation to revise rules for the oversight of Clinical Trials (Link) 115 & 118

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

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

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

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28-May-2016 Clinical Trials Regulation (EU) No 536/2014 to become applicable (Link) 102

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

01-Jul-2016 Implementation of international standards for the identification of medicinal products (IDMP) in Europe (Link)

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01-Jul-2017 Implementation of E2B(R3) in Europe (Link) 117

2. PRODUCT SAFETY ANNOUNCEMENTS

2.1 Clopidogrel (Plavix) FDA review finds that long-term treatment does not change risk of death (06-Nov-2015) The FDA has announced that it has completed an evaluation of several clinical trials which does support that an increased the risk of cancer or death from cancer is associated with long-term use of the blood-thinning drug Plavix. The results of FDA meta-analyses also indicate that long-term (12 months or longer) dual antiplatelet therapy with clopidogrel and aspirin do not appear to change the overall risk of death when compared to short-term (6 months or less) clopidogrel and aspirin, or aspirin alone. The results of this mortality meta-analysis will be reflected in the label of clopidogrel-containing products.

→ Link to FDA MedWatch alert

2.2 OTC Acetaminophen (Paracetamol) FDA issues guidance on labelling for liver damage warning (16-Nov-2015) The FDA has issued a new product-specific guidance for industry entitled “Organ-Specific Warnings: Internal Analgesic, Antipyretic, and Antirheumatic Drug Products for Over-the-Counter Human Use – Labeling for Products That Contain Acetaminophen”. The guidance is intended to inform manufacturers of certain OTC products containing acetaminophen of the circumstances for which FDA does not intend to object to the inclusion of a liver warning that differs from that required under FDA regulations, provided the warning appears as described in the guidance.

→ Link to Federal Register Notice → Link to FDA Guidance

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2.3 Iodine-containing contrast agents FDA warns about rare cases of underactive thyroid in infants (17-Nov-2015) The FDA has announced that rare cases of underactive thyroid have been reported in infants following the use of contrast media containing iodine for X-rays and other medical imaging procedures. In all cases, the infants were premature or had other serious underlying medical conditions. Available evidence suggests that this rare occurrence is usually temporary and resolves without treatment or any lasting effects, but corresponding information will be added to the labels of all iodinated contrast media (ICM) products. No changes to current practices are recommended but the FDA has required a study to investigate this issue further.

→ Link to FDA MedWatch alert

2.4 HPV vaccines (Gardasil, Cervarix) EMA confirms evidence does not support that HPV vaccines cause CRPS or POTS (20-Nov-2015) Further to the PRAC recommendation issued on 05-Nov-2015, the CHMP Committee has reviewed the findings along with further representations from patient groups and announced that the EMA has now completed its review of the evidence surrounding reports of two syndromes, complex regional pain syndrome (CRPS) and postural orthostatic tachycardia syndrome (POTS) in young women given human papillomavirus (HPV) vaccines for the prevention of cervical cancer.

The evidence does not support a causal link between the vaccines and development of CRPS or POTS and there is no reason to change the way the vaccines are used or amend the current product information as the overall rates of these syndromes in vaccinated girls are not different from expected rates in these age groups.

The assessment report containing the evidence supporting the Agency’s review has also been published, together with a virtual press briefing video.

→ Link to EMA Press Release → Link to EMA Assessment report → Link to EMA virtual press briefing video

2.5 Meningitec ANSM provides update on quality defects (03-Dec-2015) As a precautionary measure, ANSM and CSP withdrew batches of this meningitis vaccine in September 2014 due to the presence of iron and steel particles. Pharmacovigilance monitoring and investigations have not demonstrated a health risk for vaccinated people. This update however occurs in a context whereby 580 complaints have been filed for potential association with neurological symptoms.

→ Link to ANSM Press Release (in French) → Link to francetvinfo article (in French)

2.6 SGLT2 Inhibitors FDA requires labels to include Warnings about Ketoacidosis and Serious UTIs (04-Dec-2015) Following an earlier Drug Safety Communication issued in May 2015, the FDA has announced that it has completed a safety review that resulted in additional warnings to the labels of SGLT2 type 2 diabetes medicines about the risks of ketoacidosis and of serious urinary tract infections. The FDA is also requiring manufacturers of SGLT2 inhibitors to conduct a 5-year postmarketing study.

→ Link to FDA MedWatch alert

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3. DEAR DOCTOR LETTERS AND SAFETY NEWSLETTERS

3.1 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 October 2015:

• Crizotinib (Xalkori▼) – Risk of cardiac failure • Vemurafenib (Zelboraf▼) – Risk of potentiation of radiation toxicity

→ Link to MHRA Page → Link to Drug Safety Update (November)

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

• Thalidomide: reduction of the initial dosage in elderly patients • Mycophenolate: new contra-indications and pregnancy prevention measures (see Information Release) • Valproate: reminder of the timelines for the new prescribing rules • Dimethyl fumarate: new measures to minimize the risk of PML

→ Link to ANSM Page

3.3 New issues of Canadian “Health Product InfoWatch” The new issue of “Health Product InfoWatch” has been published, which provides an overview of health product advisories and safety reviews published in the previous month by Health Canada. The November issue was published on 26-Nov-2015 and includes a Vaccine safety review and a Case Report of respiratory depression in a child with ultrarapid CYP2D6 metabolism after tramadol use. The monthly recap covers several medicinal products including Allerject (epinephrine) and SGLT2 inhibitors.

→ Link to Newsletter

3.4 New issue of Australian “Medicine Safety Update” The Australian Therapeutic Goods Administration (TGA) has issued the new edition of Medicines Safety Update (Volume 6, Number 6, December 2015). The contents include:

• Proton pump inhibitors and increased cardiovascular risk • Potential interaction – allopurinol and 6-mercaptopurine/ azathioprine • Intrauterine contraceptive devices and uterine perforation • Peginterferon alfa-2a and facial palsy

→ Link to Medicines Safety Update

3.5 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 review finds long-term treatment with blood-thinning medicine Plavix does not change risk of death • FDA advises of rare cases of underactive thyroid in infants given iodine-containing contrast agents

→ Link to FDA Page

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4. OTHER PUBLICATIONS BY REGULATORY AGENCIES

4.1 US Food and Drug Administration (FDA)

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

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

4.1.2 FDA working with manufacturers to resolve challenges with the Clozapine REMS Program In September 2015, the FDA announced changes to the requirements for monitoring, prescribing, and dispensing the schizophrenia medicine clozapine, to address concerns about the risks of severe neutropenia.

A new shared risk evaluation and mitigation strategy (REMS) was approved in replacement of the six existing clozapine registries for individual clozapine medicines. Healthcare Professionals have been experiencing difficulties with the new Clozapine REMS Program, including technical issues with the website, data migration problems, and long call wait times since the launch of the program in October 2015. Pending resolution of these issues by the REMS program administrators, the FDA has extended the certification deadlines for both prescribers and pharmacies to help ensure that patient access to clozapine is maintained.

→ Link to FDA Page

4.1.3 FDA issues material from meeting on Drug Interactions with Hormonal Contraceptives As announced in earlier issues, the FDA held a public meeting to discuss the topic of drug interactions with hormonal contraceptives. The purpose was to seek input from experts on the public health concerns associated with use of hormonal contraceptives and interacting drugs that might affect efficacy and safety, PK/PD considerations in drug interaction studies, and approaches to present drug interaction information into informative labeling and communication. The presentations and webcasts of the meeting are now available on the FDA website.

→ Link to FDA Event Page

4.1.4 Drug Safety and Risk Management Advisory Committee: New material available The Drug Safety and Risk Management Advisory Committee met on 04-Jun-2015 in a Joint Meeting with the Antimicrobial Drugs Advisory Committee to discuss the Benefits and Risks of Systemic Fluoroquinolone Antibacterial Drugs in several indications. The Committees made several recommendations, which include strengthening boxed warnings, clarifying medication guides and implementing a Risk Evaluation and Mitigation Strategy (REMS). The slides, webcasts and minutes of the meeting have now been published.

→ Link to FDA Page

4.1.5 New Public Summary of Drug Safety Oversight Board meeting A new public summary for the meeting of the FDA Drug Safety Oversight Board (DSOB) has been posted. The Board met on 17-Sep-2015 and was updated on Drug Safety Communications issued since the previous meeting in May 2015. In addition, the board heard a presentation on tools and strategies for communicating and disseminating drug safety information.

→ Link to DSOB Public Summary

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4.1.6 Pediatric Advisory Committee: New material available The Pediatric Advisory Committee met on 16-Sep-2015 to discuss pediatric-focused safety reviews for a group of 18 products, which included nevirapine and the Pneumococcal Vaccine Prevnar 13 amongst others. In addition to the presentations made available earlier, the FDA has now published the meeting transcript.

→ Link to FDA Page

4.1.7 FDA provides latest FAERS Statistics The FDA has published the set of summary statistics on the type and source of reports received over the last ten years and available in the FDA Adverse Event Reporting System (FAERS) as of 31-Mar-2015.

→ Link to FDA Page

4.2 European Medicines Agency (EMA)

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

→ Link to EMA PRAC Page

The minutes of the October PRAC meeting have now been published. The PRAC discussed three ongoing referrals but it did not initiate or conclude new safety referrals at this meeting. The following new Safety Signals were discussed:

• Adalimumab – autoimmune haemolytic anaemia (AIHA) and haemolytic anaemia (HA) • Carbidopa / levodopa – intussusception • Ibrutinib – peripheral neuropathy • Peginterferon alfa-2a – acquired haemophilia • Ustekinumab – pemphigoid • Alogliptin, Linagliptin and combinations – arthralgia • Adalimumab – convulsion • Anakinra – thrombocytopenia • Boceprevir – hyponatraemia • Fluoroquinolones – retinal detachment • Mitotane – sex hormone disturbances and development of ovarian macrocysts • Sitagliptin, Sitagliptin / metformin – intestinal obstruction

→ Direct link to PRAC Meeting Minutes (05 to 08-Oct-2015)

The agenda and highlights of the November PRAC meeting have been published. As communicated through Press Releases, the PRAC completed a review of HPV vaccines and concluded that available evidence does not support an association with CRPS or POTS syndromes. According to the agenda, the following new Safety Signals have been identified and discussed:

• Axitinib – nephrotic syndrome • Bevacizumab – generalised tonic-clonic seizures • Human normal immunoglobulin – posterior reversible encephalopathy syndrome (PRES) • Mercaptopurine – lymphoproliferative disorders • Somatropin – hypersensitivity reactions • Tigecycline – hypofibrinogenaemia • Methotrexate – congenital cardiovascular anomaly • Selective serotonin reuptake inhibitors (SSRIs) – malformative risks in newborn and risk of autism

→ Direct link to PRAC Meeting Highlights (03 to 05-Nov-2015)

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The agenda and highlights of the December PRAC meeting have also been published. The PRAC discussed two ongoing referrals but it did not initiate or conclude any safety referral at this meeting. According to the agenda, the following new Safety Signals have been identified and discussed:

• Adalimumab – glomerulonephritis (GN) • Dabigatran – pulmonary alveolar haemorrhage • Flucloxacillin / paracetamol – metabolic acidosis • Infliximab – thyroid gland disorders • Olanzapine – drug reaction with eosinophilia and systemic symptoms (DRESS) • Vismodegib – angioedema

→ Direct link to PRAC Meeting Highlights (30-Nov to 03-Dec-2015)

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

As communicated through Press Releases (see section 2), the CHMP confirmed the PRAC recommendation that the available evidence does not support a causal link between HPV vaccines and development of CRPS or POTS. 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 (16 to 19-Nov-2015)

4.2.3 PRAC recommendations on Safety Signals The EMA routinely issues the PRAC recommendations resulting from the assessment of safety signals. MAHs are legally obliged to monitor this information to keep informed about the PRAC recommendations concerning their products, which may require the submission of a Safety Variation. Since January 2015, translations in all official EU languages as well as Norwegian and Icelandic are also made available.

The list of signals discussed at the November PRAC meeting was published on 30-Nov-2015 and includes recommendations to update the product information for the following combination of Product / Signal:

• Palifermin – Infection

The PRAC has not recommended corresponding product information wording but requested the submission of type II variation by the MAH to include an update of product information, Direct Healthcare Professional Communication, drug utilisation study and update of Risk Management Plan.

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

4.2.4 EMA issues new recommendations to prevent Medication Errors As presented in section 1.1 of this issue of Safety Observer, the EMA will now systematically communicate on additional measures to prevent medication errors for specific medicines. A new webpage has been created to present such product-specific guidance to patients and healthcare professionals. In addition to the communications for Velcade (bortezomib) and Strensiq (asfotase alfa) that have been populated retrospectively, the page now includes guidance for the following products:

• high-strength insulins • diabetes medicines containing insulin and a non-insulin active substance • Ionsys (Fentanyl transdermal system) • Farydak (panobinostat)

→ Link to EMA Recommendations on medication errors

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4.2.5 EMA issues material from workshop on the use of PK and PD measurements for DOACs As announced previously, the EMA has now held a workshop to discuss the utility of pharmacokinetic (PK) and pharmacodynamic (PD) measurements in the clinical use of the new direct oral anticoagulants (DOACs) and whether those could enhance the benefit-risk profile of these medicines by further reducing the risk of major bleedings while maintaining or improving the protection against thromboembolic events.

The objectives of the workshop were to improve the understanding of the clinical use of DOACs, issues in relation to PK and PD measurements as well as priorities in future research. This workshop took place on 23-Nov-2015 and a background document has been published, together with an updated programme. Presentation material and a video recording should also be made available shortly.

→ Link to EMA Event Page

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

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

The outcomes of new PSUR single assessments completed in September and October have been published and variations are required for the following substances:

• Lormetazepam • Altizide/spironolactone • Delapril • Methylprednisolone • 5 fluorouracil (topical application) • Cyproheptadine • Ampicillin/sulbactam • Amitriptyline • Argatroban • Cilostazol • Ondansetron

→ Link to PSUR Single Assessments Outcomes Page

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

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

Summaries of PSUR Assessment Reports have been published for the following products on 27-Nov-2015: benazepril/hydrochlorothiazide, ciprofloxacin hydrochloride/dexamethasone acetate (ear drops), human coagulation factor VIII inhibitor bypassing fraction, ivermectin, pravastatin, tiapiride.

→ Link to Summaries of Assessment Reports

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4.2.8 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 5 new products have been added to the list in November 2015.

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

4.2.9 EMA holds 2nd stakeholder forum on Operation of the Centralised Procedure The EMA hosted this stakeholder forum on 09-Nov-2015. The discussions at this meeting included the detailed report on the survey on post-authorisation procedures and specific aspects of variation management for risk management plan updates. The agenda and presentations from the meeting are available on the EMA website.

→ Link to EMA Meeting Page

4.2.10 Professor Guido Rasi officially appointed as EMA Executive Director As announced previously, Professor Guido Rasi has now been officially appointed as Executive Director of the EMA for a 5-year mandate. This follows his selection at an extraordinary Management Board session on 01-Oct-2015, and his statement to the European Parliament’s ENVI Committee on 13-Oct-2015.

This follows a legal challenge that led a Tribunal to annul the appointment of Guido Rasi at the end of 2014, after 3 years as Executive Director of the EMA. The challenge had been brought in early 2012 by the former head of the Bulgarian drug agency who had not been shortlisted for the position.

→ Link to EMA Press Release

4.2.11 EMA issues updated XEVMPD Controlled Vocabularies 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 been released, including for Substances and Organisations.

→ Link to Data Submission Guidance 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 November 2015, ANSM has issued a document to summarise PRAC activities. Following the evaluation of the association of HPV vaccines and two complex syndromes, which concluded to the absence of causality, ANSM recommends to use the vaccines according to the current vaccination calendar. In addition, during the review of the possible association of corticoids with chronic obstructive pulmonary disease, ANSM recommends to strictly follow the recommendations of the SmPC.

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

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

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

In the same way, following the CHMP meeting of November 2015, ANSM has issued documents to summarise the decisions taken. No specific French position or recommendation has been issued.

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

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4.4.2 Commissions / Committees in relation with Pharmacovigilance The commission in charge of the monitoring of the risk / benefit profile issued the minutes of the meeting of 30-Jun-2015, where the following topics were discussed:

• Distilbene (diéthylstilbestrol): risk / benefit profile remains favourable with prescribing restrictions • Prostigmine (Neostigmine): risk / benefit profile remains favourable with SmPC modifications • Colpotrophine and Colposeptine (promestriene): abstention of the Commission • Opalgyne (Benzydamine): risk / benefit profile remains favourable with SmPC modifications

→ Link to the Minutes of the Commission – 30-June-2015 (in French)

4.4.3 ANSM issues guidelines on the financial penalties Based on inspections, quality controls results or other elements associated with noncompliance, the Head of the French Agency may issue financial penalties, which may be published on its website.

The amount is based on the turnover for the concerned products and the nature of the noncompliance. ANSM has issued its guideline and the grid for drugs and also for medical devices.

→ Link to the ANSM Page (in French)

4.4.4 ANSM issues an update on antibiotics use and antimicrobial resistance The data published cover the period 2004 – 2014 and includes pharmacovigilance data for each class. Regarding resistance, data varied depending on the concerned bacteria. Pharmacovigilance data showed more than 60% of adverse reactions are serious with mostly cutaneous and haematological effects. Penicillin and Beta lactam antibiotics represent half of the notified cases.

→ Link to the ANSM webpage (in French)

5. QUALITY ASSURANCE, INSPECTIONS AND AUDITS

5.1 MHRA issues new set of Pharmacovigilance Inspection metrics The MHRA has published a new Pharmacovigilance inspection metrics report on its website, which covers inspections conducted from April 2014 to March 2015. The metrics provide information on the number and type of MAHs inspected, the areas associated with common inspection findings, as well as the number of critical, major and other findings.

The MHRA performed 47 Pharmacovigilance inspections of MAHs in the period (compared with 56 the previous year), which included 10 triggered inspections and 20 in relation to the EMA inspection programme. One additional inspection was performed at a Pharmacovigilance Service Provider.

The average number of both Critical and Major Findings has risen again compared to previous years. The greatest part of critical findings concerned again failures in relation to safety variations and their implementation. A significant increase of Critical Findings associated with signal management was identified with 7 Critical findings due to failures to conduct signal detection activities, failures to incorporate all available data and significant delays in completing signal evaluation.

→ Link to MHRA Metrics Report

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5.2 New FDA Warning Letter issued over ADE reporting failures The FDA has just published a new Warning Letter for deviations to the Postmarketing Adverse Drug Experience Reporting Requirements identified during an inspection conducted at Heritage Pharmaceuticals in May 2015.

According to the Warning Letter, the inspectors identified failures in the Periodic Adverse Drug Experience Reports (PADERs) with the complete omission of non-expedited ICSRs in some of the PADERs submitted to the FDA. The inspectors considered that the response is insufficient to provide the required assurance that these deficiencies have been addressed appropriately and will not reoccur.

Another finding relates to the lack of appropriate procedures to ensure that ADEs from all sources are correctly collected, assessed, followed-up and reported to FDA in accordance with applicable requirements.

→ Link to FDA Warning Letter

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 presentation material The Australian Therapeutic Goods Administration (TGA) has published the material used to support presentation at recent events.

This includes presentations given at the ARCS-TGA workshop on 11-Nov-2015, where the TGA presented on approaches to designing risk minimisation programmes for medicines.

→ Link to TGA Page

This also includes a presentation given at the ARCS Pharmacovigilance Interest Area meeting on 17-Nov-2015, where the TGA provided a brief overview of the Adverse Event Management (AEM) project objectives and implementation plan. The TGA called for volunteers to help define for ICSRs exchange capabilities.

→ Link to TGA Page

7.2 New ENCePP Plenary Meeting ENCePP has published the material from its last Plenary Meeting, which took place on 24-Nov-2015. The list of topics included Post-Authorisation Studies, the use of existing data and joint studies and methods for measuring the impact of regulatory activities. The information available includes the Meeting Report and the Presentations made at the meeting.

→ Link to ENCePP Page

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8. CONFERENCES AND TRAINING EVENTS

DIA Events → Webinar: Getting Compliant with FDA's Regional Guidance on eVAERS Reporting Requirements

December 16, 11:00 AM to 12:30 PM (ET)

→ Pharmacovigilance and Risk Management Strategies 2016 January 25 – 27 in Washington DC, USA

→ Pre-Marketing Clinical Safety January 26 – 27 in London, UK

→ MHRA/DIA Excellence in Pharmacovigilance February 01 – 05 in London, UK

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

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

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

DSRU Events → Medical Aspects of Adverse Drug Reactions

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

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

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

March 09 – 10 in London, UK

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

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

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

January 29 in Paris, France → Virtue Insight – 10th Pharmacovigilance 2016

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

March 08 – 10 in Cambridge, UK