Safety Observer N°96 – December 2013 page 1/21
Safety Observer
Clinical Safety & Pharmacovigilance
Intelligence Review
Issue N°96 – December 2013
Highlights
The EMA has issued Revision 8 of the interim ICSRs reporting requirements in Europe.
The FDA has issued a proposed rule to align the process for safety label changes for
both originator and generic drug products in the USA, which would close the current
regulatory loophole protecting generic drugmakers from injury lawsuits.
Following the decision to suspend the sales and marketing of Iclusig in the USA, the
EMA has announced that it is performing an in-depth review of the risks and benefits of
the leukaemia medicine. It remains authorized in Europe in a narrow indication while the
FDA has announced measures to allow treatment continuation in the USA.
The FDA has reached a landmark decision and followed the recommendation of Advisory
Committees to lift the restrictions on Avandia more than 3 years after severe regulatory
action was taken around the world to limit the use of the diabetes blockbuster due to
cardiovascular safety concerns.
The EMA has provided an update on the infringement procedure following the Roche
Pharmacovigilance Inspection by the MHRA, where the Agency announced that the
alleged non-compliance had no effect on the benefit-risk balance of the medicines.
PROTECT has now published a report containing recommendations for the methodology
and visualisation techniques used for benefit-risk assessment of medicines.
Registration is now open for the 2014 MHRA Pharmacovigilance Inspections
Symposium, which will take place on 14-Mar-2014.
Safety Observer N°96 – December 2013 page 2/21
In this issue
1. Regulatory Update .................................................................................................................... 3
1.1. Applicable Regulations, Guidelines and other Standards ............................................................ 3 1.1.1. EMA issues updated interim ICSRs reporting requirements .......................................................... 3 1.1.2. New EU Guidance for Non-eCTD electronic Submissions (NeeS) .................................................... 3 1.1.3. EMA updates EURD list and interim PSUR submission requirements ............................................. 3 1.1.4. CMDh updates information on PSUR Submission for NAPs ........................................................... 3
1.2. Developments to watch ............................................................................................................ 4 1.2.1. Europe makes progress in reform of data protection legislation .................................................... 4 1.2.2. FDA Proposed Rule to change responsibilities for generics safety labels ....................................... 4 1.2.3. FDA plans guidance on meta-analyses for safety risks evaluation .................................................. 5 1.2.4. Europe launches new project for benefit-risk monitoring of vaccines .............................................. 5 1.2.5. EMA to prepare guidance on Post-Authorisation Efficacy Studies ................................................... 5 1.2.6. Update from ICH November 2013 Meetings in Osaka, Japan ........................................................ 5
1.3. Beyond the borders of Safety Observer ...................................................................................... 6 1.3.1. German BfArM issues updated PSUR submission form ................................................................ 6 1.3.2. Australia to accept E2B submissions .......................................................................................... 6
1.4. The Safety Observer Tracker ..................................................................................................... 6
2. Safety Update .......................................................................................................................... 7
2.1. Ponatinib (Iclusig®).................................................................................................................. 7
2.2. Diacerein-containing medicines ................................................................................................. 8
2.3. Acipimox-containing medicines ................................................................................................. 8
2.4. OTC Topical Antiseptic Products ............................................................................................... 8
2.5. Regadenoson (Lexiscan®) and adenosine (Adenoscan®) ........................................................... 8
2.6. Combined Hormonal Contraceptives (CHCs) .............................................................................. 8
2.7. Thiocolchicoside-containing medicines ...................................................................................... 9
2.8. Rosiglitazone (Avandia®, combined products and generics) ....................................................... 9
2.9. Vitamin D and Vitamin ADEC (Uvesterol®) ................................................................................. 9
2.10. Clobazam (Onfi®) ................................................................................................................... 10
2.11. Recombinant factor VIII (Kogenate® or Helixate NexGen®) ..................................................... 10
3. Quality Assurance, Inspections and Audits .............................................................................. 10
3.1. MHRA Pharmacovigilance Inspections Symposium 2014 – Register Now ! ................................ 10
3.2. EMA provides update on impact of Roche Pharmacovigilance Inspection .................................. 10
3.3. New MHRA risk-based inspections questionnaire expected in December .................................. 11
4. Drug Safety and Business Risk................................................................................................ 11
5. Other relevant Information and Resources ............................................................................... 12
5.1. US Food and Drug Administration (FDA) .................................................................................. 12
5.2. European Medicines Agency (EMA) ......................................................................................... 13
5.3. UK Agency (MHRA) ................................................................................................................ 15
5.4. French Agency (ANSM)........................................................................................................... 16
5.5. Other Sources ........................................................................................................................ 18
6. Time to Register ..................................................................................................................... 20
7. About the Authors .................................................................................................................. 21
Safety Observer N°96 – December 2013 page 3/21
1. Regulatory Update
1.1. Applicable Regulations, Guidelines and other Standards
1.1.1. EMA issues updated interim ICSRs reporting requirements (08-Nov-2013)
The Agency has updated the document describing the transitional reporting requirements
for individual case safety reports (ICSRs) applicable to MAHs during the interim period.
The current revision (Rev. 8) clarifies that the requirement for the reporting of non-serious
EU ICSRs in Italy does not apply to literature cases. It also clarifies that the reporting of
non-EU ICSRs in the UK only applies to serious cases confirmed by a healthcare
professional.
Link to EMA Page
Direct Link to ICSRs Reporting Requirements (EMA/321386/2012 Rev. 8)
1.1.2. New EU Guidance for Non-eCTD electronic Submissions (NeeS) (11-Nov-2013)
A revised Technical Guidance document has been issued by the European Telematics
Implementation Group for electronic submission and ICH Implementation (TIGes). The
associated Release Notes highlight the changes made in the new version.
This guidance is not applicable to the centralised procedure but it applies to all other
submissions including PSURs. The EMA eSubmission Gateway/Web Client should be
used for submissions to the EMA in the PSUR Single Assessment (PSUSA) procedure of
Nationally Authorised Products.
Link to Nees Guidance Document
Link to Release Notes
1.1.3. EMA updates EURD list and interim PSUR submission requirements (29-Nov-2013)
A new update of the EURD list was published on 29-Nov-2013, which provides the
European Union Reference Dates, frequencies for submission of PSURs and related data
lock points for a list of active substances and combinations. The changes to the EURD
list are highlighted and include 29 new products and 6 amendments.
The guidance document describing National Competent Authorities (NCAs) and European
Medicines Agency (EMA) requirements for PSUR submission during the transitional
period has also been revised to make a correction regarding the submission of PSURs
to the PRAC for NAPs subject to an EU single assessment.
Link to EMA Guidance Page (EURD list and PSUR Submission)
1.1.4. CMDh updates information on PSUR Submission for NAPs (04-Dec-2013)
The European CMDh (Co-ordination Group for Mutual Recognition and Decentralised
Procedures – Human) has issued an updated “List of substances under PSUR Work
Sharing scheme and other substances contained in Nationally Authorised Products with
DLP synchronised”. This list contains substances and combinations that have been
removed from the EURD list until they follow the EU single assessment procedure of
PSURs. The list is provided in pdf and Excel format, where all changes since the previous
publication are highlighted.
Safety Observer N°96 – December 2013 page 4/21
The Best Practice Guide for PSUR Work Sharing during the transition period has also
been updated, which describes the Assessment Procedure and includes the associated
templates.
In addition, the CMDh has set up a new page where Summaries of PSUR Assessment
Reports are posted. The summaries for 5 products are now available (Alprostadil,
Ciclosporin, Dexketoprofen, Econazole and Ketoprofen for topical use).
Link to HMA Page
Direct link to list (pdf)
Link to Summaries of Assessment Reports
1.2. Developments to watch
1.2.1. Europe makes progress in reform of data protection legislation (22-Oct-2013)
An important step has been reached with the endorsement of the European
Commission's data protection reform proposals by a European Parliament Committee.
The European Commission's data protection reform is intended to establish a single
European law for data protection to replace the current patchwork of national laws, with
a single supervisory authority.
The reform will now be discussed by the European Council and President Barroso called
for a swift adoption of the data protection reform before the end of this parliamentary
term in May 2014.
Link to EC Memo
1.2.2. FDA Proposed Rule to change responsibilities for generics safety labels (08-Nov-2013)
The FDA has announced a proposed rule to speed up the dissemination of new safety
information about generic drugs by allowing generic drug makers to use the same
process as originators to update safety information in the product labeling.
Under the proposal, generic manufacturers would also be required to inform the brand
name manufacturer about the change. The FDA would evaluate the proposed change
and make a decision applicable to both generic and brand drug. The FDA also plans to
create a web page where safety-related changes proposed by all drug manufacturers
would be posted while the FDA is reviewing the change.
The FDA is expecting comments on the proposed rule by 13-Jan-2014.
This new proposed rule would make generic manufacturers responsible for their product
label, thus closing a regulatory loophole currently protecting these companies from injury
lawsuits. Critics are arguing this could drive up the cost of generic drugs.
Link to FDA News Release
Link to Federal Register Notice
Direct Link to Proposed Rule
Link to PharmaTimes article
Link to The New York Times article
Safety Observer N°96 – December 2013 page 5/21
1.2.3. FDA plans guidance on meta-analyses for safety risks evaluation (25-Nov-2013)
The FDA held a public meeting on 25-Nov-2013 to obtain input on scientific approaches
for the conduct and assessment of meta-analyses of randomized controlled clinical trials
(RCTs) to evaluate safety risks associated with the use of human drugs or biological
products within the framework of regulatory decision-making. The FDA was also calling
for comments on a white paper it published to facilitate the discussion at the meeting,
which can still be submitted until 16-Dec-2013.
The input from the meeting will be used to develop a draft guidance that describes best
practices for the conduct of meta-analyses and FDA’s intended approach for the use of
meta- analyses in regulatory decision-making.
Links to the recorded Webcast from the meeting are available on the Event Page.
Link to Event Page
Link to Federal Register Notice
Direct link to FDA White Paper
1.2.4. Europe launches new project for benefit-risk monitoring of vaccines (26-Nov-2013)
The EMA has engaged with other organisations in a new project intended to deliver a
pan-European framework for the monitoring the benefits and risks of vaccines.
The five-year project, called accelerated development of vaccine benefit-risk
collaboration in Europe (ADVANCE), brings together various stakeholders including the
EMA and the European Centre for Disease Prevention and Control (ECDC). The goal of
ADVANCE is to support the ultimate delivery of data for the assessment of the benefits
and risks of vaccines in Europe.
Link to EMA News Release
1.2.5. EMA to prepare guidance on Post-Authorisation Efficacy Studies (27-Nov-2013)
The EMA held a two-day workshop on 24 and 25-Oct-2013 to discuss “methods for
efficacy studies in everyday medical practice”, which is the first step in the development
of guidance on post-authorisation efficacy studies (PAESs) as defined in the new
pharmacovigilance legislation. The highlights from this workshop are now available and
provide a summary of the discussions on the main topics: pragmatic trials, observational
studies, registries, the use of electronic health records and methods to control for
confounding.
Link to EMA Event Page
1.2.6. Update from ICH November 2013 Meetings in Osaka, Japan (02-Dec-2013)
The ICH Steering Committee (SC) continued discussions previously engaged regarding
governance and agreed on organisational reform to foster international cooperation. In
addition, the SC agreed to develop a 5-year plan for future ICH work and reviewed
proposals for new topics, which included further harmonisation on requirements for
clinical trials.
The E2C(R2) IWG has made progress on the planned Questions and Answers (Q&As)
Document regarding the implementation and technical maintenance of the “Periodic
Benefit-Risk Evaluation Report”, which should reach Step 4 by the end of 2013.
Safety Observer N°96 – December 2013 page 6/21
ICH has decided that a new Call for Tender should be undertaken for the maintenance
and support of MedDRA, which is currently contracted to the Maintenance and Support
Services Organisation (MSSO). ICH will issue a Call for Expression of Interest in early
2014, in order to identify interest from potential service providers.
The next round of meetings will take place in May 2014 in Minneapolis MN, USA.
Link to ICH Press Release
Link to MedDRA Press Release
1.3. Beyond the borders of Safety Observer
1.3.1. German BfArM issues updated PSUR submission form (05-Nov-2013)
The BfArM has updated its template of PSUR submission form, which is available in
English only. The PSUR FAQs have been updated accordingly.
Link to BfArM Announcement (in German)
Link to BfArM PSUR FAQs (in German)
Link to BfArM PSUR FAQs (in English)
1.3.2. Australia to accept E2B submissions (12-Nov-2013)
The Australian TGA has announced that MAHs will now be able to submit ADR reports in
E2B format by email, which can be uploaded to the TGA database. A dedicated email
address has been established for this purpose. It is however important to note that the
current submission methods will continue to be available.
The TGA Pharmacovigilance guidance page has been updated accordingly.
Link to TGA Announcement
Link to TGA Pharmacovigilance guidance page
1.4. The Safety Observer Tracker
This section includes a cumulative list of the future deadlines for implementation and
end of consultation periods, which are associated to the most important announcements
made in the current and previous issues of Safety Observer. For your convenience, a link
to the main sources is provided and we also specify the issue where the corresponding
article can be found.
By When ? What ? Issue
31-Dec-2013 Deadline to implement inverted equilateral triangle (▼) for
products subject to additional monitoring approved in the
EU before 01-Sep-2013 (Link)
89
13-Jan-2014 FDA consultation on Proposed Rule for generics safety
label changes (Link)
96
Safety Observer N°96 – December 2013 page 7/21
2. Safety Update
2.1. Ponatinib (Iclusig® )
FDA takes measures to allow treatment continuation (07-Nov-2013)
Following the October announcement that Iclusig sales and marketing will be suspended
in the USA, the FDA has issued an update to provide instructions for health care
professionals about how to avoid treatment interruptions in patients who are benefiting
from this leukemia treatment. After careful consideration of the risk of vascular occlusive
events, Iclusig treatment may be continued for appropriate patients under an emergency
Investigational New Drug (IND) application.
Link to FDA Drug Safety Communication
PRAC requests strengthened warnings on vascular occlusive risks (08-Nov-2013)
The PRAC reviewed the information on the cancer medicine Iclusig and the frequency of
vascular occlusive events, which is higher than initially observed when the marketing
authorisation was granted in July 2013.
Conditions related to thrombosis are known side effects of Iclusig, which are mentioned
in the current product information. The PRAC advised that the product may continue to
be used with increased caution in the EU where it is only approved in patients who had
no other available treatment options with medicines of this class. The product
information should however be updated to include strengthened warnings on the
cardiovascular risk and associated guidance.
Link to EMA Press Release
CHMP makes recommendations to minimise the risk of blood clots (22-Nov-2013)
In line with the PRAC recommendation, the EMA’s CHMP has advised that Iclusig should
not be used in patients who have had a heart attack or stroke in the past, unless the
potential benefits to them outweigh the risks. In addition, measures should be taken to
reduce cardiovascular risks before and during treatment.
As recommended by the PRAC, the EMA now plans to conduct an in-depth review of the
benefit-risk profile for this medicine, which has been suspended in the USA.
Link to EMA Press Release
The MHRA has issued a corresponding statement.
Link to MHRA Press Statement
EMA requested to initiate in-depth review of benefits and risks (06-Dec-2013)
The EMA has now started an in-depth review of the benefits of the leukaemia medicine
in light of the risk of blood clots or blockages in the arteries or veins.
The Agency has recommended a number of measures to help minimise this risk but a
number of issues require further investigation to gain a better understanding of the
issue, the potential mechanism involved and the possible need to revise dosing
recommendation. The European Commission has therefore requested the EMA to review
all relevant data and assess the need for further changes.
Link to EMA Press Release
Safety Observer N°96 – December 2013 page 8/21
2.2. Diacerein-containing medicines
PRAC recommends suspension due to safety concerns (08-Nov-2013)
The PRAC recommendation follows a review initiated by France which concluded that the
limited benefits of diacerein in the treatment of osteoarthritis and degenerative joint
diseases did not outweigh the risk of severe diarrhoea and liver toxicity.
The PRAC recommendation will be considered at the December CMDh meeting.
Link to EMA Press Release
2.3. Acipimox -containing medicines
PRAC recommends restrictions to optimise benefit-risk (08-Nov-2013)
The PRAC has recommended that medicines containing acipimox should have their
authorisations amended so that they are used only as an additional or alternative
treatment in type IIb and type IV hyperlipoproteinaemia. The PRAC also recommended
expanding the warnings concerning a possible increased risk of painful muscle damage
when acipimox is used together with a statin.
The review follows the publication of the results of a large study, which already led the
EMA to suspend medicines containing the combination of nicotinic acid and laropiprant
in January 2013. As a related substance, the benefit-risk balance of Acipimox was
reviewed in the light of the latest evidence.
The PRAC recommendation will be considered at the December CMDh meeting.
Link to EMA Press Release
2.4. OTC Topical Antiseptic Products
FDA requests changes to decrease Risk of Infection (13-Nov-2013)
The FDA has requested label and packaging changes to promote the safe use of certain
OTC topical antiseptic products. In particular, the FDA is requesting that manufacturers
package antiseptics indicated for preoperative or preinjection skin preparation in single-
use containers. This follows continuing reports of infections resulting from antiseptic
products after contamination by users, which included several serious and fatal reports.
Link to FDA MedWatch alert
2.5. Regadenoson (Lex iscan® ) and adenosine (Adenoscan® )
FDA warns about rare but Serious Risk of Heart Attack and Death (20-Nov-2013)
The FDA has issued a warning about the rare but serious risk of heart attack and death
associated with the use of the cardiac nuclear stress test agents Lexiscan and
Adenoscan. The drug labels will be updated accordingly with updated advice.
Link to FDA MedWatch alert
2.6. Combined Hormonal Contraceptives (CHCs)
Benefits outweigh risks – CHMP endorses PRAC recommendation (22-Nov-2013)
The EMA has now completed its review of combined hormonal contraceptives (CHCs)
and the risk of venous thromboembolism, which was initiated by France. The EMA
concluded that the benefits of CHCs continue to outweigh risks, and that the well-known
risk of VTE with all CHCs is small.
Safety Observer N°96 – December 2013 page 9/21
In agreement with the October 2013 PRAC recommendation, the Product information
should however be updated to help women make informed decisions about their choice
of contraception. The CHMP opinion will now be sent to the European Commission for a
legally binding decision.
Link to EMA Press Release
Link to EMA CHC Page
The MHRA has issued a corresponding statement.
Link to MHRA Press Statement
2.7. Thiocolchicoside-containing medicines
EMA recommends restrictions applicable to oral and injection forms (22-Nov-2013)
Following a review initiated by Italy, the EMA’s CHMP has recommended that the
authorised uses for thiocolchicoside-containing medicines by mouth or injection should
only be used as an add-on treatment for painful muscle contractures resulting from
spinal conditions in adults and adolescents 16 years of age or older. In addition, the
dose of thiocolchicoside by mouth or injection should be restricted and use is contra-
indicated in pregnancy and lactation or in women of childbearing potential not using
contraception.
Preparations for local application to the skin are not affected by this review.
Link to EMA Press Release
2.8. Rosiglitazone (Avandia® , combined products and generics)
FDA requires removal of certain restrictions (25-Nov-2013)
The FDA has announced it is requiring the removal of certain restrictions on the diabetes
drug Avandia in accordance with the recommendations of expert advisory committees
and based on the results of the RECORD clinical trial after readjudication, which showed
no elevated risk of heart attack or death. The data do not confirm the signal found in a
meta-analysis reported in 2007, which led the EMA to suspend the medicine in
September 2010, while the FDA decided to impose severe restrictions.
The FDA requirements include modifications to labeling about cardiovascular safety and
changes to the REMS program. It is anticipated that the drug may be used again in
indications similar to other diabetes drugs currently available, and the REMS enrolment
requirements will be lifted. The FDA has also decided to release GSK from the
postmarket requirement to conduct an additional clinical trial, which is no longer
considered necessary.
The press has widely covered this landmark decision.
Link to FDA News Release
Link to FDA MedWatch alert
Link to PharmaTimes article
Link to PharmaLive article
Link to The New York Times article
2.9. V itamin D and V itamin ADEC (Uvesterol® )
ANSM warns about new cases of fainting in infants (28-Nov-2013)
New cases of fainting in infants (in particular in newborns and premature children) were
notified to ANSM for this product used to prevent /treat vitamins deficiency. New
measures will be set up, including a new medication guide provided to parents.
Link to ANSM Press Release (in French)
Safety Observer N°96 – December 2013 page 10/21
2.10. Clobazam (Onfi® )
FDA warns about Risk of Serious Skin Reactions (03-Dec-2013)
The FDA has warned that the anti-seizure drug Onfi can cause rare but serious skin
reactions (SJS and TEN), which can result in permanent harm and death. The FDA has
approved corresponding changes to the label and the patient Medication Guide.
Link to FDA MedWatch alert
2.11. Recombinant factor V III (Kogenate® or Helix ate NexGen® )
PRAC considers benefits outweigh risks in previously untreated patients (06-Dec-2013)
The EMA’s PRAC has completed its review of Kogenate Bayer and Helixate NexGen and
concluded that current evidence did not confirm an increased risk of developing
antibodies (factor VIII inhibitors) against these medicines when compared with other
factor VIII products in previously untreated haemophilia A patients. The review followed
the results from a study that raised this concern.
The existing risk minimisation measures are considered adequate for both Kogenate
Bayer and Helixate NexGen but the PRAC recommended that the Product Information
should be updated to reflect currently available information. The PRAC recommendation
will be considered at the CHMP meeting of 16 to 19-Dec-2013.
Link to EMA Press Release
3. Quality Assurance, Inspections and Audits
3.1. MHRA Pharmacovigilance Inspections Symposium 2014 – Register Now !
Registration is now open for the next MHRA Pharmacovigilance Inspections Symposium,
which will take place on 14-Mar-2014 in London, UK. This event is a popular opportunity
to gain a greater understanding of the MHRA Inspectors’ expectations for
Pharmacovigilance Systems. In addition to common Inspection Findings, the topics
covered will include Reference Safety Information, PSURs, and generic Risk Management
Plans.
Link to MHRA Event Page
3.2. EMA provides update on impact of Roche Pharmacovigilance Inspection
The EMA has announced that it has now completed a review of all concerned Roche
medicines and the Agency has not identified any new safety concerns. This review
follows the results of an MHRA Inspection conducted in May 2012, which led the EMA
to announce an infringement procedure against Roche based on allegations that the
company had failed to meet its Pharmacovigilance obligations.
The inspection results suggested that 80,000 case reports, including more than 15,000
deaths had been collected through a Patient Support Programme in the USA but had not
been evaluated to check if they qualified for reporting to EU authorities.
The EMA review shows that the resulting data did not impact on the benefit-risk balance
of the medicines, but this conclusion is without prejudice to the infringement procedure
against Roche who may still face penalties.
Link to EMA Press Release
Link to PharmaTimes article
Link to Bloomberg article
Safety Observer N°96 – December 2013 page 11/21
3.3. New MHRA risk-based inspections questionnaire expected in December
As part of the MHRA risk-based inspection process, MAHs are encouraged to complete
a Compliance Report every two years. MAHs were last requested to submit a compliance
report in November 2011 and it is planned for the new 2013 Compliance Report to be
made available shortly, which should be submitted by 31-Mar-2014.
Link to MHRA Page
4. Drug Safety and Business Risk
4.1. Sanofi-Pasteur and Gardasil
French patient files a lawsuit against Sanofi-Pasteur and the French Agency
A French young woman has filed a lawsuit against Sanofi-Pasteur and the French Agency
ANSM after she developed multiple sclerosis, which she suspects was caused by
Gardasil, the anti-cervical cancer vaccine. She charged Sanofi-Pasteur and ANSM after
the conclusions of a Commission concluded that Sanofi-Pasteur should indemnify up to
50% of the damages caused by the pathology. Sanofi-Pasteur challenged the
conclusions considered inconsistent with the opinion of the authorities. Additional
plaintiffs announced they will file lawsuits.
Link to Yahoo article
Link to Le Figaro (in French)
4.2. Thalidomide
Spanish court orders Grünenthal to compensate thalidomide victims
The court has announced that it convicted Grünenthal in the first trial brought in Spain
against the producer of thalidomide, which caused severe birth defects more than 50
years ago. The court ordered the company to compensate each plaintiffs depending on
the severity of their disability.
Link to AFP article
Distributor Diageo accepts settlement with Australian victims
The class-action suit against the drug's British distributor Diageo Scotland Ltd. has been
settled for 89 million Australian dollars (€62 million) and a suit against the drug's
manufacturer Grünenthal will be discontinued.
Link to The Telegraph article
Safety Observer N°96 – December 2013 page 12/21
5. Other relevant Information and Resources
5.1. US Food and Drug Administration (FDA)
5.1.1. FDA provides new results of Postmarketing Drug Safety Evaluations
In accordance with the Food and Drug Administration Amendments Act of 2007 (FDAAA)
the FDA is required to perform postmarketing evaluations of new Drugs and Biologics 18
months after approval of the drug or after its use by 10,000 individuals.
The FDA website has been updated to provide the summaries of the evaluations
completed in the period July to September 2013. The information posted includes a
table identifying the Drug and Biological products concerned and a summary of the
evaluation findings, together with actions taken and ongoing surveillance activities.
The Summary of Evaluation Findings include the following combinations of Product /
Signal, which are under evaluation by the FDA:
Xarelto (Rivaroxaban) / thrombocytopenia and venous thromboembolic events
Zytiga (Abiraterone) / pneumonitis, pulmonary embolism and rhabdomyolysis
Caldolor (Ibuprofen) injection / infusion-site reactions
Edarbyclor (Azilsartan kamedoxomil and chlorthalidone) / hyponatremia and
angioedema
Link to FDA’s Postmarketing Drug Safety Evaluations Page
5.1.2. FDA announces 6th Annual Sentinel Initiative Public Workshop
The Sixth Annual Sentinel Initiative Public Workshop will take place on 14-Jan-2014 in
Washington, DC. The topics for discussion will include an update on the Sentinel
Initiative and highlights from key Mini-Sentinel activities.
In addition, this workshop will engage stakeholders to discuss new Sentinel projects
that would be appropriate to evaluate safety issues that may require regulatory action.
Link to Federal Register Notice
Link to Event Page
5.1.3. New Public Summary of Drug Safety Oversight Board meeting
A new public summary for the meetings of the FDA Drug Safety Oversight Board (DSOB)
has been posted. The Board met on 19-Sep-2013 and heard presentations on the
following topics:
Mitoxantrone use in multiple sclerosis: Compliance with cardiac monitoring
Drug-induced methemoglobinemia: Local anaesthetic sprays
Home administration of a chemotherapeutic
Link to DSOB Public Summary
5.1.4. FDA updates Drug Code Lists
The FDA is now updating the National Drug Code Directory on a weekly basis, and it can
be downloaded from their website.
Link to National Drug Code Directory Page
The “Drugs@FDA” Downloadable Data Files were last updated on 04-Dec-2013.
Link to Drugs@FDA Page
Safety Observer N°96 – December 2013 page 13/21
5.1.5. 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:
Updated recommendations to decrease risk of spinal column bleeding and paralysis
in patients on low molecular weight heparins
FDA requests label changes and single-use packaging for some over-the-counter
topical antiseptic products to decrease risk of infection
FDA warns of rare but serious risk of heart attack and death with cardiac nuclear
stress test drugs Lexiscan (regadenoson) and Adenoscan (adenosine)
FDA requires removal of some prescribing and dispensing restrictions for
rosiglitazone-containing diabetes medicines
Link to FDA Page
5.2. European Medicines Agency (EMA)
5.2.1. PRAC recommendations on Safety Signals
The EMA now 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 recommendations on signals adopted at the November PRAC meeting were
published on 28-Nov-2013 and includes recommendations to update the product
information for the following combinations of Product / Signal:
Leflunomide / Drug reaction with eosinophilia and systemic symptoms (DRESS)
Lenograstim / (Systemic) capillary leak syndrome (CLS)
Levetiracetam / Hyponatraemia and inappropriate antidiuretic hormone secretion
(SIADH)
Teriparatide / Anaphylactic shock
The cumulative 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.
The EMA has also posted a new document to cover the PRAC signal recommendations
to update the product information made in the period from September 2012 to July
2013, i.e. before the EMA started the publication of these recommendations resulting
from each PRAC meeting.
It should be highlighted that an update to the recommendations on signals adopted at
the October PRAC meeting were published on 18-Nov-2013.
Link to EMA Page
5.2.2. EMA updates information related to the list of Black Triangle Products
As described in GVP Module X, the EMA is publishing the list of medicines under
additional monitoring, which will be identified by a Black Triangle (▼) throughout Europe.
6 products have been added to the list, which specifies the reason for a product to be
subject to additional monitoring. It includes Trimetazidine-containing products and a full
list of these products has also been made available. The previously existing list of
cyproterone-acetate / ethinylestradiol-containing products has also been updated.
Link to EMA Page: Pharmacovigilance / List of Black Triangle Products
Safety Observer N°96 – December 2013 page 14/21
5.2.3. 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). The information available now
includes a glossary of Acronyms and abbreviations used in PRAC minutes.
Link to EMA PRAC Page
The minutes of the October PRAC meeting have now been published. As communicated
separately, the PRAC has confirmed that the benefits of all Combined Hormonal
Contraceptives (CHCs) continue to outweigh the risk of venous thromboembolism. The
re-examination of hydroxyethyl-starch solutions (HES) has also led the PRAC to let the
product on the market for restricted indications. A new referral procedure was started
for valproate and related substances and their use in pregnant women after study results
suggested development problems in some children.
The products concerned by new Safety Signals included Aflibercept, Amiodarone,
Cabazitaxel, Cefuroxime, Doxycycline, Exenatide & Liraglutide, Gabapentin, Human
Papillomavirus Vaccine, Quetiapine and Mefloquine.
Direct link to PRAC Meeting Minutes (07 to 10-Oct-2013)
The agenda and highlights of the November PRAC meeting have been published.
As communicated separately, the PRAC reviewed information on the cancer medicine
Iclusig (ponatinib) suggesting that vascular occlusive events occur at a higher rate than
initially expected. The PRAC also recommended the suspension of diacerein-containing
medicines, and restrictions of use for acipimox.
According to the agenda, new Safety Signals have been identified for the following
products: Adalimumab, Bupropione, Glycopyrronium bromide, Goserelin, Leflunomide,
Teriparatide, Paracetamol, and Calcium channel blockers.
Direct link to PRAC Meeting Highlights (04 to 07-Nov-2013)
The agenda and highlights of the December PRAC meeting have also just been
published. Some MAHs for diacerein-containing medicines have requested a re-
examination of the PRAC’s November 2013 recommendation to suspend these
medicines.
As communicated separately, the PRAC has started an in-depth review of Iclusig and
concluded that the benefits of Kogenate Bayer and Helixate NexGen continue to
outweigh the risks in previously untreated haemophilia A patients.
According to the agenda, new Safety Signals have been identified for the following
products: Clindamycin, Lamotrigine, Strontium ranelate, and Fentanyl transdermal patch.
Direct link to PRAC Meeting Highlights (02 to 05-Dec-2013)
5.2.4. EMA issues new CHMP Monthly Meeting Highlights
The highlights for the November meeting of the Committee for Medicinal Products for
Human Use (CHMP) have now been published.
As communicated separately, the CHMP has completed its review of combined hormonal
contraceptives (CHCs) and endorsed the PRAC recommendation that benefits continue
to outweigh the small risk of VTE.
The CHMP also issued recommendations on the leukaemia medicine Iclusig and
thiocolchicoside-containing medicines, and recommended new contraindications for
ivabradine.
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 as well as
community reviews initiated.
Safety Observer N°96 – December 2013 page 15/21
Link to CHMP Meeting Highlights (18 to 21-Nov-2013)
5.2.5. Article explores the impact of risk aversion in medicines regulation
Excessive risk aversion in regulatory decision-making is not in the best interest of
patients, according to a new article published in Nature Reviews Drug Discovery by EMA
staff, members of EMA committees, and representatives of national authorities.
The authors argue that risk aversion could lead to denying a marketing authorisation,
withdrawing it from the market or restricting its use when it would in fact cause more
good than harm. They also highlight that the costs of producing additional data at the
request of regulators may render resources unavailable for other R&D programmes.
The authors make some suggestions to align acceptance of risk and uncertainty by
regulators with the best interests of public health.
Link to EMA News item
5.2.6. EMA updates information on submission of medicines information
The EMA has published revised versions for a couple of Extended EudraVigilance product
report message (XEVMPD) controlled vocabularies, which support compliance with Article
57(2) of new EU Pharmacovigilance legislation whereby MAHs are required to perform
electronic submission of medicinal product information.
The controlled vocabularies are updated regularly to improve the standardisation of the
terminology used. MAHs are however not required to resubmit if medicine information
has already been submitted using a previous version of the controlled vocabularies.
The EMA has also issued a series of documents on “Controlled vocabularies quality
control”. It includes 4 documents describing the main changes in the XEVMPD
production environment, the remapping of Pharmaceutical Dose Forms and Routes of
Administration, the changes to the business rules for submission of substance
information, and the legacy product data, which reminds MAH that they do not need to
maintain the data submitted in the previous EVPRM.
Link to EMA Page: Electronic submission of information on medicines
5.3. UK Agency (MHRA)
5.3.1. MHRA issues Pharmacovigilance Expert Advisory Group summary minutes
The MHRA has published new summary minutes of the Pharmacovigilance Expert
Advisory Group. On 02-Oct-2013, the topics discussed included Risk Assessments for
Azithromycin, Clarithromycin, and Sodium valproate.
On 30-Oct-2013, the topics discussed included:
Ibuprofen: risk of skin and soft tissue infection after use in children with chickenpox
Simvastatin: review of 80mg dose
Link to Summary Minutes (02-Oct-2013)
Link to Summary Minutes (30-Oct-2013)
Safety Observer N°96 – December 2013 page 16/21
5.3.2. MHRA appointed to coordinate the SCOPE project
The MHRA has been officially appointed to coordinate the SCOPE project (Strengthening
Collaboration for Operating Pharmacovigilance in Europe), which is a three year EU-wide
Pharmacovigilance project to help member states meet the requirements of the new
legislation. The key objective of SCOPE is to enable National Authorities to operate the
new requirements to the highest possible standards against agreed benchmarks and
best practice.
Link to MHRA News item
5.3.3. New issues of MHRA “Drug Safety Update” Bulletin
The latest issue of Drug Safety Update (Volume 7, Issue 4, November 2013) was
published on 15-Nov-2013. It includes the following topics:
Antiepileptic drugs: new advice on switching between different manufacturers’
products for a particular drug
Sodium valproate: special reminder on risk of neurodevelopmental delay in children
following maternal use
Short-acting β2 agonists: restricted use for tocolysis in premature labour
Cabazitaxel (Jevtana▼): risk of medication error resulting in overdose
Mefloquine: strengthened warnings on neuropsychiatric side effects
Risperidone and paliperidone: risk of intraoperative floppy iris syndrome in patients
undergoing cataract surgery
Drug Safety Update is available as a fully searchable online resource.
Link to MHRA Newsletter Page
5.3.4. MHRA Dear Doctor Letters
The letters sent to Healthcare Professionals are routinely posted on the Agency’s
website. The letters from October include the following safety information:
Nizoral (ketoconazole): Discontinued due to risk of hepatotoxicity
Mabthera (rituximab): Screen people for HBV infection before start of treatment
Gilenya▼ (fingolimod): 2 fatal cases of haemophagocytic syndrome
Link to MHRA Page
5.4. French Agency (ANSM)
5.4.1. ANSM Dear Doctor Letters
Dear Doctor Letters sent in November 2013 are now available on the French Agency's
website (all in French). Letters associated to safety concerns include the following:
Clopidogrel® and cases of acquired haemophilia
Rituximab (Mabthera®): Hepatitis B test to be performed before initiation
hydroxyethyl-starch (HES)-containing solutions: new PRAC recommendations
Fingolimod (Gilenya®): Cases of letal Hemophagocytic Syndrome
Cabazitaxel (Jevtana®): important information on overdose and preparation errors
Iron Injection: use restricted to hospital due to severe hypersensitivity
Link to ANSM Page
Safety Observer N°96 – December 2013 page 17/21
5.4.2. Commissions / Committees in relation with Pharmacovigilance
The Commission for the benefit-risk follow up had meetings on 24-Sep-2013 and 29-Oct-
2013 and the minutes are now available.
24-Sep-2013: opinion was given on modifications of SmPC for CHCs
29-Oct-2013: no safety opinion
Link to Minutes of the Commission – 24-Sep-2013 (in French)
Link to Minutes of the Commission – 29-Oct-2013 (in French)
The Pharmacovigilance Committee issued minutes of the meetings on 18-Jun-2013 and
02-Jul-2013. The discussion concerned the following products:
18-Jun-2013: Etonogestrel, Incretinomimetics, Quetiapine, Chloroquine,
Hydroxychloroquine, Proguanil
02-Jul-2013: Olanzapine, Ulipristal
In addition, the Pharmacovigilance Committee issued a synthesis dated 12-Nov-2013
on new anti-coagulants.
Link to the minutes of the Committee – 18-Jun-2013 (in French)
Link to the minutes of the Committee – 02-Jul-2013 (in French)
Link to the synthesis of the Committee on new anti-coagulants – 12-Nov-2013 (in French)
5.4.3. ANSM provides update on safety of HPV vaccine
In the context of increased media attention related to a new lawsuit, the French Agency
has provided information regarding the current knowledge about the safety of HPV
vaccines. In France, 5 million doses were administered and 435 cases of suspected
serious adverse reactions have been reported (135 auto-immune pathologies including
15 cases of Multiple Sclerosis). The review of data currently available however does not
any causal association. The medical service provided by this vaccine is considered
important and the balance of risks and benefits remains favourable.
Link to ANSM Press Release (in French)
5.4.4. ANSM updates its website to facilitate ADR Reporting
A new webpage is available on the ANSM website to report adverse reactions. The
reporter can navigate by type of product (drug, medical device, etc.) and obtain the
applicable form. The report is transmitted directly from the webpage to the appropriate
Regional Center for Pharmacovigilance.
Link to the ANSM press release (in French)
Link to the ANSM webpage (in French)
Link to the Notification form for patients (in French)
Link to the Notification form for HCP (in French)
5.4.5. ANSM provides update on PRAC and CHMP activities
Following the issuance of PRAC minutes, ANSM issued a document in French which
summarises the discussions and decisions taken by the PRAC, together with ANSM
positions and recommendations for Healthcare Professionals.
Link to ANSM synthesis for the PRAC meeting of November 2013 (in French)
In the same way, ANSM issued a summary of the discussions and decisions taken by
the CHMP on Combined hormonal contraceptives (CHCs) and for other products.
Link to ANSM synthesis on CHCs from the CHMP meeting of November 2013 (in French)
Link to ANSM synthesis of the CHMP meeting of November 2013 (in French)
Safety Observer N°96 – December 2013 page 18/21
5.4.6. ANSM issues information on RMP
A new summary of the RMP (and risks minimization measures) approved by ANSM is
made available on ANSM website for the following product:
Vit D and Vit ADEC
Link to ANSM Page for Vit D and Vit ADEC
5.4.7. ANSM issues syntheses on the safe use of various products
ANSM has issued the following new synthesis:
Link to ANSM Synthesis on new oral anti-coagulants (Dabigatran, Rivaroxaban, Apixaban)
Link to ANSM Action Plan for new oral anti-coagulants
5.4.8. ANSM Presentation Material
ANSM has made available two new presentations for a press conference:
New anti-coagulants: clinical benefit and iatrogenic risks
New anti-coagulants: under monitoring
5.5. Other Sources
5.5.1. PROTECT issues recommendation report for benefit - risk assessment
The Pharmacoepidemiological Research on Outcomes of Therapeutics by a European
ConsorTium (PROTECT) has now published its recommendations for methodology and
visualisation techniques in benefit-risk assessment of medicines.
This follows the publication of the results of real-life case studies comparing methods
with different levels of complexity concerning selected medicines, which led to this new
set of practical recommendations for benefit-risk decision processes and tools.
Link to PROTECT Page
Direct Link to Recommendations Report
5.5.2. PROTECT new study reports on masking effect of disproportionality analyses
The PROTECT WP 3.7 has published two studies on the masking effect of measures of
disproportionality analyses. These studies have been published in
Pharmacoepidemiology and Drug Safety and are available on-line.
Link to PROTECT Page
5.5.3. Study shows effectiveness of label change for OTC cough and cold medicine
A study published in Pediatrics explores the effect of the changes in labeling for cough
and cold medicines, after safety concerns pushed the FDA to limit the use of these
products in young children in 2007. The study shows that these changes have resulted
in a significant decrease in emergency department visits by children under 4 for
suspected drug reactions.
Link to The New York Times article
5.5.4. OHRP new International Compilation of Human Research Standards
The US Office for Human Research Protections (OHRP) has released the 2014 version
of its Compilation of Human Research Standards, which is a listing of over 1,000 laws,
regulations, and guidelines on human subjects protections in over 100 countries.
Link to OHRP Page
Safety Observer N°96 – December 2013 page 19/21
5.5.5. New issue of Australian “Medicine Safety Update”
The new edition of Medicines Safety Update (Volume 4, Number 6, December 2013) is
now available. The contents include:
Pioglitazone risk-benefit review
5-alpha reductase inhibitors and risk of high-grade prostate cancer
Duloxetine and serotonin syndrome
Minocycline and intracranial hypertension
Link to Medicines Safety Update
5.5.6. New issue of IMB Drug Safety Newsletter
The last edition of the Irish Medicine Board Drug Safety Newsletter (Issue N°56) was
made available on 01-Nov-2013. The contents include:
Novel Oral Anticoagulants and risk of bleeding - Risk minimisation advice for
dabigatran (Pradaxa), rivaroxaban (Xarelto) and apixaban (Eliquis)
Metoclopramide-containing medicines - Revised recommendations for use
Link to Newsletter
5.5.7. New issue of Japanese PMDSI Newsletter
The Pharmaceuticals and Medical Devices Safety Information (PMDSI) Newsletter is
issued based on safety information collected by the Japanese Ministry of Health, Labour
and Welfare (MHLW) and is intended to promote safer use of pharmaceuticals and
medical devices by healthcare providers. The English Summary of the latest edition of
the Newsletter (Issue N°307) is now available and includes:
Summary of the Relief System for sufferers from Adverse Drug Reactions and the
Cases of Non-payment of Relief Benefits Due to Improper Use of Drugs
Important Safety Information: Axitinib, and Bevacizumab
Revision of Precautions: Clobazam (and 9 others)
List of Products Subject to Early Post-marketing Vigilance
Link to PMDA Page
5.5.8. Japanese PMDA provides updated list of drugs under review
The Pharmaceuticals and Medical Devices Agency (PMDA) has updated its webpage
where it provides information on drug risks under review by the PMDA/MHLW, which can
be based on safety information submitted to the Japanese Agency or due to
communication from foreign drug agencies. The new signals added in December concern
Clopidogrel, Rufinamide, Sodium Valproate, Amphotericin B, Atazanavir, Crizotinib, and
a list of product suspected to impair ability to drive.
Link to PMDA Page
5.5.9. UMC Newsletter
The Uppsala Monitoring Center has published its Newsletter Issue N°4, December 2013.
It highlights the release of the December 2013 version together with WHO Drug
Dictionary China. It also provides the schedule of educational webinars.
Link to UMC Newsletter
Safety Observer N°96 – December 2013 page 20/21
6. Time to Register
EMA/DIA Events
EudraVigilance and Electronic Reporting of ICSRs in the EEA
3 day-training course (see schedule for venues and dates)
Extended EudraVigilance Medicinal Product Dictionary (XEVMPD) Training Course
2 day-training course (see schedule for venues and dates)
Excellence in Pharmacovigilance: Clinical Trials and Post-Marketing
February 17 – 21 in London, UK
DSRU Events
Medical Aspects of Adverse Drug Reactions
January 22 – 24 in Southampton, UK
Monitoring Safety in Clinical Trials & Drug Development
February 05 – 06 in London, UK
Back to Basics in Pharmacovigilance
February 26 – 27 in Southampton, UK
DIA Events
Pharmacovigilance and Risk Management Strategies 2014
January 12 – 15 in Washington DC, USA
Benefit-Risk Assessment from Inception to Maturation: Aligning Regulatory and Industry Goals
February 09 – 11 in Bethesda MD, USA
Barnett Events
Webinar – Quality Risk Management in Clinical Trials and Pharmacovigilance
January 21, 12:OO PM to 01:30 PM Eastern
Webinar – Adverse Event Monitoring for CRAs
January 24, 12:OO PM to 02:00 PM Eastern
The Pharmacovigilance Audit: How to Prepare for an Inspection
January 30 in San Diego CA, USA
Webinar – Drug Safety and Pharmacovigilance
March 04, 01:OO PM to 02:30 PM Eastern
Other Events
IFIS – Pharmacovigilance : Qualified Pharmacist missions / responsibilities (event in French)
December 17 in Paris, France
EGA – 7th EGA Pharmacovigilance Discussion Forum
January 22 in London, UK
IFIS – Quality in Pharmacovigilance (event in French)
January 23 in Paris, France
Management Forum – Pharmacovigilance and MedDRA
January 23 in London, UK
Management Forum – MedDRA Coding and practical aspects
January 24 in London, UK
Virtue Insight – 6th Pharmacovigilance 2014
March 04 – 05 in London, UK
Management Forum – Essential Pharmacovigilance
February 11 in London, UK
Management Forum – Advanced Pharmacovigilance
March 03 – 05 in London, UK
Safety Observer N°96 – December 2013 page 21/21
7. About the Authors
SUNNIKAN Consulting is offering a wide range of services related to Risk, Quality and
Process Management Systems for Pharmaceutical Industry since 1996. SUNNIKAN
Consulting’s areas of expertise cover Clinical Research, Regulatory Affairs,
Pharmacovigilance, Computerized Systems, and more.
For more information please visit SUNNIKAN Consulting’s website at:
www.sunnikan.com
PV Focus is a small specialty company established since December 2004. Based in
France, PV Focus has successfully centered its business on the provision of
Pharmacovigilance Audits and related services to the Pharmaceutical Industry.
Due to its experience of both Audits and Regulatory Inspections at a global level, PV
Focus is a partner of choice to assist with the performance of Pharmacovigilance System
Audits and can also support the preparation of Regulatory Inspections.
For more information please visit www.pvfocus.com
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