Safety Observer N°98 – February 2014 page 1/19

Safety Observer Clinical Safety & Pharmacovigilance Intelligence Review

Issue N°98 – February 2014 Highlights The FDA has published its final guidance on Dear Health Care Provider Letters. The EMA has announced the next steps for the maintenance of information on medicinal products, which comes with the requirement for companies to update all their XEVMPD submissions by the end of 2014. New progress has been made with the future European Clinical Trials Regulation, which is planned to repeal Directive 2001/20/EC. The European PRAC has recommended the suspension of Strontium ranelate (Protelos/Osseor), but the CHMP has delayed its opinion until additional information is provided and considered. The EMA has announced that it will review a possible link between bodyweight and reduced efficacy of emergency contraceptives. The FDA has initiated the review of the risk of stroke, heart attack and death associated to testosterone Products. The MHRA has published its new PV compliance report, which companies are encouraged to complete for the Agency to define its inspections priorities.

Safety Observer N°98 – February 2014 page 2/19

In this issue

1. Regulatory Update .................................................................................................................... 3

1.1. Applicable Regulations, Guidelines and other Standards ............................................................ 3 1.1.1. EMA issues revised GVP Annex I: Definitions ............................................................................... 3 1.1.2. EMA provides guidance on Article 31 Pharmacovigilance Referrals ................................................ 3 1.1.3. FDA issues final guidance on Dear Health Care Provider Letters ................................................... 3 1.1.4. France implements legislation on financial penalties .................................................................... 3 1.1.5. EMA updates EURD list.............................................................................................................. 4 1.1.6. CMDh updates information on PSUR Submission for NAPs ........................................................... 4 1.1.7. CMDh updates Q&As on transitional arrangements for the PV legislation ....................................... 4

1.2. Developments to watch ............................................................................................................ 4 1.2.1. Europe makes progress on the future Clinical Trials Regulation .................................................... 4 1.2.2. EMA issues draft guidance on Pharmacogenomics in Pharmacovigilance ....................................... 5 1.2.3. EMA issues new guidance on submission of medicines information .............................................. 5

1.3. Beyond the borders of Safety Observer ...................................................................................... 6 1.3.1. Belgium clarifies requirements for local Pharmacovigilance Contact .............................................. 6

1.4. The Safety Observer Tracker ..................................................................................................... 6

2. Safety Update .......................................................................................................................... 6

2.1. OTC Sodium Phosphate Products (Fleet® and generics) ............................................................ 6

2.2. Strontium ranelate (Protelos®/Osseor®) .................................................................................. 7

2.3. Acetaminophen Prescription Combination Products (Paracetamol) ............................................. 7

2.4. Emergency contraceptives ........................................................................................................ 7

2.5. Testosterone Products.............................................................................................................. 7

2.6. Iron Injection ............................................................................................................................ 8

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

3.1. New MHRA risk-based inspections questionnaire now available .................................................. 8

3.2. MHRA issues minutes of Stakeholder Engagement Meeting (StEM) ........................................... 8

3.3. Swissmedic information on GCP and Pharmacovigilance Inspections .......................................... 8

4. Drug Safety and Business Risk.................................................................................................. 9

4.1. Wyeth and Redux ..................................................................................................................... 9

4.2. Sanofi-Pasteur and Revaxis ....................................................................................................... 9

4.3. UCB and Distilben .................................................................................................................... 9

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)........................................................................................................... 14

5.5. Other Sources ........................................................................................................................ 15

6. Time to Register ..................................................................................................................... 17

7. About the Authors .................................................................................................................. 19

Safety Observer N°98 – February 2014 page 3/19

1. Regulatory Update

1.1. Applicable Regulations, Guidelines and other Standards

1.1.1. EMA issues revised GVP Annex I: Definitions (08-Jan-2014) The GVP Annex I - Definitions has been updated and Revision 2 includes recent changes and additions from GVP documents recently introduced, including Module XV (Safety Communication) and the product-specific considerations for Vaccines. It also contains a new explanatory note for the definition of Off-Label Use, which clarifies that it does not include use outside the EU in an indication authorised in that territory but not in the EU. The Introductory Cover Note has been updated accordingly.

Link to EMA GVP Page

Direct link to GVP Annex I Rev.2

1.1.2. EMA provides guidance on Article 31 Pharmacovigilance Referrals (22-Jan-2014) The EMA has published a new list of Questions and Answers, which provides guidance on the procedure for Article 31 Pharmacovigilance Referral. It covers various aspects of the procedure, including the initiation, assessment, PRAC recommendation and final position by CHMP or CMDh.

Link to EMA Q&As on Article 31 Referral

1.1.3. FDA issues final guidance on Dear Health Care Provider Letters (23-Jan-2014) The FDA has now published the final guidance entitled “Dear Health Care Provider Letters: Improving Communication of Important Safety Information”. This guidance offers specific recommendations to industry on the content and format of Dear Health Care Provider (DHCP) letters. It provides recommendations on when to use a DHCP letter, the types of information to include and how to organize it, and formatting techniques to make the information more accessible. This guidance finalizes the draft guidance issued in November 2010.

Link to Federal Register Notice

Link to FDA Final Guidance

1.1.4. France implements legislation on financial penalties (31-Jan-2014) The decree n° 2014-73 of 30 January 2014 (applicable 01-Feb-2014) defines the modalities of implementation of the financial penalties introduced by the Order n°2013-1183 dated 19-Dec-2013. Based on inspection results, the ANSM Director may initiate a financial sanctions procedure towards the authors of failures, which includes failure to meet Pharmacovigilance obligations. A new article (R. 5421-1) has also been created for Healthcare Professionals (physician, dentist, midwife, pharmacist). The ignorance of the obligations to report serious adverse reactions can be punished by a fine of 1,500 Euros.

Link to decree (in French)

Safety Observer N°98 – February 2014 page 4/19

1.1.5. EMA updates EURD list (31-Jan-2014) Update of the EURD list have been published, 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 all dated and highlighted. The changes introduced on 08-Jan-2014 include 11 new products and 7 amendments. The list was revised again on 31-Jan-2014 to include 14 new products and 7 amendments.

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

1.1.6. CMDh updates information on PSUR Submission for NAPs (05-Feb-2014) 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. The Best Practice Guide for PSUR Work Sharing during the transition period has also been updated. The update relates to the requirement for the MAH to implement changes required as a result of a PSUR assessment, which should be done within a maximum of 90 days, as opposed to 4 months previously.

Link to HMA Page

Direct link to list (pdf)

1.1.7. CMDh updates Q&As on transitional arrangements for the PV legislation (05-Feb-2014) The CMDh has issued a minor updated to its Q&A document. The changes relate to the category of variation for the submission of an RMP. Question 4 regarding the grouping of variations has been deleted.

Link to CMDh Q&As (Rev.8 – January 2014)

Link to CMDh Q&As (track changes)

1.2. Developments to watch

1.2.1. Europe makes progress on the future Clinical Trials Regulation (22-Jan-2014) The work continues in Europe on the new Clinical Trials Regulation, for which the European Commission adopted a first Proposal in July 2012. The new regulation is intended to speed up and simplify the authorization and reporting procedures, with obligations adjusted to the risk-profile of the trial. The proposed legislation will replace the 2001 Clinical Trials Directive and take the form of a Regulation to ensure that the rules are identical throughout the EU and prevent the issues caused by the divergent transposition of Directive 2001/20/EC. The Regulation is planned to come into effect in 2016, and a revised draft regulation is now available, as approved by the Permanent Representatives Committee, and subsequently approved by the European Parliament’s ENVI Committee.

Safety Observer N°98 – February 2014 page 5/19

As mentioned earlier, the safety reporting rules would be greatly simplified with single reporting by the Sponsor to an EU Portal and Database. The database should be publicly accessible and easily searchable, and no additional reporting to National Authorities, investigators and Ethics Committees is required in the current draft. The portal should be used to submit various information, including unexpected events that affect the benefit-risk balance of the trial, Urgent Safety Measures, and also all inspection reports of third country authorities (articles 50 and 51).

Link to European Council Note 17866/13

Link to Sidley Update

1.2.2. EMA issues draft guidance on Pharmacogenomics in Pharmacovigilance (30-Jan-2014) The EMA has released a new draft guideline for consultation to address how pharmacogenomics can support pharmacovigilance activities. The draft guideline 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 and provides concrete examples. Comments on the draft guideline are expected by 30-Jul-2014.

Link to EMA News Release

Link to EMA Draft Guideline Page

1.2.3. EMA issues new guidance on submission of medicines information (31-Jan-2014) The EMA has released new guidance to support MAHs updating the information on authorised medicines that they have submitted in accordance with Article 57(2) of the 2010 pharmacovigilance legislation. As of 16-Jun-2014 and by 31-Dec-2014, MAHs will be required to update information on their authorised medicines. This will require completing additional data elements included in the new data submission format and checking the quality of the information in line with the updated reporting requirements. The new guidance includes updates to the legal notice, detailed-guidance documents and controlled vocabularies and the EMA urges MAHs to adapt their data-submission tools before they begin to update the information on their medicines in June. The EMA plans to release additional guidance on Quality Control in March 2014. Following the update of the information, MAHs will be required to follow transition maintenance submission processes until the implementation of the International Standards on Identification of Medicinal Product (i.e. ISO IDMP standards) in 2016. The information presented on the EMA website includes a “Training and best practice” Page, where a free e-learning course is available. The slides can be downloaded as well as the XEVMPD data-entry tool (EVWEB) user manual.

Link to EMA News Release

Link to EMA Data Submission Page

Link to EMA Data Submission Guidance Page

Link to EMA Data Submission Training Page

Safety Observer N°98 – February 2014 page 6/19

1.3. Beyond the borders of Safety Observer

1.3.1. Belgium clarifies requirements for local Pharmacovigilance Contact (Jan-2014) Circular Letter N°600 was issued in July 2013 and describes the requirements applicable to the Local Contact Person for Pharmacovigilance, which comes in replacement of the former Local Qualified Person. The qualification and registration requirements have been simplified and the Agency requires all MAHs to submit two notifications containing respectively details about the Local Contact Person and Pharmacovigilance System. An additional Q&A Document has been published to further describe Belgian expectations regarding the Local Contact Person for Pharmacovigilance.

Link to Q&A Document

Link to Circular Letters Page

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 13-Mar-2014 FDA consultation on Proposed Rule for generics safety

label changes (Link + Link) 96 + 97

30-Jul-2014 EMA consultation on Draft Guideline on the use of pharmacogenomics in Pharmacovigilance (Link)

98

16-Jun-2014 to 31-Dec-2014

MAHs will be required to update XEVMPD information (Link)

98

2. Safety Update

2.1. OTC Sodium Phosphate Products (Fleet® and generics) FDA warns of possible harm from exceeding recommended dose (08-Jan-2014) The FDA has warned that using more than one dose in 24 hours of over-the-counter (OTC) sodium phosphate drugs to treat constipation can cause severe dehydration and changes in the levels of serum electrolytes, which may lead to serious adverse effects on organs, such as the kidneys and heart, and can result in death.

Link to FDA MedWatch alert

Safety Observer N°98 – February 2014 page 7/19

2.2. Strontium ranelate (Protelos®/Osseor®) PRAC recommends product suspension (10-Jan-2014) Following restrictions in April 2013 to reduce the risk of heart problems, an in-depth review of the product was initiated by the PRAC. The PRAC has now conducted its review of the benefits and risks of the medicine and concluded that the balance was no longer favourable in the treatment of osteoporosis. The PRAC recommended that Protelos/Osseor be suspended until there are new data showing a favourable balance in a defined patient group. The PRAC recommendation has been considered by the CHMP but the Committee requested additional information from the company before it issues a final opinion, which is now expected at the February meeting.

Link to EMA Press Release

Link to CHMP Meeting Highlights

2.3. Acetaminophen Prescription Combination Products (Paracetamol) FDA recommends discontinuation of products containing over 325 mg (14-Jan-2014) The FDA has recommended that Health Care Professionals discontinue prescribing and dispensing prescription combination drug products that contain more than 325 mg of acetaminophen (paracetamol) per tablet, capsule or other dosage unit. There are no available data to show that taking more than 325 mg of acetaminophen per dosage unit provides additional benefit that outweighs the added risks for liver injury from inadvertent overdose. This communication follows the January 2011 request that manufacturers limit the amount of acetaminophen to no more than 325 mg by 14-Jan-2014. More than half have complied with the FDA request but some products containing more than 325 mg remain available. The FDA intends to institute proceedings to withdraw approval of these products in the near future, and the FDA is also planning to address OTC products in a separate regulatory action.

Link to FDA MedWatch alert

2.4. Emergency contraceptives EMA to review possible link between bodyweight and reduced efficacy (24-Jan-2014) At the request of the Swedish Agency, the EMA has started a review of emergency contraceptives to assess whether increased bodyweight and body mass index (BMI) reduce the efficacy of these medicines in preventing unintended pregnancies, as suggested by new data. Emergency contraceptives contain levonorgestrel or ulipristal acetate, and act by blocking and/or delaying ovulation.

Link to EMA Press Release

2.5. Testosterone Products FDA to evaluate risk of stroke, heart attack and death (31-Jan-2014) The FDA has initiated a review of the risk of stroke, heart attack, and death in men taking testosterone products. The FDA has been monitoring this risk and decided to reassess this issue after the recent publication of two studies suggesting an increased risk of cardiovascular events associated to testosterone therapy.

Link to FDA MedWatch alert

Safety Observer N°98 – February 2014 page 8/19

2.6. Iron Injection ANSM informs on the new modalities of administration (31-Jan-2014) This follows the re-evaluation at the European Level of the Risks and Benefits and the resulting changes to the product information. Because of the important risks of hypersensitivity, these products will only be prescribed and used in hospital setting.

Link to ANSM Press Release (in French)

3. Quality Assurance, Inspections and Audits

3.1. New MHRA risk-based inspections questionnaire now available As part of the MHRA risk-based inspection process, MAHs are encouraged to complete a Compliance Report every two years. MAHs were last requested to submit a compliance report in November 2011 and as previously announced, the new 2013 Compliance Report is now available together with associated guidance. The deadline for submissions is 30-May-2014.

Link to MHRA GPvP Risk-based inspections Page

3.2. MHRA issues minutes of Stakeholder Engagement Meeting (StEM) The StEM was established in October 2013 and meets annually, replacing the previously separate GCP, GPvP and GLP Consultative Committees to discuss key issues on Good Practices and associated inspections. The MHRA has now published the minutes of the last meeting, which took place on 25-Oct-2013. The meeting included a presentation on the Risk-Based Inspections software and process implemented by the MHRA, explaining how the system takes identified risks into account to define the inspection priorities. The separate GPvP session covered aspects related to PSMF maintenance and processing of off-label use reports. The MHRA provided an update on the proposal to conduct GPvP inspections of service providers, and clarified that the GPvP Purple Guide will not be revised until a later point in time, when the inspectorate has develop further understanding of the new legislation and identified the need for further guidance.

Link to MHRA Page

3.3. Swissmedic information on GCP and Pharmacovigilance Inspections The Swiss Agency has published information about GCP and Pharmacovigilance Inspections, which describes the approach of the Agency. The information covers the legal basis, inspection types, criteria for selecting inspection targets, the inspection process and the classification of findings.

Link to Swissmedic Page

Safety Observer N°98 – February 2014 page 9/19

4. Drug Safety and Business Risk

4.1. Wyeth and Redux High Court concludes that Pharma can be liable for " lack of due care" The Pennsylvania Supreme Court has ruled that pharmaceutical companies can be liable for failing to stop the marketing of drugs known to be unreasonable harmful. The ruling stems from a 2006 lawsuit filed against Wyeth by the mother of a woman who died after taking the weight loss medicine. The suit alleges Wyeth did not take Redux off the market despite reports linking the medicine to valvular heart disease.

Link to Philadelphia Business Journal article

4.2. Sanofi-Pasteur and Revaxis A Patients association files a lawsuit French victims of suspected adverse reactions have filed a complaint for injury and deception in Paris. They accuse aluminium-based adjuvants to cause macrophagic myofasciitis. In addition, they accuse Sanofi Pasteur of data falsification regarding their previous vaccine (DTPolio) which did not contain such adjuvants.

Link to Yahoo article (In French)

4.3. UCB and Distilben Two daughters of exposed women file a lawsuit Two daughters of exposed women have filed a complaint in Nanterre (France). One experienced a uterus ablation, two pathologic pregnancies and she has had a son with multi-handicap whereas the other one experienced sterility problems.

Link to Le Parisien article (In French)

5. Other relevant Information and Resources

5.1. US Food and Drug Administration (FDA)

5.1.1. FDA updates information on Potential Safety Signals The FDA has updated the information posted on its website regarding drugs with potential safety signals, as required by the 2007 FDA Amendments Act. Drugs that appear on the list 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 third quarter of 2013 and includes the following combination of Product / Signal: Topical acne products containing benzoyl peroxide and/or salicylic acid -

Hypersensitivity and anaphylactic reactions

Link to FDA’s Potential Signals Page

Safety Observer N°98 – February 2014 page 10/19

5.1.2. FDA Workshop on Uncertainty in the Benefit-Risk Assessment The FDA has announced a workshop convened by the Institute of Medicine (IOM): “Characterizing and Communicating Uncertainty in the Assessment of Benefits and Risks in Drug Regulatory Decision-Making”. The purpose of the workshop is to explore potential approaches for addressing uncertainty into the assessment of benefits and risks in the drug review process. The workshop will be held on 12 and 13-Feb-2014. Registration is now closed but comments can be submitted until 14-Mar-2014.

Link to Federal Register Notice

5.1.3. Risk Communication Advisory Committee: New material available As previously reported, the Committee met on 17-Dec-2013 to discuss new methods for communicating risk information as part of Risk Evaluation and Mitigation Strategies (REMS) to Healthcare Providers and how to evaluate their effectiveness. In addition to the webcasts and presentations made available earlier, the transcript of the meeting has now been published.

Link to FDA Page

5.1.4. 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 12 and 13-Mar-2014 in Newport Beach, CA.

Link to Federal Register Notice

5.1.5. 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 warns of possible harm from exceeding recommended dose of over-the-counter

sodium phosphate products to treat constipation FDA evaluating risk of stroke, heart attack and death with FDA-approved

testosterone products

Link to FDA Page

5.1.6. 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 05-Feb-2014.

Link to Drugs@FDA Page

Safety Observer N°98 – February 2014 page 11/19

5.2. European Medicines Agency (EMA)

5.2.1. 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). The information available now includes a glossary of Acronyms and abbreviations used in PRAC minutes.

Link to EMA PRAC Page

The minutes of the December PRAC meeting have now been published. Some MAHs for diacerein-containing medicines have requested a re-examination of the PRAC’s November 2013 recommendation to suspend these medicines. As communicated separately, the PRAC started an in-depth review of Iclusig and concluded that the benefits of Kogenate Bayer and Helixate NexGen continue to outweigh the risks in previously untreated haemophilia A patients. The products concerned by new Safety Signals included Clindamycin, Lamotrigine, Strontium ranelate, and Fentanyl transdermal patch.

Direct link to PRAC Meeting Minutes (02 to 05-Dec-2013)

The agenda and highlights of the January PRAC meeting have also just been published. As communicated separately, the PRAC has concluded an in-depth review of Protelos/Osseor (strontium ranelate) and recommended that this product should no longer be used to treat osteoporosis. According to the agenda, new Safety Signals have been identified for the following products: Abatacept, Duloxetine, Fluticasone furoate, Leuprorelin, Pazopanib, and Tenofovir disoproxil fumarate.

Direct link to PRAC Meeting Highlights (06 to 09-Jan-2014)

5.2.2. EMA issues new CHMP Meeting Material The highlights for the January meeting of CHMP have been published. As communicated separately, the CHMP started a review of emergency contraceptives to assess whether increased bodyweight and body mass index (BMI) reduce the efficacy of these medicines in preventing an unintended pregnancy. The PRAC recommendation that Protelos and Osseor should no longer be used to treat osteoporosis is still under consideration, as the Committee requested additional information to inform its decision-making. The MAH for Linoladiol N and Linoladiol HN has requested a re-examination of the CHMP’s December 2013 opinion to restrict the use of Linoladiol N. 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 as well as community reviews initiated.

Link to CHMP Meeting Highlights (20 to 23-Jan-2014)

Safety Observer N°98 – February 2014 page 12/19

5.2.3. PRAC recommendations on Safety Signals The EMA now routinely issues the PRAC recommendations resulting from the assessment of safety signals. MAHs are legally obliged to monitor this information to keep informed about the PRAC recommendations concerning their products, which may require the submission of a Safety Variation. The recommendations on signals adopted at the January PRAC meeting were published on 28-Jan-2014 and includes recommendations to update the product information for the following combination of Product / Signal: Orlistat - Drug interaction with highly active antiretroviral therapy (HAART) Triamcinolone acetonide (suspension for injection) - Postmenopausal haemorrhage The cumulative 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. The EMA has also revised the list of PRAC signal recommendations to update the product information in the period from September 2012 to July 2013, i.e. before the EMA started the publication of recommendations after each PRAC meeting.

Link to EMA Page

5.2.4. 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. 6 products have been added to the list, which specifies the reason for a product to be subject to additional monitoring. Most of the new additions in January 2014 are justified by the conduct of a PASS Study. 3 new annexes to the list have been published, which provide the list of medicinal products that contain new active ingredients under additional monitoring, i.e. hydroxyethyl starch (HES), thiocolchicoside and intravenous iron.

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

5.2.5. EMA updates information on submission of medicines information The EMA has published revised versions for a number of 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.

Link to EMA Page: Electronic submission of information on medicines

Safety Observer N°98 – February 2014 page 13/19

5.2.6. CMDh issues new PSUR Assessment Reports for NAPs (05-Feb-2014) 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. The MAHs of products for which there are no routine PSUR submission requirements have an obligation to keep their product information up-to-date and take account of final assessment conclusions and recommendations. Summaries of PSUR Assessment Reports have been published for the following products on 04-Feb-2014: Acebutolol/acebutolol + hydrochlorothiazide Cefotaxime Fixed combination containing: dimethyl sulfoxide, camphor, terebinthini

aetheroleum, benzyl nicotinate and nonivamide Glatiramer Indium (In-111) chloride solution Nifedipine Nilvadipine Technetium (99mTC)

Link to HMA Page

Link to Summaries of Assessment Reports

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 6, January 2014) was published on 23-Jan-2014. It includes the following topics: Prasugrel (Efient): increased risk of bleeding Ofatumumab: screen for hepatitis B virus before treatment Temozolomide: risk of hepatic injury, including fatal hepatic failure Capecitabine: risk of severe skin reactions

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 December include the following safety information: Iclusig ▼ (ponatinib): Risk of myocardial infarction or stroke Efient (prasugrel): Measures to minimise bleeding risk Temodal (temozolomide): Reports of hepatic injury, including hepatic failure Xeloda (capecitabine): Reports of severe skin reactions Arzerra (ofatumumab): Patients to be screened for HBV infection before treatment

Link to MHRA Page

The letters from January include the following safety information: Erbitux (cetuximab): contraindication in mutant RAS or unknown RAS status Combined hormonal contraceptives (CHCs): Conclusions of Europe-wide review Rienso (Ferumoxytol): Risk of serious hypersensitivity reactions

Link to MHRA Page

Safety Observer N°98 – February 2014 page 14/19

5.3.3. MHRA issues Pharmacovigilance Expert Advisory Group summary minutes The MHRA has published new summary minutes of the Pharmacovigilance Expert Advisory Group. On 27-Nov-2013, the topics discussed included Risk Assessments for Domperidone, Diclofenac, and Tiotropium.

Link to Summary Minutes

5.4. French Agency (ANSM)

5.4.1. ANSM Dear Doctor Letters Dear Doctor Letters sent in January 2014 are now available on the French Agency' s website (all in French). Letters associated to safety concerns include the following: Buprenorphine: important information on the safe use Paclitaxel in nanoparticles: filaments due to albumin and silicone oil interactions Diane 35 (cyproterone/ethinylestradiol): back to the market and restrictions Vismodegib (Erivedge®): labelling issues Erbitux (cetuximab): importance of determining RAS status before treatment

Link to ANSM Page

5.4.2. Commissions / Committees in relation with Pharmacovigilance The Pharmacovigilance Committee issued minutes of the meetings of 14-Oct-2013 and 12-Nov-2013. The discussion concerned the following products: 14-Oct-2013: interferon, fluoxetine, sertraline, fluvoxamine, colchicine and

agomelatine 12-Nov-2013: dabigatran, rivaroxaban, telaprevir and boceprevir.

Link to the minutes of the Committee – 14-Oct-2013 (in French)

Link to the minutes of the Committee – 12-Nov-2013 (in French)

5.4.3. ANSM provides update on PRAC/CHMP activities Following the PRAC and CHMP meetings of January, ANSM issued a document in French which provides a summary of the discussions and decisions together with ANSM positions and recommendations for Healthcare Professionals. Pending the CHMP opinion for Strontium Ranelate (Protelos), Healthcare Professionals should not initiate new treatment and patients should consult their physicians.

Link to ANSM synthesis of Strontium Ranelate (in French)

Link to ANSM synthesis of the CHMP meeting of January 2014 (in French)

5.4.4. ANSM revises thesaurus of drug interactions The ANSM has issued an updated and consolidated version of the Thesaurus. A document showing the differences with the previous version from July 2013 is also available.

Link to the ANSM web page (in French)

5.4.5. ANSM issues information on RMP New summaries of the RMP (and risks minimization measures) approved by ANSM are made available on ANSM website for the following products:

Link to ANSM Page for Leflunomide

Link to ANSM Page for Buprenorphine

Safety Observer N°98 – February 2014 page 15/19

5.4.6. ANSM launches phase 2 of the pilot for the use of CESP After the launch in October 2013 of the phase 1 pilot for the use of the Common European Submission Platform (CESP), ANSM has now launched phase 2. It will cover the submission of variations IB and II dossiers. New versions of the Notice to Applicants (in French and in English) are available.

Link to the ANSM Press Release (in French)

Link to the ANSM Page

5.4.7. ANSM issues syntheses on the safe use of various products ANSM has issued the following new synthesis:

Link to ANSM Synthesis on the use of benzodiazepines

5.4.8. ANSM issues its work program for 2014 ANSM work program is divided in five main topics: innovation access, safety, information and transparency, European and international engagement and modernisation.

Link to the ANSM program (in French)

5.4.9. ANSM launches a new call for safety research projects For a period of three years, ANSM is calling for research projects on the safety of health products (medical devices, drugs, etc.). In 2012 and 2013, ANSM financed 39 projects. The call for 2014 is focused on young researchers.

Link to the ANSM web

page (in French)

5.5. Other Sources

5.5.1. PROTECT issues updated version of the Drug Consumption Databases The Pharmacoepidemiological Research on Outcomes of Therapeutics by a European Consortium (PROTECT) has released an update of their database of European sources of data on drug utilisation in the out- and inpatient healthcare setting. Information is available for most Member States and up-to-date as of December 2013.

Link to PROTECT Page

5.5.2. The use of Genomics to predict and prevent Drug Reactions A Wall Street Journal reports that scientists hope they can use patients’ DNA to prevent prescribing them medications that would cause Adverse Reactions. The paper presents the results obtained by Max Planck Institute researchers, who are looking for genetic markers indicating increased risks of suicidal ideation among patients receiving treatment for depression.

Link to Wall Street Journal article

5.5.3. Health Canada provides updated Adverse Reaction Online Database The Canada Vigilance Adverse Reaction Online Database contains information about suspected adverse reactions reports submitted to Health Canada. The accessible database now includes data from 1965 to 30-Sep-2013.

Link to Health Canada Page

Safety Observer N°98 – February 2014 page 16/19

5.5.4. New issue of Canadian Adverse Reaction Newsletter The new Canadian Adverse Reaction Newsletter, Volume 24, No. 1, January 2014 was issued on 14-Jan-2014. The contents include: VEGF receptor inhibitors and thrombotic microangiopathy Incidents involving the combined use of Durepair Dura Regeneration Matrix with

ancillary wound closure products

Link to Newsletter

5.5.5. New issue of Australian “Medicine Safety Update” The new edition of Medicines Safety Update (Volume 5, Number 1, February 2014) is now available. The contents include: Quetiapine and QT prolongation bioCSL Fluvax - not for children under 5 years

Link to Medicines Safety Update

5.5.6. 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°309) is now available and includes: Precautions for Use of Closure Devices at Puncture Site List of Products Subject to Early Post-marketing Vigilance

Link to PMDA Page

5.5.7. 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. The new signals added in January concern Salazosulfapyridine, Bixalomer, Rivaroxaban, Mianserin HCl, Sulfamethoxazole / Trimethoprim, Felbinac, Hormonal Contraceptives, Minodronic Acid Hydrate, Yokukansan and Regorafenib Hydrate.

Link to PMDA Page

5.5.8. New issue of Uppsala Reports Uppsala Reports 64 – January 2014 is now available. It provides a report from the ISoP’s annual meeting in Pisa. It also includes an article on the HSA experience of Linking Pharmacovigilance with Pharmacogenetics. It also provides an update on the launch of SCOPE, a project aimed at improving the abilities of the EU regulators to operate the EU Pharmacovigilance legislation.

Link to Uppsala Reports

Safety Observer N°98 – February 2014 page 17/19

6. Time to Register

EMA/DIA Events EudraVigilance and Electronic Reporting of ICSRs in the EEA

3 day-training course (see schedule for venues and dates) Extended EudraVigilance Medicinal Product Dictionary (XEVMPD) Training Course

2 day-training course (see schedule for venues and dates) Excellence in Pharmacovigilance: Clinical Trials and Post-Marketing

February 17 – 21 in London, UK Introduction to Pharmacovigilance and Rules for Expedited Reporting of ICSRs in Europe

February 25 in London, UK 15th EudraVigilance Information Day

March 12 in London, UK

DIA Events Risk Management and Safety Communication Strategies

March 03 – 04 in Horsham PA, USA

Premarketing Clinical Safety & Pharmacovigilance March 10 – 11 in Horsham PA, USA

Conference on Pharmacovigilance & Drug Safety - A New Era March 21 – 22 in Mumbai, India

26th Annual EuroMeeting March 25 – 27 in Vienna, Austria

Online Training Course: How to Prepare for a Safety Inspection May 06 – 08, 11:00AM - 01:00PM

Drug-Induced Injury of Liver, Heart, Kidney, and Skin: Recent Advances May 07 – 09 in Bethesda MD, USA

8th European Forum for Qualified Person for Pharmacovigilance May 14 – 15 in London, UK

Benefit/Risk Management May 19 – 20 in Prague, Czech Republic

Signal Management in Pharmacovigilance May 21 – 22 in Prague, Czech Republic

DSRU Events Back to Basics in Pharmacovigilance

February 26 – 27 in Southampton, UK EU Regulations and Guidelines for Pharmacovigilance

March 12 – 13 in London, UK Introduction to Pharmacoepidemiology

April 02 – 03 in Southampton, UK

Safety Observer N°98 – February 2014 page 18/19

Barnett Events Web inar – Drug Safety and Pharmacovigilance

March 04, 01:OO PM to 02:30 PM Eastern Adverse Events: Managing and Reporting for Pharmaceuticals

March 06 – 07 in Philadelphia PA, USA Drug Safety and Pharmacovigilance

March 11 – 12 in San Francisco CA, USA Web inar – Quality Risk Management in Clinical Trials and Pharmacovigilance

March 18, 09:OO AM to 10:30 AM Eastern Web inar – Introduction to Signal Detection and Data Mining

April 09, 01:OO PM to 02:30 PM Eastern Signal Detection and Pharmacovigilance

April 10 in Philadelphia PA, USA Web inar – Final FDA Guidance: Reporting of Safety Information from Clinical Trials to IRBs

April 30, 12:0O PM to 01:30 PM Eastern Web inar – Adverse Event Monitoring for CRAs

May 09, 12:OO PM to 02:00 PM Eastern Web inar – The European Pharmacovigilance Legislation

May 14, 01:OO PM to 02:30 PM Eastern

Other Events Management Forum – Advanced Pharmacovigilance

March 03 – 05 in London, UK Virtue Insight – 6th Pharmacovigilance 2014

March 04 – 05 in London, UK RQA – Practical Pharmacovigilance Auditing

March 10 – 12 in Cambridge, UK MHRA Pharmacovigilance Inspections Symposium 2014

March 14 in London, UK IFIS – Pharmacovigilance : Responsible Pharmacist missions / responsibilities (event in French)

March 17 in Paris, France IFIS – Pharmacovigilance : role, missions and responsibilities (event in French)

March 20 – 21 in Paris, France IFIS – Pharmacovigilance in clinical trials (event in French)

March 24 in Paris, France Management Forum – New Pharmacovigilance legislation – The Complete Picture

March 24 – 25 in London, UK ISoP – Proactive Pharmacovigilance, Risk Management and Pharmacovigilance

April 03 – 04 in Zagreb, Croatia ISPE – 2014 Mid-Year Meeting

April 05 – 08 in Rotterdam, The Netherlands 4th Global QA Conference

April 06 – 11 in Las Vegas NV, USA Health Network – World Drug Safety Americas Congress

April 09 – 10 in Boston MA, USA 4th Bordeaux Pharmacoepi Festival

April 09 – 11 in Bordeaux, France

Safety Observer N°98 – February 2014 page 19/19

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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