Legal basis

Back to Basics – Regulatory 101 – Legal basis of your MA application in the EU and UK

With our new logo and new website we expect some new visitors, so, I decided to go back to basics for those who may be new to Regulatory Affairs.
(If you need help with the jargon visit our A-Z Glossary of Regulatory abbreviations)

So, let’s start with the Legal Basis which forms the first step of your MA application (MAA for short). You need to know the legal basis before you can finish compiling your application.
The legal requirements and necessary procedures for submitting an initial application for an EU marketing authorisation (MAA) are set out in Directive 2001/83/EC, as amended, and in Regulation (EEC) No. 726/2004 (the latter for CP applications).
The legal requirements for a UK MAA are set out in the Human Medicines Regulations.

The relevant articles and regulations from this legislation are provided below followed by a brief description of each legal basis:

Table

1. Full/Complete
An application for a marketing authorisation (MAA) must be accompanied by the particulars set out in Article 8(3) of Directive 2001/83/EC, as amended, and as well as all the usual documentation will also require the results of
• Physico-chemical, biological or microbiological tests,
• Pharmacological and toxicological tests,
• Full Clinical trials in human subjects
This Legal basis is most often used for brand new medicines (Drug Product) or active substances (Drug Substance) which have never been authorised in EU or UK before. It results in 10 years or 8+2+1 years of data exclusivity. No generic version can be marked until this exclusivity expires.

2. Generic
This is used when the medicinal product (Drug Product) for which an MA is sought is considered essentially similar to and interchangeable with a medicinal product that has already been authorised via Article 8(3) in the EU or UK.
Essentially similar means it has the same active substance, the same amount of active substance (strength), and the same pharmaceutical form.
In this case the Applicant cross refers to an already approved EU/UK reference medicinal product (RMP for short) to use its already approved data on the Pharmaco-toxicological and Clinical aspects of the application and so does not need to repeat these trials. Instead a bioequivalence study in human subjects is required. This data will show that the product is safe and works the same way inside the human body as the RMP does.

3. Hybrid
These are applications which rely on a mixture of data – i.e. a cross reference to the RMP for some aspects of the clinical and pre-clinical data requirement plus provision of additional data in support of any aspect of the proposed drug product which is different to the RMP (i.e. where it is not essentially similar).
This type of application is used when the proposed product has a different/new indication, different/new dosage form, different/new strength, etc. that is not currently approved for the RMP.

4. Biosimilar
These are generic products which are derived from a biological source rather than a chemically synthesised molecule.
It is often difficult to treat biosimilar generic products in the same way as we treat ‘regular’ generics as it is very tricky to prove essential similarity in the conventional ways – therefore provision of some preclinical and clinical data may be necessary to prove safety and efficacy of the biosimilar product.
The Guideline on similar biological medicinal products should be consulted when considering using a non-EEA authorised comparator (i.e. a non- EEA authorised version of the RMP) in the development of a biosimilar.

5. Well Established Use/Bibliographical
It is possible to replace results of pharmacological and toxicological tests or clinical trials with detailed references to published scientific literature if it can be shown that the drug has a ‘well established use’ with recognised efficacy and known safety.
The minimum criterion for using this legal basis of application is that the drug substance concerned has to have been marketed (i.e. in use) in the EU for at least 10 years. It is commonly used when no RMP exists to refer to or to perform a bioequivalence study against.
This type of application, although allowed for under the legislation, is not always accepted by member states (and they have been known to request clinical data, during assessment) but with the use of real-world data and evidence on the increase this type of application may become more common. Only Time will tell.

6. Fixed Combination
In the case of new drug products containing known active ingredients (drug substances), not before used in combination for therapeutic purposes, the results of pharmacological and toxicological tests as well as clinical trials in human subjects, relating to that combination, must be provided.
This legal basis covers entirely new products that are a mixture of two or more drug substances (sometimes called monocomponents), which have already been authorised and marketed in the EU in their own right. Because this is theoretically a full, stand-alone application (not unlike Article 8(3)), the product enjoys the full 10 or 8+2+1 years data of exclusivity.
Please note that the concept of the global marketing authorisation applies here so once a combination is approved any new application(s) for the ‘same’ product cannot be considered new combinations anymore and so an article 10b would not be acceptable in this situation.

7. Informed consent/Duplicate
The Marketing Authorisation Holder (MAH for short) of a complete/standalone dossier (i.e. the originator/innovator/RMP) can consent in writing to allow a new applicant/MAH to refer to the contents of their approved MA (on file with Competent Authority) for the purpose of obtaining a new MA.
The reference dossier must be a complete dossier (Article 8(3)) and consent must be obtained for all three modules containing the pharmaceutical (Module 3), preclinical (Module 4) and clinical data (Module 5).

The Applicant must choose the correct legal basis in advance of submission and selecting the wrong one will delay your application.

If you need any clarification or support contact us and we will gladly assist you.

If you are starting out in Regulatory Affairs and you now have a long list of questions after reading this article, we can help. We provide detailed training for all levels of Regulatory experience. You or your manager can contact us for details and our training menu.

Written by

Fiona Downey 1

Fiona Downey 1

ICH Elemental impurities

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

A revised ICH Q3D guideline (R2) on ‘Elemental Impurities’ (EMA/CHMP/ICH/353369/2013) will come into effect on 24 September 2022.

The guideline is revised:

  • To amend permitted daily exposure (PDE)
  • To amend monographs
  • To add a section on limits for elemental impurities for cutaneous and transcutaneous formulations.

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

If Risk Assessment (RA) fails to demonstrate that an Elemental Impurities (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.

Ivowen is 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

Nanda Naik

Vet article feature image 05 04 22

The new veterinary regulation (Regulation 2019/6) and its implications on regulatory submissions for veterinary medicinal products

The new veterinary regulation (NVR), Regulation 2019/6 applied to all EU Member States from 28 January 2022. The new legislation represents a significant change in how veterinary medicinal products are authorised, monitored and controlled in the EU.

The Regulation was developed in order to implement a fit-for-purpose veterinary legislation which would no longer be based on the equivalent human medicines authorisation system.

The legislation repeals Directive 2001/82/EC.

The changes are intended to:

  • reduce the administrative burden on companies and regulatory authorities
  • enhance the availability of veterinary medicinal products
  • stimulate innovation of new and existing medicines
  • strengthen the EU response to fight antimicrobial resistance.

The new Regulation 2019/6 is broken down into the following chapters:

I. Subject matter, scope and definitions

II. Marketing authorisations

III. Procedures for marketing authorisations

IV. Post marketing authorisation measures

V. Homeopathic veterinary medicinal products

VI. Manufacturing, import and export

VII. Supply and use

VIII. Inspections and controls

IX. Restriction sand penalties

X. Regulatory network

XII. Common and procedural provisions

XII. Transitional and final provisions

Here is a summary of some of the noteworthy regulatory changes that have been introduced in chapters II, III & IV of the new veterinary regulation:

Chapter II – Marketing Authorisations:

An MA for a veterinary medicinal product shall be valid for an unlimited period of time. Hence, there is no longer a requirement for a renewal procedure or the sunset clause.

Chapter III – Procedures for marketing authorisations

  • Decentralised Procedure:
    • Scope and timelines remain unchanged
    • Responsibilities of RMS, CMS and applicant have changed at some steps of the procedure. For example,
      – CMSs will also provide comments directly to the applicant at Day 100 and Day 145 instead of to the RMS only (therefore, comments are no longer anonymised).
      – at Day 100-105 and Day 145-150, the applicant will now compile and circulate the LoQs.
      – at Day 210, RMS will now be required to circulate a Final Assessment Report (FAR).
    • Possibility now for re-examination request by applicant according to Article 50 of the NVR. For further information on this change, note that CMDv have published a Best Practice Guide for Re-examination of RMS assessment report procedure.
  • Mutal Recognition Procedure:
    • Scope remains the same. However, a minimum of six months is required between the decision granting the national MA and submission of an application for a MRP.
    • 90 day procedure length remains unchanged but there are changes to some of the time-points in the procedure.
    • Responsibilities of RMS, CMS and applicant have changed at some steps of the procedure, similar to those outlined above for the DCP.
  • Centralised Procedure:
    • Scope of the mandatory use of the procedure has been widened. Refer to Article 42 (point no. 4) for details.
  • National Procedure:
    • No significant changes.
  • Subsequent Recognition Procedure (SRP):
    • Previously known as the “Repeat Use Procedure” is now officially recognised under Article 53 of the NVR.
    • Timelines and other requirements have been changed.

Due to the changes caused by the new regulation, CMDv have published updated guidance for DCP, MRP and SRP procedures:

https://www.hma.eu/veterinary-medicines/cmdv/procedural-guidance/applications-for-marketing-authorisation/authorisation-procedures.html

Chapter IV: Post marketing authorisation measures (Variations)

In terms of variations to marketing authorisations, one of the main changes arising from Regulation EU 2019/6 is that instead of the previous categories of Type IA, IB and II variations there will now only be two categories of variations:

  • Variations Not Requiring Assessment = VNRA
  • Variations Requiring Assessment = VRA

Vet article image 05 04 22

 

 

 

VNRAs consist of all the previous type IA and some Type IB variation categories.

VRAs will consist of most of the previous Type IB and all of the Type II variation categories.

Commission Regulation 1234/2008 will now no longer apply to veterinary medicinal products due to the introduction of new veterinary regulation (2019/6).

 Variations Not Requiring Assessment (VNRA)

The Implementing Regulation (EU) 2021/17*, includes a list of all variations not requiring assessment along with any associated conditions and documentation requirements and is published in the EU Official Journal here.

The variations are classified as follows:

  1. Administrative changes
  2. Changes to the quality part of the dossier
  3. Changes to the safety, efficacy and pharmacovigilance part of the dossier
  4. Changes to the vaccine antigen master file (VAMF) part of the dossier

VNRAs will be processed as follows:

  • The MAH will:

– Record the change in the Product Union Database (UPD) within 30 days of implementation including required documents (no application form is necessary).
– Documents submitted directly to UPD. No CESP submission. Documents include those listed in the Implementing Act as well as SPC, package leaflet, labels.

  • The relevant CA/RMS will

– Approve/reject the variation
– Inform MAH & CMS by recording decision in database and by e-mail

CMDv has written a Best Practice Guide for variations not requiring assessment in order to provide detailed guidance on the new process.

The EMA website includes a video tutorial showing how to submit a VNRA via the Union Product Database here.

Variations Requiring Assessment (VRA)

Every change not listed in the Implementing act mentioned above (2021/17)* will require a variation that needs to be assessed.

CMDv and EMA have written a new classification guideline for the VRAs:
Guidance on the details of the classification of variations requiring assessment according to Article 62 of Regulation (EMA/CMDv/7381/2021).

The format and categorisation is similar to the previous regulation which applied (Commission Regulation 1234/2008 ), however there are many differences.

The variations are divided into chapters as follows:

E. Administrative changes
F. Quality changes
G. Safety, Efficacy and Pharmacovigilance changes
H. VAMF or, PTMF changes
I. Changes of active substance(s), strength, pharmaceutical form, route of administration or food producing target species

Z-categories have also been included to address unlisted variations and VNRA, if requirements laid down in the Implementing Regulation are not met.

The timetable for VRAs is also outlined in the new guidance as follows:

  • a standard timetable, denoted by ‘S’ which will be 60 days
  • a reduced timetable, denoted by ‘R’ which will be 30 days
  • an extended timetable, denoted by ‘E’ which will be 90 days

For details on how to submit a VRA, CMDv have written a Best Practice Guide for Variations Requiring Assessment (EMA/CMDv/144277/2021). It has been prepared in order to facilitate the processing of VRAs for MRP/DCP products. The same general principles will apply to purely nationally authorised products.

Recommendation for the classification of variations not already listed

A procedure for requesting a recommendation for the classification of variations not already listed in either the above-mentioned Implementing Regulation or the EMA/CMDv Guidance on variations requiring assessment has also been established. This is similar to the previous CMDv recommendations for classification of unforeseen variations, according to Article 5 of Regulation 1234/2008.

Refer to CMDv new guideline for detailed advice this new process entitled: Procedural advice for requests for the classification of variations not already listed in Commission Implementing Regulation (EU) 2021/17 or EMA/CMDv Guidance on the details of the classification of variations requiring assessment according to Article 62 of Regulation 2019/6 (EMA/CMDv/144284/2021).

Worksharing and Grouping

Grouping and worksharing procedures do not apply to VNRA, they only apply to VRA.
As a consequence, no VNRAs can be included in a grouping or worksharing even if they are consequential or related to the VRAs included in the grouping or worksharing procedure.
However, the introduction section of CMDv Best Practice Guide for Variations Requiring Assessment (which also covers grouping), outlines the different approaches to follow when there is a need to co-ordinate changes that are related or consequential but are classified as VNRA and VRA.

The worksharing procedure is outlined in Article 65 of the NVR and it will be compulsory to follow this procedure, when the same change is being applied in different member states. Information related to worksharing is also mentioned in the CMDv BPG for Variations Requiring Assessment. However a specific guide on worksharing has also been written by CMDv: Best Practice Guide for Worksharing (EMA/CMDv/204024/2021).

Union Product Database

Due to the new regulation, the EMA has introduced new IT systems. The main one will be the Union Product Database (UPD).

It will contain information for all authorised veterinary medicines in the EU (including all nationally authorised products). For MAHs, it will provide self-service access for specific regulatory activities, including the management of variations that do not require assessment.

For more information on implementation, training, registration and access of the UPD, refer to the following link here on the EMA website.

The UPD will be linked to the other 3 other databases in the future. These databases are at different stages of development and introduction:

  • Union Pharmacovigilance Database

On 28 January 2022, the Union Pharmacovigilance Database (EVV) was successfully released. User guidance and the release notes are available here.

  • Manufacturing and Wholesale Distribution Database

The Manufacturers and Wholesale Distributors database (MWD) was released on 28 January 2022. The system is an enhanced and upgraded version of EudraGMDP, the EU database of manufacturing authorisations and certificates of good manufacturing practice, with changes affecting both the veterinary and the human domains. The MWD Project Group has also adopted requirements for aligning the GDP module with the change made to the system so far. Changes to the module will be delivered in a subsequent release scheduled for Q1 2022. In addition, enhanced search facilities on the GMP module will be delivered in the same release.

  • Database for the Collection of Data on Sales and Use of Antimicrobials in Animals.

IT development on the Collection of Antimicrobials Sales and Use Data (ASU) project started in January 2022. Information on the progress of this project will be published on the EMA website as this project develops.

Q&A on transitional arrangements

CMDv has prepared a Q&A document in order to assist both MAHs and NCAs in the management of the transition between the requirements of Directive 2001/82/EC and Regulation (EU) 2019/6. This Q&A document will be regularly updated and can be found under the following link.

This document includes an Annex which outlines how individual Member States will handle renewals of marketing authorisations after 28 January 2022.

Should you need any support with Veterinary Procedures feel free to contact us & the Ivowen team will be here to help.

Written by Claire Brown

Claire Brown

Hot Air Baloon

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.

Alice Dalton

Ivowen stand 1 02 10 19

Ivowen attended TOPRA Symposium 2019

This year’s TOPRA Annual Symposium was held in Dublin in October. The Annual Symposium is an essential meeting for regulatory professionals to gain both an understanding of current and evolving regulatory requirements, as well as insights into future plans for regulations in the Human medicines, Veterinary medicines and Medical Device sectors.

Three members of our Team attended the Symposium this year, Majella Ryan, Alice D’Alton and Nanda Naik. This year was particularly satisfying for Ivowen as we had an exhibition stand at the three day event.

As well as exhibiting, Ivowen attended the sessions including ‘Life after Brexit’. This session was a live discussion of predictions and concerns about the possible outcome of ongoing negotiations with the EU.

Now that an extension has been granted, which will delay the UK exit until January 2020, we are left wondering if we will finally know the UK position when Ivowen attend the Medicines for Europe regulatory conference being held in Amsterdam on 29th – 31st January.

In the meantime, we await instruction from the regulators on whether UK will still be available on the CESP portal later this week. Ivowen is registered on the new MHRA submissions portal so either way we have you covered.

Ivowen will keep you up to date in the coming days and weeks

Please contact us, Ivowen are dedicated to keeping you up to date with the latest regulatory updates and innovations. We remain at your disposal to assist in all of your regulatory endeavours today and into the future.

Written by Alice D’Alton.

Brexit3

Brexit – because it affects you too…

The European Union is arguably the world’s most powerful bloc and very soon it’s about to lose the United Kingdom, one of its biggest members. How and when the UK leaves the EU will have further implications that ripple around the globe.

So if you’ve heard about Brexit but haven’t been keeping up with every twist and turn of the developments, no worries! Ivowen team will provide you with everything you need to know to have your products designed for UK and Brexit affected markets authorised successfully.

What is happening?

EMA

The European Medicines Agency (EMA) will physically relocate to the Netherlands in early March 2019.

https://www.ema.europa.eu/documents/press-release/ema-relocation-updates_en.pdf

EMA will leave its premises in London on 1 March 2019.

It was confirmed that from 4 to 8 March, the Agency will operate on the basis of extended teleworking. During the course of the following week  EMA staff will gradually move into the Spark building.

From 4 March 2019 onwards the official address of EMA will be that of the permanent building, located in Amsterdam Zuidas:

European Medicines Agency, Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands

Meetings and visits will take place at the Spark building:

Orlyplein 24, 1043 DP Amsterdam, The Netherlands

 

UK guidance on Brexit

Following the outcome of the EU referendum, MHRA still feels responsible for playing a crucial role in medicines and devices regulations as well as vigilance and market surveillance.

As part of the MHRA response to exiting the EU the following Brexit guidance was issued:

Technical information on what the implementation period means for the life science sector

Update on negotiations and further guidance for pharmaceutical companies planning in advance of the final negotiated settlement

Further guidance note on the regulation of medicines, medical devices and clinical trials if there’s no Brexit deal

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.

 

MHRA guidance on Brexit

Bearing in mind the worst-case scenario if the UK leaves the EU with no deal, the UK would no longer be part of the EU medicines and medical devices regulatory networks and  consequently submissions related to human medicines would need to be submitted directly to the MHRA.

The webinar below is relevant for all pharmaceutical companies involved in making medicines regulatory submissions and vigilance activities. It also ensures that stakeholders can be informed of any IT plans and preparations. There is also a section on how all medicines related clinical trial sponsors will register and submit:

https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/772918/Making_submissions_to_the_MHRA.pdf

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.

 

UK legislation on medicines and medical devices

Legislation has been published which, in the event of the UK leaving the EU with no agreement, will cover the regulation of medicines, medical devices and clinical trials and allow for the continued sale.  The Brexit guidance is available here:

  1. Human Medicines Regulations 2012, as amended by the Human Medicines (Amendment etc) (EU Exit) Regulations 2019
  2. The Medical Devices (amendment) (EU exit) Regulations 2019
  3. The Medicines for Human Use (Clinical Trials) (amendment) (EU exit) Regulations 2019

The 2012 Regulations (as amended by the 2019 Regulations) make reference to various pieces of EU guidance, as that stood immediately before the exit day (29 March 2019).

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.

 

EU Commission and EMA Q&As

The EU Commission & EMA have published an updated list of questions and answers related to the UKs withdrawal from the EU on the 1st February:

https://ec.europa.eu/info/sites/info/files/medicinal_products_for_human_and_veterinary_use-qa_en.pdf

This confirms that dual labelling between UK & Ireland is acceptable where the labels meet the requirements of the Directive and reflect the SPC in Ireland (see Q24).

The focus of this Q&A is on the regulation of medicinal products  within the centralised procedure.

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.

 

Brexit Stakeholder Event

Brexit Stakeholder Event – Ivowen was there

Following the UK’s departure from the European Union, the HPRA, together with medicines agencies in Europe, is making preparations to ensure continuity to deliver on patient and animal health remits even if the UK fully exits the current systems as scheduled. There are potential implications for the European network as a whole and particularly for Ireland with its shared marketplace, see meeting agenda below:

Agenda for Brexit Stakeholder event 1 Feb 2019

Contact us if you would like some more information on this event or Brexit in general

 

KD

Written by Karolina Dobrychłop

CT banner 1

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

CT

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

fiona downey

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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