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Safety Observer Issue N°153 - February 2019

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Clinical Safety & Pharmacovigilance Regulatory Intelligence Review

Issue N°153 - February 2019

HIGHLIGHTS

Updated Brexit Guidance The European Authorities have updated the available guidance to help MAHs prepare for Brexit. The latest update is intended to address the situation whereby the UK becomes a third country on 30-Mar-2019 without a withdrawal agreement, i.e. in case of “no-deal Brexit”. The UK Government has also published new information on how to make regulatory medicines submissions to the MHRA in such a scenario.

Europe consults on ePI The EMA has launched a six-month public consultation on draft key principles for the implementation of electronic product information (ePI) in the EU, which is intended to improve accessibility to medicines’ information by patients and healthcare professionals.

FDA consults on REMS Assessment The FDA has published two new draft guidance documents to support the assessment of Risk Evaluation and Mitigation Strategies (REMS). One of the documents describes how to plan and report such a REMS Assessment, whereas the other provides recommendations for the conduct of associated knowledge surveys.

TGA to start GCP Inspections Pilot The Australian TGA has launched a new consultation on a pilot Good Clinical Practice (GCP) Inspections Program. The consultation paper includes a call for volunteers to participate in this pilot.

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

1.1 Newly Applicable Standards .............................................................................................................................. 3 1.1.1 EMA issues revised set of Questions and Answers on Signal Management ................................................. 3 1.1.2 FDA issues Final Guidance on Labeling for Accelerated Approval Products ................................................ 3 1.1.3 EMA issues revised Q&As on Pharmacovigilance Referral Procedures ........................................................ 3

1.2 Developments to Watch ..................................................................................................................................... 4 1.2.1 ICH issues minutes of November 2018 Meetings in Charlotte NC, USA ........................................................ 4 1.2.2 EMA provides new guidance for ISO IDMP implementation ......................................................................... 4 1.2.3 EMA provides update on Brexit preparedness .............................................................................................. 4 1.2.4 FDA issues new Draft Guidance Documents to support REMS Assessment ................................................. 5 1.2.5 Europe consults on Key Principles for electronic Product Information ....................................................... 5 1.2.6 UK provides new guidance to prepare for “no-deal Brexit” ......................................................................... 6 1.2.7 EU Authorities issue updated guidance for Brexit preparedness ................................................................. 6 1.2.8 FDA extends comment period for Real-World Evidence Program Framework ............................................ 6

1.3 Beyond the Scope of Safety Observer ............................................................................................................... 7 1.4 The Safety Observer Tracker ............................................................................................................................. 8

2. Product Safety Announcements ............................................................................................................................ 8 2.1 Paclitaxel-coated devices .................................................................................................................................. 8 2.2 Olaratumab (Lartruvo) ....................................................................................................................................... 8 2.3 Direct Oral Anticoagulants (DOACs) .................................................................................................................. 9 2.4 Angiotensin II receptor blockers ........................................................................................................................ 9 2.5 Finasteride .......................................................................................................................................................... 9

3. Dear Doctor Letters and Safety Newsletters ......................................................................................................... 9

4. Other Publications by Regulatory Agencies ........................................................................................................ 10 4.1 US Food and Drug Administration (FDA) ......................................................................................................... 10 4.2 European Medicines Agency (EMA) .................................................................................................................. 12 4.3 UK Agency (MHRA) ........................................................................................................................................... 14 4.4 French Agency (ANSM) ..................................................................................................................................... 14

5. Quality Assurance, Inspections and Audits ......................................................................................................... 15

6. Drug Safety and Liability Risk .............................................................................................................................. 16

7. Other News and Resources .................................................................................................................................. 16

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

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1. REGULATIONS, GUIDELINES AND OTHER STANDARDS

1.1 Newly Applicable Standards

1.1.1 EMA issues revised set of Questions and Answers on Signal Management (14-Jan-2019) The EMA has released a new version of its Questions & Answers Document on Signal Management. The entire document has been updated and improved and the main changes are highlighted on the cover page.

This includes revised information on the implementation of the legal requirement for MAHs to monitor EudraVigilance data and inform competent authorities of validated signals in the context of the ongoing pilot (questions 5 and 6). In addition, the revision includes an update of the requirements for the submission of additional data (question 11) and some clarifications regarding the variation category (question 15).

→ Link to EMA Signal Management Page → Direct link to Q&As on Signal Management

1.1.2 FDA issues Final Guidance on Labeling for Accelerated Approval Products (22-Jan-2019) The FDA has published the final guidance entitled “Labeling for Human Prescription Drug and Biological Products Approved Under the Accelerated Approval Regulatory Pathway”.

This guidance finalizes the draft guidance issued on 25-Mar-2014 and provides recommendations for developing the indication and usage statements in the prescribing information for drugs approved under the accelerated approval regulatory pathway. The guidance also discusses labeling considerations, including safety information, for those indications approved under accelerated approval when the FDA terminates the conditions of approval, or when the FDA withdraws approval of an indication.

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

1.1.3 EMA issues revised Q&As on Pharmacovigilance Referral Procedures (05-Feb-2019) The EMA has issued revised Questions and Answers documents to cover referral procedures, including Article 20 Pharmacovigilance Procedures, Article 31 Pharmacovigilance Referrals and Article 107i Urgent Union procedures.

Many questions have been updated, which cover all steps of these procedures from initiation, conduct of the assessment, PRAC recommendation and final CMDh or CHMP Position, as applicable.

→ Link to EMA Referral Procedures Page → Direct link to Q&As on Article 20 Pharmacovigilance Procedures → Direct link to Q&As on Article 31 Pharmacovigilance Referrals → Direct link to Q&As on Article 107i Urgent Union procedures

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1.2 Developments to Watch

1.2.1 ICH issues minutes of November 2018 Meetings in Charlotte NC, USA (10-Jan-2019) As already reported previously, the ICH Assembly and Management Committee met in Charlotte from 10 to 15-Nov-2018 and the corresponding minutes are now available.

The Final Minutes reflect the main decisions made by the ICH Assembly and the MedDRA Management Committee. Amongst other discussions, a future strategic area was presented as a potential new work area: “Strategic Approach to International Harmonization of Technical Scientific Requirements for Pharmacoepidemiological Studies Submitted to Regulatory Agencies to Advance More Effective Utilization of Real-World Data”.

The Assembly endorsed the establishment of the E14/S7B Implementation Working Group (IWG) for the development of Q&As for the ICH E14 and ICH S7B Guidelines, which describe the Clinical and non-Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential.

The MedDRA Management Committee noted significant achievements in supporting the global implementation and use of MedDRA through training activities and local support.

The next rounds of ICH meetings will be held from 01 to 06-Jun-2019 in Amsterdam, the Netherlands

→ Link to ICH Assembly Minutes

1.2.2 EMA provides new guidance for ISO IDMP implementation (11-Jan-2019) 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).

A new Guidance Document has been published in relation to the Organisations management service (OMS), which represents one of the four domains of Substance, Product, Organisation and Referential (SPOR) master data in pharmaceutical regulatory processes.

By the end of Q2 2019, OMS dictionary will contain manufacturers organisations and in Q3 2019, the EMA will invite stakeholders to start submitting Change Requests for manufacturers. This new document is intended to clarify the responsibilities between stakeholders (i.e. applicant, MAH or manufacturer) for the registration and update of organisation data about manufacturers in the OMS in the context of marketing application submissions.

→ Link to EMA Page on OMS → Direct link to EMA Guidance: Manufacturer organisations in the OMS dictionary

1.2.3 EMA provides update on Brexit preparedness (23-Jan-2019) The EMA has published an update to announce that the Agency’s Brexit preparedness business continuity plan (BCP) entered into its fourth phase on 01-Jan-2019. This brings additional temporary suspension or reduction of activities to help manage core activities in the context of Brexit, including the relocation of the Agency to Amsterdam and the anticipated staff loss of 25% of its total workforce.

The Annex 1 to the EMA Brexit preparedness BCP – Phase 4 has been published, which defines the EMA activities that will continue in 2019. The EMA will review in April 2019 which activities can resume in the second half of 2019 once it has moved to its temporary building in Amsterdam.

The EMA took this opportunity to provide an update on the progress of the relocation, with a description of the arrangements for the physical relocation of the Agency to Amsterdam at the beginning of March 2019.

→ Link to EMA Press Release → Link to EMA Brexit Page → Link to EMA relocation tracking tool

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1.2.4 FDA issues new Draft Guidance Documents to support REMS Assessment (24-Jan-2019) The FDA has published a new draft guidance on the assessment of Risk Evaluation and Mitigation Strategies (REMS), which is entitled “REMS Assessment: Planning and Reporting”.

This draft guidance describes how to develop a REMS Assessment Plan, including the selection of metrics and data sources which will be used to assess whether the REMS is meeting its risk mitigation goals. The draft guidance recommends using both process measures and outcome measures and provides examples of metrics and data sources. It also provides recommendations on a standardized approach for reporting REMS assessment findings to the FDA through the REMS Assessment Report.

In association to the above guidance, the FDA has also published a draft guidance entitled “Survey Methodologies to Assess REMS Goals That Relate to Knowledge”. This document provides recommendations for the conduct of surveys to evaluate respondent knowledge of REMS-related information, as a component of the overall REMS assessment.

Comments on these draft guidance documents are requested by 02-Apr-2019.

→ Link to statement from FDA Commissioner → Link to Federal Register Notice (REMS Assessment) → Link to Draft Document (REMS Assessment) → Link to Federal Register Notice (Survey Methodologies) → Link to Draft Document (Survey Methodologies)

1.2.5 Europe consults on Key Principles for electronic Product Information (31-Jan-2019) 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.

The EMA has just announced the launch a six-month public consultation on draft key principles to form the basis on which the electronic product information (ePI) for human medicines will be developed and used in the EU. All stakeholders are invited to submit their comments by 31-Jul-2019.

The key principles define an EU-wide approach to support harmonised development and implementation of ePI. They define the various concepts, give examples of the expected benefits and explain how ePI can fit in the existing legislative framework as a complement to the paper package leaflet. They also outline the processes, roles and responsibilities, and describe how ePI can be supported in all official EU languages.

The draft key principles derive from earlier discussions and consultations with representatives of all stakeholder groups, including the workshop held on 28-Nov-2018 where the experience made in several countries was presented. In addition to the presentation material published earlier, a report and the video from this workshop are now available.

→ Link to EMA Press Release → Direct link to Draft Key Principles for ePI → Link to EMA Page on PI Requirements → Link to EMA ePI Workshop Page

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1.2.6 UK provides new guidance to prepare for “no-deal Brexit” (31-Jan-2019) As reported earlier, the UK Government has published guidance on the regulation of medicines and clinical trials in the event that the discussions about the Brexit fail, which is intended to update stakeholders on the proposed arrangements for the regulation of medicines if the UK leaves the EU on 29-Mar-2019.

The UK Government has published new information on how to make regulatory medicines submissions to the MHRA in such a scenario. The information includes the recording of a recent webinar for pharmaceutical companies involved in making medicines regulatory submissions and vigilance activities.

A new webpage has been published to present the collection of MHRA guidance and publications on a possible no deal scenario, including the recently published Contingency Legislation for the regulation of medicines.

→ Link to MHRA Brexit Page → Direct link to new MHRA Guidance Page → Link to MHRA Collection for “no-deal scenario”

1.2.7 EU Authorities issue updated guidance for Brexit preparedness (01-Feb-2019) Both the EMA and the CMDh have updated the available guidance to help MAHs prepare for Brexit, which is intended to ensure that they prepare sufficiently in advance to avoid any impact on the supply of medicines within the EU. Further to the revisions made in 2018, this new update is intended to address the situation whereby the UK becomes a third country on 30-Mar-2019 without a withdrawal agreement and hence without the transition period that was planned in the draft Withdrawal Agreement.

In addition to a revised Notice to MAHs, the EMA has published updated versions of the Questions-and-Answers and Practical Guidance documents with new questions to address the “no-deal” scenario, including the impact on ICSR and PSUR submission requirements.

For those medicines that are not Centrally Approved by the EMA, the CMDh has also issued an updated Notice to MAHs and a revised Questions-and-Answers document. The revision of the Practical Guidance document by the CMDh is however pending at the time of this issue.

All updates of the Q&A and Practical Guidance published on the EMA website are marked ‘NEW’, and the CMDh website also includes a version with tracked changes.

→ Link to EMA Brexit Guidance Page → Link to CMDh Brexit Page

1.2.8 FDA extends comment period for Real-World Evidence Program Framework (05-Feb-2019) As announced on 06-Dec-2018, the FDA established a public docket to collect comments on a framework created for implementing a program to evaluate the potential use of real-world evidence (RWE) in regulatory decision making.

Comments on the draft document were initially requested by 05-Feb-2019, but the FDA has now announced the comment period is extended by another 60 days.

→ Link to FDA Announcement (Reopening of comment period) → Link to Federal Register Notice → Link to Draft Document → Link to Statement by FDA Commissioner

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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 Swissmedic issues updated Pharmacovigilance guidance documents (01-Jan-2019) The Swiss Agency has published a new Guidance Document describing the signal reporting obligations of MAHs and the timely implementation of resulting measures, including the possible modification of the product information (see MU101_20_001e_WL Guidance document Drug Safety Signals HMV4). This document comes in replacement of the former Information Sheet (see MU101_20_005e_MB Drug Safety Signals), which is still available on the Swissmedic website. The revisions reflect the implementation of the revised TPO (Therapeutic Products Ordinance) and the timelines for the reporting of completion of Signal Evaluation procedures by foreign authorities have been extended from 7 to 15 days.

Subsequently to the implementation of the revised TPO, the guidance documents for PSUR/PBRER and RMP submissions have also been updated and the revisions all apply from 01-Jan-2019.

→ Link to Swissmedic PV Instructions Page (Drug Safety Signals) → Link to Swissmedic Risk Management Page (PSURs and RMPs)

1.3.2 Canada consults on Regulatory Activity Types for Vigilance Submissions (15-Jan-2019) Health Canada is proposing a set of new regulatory activity types to be used in lieu of the Undefined Data Post-market Vigilance (UD-PV) regulatory activity filed to the Marketed Health Products Directorate (MHPD).

The proposed regulatory activity types reflect more accurately the information contained in the submission, which is intended to improve the processing of these regulatory transactions. Health Canada intends to implement the change from 01-May-2019 for regulatory transactions in both eCTD and non-eCTD formats.

Feedback from stakeholders is requested by 15-Mar-2019.

→ Link to Health Canada Consultation Page → Direct link to Notice for Consultation

1.3.3 Hungary updates Pharmacovigilance and Clinical Trial Safety Guidance (25-Jan-2019) The Hungarian National Institute of Pharmacy and Nutrition (OGYÉI) has updated the information available on its website regarding Pharmacovigilance obligations during Clinical Trials and Post-Marketing.

New Information has been published regarding the requirements for Direct Healthcare Professional Communications (DHPCs) submissions. The set of Questions & Answers reflects the change in requirements whereby from now on, MAHs should submit the Hungarian translation of DHPCs for regulatory approval even if the medicinal product is not marketed in Hungary (see Question 2).

The guidance regarding ADR Reporting during Clinical Trials has also been updated to bring some clarifications and to include new contact details.

→ Link to OGYÉI DHPC Q&As → Link to OGYÉI Clinical Trial ADR Reporting Guidance

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1.4 The Safety Observer Tracker This section includes a cumulative list of the future implementation and consultation deadlines. For your convenience, a link is provided and we also specify the issue where the corresponding article can be found.

When? What? Issue

21-Mar-2019 Deadline for comments to FDA draft guidance on “Developing and Submitting Proposed Draft Guidance Relating to Patient Experience Data” (Link)

151

02-Apr-2019 Deadline for comments to FDA draft guidance on “REMS Assessment: Planning and Reporting” (Link), and to the associated FDA draft guidance document on “Survey Methodologies” (Link)

153

30-Jun-2019 Deadline for comments to EMA discussion paper on methodological and operational considerations in the use of patient disease registries (Link)

151

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

148

31-Jul-2019 Deadline for comments to EMA on draft key principles for the electronic Product Information (ePI) (Link)

153

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

149

2. PRODUCT SAFETY ANNOUNCEMENTS

2.1 Paclitaxel-coated devices FDA to investigate potential for increased long-term mortality (17-Jan-2019) The FDA has issued a Letter to Health Care Providers informing them that the Agency is evaluating the results of a recent meta-analysis suggesting a potential for increased long-term mortality after use of paclitaxel-coated balloons or stents to treat peripheral arterial disease (PAD) in the femoropopliteal artery.

→ Link to FDA Letter

2.2 Olaratumab (Lartruvo) EMA recommends that no new patients start treatment due to efficacy concerns (23-Jan-2019) The EMA has announced that the preliminary results of the ANNOUNCE study show that Lartruvo in combination with doxorubicin is not more effective at prolonging the lives of patients with soft tissue cancer than doxorubicin alone.

Consequently, the EMA is recommending that no new patients should start treatment with the medicine until the full results from the study are reviewed, whereas doctors need to evaluate the benefit of continuing treatment in patients already using the medicine.

→ Link to EMA Press Release

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2.3 Direct Oral Anticoagulants (DOACs) EMA starts review of study on bleeding risk (01-Feb-2019) The EMA has announced that it is reviewing the results of a study with the direct oral anticoagulants Eliquis (apixaban), Pradaxa (dabigatran etexilate) and Xarelto (rivaroxaban). This observational study was commissioned by the EMA to assess the risk of major bleedings with these medicines when used in patients with non-valvular atrial fibrillation in comparison with other oral anticoagulants.

Results from this study show differences in the risk of major bleedings between these medicines and they also raise concerns about the level of adherence to the conditions of use described in the product information.

An abstract of the results will be available shortly in the EU PAS register (study register N°16014) and the review will define whether changes may be required in the current conditions of use and risk minimisation measures.

→ Link to EMA Announcement

2.4 Angiotensin II receptor blockers EMA completes evaluation of cancer risk associated to nitrosamine impurities (01-Feb-2019) A new review by the EMA concluded that up to 30 extra cases of cancer may be caused by the nitrosamine impurities over the lifetimes of 100,000 patients. The estimates have been extrapolated from animal studies and remain very low compared with the lifetime risk of cancer in the EU.

Nevertheless, companies that make sartan blood pressure medicines are being required to review their manufacturing processes so that they do not produce these impurities. Companies will have a 2-year transition period to make necessary changes, during which strict temporary limits on levels of these impurities will apply.

→ Link to EMA Press Release → Link to EMA Referral Page

2.5 Finasteride ANSM alerts on risks of psychiatric disorders and sexual dysfunction (01-Feb-2019) The ANSM has issued a reminder of the information first issued in 2017 regarding the risk of psychiatric disorders and the measures that can be taken. The ANSM also alerts on the risk of sexual dysfunction that has been identified. A new document will be published very shortly to better inform patients about the risks and benefits of Finasteride, which is used in the treatment of alopecia and benign prostatic hyperplasia (BPH).

→ Link to ANSM Press Release (in French)

3. DEAR DOCTOR LETTERS AND SAFETY NEWSLETTERS

3.1 ANSM Dear Doctor Letters Dear Doctor Letters sent in January 2019 are now available on the French Agency's website (all in French). Letters associated to safety concerns include the following:

• Mydriaticum (tropicamide): Prescription and dispensing restrictions • Finasteride: Risk of psychiatric disorders and sexual dysfunction • Carbimazole and thiamazole (a.k.a. methimazole): Risk of acute pancreatitis and new recommendations

regarding contraception

→ Link to ANSM Page (in French)

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3.2 New issue of MHRA “Drug Safety Update” The January issue of Drug Safety Update was published on 09-Jan-2019. It includes the following topics:

• Tapentadol (Palexia): Risk of seizures and reports of serotonin syndrome when co-administered with other medicines

• Ipilimumab (Yervoy): Reports of cytomegalovirus (CMV) gastrointestinal infection or reactivation • Yellow Card App: Download the updated App to receive the latest MHRA safety news and report suspected

side effects, including in pregnancy

→ 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 provides an overview of safety labelling updates and safety reviews from the previous month.

The January issue was published by Health Canada on 31-Jan-2019. The monthly recap includes the results of the safety review on the risk of artery dissections and artery aneurysms associated with vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR TKIs). It also reports on the recent Health Professional Risk Communication for Xarelto (rivaroxaban) and presents the Product Information updates for Biaxin (clarithromycin), Lamictal (lamotrigine) and Revlimid (lenalidomide).

This issue also includes the biannual vaccine safety summary and a Review Article on the risk of non-melanoma skin cancer associated with prolonged use of hydrochlorothiazide.

→ Link to Newsletter

4. OTHER PUBLICATIONS BY REGULATORY AGENCIES

4.1 US Food and Drug Administration (FDA)

4.1.1 FDA workshop on Assessment of Pressor Effects As reported prior to the event, the FDA held a public workshop entitled “Evaluating the Pressor Effects of Drugs”, which took place in Washington DC on 04-Feb-2019.

The purpose of this workshop was to discuss the premarketing assessment of a drug's effect on blood pressure, which can increase the risk of stroke, heart attack, and death and therefore represents an important consideration in benefit-risk assessment. As a reminder, the FDA issued a draft guidance entitled “Assessment of Pressor Effects of Drugs” at the end of May 2018 and the comment period closed on 30-Jul-2018.

Material from this workshop is available on the event website, which includes the agenda and video recording.

→ Link to Event Page

4.1.2 Drug Safety and Risk Management Advisory Committee: New material available The Drug Safety and Risk Management Advisory Committee met on 14-Nov-2018 in a Joint Meeting with the Anesthetic and Analgesic Drug Products Advisory Committee where panelists recommended the approval for MNK-812, an immediate-release (IR) oral tablet formulation of oxycodone that is intended to resist manipulation and prevent abuse. In addition to the material made available earlier, the FDA has now published the minutes of the meeting.

→ Link to FDA Page

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4.1.3 FDA issues Drug Safety Priorities Report for 2018 The FDA’s Center for Drug Evaluation and Research (CDER) has released its Drug Safety Priorities report, which provides an update on activities conducted in 2018 in various areas related to Pharmacovigilance for prescription drugs and generics, including FAERS and the Sentinel System. The report also presents achievements and milestones in other areas, including the communication of Drug Safety Information and the Safe Use Initiative, amongst others.

→ Link to FDA’s Drug Safety Priorities Report for 2018

4.1.4 FDA issues Sentinel System Five-Year Strategy Report The FDA has published the Five-Year Strategy Report (2019 – 2023) for its Sentinel System, which was first launched in 2007 and fully implemented in 2016 to support FDA’s post-market safety surveillance. With due consideration for a changing drug development and safety ecosystem, the FDA proposes this five-year strategy and road map to drive the development of the System.

This plan includes a focus on innovations emerging from new data science disciplines, such as natural language processing and machine learning in order to make better use of electronic health records (EHRs).

Ultimately the FDA envisions a more robust Sentinel System that can be used to support all aspects of healthcare decision-making. Five strategic pillars have been identified to achieve this goal, which include the enhancement and expansion of the System’s foundation, and the improvement of the safety analysis capabilities using advances in data science and signal detection. The increased use of real-world data (RWD) for real-world evidence (RWE) is also highlighted.

→ Link to FDA’s Sentinel Five-Year Strategy Report

4.1.5 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 third quarter of 2018. The FDA is evaluating the need for regulatory action for the following combinations of Product / Signal:

• Atypical antipsychotics – Serotonin syndrome • Amphetamines and amphetamine congeners for management of obesity – Death and sudden death • Brilinta (ticagrelor) – Central sleep apnea • Drug-Drug Interaction between ticagrelor and certain HMG-CoA reductase inhibitors (atorvastatin and

rosuvastatin) – Rhabdomyolysis • Direct Oral Anticoagulants (DOACs) – Acute kidney injury • Antiviral medicines (various combinations) – Hypersensitivity • Intravenous iron replacement products – Fatal and severe hypersensitivity reactions • Pegfilgrastim injection products – Alveolar hemorrhage, hemoptysis • Ocrevus (ocrelizumab) injection – Anaphylaxis • Phenol – Serious adverse events associated with teething • Rituximab for injection products – Incorrect route of administration • Xifaxan (rifaximin) tablets – Rhabdomyolysis

→ Link to FDA’s Potential Signals Page

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4.2 European Medicines Agency (EMA)

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

→ Link to EMA PRAC Page

The highlights of the January PRAC meeting were published on 18-Jan-2019. 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:

• Atezolizumab – Anaphylactic reaction • Acetylsalicylic acid – Evaluation of data on cancer-related mortality from a single study in elderly adults • Dabigatran – Alopecia • Dimethyl fumarate – Arthritis and arthralgia • DPP-4 inhibitors; GLP-1 receptor agonists – Increased risk of cholangiocarcinoma in adults with T2DM • Pantoprazole – Colitis microscopic • Pregabalin – Respiratory depression with and without concomitant opioid use • Sertraline – Maculopathy • Temozolomide – Drug reaction with eosinophilia and systemic symptoms (DRESS) • Topiramate – Uveitis

→ Link to PRAC Meeting Highlights (14 to 17-Jan-2019)

4.2.2 EMA issues “Meeting Highlights” of last CHMP Meeting The highlights of the January meeting of the CHMP have been published. As communicated separately (see Section 2), the review of impurities in sartan medicines has been completed. The Committee also started a review of a study to assess the risk of major bleedings with Direct Oral Anticoagulants (DOACs) in patients with non-valvular atrial fibrillation, and a separate review of the cancer medicine Lartruvo due to efficacy concerns.

As reported after the December meeting, the CHMP concluded that omega-3 fatty acid medicines are not effective in preventing further heart and blood vessels problems in patients who have had a heart attack, and recommended that Marketing Authorisations are changed accordingly. Some of the MAHs involved with this review have however requested a re-examination, which will be started shortly.

→ Link to CHMP Meeting Highlights (28 to 31-Jan-2019)

4.2.3 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 the latest revision (Rev. 06) was published on 10-Jan-2019.

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

4.2.4 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.

A new version of the Controlled Vocabulary has been released for Units of measurement.

→ Link to Data Submission Guidance Page

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4.2.5 EMA issues updated EURD list The EMA has published a revised EURD list, which was last updated on 06-Feb-2019. 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.

→ Link to EMA PSUR Page

4.2.6 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.

5 products were added to the list in January 2019, whereas 7 products were removed, as identified in the Summary of Changes presented on the EMA webpage. In addition, the list of products containing Valproate and related substances (Annex XIII) has been updated. A corrected version of the list of Ethinylestradiol-containing products (Annex I) was also published on 15-Jan-2019.

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

4.2.7 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 a new update to the list that presents safety concerns of approved Risk Management Plans (RMPs) per product/active substance. The latest revision to the list (Rev.19, January 2019) was published on the CMDh website on 05-Feb-2019.

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

4.2.8 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:

• Lorazepam • BCG vaccine (freeze-dried) • Nitrofurantoin, nifurtoinol • Ciprofloxacin (systemic use) • Isotretinoin (oral formulations) • Fluorodopa (18F) • Fenspiride • Deoxycholic acid • Nadroparin • Oxaliplatin

→ Link to PSUSAs Search Page (sorted for Human/PSUSA/Variations)

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4.3 UK Agency (MHRA)

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

4.4 French Agency (ANSM)

4.4.1 Commissions/Committees in relation with Pharmacovigilance The Committee in charge of the interfaces with the Pharmaceutical Industry has issued the minutes of its meeting of 29-Nov-2018 where the process and timelines for variations were discussed. The topics to be covered in 2019 have also been identified, including the harmonisation of Products Information.

→ Link to ANSM Interface Committee Minutes –29-Nov-2018 (in French)

4.4.2 ANSM provides update on PRAC/CHMP/CMDh meetings Following the PRAC meeting of January 2019, the ANSM issued a summary document of the ANSM request to the PRAC regarding fluoropyrimidines, whereby Product Information should reflect the recommendations of the INCA (French Institute of Cancer) and the HAS (French Health Authority) on the detection of DPD deficit before treatment. This follows the request of the ANSM to Healthcare Professionals to follow these new recommendations in December 2018 in order to avoid severe toxicity.

→ Link to ANSM release – January 2019 PRAC (in French)

4.4.3 ANSM reminds that Aubagio is contraindicated during pregnancy The French Agency has issued a reminder that Aubagio (teriflunomide), which is indicated in the treatment of multiple sclerosis, is strictly contraindicated during pregnancy and in women of childbearing age who are not using effective contraception. This reminder follows the results of a study showing several cases of pregnancy exposure with teriflunomide, which has shown teratogenic and embryotoxic effects in animals.

→ Link to the ANSM report of the study "Safety – Pregnancy - Aubagio – Multiple Sclerosis" → Link to ANSM Point of Information (in French)

4.4.4 ANSM issues guidance for Quinolones and Fluoroquinolones variations Following the European re-evaluations of Quinolones and Fluoroquinolones finalised in September and November 2018, the ANSM has published instructions to support the variation application process and to provide the official SmPC translations.

→ Link to ANSM webpage on Quinolones MA modifications (in French)

4.4.5 ANSM sets up new email address for whistleblowers In order to facilitate the reporting of alerts made by whistleblowers, the ANSM has established the new email address: lanceur.alerte@ansm.sante.fr. It will allow any person to easily file reports of serious regulatory violation or serious threat to public health. The ANSM will ensure that the confidentiality will be strictly respected and that protection measures will be implemented.

→ Link to ANSM webpage on Whistleblowers (in French)

4.4.6 France updates certificate to be provided with MA translations In 2017, the ANSM issued recommendations for the submission of good quality translation in variations and marketing authorisation applications and renewals under the mutual recognition or decentralized procedure. Further to this publication, the French Agency has issued a revised certificate of translation, which should be used as of 15-Jan-2019.

→ Link to ANSM MA certificate of translation (in French)

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4.4.7 ANSM launches EPI-PHARE EPI-PHARE is a structure of scientific expertise in pharmacoepidemiology for health products that has been established by the National Health Insurance (CNAM) and the ANSM. It will coordinate and carry out pharmacoepidemiology studies to support Authorities in decision-making using the complex and massive data of the National Health Data System (SNDS, formerly SNIIRAM).

→ Link to ANSM Press Release (in French) → Link to ANSM webpage on EPI-PHARE (in French)

5. QUALITY ASSURANCE, INSPECTIONS AND AUDITS

5.1 New MHRA blogpost argues that compliance can save money The MHRA Inspectorate has posted a new article on its blog, which explains that the Inspectorate intends to apply the existing office-based assessment (OBA) fee more broadly. Until now, the Inspectorate has applied an additional OBA fee only on an ad-hoc basis, which was used to charge for inspector time in completing various follow-up activities including the review of Corrective and Preventative Actions (CAPA), risk assessments, investigation reports, interim update responses, etc.

The new approach is intended to drive improved compliance and encourage companies to submit high quality responses to Inspection Findings as companies demonstrating poor control with inadequate responses and actions will be charged additional re-inspection and/or OBA fees.

→ Link to MHRA Blogpost

5.2 MHRA updates information on Good Pharmacovigilance Practice (GPvP) The MHRA Inspectorate has updated the information published on its website to describe the Good pharmacovigilance practice (GPvP) Inspection process. The updates published in January 2019 concern the information on Inspection preparation, and the change in policy regarding the fees that can be charged for inspector time in completing various follow-up activities (see also section 5.1 of this issue).

→ Link to MHRA GPvP Page

5.3 Australian TGA starts consultation over GCP Inspections Program The Australian TGA has launched a new consultation on a pilot Good Clinical Practice (GCP) Inspections Program of 12 months duration, which will help define the future routine GCP Inspections Program. All stakeholders are invited to respond to the consultation by 22-Feb-2019.

The consultation paper outlines the rationale for introducing a domestic GCP Inspections Program for clinical trials conducted in Australia. It also provides preliminary information on a risk-based approach to selection of inspections sites, and on the management of Inspection Findings. In addition, the consultation paper calls for volunteers to participate in this pilot Inspections Program.

→ Link to TGA Consultation Page

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6. DRUG SAFETY AND LIABILITY RISK

6.1 Fluoropyrimidines Families of French victims file lawsuit The plaintiffs claim that Health Authorities should have recommended earlier a screening test to detect the sensitivity to the Cancer treatment. Three patients died and one was injured after the administration of the treatment due to their enzyme deficit. In December 2018, the French Health Authorities recommended screening tests to be carried out systematically before treatment.

→ Link to Le Monde article (in French)

7. OTHER NEWS AND RESOURCES

7.1 OHRP issues updated Compilation of Human Research Standards The US Office for Human Research Protections (OHRP) has released the 2019 edition of its Compilation of Human Research Standards, which provides a listing of over 1,000 laws, regulations, and guidelines on human subjects’ protection in 131 countries, as well as standards issued by a number of international and regional organizations. One new country is included in the 2019 edition: El Salvador. Most of the listings include a hyperlink that allows direct access to the standard referred to.

→ Link to OHRP Page

7.2 FDLI to sponsor Webinar on Patient Assistance Programs The U.S. Food and Drug Law Institute (FDLI) has announced a new webinar to discuss recent Enforcement and Best Practices associated to Patient Assistance Programs (PAPs), which will be held on 07-Feb-2019. The Webinar recording will also be made available for purchase.

The webinar will cover the various forms of PAPs, recent enforcement actions, best practices from both the manufacturer and charity perspectives, advertising and promotion implications, adverse event reporting, and anticipated future developments.

→ Link FDLI Webinar Page

7.3 ENCePP issues 2018 activity report The European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP) has published a summary of the network's activities in 2018. The report includes a list of key achievements, a number of metrics relating to the network's expertise and experience, plus some website statistics. One of the figures highlighted is the number of studies registered in the EU PAS Register, which reached a total of 1419 studies at the end of 2018 (a 17% increase over twelve months).

→ Link to ENCePP activity report 2018

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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)

DIA Events → DIA Singapore Annual Meeting 2019

March 05 – 06 in Singapore → Pharmacovigilance Strategies Workshop

June 05 – 06 in London, UK → Annual Meeting 2019

June 23 – 27 in San Diego CA, USA

DSRU Events → Back to Basics in Pharmacovigilance

February 27 – 28 in Fareham, UK → EU Regulations and Guidelines for Pharmacovigilance

March 20 – 21 in London, UK → Introduction to Pharmacoepidemiology

April 01 – 04 in Southampton, UK → Periodic Safety Reports: PSURs and PBRERs

May 08 – 09 in Fareham, UK → How to Manage an Audit and Inspection

May 15 in London, UK

Other Events → FDLI Webinar - Patient Assistance Programs: Recent Enforcement and Best Practices

February 07, 02:00 PM – 03:30 PM ET → MHRA – GCP Symposium

February 14 in London, UK → ISPE Webinar – Pharmacoepidemiological studies of drug-cancer associations

February 18, 03:00 PM – 04:00 PM CET → Virtue Insight – 18th Pharmacovigilance 2019

February 27 – 28 in London, UK → ADVANCE - EU Ecosystem for Monitoring of Post-Licensure Vaccine Benefit And Risk

March 09 in Brussels, Belgium → Q1 Productions – Pharmacovigilance & Drug Safety: Risk Management & Regulatory Compliance

March 12 – 13 in Arlington VA, USA → RQA – Practical Pharmacovigilance Auditing

March 12 – 14 in Cambridge, UK → IFIS – Pharmacovigilance: Role, missions and responsibilities (event in French)

March 14 – 15 and April 05 (3 days) in Paris, France → IFIS – Pharmacovigilance of clinical trials (event in French)

March 19 in Paris, France

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Other Events (Continued) → ExL – 2nd Pharmacovigilance Audits & Inspections Forum

March 25 – 26 in Philadelphia PA, USA → ISPE – 2019 Mid-Year Meeting

April 06 – 09 in Rome, Italy → Sunnikan – How to prepare the local PSMF for French "Exploitant" (event in French)

April 09 in Paris, France → Marxo Smith – 3rd Annual Global Pharmacovigilance & Risk Management Summit

April 09 – 11 in Amsterdam, Netherlands → IFIS - Processing a pharmacovigilance case (event in French)

April 11 in Paris, France → ISoP Mid Year Training Course

May 06 – 08 in Nairobi, Kenya → FDLI - Annual Conference: Exploring Advanced Topics in Food and Drug Law

May 02 – 03 in Washington DC, USA → ISoP Israel: Drug Safety from all Angles

June 03 – 04 in Herzliya, Israel

Featured Event :