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Safety Observer Issue N°144 - April 2018

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Clinical Safety & Pharmacovigilance Regulatory Intelligence Review

Issue N°144 - April 2018

HIGHLIGHTS

New Eudralex Volume 10 The European Commission website has been revised to include a new section in Eudralex Volume 10, which presents the guidelines that will be applicable to Clinical Trials authorised under the New Regulation (EU) No 536/2014.

EU Q&As on RSI in Clinical Trials As reported earlier, the EU Heads of Medicines Agencies have published a new version of the “Questions and Answers – Reference Safety Information (RSI)”. In a new Cover Note, the Clinical Trials Facilitation Group (CTFG) sets a 1-year transition period until Competent Authorities enforce the new requirements more strictly from 01-Jan-2019.

EMA Good Pharmacogenomic Practice Following a consultation in May 2016, the EMA has now published the adopted Guideline on Good Pharmacogenomic Practice, which will enter into effect on 01-Sep-2018.

New EudraVigilance System The EMA has published updated information and guidance related to the new EudraVigilance System. This includes a revised version of the Questions and Answers document on the launch of the new EudraVigilance system.

FDA Reporting & Combination Products The FDA has issued a “Compliance Policy” that delays the enforcement of some provisions of the December 2016 final rule describing postmarketing safety reporting requirements for combination products. In addition, the FDA has published for comments a Draft Guidance to support compliance with the final rule.

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

1.1 Newly Applicable Standards .............................................................................................................................. 3 1.1.1 EU Heads of Agencies set compliance date for Q&As on RSI in Clinical Trials ............................................. 3 1.1.2 EMA releases new Important Medical Event Terms list ................................................................................ 3 1.1.3 ENCePP issues revised Code of Conduct ....................................................................................................... 3 1.1.4 EMA issues Final Guideline on Good Pharmacogenomic Practice ............................................................... 4 1.1.5 EMA issues revised guidance & information on New EudraVigilance System .............................................. 4 1.1.6 EMA updates list of products for Signal Detection Pilot ............................................................................... 4

1.2 Developments to Watch ..................................................................................................................................... 5 1.2.1 EMA provides update on EU Clinical Trial Regulation implementation ....................................................... 5 1.2.2 FDA issues new guidance on Safety Reporting for Combination Products .................................................. 5 1.2.3 EMA provides update on ISO IDMP implementation .................................................................................... 5 1.2.4 European Commission discusses Brexit preparedness ................................................................................ 6 1.2.5 FDA issues revised draft Implementation Plan for Benefit-Risk Assessment .............................................. 6

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

2. Product Safety Announcements ............................................................................................................................ 7 2.1 Quinolone and fluoroquinolone antibiotics ..................................................................................................... 7 2.2 Daclizumab (Zinbryta) ....................................................................................................................................... 7 2.3 Valproate (Depakine, etc.) ................................................................................................................................. 7 2.4 Flupirtine ............................................................................................................................................................ 7 2.5 Oral retinoids...................................................................................................................................................... 8 2.6 Polyfructosane (a.k.a. sinistrin) solutions for injection .................................................................................... 8

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) .................................................................................................................... 9 4.3 UK Agency (MHRA) ........................................................................................................................................... 11 4.4 French Agency (ANSM) ..................................................................................................................................... 12

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

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

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

8. Conferences and Training Events ........................................................................................................................ 14

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1. REGULATIONS, GUIDELINES AND OTHER STANDARDS

1.1 Newly Applicable Standards

1.1.1 EU Heads of Agencies set compliance date for Q&As on RSI in Clinical Trials (08-Mar-2018) As reported in our December 2017 issue, the Heads of Medicines Agencies (HMA) have published a new version of their guidance document entitled “Questions and Answers – Reference Safety Information (RSI)”, which is a deliverable of the Clinical Trials Facilitation Group (CTFG).

The CTFG has now published a Cover Note where it acknowledges that the changes brought by the revised Q&As are significant. Although the document should be considered as applicable from the publication date, the Cover Note refers to a 1-year transition period until National Competent Authorities enforce the new requirements more strictly from 01-Jan-2019. The MHRA has updated its website accordingly.

As a reminder, the revised Q&A Document brings updated and extended guidance to describe the expectations for the RSI, which should provide the list of expected adverse reactions in the dedicated section of the Investigators Brochure (IB) or Summary of Product Characteristics (SmPC).

Moreover, it explains how the RSI should be used in the context of applicable expedited (i.e. SUSAR) and periodic (i.e. DSUR) reporting. As previously highlighted by the MHRA, it clearly states that an updated RSI can only be used for assessment of expectedness after approval of the corresponding substantial amendment in all of the Member States where trials are ongoing.

→ Link to HMA CTFG Page → Direct link to CTFG Q&As on RSI → Direct link to CTFG Cover Note → Link to MHRA Clinical trial Guidance

1.1.2 EMA releases new Important Medical Event Terms list (13-Mar-2018) The EudraVigilance Expert Working Group (EV-EWG) coordinates the development of the Important Medical Event Terms (IME) list, which includes a list of MedDRA Preferred Terms that are considered Serious in line with ICH criteria. Since 2009, the IME list is available for guidance purposes only and a new update is released with each new version of the MedDRA dictionary.

The new version of the IME list has been published, which is based on MedDRA version 21.0. The document describing the inclusion/exclusion criteria for terms in the list has also been updated.

→ Link to EMA EudraVigilance Overview Page → Direct link to IME list

1.1.3 ENCePP issues revised Code of Conduct (16-Mar-2018) The European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP) has just issued the 4th revision of its Code of Conduct, which provides a set of principles and recommendations to promote scientific independence and transparency of observational research including research conducted with authorised medicines in the context of post-approval requirements for MAHs. A summary of the main changes introduced is also made available.

→ Link to ENCePP Page

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1.1.4 EMA issues Final Guideline on Good Pharmacogenomic Practice (19-Mar-2018) Following a public consultation on the draft document in May 2016, the EMA has now published the adopted Guideline on Good Pharmacogenomic Practice, which will enter into effect on 01-Sep-2018.

This guideline provides recommendations for the conduct of genomic studies in order to provide information on the impact of genomic variability on drug response, including the prediction of adverse drug reactions.

This new guideline complements the EMA guideline on key aspects for the use of pharmacogenomics in pharmacovigilance, which came into effect on 01-Apr-2016.

→ Link to EMA Pharmacogenomics Page → Direct link to adopted Guideline on Good Pharmacogenomic Practice

1.1.5 EMA issues revised guidance & information on New EudraVigilance System (28-Mar-2018) The new EudraVigilance System went live in November 2017 and the EMA has published updated information and guidance related to this new system, including a new revision of the EudraVigilance release notes (latest Version 1.10 dated 16-Mar-2018).

→ Link to EudraVigilance Training and Support Page

The new EudraVigilance System brought the implementation of the ISO ICSR (E2B(R3)) format in Europe. The EMA has posted updated versions of the BFC conversion tool and EU ICSR implementation guide business rules spreadsheets, which both represent components of the EU implementation guidance for ICH E2B(R3).

→ Link to EudraVigilance Change Management Page

The EudraVigilance Registration page has also been updated with a revised document describing the EVDAS user registration steps and the corresponding Training slides (Module EV-M1) have also been revised.

→ Link to EudraVigilance Registration Page → Direct link to EVDAS User Registration Guidance → Direct link to Training Module EV-M1: How to register with EudraVigilance and EVDAS

Most importantly, the EMA has published a revised version of the Questions and Answers document on the launch of the new EudraVigilance system (Version 1.4 dated 28-Mar-2018). As highlighted in the document, the revision brings a number of new or updated Questions and Answers.

→ Direct link to Q&As on the launch of the EudraVigilance system

1.1.6 EMA updates list of products for Signal Detection Pilot (06-Apr-2018) The Signal Detection Pilot started on 22-Feb-2018 for a period of one year. For the products concerned, MAHs are now subject to the new requirements to continuously monitor EudraVigilance data and inform Competent Authorities of validated signals detected in the database, as described in GVP Module IX.

The list of products included in this pilot was published for the first time on 27-Oct-2017 and a new version (Corr 4) was issued on 12-Mar-2018 to remove alipogene tiparvovec from the list as the authorisation for Glybera has expired. In the same way, the latest correction (Corr 5) was published on 06-Apr-2018 to remove daclizumab, simeprevir and telavancin as these products have been withdrawn.

→ Link to EMA Signal Management Page

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1.2 Developments to Watch

1.2.1 EMA provides update on EU Clinical Trial Regulation implementation (16-Mar-2018) The EMA has issued updated information regarding the implementation of the new Clinical Trial Regulation. As a reminder, the new Clinical Trial Regulation (EU No 536/2014) will not apply until six months after the EU portal and EU database have become fully functional.

The EMA Management Board was provided with an update at its March 2018 meeting. Based on the experience so far, the developer has submitted a revised project plan and the auditable version of the EU portal and database should be available for audit in early 2019, as required by the Clinical Trial Regulation.

→ Link to EMA Clinical Trial Regulation Page → Link to Highlights of EMA Management Board March 2018 meeting

1.2.2 FDA issues new guidance on Safety Reporting for Combination Products (21-Mar-2018) In December 2016 the FDA issued the final rule describing postmarketing safety reporting requirements that apply to combination products, which refers to products with two or more constituents that belong to different types of regulated medical products (i.e. drugs, devices, and biological products).

The purpose of this final rule is to ensure consistent and complete postmarketing safety reporting requirements for combination products while avoiding duplicative reporting for various types of events, including manufacturing events and device malfunctions.

The final rule became effective on 19-Jan-2017 with a compliance date 18 months following the effective date of the rule for some of the provisions, as specified within the rule.

The FDA has now issued a “Compliance Policy” that delays the enforcement of the provisions regarding ICSR Submission and Record Keeping. As specified in the policy, the enforcement date will be 31-Jul-2019 for Applicants using the FAERS and eMDR Reporting Systems to submit ICSRs, and 31-Jan-2020 for Applicants using the VAERS Reporting System.

In addition, the FDA has published a Draft Guidance to support compliance with the final rule. It includes an overview of which entities are subject to the final rule and what safety reporting requirements apply. It also provides guidance on where, how, and when to submit reports to FDA. Comments on this Draft Guidance are expected by 19-Jun-2018.

→ Link to Final Rule (20-Dec-2016) → Link to Federal Register Notice (Compliance Policy / 21-Mar-2018) → Link to FDA Page and Guidance (Compliance Policy) → Link to Federal Register Notice (Draft Guidance / 21-Mar-2018) → Link to FDA Page and Guidance (Draft Guidance)

1.2.3 EMA provides update on ISO IDMP implementation (23-Mar-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 concern the Product Management Service (PMS) and Substance Management Service (SMS), which represent two of the four domains of Substance, Product, Organisation and Referential (SPOR) master data in pharmaceutical regulatory processes.

The EU Telematics Enterprise Architecture Board (EU TEAB) has endorsed using the draft international data standard known as Fast Healthcare Interoperability Resources (FHIR, pronounced “fire”) as the basis for the application programming interface (API) for the PMS. The EMA and the FDA will work together with Health Level Seven (HL7) to incorporate the ISO IDMP standards into the FHIR specification, which will allow SPOR to become compatible with HL7 standards.

→ Link to EMA Page on PMS & SMS

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1.2.4 European Commission discusses Brexit preparedness (28-Mar-2018) The European Commission DG SANTE convened a technical expert seminar on 08-Mar-2018 in order to discuss matters related to preparedness of the UK withdrawal with Member States. The minutes of the meeting and presentations are now available, which show that despite the activities undertaken to raise awareness many MAHs have not yet taken the necessary regulatory actions, including relocation of QPPV.

→ Link to EC Page

1.2.5 FDA issues revised draft Implementation Plan for Benefit-Risk Assessment (02-Apr-2018) The FDA has announced the publication of a new draft 5-year plan describing the Agency's approach to further the implementation of structured benefit-risk assessment. Comments are expected by 01-Jun-2018.

The new draft plan is an update to the 5-year plan published in February 2013 and describes the progress made so far, which includes various activities to incorporate FDA's approach to benefit-risk assessment. The plan also includes an overview of FDA's commitments for continued implementation of structured benefit-risk assessment over the next 5 years. Amongst others, this includes the publication of a draft guidance on benefit-risk assessment for new drugs and biologics.

→ Link to Federal Register Notice → Direct link to Draft Implementation Plan

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 Austria issues revised Q&As on Pharmacovigilance (08-Mar-2018) The Austrian Agency has issued a revised set of Questions and Answers, which provides guidance on a number of Pharmacovigilance requirements including PSURs, RMPs and E2B Reporting, amongst other topics. The changes reflect the implementation of the latest versions of GVP Modules VI and IX on ICSR and Signal Management. The page is available in both German and English language but question 7 regarding Pharmacovigilance obligations associated to parallel import is only available in German at this time.

→ Link to BASG/AGES 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

30-Apr-2018 Deadline of consultation on EMA Draft Guidance on safety and efficacy follow-up and risk management of advanced therapy medicinal products (ATMPs) (Link)

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25-May-2018 New EU General Data Protection Regulation (GDPR – Regulation (EU) No 2016/679) comes into force (Link)

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01-Jun-2018 Deadline for comments to FDA revised draft Implementation Plan for Benefit-Risk Assessment (Link)

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19-Jun-2018 Deadline of consultation on FDA Draft Guidance on Postmarketing Safety Reporting for Combination Products (Link)

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

Q3/Q4-2019 Planned date for implementation of Clinical Trial Regulation (EU) No 536/2014 (Link)

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2. PRODUCT SAFETY ANNOUNCEMENTS

2.1 Quinolone and fluoroquinolone antibiotics EMA to hold public hearing in June (12-Mar-2018) As communicated through the highlights of the March PRAC meeting, the committee has decided to organise a public hearing as part of its on-going review of quinolone and fluoroquinolone antibiotics, which will take place at the PRAC meeting in June 2018.

The EMA will publish further information shortly, including a summary of safety concerns, a list of specific questions and practical information on how to participate.

→ Link to EMA Public Hearings Page → Link to EMA Quinolone Referral Page

2.2 Daclizumab (Zinbryta) FDA informs about withdrawal from the market in the USA (14-Mar-2018) The FDA has issued a statement to inform that Biogen and Abbvie have initiated a voluntary withdrawal of the multiple sclerosis drug globally due to concerns about the drug’s evolving benefit/risk profile.

This follows the decision by the EMA to recommend the suspension and recall of the product following reports of serious inflammatory brain disorders.

→ Link to FDA Statement

2.3 Valproate (Depakine, etc.) New measures to avoid pregnancy exposure now endorsed (23-Mar-2018) The CMDh has now endorsed the measures recommended by the PRAC to avoid pregnancy exposure to valproate-containing medicines, which are approved to treat epilepsy, bipolar disorder and in some countries for the prevention of migraine. As mentioned earlier, this review was started at the request of the French Agency to assess the effectiveness of existing measures to minimise the risk of malformations and developmental problems in exposed babies and this was the first review to include a public hearing, which took place on 26-Sep-2017.

The new measures include strengthened restrictions, a new pregnancy prevention programme and a visual warning of the pregnancy risks on the packaging. Companies marketing these medicines are also required to carry out additional studies on the nature and extent of the risks and to monitor valproate use and the long-term effects from affected pregnancies.

→ Link to EMA Press Release

The MHRA has updated its current advice accordingly, highlighting that the existing toolkit is being updated.

→ Link to MHRA Advice

2.4 Flupirtine CMDh agrees with PRAC recommendation on withdrawal (23-Mar-2018) The CMDh has now endorsed the PRAC recommendation to withdraw the marketing authorisation for the pain medicine flupirtine due to the risk of serious liver injury. This decision follows a previous review in 2013 when the EMA required restrictions but studies have shown that these measures were not sufficiently effective and no further measures to reduce the risk of liver problems could be identified.

→ Link to EMA Release

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2.5 Oral retinoids CHMP confirms new warning and pregnancy prevention measures (23-Mar-2018) Further to the PRAC recommendations published in February 2018, the EMA has now announced that it has completed its review of retinoid medicines, and confirmed that an update of measures for pregnancy prevention is needed. This includes an updated and harmonised Pregnancy Prevention Programme (PPP) for the oral retinoids acitretin, alitretinoin and isotretinoin.

In addition, a warning on the possible occurrence of neuropsychiatric disorders (such as depression, anxiety and mood changes) will be included in the prescribing information for oral retinoids, even though the review did not clearly establish whether this risk was caused by the use of retinoids or due to the nature of the severe skin conditions targeted by the treatment.

→ Link to EMA Release

2.6 Polyfructosane (a.k.a. sinistrin) solutions for injection Batch recall following serious anaphylactic reactions (23-Mar-2018) The Laboratoires SERB, in agreement with the French Agency, have initiated the recall of all non-expired batches of Proinuline Serb 25 % and Inutest 25 % following several serious anaphylactic reactions.

→ Link to ANSM updated safety announcement (in French)

3. DEAR DOCTOR LETTERS AND SAFETY NEWSLETTERS

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

• Exacyl solution for injection (tranexamic acid): warning on the potential risk of acute renal impairment in Postpartum Hemorrhages with doses over 2 g (total doses)

• Radium-223 dichloride (Xofigo)▼: contraindication in combination with abiraterone acetate and prednisone/prednisolone

• Precautionary measures to limit the risk of veno-occlusive liver disease (VOLD) in lymphoma patients receiving an autograft

→ Link to ANSM Page (in French)

3.2 New issue of Australian “Medicine Safety Update” The Australian Therapeutic Goods Administration (TGA) has issued the new edition of Medicines Safety Update (Volume 9, Number 1, February-March 2018). The contents include:

• First-generation oral sedating antihistamines – use in children • Suvorexant (Belsomra) – next day residual effects • Desvenlafaxine (Pristiq) recommended dose • Miconazole and potential interaction with warfarin

→ Link to Medicines Safety Update

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3.3 New issue of Canadian “Health Product InfoWatch” The 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 March issue was published by Health Canada on 28-Mar-2018. The monthly recap of safety reviews covers several products including SGLT2 inhibitors and Jakavi (ruxolitinib). The newsletter also describes Product Information changes for Tecentriq (atezolizumab), which led to a Health Professional Risk Communication.

→ Link to Newsletter

3.4 New issue of WHO Drug Information The latest edition of the WHO Drug Information, Vol. 32 No 1, is now available. As usual, the Safety news section provides the latest information on safety warnings and labelling changes. This issue also features an article on the Pharmacovigilance Programme of India (PvPI).

→ Link to WHO Drug Information

4. OTHER PUBLICATIONS BY REGULATORY AGENCIES

4.1 US Food and Drug Administration (FDA)

4.1.1 New Public Summary of Drug Safety Oversight Board meeting A new public summary for the meeting of the FDA Drug Safety Oversight Board (DSOB) has been posted. The Board met on 18-Jan-2018 and was updated on Drug Safety Communications issued since the previous meeting in May 2017. In addition, the Board heard presentations associated to the use of Gabapentinoids.

→ Link to DSOB Public Summary (18-Jan-2018)

4.1.2 Risk Communications Advisory Committee: New material available The Risk Communications Advisory Committee met on 05 and 06-Mar-2018 to discuss the impact of pregnancy and lactation labeling information in prescription drug and biological products as modified under the Pregnancy and Lactation Labeling Rule (PLLR). The material published on the FDA website includes the slides and webcasts of the meeting.

→ Link to FDA Page

4.2 European Medicines Agency (EMA)

4.2.1 EMA issues “Meeting Highlights” of last CHMP Meeting The highlights of the March meeting of the CHMP have been published. As communicated separately (see Section 2), the Committee concluded its review of retinoid medicines and confirmed that pregnancy prevention measures need to be updated whereas a warning on possible neuropsychiatric disorders will be included in the prescribing information for oral retinoids.

→ Link to CHMP Meeting Highlights (19 to 22-Mar-2018)

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4.2.2 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 05 to 08-Mar-2018 was published on 03-Apr-2018. It includes a recommendation to update the product information for the following signals:

• Cefalexin – Acute generalised exanthematous pustulosis (AGEP) • Norepinephrine – Stress cardiomyopathy

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

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

→ Link to EMA Page

4.2.3 EMA issues 2017 Annual Report on EudraVigilance The EMA has published the 2017 annual report on EudraVigilance for the European Parliament, the Council and the Commission, which shows that the number of reports received has increased significantly, which results from increased patient reporting and also due to the reporting of non-serious ICSRs after the go-live of the new EV system in November 2017. The report also shows that the PRAC assessed 82 confirmed signals in 2017 (84 in 2016), with 40% resulting in updates of product information.

The report also presents other activities initiated or completed in 2017, such as training and data quality activities and the development of EudraVigilance functionalities.

→ Link to 2017 EudraVigilance Report

4.2.4 EMA issues work programmes The EMA has published the PRAC Work Plan for 2018, which was adopted by the Committee on 31-Jan-2018. The document lists the key objectives and the corresponding activities planned for the year in various areas, including the development of new guidance. The EMA has also published its multiannual work programme 2018-2020, which describes the agency’s objectives in relevant themes.

→ Link to PRAC work plan 2018 → Link to EMA multiannual work programme 2018-2020

4.2.5 EMA issues updated EURD list The EMA has published an updated EURD list, which was last revised on 27-Mar-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.

→ 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 and 2 products were added to the list in March 2018, whereas 4 products were removed, as identified in the Summary of Changes presented on the EMA webpage. Additionally, the list of Cyproterone acetate / Ethinylestradiol-containing medicinal products has been updated (Annex I).

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

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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, which was already updated earlier this year.

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:

• Misoprostol (gynaecological indication - termination of pregnancy) • Candesartan, candesartan / hydrochlorothiazide • Interferon alpha-2a • Bilastine • Ibuprofen / pseudoephedrine

→ Link to PSUSAs Search Page

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

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

The summary of the PSUR Assessment Reports for fluvoxamine and naloxone were published on 05-Apr-2018.

→ Link to Summaries of Assessment Reports

4.2.10 EMA issues new recommendations to prevent Medication Errors As introduced in November 2015, the EMA now systematically communicates on additional measures to prevent medication errors for specific medicines.

A dedicated webpage presents this product-specific guidance to patients and healthcare professionals, which has been updated to include information about the colour change for insulin injection Fiasp in order to avoid mix ups with Tresiba.

→ Link to EMA Recommendations on medication errors

4.3 UK Agency (MHRA)

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

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4.4 French Agency (ANSM)

4.4.1 ANSM provides update on PRAC/CHMP/CMDh meetings Following the PRAC meeting of March 2018, the ANSM has issued a summary of the PRAC decisions. Following the PRAC recommendation to suspend the marketing authorisation for Zinbryta (daclizumab), the French Agency decided to stop the administration of the product in the single clinical trial running in France (Zinbryta is not marketed in France).

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

Following the CHMP meetings of February and March 2018, the ANSM issued a summary of the CHMP decisions. The documents do not include any ANSM recommendation.

→ Link to ANSM release – February 2018 CHMP (in French) → Link to ANSM release – March 2018 CHMP (in French)

4.4.2 Commissions/Committees in relation with Pharmacovigilance The consultative Commission in charge of the surveillance of the risk/benefit profile of medicinal products has issued the final minutes of its joint meeting with the Commission in charge of the initial evaluation of the risk/benefit profile which took place on 16-Nov-2017. The discussions included the labelling of solid oral forms and the naming of medicinal products in relation to the risk of Medication Errors.

→ Link to ANSM R/B Commission Minutes – 16-Nov-2017 (in French)

The Pharmacovigilance Committee has issued the minutes of its 10-Oct-2017 meeting, where the following topics were discussed:

• Levothyrox: update on the enquiry on the new formulation: no new toxicity • Levonergestrel IUD: investigations to be continued and update of the product safety information • Entresto (sacubitril/valsartan): national enquiry to be continued • EllaOne (ulipristal): national enquiry to be closed, need for a specific enquiry on the hepatic risks to be

determined based on the results of the Esmya European signal assessment (same active substance) • Duoplavin (clopidrogel/acetylsalicylic acid): national monitoring to be closed and

pharmacoepidemiologic study to be continued • Methylprednisolone: update of product safety information • Combined hormonal contraception and intracranial hypertension: closure of the unconfirmed signal

→ Link to ANSM PV Committee minutes – 10-Oct-2017 (in French)

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5. QUALITY ASSURANCE, INSPECTIONS AND AUDITS

5.1 MHRA issues final data integrity guide The MHRA has now published its final GxP data integrity guide, which is intended to be a useful resource on the core elements of a compliant data governance system across all GxP sectors, including pharmacovigilance. This follows a consultation on the draft document initiated in July 2016.

→ Link to MHRA Blog Post → Direct link to MHRA’s GXP data integrity guide

5.2 FDA issues Guidance for REMS Reporting Inspections The FDA has published a new chapter to the Compliance Program Guidance Manual, which covers Risk Evaluation and Mitigation Strategies (REMS) Reporting Inspections.

The document provides instructions to FDA personnel for the conduct of these inspections and highlights the content areas that a REMS inspection should focus on, knowing that each REMS is unique.

→ Link to FDA Guidance on REMS Reporting Inspections

5.3 European Commission presents new set of Volume 10 Guidelines The European Commission website has been enriched with a new section in Eudralex Volume 10 to present the guidelines that will be applicable to Clinical Trials authorised under the New Regulation (EU) No 536/2014. The guidelines that apply to trials authorised under Directive 2001/20/EC are presented in a separate area.

Until the Clinical Trials Regulation becomes applicable, sponsors should follow the documents relevant to the Clinical Trials Directive but they are encouraged to take into consideration a number of aspects that are outlined in the new or updated documents related to the Clinical Trial Regulation.

The new Clinical Trial Regulation guidelines available at this stage cover Quality and Inspection aspects and new documents have been published regarding the coordination of GCP Inspections. In addition to guidance for the preparation, conduct and reporting of GCP Inspection, the page also presents the annexes relevant to specific types of GCP inspections including Sponsor and CRO, as well as Computer Systems.

→ Link to Eudralex Volume 10 for Regulation (EU) No 536/2014

5.4 EMA issues 2018 Work Plan for GCP Inspectors Working Group The EMA has published the Work Plan for 2018 for its GCP Inspectors Working Group (GCP IWG). The document describes the priorities for the group to support the performance of GCP Inspections as well as the upcoming implementation of the new Clinical Trials Regulation.

→ Link to EMA GCP IWG Work Plan 2018

5.5 MHRA Pharmacovigilance Inspections Symposium 2018 As reported previously, the MHRA will hold the next Pharmacovigilance Inspections Symposium in May 2018 and there are seats remaining available on 04-May-2018 only. The topics to be discussed include Brexit, Service Providers and Outsourcing, and Signal Detection in EudraVigilance.

→ Link to MHRA Symposium Registration Page → Link to MHRA Blog Post

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6. DRUG SAFETY AND LIABILITY RISK

6.1 Yellow Fever vaccine and Multiple Sclerosis French Army sentenced to compensate former military member Despite the lack of scientific certainty regarding the link between the vaccine and the disease, the judges decided that the absence of other possible "causal factors" is sufficient to compensate a former member of the military who contracted multiple sclerosis after receiving a yellow fever vaccine.

→ Link to Top Santé article (in French)

7. OTHER NEWS AND RESOURCES

7.1 New issue of CIOMS Newsletter Amongst other topics, the March 2018 Newsletter (Issue 21) highlights the recent publication of the CIOMS Guide to Vaccine Safety Communication and presents the new Working Group XI, which will work on “Patient Involvement in Development and Safe Use of Medicines”.

→ Link to CIOMS Newsletter

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)

DSRU Events → Introduction to Pharmacoepidemiology

April 25 – 26 in Southampton, UK → Medical Aspects of Adverse Drug Reactions

May 02 – 04 in Fareham, UK → Periodic Safety Reports: PSURs and PBRERs

May 16 – 17 in Fareham, UK → Global Pharmacovigilance Regulatory Requirements: What’s New?

June 06 – June 07 in London, UK → Big Data for Pharmacovigilance

June 20 – 21 in London, UK

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DIA Events → DIA Europe 2018

April 17 – 19 in Basel, Switzerland → Global Labeling Conference

April 24 – 25 in North Bethesda MD USA → Complimentary Webinar: Automation in Pharmacovigilance and Regulatory

May 09, 10:00 – 11:00AM ET → 10th DIA China Annual Meeting

May 23 – 25 in Beijing, China → Pharmacovigilance Conference

June 05 – 06 in London, UK → Medical Approach in Diagnosis and Management of ADRs

June 12 – 13 in Paris, France → Benefit-Risk Management

July 02 – 03 in Basel, Switzerland → Signal Management in Pharmacovigilance

July 04 – 05 in Basel, Switzerland

Other Events → ISPE – 2018 Mid-Year Meeting

April 21 – 24 in Toronto, Canada → MHRA – Pharmacovigilance Symposium 2018

May 03, repeated on May 04 in London, UK → Faculté de Pharmacie – Paris V – Audit and Inspection in Pharmacovigilance (event in French)

May 17 – 18, France → Graviton – Pharmacovigilance Europe Congress 2018

May 22 – 23 in London, UK → IFIS – Missions and responsibilities of the "Pharmacien Responsable" (event in French)

May 24 in Paris, France → RQA – Systems Approach to Good Pharmacovigilance Practice (GPvP)

May 29 – 31 in Cambridge, UK → IFIS – Implementation and Follow-Up of Risk Management Plans (event in French)

June 04 in Paris, France → IFIS – Handling of Pharmacovigilance Cases (event in French)

June 08 in Paris, France → SMi – Drug Safety 2018

June 11 – 12 in London, UK → IFIS – Strengthening Pharmacovigilance through relevant Quality Criteria (event in French)

June 12 in Paris, France → Conference Series – Pharmacovigilance & Drug Safety

June 21 – 22 in London, UK → Equip Global – Risk Management Planning & Signal Management in Pharmacovigilance

July 03 – 05 in Singapore → RQA – Practical Pharmacovigilance Auditing

July 09 – 11 in Cambridge, UK