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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