Safety Observer N°94 – October 2013 page 1/18

Safety Observer Clinical Safety & Pharmacovigilance Intelligence Review

Issue N°94 – October 2013 Highlights The EMA has now begun to publish the PRAC recommendations resulting from the assessment of safety signals, which MAHs are legally obliged to monitor to keep informed about the recommendations concerning their products and to initiate corresponding variations, where applicable. The EMA has produced guidance on this process and a cumulative list of all signals discussed at the PRAC since September 2012 is also available. The FDA has issued a new Draft Guidance on the content of the “Patient Counseling Information” section of the labeling, which may be linked with a REMS program. But the main story in the USA is the Federal Government Shutdown, which has many practical consequences on the activities at the FDA since 01-Oct-2013. Regarding product-specific announcements, the FDA has announced new measures to try to curb the incidence of ADR reports with opioid analgesics. The EMA has recommended the suspension of the intravenous nutrition product Numeta G13%E due to the risk of hypermagnesaemia. In other news, the EMA has provided details about its new organisational structure.

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Safety Observer N°94 – October 2013 page 2/18

In this issue

1. Regulatory Update .................................................................................................................... 3 1.1. Applicable Regulations, Guidelines and other Standards ............................................................ 3 1.1.1. EudraVigilance updates Important Medical Event Terms list .......................................................... 3 1.1.2. CMDh updates information on PSUR Submission for NAPs ........................................................... 3 1.1.3. Updated MedDRA “Points to Consider” documents now available ................................................. 3 1.1.4. EMA updates EURD list and introductory cover note ..................................................................... 3 1.1.5. EMA starts publication of PRAC recommendations on Safety Signals ............................................ 4 1.2. Developments to watch ............................................................................................................ 4 1.2.1. FDA issues Draft Guidance on Patient Counseling Section of Labeling ........................................... 4 1.2.2. FDA clarifies impact of Federal Government Shutdown ................................................................. 4 1.3. Beyond the borders of Safety Observer ...................................................................................... 5 1.3.1. Germany issues interim guidance for Non-Interventional Studies ................................................... 5 1.3.2. Belgium issues guidance for Risk Minimisation activities ............................................................. 5 1.4. The Safety Observer Tracker ..................................................................................................... 5

2. Safety Update .......................................................................................................................... 6 2.1. Opioid analgesics ..................................................................................................................... 6 2.2. Piribedil (Trivastal®) ................................................................................................................. 6 2.3. Dextropropoxyphene-containing products (Di-Gesic®, Doloxene®) .............................................. 6 2.4. Numeta .................................................................................................................................... 6 2.5. Fentanyl Transdermal Systems (Duragesic® and generics) ......................................................... 7 2.6. Fentanyl Transmucosal ............................................................................................................. 7 2.7. Ofatumumab (Arzerra®) and Rituximab (Rituxan®) .................................................................... 7 2.8. HPV vaccine Cervarix® ............................................................................................................. 7 2.9. Tigecycline (Tygacil®) .............................................................................................................. 8

3. Quality Assurance, Inspections and Audits ................................................................................ 8

4. Drug Safety and Business Risk.................................................................................................. 8

5. Other relevant Information and Resources ................................................................................. 9 5.1. US Food and Drug Administration (FDA) .................................................................................... 9 5.2. European Medicines Agency (EMA) ......................................................................................... 11 5.3. UK Agency (MHRA) ................................................................................................................ 13 5.4. French Agency (ANSM)........................................................................................................... 13 5.5. Other Sources ........................................................................................................................ 14

6. Time to Register ..................................................................................................................... 16

7. About the Authors .................................................................................................................. 18

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1. Regulatory Update

1.1. Applicable Regulations, Guidelines and other Standards

1.1.1. EudraVigilance updates Important Medical Event Terms list (10-Sep-2013) The EudraVigilance Expert Working Group (EV-EWG) has released an updated Important Medical Event Terms (IME) list, which purpose is to facilitate the classification of suspected adverse reactions. The IME list was first made available in January 2009 for guidance purposes only and the new release is based on MedDRA version 16.1. As of version 15.0, it has been agreed to drop the extended terms list and the IME list contains Core Serious events only, i.e. events that would be “always” serious.

Link to EudraVigilance Page

1.1.2. CMDh updates information on PSUR Submission for NAPs (27-Sep-2013) The European CMDh (Co-ordination Group for Mutual Recognition and Decentralised Procedures – Human) has issued an updated “List of substances under PSUR Work Sharing scheme and other substances contained in Nationally Authorised Products with DLP synchronised”. This list contains substances and combinations that have been removed from the EURD list until they follow the EU single assessment procedure of PSURs. The list is provided in pdf and Excel format, where all changes since the previous publication are highlighted.

Link to HMA Page

Direct link to list (pdf)

1.1.3. Updated MedDRA “Points to Consider” documents now available (01-Oct-2013) Following the release of MedDRA Version 16.1 on 01-Sep-2013, the two “Points to Consider” documents have been updated to address MedDRA Term Selection and MedDRA Data Retrieval and Presentation. The MedDRA translations for Version 16.1 have also been made available.

Link to MedDRA Page

1.1.4. EMA updates EURD list and introductory cover note (01-Oct-2013) A new update of the EURD list was published on 01-Oct-2013, which provides the European Union Reference Dates, frequencies for submission of PSURs and related data lock points for a list of active substances and combinations. The changes to the EURD list are highlighted and include 21 new products and 6 amendments. One of the new entries concerns all products used in connection with allergen diagnostics. The introductory cover note has been updated with revisions to the annex “Summary of PSUR submission requirements for single assessment procedures”, where links to the formatted table cover note have been added. A Notice to MAHs has also been included (see end of section 5) to announce that PSURs subject to a single assessment will be jointly assessed by the lead PRAC Rapporteur and the PRAC with a view to forming a single assessment report. The preliminary and updated single assessment reports by the PRAC Rapporteur, the PRAC recommendation and the single CHMP Opinion (if applicable) will be circulated amongst all MAHs whose product(s) are part of the PSUR single assessment procedure.

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

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1.1.5. EMA starts publication of PRAC recommendations on Safety Signals (04-Oct-2013) The EMA has announced that it has now begun to publish 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 EMA has published the first overview list, which covers all safety signals discussed during the September 2013 PRAC meeting and the corresponding recommendations for both centrally and nationally authorised medicines. The Agency will publish future overviews following each month' s CHMP and CMDh meetings. We will now include this item in our review, which will be reported in section 5.2 of Safety Observer. The information published by the EMA includes a Questions & Answers document on Signal Management, which provides guidance on the process and responsibilities of the stakeholders. A cumulative list of all signals discussed at the PRAC since September 2012 has also been made available, which includes links to the corresponding PRAC minutes.

Link to EMA News Release

1.2. Developments to watch

1.2.1. FDA issues Draft Guidance on Patient Counseling Section of Labeling (18-Sep-2013) The FDA has announced the availability of a draft guidance entitled “Patient Counseling Information Section of Labeling for Human Prescription Drug and Biological Products – Content and Format”. This document includes recommendations to ensure that the “Patient Counseling Information” section of the labeling is clear, useful, informative, and consistent in content and format. The information provided in this section of the label typically focuses on major risks of the drug and associated measures, which may refer to a Risk Evaluation and Mitigation Strategies (REMS) program. Comments are expected by 18-Nov-2013.

Link to Federal Register Notice

Link to Draft Guidance

1.2.2. FDA clarifies impact of Federal Government Shutdown (01-Oct-2013) The FDA has published some information to explain how the activities at the Agency are impacted by the Federal Government Shutdown resulting from the budget standoff. Beginning on 01-Oct-2013 and until resolution, the Agency operations will be limited to emergency work, criminal law enforcement work and activities funded by carryover user fee balances. During the lapse period, the FDA will not be able to accept any regulatory submissions for FY 2014 that require a fee payment. The press has highlighted the impact the standoff has on some other government bodies like NIH, with cancer patients turned away from clinical studies. Regulatory Focus has also issued an overview of the practical consequences of the shutdown.

Link to FDA Notice

Link to Regulatory Focus article

Link to The Washington Post article

Link to PharmaLive article

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1.3. Beyond the borders of Safety Observer

1.3.1. Germany issues interim guidance for Non-Interventional Studies (04-Sep-2013) The two German Agencies BfArM and PEI have jointly published new information related to Non-Interventional Studies. The information available includes a set of Frequently Asked Questions (FAQs) and updated templates for the required notifications to Authorities. Although it remains available for information, the current recommendations document is not in line with the new legislation and a corresponding revision is planned in the near future.

Link to BfArM Page (in German)

Link to PEI Page (in German)

1.3.2. Belgium issues guidance for Risk Minimisation activities (30-Sep-2013) The Belgian Agency has issued a Circular Letter (N°603) to MAHs which explains the new procedure for approval of Risk Minimisation activities, and includes some guidance regarding the format and content of associated material.

Link to famhp Announcement (in French)

Link to famhp Announcement (in Dutch)

1.4. The Safety Observer Tracker This section includes a cumulative list of the future deadlines for implementation and end of consultation periods, which are associated to the most important announcements made in the current and previous issues of Safety Observer. For your convenience, a link to the main sources is provided and we also specify the issue where the corresponding article can be found.

By When ? What ? Issue 28-Oct-2013 Deadline for national transposition of Directive

2012/26/EU (amending Directive 2001/83/EC) (Link) 85

18-Nov-2013 FDA consultation on draft guidance on Patient Counseling Section of Labeling (Link)

94

31-Dec-2013 Deadline to implement inverted equilateral triangle (▼) for products subject to additional monitoring approved in the EU before 01-Sep-2013 (Link)

89

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2. Safety Update

2.1. Opioid analgesics FDA announces new label changes and postmarket study requirements (10-Sep-2013) The FDA has issued a News Release to announce class-wide safety labeling changes and new postmarket study requirements for all extended-release and long-acting opioid analgesics. The goals of the required postmarket studies are to further assess the known serious risks of misuse, abuse, hyperalgesia, addiction, overdose, and death. As part of the safety labeling changes, the FDA is also requiring a new boxed warning to caution that chronic maternal use of these products during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening. Once the labeling changes are finalized, modifications will also be made to the Risk Evaluation and Mitigation Strategy (REMS), to reflect the updated information.

Link to FDA News Release

Link to FDA Media Transcript (text and audio)

2.2. Piribedil (Trivastal®) ANSM decides to limit the indications to Parkinson Disease (18-Sep-2013) Following the re-evaluation concluded in July 2012, the French Agency has issued a press release to inform that the product is now only indicated in the Parkinson Disease and that the R/B ratio is unfavourable in other indications (e.g. vascular indications).

Link to ANSM Press Release

2.3. Dextropropoxyphene-containing products (Di-Gesic®, Doloxene®) Australian TGA provides update on decision to maintain authorisation (19-Sep-2013) The Australian Administrative Appeals Tribunal (AAT) has issued a new decision imposing conditions on the registration of Di-Gesic and Doloxene. These conditions require arrangements to ensure that pharmacists do not dispense these products without seeing a form signed by a doctor or dentist about the suitability of the product for each particular patient. This new decision follows the April 2013 decision to maintain Di-Gesic and Doloxene in the Australian Register of Therapeutic Goods (ARTG), which reverted the December 2011 decision by the TGA to cancel all dextropropoxyphene-containing products.

Link to TGA Page

2.4. Numeta Europe takes action to tackle risks of Numeta G13%E and G16%E (20-Sep-2013) The Coordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh) has endorsed the recommendations of the PRAC, which include the suspension of Numeta G13%E due to the risk of hypermagnesaemia with this intravenous nutrition product used in premature babies. Numeta G13%E will remain suspended until a reformulated preparation is made available. Numeta G16%E is used in full-term newborns and children up to two years and the benefit-risk balance remains positive in this population, provided that blood magnesium levels are appropriately monitored.

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The review was carried out by the PRAC following reports of hypermagnesaemia in preterm infants. As a precautionary measure, the manufacturer decided to voluntarily recall Numeta G13%E in the EU. The PRAC recommendations were endorsed by consensus by the CMDh and will now be implemented directly in all Member States.

Link to EMA Press Release

2.5. Fentanyl Transdermal Systems (Duragesic® and generics) FDA requires packaging changes to reduce risk of Accidental Exposure (23-Sep-2013) The FDA has issued a Drug Safety Communication to inform that the Agency has required color changes to the writing on Duragesic (fentanyl) pain patches so they can be seen more easily. This corresponds to a new effort to minimize the risk of accidental exposure to fentanyl patches, which can cause serious harm and death in children, pets, and others.

Link to FDA MedWatch alert

2.6. Fentanyl Transmucosal ANSM issues new advice on appropriate use (25-Sep-2013) Following recent safety data showing adverse reactions at the administration site and increasing misuse, the French Agency reminds about indications and warns about misuse of this opioid drug indicated in breakthrough pain in cancer patients. Misuse is mainly related to administration in patients not suffering from cancer, insufficient chronic pain treatment or excessive dosage. Modifications of the conditions of delivery to limit misuse are under discussion.

Link to ANSM Press Release

2.7. Ofatumumab (Arzerra®) and Rituximab (Rituxan®) FDA requires label changes to decrease risk of Hepatitis B Reactivation (25-Sep-2013) The FDA has issued a Drug Safety Communication to announce that it has approved changes to the prescribing information of the immune-suppressing and anti-cancer drugs Arzerra and Rituxan to add a new Boxed Warning about the risk of reactivation of hepatitis B virus (HBV) infection. The revised labels include recommendations for screening, monitoring, and managing patients on these drugs to decrease this risk, which may result in fulminant hepatitis, hepatic failure, and death.

Link to FDA MedWatch alert

2.8. HPV vaccine Cervarix® MHRA finds no evidence that Cervarix causes chronic fatigue syndrome (26-Sep-2013) The MHRA has announced that a study performed by the Agency found no evidence that Cervarix – the human papillomavirus (HPV) vaccine – may cause chronic fatigue syndrome. The study involved the analysis of patient record data from the Clinical Practice Research Datalink (CPRD) and was published in the journal Vaccine.

Link to MHRA Press Release

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2.9. Tigecycline (Tygacil®) FDA warns about Increased Risk of Death (27-Sep-2013) The FDA has issued a Drug Safety Communication to notify health professionals of a new Boxed Warning describing an increased risk of death with intravenous Tygacil. This new information is based on an additional analysis following the Drug Safety Communication issued in September 2010 about this safety concern, which showed a higher risk of death compared to other antibacterial drugs (2.5% vs. 1.8%).

Link to FDA MedWatch alert

3. Quality Assurance, Inspections and Audits

3.1. MHRA Pharmacovigilance Inspections Symposium 2014 – Save the date ! As already announced, the MHRA has published preliminary information about the next Pharmacovigilance Inspections Symposium, which will take place on 14-Mar-2014 in London, UK. This event is a popular opportunity to gain a greater understanding of the MHRA Inspectors’ expectations for Pharmacovigilance Systems. Registration will open later in the autumn when further information about the event will be available.

Link to MHRA Event Page

3.2. MHRA updates Good Pharmacovigilance Practice FAQs The MHRA has updated the list of Frequently Asked Questions (FAQs) for Good Pharmacovigilance Practice, which is published on its website. The change relates to Question 35 and the Inspectorate' s expectation of timeframes for publication and distribution of updated SPCs and PILs. It clarifies that for centrally authorised products, the timeframes for implementation of safety variations generally starts with the CHMP opinion but there may be instances where the MAH will need to wait for the Commision Decision before implementing.

Link to MHRA GPvP FAQs Page

4. Drug Safety and Business Risk

4.1. Takeda and Actos® Jury rules in favour of company in Diabetes Drug verdict Takeda has announced that the jury ruled in favor of the company in the second Actos case to go to trial. Although the jury found that Takeda failed to warn of the potential risk of bladder cancer, the jury also found that the plaintiff failed to exercise care for his own health and safety.

Link to PharmaLive article

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5. Other relevant Information and Resources

5.1. US Food and Drug Administration (FDA)

5.1.1. FDA to hold Mini-Sentinel Webinar on Active Medical Product Surveillance The FDA has announced that a Brookings Roundtable Webinar will take place on 16-Oct-2013 to provide an overview of the Innovation in Medical Evidence Development and Surveillance (IMEDS) program. One of the goals of this public-private partnership program is to develop better methods and tools for using electronic health care data for safety evaluations.

Link to FDA Page

5.1.2. FDA updates information on Potential Safety Signals The FDA has updated the information posted on its web site with a new quarterly report identifying drugs with potential safety signals, as required by the 2007 FDA Amendments Act. Drugs that appear on the list entitled " Potential Signals of Serious Risks/New Safety Information" are identified based on reports from the FDA Adverse Event Reporting System (FAERS). The new report covers the second quarter of 2013 and includes only 1 medicinal product: Regadenoson (Lexiscan).

Link to FDA’s Potential Signals Page

5.1.3. FDA provides new results of Postmarketing Drug Safety Evaluations In accordance with the Food and Drug Administration Amendments Act of 2007 (FDAAA) the FDA is required to perform postmarketing evaluations of new Drugs and Biologics 18 months after approval of the drug or after its use by 10,000 individuals. The FDA website has been updated to provide the summaries of the evaluations completed in the period April to June 2013. The information posted includes a table identifying the Drug and Biological products concerned and a summary of the evaluation findings, together with actions taken and ongoing surveillance activities.

Link to FDA’s Postmarketing Drug Safety Evaluations Page

5.1.4. Drug Safety and Risk Management Advisory Committee: New material available The Drug Safety and Risk Management Advisory Committee met on 10-Jul-2013 to discuss the risk management of Lotronex (alosetron hydrochloride), which is approved for the treatment of women with severe diarrhea predominant irritable bowel syndrome. In addition to meeting material previously published, the minutes are now available. The Drug Safety and Risk Management Advisory Committee met on 05 and 06-Jun-2013 in a joint meeting with the Endocrinologic and Metabolic Drugs Advisory Committee to discuss the results of an independent readjudication of the RECORD trial on Rosiglitazone (Avandia). The minutes and transcript of this meeting have been published, where the experts voted in favour of easing the safety restrictions on the former diabetes blockbuster.

Link to FDA Page

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5.1.5. New Public Summary of Drug Safety Oversight Board meeting The public summary for the last meeting of the FDA Drug Safety Oversight Board (DSOB) has been posted. The Board met on 18-Jul-2013 and heard a presentation on “Healthy People 2020”, a programme of health-promotion and disease-prevention.

Link to DSOB Public Summary

5.1.6. FDA to hold Public Workshops on Clinical Trial Requirements The FDA has issued a Federal Register Notice to announce that it will hold a 2-day educational conference entitled “FDA Clinical Trial Requirements, Regulations, Compliance and GCP” in co-sponsorship with the Society of Clinical Research Associates (SoCRA). This is a repeat of previous events held across the USA. Adverse Event Reporting is one of the topics covered during this workshop that will take place on 06 and 07-Nov-2013 in Atlanta, GA.

Link to FDA Notice

5.1.7. 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 requiring color changes to Duragesic (fentanyl) pain patches to aid safety-

emphasizing that accidental exposure to used patches can cause death Boxed Warning and new recommendations to decrease risk of hepatitis B

reactivation with the immune-suppressing and anti-cancer drugs Arzerra (ofatumumab) and Rituxan (rituximab)

FDA warns of increased risk of death with IV antibacterial Tygacil (tigecycline) and approves new Boxed Warning

Link to FDA Page

5.1.8. FDA updates Drug Code Lists The FDA is now updating the National Drug Code Directory on a weekly basis, and it can be downloaded from their website.

Link to National Drug Code Directory Page

The “Drugs@FDA” Downloadable Data Files were last updated on 02-Oct-2013.

Link to Drugs@FDA Page

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5.2. European Medicines Agency (EMA)

5.2.1. PRAC recommendations on Safety Signals As described in section 1.1, the EMA has now started to publish 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 overview list of safety signals discussed during the September PRAC meeting was published on 03-Oct-2013 and includes recommendations to update the product information for the following combinations of Product / Signal: Brentuximab vedotin / Pulmonary toxicity Hydroxychloroquine & Chloroquine / Hypoglycaemia Nicardipine / Acute pulmonary oedema in off-label use during pregnancy The cumulative list of all safety signals discussed at the PRAC includes all signals discussed at the PRAC since September 2012, which includes links to the corresponding PRAC minutes and specifies whether a variation was recommended.

Link to EMA Page

5.2.2. EMA clarifies arrangements for transmission of EU ICSRs to WHO The new EU Pharmacovigilance legislation requires the EMA to make available promptly all reports of suspected adverse reactions that occurred in the EU to the UMC, which acts as the WHO Collaborating Centre for International Drug Monitoring. While the legislation came into force on 01-Jul-2012, the transmission of reports from the EMA to the UMC will only start after a successful audit of enhanced EudraVigilance functionalities. In the interim, EU Competent Authorities continue their reporting to the UMC in accordance with the guidelines provided in GVP Module VI.

Link to EMA Communication

5.2.3. 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 July PRAC meeting have now been published, which provides a summary of the discussions related to safety signals, RMPs, PSURs, etc. The PRAC started a new referral procedure for zolpidem and the risk of next-morning impairment. The review of Combined Hormonal Contraceptives (CHCs) continues and a recommendation from the PRAC is expected in October 2013. Some MAHs of hydroxyethyl-starch (HES)-containing solutions for infusion have requested the PRAC to re-examine its June 2013 recommendation to suspend these medicines. The implementation of the PRAC’s recommendation has been put on hold and a review procedure requested by the UK will run in parallel with the re-examination of the PRAC recommendation. The products concerned by new Safety Signals included Fondaparinux, Lopinavir/Ritonavir, Sitagliptin, Tamsulosin, Thiopental, and Human papillomavirus vaccines. The PRAC followed up on previously identified signals for Levetiracetam.

Direct link to PRAC Meeting Minutes (08 to 11-July-2013)

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5.2.4. EMA issues new CHMP Monthly Meeting Highlights The highlights for the September meeting of the Committee for Medicinal Products for Human Use (CHMP) have now been published. Following the June CHMP recommendation to impose new restrictions on medicines containing ergot derivatives in a range of indications, a MAH for dihydroergotoxine requested a re-examination, which the EMA will now initiate for this specific product. In the same way, a MAH has requested a re-examination of the July CHMP recommendation to impose new restrictions on metoclopramide. The discussion on Safety Variations included recommendations for new contraindications for azilsartan medoxomil and agomelatine. 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 and PSURs, as well as community reviews initiated.

Link to CHMP Meeting Highlights (16 to 19-Sep-2013)

5.2.5. EMA updates information related to the list of Black Triangle Products As described in GVP Module X, the EMA is publishing the list of medicines under additional monitoring, which will be identified by a Black Triangle (▼) throughout Europe. First published in April 2013, the list has been updated to include 11 additional products while Iloprost (Ventavis®) has been removed from the list, which provides the reason for a product to be subject to additional monitoring and is routinely reviewed by the PRAC. The EMA has also issued a short Factsheet and a video to explain the concept of medicines under additional monitoring, which are available in several languages on a separate web page.

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

Link to EMA Page: Additional monitoring – information materials

5.2.6. New EMA video on submission of single assessment PSURs As a key deliverable of the new Pharmacovigilance legislation, the Agency started carrying out single assessments of PSURs of active substances contained in both centrally and nationally authorised medicines in April 2013. To complement the published guidance, the EMA has now made available a video of a recent webinar on how to submit PSURs for medicines subject to EU single assessment via its eSubmission Gateway and web client.

Link to EMA Video

Link to EMA News Release & Guidance (24-Jun-2013)

5.2.7. EMA provides details of its new organisational structure The EMA has announced the changes in its structure, which are intended to reorganise the Agency in order to better support its mission. These changes mark the beginning of a transition period as the Agency revises its operating processes, which is expected to be completed in 2014. The new structure comprises four new Divisions, including the “Inspections and Human Medicines Pharmacovigilance Division”.

Link to EMA Press Release

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5.2.8. EMA updates information on submission of medicines information The EMA has published revised versions for several Extended EudraVigilance product report message (XEVMPD) controlled vocabularies, which support compliance with Article 57(2) of new EU Pharmacovigilance legislation whereby MAHs are required to perform electronic submission of medicinal product information. The controlled vocabularies are updated regularly to improve the standardisation of the terminology used. MAHs are however not required to resubmit if medicine information has already been submitted using a previous version of the controlled vocabularies.

Link to EMA Page: Electronic submission of information on medicines

5.3. UK Agency (MHRA)

5.3.1. New issues of MHRA “Drug Safety Update” Bulletin The latest issue of Drug Safety Update (Volume 7, Issue 2, September 2013) was published on 10-Sep-2013. It includes the following topics: Filgrastim and pegfilgrastim: risk of life-threatening capillary leak syndrome Panitumumab: importance of establishing wildtype RAS status before treatment Intravenous iron and hypersensitivity reactions: Recommendations for test dose

Drug Safety Update is available as a fully searchable online resource.

Link to MHRA Newsletter Page

5.3.2. MHRA Dear Doctor Letters The letters sent to Healthcare Professionals are routinely posted on the Agency’s website. The letters from September are related to the following safety information: Eliquis (apixaban), Pradaxa (dabigatran etexilate) and Xarelto (rivaroxaban):

Reminder to reduce risk of bleeding by assessing risk factors Imnovid (pomalidomide): Risk of teratogenicity if taken during pregnancy

Link to MHRA Page

5.4. French Agency (ANSM)

5.4.1. ANSM launches pilot phase for the use of the CESP ANSM has launched a pilot phase on 01-Oct-2013 during which applicants have the option to voluntarily submit their dossiers using the Common European Submission Platform (CESP), which is already used by 26 EU Authorities. It covers only new MA requests and requests for MA variations submitted through national or European procedures, whereas the submission of PSURs and RMPs are not included in this pilot. Link to ANSM Page

Link to the Notice to Applicants (in French)

Link to the Notice to Applicants (in English)

5.4.2. ANSM provides update on PRAC and CHMP activities Following the publication of PRAC minutes, ANSM has issued a document in French to summarise the discussions and decisions taken by the PRAC, together with ANSM positions and recommendations for Healthcare Professionals.

Link to ANSM synthesis for the PRAC meeting of September 2013 (in French)

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5.4.3. ANSM Dear Doctor Letters Dear Doctor Letters sent in September 2013 are now available on the French Agency's website (all in French). Letter due to safety concerns include the following: Ergot derivatives: MA suspension Piribedil (Trivastal®): restriction of indications Panitumumab (Vectibix®): RAS status to be determined before treatment Risperidone, Paliperidone (Risperdal®and generics, Invega®, Xeplion®): risks of

Floppy Iris Syndrome during cataract extraction Apixaban, Dabigatran, Rivaroxaban (Eliquis®, Praxada®, Xarelto®): hemorragic risk

factors Filgrastim, Pegfilgrastim (Neupogen®, Neulasta®): risks of capillary leak syndrome

Link to ANSM Webpage

5.4.4. ANSM communicates status of biosimilars ANSM has issued a report on the status of biosimilars and associated recommendations for Healthcare Professionals.

Link to ANSM Synthesis (in French)

5.4.5. France provides public access to drugs database The database is maintained by the Health Ministry and provides access to various information about drugs, including SmPC, Patient Leaflet, Administrative information (price, reimbursement), Important Safety Information and results of the medical benefit evaluation of the drug (Service Médical Rendu – SMR).

Link to French public database on drugs (in French)

5.5. Other Sources

5.5.1. Study finds surprising effects of warnings on drug sales Psychological research suggests that warnings of serious side effects in drug advertising can actually improve consumers’ opinions and increase sales. The authors believe that the patients may see the warnings as an indication of the firm’s honesty and trustworthiness.

Link to PharmaTimes article

5.5.2. New issue of MedDRA Messenger The MSSO (Maintenance and Support Services Organization) has published a new “Messenger” Newsletter, which highlights the main changes introduced with MedDRA Version 16.1 in September 2013. It also introduces the new MedDRA website and some of its functionalities, in particular regarding MedDRA Training resources.

Link to MedDRA Messenger

5.5.3. New Brochure: Understanding MedDRA This document provides an overview of the ICH Medical Dictionary for Regulatory Activities (MedDRA) and covers various aspects, including the structure of MedDRA and how it is used, for example in Signal Detection.

Link to MedDRA Announcement

Link to MedDRA Brochure

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5.5.4. New issue of WHO Drug Information The latest edition of the WHO Drug Information, Vol. 27 No.3, is now available. The Safety and Efficacy section provides the latest information on safety signals and reports of adverse drug reactions, with other news from around the world, including labelling changes and alerts.

Link to WHO Drug Information

5.5.5. New issue of Australian “Medicine Safety Update” The new edition of Medicines Safety Update (Volume 4, Number 5, October 2013) is now available. The contents include: Tomoxetine and suicidality in children and adolescents Rotavirus vaccination and the risk of intussusception Drug-induced liver injury

Link to Medicines Safety Update

5.5.6. New issue of Adis Pharmacovigilance eNewsletter The Adis in-touch Pharmacovigilance is a quarterly eNewsletter bringing news, views and events. This issue includes free access to highlighted articles from Adis, including an update on the recent debate and controversy surrounding the safety of incretin mimetics. The newsletter also includes a selection of ADR case reports published in Reactions Weekly and Pharmacovigilance Insight in the second quarter of 2013.

Link to Adis in-touch

5.5.7. New issue of Japanese PMDSI Newsletter The Pharmaceuticals and Medical Devices Safety Information (PMDSI) Newsletter is issued based on safety information collected by the Japanese Ministry of Health, Labour and Welfare (MHLW) and is intended to promote safer use of pharmaceuticals and medical devices by healthcare providers. The English Summary of the latest edition of the Newsletter (Issue N°305) is now available and includes: Hydroxyethyl Starch-containing Solutions and Renal Impairment Project of Japan Drug Information Institute in Pregnancy Revision of Precautions: Isoflurane Important Safety Information and Products Subject to Early Post-marketing Vigilance

Link to PMDA Page

5.5.8. Japanese PMDA provides updated list of drugs under review The Pharmaceuticals and Medical Devices Agency (PMDA) has updated its webpage where it provides information on drug risks under review by the PMDA/MHLW, which can be based on safety information submitted to the Japanese Agency or due to communication from foreign drug agencies.

Link to PMDA Page

Safety Observer N°94 – October 2013 page 16/18

6. Time to Register

EMA/DIA Events 1st Information Day on the use of MedDRA including Medication Errors

October 22 in London, UK Introduction to Pharmacovigilance and Electronic Transmission of ICSRs

November 12 in London, UK Excellence in Pharmacovigilance: Clinical Trials and Post-Marketing

November 18 – 22 in London, UK

DSRU Events Risk Benefit Assessment in Pharmacovigilance

October 16 – 17 in Fareham, UK Case Narrative Writing for Reporting Adverse Events

October 30 – 31 in Winchester, UK Pharmacovigilance in Products Subject to Licensing Agreements

November 13 – 14 in London, UK Pharmacovigilance Planning and Risk Management

November 27 – 28 in Fareham, UK

DIA Events Drug-Induced Injury of Liver, Heart, Kidney, and Skin

October 15 – 17 in North Bethesda MD, USA Postmarketing Drug Safety & Pharmacovigilance

October 21 – 22 in Horsham PA, USA Signal Detection and Data Mining

October 22 – 24 in Beijing, China 8th Annual Conference India

October 24 – 26 in Bangalore, India DIA’s Annual Canadian Meeting

October 29 – 30 in Ottawa, Canada Webinar: CDER Town Meeting: Safety Hot Topics

October 30, 2:30PM - 4:00PM EDT Webinar: CardioVascular Safety: Proarrhythmic Assessment of New Drugs

October 31, 11:00AM - 12:30PM EDT Risk Management and Safety Communication Strategies

November 04 – 05 in Horsham PA, USA

Signal Management in Pharmacovigilance November 06 – 07 in Paris, France

10th DIA Japan Annual Meeting November 06 – 08 in Tokyo, Japan

Webinar: CardioVascular Safety: Key Issues for Blood Pressure Assessment in Clinical Trials November 07, 11:00AM - 12:30PM EDT

How to Prepare for Pharmacovigilance Audits and Inspections November 07 – 08 in Paris, France

Global AE Reporting: Drug Safety Requirements in the US and EU November 12 in Bethesda MD, USA

Webinar: Using Large Datasets for Identifying and Investigating Product Safety and Effectiveness November 18, 11:00AM - 12:30PM EDT

ICH Endorsed Pharmacovigilance November 28 – 29 in Zagreb, Croatia

Safety Observer N°94 – October 2013 page 17/18

Barnett Events Webinar – Introduction to Signal Detection and Data Mining

October 09, 01:OO PM to 02:30 PM Eastern Webinar – Adverse Event Monitoring for CRAs

October 25, 12:OO PM to 02:00 PM Eastern Webinar – Final FDA Guidance: Reporting of Safety Information from Clinical Trials to IRBs

November 04, 12:0O PM to 01:30 PM Eastern Webinar – The European Pharmacovigilance Legislation

November 05, 01:OO PM to 02:30 PM Eastern Signal Detection and Pharmacovigilance

November 07 in Philadelphia PA, USA Drug Safety and Pharmacovigilance

December 03 – 04 in Boston MA, USA Adverse Events: Managing and Reporting for Pharmaceuticals

December 03 – 04 in Philadelphia PA, USA Webinar – Preparing for a Safety Inspection

December 10, 01:0O PM to 02:30 PM Eastern The Pharmacovigilance Audit: How to Prepare for an Inspection

December 12 in Philadelphia PA, USA

Other Events Management Forum – New Pharmacovigilance legislation – The Complete Picture

October 14 – 15 in London, UK IFIS – Pharmacovigilance: roles, missions and responsibilities (event in French)

October 21 – 22, November 15 in Paris, France ISPE – 8th Asian Conference on Pharmacoepidemiology

October 25 – 27 in Hong Kong Management Forum – PSURs/PBRERs

October 31 in London, UK RQA – New EU PV Legislation Challenges with Implications

November 06 in Solihull, UK RQA – Safety Reporting in Clinical Trials

November 06 in Solihull, UK PIPA: Pharmacovigilance – Regulations and Guidelines in Practice

November 06 in Hartley Wintney, UK Informa – 7th Annual Pharmacovigilance and Risk Management

November 06 – 07 in Berlin, Germany IFIS – Risk Management Plan (event in French)

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

November 22 in Paris, France RQA – Practical Pharmacovigilance Auditing

November 25 – 27 in Cambridge, UK IFIS – Writing periodic reports in Drug safety

November 28 – 29 in Paris, France Management Forum – Latest developments in Pharmacovigilance

November 28 – 29 in London, UK IFIS – Pharmacovigilance for assistants (event in French)

December 09 – 10 in Paris, France Faculté de Pharmacie Paris 5 – Pharmacovigilance and social media (event in French)

December 06 in Paris, France PTI – An Introduction to Pharmacovigilance

December 10 – 11 in London, UK Management Forum – Pharmacovigilance

December 16 – 18 in London, UK

Safety Observer N°94 – October 2013 page 18/18

7. About the Authors

SUNNIKAN Consulting is offering a wide range of services related to Risk, Quality and Process Management Systems for Pharmaceutical Industry since 1996. SUNNIKAN Consulting’s areas of expertise cover Clinical Research, Regulatory Affairs, Pharmacovigilance, Computerized Systems, and more. For more information please visit SUNNIKAN Consulting’s website at: www.sunnikan.com

PV Focus is a small specialty company established since December 2004. Based in France, PV Focus has successfully centered its business on the provision of Pharmacovigilance Audits and related services to the Pharmaceutical Industry. Due to its experience of both Audits and Regulatory Inspections at a global level, PV Focus is a partner of choice to assist with the performance of Pharmacovigilance System Audits and can also support the preparation of Regulatory Inspections. For more information please visit www.pvfocus.com

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