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Safety Observer Issue N°150 - November 2018

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Clinical Safety & Pharmacovigilance Regulatory Intelligence Review

Issue N°150 - November 2018

HIGHLIGHTS

New EU GVP Chapter on paediatrics The EMA has published the final version of the specific considerations guidelines for the paediatric population, which complements other GVP Modules.

Revised PV Guidance for MRPs The British ABPI and BHBIA have released a revised version of their joint guidance on collecting Adverse Events, Product Complaints and Special Situations Reports during Market Research Programmes (MRPs).

New ISoP GVP Manual for LATAM The International Society of Pharmacovigilance (ISoP) has published a new manual of Good Pharmacovigilance Practices for Latin America, which is available online for free in Spanish.

New FDA Guidance documents The FDA has issued a new final guidance on Testicular Toxicity, which is intended to support sponsors in the evaluation of the potential for such toxicity during clinical development. The FDA has also published two new draft documents for comments, including a guidance on Presenting Quantitative Information in DTC Promotional Materials and a guidance on the use of Meta-Analyses in Safety Evaluation.

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IN THIS ISSUE 1. Regulations, Guidelines and Other Standards ...................................................................................................... 3

1.1 Newly Applicable Standards .............................................................................................................................. 3 1.1.1 Revised BHBIA/ABPI’s Guidance on ADR collection in MRPs now available ................................................ 3 1.1.2 ENCePP issues updated Checklist for Study Protocols ................................................................................ 3 1.1.3 FDA issues new Final Guidance on Testicular Toxicity Evaluation ............................................................... 3 1.1.4 EMA issues updated guide on EudraVigilance registration process ............................................................. 3 1.1.5 EMA issues final paediatric-specific GVP guidance ....................................................................................... 4

1.2 Developments to Watch ..................................................................................................................................... 4 1.2.1 EMA provides update on Brexit preparedness .............................................................................................. 4 1.2.2 FDA issues new Draft Guidance on Risk Information in DTC materials ........................................................ 4 1.2.3 EMA provides update on Signal Detection pilot ............................................................................................ 5 1.2.4 EMA updates information on ISO IDMP implementation ............................................................................. 5 1.2.5 UK Industry Associations respond to MHRA consultation on “no-deal Brexit” ........................................... 5 1.2.6 Europe invites workshop to set principles for electronic Product Information .......................................... 6 1.2.7 FDA issues new Draft Guidance on Meta-Analyses for Safety Evaluation .................................................... 6

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

2. Product Safety Announcements ............................................................................................................................ 7 2.1 ReGen Series....................................................................................................................................................... 7

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

4. Other Publications by Regulatory Agencies .......................................................................................................... 9 4.1 US Food and Drug Administration (FDA) ........................................................................................................... 9 4.2 European Medicines Agency (EMA) .................................................................................................................. 10 4.3 UK Agency (MHRA) ........................................................................................................................................... 13 4.4 French Agency (ANSM) ..................................................................................................................................... 13

5. Quality Assurance, Inspections and Audits ......................................................................................................... 14

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

7. Other News and Resources .................................................................................................................................. 15

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

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1. REGULATIONS, GUIDELINES AND OTHER STANDARDS

1.1 Newly Applicable Standards

1.1.1 Revised BHBIA/ABPI’s Guidance on ADR collection in MRPs now available (24-Sep-2018) The ABPI (Association of the British Pharmaceutical Industry) has worked with BHBIA (British Healthcare Business Intelligence Association) to produce a revised version of their joint guidance on collecting Adverse Events, Product Complaints and Special Situations Reports during Market Research Programmes (MRPs).

In addition to changes related to Personal Data Protection, the main change concerns the collection of contact details when information is collected directly from patients/consumers in order to enable the appropriate follow-up of Adverse Events by the MAH.

It should be highlighted that the information presented on the BHBIA website also includes word templates for Data Collection and Reconciliation Forms, as well as suggested wording for Market Research Materials.

→ Link to ABPI News Release → Direct link to BHBIA/ABPI Guidance on PV in MRPs → Link to BHBIA Page

1.1.2 ENCePP issues updated Checklist for Study Protocols (18-Oct-2018) The European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP) has issued the 4th revision of its Checklist for Study Protocols. The announcement includes a reminder that the EMA Guidance for Non-Interventional PASS studies requires that the ENCePP Checklist is included in Annex to the study protocol.

→ Link to ENCePP Checklist Page

1.1.3 FDA issues new Final Guidance on Testicular Toxicity Evaluation (25-Oct-2018) The FDA has issued a new final guidance entitled “Testicular Toxicity: Evaluation During Drug Development”. The purpose of this new guidance is to assist sponsors in identifying nonclinical signals of testicular toxicity and in evaluating the potential for such toxicity in humans. The guidance includes recommendations for the clinical monitoring of adverse testicular effects in clinical development, and the design and conduct of safety clinical trials assessing drug-related testicular toxicity. This guidance finalizes the draft issued on 17-Jul-2015.

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

1.1.4 EMA issues updated guide on EudraVigilance registration process (26-Oct-2018) As announced in July 2018, the EMA has integrated the services of EudraVigilance with EMA's Account Management portal and Organisation Management Service (OMS), and all users need an active EMA account created through the EMA Account Management portal.

Further to the earlier publication of information on the registration, access and management of the account for EudraVigilance production environment, the EMA has just published a revised version of the Quick interactive guide to EudraVigilance registration process.

→ Link to EMA EudraVigilance Registration Page → Link to Interactive guide on EudraVigilance registration

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1.1.5 EMA issues final paediatric-specific GVP guidance (07-Nov-2018) The EMA has now published the final version of the specific considerations guidelines for the paediatric population. This new Chapter P IV provides additional guidance to the GVP Modules for the paediatric population, which is defined in the EU as the part of the population aged between birth and 18 years of age.

Adverse reactions in the paediatric population need a specific evaluation, as they may substantially differ from those occurring in adults. It should also be considered that medicines in the paediatric population have a different utilisation pattern and are often used off-label.

The corresponding draft guideline was published for comments in August 2017 and the new Chapter comes to replace the 2007 guideline on the “Conduct of Pharmacovigilance for Medicines Used in the Paediatric population” (EMEA/CHMP/PhVWP/235910/2005).

The paediatric use of vaccines and the safety surveillance of paediatric outcomes after exposure to medicines in utero are outside the scope as this is or will be covered in other chapters.

In addition to the final document, the comments received during the consultation and the version with tracked changes are also available in the GVP Development section of the EMA website. The GVP Introductory cover note has been updated accordingly.

→ Link to EMA GVP Page → Link to Pediatric-specific GVP Guideline → Link to EMA GVP Development Page

1.2 Developments to Watch

1.2.1 EMA provides update on Brexit preparedness (09-Oct-2018) The EMA has published a Press Release to announce that the Agency’s Brexit preparedness business continuity plan (BCP) entered into its third phase on 01-Oct-2018.

The temporary suspension or reduction of activities in this phase is intended to help manage core activities in the context of Brexit, including the relocation of the Agency to Amsterdam and the associated staff loss. The applicable measures include the scaling back of activities related to guideline development and revision, as well as non-product related working parties, although exceptions are defined based on priority.

The Agency plans additional suspensions/reductions as of 01-Jan-2019, which will be launched as part of phase 4 of the BCP. The measures are expected to apply until 30-Jun-2019, but will be reviewed in April 2019 after the Agency has completed its move to its temporary building in Amsterdam.

The EMA has also published new information on cut-off dates for appointments of (co)-rapporteurs from the UK, knowing that these activities will need to be transferred after the UK leaves the EU.

→ Link to EMA Press Release → Link to EMA Brexit Page

1.2.2 FDA issues new Draft Guidance on Risk Information in DTC materials (17-Oct-2018) The FDA has issued a new draft guidance entitled “Presenting Quantitative Efficacy and Risk Information in Direct-to-Consumer Promotional Labeling and Advertisements”, which applies to prescription human drugs and biological products. This document includes recommendations to make the language and presentation of information more consumer-friendly. Comments are requested by 17-Dec-2018.

→ Link to Federal Register Notice → Link to Draft Guidance Document → Link to FDA Law Blog post

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1.2.3 EMA provides update on Signal Detection pilot (18-Oct-2018) The EMA has published new information regarding the Signal Detection Pilot, which started on 22-Feb-2018. Although the pilot was initially planned for one year, it has now been extended until further notice.

The MAHs of the products included in the pilot have the obligation to continuously monitor EudraVigilance data and inform Competent Authorities of validated signals detected in the database, as described in GVP Module IX. Other MAHs also have access to EudraVigilance data but the new obligations will not apply to them until after the pilot is completed and the EMA defines the next phase of implementation.

In a new document, the EMA describes that it plans to produce a report outlining the first year of experience by September 2019. By end of December 2019, a decision on the next implementation phase, including scope and date of coming into effect, should be made and communicated to stakeholders.

→ Link to EMA Update on Signal Detection pilot → Link to EMA Signal Management Page

1.2.4 EMA updates information on ISO IDMP implementation (19-Oct-2018) The EMA has issued updated information related to the implementation of the ISO IDMP standards, which are due to replace the current eXtended EudraVigilance Medicinal Product Dictionary (XEVMPD).

The updates are related to the Referentials management service (RMS) and Organisations management service (OMS), which represent two of the four domains of Substance, Product, Organisation and Referential (SPOR) master data in pharmaceutical regulatory processes.

The document describing the RMS and OMS user on-boarding plan has been revised and the presentation from the OMS Data Quality Standard webinar held on 25-Sep-2018 has been published.

The EMA has also published the minutes and presentations from the SPOR Task Force meetings held on 23-Mar-2018 and 22-Jun-2018.

→ Link to EMA Page on RMS & OMS → Direct link to RMS and OMS user on-boarding plan → Link to OMS Data Quality Standard webinar presentation → Link to EU ISO IDMP / SPOR task force meeting page (23-Mar-2018) → Link to EU ISO IDMP / SPOR task force meeting page (22-Jun-2018)

1.2.5 UK Industry Associations respond to MHRA consultation on “no-deal Brexit” (01-Nov-2018) As mentioned earlier, the UK Government published information to highlight the possible consequences of a “no-deal Brexit”, while the UK and EU are still negotiating the Withdrawal Agreement, which should include an implementation period to run until 31-Dec-2020.

As reported in our previous issue, the MHRA launched a consultation to collect input on how the regulations would have to be modified in the event of the UK not securing a deal with the EU.

The joint submission of ABPI and BIA, the two Industry Associations in the UK, has now been published on the ABPI website. The response document covers all points of the consultation, including the requirement to have a Local QPPV based in the UK and the plan to collect Pharmacovigilance fees.

→ Link to ABPI News Release → Direct link to ABPI/BIA Response document

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1.2.6 Europe invites workshop to set principles for electronic Product Information (05-Nov-2018) As announced in November 2017, the EMA initiated an Action Plan to improve the Product Information (PI) for medicines. One of the key areas of this plan is to explore the possible use of electronic or digital means to improve accessibility to medicines’ information by patients and healthcare professionals.

In line with the plan, the EMA has announced that a workshop will be held on 28-Nov-2018 to develop key principles for the use of electronic formats, which will be subsequently published for public comments. This follows the mapping exercise and invitation to provide information regarding initiatives on electronic/digital formats for the PI, which the EMA launched last year.

→ Link to EMA Page on PI Requirements → Link to EMA Workshop Page

1.2.7 FDA issues new Draft Guidance on Meta-Analyses for Safety Evaluation (07-Nov-2018) The FDA has issued a new draft guidance entitled “Meta-Analyses of Randomized Controlled Clinical Trials to Evaluate the Safety of Human Drugs or Biological Products”, which provides guidance to applicants submitting relevant applications within the framework of regulatory decision-making for INDs, NDAs and BLAs. This draft guidance is also intended for FDA reviewers to support the evaluation of this information and the resulting strength of evidence. Comments are requested by 07-Jan-2019.

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

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 United Arab Emirates issue revised Good Vigilance Practice Guideline (Sep-2018) The Emirati Ministry of Health and Prevention (MoHP) has published a revised version of their GVP Guidelines, which describes local Pharmacovigilance requirements and covers various aspects of the Pharmacovigilance System including the reporting of ICSRs and PSURs, the local QPPV and PSMF.

→ Link to UAE GVP Guidelines

1.3.2 Canada implements new Risk Management Measures for Opioids (01-Oct-2018) Health Canada has published a Notice to Stakeholders to highlight that new requirements came into force on 20-Oct-2018 for a list of prescription opioids. For the concerned products, the new regulations require the use of a warning sticker and patient information handout at the time of sale. Health Canada has also published a corresponding Q&A guidance document to support successful implementation by stakeholders.

→ Link to Health Canada Page → Direct link to Notice to Stakeholders

1.3.3 Australia issues results of consultation on Boxed Warning Guidance (24-Oct-2018) As reported at the time, the TGA published in August 2018 a Consultation Paper to request feedback on draft guidance regarding the use of Boxed Warnings to highlight the most serious safety issues. Boxed Warnings are already used in Australia but the absence of guidance resulted in some inconsistencies.

The comments received in response to the consultation have now been published by the TGA together with a high level summary. The finalised guidance is planned to be published later in 2018 and will take effect immediately.

→ Link to TGA Page

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1.3.4 Australia launches new platform for ICSR submission (07-Nov-2018) The Australian TGA has issued a guidance to support the submission of ICSRs to the Agency through the new AEMS (Adverse Event Management System), which comes in replacement of the former ADRS (Adverse Drug Reaction System). This system provides a route for the electronic submission of ICSRs to the TGA as an alternative to the submission of E2B Reports via the Electronic Data Interchange.

→ Link to TGA AEMS Guidance Page

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.

When? What? Issue

Q3/Q4-2018 ?? Implementation of the ISO IDMP standards in Europe (Link) 129

17-Dec-2018 Deadline for comments to FDA draft guidance on Presenting Quantitative Efficacy and Risk Information in DTC Promotional Materials (Link)

150

07-Jan-2019 Deadline for comments to FDA draft guidance on Meta-Analyses for Safety Evaluation (Link)

150

31-Jul-2019 Deadline for comments to EMA Draft Q&As on Data Monitoring Committees issues (Link)

148

2020 Planned date for implementation of Clinical Trial Regulation (EU) No 536/2014 (Link)

149

2. PRODUCT SAFETY ANNOUNCEMENTS

2.1 ReGen Series Liveyon recalls stem cell products over safety concerns (10-Oct-2018) A recall announcement has been posted on the FDA website regarding the ReGen Series stem cell products, distributed by Liveyon and manufactured by Genetech. The decision to recall the products follows safety concerns by the FDA CBER after reports of possible adverse reactions, which are not further specified in the announcement. Liveyon has secured another manufacturer and planned to resume distribution of the new product line on 08-Oct-2018.

→ Link to Recall Announcement

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3. DEAR DOCTOR LETTERS AND SAFETY NEWSLETTERS

3.1 ANSM Dear Doctor Letters Dear Doctor Letters sent in October 2018 are now available on the French Agency's website (all in French). Letters associated to safety concerns include the following:

• Cyproterone acetate (Androcur and generics): ANSM recommendations for the management of meningioma risk (see also Information Release)

• Rivaroxaban (Xarelto): Early termination of a clinical trial in patients who received transcatheter aortic valve replacement

• Hydrochlorothiazide: Risk of non-melanoma skin cancer (basal cell carcinoma, squamous cell carcinoma) (see also Information Release)

• Fluroquinolones by systemic route or inhalation: Risk of aneurysm and aortic dissection • Sildenafil (Revatio and Viagra and its generics): Not to be used to treat intrauterine growth restriction • Ketamine: Risk of serious uro-nephrological, endocrine and hepatic damage with prolonged and/or high-

dose use

→ Link to ANSM Page (in French)

3.2 New issue of MHRA “Drug Safety Update” The October issue of Drug Safety Update was published on 11-Oct-2018. It includes the following topics:

• Rivaroxaban (Xarelto▼) after transcatheter aortic valve replacement: Increase in all-cause mortality, thromboembolic and bleeding events in a clinical trial

• Ritonavir-containing products: Interaction with levothyroxine leading to reduced thyroxine levels • Ponatinib (Iclusig▼): Reports of posterior reversible encephalopathy syndrome • Transdermal fentanyl patches: life-threatening and fatal opioid toxicity from accidental exposure,

particularly in children

→ Link to Drug Safety Update

3.3 New issue of Canadian “Health Product InfoWatch” A new issue of “Health Product InfoWatch” has been published, which provide an overview of safety labelling updates and safety reviews from the previous month.

The October issue was published by Health Canada on 24-Oct-2018. The monthly recap reports on the safety reviews for Beta-lactam antibiotics and Fibristal (ulipristal acetate), and presents information on recent Health Professional Risk Communications for Tecentriq (atezolizumab) and Tromboject (sodium tetradecyl sulfate).

The newsletter also presents Product Information updates for Lenvima (lenvatinib) and Ocaliva (obeticholic acid), which has been associated to hepatic decompensation and failure due to dose prescribing errors.

→ Link to Newsletter

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3.4 New issue of WHO Pharmaceuticals Newsletter Prepared in collaboration with the Uppsala Monitoring Center, the WHO Pharmaceuticals Newsletter includes a section on Regulatory Matters and Safety of Medicines. The newsletter also presents signals identified in the WHO VigiBase and the corresponding responses from the manufacturer, where available.

The latest edition of the WHO Pharmaceuticals Newsletter (N°5, 2018) includes a short report from a recent training activity for strengthening pharmacovigilance in Botswana. The following signals are presented:

• Desogestrel – Severe psychiatric disorders: panic attack, suicidal ideation and self-injurious behaviour • Edoxaban – Incorrect dose administered • Metamizole – Documented hypersensitivity to administered product

→ Link to WHO Pharmaceuticals Newsletter (N°5, 2018)

4. OTHER PUBLICATIONS BY REGULATORY AGENCIES

4.1 US Food and Drug Administration (FDA)

4.1.1 FDA Public Workshop on Pediatric Pharmacovigilance As announced previously, the FDA held a public workshop entitled “Advancing the Development of Pediatric Therapeutics 5 (ADEPT5): Advancing Pediatric Pharmacovigilance”, which took place on 14-Sep-2018. The purpose of this workshop was to explore the latest developments in pediatric pharmacovigilance and discuss the utility and challenges of emerging tools. The FDA has now made available the material from this event, including slides and webcasts.

→ Link to FDA Page

4.1.2 Drug Safety and Risk Management Advisory Committee: New material available As reported earlier, the Drug Safety and Risk Management Advisory Committee met on 26-Jun-2018 in a Joint Meeting with the Anesthetic and Analgesic Drug Products Advisory Committee where panelists voted against approval of the NDA for Remoxy ER (Oxycodone). Another Joint Meeting of the same committees took place on 03-Aug-2018 to discuss the results of the assessments of the REMS for Transmucosal Immediate-Release Fentanyl (TIRF) Medicines, which was approved in December 2011. In addition to the material released earlier, the transcript has now been published for both meetings.

More recently, the Drug Safety and Risk Management Advisory Committee met with the Psychopharmacologic Drugs Advisory Committee on 01-Nov-2018 and 02-Nov-2018 to discuss the NDAs for buprenorphine and samidorphan sublingual tablets, and brexanolone intravenous injection, respectively. The material available on the FDA website includes briefing information and the webcasts for these meetings.

→ Link to FDA Page

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4.2 European Medicines Agency (EMA)

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

→ Link to CHMP Meeting Highlights (15 to 18-Oct-2018)

4.2.2 Pharmacovigilance Fees raised to reflect inflation The EMA has announced that Pharmacovigilance fees are increasing by 1.7% as of 18-Oct-2018 to reflect the 2017 inflation rate. The explanatory note on Pharmacovigilance fees has been revised accordingly.

→ Link to EMA News Release → Link to explanatory note on Pharmacovigilance fees

4.2.3 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 September PRAC meeting were published on 26-Oct-2018. The PRAC elected Dr Martin Huber from Germany as its new vice-chair. In addition, the following Safety Signals were discussed:

• Fingolimod – Autoimmune haemolytic anaemia • Clomipramine, Serotonin and noradrenaline reuptake inhibitors (SNRI), Selective serotonin reuptake

inhibitors (SSRI) – Persistent sexual dysfunction after drug withdrawal • Rivaroxaban – Premature ending of the GALILEO study in patients who have received an artificial heart

valve through a transcatheter aortic valve replacement (TAVR) • Alemtuzumab – Cytomegalovirus (CMV) infection • Dimethyl fumarate – Immune thrombocytopenic purpura and thrombocytopenia • Duloxetine – Interstitial lung disease • Fluoroquinolones – Aortic aneurysm and dissection • Hydrochlorothiazide-containing products – Skin cancer • Ipilimumab – Cytomegalovirus (CMV) gastrointestinal infection • Olanzapine – Somnambulism • Sildenafil – Pulmonary hypertension and fatal cases associated with use in an off-label indication, early-

onset intrauterine growth restriction • Sitagliptin - Potential drug interaction with angiotensin-converting enzyme (ACE)-inhibitors leading to an

increased risk of angioedema

→ Link to PRAC Meeting Minutes (03 to 06-Sep-2018)

The highlights of the latest PRAC meeting were published on 31-Oct-2018. The Committee did not start or conclude any referral procedures at this meeting. According to the agenda, the following new Safety Signals have been identified and considered:

• Peramivir – Hepatic failure • Dabigatran – Hallucinations • Mepolizumab – Hypertensive crisis and hypertension • Niraparib – Sepsis • Nivolumab – Hypoparathyroidism • Paracetamol – Maternal use during pregnancy and premature ductus arteriosus closure in offspring • Rivaroxaban – Recurrent thrombosis in patients with antiphospholipid syndrome

→ Link to PRAC Meeting Highlights (29 to 31-Oct-2018)

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4.2.4 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 01 to 04-Oct-2018 was published on 29-Oct-2018. It includes a recommendation to update the product information for the following signals:

• Direct acting antivirals (DAAV) indicated for the treatment of hepatitis C – Dysglycaemia • Dolutegravir – Evaluation of preliminary data from an observational study on birth outcomes in human

immunodeficiency virus (HIV)-infected women • Hormonal contraceptives – Suicidality with hormonal contraceptives following a recent publication • Teriflunomide – Dyslipidaemia

The EMA also systematically issues 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 is also updated accordingly, which includes links to the corresponding PRAC minutes and specifies whether a variation was recommended.

→ Link to EMA Page

4.2.5 Industry stakeholder meeting on Brexit The EMA hosted this meeting on 24-Sep-2018 in order to update EU industry associations on EMA's Brexit preparedness activities and the presentations from the meeting have now been published.

→ Link to EMA Meeting Page

4.2.6 Pharmacovigilance stakeholder forum The EMA hosted the twelfth Pharmacovigilance stakeholder forum, which took place on 24-Sep-2018. The discussions included a review of the experience made with the Public Hearing process and presentations on the future of Pharmacovigilance from the perspectives of various stakeholders. The presentations from this event are now available on the EMA website.

→ Link to EMA Meeting Page

4.2.7 EMA stakeholder platform on the operation of EU Pharmacovigilance The EMA held the 14th platform meeting on 28-Sep-2018. Amongst other topics, the Meeting Agenda included an update on the implications of Brexit, the new functionalities of EudraVigilance and an update on the Signal Detection pilot. The presentations from this meeting are now available on the EMA website.

→ Link to EMA Meeting Page (14th industry stakeholder platform)

4.2.8 EMA meeting: “A common data model in Europe? – Why? Which? How?” As reported previously, the EMA held this meeting on 11 and 12-Dec-2017 in order to discuss the opportunities and challenges in applying a common data model in Europe to support regulatory decision-making. A common data model could help harmonise healthcare data across multiple data sets and provide a mechanism to conduct pan-European studies to address regulatory questions. In addition to the presentations and video recording released earlier, the workshop report has now been published.

→ Link to EMA Event Page

4.2.9 EMA issues updated XEVMPD information The EMA has issued updated material related to the electronic submission of information on authorised medicines, as required under Article 57(2) of the 2010 pharmacovigilance legislation. New versions of the Controlled Vocabulary have been released for Substances, Organisations, Routes of Administration and Pharmaceutical Dose Forms.

→ Link to Data Submission Guidance Page

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4.2.10 Article 57 database public information update Since July 2018, the EMA is publishing data from the Article 57 database on all medicines authorised in the European Economic Area (EEA). The information is made available in an excel document, which includes the country where the PSMF is located and the MAH contact email address and telephone number for Pharmacovigilance enquiries. The EMA updates this document periodically to reflect changes in the Article 57 database and revisions were published on 10 and 30-Oct-2018.

→ Link to EMA Page: Public data from Article 57 database

4.2.11 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 8 products were added to the list in October 2018, whereas 3 products were removed, as identified in the Summary of Changes presented on the EMA webpage. In addition to other minor updates, annex XI (Numeta G16%E medicinal products) has been removed due to PASS finalisation.

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

4.2.12 EMA issues updated EURD list The EMA has published an updated EURD list, which was last revised on 23-Oct-2018. It provides the EU Reference Dates, frequencies for submission of PSURs and 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 and the list should be filtered by cell colour to identify all revisions. Please note that as specified in the cover note, the “Publication Date” is not revised for all types of amendments and this date cannot be used to filter all amended substances in Excel.

A revised version of the introductory cover note has also been published.

→ Link to EMA PSUR Page

4.2.13 EMA issues new information on outcome of PSUR Assessment for NAPs Following the implementation of the PSURs Single Assessments (PSUSAs) for active substances contained only in Nationally Authorised Products (NAPs), the results of these procedures may require a safety variation. In such case, the information published by the EMA 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 PSUSAs have been published or updated since our previous issue and a variation is required for the following active substances:

• Aldesleukin • Iron parenteral preparations • Valproic acid, sodium valproate, valpromide, etc... • Amantadine • Cisplatin • 5 fluorouracil (i.v. application) • Bendroflumethiazide, bendroflumethiazide/potassium chloride • Amitriptyline, amitriptyline / amitriptylinoxide, amitriptylinoxide • Dapoxetine • Allopurinol

→ Link to PSUSAs Search Page

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4.2.14 CMDh issues new reports of PSUSA Follow-Up Procedure (PSUFU) As reported earlier, the European CMDh published guidance on the Informal Work-Sharing procedure for follow-up on the EU PSUR Single Assessment (PSUSA) for Nationally Authorised Products (NAPs), which is referred to as PSUFU. The procedure covers the situation where it is not possible to finalise an issue (e.g. new signal or risk) within a PSUSA procedure, which requires a follow-up request to be made to the MAH.

A new Assessment Report has been published on the CMDh website, which concerns Minocycline.

→ Link to CMDh Page: “Outcome of PSUFU procedures”

4.2.15 CMDh updates list of safety concerns described in approved RMPs The European CMDh (Co-ordination Group for Mutual Recognition and Decentralised Procedures – Human) has published new updates to the list that presents safety concerns of approved Risk Management Plans (RMPs) per product/active substance. The latest revisions to the list (Rev.16, October 2018) was published on the CMDh website on 22-Oct-2018.

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

→ Link to CMDh Page

4.3 UK Agency (MHRA)

4.3.1 MHRA updates guidance associated to Yellow Card Scheme The MHRA has updated the information on its website in relation to the Yellow Card Scheme. A revised version of the Guidance on Adverse Drug Reactions has been published, which describes how Yellow Card is used by the MHRA in its Signal Detection activities.

→ Link to MHRA Page

4.4 French Agency (ANSM)

4.4.1 ANSM provides update on PRAC/CHMP/CMDh meetings Following the PRAC meeting of October 2018, the ANSM issued a summary of the PRAC decisions. The document does not include any ANSM recommendation.

→ Link to ANSM release – October 2018 PRAC (in French)

4.4.2 ANSM announces new contra-indication of cutaneous retinoids in acne treatment Following the European reassessment of the risk-benefit balance of all retinoids (topical and systemic use), the decision was made to extend the contraindication in pregnant women or those planning pregnancy to the topical retinoids, which are mainly used in the treatment of acne. Although the passage of topical retinoids into the bloodstream appears negligible under normal conditions, it cannot be completely excluded.

In addition, the reassessment of the safety of systemic retinoids has led to some changes in the conditions of use for these drugs compared to the measures already in place in France. New tools to reduce these risks are being developed and a letter will inform health professionals of the availability of these documents, which is planned at the beginning of 2019.

→ Link to ANSM Point of Information (in French)

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4.4.3 ANSM reminds about cardiometabolic monitoring measures for antipsychotics The results of a survey conducted on the basis of Health Insurance data revealed insufficient compliance with biological surveillance of patients treated with antipsychotics. Therefore, the French Agency issued a reminder about the recommendations for cardiometabolic monitoring issued in 2010. It includes recommendations before and during treatment, as well as measures to implement in case anomalies are detected.

→ Link to ANSM Point of Information (in French)

4.4.4 ANSM warns about risk of confusion between adult and children influenza vaccines Errors in the delivery and injection of the Influvac Tetra vaccine to children under 18 years of age were reported to the French Agency, although there were no consequences for the health of the patients. This vaccine is only indicated in adults whereas VaxigripTetra, Fluarix Tetra or Influvac (trivalent) are indicated for children between 6 months and 17 years of age. The ANSM stated that no action is required in the event of inappropriate use of Influvac Tetra in children and its Marketing Authorisation should be extended to include children from the age of 3 in the near future.

→ Link to ANSM Point of Information (in French)

4.4.5 ANSM updates document on the submission of variations The French Agency has updated its guidance regarding the implementation of the requirements of Regulation (EC) n°1234/2008 in terms of deadlines, which applies to all variations submitted from 06-Nov-2017.

→ Link to the ANSM guidance document (in French) → Link to the ANSM guidance document (in English)

5. QUALITY ASSURANCE, INSPECTIONS AND AUDITS

5.1 India issues Guideline on Risk Based Programme for PV Inspections The Indian CDSCO (Central Drugs Standard Control Organization) has issued for consultation a Draft Guideline on Risk Based Programme for Pharmacovigilance Inspections and comments were requested by 31-Oct-2018. The document describes the procedure for a risk-based planning of routine pharmacovigilance inspections, which is intended to define priorities associated to companies and products based on defined criteria.

→ Link to CDSCO Draft Guideline

6. DRUG SAFETY AND LIABILITY RISK

No relevant announcement was identified in the period covered by this issue.

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7. OTHER NEWS AND RESOURCES

7.1 ISoP issues Manual of Good Pharmacovigilance Practices in LATAM The International Society of Pharmacovigilance (ISoP) has just published a new manual of Good Pharmacovigilance Practices, which is available online for free. Written by local experts for a Latin American audience, the manual is a great example of sharing knowledge and expertise but apart from the foreword written by the President of ISoP, the manual is only available in Spanish. The content includes a description of the Pharmacovigilance Systems in many Latin American countries, as well as a review of best practice in specific Pharmacovigilance activities or situations.

→ Link to ISoP Manual of GVPs in Latin America

7.2 ADVANCE delivers new Work Package The Accelerated Development of VAccine benefit-risk Collaboration in Europe (ADVANCE) is a public-private partnership supported by the Innovative Medicines Initiative (IMI) in order to establish a framework for the monitoring of the benefits and risks of marketed vaccines.

As announced on the project website, a new Work Package has been delivered to IMI, which presents the blueprint of a framework to rapidly provide scientific evidence on benefits and risks vaccination, in order to support better informed decisions.

→ Link to Advance Announcement

7.3 FDA warns consumers about some genetic tests claims The FDA has published a Safety Communication to warn consumers against the use of many genetic tests that carry unapproved claims to predict patient response to specific medications. The Agency highlights that these claims have not been reviewed by the FDA, and these may not be supported by sufficient scientific or clinical evidence. The FDA warns that changing treatment based on such test results could lead to inappropriate decisions and potentially results in serious health consequences for the patient, and the Agency may take action against some of the test developers.

→ Link to FDA Safety Communication → Link to FDA Press Announcement

7.4 IMI interviews WEB-RADR project coordinators The European Innovative Medicines Initiative (IMI) has published an interview with the coordinators of the WEB-RADR project, which led to the development of a mobile app that allows users to report ADRs and receive reliable information about their medicines.

The interview describes how this work is already helping in the detection of new safety signals, and how the public-private partnership helped achieve these results in record time.

→ Link to IMI Article

7.5 New issue of Uppsala Reports Uppsala Reports 79 – Autumn 2018 is now available, which contains a wide range of news from around the world of pharmacovigilance. It includes a presentation of the recent CIOMS guide to Vaccine Safety Communication and an article on the possible use of Artificial Intelligence in Pharmacovigilance. The newsletter also includes a report from the 40th anniversary conference and more.

→ Link to Uppsala Reports 79

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7.6 Health Canada provides updated Adverse Reaction Online Database The Canada Vigilance Adverse Reaction Online Database contains information about suspected ADRs submitted to Health Canada. The accessible database now includes data from 1965 to 31-Jul-2018.

As highlighted on the website, the Canada Vigilance Adverse Reaction Online Database will now be refreshed with data on a monthly basis. However, the time period of the data will remain 3 months behind, in order to account for data entry and quality control activities.

→ Link to Health Canada Page

7.7 Health Canada issues new report on trends for ADR reports Health Canada has just published a new report that provides the annual numbers and trends of adverse drug reaction cases and medical device incidents reported to Health Canada between 2008 and 2017. The figures show a significant increase in the reporting to ADR cases, which is driven by mandatory reporting whereas the volume of cases reported through voluntary reporting has remained consistent over the period.

→ Link to Health Canada Report

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8. CONFERENCES AND TRAINING EVENTS

EMA/DIA Events → The NEW EudraVigilance System and electronic reporting in the ISO/ICH E2B(R3) format

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) → EudraVigilance and Signal Management Information Day

December 07 in London, UK

DIA Events → Benefit-Risk and Medical Writing Week

November 26 – 30 in London, UK → Advanced Pharmacovigilance Auditing

December 10 – 12 in Paris, France → DIA Brexit Summit: Final steps in preparing for Day 1

December 11 in London, UK → Medical Approach in Diagnosis and Management of ADRs

December 11 – 12 in Paris, France → Pharmacovigilance and Risk Management Strategies

January 28 – 30 in Washington DC, USA → DIA Europe 2019

February 05 – 07 in Vienna, Austria

DSRU Events → 4th European Conference on Monitoring the Effectiveness of Risk Minimisation

November 19 – 21 in London, UK → Pharmacovigilance in Products Subject to Licensing Agreements

November 28 – 29 in London, UK → Monitoring Safety in Clinical Trials and Drug Development

January 30 – 31 in London, UK

Other Events → I~HD – Annual Conference: Realising the value of Health Data

November 19 – 20 in Gothenburg, Sweden → IFIS – Writing PSURs in English (event in French)

November 26 – 27 in Paris, France → IFIS – Establishing the PV Quality System to ensure patients' safety (event in French)

November 29 in Paris, France → ISoP - 2nd ISoP Seminar: Intelligent Automation in Pharmacovigilance

December 03 – 04 in Boston MA, USA → IFIS – Clinical trial pharmacovigilance (event in French)

December 6 in Paris, France → Vigipharm – 1er atelier de Pharmacovigilance (event in French)

January 23 – 25 in Montpellier, France → IFIS – Role and responsibilities of the "Pharmacien Responsable" in PV (event in French)

January 24 in Paris, France → Medicines for Europe (previously EGA) – 12th Pharmacovigilance Conference

January 30 in London, UK