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Safety Observer Issue N°127 - October 2016

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Clinical Safety & Pharmacovigilance Regulatory Intelligence Review

Issue N°127 - October 2016

HIGHLIGHTS

The FDA has published for consultation a new draft guidance on “FDA's Application of Statutory Factors in Determining When a REMS is necessary”, which is intended to clarify how FDA makes the decision about the need and the nature of a REMS for a specific product.

The EMA has issued a new report that reviews the results and impact of the PROTECT project, which led to a total of 74 original articles in peer-reviewed scientific journals and made significant contributions in the areas of signal detection and benefit-risk assessment.

Malaysia and Singapore have published revised Pharmacovigilance Guidelines that describe requirements applicable to expedited and periodic reporting, and to Risk Management Plans.

The FDA and the French Agency have published new documents reporting on non-compliances identified during Pharmacovigilance Inspections. This includes two new FDA Warning Letters sent to Elite Laboratories and Navinta, and two new ANSM injunction letters sent to Omega Pharma and Zydus.

Patients are using a newly implemented legal procedure to file a complaint against Sanofi over the safety of Depakine (Valproate), which will be the first class-action lawsuit brought against a pharmaceutical company in France.

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IN THIS ISSUE

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

1.1 Newly Applicable Standards .............................................................................................................................. 3 1.1.1 New US Final Rule on ClinicalTrials.gov ........................................................................................................ 3 1.1.2 CMDh updates guidance on Safety Variations .............................................................................................. 3

1.2 Developments to Watch ..................................................................................................................................... 3 1.2.1 US and Canada invite joint Public Meeting to prepare next ICH discussions .............................................. 3 1.2.2 EMA issues revised Terms of Reference for the EU ISO IDMP Task Force ..................................................... 4 1.2.3 ICH issues report of June 2016 Meetings in Lisbon, Portugal ....................................................................... 4 1.2.4 FDA issues draft guidance on factors for REMS decision making ................................................................. 4 1.2.5 EMA issues new training material on implementing ISO ICSR/ICH E2B(R3) ................................................ 4

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

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

2.1 Emergency contraceptive pill containing levonorgestrel................................................................................. 6 2.2 Somatotropine ................................................................................................................................................... 6 2.3 Colchicine ........................................................................................................................................................... 6 2.4 Direct-Acting Antivirals for Hepatitis C .............................................................................................................. 6

3. Dear Doctor Letters and Safety Newsletters ......................................................................................................... 7

4. Other Publications by Regulatory Agencies .......................................................................................................... 8

4.1 US Food and Drug Administration (FDA) ........................................................................................................... 8 4.2 European Medicines Agency (EMA) .................................................................................................................... 9 4.3 UK Agency (MHRA) ........................................................................................................................................... 12 4.4 French Agency (ANSM) ..................................................................................................................................... 12

5. Quality Assurance, Inspections and Audits ......................................................................................................... 13

6. Drug Safety and Liability Risk .............................................................................................................................. 14

7. Other News and Resources .................................................................................................................................. 14

8. Conferences and Training Events ........................................................................................................................ 15

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1. REGULATIONS, GUIDELINES AND OTHER STANDARDS

1.1 Newly Applicable Standards

1.1.1 New US Final Rule on ClinicalTrials.gov (21-Sep-2016) The US National Institutes of Health (NIH) has issued a Press Release related to the final rule on ClinicalTrials.gov that has been recently issued, which expands the legal requirements for submitting registration and results information for clinical trials involving FDA-regulated products.

These requirements apply to most interventional studies of drug, biological and device products. The final rule specifies how and when information collected in a clinical trial must be submitted to ClinicalTrials.gov. Important elements of the final rule include:

• Providing a checklist for evaluating which clinical trials are subject to the regulations • Expanding the scope of trials for which summary results information must be submitted to include trials

involving products that have not yet been approved, licensed, or cleared by the FDA • Requiring additional registration and summary results information data elements to be submitted to

ClinicalTrials.gov, including the race and ethnicity of trial participants, if collected, and the full protocol • Requiring additional types of adverse event information • Providing a list of potential legal consequences for non-compliance

→ Link to NIH Press Release → Link to FDA Page

1.1.2 CMDh updates guidance on Safety Variations (27-Sep-2016) The European CMDh (Co-ordination Group for Mutual Recognition and Decentralised Procedures – Human) has issued a revised version of its Q&As on Variations.

The updated question 2.8 clarifies that a variation is required to submit the new summary of the pharmacovigilance system when the MAH changes. Question 3.22 was updated to include the requirements applicable to the submission of final reports for post approval studies. Questions 4.14 and 4.19 cover safety variations for generic products.

→ Link to CMDh Q&As Page → Direct link to Q&As on Variations (Track Change Version)

1.2 Developments to Watch

1.2.1 US and Canada invite joint Public Meeting to prepare next ICH discussions (19-Sep-2016) As previously announced by Health Canada, a joint public consultation meeting will be held by Health Canada and the FDA on ICH guidelines currently under development. The meeting will take place on 24-Oct-2016 in Ottawa, Canada, and it will also be broadcast allowing participants to join via the Web.

The purpose of this initiative is to seek input from stakeholders in preparation for the next ICH face-to-face meeting, which will take place in November 2016 in Osaka, Japan.

→ Link to Federal Register Notice

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1.2.2 EMA issues revised Terms of Reference for the EU ISO IDMP Task Force (20-Sep-2016) The EMA has issued new material in relation to the implementation of the ISO IDMP standard, which is due to replace the current eXtended EudraVigilance Medicinal Product Dictionary (XEVMPD).

First published in July 2015, a revision of the Terms of Reference of the EU ISO IDMP Task Force has now been published, which describes the objectives, membership and operation of the Task Force. The main deliverables of the group include a Road Map and Implementation Guide to support the implementation of IDMP in Europe.

→ Link to EMA Page on IDMP → Direct link to Terms of Reference of the EU ISO IDMP Task Force

1.2.3 ICH issues report of June 2016 Meetings in Lisbon, Portugal (20-Sep-2016) As already reported in previous issues, the ICH Steering Committee met in June 2016 and the corresponding meeting report is now available. Highlights of the meeting included the adoption of a revised ICH guideline on format and structure of benefit-risk information in the common technical document (ICH M4E (R2)). The report includes an update on the work on E2B(R3), the progress made towards the finalisation of additional Q&As and the revision of documents in the Implementation Guide Package. The FDA also proposed that “Safety Data Collection” be the subject of a new ICH topic, which will be discussed further.

→ Link to ICH SC Report

1.2.4 FDA issues draft guidance on factors for REMS decision making (21-Sep-2016) The FDA has announced the availability of a draft guidance for industry entitled “FDA's Application of Statutory Factors in Determining When a REMS Is Necessary”. This is intended to clarify how FDA determines whether a risk evaluation and mitigation strategy (REMS) is necessary for a drug. This decision and the nature of the resulting REMS are based on six factors:

• The seriousness of any known or potential adverse events that may be related to the drug and the background incidence of such events in the population likely to use the drug

• The expected benefit of the drug with respect to the disease or condition • The seriousness of the disease or condition that is to be treated with the drug • Whether the drug is a new molecular entity • The expected or actual duration of treatment with the drug • The estimated size of the population likely to use the drug

Comments on this draft guidance are expected by 21-Nov-2016.

→ Link to Federal Register Notice → Link to FDA Draft Guidance

1.2.5 EMA issues new training material on implementing ISO ICSR/ICH E2B(R3) (30-Sep-2016) As reported when it was released in April 2016, the EMA has produced a document entitled: “EudraVigilance training plan”, which details the training curriculum to prepare all EudraVigilance Stakeholders on the changes to be introduced with the new EudraVigilance System expected to go live in November 2017.

In addition to the material previously released, a new training video is now available on Implementing ISO ICSR/ICH E2B(R3). The module PhV-M2b covers ISO ICSR/ICH E2B(R3) backwards and forwards conversion. Although this is yet not included on the EudraVigilance Training Page at the time of issue, the training video is now available on the EMA YouTube channel.

→ Link to EudraVigilance Training Page → Direct link to PhV-M2b Training Video

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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 Malaysia issues updated Pharmacovigilance Guidelines (Sep-2016) The National Pharmaceutical Regulatory Agency (NPRA) has issued the second edition of the Malaysian Pharmacovigilance Guidelines. Compared with the first edition of 17 pages, this new version is 120 pages long and describes requirements applicable to ADR reporting, PBRER reporting and Risk Management Plans. Two sections of the document are still under development regarding the requirement for the “Pharmacovigilance System Master File” and “Pharmacovigilance Audits and Inspections”.

→ Link to Malaysian PV Guidelines (2nd edition)

1.3.2 Spain prepares changes to electronic transmission of ICSRs (06-Sep-2016) As announced in our previous issue, the Spanish Agency has issued a notice to MAHs to announce that from 01-Mar-2017 it will no longer accept ICSR submission by Data Entry into the national database FEDRA and no new applications to use this system will be accepted from 01-Dec-2016. All submissions will be required to use the possibilities available through EudraVigilance (i.e. ESTRI gateway or EVWEB).

Further to this notice issued in July, the AEMPS has issued revised instructions on the electronic transmission of ICSRs and associated application forms.

→ Link to AEMPS Page (in Spanish) → Direct link to AEMPS Notice to MAHs (in Spanish)

1.3.3 Singapore provides revised Pharmacovigilance Guidance (19-Sep-2016) The Health Sciences Authority (HSA) in Singapore has published a revised guideline on Post-Marketing Vigilance Requirements for Therapeutic Products. This new document will replace the previous version dated June 2015 and become effective on 01-Nov-2016. It covers the requirements for expedited and periodic reporting. It also includes a section on Risk Management Plans and an additional companion document includes a series of Frequently Asked Questions, which clarifies that the requirement to submit RMPs will now be limited to specific types of applications.

→ Link to HAS Page → Direct link to Post-Marketing Vigilance Guideline → Direct link to RMP FAQs

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

14-Oct-2016 EMA Consultation on draft GVP Module IX (Rev.1) and Addendum I (Link) 126

14-Oct-2016 EMA Consultation on draft GVP Module VI (Rev.2) (Link) 126

21-Nov-2016 FDA Consultation on draft guidance on factors for REMS decision making (Link) 127

Nov-2017 Implementation of the new EudraVigilance system in Europe (includes centralised reporting, E2B(R3), safety signals monitoring) (Link)

125

Q3/Q4-2018 Implementation of the ISO IDMP standards in Europe (Link) 126

Oct-2018 Planned implementation of Clinical Trials Regulation (EU) No 536/2014 (Link) 119

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2. PRODUCT SAFETY ANNOUNCEMENTS

2.1 Emergency contraceptive pill containing levonorgestrel MHRA issues new advice regarding potential interaction (15-Sep-2016) The MHRA has issued a Press Release to inform the public that the efficacy of emergency contraceptive pill containing levonorgestrel may be reduced if it is used concomitantly with medicines for epilepsy and certain serious infections, or herbal remedies such as St John’s Wort.

→ Link to MHRA Press Release

2.2 Somatotropine ANSM warns about association with aromatase inhibitors and GnRH agonists (20-Sep-2016) The French Agency has issued a notice stating that the combined use of Somatotropine (growth hormone) and aromatase inhibitors or GnRH agonists has been observed in order to delay puberty, which is not in line with the Marketing Authorisations for these products. The ANSM warns that there is no data available to support the safety of such off-label use.

→ Link to ANSM website (in French)

2.3 Colchicine ANSM warns about risks of overdose (21-Sep-2016) Following the reporting of serious adverse effects including deaths due to overdose, the French Agency highlighted the new posology scheme, the indications and contra-indications presented in the new Approved Product Information in order to prevent overdose.

→ Link to ANSM website (in French)

2.4 Direct-Acting Antivirals for Hepatitis C FDA required Boxed Warning for the risk of Hepatitis B Reactivation (04-Oct-2016) The FDA has issued a warning about the risk of hepatitis B (HBV) reactivation following treatment with certain direct-acting antiviral (DAA) medicines for hepatitis C virus, which has resulted in serious liver problems or death in a few cases. The FDA is therefore requiring a new Boxed Warning about this risk and directing health care professionals to screen and monitor for HBV in all patients receiving DAA treatment.

→ Link to FDA MedWatch alert

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3. DEAR DOCTOR LETTERS AND SAFETY NEWSLETTERS

3.1 New issue of MHRA “Drug Safety Update” The September issue of Drug Safety Update was published on 15-Sep-2016. It includes the following topics:

• Levonorgestrel-containing emergency hormonal contraception: advice on interactions with hepatic enzyme inducers and contraceptive efficacy

• Posaconazole (Noxafil): tablets and oral suspension are not directly interchangeable • Idelalisib (Zydelig▼): updated indications and advice on minimising the risk of infection

→ Link to Drug Safety Update

3.2 MHRA Dear Doctor Letters The letters sent to Healthcare Professionals are routinely posted on the Agency’s website. The letters sent by the MHRA are presented in the subsequent issue of the MHRA “Drug Safety Update” bulletin. The following letter was issued in August 2016:

• Idelalisib (Zydelig▼): outcome of safety review, including the risk of infection

→ Link to MHRA Page

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

• Nexplanon: risks of implant moving • Premixed nitrous oxide and oxygen: reminder on the safe use

→ Link to ANSM Page (in French)

3.4 New issues of Canadian “Health Product InfoWatch” The new issue of “Health Product InfoWatch” has been published, which provides an overview of health product advisories and safety reviews published in the previous month by Health Canada. The September issue was published on 29-Sep-2016 and includes a monthly recap of Safety Reviews, which covers several medicinal products including Adempas (riociguat), Enbrel (etanercept), Gilenya (fingolimod) and Velcade (bortezomib) among others.

→ Link to Newsletter

3.5 New issue of WHO Drug Information The latest edition of the WHO Drug Information, Vol. 30 No 3, is now available. The Safety news section provides the latest information on ADR reports, regulatory warnings and labelling changes.

→ Link to WHO Drug Information

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4. OTHER PUBLICATIONS BY REGULATORY AGENCIES

4.1 US Food and Drug Administration (FDA)

4.1.1 FDA issues new report on CDER Drug Safety Priorities 2015-2016 The FDA has issued a new document entitled: “CDER Drug Safety Priorities: Initiatives and Innovation”, which describes a number of programs to ensure the safety of drug products and provides an overview of key safety milestones achieved over 2015 and to date in 2016. The report offers a broad picture of FDA’s safety efforts, including programs such as “Safety First” and the “Safe Use Initiative”, the Sentinel System, and tools that exploit new opportunities in social media and mobile device applications.

→ Link to FDA Report

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

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

• Antidepressants – Stress cardiomyopathy • Beta Interferons – Drug-induced lupus • Corlanor (ivabradine) – Risk of bradycardia with concomitant use of heart-slowing drugs • Dipeptidyl peptidase 4 (DPP-4) inhibitor – Pemphigoid • Diphenhydramine – QT Prolongation • Direct-acting antivirals – Hepatitis B reactivation • Entresto (sacubitril/valsartan) – Risk of rhabdomyolysis with concomitant use of statin therapy • First and second generation histamine H1 antagonists – Seizures • Fluroquinolone antibiotics – Drug-induced side effects • Granix (tbo-filgrastime) – Glomerulonephritis • Harvoni (ledipasvir and sofosbuvir) – Drug-Drug Interaction • HMG-CoA reductase inhibitors – Interstitial lung disease • hydroxyzine and hydralazine – Increase in medication error reports due to name confusion • Krystexxa (pegloticase) – Hemolytic anemia and methemoglobinemia • Opsumit (macitentan) tablets – Hepatic and hepatobiliary disorders • Rapivab (peramivir) – Anaphylaxis/Angioedema • SGLT2 inhibitors – Acute pancreatitis • Tecfidera (dimethyl fumarate) – Idiosyncratic drug-induced liver injury (DILI) • Terbinafine hydrochloride-containing oral drugs – Thrombotic microangiopathy • Tracleer (bosentan) – Anaphylaxis and DRESS • bendamustine hydrochloride – DRESS and Hepatic and hepatobiliary disorders • Unituxin (dinutuximab) – Transverse myelitis • Vistaril (hydroxyzine), Xyzal (levocetirizine) and Zyrtec (cetirizine) – AGEP • Zecuity (sumatriptaniontophoretic) – Burns and Scars • Zydelig (idelalisib) – Fatal infections

→ Link to FDA’s Potential Signals Page

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4.1.3 Drug Safety and Risk Management Advisory Committee: New material available The Drug Safety and Risk Management Advisory Committee met on 14-Sep-2016 in a Joint Meeting with the Anesthetic and Analgesic Drug Products Advisory Committee to discuss the need for label changes based on the results of a completed postmarketing study of the neuropsychiatric effects of CHANTIX (varenicline), ZYBAN (bupropion), and nicotine replacement therapy, along with other published observational studies.

The Drug Safety and Risk Management Advisory Committee met again on 15 and 16-Sep-2016 in a Joint Meeting with the Psychopharmacologic Drugs Advisory Committee and the Pediatric Advisory Committee to discuss the appropriate development plans for establishing the safety and efficacy of prescription opioid analgesics for pediatric patients, including obtaining pharmacokinetic data and the use of extrapolation.

The webcasts of these meetings are now available on the FDA website in addition to other meeting material, including slides and final questions.

→ Link to FDA Page

4.1.4 Pediatric Advisory Committee: New material available The Pediatric Advisory Committee met on 14-Sep-2016 to discuss pediatric-focused safety reviews for a group of products, which included several Vaccines, efavirenz, topiramate and omalizumab amongst others. In addition, the FDA provided an update of the ongoing analysis of a possible safety signal regarding the use of Exjade (deferasirox) in children with fever and dehydration.

The material available on the FDA website includes presentations, briefing information and meeting minutes.

→ Link to FDA Page

4.1.5 FDA announces workshop on the Sentinel PRISM Program As announced previously, the FDA has announced that a public workshop entitled “The Sentinel Post-Licensure Rapid Immunization Safety Monitoring (PRISM) Program” will be held in Bethesda, MD on 07-Dec-2016. The purpose of this workshop is to describe the Sentinel Initiative and PRISM program, which is used in the evaluation of vaccine adverse events. The workshop will present how PRISM is used by the FDA with case examples. Discussions should also cover the future direction of PRISM in terms of expansion and further integration into the regulatory review process. Registration is open until 23-Nov-2016.

→ Link to Federal Register Notice → Link to FDA Event Page

4.2 European Medicines Agency (EMA)

4.2.1 EMA issues new report on results and impact of PROTECT The EMA has issued a new report that reviews the results and impact of the Pharmacoepidemiological Research on Outcomes of Therapeutics by a European Consortium (PROTECT) project, which was funded by the Innovative Medicines Initiative (IMI) and closed in June 2015.

The project has led to a total of 74 original articles in peer-reviewed scientific journals, which all contribute to the assessment of benefits and risks of medicines. Amongst other deliverables, the project identified significant improvements to signal detection methods and issued recommendations for benefit-risk assessment methodologies.

→ Link to EMA Report

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4.2.2 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 were published on 23-Sep-2016. The EMA conducted a practice run to test the process for public hearings in order to ensure that all arrangements are now in place. the PRAC concluded the review of Zydelig and issued updated risk minimisation recommendations. Several other reviews were initiated:

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

The following new Safety Signals were considered:

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

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

The agenda and highlights of the latest PRAC meeting were published on 30-Sep-2016. The PRAC did not initiate or conclude a safety referral at this meeting. According to the agenda, the following new Safety Signals have been identified and considered:

• Lenvatinib – cholecystitis • Nivolumab – pemphigoid

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

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.

The list of signals discussed at the PRAC meeting of 30-Aug to 02-Sep was published on 26-Sep-2016 and includes recommendations to update the product information for the following signals:

• Agomelatine – Urinary retention • Direct-acting antivirals (DAAV) – Drug interaction with vitamin K antagonists leading to a reduced

international normalised ratio (INR) • Cobicistat containing products – Drug interaction with corticosteroids leading to adrenal suppression • Iomeprol – Haemolysis

In complement, the EMA has published the corresponding document entitled: “New product information wording – Extracts from PRAC recommendations on signals”, which is available in all EU languages.

The list of all safety signals discussed at the PRAC since September 2012 has been updated accordingly. It includes links to the corresponding PRAC minutes and specifies whether a variation was recommended.

→ Link to EMA Page

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4.2.4 EMA issues “Meeting Highlights” of last CHMP Meeting The highlights of the September meeting of the CHMP have been published. No safety review was initiated or concluded at this meeting.

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 (12 to 15-Sep-2016)

4.2.5 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 11 new products have been added to the list in July 2016, whereas 4 products have been removed, as identified in the Summary of Changes presented on the EMA webpage.

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

4.2.6 EMA issues updated EURD list The EMA has published an updated EURD list, which was last revised on 22-Sep-2016. It provides the EU Reference Dates, frequencies for submission of PSURs and related data lock points for a list of active substances and combinations including those contained exclusively in nationally authorised medicines.

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

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

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

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

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

• Technetium (99mtc) mebrofenin • Minoxidil (topical formulation)

→ Link to PSUR Single Assessments Outcomes Page

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

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

Summaries of PSUR Assessment Reports have been published for the following products on 04-Oct-2016: Meloxicam, Pravastatin sodium + buffered aspirin.

→ Link to Summaries of Assessment Reports

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4.2.9 EMA stakeholder forums on the new Pharmacovigilance legislation The EMA held the tenth stakeholder forum on the operation of the pharmacovigilance legislation, which took place on 21-Sep-2016. This was the latest in a series of events organised by EMA to review the progress made and to consult stakeholders on what needs to be the focus over the coming years. The presentation included recent Regulatory Science initiatives such as the PROTECT and WEB-RADR projects. The agenda, list of participants and presentations from this meeting are available on the EMA Event Page.

On the same day, the EMA hosted the Ninth industry stakeholder platform on the operation of European Union pharmacovigilance legislation. The Agenda included a presentation of recent GVP activities, including the new drafts for Modules VI and IX, and the dry-run of the Public Hearing process.

→ Link to EMA News Release → Link to EMA Meeting Page (10th stakeholder forum) → Link to EMA Meeting Page (9th industry stakeholder platform)

4.2.10 EMA schedules Patient Registries workshop As announced in our previous issue, the EMA has announced that it will hold a Patient Registries Workshop on 28-Oct-2016. Through the Patient Registry Initiative launched in September 2015, the EMA aims to facilitate interactions between registry co-ordinators and potential users of registry data.

This workshop is designed to bring together multiple stakeholders to discuss the challenges and barriers to collaboration and identify solutions. The agenda for the workshop has now been published.

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

4.3 UK Agency (MHRA)

4.3.1 MHRA updates toolkit to minimise the risks of valproate during pregnancy The MHRA has updated the information in the toolkit on the risks of valproate medicines in female patients. The Agency has worked with industry, healthcare professionals and patient groups on this toolkit to ensure female patients are better informed about the risks of the epilepsy medicine during pregnancy. The page now includes links to the Patient Information Leaflets.

→ Link to MHRA Page

4.4 French Agency (ANSM)

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

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

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

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

4.4.2 ANSM issues a new version of the thesaurus of Drug Interactions The French Agency has issued a new version of the thesaurus of Drug Interactions (previous version issued in August 2016). It includes the Thesaurus itself, the substance index and a document that describes the changes from the previous version.

→ Link to the ANSM webpage (in French)

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4.4.3 ANSM Scientific communications The ANSM has made available on its website four posters on the following topics:

• Short term risk of bleeding during heparin bridging at initiation of Vitamin K antagonist • The use of nitrofurantoin in France: assessment of compliance with therapeutic indication and guidelines • Incretin-based therapies and the risk of pancreatic cancer in patients with type 2 diabetes • Association between exposure to benzodiazepines and related drugs and survivorship of total hip

replacement in arthritis: a population-based cohort study of 246,940 patients

→ Link to the ANSM poster on Vit K antagonists (in English) → Link to the ANSM poster on Nitrofurantoine (in English) → Link to the ANSM poster on Incretin-based therapies (in English) → Link to the ANSM poster on benzodiazepines (in English)

5. QUALITY ASSURANCE, INSPECTIONS AND AUDITS

5.1 New FDA Warning Letters published The FDA has published two new Warning Letters for deviations to the Postmarketing Adverse Drug Experience Reporting Requirements identified during inspections conducted at Elite Laboratories in January/February 2016 and at Navinta in May 2016.

The Warning Letters refer to failures in relation to procedures supporting the performance of Pharmacovigilance activities, which resulted in delays in the submission of required reports to the FDA in addition to format issues. The Warning Letters also mention issues in relation to oversight of Service Providers, the assessment of individual ADE Reports, their follow-up, the quality control of the information submitted to the FDA and failure to submit the periodic PADERs.

→ Link to FDA Warning Letter (Elite) → Link to FDA Warning Letter (Navinta)

5.2 New ANSM injunction letters published Injunctions are new administrative measures taken by ANSM after inspections in case of deficiencies that should be solved within a set timeframe. Two new injunctions for pharmacovigilance deficiencies have been issued for Omega Pharma and Zydus.

During the inspection at Omega Pharma, deficiencies were identified in the follow-up of pharmacovigilance activities performed by the Corporate Structure and their Service Provider. Issues were also identified regarding the management of foreign distribution and the quality system.

During the inspection at Zydus and its Service Provider, several deficiencies were noted regarding the management of product information, the oversight of the EU QPPV, the content of the PSMF, the management of case backlog, and also regarding pharmacovigilance training and the quality system.

→ Link to Omega Pharma injunction (in French) → Link to Zydus injunction (in French)

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6. DRUG SAFETY AND LIABILITY RISK

6.1 France and Class action lawsuits France issues new legislation on class action lawsuits against drug manufacturers The decree n°2016-1249 was published on 27-Sep-2016 and it complements article L.1143-1 of the Public Health Code published in July 2016 which allows patient associations to file class action lawsuit against manufacturers of health products, including medicinal product.

→ Link to decree 2016-1249 (in French)

6.2 Sanofi and Depakine Patients announce the launch of a class action lawsuit against Sanofi Victims grouped in an association have launched a class action against Sanofi over the safety of Depakine and claims of birth defects and developmental disorders caused by pregnancy exposure to the anti-epileptic drug valproate. This is the first class action lawsuit brought against a pharmaceutical company in France, which was launched the day following the publication of the decree providing the details for such a procedure.

→ Link to Les Echos press release (in French)

The tribunal of Paris opens an investigation over possible deception The Tribunal will investigate the period between 1990 and April 2015 for aggravated deception and involuntary injury and the possibly insufficient actions taken in response to the identified risks.

→ Link to Les Echos press release (in French)

6.3 UCB and Distilben A French court sentences UCB to indemnify a patient The Court of Nanterre has sentenced UCB Pharma to pay 595,000 € in compensation to the child of a woman exposed to Distilben in utero who suffers of multiple disabilities. The Tribunal has considered an indirect relationship between the disability and Distilben.

→ Link to Le Parisien (in French)

7. OTHER NEWS AND RESOURCES

7.1 Pfizer study over the safety of Chantix questioned by FDA The safety of Pfizer's smoking cessation drug Chantix is due to be discussed by an Advisory Committee Committee very shortly and in this context, the FDA has released a report questioning the reliability of the results of a post-marketing safety study, which the company hoped would support the removal of the black box warning in the drug label. The Institute for Safe Medication Practices (ISMP) has issued a statement opposing the change.

→ Link to Bloomberg article → Link to Reuters article → Link to ISMP Statement

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7.2 Australian TGA presentation on the safety of influenza vaccines The TGA has published the material presented at a recent meeting which describes a scientific research study to investigate increased reports of allergic adverse events following influenza immunisation in 2015.

→ Link to TGA Page

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

• Lessons from Zecuity Patch Safety Withdrawal • Problems Using the Albiglutide (TANZEUM) Self-Injection Pen

→ Link to QuarterWatch

7.4 New issue of Uppsala Reports Uppsala Reports 73 – September 2016 is now available, which contains a wide range of news from around the world of pharmacovigilance, including regional initiatives. It includes reports on key discussions held at the Uppsala Forum including the use of mobile technologies to collect and present important medicines safety information. This issue also includes a presentation on Japan’s model for post-marketing medicines safety.

→ Link to Uppsala Reports

8. CONFERENCES AND TRAINING EVENTS

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

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

2 day-training course (see agenda for venues and dates) → Information Day on Medication Errors

October 20 in London, UK

→ PSUR Information Day October 28 in London, UK

→ Information Day on Risk Management Planning and Post-Authorisation Studies November 07 in London, UK

→ EudraVigilance Information Day November 08 in London, UK

→ Introduction to Pharmacovigilance and Rules for Expedited Reporting of ICSRs in Europe November 22 in Vienna, Austria

→ Signal Detection and Management Information Day: Key Principles, Processes and Responsibilities December 02 in London, UK

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DIA Events → Risk Management and Safety Communication Strategies

October 17 – 18 in Washington DC, USA → DIA Annual Canadian Meeting 2016

October 18 – 19 in Ottawa, Canada → Postmarketing Drug Safety & Pharmacovigilance

October 24 – 25 in Philadelphia PA, USA → 6th DIA Cardiac Safety Workshop in Japan

October 27 – 28 in Tokyo, Japan → MHRA/DIA Excellence in Pharmacovigilance

November 14 – 18 in London, UK

→ Benefit/Risk Management November 21 – 22 in Basel, Switzerland

→ Signal Management in Pharmacovigilance November 23 – 24 in Basel, Switzerland

→ 13th DIA Japan Annual Meeting 2016 November 13 – 15 in Tokyo, Japan

DSRU Events → Assessment and Medical Evaluation of Individual Case Safety Reports

October 12 – 13 in Fareham, UK → Risk Benefit Assessment in Pharmacovigilance

October 19 – 20 in Fareham, UK → Introduction to Pharmacoepidemiology

November 02 – 03 in Fareham, UK → Pharmacovigilance in Products Subject to Licensing Agreements

November 16 – 17 in London, UK → 3rd European Conference on Monitoring the Effectiveness of Risk Minimisation

November 22 – 24 in Prague, Czech Republic

Other Events → IFIS – Missions and Responsibilities in PV for the Qualified Pharmacist (event in French)

October 13 in Paris, France → IFIS – PV Case Management (event in French)

October 14 in Paris, France → ISoP – 16th Annual Meting: Pharmacovigilance For Safer Tomorrow

October 16 – 19 in Agra, India → Allan Lloyds – Risk Management and Pharmacovigilance America Summit

October 18 – 20 in Boston, USA → Corvus – European Pharmacovigilance and Clinical Trials 2016

October 25 – 26 in London, UK → RQA – Practical Pharmacovigilance Auditing

October 25 – 27 in Ascot, UK → RQA – 2016 Annual Conference

November 09 – 11 in Brighton, UK → IFIS – Clinical trials vigilance (event in French)

November 15 in Paris, France → IFIS – Risk Management Plan (event in French)

November 29 in Paris, France → IFIS – PSUR writing in English

November 29 – 30 in Paris, France