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.

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

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)
  • 1st Year: Clinical Trials can be submitted under old/current (Directive) or new (Regulation) system
  • 2nd & 3rd 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

CESP expands in Poland and Greece

Latest news from Poland and Greece for CESP

From 3rd April 2017 it will be possible to submit the following procedures via Common European Submission Portal (CESP) to Poland:

  • Initial Marketing Authorisation Applications (MAAs)
  • Variations
  • Renewals

The submissions may concern national and European procedures (MRP, DCP) both for human and veterinary medicinal products.

 

Also from 3rd April 2017 the following submissions should be transmitted through CESP for Greece:

  • All submissions for Mutual Recognition/Decentralised Procedures (MRP/DCP)
  • national procedures relating to approvals, variations, renewals, PSURs, ASMFs etc., as well as any other documentation should be submitted using CESP.
  • Responses to deficiencies and any other additional information that can be requested from the EOF within the claims of assessment.

 

 

What does this mean for you?

To date in Poland, only submissions concerning initial MAAs were possible via CESP. There are still some national requirements in Poland, however.  All documents that require an original signature can be either submitted

  • in electronic version with a valid electronic signature or
  • must be submitted in parallel to CESP in paper.
  • Documentation once submitted via CESP should be submitted via this channel throughout its whole lifecycle.

For submissions into Greece, additional CD/DVDs are no longer required.  In addition, for each submission, a corresponding reference number will be automatically assigned and will be sent directly to the applicant.

 

Where can I find more information?

Full details are available on the Polish Ministry’s website (in Polish) here.

Full information is for Greece (in Greek) here.

 

We can help…

Ivowen are fully equipped to prepare and submit any applications on your behalf.  Please contact us or our EuDRAcon partners for more information and for support of your dossier compilation or updates.

Written by Majella Ryan

ICH Elemental impurities

New ICH guideline Q3D on elemental impurities (EMA/CHMP/ICH/353369/2013)

Elemental impurities guideline

What is it…

The ICH has introduced this new guideline to control the elemental impurities that may be present in drug products. It replaces EMEA guidance on Specification limits for residues of metal catalysts or metal reagents (EMEA/CHMP/SWP/4446/2000).

This guideline applies to new drug products (with a new drug substance) and to drug products containing existing drug substances. There are some exemptions, which you can find in the guideline.
It does not apply to drug products used during clinical research stages of development.

CHMP implementation dates for this guideline are
•    New MA application for new products (new drug substance) – June 2016
•    New MA application for products with existing drug substance – June 2016
•    Marketed products including new MR applications of already approved products – Dec. 2017

What does this mean for you?

Elemental Impurities (EIs) in Drug Product (DP) may arise from several sources. They may be residual catalysts that were added intentionally or may be present as impurities (e.g., through interactions with processing equipment, container/closure systems or by being present in components of the drug product, i.e. drug substance, excipients or water).

Because EIs do not provide any therapeutic benefit to the patient, their levels in the drug product should be controlled within acceptable limits. These limits are outlined in the new guideline.

This guideline presents a process by which to assess and control EIs in the drug product using the principle of Risk Management as described in ICH Q9. This process provides a platform for developing a risk based control strategy to limit EIs in the DP.

The Risk Assessment (RA) should be based on scientific knowledge and principles. It should link to safety considerations for patients with an understanding of the product and its manufacturing process, and it should be focused on assessing the level of EIs in a DP in relation to the Permitted Daily Exposure (PDE) presented in the guidance.

The summary of RA and any measures taken, to ascertain compliance and the overall control strategy for EIs, including any specification as needed, should be provided in the Regulatory dossier.
The documentation of RA should be maintained in company’s quality system and should be kept for inspection (at the time of GMP inspection of the site by the competent authority).

If RA fails to demonstrate that an EI level is consistently less than the Control Threshold, then additional controls should be established to ensure that the EI levels does not exceed the PDE in the drug product. Approaches that an applicant can pursue include but are not limited to:
•    Modification of the manufacturing steps that result in reduction of EIs,
•    Implementation of in-process controls,
•    Establishment of specification limits for excipients or drug substance or drug product,
•    Selection of appropriate container closure systems.

For marketed products, if the RA concludes that additional controls are to be established then the regulatory impact of these additional controls should be evaluated to see whether it triggers a variation(s) to the existing MA.

Where can I find the relevant information…

The new guideline is available on the EMA website. You can find it by following this link.

We can help…

Ivowen are fully equipped to apply for any such variations on your behalf. Please contact us for more information and for support of your dossier compilation or updates.

Written by Nanda Naik

New ATC codes for 2017

The Anatomical Therapeutic Chemical (ATC) Classification is an internationally accepted classification system for medicines.  This system is maintained by the World Health Organisation (WHO).  The WHO assigns ATC codes to all drug substances based on their therapeutic indication. The assigned ATC code must be present in your product information.

What does this mean for you?

Marketing authorisation holders of medicinal products, authorised under the national/mutual recognition/decentralised and centralised procedures should be aware that some ATC codes have recently been changed.

Consequently, if changes have been made to your ATC code/text you must apply for an update of the Summary of Product Characteristics (namely section 5.1 Pharmacodynamic properties) via a Type IA A.6 variation.

Where can I find the ATC codes?

The updated ATC code for human and veterinary medicines can be found in the following links:

Human: https://www.whocc.no/atc_ddd_index/updates_included_in_the_atc_ddd_index/

Veterinary: https://www.whocc.no/atcvet/alterations_in_atcvet_codes/

We can help…

Ivowen are fully equipped to apply for such variations on your behalf.  Please contact us for more information and for support of your dossier compilation or updates.

Written by Fiona Downey

What do I do??

In my circle of friends I feel like I am the “Chandler Bing” and it’s not because I am the funny one; no, it’s because no one knows or understands what I do for a living.

My mother still believes I work in a laboratory and have a working knowledge of all medicines and once even asked me, while holding a single white tablet in the palm of her hand what the tablet was for.

To be honest my description of my job has changed over the years from “you know those leaflets you get with your medicines?  I help write them… do you read them? No! oh?” to “I get and control medicinal product licences in Europe”.

Sounds simple right? Unfortunately no, when I first started, the future was all “harmonisation and no more paper copies” and though it has come a long way, there are certain things that make you yell “ARE YOU SERIOUS” on a weekly basis (my colleagues have learn to ignore these outbursts). These outbursts got me thinking: what would my wish list be to make my life just that little bit easier?

 

Wish List

  1. All Member States should invoice registration fees. It’s one thing finding the fee page of Competent Authority website, it’s another thing calculating the fee (did you remember the administration fee?), to understanding how to pay.  I have a flow chart for one Member State!
  2. Fully electronic, no more original, wet signature, company stamped, revenue stamped,  dated and notarised, less than 6 month old paper copies (I think you know who I am getting at).
  3. One method of submission, i.e. no national portals, CD/DVD, paper, parallel submissions (if France can improve so can every Member state).
  4. Marketing Department: please make up your mind! A week before submission and you decide you want extra Member States added/deleted to the upcoming DCP… at least give me two weeks!
  5. Finance Department: No, I can’t shop around for a better price for a national variation.

Please let me know if you have any wishes to improve your work life and maybe Ivowen can help you (or least sympathise with your struggle).

Written by Fiona Downey

 

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Falsified Medical Directive (FMD) and updated QRD template released February 2016

Falsified medicines are fake medicines that are designed to mimic real medicines. Due to the increase of falsified medicines on the market the EU has a strong legal framework for licensing, manufacturing and distribution of medicines. In July 2011 DIRECTIVE 2011/62/EU (http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2011:174:0074:0087:EN:PDF ) came into force; this directive aims to prevent falsified medicines entering the legal supply chain and thus reaching patients. One of the Directive’s measures is the introduction of safety features on medicines.

 

Update on Safety Features on Medicines:

On February 9th 2016 the EC published an implementation plan for the introduction of the safety features on the packaging of nationally authorised medicinal products for human use:

http://www.hma.eu/fileadmin/dateien/Human_Medicines/CMD_h_/Falsified_Medicines/CMDh_345_2016_Rev00_02_2016_1.pdf

In conjunction, a Regulation was also published laying down detailed rules for the safety features appearing on the packaging of medicinal products for human use:

http://ec.europa.eu/health/files/eudralex/vol-1/reg_2016_161/reg_2016_161_en.pdf

 

What do you need to do?:

The Delegated Regulation will apply in all European countries from the 9th February 2019 (3 years after its publication). Belgium, Greece and Italy have the option of deferring the application of the rules by an additional period of up to 6 years.

There are two safety features to be placed on the packaging of most prescription medicines and certain non-prescription medicines no later than 9 February 2019.

-1). a unique identifier (a 2-dimension barcode) and

-2). an anti-tampering device (ATD).

 

How does this affect your medicinal products and applications?

 New MAAs submitted from April 2016:

  • QRD:
    • Revised QRD template.
  • Revised dossier sections:
    • In the case of medicinal products where the ATD is placed on the immediate packaging because there is no outer packaging and the ATD affects the container and its closure system(s), applicants are required to include information on the ATD and how the ATD affects the container and its closure system(s) (sections 3.2.P.2.4 and/or 3.2.P.7 of the Notice to Applicants Volume 2B)

 Ongoing MAAs

  • QRD:
    • CHMP opinion in March 2016 advised to comply Revised QRD template
    • CHMP opinion from April 2016 onwards, applicants must comply with the revised QRD template
  • Revised dossier sections:
    • As per new MAAs

 Existing MAs

  • QRD:
    • Revised QRD template within 3 years – Can be implemented in Type IA, Type IB, Type II, Renewals, Line extension etc. where the submission affects the product information (PI). Approval of submissions must be no later than the 9th February 2019. If no regulatory procedure occurs within the required timeframe a notification is requested to be submitted pursuant to article 61(3).
  • Revised dossier sections:
    • If the ATD is placed on the immediate packaging and the ATD affects the container and its closure system(s), applicants are required to submit the appropriate variations to include the information on the ATD and how the ATD affects the container and its closure system(s) (see section B.II.e of the Variation Guidelines).
    • If the ATD does not affect the container and its closure system, or is placed on the outer packaging, no regulatory procedure is necessary. However, if the addition of the ATD has an impact on the readability of the packaging information, MAHs are requested to submit mock-ups as per http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2009/10/WC500004891.pdf

Medicinal product no longer needs to bear safety features

  • QRD:
    • Regulatory procedure to remove the standard statements regarding the unique identifier and ATD.
  • Revised dossier sections:
    • ATD on immediate packaging: Regulatory procedure to remove the statements regarding the ATD in the dossier. ATD on outer packaging – no regulatory procedure necessary.

Change of Legal Status

  • QRD:
    • Non-prescription to prescription following a MAH switch application: MAH should use the regulatory procedure to comply with the revised QRD and regulations. Non-prescription to prescription following a Commission referral or a PSUR assessment, the Commission Decision will cover, inter alia, the regulatory requirements to implement the safety features.
  • Revised dossier sections:
    • Non-prescription to prescription: MAH should use the regulatory procedure to include the information on the ATD and how the ATD affects the container and its closure system(s)

 

What does the new QRD template now include?

The new QRD template includes the following sections in: Particulars to appear on <the outer packaging> <and> <the Immediate packaging:

  1. UNIQUE IDENTIFIER – 2D BARCODE
  1. UNIQUE IDENTIFIER – HUMAN READABLE DATA

Updated QRD template in track changes is available here:

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2009/12/WC500029823.pdf

 

Are any medicinal products exempt from the above?

Yes, the medicinal products exempt from the above are listed in Annex I of the Regulation located here:

http://ec.europa.eu/health/files/eudralex/vol-1/reg_2016_161/reg_2016_161_en.pdf

 

Are any medicinal products not subject to prescription but that should include the safety features above?

Yes, the medicinal products not subject to prescription that shall bear the safety features, referred to in Article 45(2) are listed in Annex II of the Regulation located here:

http://ec.europa.eu/health/files/eudralex/vol-1/reg_2016_161/reg_2016_161_en.pdf

If you have any queries on the above, if you would like any help with complying with the new regulation or if you have any other queries please contact us .

Written by Emily Fletcher.

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Points to note on the eAF

General

The eAF is mandatory for all procedures from 01/01/2016 (CP, MR, DC, National in eCTD/NeeS/Paper). However, Presubmission Meeting Requests, Article 61(3) & MAT forms remain the outside scope and can be submitted as paper or PDFs.

Please contact us if you require any assistance with any of the forms or any advice on any of the above procedures. For your convenience, the following is a summary of the important aspects of using the eAF.

  • Always check the e-submission website for the latest version of the eAF (http://esubmission.ema.europa.eu/eaf/)
    • Word versions will be removed from Notice to Applicants in January 2016
    • After 11/01/2016 only version 1.19 will be acceptable for new procedures
    • eAF should be printed for Paper submissions
    • Version 1.20 is planned for April 2016 (unless hotfixes are required before then)
    • It is important to note, and welcome news, that there is no need to update to a newer version of the eAF in the middle of a procedure
    • See the guidelines (update planned in January 2016) and release notes (lists the changes made to newer versions) for further information
    • In line with the proposed move towards a Single Submission Portal (SSP) in place of CESP and the EMA Gateway, there are plans to reformat the eAF into a data capture system that can be submitted directly through CESP. This is in a very preliminary stage.
  • Technical queries should be sent to EMA Service Desk via IT service portal (login)
    • Q&A documents should be consulted first
    • Fast web view warning in the dossier validation report for the eAF can be ignored
  • Procedural queries should be directed to the National Competent Authority (NCA) (and response sent to EMA Service Desk). Complicated queries should be sent to both parties.
  • Webinars are available for the NCAs (to try to reduce the requests for MS specific national requirements)

 

Using the eAF

  • Technical Validation of the form (internal):
    • Once signature is added and form validated, it is now locked. Locked forms cannot be amended. Therefore, the signature should be the last thing added to the form.
    • Always keep a copy of the unlocked form so that amendments can be made (e.g. during preparation or for requests from NCA for updated forms during a procedure)
    • Do not use bookmarks as these may cause invalidation issues
  • Annexes to the form should be filed separately in module 1.2 (do not use the PDF function to insert them into the eAF)
    • Form should be named; cc-form-eaf-var
    • Annex should be named; cc-form-annex-var (e.g. cc-form-5-19 or cc-form-proofpayment)
  • Electronic signature can be an image of a real signature (e.g. jpeg file – a scanned copy of wet signature. This however is not an electronic signature and is only used to close/lock the form) or can also be a line of text which states that signature is on file internally (e.g. “This form was authorised following company policies by Majella Ryan, Regulatory Affairs Manager of Ivowen with authorisation to sign. The signature is on file”)
    • The eAF does not accommodate multiple signatures at present. A separate annex should be provided if multiple signatures are mandatory for a particular NCA. Multiple name sections will be incorporated into version 2.0 but no mention of whether multiple signatures will also be accommodated.
    • The signature should be provided by the responsible MAH or can be provided by any authorised deputy
    • Please also check national requirements for signatures.
    • See Q&A guidance for further information
  • Workaround solutions (e.g. Annex B for multiple MAH or Product names) should always be mentioned in your cover letter
    • Some unforeseen variations (category z) are not adequately accounted for yet. Details of such changes should be outlined in the scope section of form and in the cover letter.
    • Duplicate sections only if products differ with regard to API or Pharmaceutical Form
    • Annex A or Annex B can be used for multiple MAH or Product names. Click on Annex A/B button in form and add the annex as a separate file in Module 1.2
    • Detailed instructions on how to use workaround solutions is available in the eAF Q&A document and the eAF Technical Guidance documents – both are published on the eAF webpage – if you need more advice contact EMA Service Desk.
  • No translations of the eAF are available, nor should they be requested.
  • Drug substances can be entered from controlled vocabulary lists or free text, and these each have different EV codes.
    • The focus should be on using substance, product, organisation and referential (SPOR)
  • Request for New Terms:
  • Strikethrough text function is not available in eAF but text can be copied and pasted (with text struck through) from Word or Outlook
  • In MRP/DCP one common application form is highly recommended, one per pharmaceutical form or strength for all member states in case of new MAA and one eAF for all involved products for all member states in case of variations and renewals.

 

Written by Majella Ryan

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Ivowen summarise TOPRA Annual Human Medicines Symposium 2015

Alice D’Alton from Ivowen was delighted to be asked to provide a summary of Session 4 at the recent TOPRA Annual Human Medicines Symposium 2015. The full summary is provided in the following link:

SESSION 4: Globalisation of pharmaceutical regulation – What do agencies discuss behind closed doors?

For further information or if you have any questions on the information provided, or any other question, please feel free to contact us.

Written by Alice D’Alton

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CESP delivery system updated

The latest CESP system, version 2.0, was officially launched on October 1st 2015 (https://cespportal.hma.eu).

Ivowen has been using this facility regularly and can help to guide you through any aspects that you may be struggling with. There are a few new features which sets it apart from the old version:

  • The delivery file creation, has a new look and layout, with similar drop down menus but in a more user friendly format. The individual member states are now represented by the National Competent Authority logos, as well as their corresponding country flag.
  • The new dashboard feature is easy to find and provides you with real time statistics on what has been uploaded and subsequently delivered.
  • It incorporates a new tracking system which includes the following details:
  1. Delivery Created
  2. Delivery Completed
  3. Data Uploaded
  4. Data Delivered

You will still receive the e-mails confirming delivery, so you can file them.

  • There are also statistics presented in this space (in the form of bar charts) which provide an overview of your CESP activity in 2014 and 2015.
  • You can now also view delivery files which have been created but have not yet been utilised, and these delivery files can now also be re-downloaded but must not be re-used..
  • Furthermore, there is an Integrated delivery file system within CESP, which is very easy to use, but if you wish you can still work with your SFTP (e.g. FileZilla) as before.”

Please contact us if you would like any help with using CESP or have any other inquiries.

Written by Alice D’Alton

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