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Safety Observer Issue N°124 - June 2016

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Clinical Safety & Pharmacovigilance Regulatory Intelligence Review

Issue N°124 - June 2016

HIGHLIGHTS

The European Commission has just launched Public Consultations on 4 different topics related to the new Clinical Trial Regulation (EU No 536/2014), which is planned to become applicable in October 2018. The first public consultation concerns "Risk proportionate approaches in clinical trials", which includes recommendations for applying a risk proportionate approach to safety reporting.

The use of the EU PSUR Repository will become mandatory from 13-Jun-2016 and the EMA has just been published new versions of the User Guidance documents for both MAHs and NCAs.

The FDA has issued a new draft guidance entitled “Use of Electronic Health Record Data in Clinical Investigations”, which provides recommendations on how to use EHRs as a source of data in clinical investigations.

The investigation to better understand the tragic death of a volunteer during a phase 1 clinical trial in France has now been completed and resulted in a list of recommendations that have all been endorsed by the French Health Minister. Concomitantly, the EMA has announced that it has started a review of the guidelines for first-in-human clinical trials in order to minimise the risk of similar accidents in the future.

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IN THIS ISSUE

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

1.1 Newly Applicable Standards .............................................................................................................................. 3 1.1.1 New User Guidance published on EU PSUR Repository ............................................................................... 3 1.1.2 EMA issues revised procedural advice for RMP changes .............................................................................. 3

1.2 Developments to Watch ..................................................................................................................................... 3 1.2.1 EU Data Protection Reform achieves key milestone..................................................................................... 3 1.2.2 EMA Workshop on technical aspects of ISO ICSR Implementation .............................................................. 3 1.2.3 FDA issues draft guidance on use of Electronic Health Record data ............................................................ 4 1.2.4 EMA initiates EU-wide review of the safety of first-in-human clinical trials ................................................. 4 1.2.5 New Public Consultations on EU Clinical Trial Regulation implementation ............................................... 4 1.2.6 FDA initiates consultation on ICH E18 ........................................................................................................... 4

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

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

2.1 Olanzapine (Zyprexa) ......................................................................................................................................... 6 2.2 Fluoroquinolone Antibacterial Drugs ................................................................................................................ 6 2.3 Recombinant factor VIII products ...................................................................................................................... 6 2.4 Canagliflozin (Invokana, Invokamet) ................................................................................................................ 6 2.5 Ketoconazole (Nizoral)....................................................................................................................................... 7 2.6 Plan B emergency contraceptives ..................................................................................................................... 7 2.7 Antidepressants ................................................................................................................................................. 7 2.8 Nitrofurantoine .................................................................................................................................................. 7 2.9 Sumatriptan (Zecuity) ........................................................................................................................................ 7

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

4. Other Publications by Regulatory Agencies .......................................................................................................... 9

4.1 US Food and Drug Administration (FDA) ........................................................................................................... 9 4.2 European Medicines Agency (EMA) .................................................................................................................. 10 4.3 UK Agency (MHRA) ........................................................................................................................................... 14 4.4 French Agency (ANSM) ..................................................................................................................................... 14

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

6. Drug Safety and Liability Risk .............................................................................................................................. 15

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

8. Conferences and Training Events ........................................................................................................................ 16

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1. REGULATIONS, GUIDELINES AND OTHER STANDARDS

1.1 Newly Applicable Standards

1.1.1 New User Guidance published on EU PSUR Repository (12-May-2016) The European PSUR Repository is intended to provide a secure electronic submission point and common storage place for PSURs, PSUR Assessment Reports, comments and final outcomes for both the PSUR Single Assessment Procedure and the pure National procedures.

As communicated previously, the use of the PSUR Repository will become mandatory from 13-Jun-2016 and Version 01.06 of the Repository has now been released, which provides important improvements. New versions of the PSUR Repository User Guidance documents for both MAHs and NCAs have been published.

→ Link to PSUR Repository Page

1.1.2 EMA issues revised procedural advice for RMP changes (02-Jun-2016) The EMA has published new guidance on the procedural management of risk management plans (RMP) submissions and on the classification of changes to the marketing authorisation post authorisation, which introduce simplified procedures for marketing authorisation holders.

The new guidance provides all relevant information on the classification of RMP changes (e.g. how RMP changes are classified, which changes can be included in an RMP update without the need for an additional variation) as well as procedural aspects of the RMP lifecycle. The guidance also simplifies the management of complex RMP updates as some changes submitted as groupings will now be accepted as a single variation.

→ Link to EMA News Release → Link to EMA Q&As on RMPs → Direct link to EMA Procedural Advice (post-authorisation with track changes)

1.2 Developments to Watch

1.2.1 EU Data Protection Reform achieves key milestone (10-May-2016) Following the December 2015 agreement on the new data protection rules, the official texts of the corresponding Regulation and Directive have now been published in the EU Official Journal.

The Regulation is intended to strengthen citizens' rights in the digital age and facilitate business by simplifying and harmonising rules for companies. The Directive applies to the police and criminal justice sector to ensure that the personal data of victims, witnesses, and suspects of crime are duly protected and to facilitate cross-border cooperation in the fight against crime and terrorism.

The Regulation will apply from 25-May-2018, and EU Member States have to transpose the Directive into their national law by 06-May-2018.

→ Link to EU Data Protection Reform Page

1.2.2 EMA Workshop on technical aspects of ISO ICSR Implementation (12-May-2016) The EMA has published the presentations used at the workshop on the implementation of the ISO standard for ICSRs, which took place on 04-Mar-2016. The discussions focussed on implementing the HL7 XML message and was specifically aimed at software vendors, service provides and pharmacovigilance system implementers.

→ Link to EMA Event Page

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1.2.3 FDA issues draft guidance on use of Electronic Health Record data (16-May-2016) The FDA has issued a new draft guidance entitled “Use of Electronic Health Record Data in Clinical Investigations”, which is intended to assist sponsors and other stakeholders on the use of electronic health record (EHR) data in FDA-regulated clinical investigations.

The document provides recommendations on deciding whether and how to use EHRs as a source of data in clinical investigations. Other topics covered include systems interoperability, data quality and integrity.

Comments on the draft guidance are expected by 18-Jul-2016.

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

1.2.4 EMA initiates EU-wide review of the safety of first-in-human clinical trials (27-May-2016) The EMA has started a review of the guidelines that describe first-in-human clinical trials and the data needed to enable their appropriate design and allow initiation in a joint effort with the European Commission and EU Member States. The review will identify which areas may need to be revised in the light of the tragic incident during a Phase I clinical trial in France in January 2016, which led to the death of one participant and hospitalisation of five others.

The review will take into account the findings from two in-depth investigations performed at the request of French authorities, which include recommendations to minimise the risk of similar accidents. The EMA review has started with two groups of experts who are looking at both clinical and pre-clinical aspects.

The objective is to agree on a concept paper, which will form the basis for an EU-wide review of the guidelines. This process will include targeted discussions with stakeholders and a public consultation later in 2016.

→ Link to EMA News Release

1.2.5 New Public Consultations on EU Clinical Trial Regulation implementation (01-Jun-2016) The European Commission has just launched Public Consultations on 4 different topics related to the new Clinical Trial Regulation (EU No 536/2014), which is planned to become applicable in October 2018.

The first public consultation concerns "Risk proportionate approaches in clinical trials", which includes the recommendations of the expert group for applying a risk proportionate approach to safety reporting. Such adaptation refers to the recording of adverse events in the CRF and to the requirements of immediate reporting by the investigator to the sponsor, which should be clearly stated and justified in the protocol in line with the risk assessment and mitigation plan produced in conjunction with the protocol development.

The other 3 consultations cover the following topics:

• "Summary of Clinical Trial Results for Laypersons" • Revision of the "Definition of Investigational Medicinal Products (IMPs) and use of Auxiliary Medicinal

Products (AMPs)" (previously called "Guidance on Investigational Medicinal Products (IMPS) and Non-Investigational Medicinal Products (NIMPs))

• Revision of "Ethical Considerations for Clinical Trials on Medicinal products conducted with Minors"

Contributions on all 4 consultations should be sent by 31-Aug-2016.

→ Link to European Commission Page

1.2.6 FDA initiates consultation on ICH E18 (03-Jun-2016) Following its publication by ICH in December 2015, the FDA has now launched a consultation on the ICH E18 Guideline on Genomic Sampling and Management of Genomic Data. This new guideline provides guidance on genomic sample collection to evaluate efficacy and safety of a drug for regulatory approval.

Comments are expected by 02-Aug-2016.

→ Link to Federal Register Notice → Link to Draft Guidance

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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 Canada consults on mandatory reporting for Healthcare Institutions (13-May-2016) The Protecting Canadians from Unsafe Drugs Act (Vanessa's Law) introduces a new power to require certain healthcare institutions to report serious adverse drug reactions and medical device incidents, which is intended to enable the timelier identification of emerging safety issues.

A series of consultations occurred throughout 2015 and 2016 and an issue identification paper has now been published by Health Canada, who is seeking general feedback by 11-Jul-2016.

→ Link to Health Canada 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.

By When? What? Issue

13-Jun-2016 European PSUR Repository will become mandatory to use (Link) 114

15-Jun-2016 ANSM Consultation on French Good Pharmacovigilance Practices (Link) 123

01-Jul-2016 Start of the transition phase for the implementation of international standards for the identification of medicinal products (IDMP) in Europe (Link)

118

29-Jul-2016 EMA Consultation on Draft Reflection Paper on collecting and reporting information on off-label use in pharmacovigilance (Link)

123

02-Aug-2016 FDA Consultation on ICH E18 on genomic sampling and management of genomic data (Link)

123

31-Aug-2016 Public Consultations on aspects of the EU Clinical Trial Regulation (Link) 123

Jul-2017 Implementation of the new EudraVigilance system in Europe (includes centralised reporting, E2B(R3), MAH obligation to monitor EudraVigilance for safety signals) (Link)

117

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

119

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2. PRODUCT SAFETY ANNOUNCEMENTS

2.1 Olanzapine (Zyprexa) FDA warns about risks of rare but serious skin reactions (10-May-2016) The FDA has issued an alert to warn that the antipsychotic medicine olanzapine can cause Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) and this new warning has been added to the drug labels for all olanzapine-containing products. A search of the FDA Adverse Event Reporting System (FAERS) database identified 23 cases of DRESS reported with olanzapine worldwide, including a fatal case.

→ Link to FDA MedWatch alert

2.2 Fluoroquinolone Antibacterial Drugs FDA advises restricting use for certain uncomplicated infections (12-May-2016) The FDA has issued new information advising that the serious side effects associated with fluoroquinolone antibacterial drugs generally outweigh the benefits for patients with sinusitis, bronchitis, and uncomplicated urinary tract infections who have other treatment options. For patients with these conditions, fluoroquinolones should be reserved for those who do not have alternative treatment options.

An FDA safety review has shown that fluoroquinolones when used systemically are associated with disabling and potentially permanent serious side effects that can occur together and involve the tendons, muscles, joints, nerves, and central nervous system. The FDA is requiring the drug labels and Medication Guides for all fluoroquinolones to be updated to reflect this new safety information.

→ Link to FDA MedWatch alert

2.3 Recombinant factor VIII products PRAC concludes on meta-analysis on the risk of inhibitor development (13-May-2016) The PRAC has adopted a summary report following the review of a meta-analysis of data from three observational studies, aiming to assess the risk of developing inhibitors against individual recombinant factor VIII products in previously untreated patients with severe haemophilia A, which can lead to a reduction of the therapeutic effect.

The PRAC concluded that the currently available evidence does not confirm that Kogenate Bayer/Helixate NexGen is associated with an increased risk of factor VIII inhibitors compared with other recombinant factor VIII products, which is consistent with the previous review carried out in 2013. The PRAC recommended that MAHs should monitor published studies on drug inhibitor development so as to keep the product information up to date.

→ Link to EMA Public Summary Report

2.4 Canagliflozin (Invokana, Invokamet) FDA highlights possible increased risk of leg and foot amputations (18-May-2016) The FDA has announced that interim safety results from an ongoing clinical trial found an increase in leg and foot amputations, mostly affecting the toes, in patients treated with the diabetes medicine canagliflozin. FDA has not confirmed a causal association at this stage and is investigating this new safety issue.

→ Link to FDA MedWatch alert

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2.5 Ketoconazole (Nizoral) FDA warns against prescribing of oral ketoconazole for unapproved uses (19-May-2016) The FDA has issued a new warning to remind health care professionals that the antifungal medicine ketoconazole oral tablets should not be prescribed to treat skin and nail fungal infections. This medication carries risks of serious liver damage, adrenal gland problems, and harmful interactions with other medicines that outweigh its benefit in treating these conditions, which are not approved indications since the restrictions decided by the FDA in 2013. However, an FDA safety review found that oral ketoconazole continues to be prescribed for these types of conditions, which caused one patient death due to liver failure.

→ Link to FDA MedWatch alert

2.6 Plan B emergency contraceptives FDA considers products remain effective regardless of bodyweight (24-May-2016) The FDA has published new Questions and Answers for Healthcare Professionals and Consumers over the effectiveness of levonorgestrel emergency contraceptives in women with increased bodyweight. This follows a review by the FDA, who determined that available data are conflicting and too limited to make a definitive conclusion. The FDA does not believe that a change in the labeling is warranted at this time and continues to believe that all women, regardless of how much they weigh, can use these products to prevent unintended pregnancy. The EMA had communicated a similar conclusion in July 2014.

→ Link to FDA Q&As for Healthcare Professionals → Link to FDA Q&As for Consumers

2.7 Antidepressants ANSM warns about risks of pregnancy exposure to SSRI and SNRI antidepressants (26-May-2016) Although some studies do not confirm a causal association, several epidemiological studies have suggested a risk of neurological development problems associated to pregnancy exposure to SSRI and SNRI antidepressants. In this context, the French Agency recommends caution when prescribing these drugs during pregnancy while the enhanced surveillance continues.

→ Link to ANSM website (in French)

2.8 Nitrofurantoine ANSM warns about continued off-label use (26-May-2016) Nitrofurantoine is an antibiotic mainly used for curative treatment of documented cystitis when no other antibiotics can be prescribed due to its pulmonary and hepatic effects. It should not be used in men and for prophylactic treatments. A study made on social security data shows that 60% of the prescriptions are not in line with the Marketing Authorisation. The product information has been revised to promote safe use.

→ Link to ANSM website (in French)

2.9 Sumatriptan (Zecuity) FDA investigating risks of serious burns and potential permanent scarring (02-Jun-2016) The FDA has announced that it is investigating the risk of serious burns and potential permanent scarring with the use of Zecuity (sumatriptan iontophoretic transdermal system) patch for migraine headaches. Since marketing of the Zecuity patch began in September 2015, a large number of patients have reported they experienced burns or scars on the skin where the patch was worn. As a result, the FDA is investigating these adverse events to determine whether future regulatory action is needed.

→ Link to FDA MedWatch alert

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3. DEAR DOCTOR LETTERS AND SAFETY NEWSLETTERS

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

• Ketoconazole (topic): modifications of the SmPC (use in children limited, warnings and side-effects)

→ Link to ANSM Page (in French)

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

• Canagliflozin-containing medicines (Invokana▼, Vokanamet▼): risk of lower limb amputation • BCR-ABL tyrosine kinase inhibitors (imatinib▼, dasatinib, nilotinib, bosutinib▼, ponatinib▼): risk of

hepatitis B reactivation • Pomalidomide (Imnovid▼): risk of hepatitis B reactivation • Retigabine (Trobalt): risk of acquired vitelliform maculopathy

→ Link to MHRA Page

3.3 New issue of MHRA “Drug Safety Update” The May issue of Drug Safety Update was published on 10-May-2016. It includes the following topics:

• BCR-ABL tyrosine kinase inhibitors: risk of hepatitis B reactivation • Pomalidomide (Imnovid▼): risk of hepatitis B reactivation • Idelalisib (Zydelig▼): interim measures following signal of serious infections and deaths due to infection

→ Link to Drug Safety Update (May)

3.4 New issues of Canadian “Health Product InfoWatch” The new issue of “Health Product InfoWatch” has been published, which provides an overview of health product advisories and safety reviews published in the previous month by Health Canada. The May issue was published on 26-May-2016 and includes a Vaccine Safety Review summarizing reports received by the Canada Vigilance Program between 01-Jul-2015 and 30-Sep-2015. The monthly recap covers several medicinal products including Celebrex (celecoxib), Perjeta (pertuzumab), Uloric (febuxostat) and Yervoy (ipilimumab).

→ 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 7, Number 3, June 2016). The contents include:

• Bromhexine-containing cough and cold medicines – risk of allergy and skin reactions • Lercanidipine – cloudy peritoneal effluent in patients on peritoneal dialysis • Marcain Spinal 0.5% Heavy – reports of failed or incomplete spinal anaesthesia

→ Link to Medicines Safety Update

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3.6 New FDA Drug Safety Podcasts The FDA Drug Safety Podcasts provide emerging safety information about drugs in conjunction with the release of Public Health Advisories and other drug safety issues. Both Podcasts and Transcripts are posted on the FDA website and the following communications have been recently added:

• FDA warns about new impulse-control problems associated with mental health drug aripiprazole (Abilify, Abilify Maintena, Aristada)

• FDA warns about rare but serious skin reactions with mental health drug olanzapine (Zyprexa, Zyprexa Zydis, Zyprexa Relprevv, and Symbyax)

• FDA advises restricting fluoroquinolone antibiotic use for certain uncomplicated infections; warns about disabling side effects that can occur together

• Interim clinical trial results find increased risk of leg and foot amputations, mostly affecting the toes, with the diabetes medicine canagliflozin (Invokana, Invokamet); FDA to investigate

• FDA warns that prescribing of Nizoral (ketoconazole) oral tablets for unapproved uses including skin and nail infections continues; linked to patient death

→ Link to FDA Page

4. OTHER PUBLICATIONS BY REGULATORY AGENCIES

4.1 US Food and Drug Administration (FDA)

4.1.1 FDA to hold OpenFDA Public Workshop The FDA has just announced a public workshop on OpenFDA, which was launched in June 2014 to facilitate access to large public health datasets collected by the agency for web developers, researchers, and the public.

The FDA decided to begin with an initial pilot program involving the millions of reports of drug adverse events and medication errors submitted to the FDA in order to support the development of software to help signal potential safety information.

The purpose of the workshop is to engage in a discussion with the user community regarding the openFDA platform, application programming interfaces (APIs), downloadable datasets, and possible enhancements. It will also include demonstration of various applications developed for utilization of openFDA data.

This public workshop will be held at the FDA White Oak campus in Silver Spring MD, USA on 20-Jun-2016, and interested parties can also register to attend via Webcast.

→ Link to Federal Register Notice

4.1.2 Drug Safety and Risk Management Advisory Committee: New material available The Drug Safety and Risk Management Advisory Committee met on 03 and 04-May-2016 in a Joint Meeting with the Anesthetic and Analgesic Drug Products Advisory Committee Meeting to discuss the results from assessments of the extended-release and long-acting Opioid Analgesics REMS. The same committees met again on 05-May-2016 to discuss a NDA for benzhydrocodone/acetaminophen oral tablets, submitted by KemPharm for short-term management of acute pain, and which has been formulated with the intent to provide abuse-deterrent properties.

The webcasts of both meetings are now available on the FDA website in addition to other meeting material, including slides and final questions. Minutes are also available for the May 05 Meeting.

→ Link to FDA Page

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4.1.3 FDA issues material from Workshop on Drug Safety during Lactation As reported prior to the meeting, the FDA held a public workshop entitled “Evaluation of the Safety of Drugs and Biological Products used during Lactation” on 27 and 28-Apr-2016.

The purpose of this workshop was to discuss approaches to the collection of data on the potential risks when drugs are used or expected to be used during lactation. The workshop also included discussions about novel approaches to improve the quality and quantity of data and to communicate safety information related to maternal use of medications during lactation.

The webcast of this meeting is now available on the FDA website in addition to presentation slides.

→ Link to FDA Event Page

4.1.4 Pediatric Advisory Committee: New material available The Pediatric Advisory Committee met on 12-Apr-2016 to discuss pediatric-focused safety reviews for a group of 13 products, which included several Influenza Virus Vaccines, rabeprazole and fluoxetine amongst others. In addition to the presentations and briefing material previously released by the FDA, the minutes of the meeting have now been published on the FDA website.

→ Link to FDA Page

4.1.5 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 21-Jan-2016 and was updated on Drug Safety Communications issued since the previous meeting in September 2015. In addition, the board heard presentations on the evolving Risk/Benefit concerns associated to Fluoroquinolones and on the impact of Statins on Influenza Vaccine effectiveness.

→ Link to DSOB Public Summary

4.2 European Medicines Agency (EMA)

4.2.1 EMA to hold workshop on measuring the impact of pharmacovigilance activities As reported in our previous issue, the PRAC committee adopted a strategy for measuring the impact of pharmacovigilance activities and the EMA is now calling for expressions of interest in an associated workshop. Requests to participate should be communicated to the Agency by 30-Sep-2016.

→ Link to call for expressions of interest → Link to PRAC Strategy Document

4.2.2 EMA issues new EudraVigilance support guide As reported at the time, the EMA launched an online EMA Service Desk portal in February 2016, which should be used to report an issue, request a service or ask a question about EMA systems in replacement of previously existing functional mailboxes.

The EMA has now published a new EudraVigilance support guide to clarify where queries should be directed depending on their nature. In particular, Pharmacovigilance questions should be directed to the “Ask EMA” service and EudraVigilance registration questions should go to the dedicated email address. Users are therefore not supposed to use the EMA Service Desk portal for this type of enquiries.

→ Link to EMA EudraVigilance Page → Direct link to EudraVigilance support guide

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

→ Link to EMA PRAC Page

The minutes of the April PRAC meeting were published on 02-Jun-2016. The PRAC started a review of the diabetes medicine canagliflozin after an increase in amputations mostly affecting toes was observed in an ongoing clinical trial. The PRAC also extended the scope of its ongoing safety review of direct-acting antivirals used for treating chronic hepatitis C to also assess the risk of liver cancer, in addition to the risk of hepatitis B re-activation. In addition, the following new Safety Signals were discussed:

• Adalimumab – acute febrile neutrophilic dermatosis (Sweet's syndrome) • Agomelatine – urinary retention and leukopenia • Cobicistat-containing products – drug interaction with corticosteroids leading to adrenal suppression • Iomeprol – haemolysis • Fulvestrant – interference with oestradiol assay leading to false oestradiol results

→ Direct link to PRAC Meeting Minutes (11 to 14-Apr-2016)

The agenda and highlights of the May PRAC meeting were published on 13-May-2016. As reported separately (see section 2), the PRAC adopted a summary report following the review of the risk of inhibitor development in severe haemophilia patients receiving recombinant factor VIII products. The PRAC agreed that overall, the available evidence does not confirm that Kogenate Bayer/Helixate NexGen is associated with an increased risk of factor VIII inhibitors, which is consistent with the previous conclusions of the 2013 review.

According to the agenda, the following new Safety Signals have also been identified and discussed:

• Anakinra; canakinumab – weight increase • Metronidazole – severe hepatic and neurologic toxicity in patients with Cockayne syndrome • Regorafenib – angioedema • Vedolizumab – hepatotoxicity • Dexlansoprazole; lansoprazole – unexpected histopathological findings from a juvenile rat toxicity study • Fluconazole – spontaneous abortion during pregnancy and stillbirth • Fluoroquinolones – aortic aneurysm and dissection

→ Direct link to PRAC Meeting Highlights (10 to 13-May-2016)

4.2.4 PRAC recommendations on Safety Signals The EMA routinely issues the PRAC recommendations resulting from the assessment of safety signals. MAHs are legally obliged to monitor this information to keep informed about the PRAC recommendations concerning their products, which may require the submission of a Safety Variation.

The list of signals discussed at the April PRAC meeting was published on 10-May-2016 and includes recommendations to update the product information for the following combination of Product / Signal:

• Olanzapine – Drug reaction with eosinophilia and systemic symptoms (DRESS)

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

The “Meeting Highlights” are presented in a tabular format, which allows users to view the main opinions adopted at the meeting, including on safety variations/PSURs.

→ Link to CHMP Meeting Highlights (23 to 26-May-2016)

4.2.6 EMA issues updated EURD list The EMA has published an updated EURD list, which was last revised on 03-May-2016 following the previous revision of 23-May-2016. It provides the EU Reference Dates, frequencies for submission of PSURs and related data lock points for a list of active substances and combinations including those contained exclusively in nationally authorised medicines.

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

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

4.2.7 EMA 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 7 new products have been added to the list in May 2016, as identified in the Summary of Changes presented on the EMA webpage.

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

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

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

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

• Everolimus • Chloroquine • Thiocolchicoside

→ Link to PSUR Single Assessments Outcomes 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.

Summaries of PSUR Assessment Reports have been published for the following products on 16-May-2016: carboplatin and ethinylestradiol/levonorgestrel.

→ Link to Summaries of Assessment Reports

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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 the educational brochure for healthcare professionals and the diary for patients using Uptravi (selexipag), which is used to treat adults with pulmonary arterial hypertension (PAH).

→ Link to EMA Recommendations on medication errors

4.2.11 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 an update to the list that presents safety concerns of approved Risk Management Plans (RMPs) per product/active substance, which was first published in April 2015. The lack of publicly available information on approved RMPs is a significant challenge for generic products if no information is available on the safety concerns for the reference product and this has resulted in inconsistencies between separate RMPs for the same active substance.

The purpose of this list is to support the harmonisation of RMPs for 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 where the safety concerns are specified.

→ Link to CMDh Page

4.2.12 Industry stakeholder platform on the operation of EU PV legislation As reported earlier, the EMA hosted the Seventh industry stakeholder platform on the operation of European Union pharmacovigilance legislation on 04-Apr-2016.

Discussion included a roadmap for PSURs, scientific advice for post-authorisation studies and signal management. In addition, to the agenda and presentations released earlier, the EMA has now published the highlights from this meeting.

→ Link to EMA Meeting Page

4.2.13 EMA publishes 2015 annual report The EMA has published its 2015 annual report, which describes the Agency’s key activities and achievements last year with more than 1.2 million ADR reports recorded in EudraVigilance, an increase of 8.5%. Over 48,000 reports originated from patients in the European Economic Area, a 30% rise showing that patients increasingly make use of the opportunity to directly report side effects.

EMA’s annual report highlights some of the main projects, initiatives and achievements in 2015 that have had a significant impact on the way the Agency operates, including a range of activities to strengthen the safety monitoring of medicines.

The report also contains interviews with stakeholders and EMA representatives on topics of major interest in the area of medicines and health in 2015, including the use of big data in healthcare.

→ Link to EMA News Release

4.2.14 EMA provides guidance on accessing key information on human medicines The EMA has published a new guide that describes information the Agency publishes on centrally and non-centrally authorised medicines for human use. It provides an overview of the range of documents produced by EMA during the life span of a medicine, including post-authorisation changes and safety reviews.

Details of types of EMA documents, their publication times and where to find them on the EMA’s website are listed in an easy-reference annex, including PSURs, Safety Signals, etc.

→ Link to EMA News Release

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4.3 UK Agency (MHRA) No relevant announcement was identified in the period covered by this issue.

4.4 French Agency (ANSM)

4.4.1 ANSM provides updated data on Benfluorex pharmacovigilance monitoring The French Agency has issued the results of a global retrospective study and the results of a new inquiry, which confirm the previous signals of valvulopathies and pulmonary hypertensions and show that Benfluorex is a possible but rare cause of pleural fibrosis. It is not recommended to systematically screen for pleural fibrosis but it should be considered in patients with respiratory problems.

The anti-diabetic drug is suspected to have caused up to 2,000 deaths due to cardiac valvulopathies until it was withdrawn at the end of 2009.

→ Link to the ANSM webpage (in French)

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

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

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

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

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

→ Link to ANSM release – May 2016 PRAC (in French)

4.4.3 Commissions/Committees in relation with Pharmacovigilance The Pharmacovigilance Committee has issued the minutes of the meeting of 17-Nov-2015 where the following topics were discussed:

• Benfluorex: the national monitoring will be closed for valvulopathies and pleural fibrosis and continued for pulmonary hypertension

• HPV vaccines: no new signal, continuation of the national monitoring • Brentuximab, adalimumab: transmission of signals to EMA and Member States.

→ Link to ANSM PV Committee minutes – 17-Nov-2015 (in French)

The Pharmacovigilance Committee has issued the minutes of the meeting of 15-Dec-2015 where the following topics were discussed:

• Baclofen and off-label use: national monitoring to be continued • Nalmefene: information of health professionals, monitoring continuation • ARBs: national enquiry to be closed and modification of SmPC

→ Link to ANSM PV Committee minutes – 15-Dec-2015 (in French)

4.4.4 ANSM issues reminder on responsibilities of the “Pharmacien Responsable” The letter is co-signed with the French Chamber of Pharmacists (Ordre des Pharmaciens) and reminds about the responsibilities of the Chief Pharmaceutical Officer (Pharmacien Responsable) in a pharmaceutical company, insisting on his/her actual capacity to fully exercise this responsibility. It is important to note that the organisation of pharmacovigilance is one of the mission of the Chief Pharmaceutical Officer.

→ Link to the ANSM Letter (in English)

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5. QUALITY ASSURANCE, INSPECTIONS AND AUDITS

5.1 MHRA issues new GCP Stakeholder Engagement Meeting minutes The MHRA GCP Stakeholder Engagement Meeting (StEM) now meets on an annual basis to provide a forum for discussion between the MHRA GCP inspectorate and represented stakeholders on key topics related to the conduct of clinical trials. The Minutes of the March 2016 meeting have now been published, which included discussions regarding the GCP inspection programme in the context of the implementation of the Clinical Trial regulation. It also included a presentation and Q&A session on Reference Safety Information (RSI) and common inspection findings. The presentations used at the meeting have been made available by EFGCP, who participated in the meeting.

→ Link to MHRA GCP StEM Minutes (March 2016) → Link to MHRA GCP StEM Presentations (EFGCP)

6. DRUG SAFETY AND LIABILITY RISK

6.1 Hepatitis B Vaccine Hospital sentenced to indemnify a nursing auxiliary for her myofasciitis The plaintiff was vaccinated in the framework of her professional activities and developed a muscular disease following vaccination. The court recognized a link between the vaccine and her pathology whereas another judgement dismissed the alleged link between Hepatitis B Vaccines and multiple sclerosis.

→ Link to JIM.fr article (in French)

7. OTHER NEWS AND RESOURCES

7.1 Investigation of death during Phase 1 Clinical Trial in France Following the death of one volunteer and the hospitalisation of five others in a phase 1 clinical trial on an endogenous neurotransmitter (Fatty Acid Amide Hydrolase) sponsored by the Portuguese drugmaker Bial, the French General Inspection of Social Affairs has now issued the results of its investigations including the responses / comments of the organisations involved. The report confirms the responsibility of the drugmaker Bial and the Phase 1 Center, Biotrial and includes a list of 19 recommendations, which have been endorsed by the Health Ministry to propose an action plan in 4 areas:

• An action plan is requested from the CRO BIOTRIAL, whose authorisation to conduct clinical research may be suspended

• The medical files of the 90 volunteers will be reviewed by independent experts and will be transmitted to a European Group of Experts

• The conditions of authorisation for first in men studies will be reinforced • France will support the improvement of European legislation applicable to Phase 1 studies

→ Link to an article of In-Pharma (in English) → Link to the French Health Ministry Press Release (in French) → Link to IGAS final Report with answers from the involved structures (in French)

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7.2 Eu2P Education & Training: Applications now open for 2015-2016 As part of the European Innovative Medicines Initiative (IMI), the Education & Training project Eu2P project runs numerous courses covering various aspects of medicines research and development, including pharmacovigilance. The courses range from short online courses to full Master’s programmes.

The project has released a guide that provides students with a simple overview of the types of courses available, the workload involved, and the certificates offered upon completion of the course. Applications for the short online courses are always open. The deadline for applications for the next intake of Masters students is 26-Jun-2016, and the next deadlines for applying for the shorter certificates are in early September.

→ Link to Eu2P guide

7.3 WEB-RADR launches Croatian version of side effect reporting app As mentioned previously, the WEB-RADR project included activities to explore the use of mobile technologies and social media in pharmacovigilance, which project the MHRA has been appointed to lead as part of the European Innovative Medicines Initiative (IMI).

Following the UK and the Netherlands, Croatia has now become the third country in Europe to benefit from the WEB-RADR mobile app for reporting suspected adverse drug reactions.

→ Link to HALMED Press Release

7.4 New issue of Uppsala Reports Uppsala Reports 72 – April 2016 is now available. After several months of absence, the publication has undergone an intensive revamp. The latest edition contains a wide range of news from around the world of pharmacovigilance, including regional initiatives from all corners of the globe. It also includes a review of current trends in adverse drug reaction reporting and features the recent UMC research paper “Quantitative benefit–risk assessment of methylprednisolone in multiple sclerosis relapses”.

→ Link to Uppsala Reports

8. CONFERENCES AND TRAINING EVENTS

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

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

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

June 21 in London, UK

→ Information Day on Medication Errors October 20 in London, UK

DSRU Events → Medical Aspects of Adverse Drug Reactions

June 22 – 24 in Southampton, UK → Back to Basics in Pharmacovigilance

September 07 – 08 in Fareham, UK

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DIA Events → Medical Approach in Diagnosis and Management of ADRs

June 13 – 14 in London, UK → Post-Authorisation Studies (PAS)

June 13 – 14 in London, UK → Diagnosis and Management of DILI: Clinical Trials and Post-Marketing

June 14 – 15 in London, UK → Signal Management in Pharmacovigilance

June 14 – 15 in London, UK → 10th Annual Forum for Qualified Persons in Pharmacovigilance (QPPV)

October 05 – 06 in London, UK

Other Events → Recunnect – 2nd Pharmacovigilance 2016

June 14 – 15 in London, UK → Management Forum – Pharmacovigilance

June 20 – 22 in London, UK → IFIS – Pharmacovigilance Mission and Responsibilities of the Qualified Pharmacist (event in French)

June 21 in Paris, France → IFIS – Rencontre 2016 avec l'ANSM (event in French)

June 23 in Paris, France → RQA – Practical Pharmacovigilance Auditing

June 28 – 30 in Cambridge, UK → ISPE – 32nd International Conference on Pharmacoepidemiology & Therapeutic Risk Management

August 25 – 28 in Dublin, Ireland → Healthnetwork – World Drug Safety Congress Europe 2016

September 14 – 15 in Munich, Germany → RQA – Systems Approach to Good Pharmacovigilance Practice (GPvP)

September 20 – 22 in Cambridge, UK → Allan Lloyds – 3rd Annual Pharmacovigilance Summit

September 27 – 29 in Vienna, Austria

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