Are you Brexit ready?

18th October 2018

Brexit in:

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Test your knowledge, take our Brexit quiz here

What do you want to do next? Do you want to continue to market your product in the EU only, or are you interested in both the EU and UK markets? Read on to find out what you need to do for both scenarios.

If you would like to continue to market your product in the EU there are a few things that need to be finalised before Brexit on the 29^th March 2019:

Reference Member State (RMS transfer)

This should have been done yesterday(!) The time it takes depends on the requested RMS’s workload.

Since July 2018 the MHRA is no longer accepting new applications with UK as RMS. However there are some currently authorised products wherein the UK is still the RMS.

If you have products and the UK is currently the RMS then it is vital a RMS transfer is initiated immediately. If there is only one CMS then this CMS should become the RMS (submission required). If there is more than one CMS, the preferred CMS needs to be consulted and a request sent asking them to be RMS. It is the responsibility of the MAH to secure a new RMS. The timeline for such transfers are solely dependent on the workload of the requested RMS.

Marketing Authorisation Holder (MAH) transfer

Needs to be done immediately – the time it takes is dependent on where the application is submitted.

From the 29^th March 2019 the MAH for a product licensed in an EU Member State (MS) other than the UK must be based in the EU. Therefore if the MAH is currently based in the UK there needs to be a MAH transfer to one based in the EU.

If this involves purely an address change (i.e. the marketing authorisation holder remains the same legal entity but they have an address in the EU) then this is a simple type IAin (A.1).
If the new MAH is a different legal entity then the MAH transfer must follow the guidelines of the currently registered RMS and CMS, at the very least documents such as transfer agreement, proof of establishment, , power of attorney(s), Pharmacovigilance (PV) update, etc., should be in place before submission of the request.

Batch release

Needs to be done within the next 4-8 weeks unless a product is a biological / immunological product in which case submission needs to be immediate.

Products that only have batch release and quality control testing sites for finished product in the UK will have to change the batch release and testing sites for their EU products. For products that have other batch release and testing sites the MAH may choose to delete the UK site(s) or may choose to replace them. For finished products manufactured in the UK an importation site (in EEA) will need to be introduced. In many cases, a single site can perform manufacturing, testing, importation and/or batch release activities.

The timelimes will follow the type IA/IB or type II (biological / immunological product) categories depending on what change is applied for. Please see https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-2/c_2013_2008/c_2013_2008_doc/c_2013_2804_en.doc

PV

Needs to be done asap and in association with any MAH transfers – usually a type IA or type IAin

The Qualified Person for Pharmacovigilance (QPPV) and Pharmacovigilance Site Master File (PSMF) must be based in the EU/EEA.

If you wish to continue to market the product in the UK in addition to the EU:

The MHRA have stated that after Brexit, all currently approved authorisations will be transferred into national procedures and will remain valid.

If an application is in-progress at the time of Brexit the application will need to be submitted to the MHRA again as a national application in the case of CP procedures and that for MR or DC procedures a transitional provision will be made. HOWEVER, this is contingent on a Brexit deal that allows for a transition period. This has not yet been agreed.

To ensure the product can remain on the market / licensed, the UK are proposing the following if there is a no-deal Brexit

a MAH should be established in the UK by the end of 2020. Until then, the MHRA will require a contact in the UK. A Change of Ownership will need to be submitted to MHRA to change from an EU MAH to a UK MAH for UK MAs
the Qualified Person for Pharmacovigilance (QPPV) should be established in the UK on day one, although those without a current UK presence will have until the end of 2020 at the latest to do so, but would nevertheless be required to make arrangements for providing the MHRA with access to the relevant safety data related to UK Marketing Authorisations (MAs) at any time. Companies may choose to have the EU QPPV take on responsibility for UK MAs until the UK QPPV can be established. A variation should be submitted to the MHRA to change QPPV. Exact details of this will be consulted upon
a Qualified Person (QP) for products manufactured in the UK or directly imported into the UK from outside a country on a designated country list (whitelist) must reside and operate in the UK. A QP for products manufactured in a country on a whitelist or manufactured in a third country and imported into the UK from a country on a whitelist can reside in a country on the whitelist.

(https://www.gov.uk/government/publications/how-medicines-medical-devices-and-clinical-trials-would-be-regulated-if-theres-no-brexit-deal/how-medicines-medical-devices-and-clinical-trials-would-be-regulated-if-theres-no-brexit-deal)

Do you need help with any of the above or any other regulatory issue?

Contact us! We’re here to help.

Written by Emily Fletcher

Emily Fletcher

Launch of the new EudraVigilance System – National arrangements for Ireland and what this means for you

15th November 2017

With the launch of the improved EudraVigilance (EV) System, and the move to the simplified reporting of adverse reaction reports (ADRs) on 22^nd November 2017, Marketing Authorisation Holders and EV users in Ireland must familiarise themselves with the HPRA’s national arrangements that will be in place during the changeover period.

As of 4^th November the HPRA closed its reporting gateway and MAH’s must not submit ICSRs/SUSARs to HPRA from this time, as all submissions will be lost upon go-live date (22^nd November) in the system (EudraVigilance Go-Live Plan).

To facilitate EV users, there will be a 3-day ‘cutover legacy’ period from 22^nd – 24^th November when all ‘backlog’ ICSRs can be submitted to EudraVigilance with Compliance timelines adjusted to reflect the downtime during this period.

Any SUSARs sent to EVCTM from 4^th to 7^th November should be submitted to HPRA after 22^nd November along with the other cutover legacy SUSARs. Sponsors and investigators are also obliged to notify the HPRA within 3 days of any action needed to protect the health and safety of clinical trial subjects, in accordance with the HPRA Guide to clinical trial applications

New Simplified reporting of Adverse Reaction Reports

From 22^nd November all serious ICSRs that occur within or outside the EU will be reportable directly to EudraVigilance and no longer to individual National Competent Authorities (NCAs)/ Marketing Authorisation Holders (MAHs).

All non-serious cases occurring in the EU will also be reportable to EudraVigilance by NCAs and MAHs. These final reporting arrangements are further described in Revision 2 of Module VI of the Good Pharmacovigilance Practice guide.

All reporting shall be in line with the final reporting arrangements as described in Directive 2001/83/EC as amended. Therefore all serious and non-serious ICSRs that occur in Ireland will be reportable directly to EudraVigilance by the MAH and not to the HPRA.

A key aspect of the new EudraVigilance system is its compatibility with the E2B(R3) format. Stakeholders may submit and receive ICSRs and SUSARs in the E2B(R3) format from 22^nd November 2017 onwards, if their internal systems have been updated to meet this requirement.

For MAH EVWEB users any reports will automatically be generated in the E2B(R3) format and so it is recommended that these MAHs undergo training on EVWEB and the new ICH E2B(R3) format to gain familiarity with new functionalities and changes as there will be a new interface and improved functionalities.

We can help

Ivowen are fully equipped to advise and assist during this changeover period and beyond. Please see our Pharmacovigilance services page or contact us for more information.

Written by:

Edel Behan

EMA eSubmission Gateway – tips & tricks

28th August 2017

Current State of Play

As many of you know, the EMA eSubmission Gateway/Web Client has been mandatory for all submissions for human medicinal products made through the Centralised Procedure since March 2014 and for veterinary products since January 2017. In addition, all PSUSA/PBRER submissions are also made through this EMA eSubmission Gateway, and have been mandatory since June 2016.

Unfortunately, as many of you also know, there are some glitches and issues with this portal. Below are the workarounds for some of these glitches.

Contact us

Please feel free to contact us if you need any help submitting through the EMA eSubmission Gateway/Web Client

“Click to send documents totalling more than 10 MB”

To send any submission through the portal and get an acknowledgement (“ACK”) for this submission, you have to use the “Click to send documents totalling more than 10 MB” option. When you first log in or register for the EMA eSubmission Gateway, and go to the “SEND DOCUMENT” page, this option is not available. This is down to Java settings and security. The way around this is to set your Java security settings and exceptions as follows:

At the moment, you may find that the “Click to send documents totalling more than 10 MB” option is still not available, even when your security settings and exception list are correct. The EMA Service Desk has assured me that they are working on this issue, but in the meantime you can follow the instructions below to work around this issue/

Open Internet Explorer and log into EMA portal. Go to “Send document”.
If you see the “Click to send documents totalling more than 10 MB” then continue to send your submission as normal.
If you don’t see the “Click to send documents…” link, like this example, then follow the instructions below:

3.1 In the top right hand corner is a Settings button that looks like a machine wheel

3.2 Click on this Settings button and then click “F12 Developer Tools”:

3.3 If you see that the Document Mode is “11 (default)” like the screenshot below:

3.4 Change this to “10” and the “Click to send documents…” will appear:

3.5 You need to leave the F12 Developer Tools window with these settings OPEN until you have completed your submission. The EMA Gateway Service desk is working on a fix for this problem, but this is the workaround for now.

Clinical Trials Regulation EU No 536/2014 – What does this mean for you?

8th May 2017

When the Clinical Trial Regulation (No. 536/2014) comes into effect in 2018, there will be a major change on how clinical trial applications are submitted and how clinical trials are conducted in the EU.

The goal of the new Regulation is to create an environment that is favourable to conducting clinical trials in the EU, with the highest standards of safety for participants and increased transparency of trial information.

Below you will find a brief summary of the changes:

Directive 2001/20/EC (Current)

Multiple submission for one trial (1 submission per each MS)
Double submission with a MSC: to NCA and EC
Individual assessment by Each MSC with no IT collaboration tool available
No Single MSC decision (NCA and ECs)
Limited EudraCT data availability to the public

Regulation 536/2014 (New)

Single e-submission to all MSCs
Harmonised dossier for one trial and
e-submission of structured data and documents by MSCs
Specific timeline
Joint assessment for PART I facilitated by collaboration tool
Single MSC decisions
Single web-based EU portal
Distribution of the burden among users
View all CT relation information

Transition period (3 years) Directive 2001/20/EC (current) to Regulation 573/2014

Starts when Regulation becomes applicable (~ Oct 2018)
1^st Year: Clinical Trials can be submitted under old/current (Directive) or new (Regulation) system
2^nd & 3^rd Year: Trials authorised under old system can remain under that system, New/initial Clinical Trials should comply the Regulation System
All Clinical Trials to switch to the Regulation 3 years after implementation (~ Oct 2021)

Typical Documents to be submitted:

Part I: Cover letter (very important), EU AF, Protocol, IB, GMP compliance documents, IMPD, Auxiliary Medicinal Product Dossier, Scientific Advice, PIPs, and labelling, proof of payment, etc.
Part II: Recruitment arrangements, SI/ICF/ICF procedure, suitability of the investigator, suitability of the facilities, proof of insurance cover or indemnification, financial and other arrangement, proof of payment, etc.

Part I Timetable Coordinated assessment (also applies to Mono-national Clinical Trials)

Day 0: Validation
D26: Draft Part I Assessment Report made available by the RMS (reporting MS) to the CMS
D38: All CMS share considerations
D45: RMS finalises the Part Assessment Report
D57: Sponsor submits response (w/n 12days)
D69: Co-ordinated assessment between MSs (12 days)
D76: RMS files conclusion (7days)

Part II Timetable National evaluation

D0: Validation

D45: Final assessment report from each MSC submitted

D57: Sponsor submits response

D76: Final assessment by the MSC shall be performed (w/n 19 days)

Submission of Part I and II in parallel (recommended) or submission of Part I followed by Part II (not less than 2 years after Part I)

Important Notes:

New MSs can only be added after the notification date of the initial authorisation decision
Withdrawal of MS: the whole application has to be withdrawn and resubmitted

Transparency:

EU Database will be publically accessible by default, with exceptions justified on any of the following grounds

Protection of personal data
Protection of commercially confidential information in particular taking into account the MA status of the medicinal product, unless there is an overriding public interest in disclosure
Protecting confidential communication between Member State in relation to the preparation of the assessment report
Ensuing effective supervision of the conduct trial Member States

Where can I find more information?

Information on Clinical trials – Regulation EU No 536/2014, General information, Guideline EU

Clinical Trial Portal and Database, Transparency, Safety reporting, Clinical trials conducted outside the EU, Contact points can be found here: https://ec.europa.eu/health/human-use/clinical-trials/regulation_en

We can help…

Ivowen are fully equipped to submit for Clinical Trials Applications on your behalf. Please contact us for more information and for support of your dossier compilation or updates.

Written by: Fiona Downey

Ivowen attends EudraVigilance Training Course on Reporting of ICSRs/SUSARs in the EEA – Suspected Adverse Reactions to Medicines

30th November 2016

What is EudraVigilance?

EudraVigilance (http://eudravigilance.ema.europa.eu) is a centralised European database of suspected adverse reactions to medicines that are authorised or being studied in clinical trials in the European Economic Area (EEA) and supports the safe and effective use of medicines (Figure 1 – EudraVigilance System Components). Adverse reactions (ADRs) can be reported during the development and following the marketing authorisation of medicinal products in the EEA. The European Medicines Agency (EMA) operates the system on behalf of the European Union (EU) medicines regulatory network.

ICSR, SUSAR and Safety Signals

Specifically, EudraVigilance is a system for managing and analysing information on suspected adverse reactions to medicines by facilitating electronic exchange of adverse event Individual Case Safety Reports (ICSRs) between EMA and all stakeholders including national competent authorities (NCAs), marketing authorisation holders (MAHs) and sponsors of clinical trials in the EEA. Within clinical trials such a case is referred to as a SUSAR (a Suspected Unexpected Serious Adverse Reaction). The reporting of ICSRs allows for the early detection and evaluation of possible safety signals leading to improved product information and benefit-risk balance for marketed medicines authorised in the EEA. A Safety Signal is defined as information on a new or known adverse event that is potentially caused by a medicine and that warrants further investigation. Signals are generated from several sources such as spontaneous reports, clinical studies and the scientific literature.

Taking into account the pharmacovigilance activities in the pre- and post-authorisation phase, EudraVigilance provides two reporting modules:

The EudraVigilance Post-Authorisation Module (EVPM)
The EudraVigilance Clinical Trial Module (EVCTM)

Figure 1. EudraVigilance System Components

Data Publishing, Review and PRAC Evaluation

EMA publishes data from EudraVigilance in the European database for suspected adverse drug reaction reports – http://www.adrreports.eu/. EMA, NCAs and MAHs are responsible for reviewing EudraVigilance data to detect safety signals. The Pharmacovigilance Risk Assessment Committee (PRAC) evaluates the safety signals detected in EudraVigilance and may recommend regulatory action as a result – http://www.ema.europa.eu/ema/index.jsp?curl=pages/about_us/general/general_content_000537.jsp&mid=WC0b01ac058058cb18.

What we can do for you:

Electronic reporting of suspected adverse reactions to medicines is mandatory for MAHs and sponsors for clinical trials. Ivowen can advise and assist you in the following areas of reporting to EudraVigilance along with updating product information for PRAC recommendations:

Describe the Registration process with EudraVigilance
Create, validate and send safety messages (initial, follow-up reports, nullification reports, literature reports, parent-child , study reports, reports with medical and drug history)
Create and send acknowledgments of received ICSR messages
Query, view, browse and download safety reports
Query, view and browse MedDRA through the EVWEB

Please contact us for further information.

Written by Laura Oakey.

PSUR repository updated

25th August 2015

On the 26th of January 2015, the EMA introduced the pilot phase on the use of the XML delivery file for submissions of PSURs via the eSubmission Gateway/Web Client.

This introduction,

1) Simplified package file names for PSURs and

2) Introduced the requirement of an XML delivery file.

The XML delivery file is created in the PSUR Repository user interface

The PSUR Repository user interface is basically broken down into 4 sections:

Section 1: Regulatory Activity

This is a simple drop down list and is currently only available for PSUR submissions and Supplementary information which is related to a PSUR submissions.

Section 2: Details of assessment procedure

This section requires you to enter the Procedure Number as per the EURD list, all other information (Submission deadline, DLP, Active name, Rapporteur name and Rapporteur country) will prepopulate based on this Procedure Number. Carefully check if all information is correct, if prepopulated information is wrong contact the EMA.

Section 3: Product Selection

Select your Submission Format (eCTD or NeeS)
Enter the product name(s) in the section products to which the submission relates for all your products to which the submission relates. This is a drop down menu based on the Art 57 database. Therefore you must first ensure that all your product information entered in the Art 57 database is up to date and correct.
Select your products, enter your procedure number (where relevant) and the sequence number of your submission.

Section 4 Routing information

Enter EMA routing ID (e.g. ESUBPROD) and your Routing ID (e.g. ESUBPTESTPROD123)
The XML delivery file will always be called xml, this should not be renamed/edited
Save the XML delivery file inside the PSUR submission folder (zipped).
Your PSUR folder should have a meaningful file name and examples of these can be found in Annex 3.
Your Submission file can be send in the normal manner via the eSubmission Gateway/Web Client.

From September 2015, it will be mandatory to use the XML delivery file for all PSUR submission to the EMA via the eSubmission/Web Client.

Please contact us if you require any further information or help with this process.

Written by Fiona Downey.

Are you Brexit ready?

Brexit in:

Test your knowledge, take our Brexit quiz here

If you would like to continue to market your product in the EU there are a few things that need to be finalised before Brexit on the 29^th March 2019:

Reference Member State (RMS transfer)

Marketing Authorisation Holder (MAH) transfer

Batch release

PV

If you wish to continue to market the product in the UK in addition to the EU:

Do you need help with any of the above or any other regulatory issue?

Launch of the new EudraVigilance System – National arrangements for Ireland and what this means for you

EMA eSubmission Gateway – tips & tricks

Current State of Play

Contact us

“Click to send documents totalling more than 10 MB”

Clinical Trials Regulation EU No 536/2014 – What does this mean for you?

Where can I find more information?

We can help…

Ivowen attends EudraVigilance Training Course on Reporting of ICSRs/SUSARs in the EEA – Suspected Adverse Reactions to Medicines

PSUR repository updated

Need help with all the regulatory jargon?

Links

Our Policy

Find Us

Brexit in:

Test your knowledge, take our Brexit quiz here

If you would like to continue to market your product in the EU there are a few things that need to be finalised before Brexit on the 29th March 2019:

Reference Member State (RMS transfer)

Marketing Authorisation Holder (MAH) transfer

Batch release

PV

If you wish to continue to market the product in the UK in addition to the EU:

Do you need help with any of the above or any other regulatory issue?

Current State of Play

Contact us

“Click to send documents totalling more than 10 MB”

Where can I find more information?

We can help…

Need help with all the regulatory jargon?

Links

Our Policy

Find Us

If you would like to continue to market your product in the EU there are a few things that need to be finalised before Brexit on the 29^th March 2019: