BREXIT – MHRA post-transition period information

The UK has left the EU and the transition period after Brexit comes to an end this year.

The MHRA have issued new guidance for industry and organisations effective from 01st January 2021.  From this date the MHRA will be the UK’s standalone medicines and medical devices regulator.

Areas covered in the new guidance include:

Clinical Trials

From 1 January 2021, for registering clinical trials, existing and established international registers will still be used, such as ISRCTN registry (UK), or ClinicalTrials.gov (USA), to ensure the public is aware of your trial. For trials involving both UK and EU sites a record in the EU Clinical Trials Register will exist (other than adult Phase 1 studies).  In the UK, any favourable opinion given by a research ethics committee is subject to the condition that the clinical trial is registered on a publicly accessible database. The time frame for publishing the summary of results is within 6 months of the end of trial for paediatric clinical trials or within one year of the end of trial for non-paediatric clinical trials. You do not need to submit this clinical trial summary report to the MHRA as well; however, you must send a short confirmatory email to CT.Submission@mhra.gov.uk once the result-related information has been uploaded to the public register and provide a link.

 

Pharmacovigilance

Guidance on qualified person responsible for pharmacovigilance (QPPV) including pharmacovigilance system master files (PSMF) from 1 January 2021

From 1 January 2021, the following legal obligations will apply to holders of UK marketing authorisations (MA). These include those that cover the whole of the UK, or are specific to Northern Ireland or to Great Britain (England, Wales and Scotland):

  • To operate a pharmacovigilance system for UK authorised products.
  • To have an appropriately qualified person responsible for pharmacovigilance (QPPV) that resides and operates in the EU or the UK and is responsible for the establishment and maintenance of the pharmacovigilance system for UK authorised products.
  • To maintain and make available upon request a pharmacovigilance system master file (PSMF) that describes the pharmacovigilance system for UK authorised products. The PSMF must be accessible electronically or physically from the UK at the same site at which reports of suspected adverse reaction may be accessed.

Statutory guidance concerning the QPPV for UK authorised products is described in the Good Pharmacovigilance Practices (GVP) Module I. This guidance will be supplemented by the ‘Exceptions and modifications to the EU guidance on good pharmacovigilance practices that apply to UK marketing authorisation holders’, which will be published in due course.

Updated guidance on pharmacovigilance procedures

Detailed guidance on pharmacovigilance procedures from 1 January 2021 is published on the MHRA website: https://www.gov.uk/government/publications/guidance-on-pharmacovigilance-procedures-in-the-event-from-1-january-2021/updated-guidance-on-pharmacovigilance-procedures

 

Marketing Authorisations

New guidelines have been outlined for Marketing Authorisations, to include Conditional MAs, registering new packaging information, guidance on the handling of applications for Centrally Authorised Products (CAPs),  Article 29 applications, converting parallel distribution notices to UK parallel import licences, handling of ASMFs and CoS from January 2021, reference medicinal products, converting CAPs to UK MAs, guidance on licencing biosimilars, bioequivalence/therapeutic equivalence studies and renewing marketing authorisations.

 New Submission Registrations

For planned applications for submission to the UK (for example, a Marketing Authorisation for the UK market), you will need to submit the information through the MHRA national portals.

All current Eudravigilance Gateway users who wish to gain access to the new MHRA Gateway will need to first gain access to MHRA Submissions. The steps for gaining MHRA Gateway access are contained within MHRA Submissions.  MHRA Submissions will not be used to send or receive ICSRs.

A useful webinar on how to gain access to MHRA submissions portal is available on the MHRA website at the following link https://www.gov.uk/government/publications/webinars-preparing-to-make-submissions-to-the-mhra-from-1-january-2021

Within the recent MHRA guidelines, the following areas are also covered:

  • Devices
  • Importing and Exporting
  • IT Systems
  • Paediatrics

IN DEPTH DETAILS ON THE NEW MHRA GUIDANCE CAN BE FOUND ON THE LINK BELOW:-

https://www.gov.uk/government/collections/mhra-post-transition-period-information

 

If you need any clarification or support to help you to navigate the end of transition period please contact us and Ivowen will gladly assist you in a timely manner.

 

Written by Mary Canning

European Procedural Guidance during COVID-19 Pandemic

In response to the significant impact the COVID-19 pandemic is having on European regulatory activity, the European Commission, the European Medicines Agency and the Heads of Medicines Agencies network (EC, EMA and HMA, respectively) have approved a number of measures to help the management of marketing authorisations for human medicinal products considered crucial during the pandemic period.

The objective of these measures agreed at European level is to promote regulatory flexibility, facilitate, simplify and accelerate the administrative procedures, as far as possible, in order to respond more efficiently to emerging needs during this period.

As a result, the EC recently published questions and answers on regulatory expectations for medicinal products for human use during the COVID-19 pandemic:

Questions and Answers on Regulatory Expectations for Medicinal Products for Human Use during the COVID-19 Pandemic

This Q & A document which provides guidance to marketing authorisation holders (MAH) includes the following topics:

  • renewal applications
  • sunset clause
  • an exceptional change management process (ECMP) for crucial medicines for use in COVID-19 patients
  • circumstances under which the validity GMP certificates and authorisations to manufacture/import can be extended
  • circumstances under which the validity GDP certificates and wholesale authorisations can be extended
  • adaptions to the work of a Qualified Person (QP)
  • the possibility of adapting quality requirements for medicines intended to be used for the treatment of COVID-19 patients
  • the impact on reporting into EudraVigilance of Individual Case Safety Reports (ICSRs)
  • flexibility in the labelling and packaging requirements to facilitate the movement of medicinal products within the EU

Further to the European Commission’s Q&A document, the CMDh has agreed additional questions and answers that provide practical information on how to specifically address and apply the provisions determined by the European Commission for MR/DC procedures:

Practical Guidance of the CMDh for facilitating the Handling of Processes during the COVID-19 Crisis

The CMDh document addresses issues such as the impact of COVID-19 on assessment timelines, how to use the ECMP procedure (which is only applicable for products that are crucial for the treatment of COVID-19 patients) and QP declarations based on a desktop audits. It also includes a useful annex that details Member States’ email addresses and links to relevant published guidance on MS websites.

Both documents will be updated and supplemented with additional information, as appropriate during the pandemic.

Everyone at Ivowen is working tirelessly to keep our clients applications on track. We are liaising with the National Competent Authorities all the time to ensure we avoid delays and get the best results possible in these unprecedented times.

If you need any assistance in this regard please don’t hesitate to contact us.

 

 

 

 

 

 

Written by Claire Brown.

Pharmacovigilance most of all

The European Medicines Agency (EMA) has recently published an overview of pharmacovigilance activities that outlines just how strong and reliable a system we have in the EU. The report was prepared by EMA in collaboration with the National Competent Authorities (NCA).  The report includes quantitative data covering the period between 2015 and 2018 and shows that the European regulatory network for medicines is held accountable for the implementation of the pharmacovigilance legislation.

The measurement of impact is based on a strategy and action plan for measuring the impact of pharmacovigilance activities, adopted by EMA’s safety committee (PRAC) in 2017.

It shows that the EU pharmacovigilance system is strong and protects public health.

 Some key outcomes 2015-2018

  • More than 500 new or updated risk management plans were assessed by the PRAC each year, ensuring the safety monitoring and risk minimisation is proportionate and planned. In addition, nearly 7,000 risk management plans were assessed by the Member States for nationally authorised medicines during the reporting period.
  • Enhanced EudraVigilance database of suspected side effects, resulting in improved reporting and greater analytical power;
  • Evaluation of nearly 9,000 potential signals (information about new or changing safety issues potentially caused by a medicine) by EMA’s signal management team over the period covered by the report, and a similar number of potential signals assessed by Member States;
  • Radical simplification and improvement of the way periodic safety update reports are handled, by establishing a common repository with a single portal for access;
  • Development of criteria to determine when a public hearing on issues of medicines’ safety would be of value, and the successful holding of the first such hearings, for valproate-containing medicines in 2017 and for quinolone and fluoroquinolone antibiotics in 2018;
  • Continued development of the ‘Article 57 database’, which now contains information on more than 800,000 medicinal products authorised through central, decentralised, mutual recognition and national procedures across the European Economic Area.

For more details on the report please refer to EMA web page where you can access the press release issued.

The pharmacovigilance legislation established now reinforces the need for and format of various reports, including:

  • Risk Management Plans (RMP);
  • Periodic Safety Update Reports (PSUR);
  • Post-Authorisation Safety and efficacy Studies (PASS);
  • Pharmacovigilance System Master Files (PSMF).

Should you require assistance with respect to setting up a pharmacovigilance system, or the preparation and submission of pharmacovigilance related data we encourage you to contact us.

Written by Alice D’Alton.

BREXIT – EVERYTHING stays the same for 2020

 The United Kingdom has formally left the EU as of 31 January 2020 and has become what is referred to as a third country.

On 1 February 2020 a transition period started which is due to end on 31 December 2020.

During the transition period, EU pharmaceutical law will continue to be applicable to the UK, meaning that pharmaceutical companies can continue to carry out activities in the UK until the end of 2020.

Companies have until 31 December 2020 to make the necessary changes to ensure that their authorised medicines comply with EU law and can remain on the EU market.

  • The UK will remain on CESP for the duration of transition period (after that, if no further extension to the transition period is proposed, it will be necessary to use the MHRA portal for submissions https://pclportal.mhra.gov.uk/)
  • Marketing authorisation holders and applicants can still be established in the UK in 2020
  • Qualified Persons for Pharmacovigilance (QPPVs) and pharmacovigilance system master files (PSMFs) can still be based in the UK until the end of 2020.
  • Manufacturing sites, Quality control testing and Batch release sites can also still be based in the UK until the end of 2020
  • orphan designation holders can still be located in the UK until 31 December 2020
  • minor use/minor species (MUMS)/limited markets classification holders can still be located in the UK until 31 December 2020

The withdrawal agreement foresees that following its departure from the EU on 31 January 2020, the UK will no longer participate in EU institutions and their decision-making. For the CMDh this means that as of 1 February 2020, no one who represents the UK, or is appointed or nominated by the UK can systemically participate in the CMDh meetings.

During the transition period, the UK will not be able to act as RMS in MRP/DCP, but the UK can participate in MRP/DCP as CMS.

Ivowen are here to assist you with all your Brexit related needs and dossier amendments.

For more information on Ivowen’s services and how we can help you, contact us.

Written by Alice D’Alton

2019 – What a year

Ivowen attended the Medicines for Europe conference in January (Regulatory and Pharmacovigilance), the annual EuDRAcon conference in May, exhibited at TOPRA in October and joined our clients from around the world at CPhI in November.

We all saw Brexit come and go, Twice !! We wait to see what lies in store for the next deadline in January 2020.

The FMD came into effect across Europe in February in most member states.

Bulgaria joined CESP, eCTD became mandatory for all human procedures, lots of new guidance was published (to keep us all on our toes) and Nitrosamines in medicinal products moved to the top of everyone’s agenda.

With the festive season now upon us and 2020 on the horizon, Ivowen are setting our sights on the year ahead.

We will be attending the Medicines for Europe conference in January 2020 (Regulatory and Pharmacovigilance) and we encourage you to contact us before mid-January with any specific questions you might like us to ‘ask the regulators’. This is a great opportunity to ask those difficult questions that you just could not get a straight answer to in 2019, on the ever present grey areas of Regulatory procedures.

To help you to plan ahead here are some helpful updates, in brief, as full articles will be posted in 2020:

Falsified Medicines Directive – Where we are now:

  • Implemented on 9th Feb 2019 in all MS except Greece, Italy and Belgium
  • The European Commission has produced a video to explain more about the safety features.
  • The HPRA have extended the use and learn period, initially to Sep 2019 and extended it again to end on a phased basis starting from 31st January 2020.
  • The MHRA is also taking a pragmatic, flexible approach to how they enforce the new legal requirements.

Nitrosamines

 

Ivowen are here to assist you in 2020 and will continue to provide the top quality service you have come to expect from us.

For more information on Ivowen’s services and how we can help you, contact us.

Written by Alice D’Alton.

Brexit… it’s getting closer…

Ivowen have provided some practical guidance and documents below, which may help you prepare for Brexit for products authorised by the DCP and MRP procedures.

Take our Brexit quiz to see if you are ready.

Do you still need to change your MAH(s) in any of the EU Member States because of Brexit?

If so, refer to the following updated guidance issued in January 2019 which details the documentation and requirements to submit a Marketing Authorisation Holder transfer:

CMDh guidance on Brexit, Jan 2019

If you need any clarification or support to complete a Marketing Authorisation Holder transfer, Ivowen will gladly assist you in a timely manner.  Contact us for more information or to make an enquiry.

 

Is the UK your current RMS?

If so, you need to initiate an RMS switch as soon as possible. The guidance issued in July 2018 along with the template issued in June 2018 is required to complete this process. This template needs to be completed and sent to a specific e-mail address at the proposed new RMS. The list of contacts points to send the completed template is provided below:

Guidance:

CMDh guidance on changing RMS

Template for RMS change

List of RMS contacts can be found in the excel spread sheet in the link Contact Points, which can be found here:

MS contact points

If you need any clarification or support a RMS switch, Ivowen will gladly assist you in a timely manner.  Contact us for more information or to make an enquiry.

 

 

Do you need to change your UK batch release site, etc., if it currently within the UK?

If so, you can refer to the updated guidance document issued in December 2018, which provides information on the type of variation that is required to change functions such as batch release site(s), QC testing site(s), packaging site(s), deletion of site(s) for batch release and changes to the QP for Pharmacovigilance (QPPV) and PSMF where these functions still reside within the UK:

CMDh practical guidance for Brexit & DCP/MRP

If you need any clarification or support to complete variations to support changes needed as a result of Brexit, Ivowen will gladly assist you in a timely manner.  Contact us for more information or to make an enquiry.

 

Do you supply product to Cyprus?

If so, the Cypriot Competent Authority has issued a newsletter to Stakeholders on the 14 January 2019 which lists 105 products authorised via an exceptional marketing authorisation affected by Brexit which are considered critical. The Drugs Council in Cyprus recommends that pharmaceutical companies register these products via an exceptional marketing authorisation using another reference state other that the UK.

Cyprus list of essential medicines

If you need any clarification or support to complete an Exceptional Marketing Authorisation to avoid no supply of these critical products on the Cypriot market, Ivowen will gladly assist you in a timely manner.  Contact us for more information or to make an enquiry.

 

 Written by Marian Winder

To 2019 and beyond (Brexit)…

With the festive season upon us and 2019 on the horizon, Ivowen are setting our sights on the year ahead.  So what’s going on in 2019 and beyond, including and excluding Brexit…

What’s happening in early 2019?

We will be attending the Medicines for Europe Regulatory and Scientific Affairs and Pharmacovigilance conferences in January and we encourage you to contact us before mid-January with any specific questions you might like us to ‘ask the regulators’.

Brexit follows quickly on the tail of the new year, and we will all be hopefully ready and able for this new challenge.  Take our Brexit quiz here to see if you are Brexit ready and contact us to help.

What’s happening in later on in 2019?

We are also looking forward to attending the annual TOPRA symposium this year, hosted in Dublin, and we hope to see you at our stand to discuss how we can assist you with your regulatory needs in 2019 and beyond.

What about us?

Ivowen consists of an amazing team with extensive experience of the pharmaceutical industry. Our aim is to understand our customer’s needs and offer services that meet those needs in a timely and efficient way.
As part of EuDRAcon, a pan European network of regulatory consultants, we can provide expert advice on all matters regulatory for the EU and beyond, including Brexit

We hope that in 2019 Ivowen can help you with your specific and unique requests.

And for now…

The office will be closed from the afternoon of Friday 21st December 2018 until Wednesday 2nd January 2019. Merry Christmas and a Happy New Year for 2019!

For more information on Ivowen’s services and how we can help you, contact us

 

 

Written by Mary Canning

Are you Brexit ready?

Brexit in:

[wpcdt-countdown id=”796″]

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 29th 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 29th 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

With the launch of the improved EudraVigilance (EV) System, and the move to the simplified reporting of adverse reaction reports (ADRs) on 22nd 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 4th 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 (22nd November) in the system (EudraVigilance Go-Live Plan).

To facilitate EV users, there will be a 3-day ‘cutover legacy’ period from 22nd – 24th 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 4th to 7th November should be submitted to HPRA after 22nd 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 22nd 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 22nd 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

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/

 

  1. Open Internet Explorer and log into EMA portal. Go to “Send document”.
  2. If you see the “Click to send documents totalling more than 10 MB” then continue to send your submission as normal.
  3. 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.