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Clinical Safety & Pharmacovigilance

Regulatory Intelligence Review
Issue N°147 - July 2018

HIGHLIGHTS
 French GVP Update
The ANSM has published a new Q&A Document that brings important clarifications about the French requirements
described in the French Good Pharmacovigilance Practices document published in February 2018.

 June 2018 ICH Meetings

A number of guidance documents were adopted by the ICH Assembly at the Kobe meeting, which includes a revision
of the Q&As for the Electronic Submission of Individual Case Study Reports (E2B(R3)). The MedDRA Management
Committee also endorsed the first edition of the companion document to the “Points to Consider” documents.

 Product Safety News

The EMA held its second public hearing in June 2018 to contribute to the review of quinolone and fluoroquinolone
antibiotics and the resulting information has been published by the Agency. Following earlier recommendations by
the PRAC to suspend the Marketing Authorisations, the CMDh eventually decided that HES solutions for infusion
should remain on the market provided that additional measures are implemented to protect patients.

 Pharmacovigilance and Inspections

The MHRA Inspectorate has updated the information on what to expect from a Pharmacovigilance Inspection and the
next GCP Symposium will take place in September 2018. The French ANSM has published a new Injunction Letter over
deficiencies identified during a Pharmacovigilance Inspection.

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Safety Observer Issue N°147 - July 2018
IN THIS ISSUE
1. Regulations, Guidelines and Other Standards ...................................................................................................... 3
1.1 Newly Applicable Standards .............................................................................................................................. 3
1.1.1 US further delays effective date of revised rules for Clinical Trial oversight ............................................... 3
1.1.2 EMA provides updated EudraVigilance information ..................................................................................... 3
1.1.3 First Edition of the MedDRA PtC Companion Document now available ...................................................... 3
1.1.4 France issue new Q&As on French Good Pharmacovigilance Practices....................................................... 4
1.2 Developments to Watch ..................................................................................................................................... 4
1.2.1 EMA provides update on EU Clinical Trial Regulation implementation ....................................................... 4
1.2.2 EU Authorities make progress with Brexit preparations .............................................................................. 4
1.2.3 EMA provides details to support SPOR User Registration ............................................................................ 4
1.2.4 EU Authorities provide updated guidance for Brexit preparedness ............................................................ 5
1.2.5 Update from ICH June 2018 Meetings in Kobe, Japan .................................................................................. 5
1.3 Beyond the Scope of Safety Observer ............................................................................................................... 6
1.4 The Safety Observer Tracker ............................................................................................................................. 7
2. Product Safety Announcements ............................................................................................................................ 7
2.1 Prolia (denosumab) ........................................................................................................................................... 7
2.2 Quinolone and fluoroquinolone antibiotics ..................................................................................................... 7
2.3 Celebrex (celecoxib) ........................................................................................................................................... 8
2.4 Hydroxyethyl-starch solutions (HES) ................................................................................................................ 8
3. Dear Doctor Letters and Safety Newsletters ......................................................................................................... 8
4. Other Publications by Regulatory Agencies ........................................................................................................ 10
4.1 US Food and Drug Administration (FDA) ......................................................................................................... 10
4.2 European Medicines Agency (EMA).................................................................................................................. 10
4.3 UK Agency (MHRA) ........................................................................................................................................... 13
4.4 French Agency (ANSM) ..................................................................................................................................... 13
5. Quality Assurance, Inspections and Audits ......................................................................................................... 14
6. Drug Safety and Liability Risk .............................................................................................................................. 15
7. Other News and Resources .................................................................................................................................. 15
8. Conferences and Training Events ........................................................................................................................ 16

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Safety Observer Issue N°147 - July 2018
1. REGULATIONS, GUIDELINES AND OTHER STANDARDS

1.1 Newly Applicable Standards

1.1.1 US further delays effective date of revised rules for Clinical Trial oversight (19-Jun-2018)
As announced at the time, the U.S. Department of Health and Human Services (HHS) and other Federal
Departments and Agencies agreed on revisions to modernize, strengthen, and make more effective the
“Federal Policy for the Protection of Human Subjects” that was promulgated as a Common Rule in 1991.
The Final Rule was published on 19-Jan-2017 and most of the requirements were planned to become effective
on 19-Jan-2018. An Interim Final Rule was however published on 17-Jan-2018 to delay the effective date of the
revisions to 19-Jul-2018.
As reported when it was published on 20-April 2018, a Notice of Proposed Rulemaking (NPRM) proposed to
delay for an additional 6 months the general compliance date of the revisions to the Common Rule. The
proposals of this NPRM have now been adopted through a final rule, which requires regulated entities to
continue to comply with the requirements of the current Common Rule until 21-Jan-2019.
As a reminder, the new rule strengthens protections for subjects involved in research while ensuring that the
oversight system does not add inappropriate administrative burdens. The main changes brought by this rule
relate to the informed consent process and the oversight system through risk-based IRB review.
→ Link to Federal Register Notice
→ Link to HHS Statement
→ Link to CenterWatch article

1.1.2 EMA provides updated EudraVigilance information (19-Jun-2018)

A revised version of the Questions and Answers (Q&A) from stakeholders on the launch of the new
EudraVigilance system has been published. In this new version, 3 questions have been updated in relation to
the ICSR downloads i.e. 2.3, 2.89 and 4.55. The latter relates to the changes in Italy where MAHs are no longer
able to retrieve cases from the National Database as we reported in our June issue. In addition, the document
includes 3 new questions i.e. 2.128, 2.129 and 2.130. The latter clarifies that the MAH does not have any
obligation to process cases identified through EVDAS for Signal Detection.
The EMA has also published the EudraVigilance Operational Plan from 2018 to 2020, which will be updated
regularly. The document has been adopted by the PRAC and describes the planned activities and
developments and their impact on EudraVigilance and its stakeholders.
Finally, the EMA has issued a new revision to the EudraVigilance release notes (latest Version 1.15 dated 11-
Jun-2018). This document is available in the “User guidance” section of the EudraVigilance Training and
Support Page of the EMA website.
→ Link to EMA EudraVigilance Page
→ Link to EudraVigilance Training and Support Page
→ Direct link to Q&As from stakeholders

1.1.3 First Edition of the MedDRA PtC Companion Document now available (27-Jun-2018)
As announced after the latest ICH MedDRA Management Committee meeting in Kobe, the First Edition of the
MedDRA Points to Consider (PtC) Companion Document is now available in English and Japanese.
This Companion Document supplements the existing PtC documents with additional details, examples, and
guidance and this first edition includes sections on Data Quality and Medication Errors.
→ Link to MedDRA News Release
→ Link to MedDRA Support Documentation Page
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1.1.4 France issue new Q&As on French Good Pharmacovigilance Practices (29-Jun-2018)
The French ANSM has published a new Q&A Document focusing on the role of the Marketing Authorization
Holder and "Exploitant". In line with the information we shared in our June issue, the document clarifies that
it is not mandatory for Pharmaceutical Companies to submit Medication Errors without adverse reactions to
the dedicated ANSM Medication Error Desk. In the same way, they do not have an obligation to report cases of
abuse or dependence to medicines containing psychoactive substances through the Dependence Evaluation
and Information Center (CEIP). The French Good Pharmacovigilance Practices document published in
February 2018 will be updated accordingly. The Q&A Document also clarifies the expectations regarding
various aspects of the local Pharmacovigilance System including the responsibilities of the local contact
person for Pharmacovigilance, local PSMF, local Signal Detection activities and Risk Management, etc.
→ Link to ANSM Q&A on the French GVPs (in French)

1.2 Developments to Watch

1.2.1 EMA provides update on EU Clinical Trial Regulation implementation (07-Jun-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 100th meeting in June 2018. The development
of the auditable release of the portal and database is nearing completion. Some adjustments to the project
planning may however be required as a result of the Agency’s relocation plans, which may impact the User
Acceptance Testing (UAT) planned for November 2018 and the subsequent audit due to start in early 2019.
Planning adjustments are underway but these are not currently expected to have a major impact on the overall
timing for the project.
→ Link to EMA Clinical Trial Regulation Page
→ Link to Highlights of EMA Management Board June 2018 meeting

1.2.2 EU Authorities make progress with Brexit preparations (07-Jun-2018)

The EMA Management Board met for its 100th meeting in June 2018 and was provided with an update of the
Brexit preparation activities.
As previously announced, the EU Authorities have completed the redistribution of the UK's portfolio of over
370 Centrally Authorised Products to rapporteurs and co-rapporteurs from other EEA Member States. The EMA
has now informed MAHs accordingly and activities have been initiated to facilitate knowledge transfer to the
new rapporteurs and co-rapporteurs, who will only take full responsibility for the products as of 30-Mar-2019.
The Board also discussed and endorsed the next phase of EMA’s Brexit preparedness business continuity plan,
which is intended to help prepare for a scenario with higher than anticipated staff losses at the EMA as a result
of the planned relocation.
→ Link to Highlights of EMA Management Board June 2018 meeting
→ Link to EMA Brexit Page

1.2.3 EMA provides details to support SPOR User Registration (18-Jun-2018)

The EMA has issued new information related to the implementation of the ISO IDMP standards, which are due
to replace the current eXtended EudraVigilance Medicinal Product Dictionary (XEVMPD).
The new information provides details for the SPOR user registration, which relates to the Substance, Product,
Organisation and Referential (SPOR) master data in pharmaceutical regulatory processes.
As described, users can now access the EMA available master data services via the SPOR portal. All users have
read-only access but users need to register to carry out actions via the portal such as requesting changes to
the master data held by EMA.
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Safety Observer Issue N°147 - July 2018
 The EMA has published new guidance describing how companies can register their first Industry Super Users,
and how to approve or revoke subsequent Industry Super Users or Industry Users. The EMA recommends that
each organisation should have at least two registered Industry Super Users but there are no technical or
recommended limits on the number of registered users per organisation.
→ Link to EMA Page on SPOR user registration

1.2.4 EU Authorities provide updated guidance for Brexit preparedness (19-Jun-2018)

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.
The Notice to MAHs published on the CMDh Brexit Page has now been revised to reflect the changes made to
the Notice to MAHs available on the EMA website. The latter was revised in January 2018 to highlight that in a
context of uncertainty, all EU regulations will cease to apply to the UK from 30-Mar-2019 unless another date
is agreed jointly or specified in the withdrawal agreement, which may also describe transitional arrangements.
The Questions-and-Answers document has been revised on both the EMA and CMDh websites to include new
information on various topics, including the impact of Brexit on the status of inspection outcomes. In addition,
it includes new information on back-up arrangements for EU QPPVs to clarify that the deputy QPPV should be
established and perform his/her tasks in the EEA.
An updated version of the Practical Guidance for industry has also been published on the EMA website. Only
one new question was added in relation to Pharmacovigilance for Human Medicines, which relates to the
change of PSMF location from the UK to an EEA Member State.
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 News Release
→ Link to EMA Brexit Guidance Page
→ Link to CMDh Brexit Page

1.2.5 Update from ICH June 2018 Meetings in Kobe, Japan (22-Jun-2018)
The International Council for Harmonisation (ICH) met in Kobe from 02 to 07-Jun-2018. The Assembly elected
additional members to the Association’s Management Committee whereas the TFDA, Chinese Taipei was
approved as a new Regulatory Member and additional authorities were approved as Observers.
A number of guidance documents related to the eCTD were adopted by the Assembly at the Kobe meeting
(Step 4 of the ICH process). In addition, a Revision of the Q&As for the Electronic Submission of Individual Case
Study Reports (E2B(R3)) was also adopted and the Assembly noted the publication of revised
recommendations on Electronic Transfer of Regulatory Information (ESTRI) (M2). Two new topics were also
adopted to cover Adaptive Clinical Trials and Drug interaction Studies.
The Assembly also discussed the development of training tools to support the consistent implementation of
ICH guidelines. In parallel, efforts are underway to map the implementation of ICH guidelines by current and
future ICH Members and better identify how ICH guidelines are implemented across regions.
The MedDRA Management Committee discussed the achievements towards global uptake of MedDRA through
multiple training activities conducted across the world, as well as support in the local language.
The Committee also endorsed the first edition of the companion document to the PtC (Points to Consider)
documents, which is now available (see 1.1.3 in this issue). This document will provide more detailed guidance,
examples, and “Questions and Answers” in relation to data quality issues and medication errors.
The next rounds of ICH meetings will be held from 10 to 15-Nov-2018 in Charlotte NC, USA.
→ Link to ICH Press Release
→ Link to MedDRA Press Release

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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 Netherlands amends policy for DHPCs and additional RMMs (11-Jun-2018)
The Dutch Medicines Evaluation Board (MEB) has amended its policy for Direct Healthcare Professional
Communications (DHPCs) and the national implementation of additional Risk Minimisation Measures (RMMs).
Policy documents MEB 44 and 45 respectively describe the procedure for the implementation of DHPCs and
additional RMMs in the Netherlands and provide recommendations for the translation of the material, the
identification of the target groups and the distribution of the material, including the use of electronic means.
→ Link to MEB Announcement
→ Direct link to Policy MEB 44 (DHPCs)
→ Direct link to Policy MEB 45 (additional RMMs)

1.3.2 Canada to require Hospitals to report Serious Adverse Drug Reactions (15-Jun-2018)
Health Canada has announced the publication of proposed regulations to amend the Food and Drug
Regulations and Medical Devices Regulations. Under the proposed regulations, hospitals will be required to
report to Health Canada all serious adverse drug reactions and medical device incidents within 30 days.
The proposed regulations are based on feedback received during consultations to date and stakeholders are
invited to provide comments on the proposal by 29-Aug-2018.
→ Link to Health Canada News Release
→ Link to the Canada Gazette Publication

1.3.3 Denmark updates Q&As on Clinical Trials (19-Jun-2018)

The Danish Medicines Agency has revised the set of Questions and Answers (Q&As) on Clinical Trial
requirements that is available on its website. All Q&As have been grouped in a short list of key themes,
including “Adverse reactions and safety monitoring”. A couple of new Q&As have also been added to address
Data Protection and the General Data Protection Regulation (GDPR).
→ Link to DKMA Q&As on Clinical Trials

1.3.4 Australia issues new Safety Reporting Guidance (02-Jul-2018)

The Australian TGA has issued a minor update of its Pharmacovigilance Guidance document entitled:
“Pharmacovigilance responsibilities of medicine sponsors – Australian recommendations and requirements”.
This update (Version 2.1, June 2018) includes revised links to online adverse event reporting forms.
On the other hand, the TGA has issued a new Guidance document on electronic ICSR submission in the E2B(R2)
format. This implementation guide (Version 1.1, July 2018) specifies how stakeholders can submit ICSRs for
medicines and vaccines to the TGA using the E2B(R2) EDI service, including Clinical Trials ICSRs.
A set of Frequently Asked Questions on E2B reporting has also been added to the TGA website.
→ Link to TGA Pharmacovigilance Guidance
→ Link to TGA Guidance on ICSR e-Submission
→ Link to TGA FAQs on E2B Reports

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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

31-Jul-2018 Deadline for comments to FDA draft guidance on Development of a Shared 146
System REMS (Link)

30-Aug-2018 Deadline for comments to FDA draft guidance on Waivers of the Shared System 146
REMS requirement (Link)

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 139
(Link)

2. PRODUCT SAFETY ANNOUNCEMENTS

2.1 Prolia (denosumab)

ANSM launches inquiry on risk of vertebral fractures after discontinuation (18-Jun-2018)
The French Agency reported that 11 cases of multiple vertebral fractures have been reported in France upon
discontinuation of Prolia, which is indicated for the treatment of osteoporosis. The causal relationship has not
been established at this stage and the risk-benefit balance of the treatment remains positive. In order to better
investigate this signal, the French Agency has however launched a specific pharmacovigilance inquiry in
addition to the ongoing national pharmacovigilance monitoring. This inquiry will be extended to Xgeva which
contains the same active substance and the results are expected before end 2018.
The ANSM also reminds that the risk of vertebral fractures following discontinuation of Prolia was the subject
of an analysis by the EMA which was initiated in 2016. The EU Agency concluded in 2017 that the available data
were not sufficient to confirm a causal relationship.
→ Link to ANSM situation update (in French)

2.2 Quinolone and fluoroquinolone antibiotics

EMA issues proceedings of its second public hearing (20-Jun-2018)
As reported previously, the PRAC decided to have a public hearing as part of the review of quinolone and
fluoroquinolone antibiotics. This hearing took place on 13-Jun-2018 during the June PRAC meeting and the
EMA has published resulting information.
As communicated with the Agenda of the hearing, the EMA announced that it received 115 applications to
attend, with 55 requests to speak from various stakeholders including patients and healthcare professionals.
23 speakers from 11 EU Member States were selected to share their views directly with the PRAC whereas
others contributed in writing to the PRAC decision process.
The hearing was broadcast live and a recording is available on EMA’s website, together with written
interventions, the agenda and list of participants, and a short Summary Report of the hearing were the main
points raised and associated proposals are highlighted.
→ Link to EMA Press Release
→ Link to EMA Quinolone Referral Page (see “Public hearing” tab)
→ Link to EMA Public Hearings Page
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Safety Observer Issue N°147 - July 2018
2.3 Celebrex (celecoxib)
FDA Approves Labeling Supplement to reflect results of new postmarketing study (28-Jun-2018)
The FDA has approved a labeling supplement for Celebrex to include results from the postmarketing
PRECISION trial, which found that at the lowest dose, Celebrex was similar to moderate doses of naproxen and
ibuprofen with regard to cardiovascular safety.
As reported earlier, the implications of the results of the PRECISION trial were discussed at a Joint Meeting of
the Drug Safety and Risk Management Advisory Committee with the Arthritis Advisory Committee, which took
place on 24 and 25-Apr-2018. The slides and video recordings of the meeting are available on the FDA website.
→ Link to FDA CDER Statement
→ Link to FDA Drug Safety and Risk Management Advisory Committee Page

2.4 Hydroxyethyl-starch solutions (HES)

CMDh keeps products on the market with new measures to protect patients (29-Jun-2018)
The CMDh has decided that hydroxyethyl starch (HES) solutions for infusion should remain on the market
provided that additional measures to protect patients are implemented for these products, which are used as
plasma volume replacement following acute blood loss.
The new measures include the implementation of a controlled access programme to ensure that these
medicines are only supplied to hospitals that are accredited following appropriate training. Additional
warnings are required to remind healthcare professionals that these medicines must not be used in patients
with sepsis or kidney impairment or in critically ill patients. The CMDh has also requested MAHs to conduct
additional studies to monitor the appropriate use of these medicines.
This decision represents a rare occurrence of the CMDh not following the PRAC recommendation. In January
2018, the PRAC recommended suspending the marketing authorisations for HES solutions for infusion because
drug utilisation studies showed they continued to be used in critically ill patients and patients with sepsis
despite restrictions introduced in 2013 to reduce the risk of kidney injury and death in such patients. This
recommendation was endorsed by the CMDh at the time but in April 2018, the European Commission
requested the PRAC to consider whether the suspension could result in an unmet medical need. The PRAC
confirmed its suspension recommendation at its May 2018 meeting but the CMDh gave further consideration
to the place of HES in the clinical practice of some countries, and concluded that new risk minimisation
measures would ensure that HES solutions are not used in patients at risk.
→ Link to EMA Press Release
→ Link to PRAC Meeting Highlights (14 to 17-May-2018)

3. DEAR DOCTOR LETTERS AND SAFETY NEWSLETTERS

3.1 ANSM Dear Doctor Letters

Dear Doctor Letters sent in June 2018 are now available on the French Agency's website (all in French). Letters
associated to safety concerns include the following:
• Fluconazole (Triflucan and generics) : change of administration device and dosage expression (see also
Information Release)
• Mycophenolate mofetil (CellCept and generics): update of the risk minimization measures regarding birth
control (see also Information Release)
→ Link to ANSM Page (in French)

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3.2 MHRA Dear Doctor Letters
The letters sent by the MHRA are presented in the subsequent issue of the “Drug Safety Update” bulletin and
concomitantly posted on the Agency’s website. The letters issued in May 2018 include the following:
• Azithromycin: increased rate of relapses of haematological malignancies and mortality in hematopoietic
stem cell transplantation (HSCT) patients treated with azithromycin
• Lynparza▼(Olaparib): Risk of medication errors with new pharmaceutical form
• Xgeva▼ (denosumab): risk of new primary malignancy
• Tivicay▼ (dolutegravir), Triumeq▼ (dolutegravir, abacavir, lamivudine), Juluca▼ (dolutegravir,
rilpivirine): neural tube defects reported in infants born to women exposed to dolutegravir at the time of
conception
→ Link to MHRA Page

3.3 New issue of MHRA “Drug Safety Update”

The June issue of Drug Safety Update was published on 22-Jun-2018. It includes the following topics:
• Dolutegravir (Tivicay▼, Triumeq▼, Juluca▼): signal of increased risk of neural tube defects; do not
prescribe to women seeking to become pregnant; exclude pregnancy before initiation and advise use of
effective contraception
• Denosumab (Xgeva▼) for giant cell tumour of bone: risk of clinically significant hypercalcaemia following
discontinuation
• Denosumab (Xgeva▼) for advanced malignancies involving bone: study data show new primary
malignancies reported more frequently compared to zoledronate
→ Link to Drug Safety Update

3.4 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 June issue was published by Health Canada on 27-Jun-2018. The monthly recap of safety reviews covers
several products including Gadolinium-based contrast agents (GBCAs), Isoniazid and Pradaxa (dabigatran
etexilate). The newsletter also presents Product Information updates for Proscar and Propecia (finasteride).
→ Link to Newsletter

3.5 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 2, June 2018). The contents include:
• Misadventures in oral methotrexate dosing
• Medicines associated with a risk of neuropsychiatric adverse events
• Clozapine and gastrointestinal effects
→ Link to Medicines Safety Update

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Safety Observer Issue N°147 - July 2018
4. OTHER PUBLICATIONS BY REGULATORY AGENCIES

4.1 US Food and Drug Administration (FDA)

4.1.1 FDA requests Boxed Warning about existence of REMS for Opioid Analgesics
As reported in previous issues, the FDA initiated actions against the opioid crisis in the US and notified
manufacturers of Immediate Release (IR) opioids that their drugs will also be subject to a stringent set of
requirements under a Risk Evaluation and Mitigation Strategy (REMS). This expanded the number of products
covered by the REMS, which included only extended release/long-acting (ER/LA) formulations until then.
The FDA has issued the template letter it has sent manufacturers to require that the safety labels for both IR
and ER/LA opioid products be revised to include a Boxed Warning about the existence of the REMS.
According to the template letter, this action is intended to increase REMS awareness of prescribers as the 60-
month REMS assessment report showed that less than half the target number of prescribers have completed
accredited REMS-compliant training activities.
→ Link to FDA Page on Opioid Medications
→ Direct link to Template Letter

4.1.2 FDA workshop on the use of real-world data and real-world evidence
As reported previously, the FDA held a public workshop entitled “Developing a Framework for Regulatory Use
of Real-World Evidence”, which took place on 13-Sep-2017 in Washington DC. The purpose was to discuss the
use of real-world data (RWD) and real-world evidence (RWE) in drug development and regulatory decision
making, including opportunities to improve data development activities, study designs, and analytical
methods. In addition to the information made available at the time of the workshop, a Summary of the
comments received on the White Paper has now been published.
→ Link to Event Page: A Framework for Regulatory Use of Real-World Evidence

4.2 European Medicines Agency (EMA)

4.2.1 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 14 to 17-May-2018 was published on 11-Jun-2018. It
includes a recommendation to update the product information for the following signals:
• Apixaban and edoxaban – Drug interaction between apixaban or edoxaban and selective serotonin
reuptake inhibitors (SSRI) and/or serotonin and noradrenaline reuptake inhibitors (SNRI) leading to
increased risk of bleeding
• Lenalidomide – Progressive multifocal leukoencephalopathy (PML)
• Lenograstim, lipegfilgrastim and pegfilgrastim – Pulmonary haemorrhage
• Pembrolizumab – Aseptic meningitis
In complement, the EMA has published the corresponding document entitled: “New product information
wording – Extracts from PRAC recommendations on signals”, which is available in all EU languages.
The list of all safety signals discussed at the PRAC since September 2012 has been updated accordingly. It
includes links to the corresponding PRAC minutes and specifies whether a variation was recommended.
→ Link to EMA Page
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4.2.2 EMA issues new Pharmacovigilance Risk Assessment Committee (PRAC) material
The EMA routinely makes available the agendas, minutes and highlights of the Pharmacovigilance Risk
Assessment Committee (PRAC).
→ Link to EMA PRAC Page
The minutes of the April PRAC meeting were published on 11-Jun-2018. At this meeting, the PRAC started a
review of the risk of dosing errors with methotrexate medicines. In addition, the European Commission
requested the PRAC to further consider any possible unmet medical need that could result from the proposed
suspension of hydroxyethyl-starch (HES) solutions for infusion (see also Section 2). In addition, the following
new Safety Signals were considered:
• Lenograstim, Lipegfilgrastim and Pegfilgrastim – Pulmonary haemorrhage
• Dienogest / ethinylestradiol – New information on the known risk of venous thromboembolism
• Emicizumab – New information on the known risk of haemorrhagic events
• Alemtuzumab – Cytomegalovirus (CMV) infection
• Belimumab – Lupus nephritis
• Daratumumab – Encephalopathy
• Dimethyl fumarate – Immune thrombocytopenic purpura, thrombocytopenia
• Parathyroid hormone – Nephrolithiasis
• Sitagliptin - Potential drug interaction with angiotensin-converting enzyme (ACE)-inhibitors leading to an
increased risk of angioedema
• Tocilizumab – Hypofibrinogenaemia
• Duloxetine – Interstitial lung disease
• Olanzapine – Somnambulism
→ Direct link to PRAC Meeting Minutes (09 to 12-Apr-2018)
The highlights of the June PRAC meeting were published on 15-Jun-2018. As communicated separately (see
Section 2), the PRAC held a public hearing on quinolone and fluoroquinolone antibiotics as part of the safety
review investigating the persistence of serious side effects affecting muscles, joints and the nervous system.
According to the agenda, the following new Safety Signals have been identified and considered:
• Dulaglutide, Exenatide and Liraglutide – Diabetic ketoacidosis
• Nivolumab – Keratoacanthoma
• Rivaroxaban – Acquired haemophilia
• Tacrolimus – Hepatitis E infection
• Xylometazoline – Serious ventricular arrhythmia in patients with long QT syndrome
• Carbimazole and Thiamazole – New information on the known risk of birth defects and neonatal disorders
in case of exposure during pregnancy
• Nabumetone – Drug reaction with eosinophilia and systemic symptoms (DRESS)
→ Link to PRAC Meeting Highlights (11 to 14-Jun-2018)

4.2.3 EMA issues “Meeting Highlights” of last CHMP Meeting

The highlights of the June meeting of the CHMP have been published. The Committee started a review of
Septanest (articaine / adrenaline solutions for injection) to harmonise the way the products are used as a local
anaesthetic during dental procedures. The CHMP also started a review of the effectiveness of bacterial lysate
medicines in reducing the number and severity of respiratory infections.
→ Link to CHMP Meeting Highlights (25 to 28-Jun-2018)

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Safety Observer Issue N°147 - July 2018
4.2.4 EMA Working Parties with Patients’ and Healthcare Professionals’ Organisations
The EMA has published the material from the latest joint meeting of the Working Parties with Patients’ and
Consumers’ Organisations (PCWP) and Healthcare Professionals’ Organisations (HCPWP), which took place on
17 and 18-Apr-2018.
The meeting covered a range of topics including Digital Media and recent developments in Real-Word Evidence
(RWE) and electronic product information. It also included an update on the implementation of the Clinical
Trial Regulation and a discussion on a survey on “additional monitoring” awareness. The material now
available on the EMA website includes the presentations from the meeting, as well as the Meeting Summary.
→ Link to EMA Event Page

4.2.5 EMA issues updated EURD list

The EMA has published an updated EURD list, which was last revised on 06-Jun-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 June 2018, whereas 9 products were
removed, as identified in the Summary of Changes presented on the EMA webpage.
→ Link to EMA Page: Pharmacovigilance / List of Black Triangle Products

4.2.7 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:
• Permethrin
• Finasteride
• Naproxen
• Dexamfetamine
• Quetiapine
• Thiocolchicoside
→ Link to PSUSAs Search Page

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Safety Observer Issue N°147 - July 2018
4.3 UK Agency (MHRA)
4.3.1 MHRA adds ADR Reporting to e-learning modules
The MHRA has added its module on Adverse Drug Reactions (ADRs) to the series of e-learning modules on
Medicines. As reported when it was first made available, this 45-minute training was developed as part of the
SCOPE project to raise awareness about ADR reporting and its completion qualifies for Continuing Medical
Education credits in the UK.
→ Link to MHRA Page

4.3.2 MHRA updates document describing the contribution of the Yellow Card Scheme
The MHRA has updated its document on the Yellow Card Scheme, which is intended to complement other
information available to Healthcare Professionals and demonstrate how the system contributes to the
identification of safety issues. This document includes a table of safety issues identified since 2013 and
provides detailed case study examples.
→ Link to MHRA HCP Guidance Page
→ Direct link to MHRA Document: Contribution of Yellow Cards

4.4 French Agency (ANSM)

4.4.1 ANSM provides update on PRAC/CHMP/CMDh meetings
Following the PRAC meeting of May 2018, the ANSM issued a summary of the PRAC decisions. The document
does not include any ANSM recommendation.
→ Link to ANSM release – May 2018 PRAC (in French)

4.4.2 ANSM communicates on valproate additional risk minimization measures

The French Agency has issued updated information following the final decision of the European Commission
on the contraindication of valproate-containing medicines in pregnant women and in girls and women of
childbearing potential. Such contraindication was implemented in France in July 2017 in the bipolar disorders
indication, and it is now extended to the epilepsy indication. This will be reflected in the near future in an
update of the Marketing Authorization of the concerned products and the corresponding additional Risk
Minimization Measures including pregnancy pictogram, patient leaflet, etc.
→ Link to ANSM Press Release (in French)

4.4.3 ANSM confirms quality of the new formula for Levothyrox

In response to the publication by the French Association of Patients with Thyroid Disorders (AFMT) of the
results of their analyses of the new formulation of Levothyrox, the ANSM has issued a statement reminding
that the 3 sets of analyses performed in the ANSM laboratory confirmed that the new formulation is in
conformity to the Marketing Authorization dossier. The French Agency highlights that it is not possible to
confirm the validity of the AFMT results since they do not include sufficient detail regarding the laboratory and
the methodology used.
→ Link to ANSM Press Release (in French)

4.4.4 ANSM to propose plan to reduce overdose and death with opioid substitution therapy
The French Agency Narcotics and Psychoactive Medicines Commission held a workshop on 21-Jun-2018 with
the main stakeholders involved in the addiction field in order to present within a few months a plan to reduce
the number of overdoses linked to misuses of buprenorphine and methadone.
→ Link to ANSM Press Release (in French)

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4.4.5 Study on the risk of early neurodevelopmental disorders with epilepsy treatments
The ANSM and the French Social Security (CNAM) presented during the first "Antiepileptic medicines and
Pregnancy" Steering Committee the results of a study on the risk of early neurodevelopmental disorders in
children (under 6) exposed in utero to valproate or other antiepileptic monotherapy in France, compared to
unexposed children. The study included over 1.7 million children born between January 2011 and December
2014, without a diagnosis of brain malformation at birth. The results show that:
• The risk of early neurodevelopmental disorders is confirmed for valproate
• The risk appears higher with exposure during the second and/or third trimester of pregnancy
• The risk is less important with other epilepsy products with differences depending on the substances.
→ Link to ANSM Press Release (in French)

4.4.6 ANSM issues report on baclofen in alcohol-dependent patients

As announced in our May issue, the French Agency has now published the full report on the assessment of the
benefits and risks of baclofen in the treatment of alcohol dependence. The Temporary Specialised Scientific
Committee (CSST) concluded that the efficacy of baclofen in the reduction of alcohol consumption in adult
patients with alcohol dependence is insufficient and the benefit risk balance is considered negative.
→ Direct link to CSST Report (in French)

4.4.7 ANSM starts consultation on communication of safety data for mandatory vaccines
Since January 2018, 11 vaccine strains have become mandatory in France for children under 2 and the French
Agency has established a Temporary Specialised Scientific Committee (CSST) to advise on the type of safety
information that should be made available to the public as well as on the associated methods of
communication. For that purpose, the consultation via the CSST will include a public hearing, which will take
place on 10-Jul-2018 and will be broadcast live on the ANSM Dailymotion channel.
→ Link to ANSM Information Release (in French)
→ Direct link to ANSM Decision (in French)

4.4.8 ANSM issues 2018 work program

With regards to Pharmacovigilance, the ANSM plans to strengthen its position within the European
Pharmacovigilance system and to prioritise the Pharmacovigilance inspections using a risk-based approach.
→ Link to the ANSM 2018 Work Program (in French)

5. QUALITY ASSURANCE, INSPECTIONS AND AUDITS

5.1 2018 MHRA GCP Symposium now open for registration

As already reported in our June issue, the MHRA has announced that the next GCP Symposium will take place
in Leeds, UK on 05-Sep-2018 and a repeat session is also offered on 06-Sep-2018. Amongst the themes covered
by the Agenda, the symposium will include a session on the CTFG Updated Guidance on Reference Safety
Information (RSI), as well as a Joint FDA & MHRA Unblinding Session.
→ Link to MHRA Event and Registration Page

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Safety Observer Issue N°147 - July 2018
5.2 MHRA updates information on Pharmacovigilance Inspections
The MHRA Inspectorate has updated the information on its website to include additional information on what
to expect from a Pharmacovigilance Inspection. This includes a description of the process for the Inspection
Report and the management of responses from the company, as well as the escalation mechanisms through
the GPvP Compliance Management Team (CMT) and Inspection Action Group (IAG2).
→ Link to MHRA Page

5.3 New ANSM injunction letter published

Injunctions are administrative measures taken by the French Agency after inspections in case of deficiencies
that should be resolved within a set timeframe. A new injunction letter has been issued to Cooperation
Pharmaceutique Française. The deficiencies identified concern mainly the following aspects:
• The benefit-risk assessment process and risk management system
• The process to maintain the product safety information up-to-date
• The organisation of the pharmacovigilance system to ensure business continuity
• The collection of safety data through medical information enquiries
• The qualification and training of the EU QPPV and the French contact person for Pharmacovigilance
• The internal and external audit process
• The oversight of partners and service providers and reconciliations
→ Link to Cooperation Pharmaceutique Française Injunction (in French)

6. DRUG SAFETY AND LIABILITY RISK

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

7. OTHER NEWS AND RESOURCES

7.1 PIPA issues interim guidance notes on UK data protection

The Pharmaceutical Information and Pharmacovigilance Association (PIPA) has published these Interim
Guidance Notes on UK Data Protection in Post-Marketing Pharmacovigilance to support the industry in
complying with the data protection obligations under the new GDPR. PIPA will publish the final version of the
guidance notes when it becomes available.
→ Link to PIPA Page

7.2 New issue of CIOMS Newsletter

The June 2018 Newsletter (Issue 22) highlights the First Meeting of CIOMS Working Group XI on “Patient
Involvement in the Development and Safe Use of Medicines”. Amongst other topics, it also provides an update
on the progress of the CIOMS Working Group on Drug-induced Liver Injury (DILI).
→ Link to CIOMS Newsletter

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Safety Observer Issue N°147 - July 2018
7.3 IMI Newsletter articles highlight contributions to Drug Safety
In its latest newsletter, the Innovative Medicines Initiative (IMI) highlights how some of its projects are
contributing to the detection of safety issues associated to medicines.
In the pre-clinical safety area, the MARCAR project found special features of genes known as epigenetic
biomarkers, which changed when exposed to a cancer-causing drug. Such epigenetic mechanisms can help
identify carcinogenic drugs much earlier by assessing drug safety at the molecular level.
On the other hand, the WEB-RADR project has developed an app that enables patients to directly report ADRs
to relevant health authorities, find out about reported side effects and opt to receive alerts on specific
medicines. The project team also worked on the possible use of social media data and its recommendations
have been passed on to the EMA for implementation into future guidance.
→ Link to IMI article on MARCAR Project
→ Link to IMI article on WEB-RADR Project

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)
→ Risk Management Plan Information Day Information Day
October 25 in London, UK

DIA Events
→ Clinical Trial Regulation Conference
September 17 – 18 in London, UK
→ 2018 European Forum for Qualified Persons for Pharmacovigilance (QPPV)
October 10 – 11 in London, UK
→ MHRA/DIA Excellence in Pharmacovigilance
October 15 – 19 in London, UK
→ Canadian Pharmacovigilance and Risk Management Strategies Conference
October 29 in Ottawa, Canada
→ DIA Annual Canadian Meeting 2017
October 30 – 31 in Ottawa, Canada

DSRU Events
→ Back to Basics in Pharmacovigilance
September 05 – 06 in Fareham, UK
→ Pharmacovigilance Planning and Risk Management
September 26 – 27 in Fareham, UK
→ Risk Benefit Assessment in Pharmacovigilance
October 03 – 04 in Fareham, UK
→ Assessment and Medical Evaluation of Individual Case Safety Reports
October 10 – 11 in Fareham, UK

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Safety Observer Issue N°147 - July 2018
Other Events
→ RQA – Practical Pharmacovigilance Auditing
July 09 – 11 in Cambridge, UK
→ ICPE – 34th International Conference on Pharmacoepidemiology & Therapeutic Risk Management
August 22 – 26 in Prague, Czech Republic
→ Terrapinn – World Drug Safety Congress Europe 2017
September 10 – 11 in Amsterdam, Netherlands
→ Allan Lloyds – 5th Annual Risk Management & Pharmacovigilance Summit
September 18 – 20 in Vienna, Austria
→ 6th ISoP-UMC Training
September 24 – 26 in Guayaquil, Ecuador
→ IFIS – Clinical trial pharmacovigilance (event in French)
September 25 in Paris, France
→ RQA – Practical Pharmacovigilance Auditing
October 02 – 04 in Cambridge, UK
→ PIPA – Annual Conference 2018
October 03 – 04 in Windsor, UK
→ IFIS – Responsibilities of the Responsible Pharmacist in Pharmacovigilance (event in French)
October 16 in Paris, France
→ RQA – Systems Approach to Good Pharmacovigilance Practice (GPvP)
October 16 – 18 in Cambridge, UK
→ IFIS – Pharmacovigilance: Roles and Responsibilities (event in French)
October 22 – 23 and November 09 in Paris, France
→ Allan Lloyds – 3rd Risk Management & Pharmacovigilance America Summit
October 23 – 25 in Boston MA, USA
→ RQA – Annual Conference 2018
October 31 – November 02 in Manchester, UK

Featured Event :

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Safety Observer Issue N°147 - July 2018