Last updated: 14 July 2024
Click on the + sign below to see the updates to this post.
ICH eCTD v4.0 package updated
The ICH eCTD v4.0 package has been updated in response to the change requests and/or discussion within the EWG after its initial release.
- There have been number of updates to the ICH IG and both the Support Documentation and the Orientation Material presentations have been updated.
- Additionally, as of May 2024, the Implementation Guide and Controlled Vocabulary documents were split into two different packages to enable Controlled Vocabulary Versioning.
- More information can be found on the ICH Official web site: ICH.
eCTD 3.2.2 new package available
A new version of the EU eCTD M1 Specification, version 3.1, is now published on the eSubmission website
The version 3.1 sees the introduction of a number of changes across the specification, however, more specifically, the introduction of a new annex detailing the list of accepted file formats
(Reminder: the generally accepted file format is the PDF, however, in specific cases, other formats will be exceptionally accepted in the eCTD modules). The changes are reflected in the Release Notes.
The same changes are reflected in the additional files of the EU M1 Implementation Guide package (i.e. eu-envelope.mod, eu-regional.dtd, eu-regional.xsl)
A new version of the validation criteria has been published on the eSubmission website. The version is related to the EU Module 1 Specification version 3.1 and should be used in case of submitting a new sequence according to EU M1 specification v3.1. The new validation criteria will be used for the technical validation for all v3.1 electronic submissions received as of 1 March 2025 to the NCAs and EMA. The changes are reflected in the Release Notes.
| Date | Notes |
|---|---|
| During the initial period of 6 months from 18 June 2024 to 30 November 2024 | applicants can only submit eCTD format submissions compliant with EU M1 v3.0.4 and validation criteria version 7.1. |
| From 1 December 2024 (start of the transition period) until 28 February 2025 (End of the transition period). | eCTDs compliant with EU M1 v3.0.4 or v3.1 and validation criteria v7.1 or v8.0 will be accepted. |
| From 1 March 2025 Mandatory use | Only eCTDs compliant with EU M1 v3.1 and validation criteria v8.0 will be accepted. |
Further information is available at the link below.
Source: eSubmission
Stakeholder consultation on the proposed amendments to the European Commission guidelines on variations categories and procedures
As part of the 2020 Pharmaceutical Strategy for Europe, the Commission is reviewing the current rules governing the procedures for post-authorisation changes to the terms of a marketing authorisation for medicines products for human use, with the purpose to make the lifecycle management of medicines more efficient and future proof and ensuring the protection of public health in the European Union.
The draft delegated regulation was adopted on 11 March 2024 and Commission Delegated Regulation (EU) 2024/1701 was published in the OJEU on 17 June 2024.
- As a next step, the Commission is reviewing the Guidelines on the details of the various categories of variations and operation of the procedures (Variations Guidelines) and, in this respect, proposed amendments compatible with the current legal context are hereby released for the stakeholders consultation with a commenting period until 23 August 2024.
- Overall, the main changes proposed to the Introduction and Procedural section of the Variations Guidelines include:
You can read more about the consultation and where provide feedback in this blog post.
Accelerating Clinical Trials in the EU (ACT EU) initiative launches two advice pilots aimed at improving the quality of applications for clinical trials
ACT EU:
- is a collaboration between the European Medicines Agency (EMA), the Heads of Medicines Agencies (HMA) in the Member States and the European Commission (EC), which seeks to transform how clinical trials are initiated, designed, and run.
- was launched in January 2022 and aims to further develop the EU as a focal point for clinical research, to promote the development of high-quality, safe and effective medicines, and to better integrate clinical research in the European health system. ACT EU features priority action areas that are the basis for the ACT EU multi-annual workplan 2023-2026.
ACT EU has launched the following two advice pilots:
Pilot 1
The first pilot offers developers of medicinal products scientific advice on clinical trials and on requirements for marketing authorisation applications (MAA).
- Assessors of clinical trials are not consistently involved in scientific advice procedures for MAAs, and vice versa.
- In this pilot programme, the Scientific Advice Working Party (SAWP), coordinated by EMA, and the Clinical Trials Coordination Group (CTCG), managed by HMA, will be the bodies assessing incoming requests of a scientific nature.
- The SAWP is responsible for advice on marketing authorisation applications and the Member States represented at CTCG oversee clinical trial applications (CTA).
- This pilot consolidates the views of these two groups to minimise avoidable divergences.
- It is the first time that both entities are providing joint scientific advice on clinical trials.
Pilot 2
The second pilot is coordinated by the CTCG and provides technical and regulatory support on the dossier of a CTA prior to its submission through the Clinical Trials Information System.
- Before this pilot, applicants could only receive technical and regulatory support at national level from the Member State evaluating the application.
- The pre-CTA pilot will provide consolidated views of the Member States concerned on pre-submission topics.
- The scope of this pilot covers a number of areas such as advice on regulatory aspects of low interventional clinical trial status and submission of trials with decentralised elements or complex designs, to name a few.
Starting 10 June 2024, developers of medicinal products who wish to receive advice on the requirements for a MAA or a CTA may apply to these pilots.
- The duration of both pilots will be evaluated over time based on data and feedback collected from applicants.
- All this information will inform a possible change of scope and a final decision from the ACT EU steering group on how to optimise clinical trial support in the future.
Guidance for applicants: pre-CTA advice pilot is available here. Further information and other documents are available at the link below.
Source: EMA
Report and minutes from the CMDh meeting held on 28-29 May 2024
The reports from the CMDh meetings (also called press releases) reflect highlights/important outcomes of each meeting and are usually published in the week following the CMDh meeting. The reports therefore only contain a subsection of the complete CMDh agenda and are used for a more timely communication of the most important outcomes.
The CMDh minutes are a full record of the CMDh meetings (minus redaction of confidential content). They are adopted at the following CMDh meeting and subsequently published.
The report and minutes from the above meeting include (but are not restricted to) the following items:
1. Regulation (EC) No 1234/2008 on variations
The CMDh agreed an update of its Questions and Answers on Variations.
- The Working Party agreed that for Q&A 3.23 of the CMDh Questions and Answers on Variations, in relation to adaptation of the product information (PI) of a generic product following the assessment of the same change for the RefMP which is partially harmonised, the relevant harmonised sections means the sections where the MAH proposes to update information and section within the scope of the variation application.
- CMS can raise comments on other sections of the SmPC if relevant for the scope of the variation (change applied for), however unrelated sections of the PI may not be harmonised within the same procedure.
- The MAH could be encouraged to consider revision of the sections that have been commented on but where not part of the procedure via another type II variation.
- A new Q&A (3.32) has been added to provide guidance on how a change should be submitted to update section 5.1 of the SmPC to include EUCAST breakpoints in line with the Guideline on the evaluation of medicinal products indicated for treatment of bacterial infections (CPMP/EWP/558/95).
- For this purpose a heading and text to be inserted in section 5.1 of the SmPC in all EU languages can be found on EMA’s website.
- The change can be applied for as a type IA variation under category C.I.z with reference to the article 5 recommendation “Change(s) in the SmPC, labelling or package leaflet of human medicinal products in order to adapt to a recommendation of a competent authority, e.g. a Core SmPC, following the assessment of an Urgent Safety Restriction, etc.”.
- In cases where the SmPC wording has to be adapted the change should be upgraded to a variation type IB.
- The updated document has now been published on the CMDh website under “Questions & Answers”.
- Here, you can view the track changed (Dec 2023) and clean (May 2024) versions of the document.
2. Data requested for New Applications in the MRP/DCP
The CMDh agreed an update of the document “Data requested for New Applications in the MRP/DCP which are not stated in the current EU legislation and/or in Volume 2B, Presentation and format of the dossier Common Technical Document (CTD) and/or in the EEA approved Guidelines/Recommendation papers”.
- The document has been reorganised and the information for some Member States has been updated where needed.
- The updated document has been published on the CMDh website under “Procedural Guidance > Application for MA”.
- Here, you can view the track changed (April 2021) and clean (May 2024)versions of the document. This document has been updated substantially.
3. Mock-ups, specimens and samples for variations
The CMDh agreed an update of the document “Mock-ups, specimens and samples for variations”.
- The procedural guidance document has been revised in accordance with current Member States’ practices, where necessary.
- The updated document has been published on the CMDh website under “Procedural Guidance > Variation”. Here, you can view the track changed and clean versions of the document.
4. Active Substance Master File worksharing
In January 2024, the CMDh agreed an update of the document “The worksharing procedure for the assessment of Active Substance Master File (ASMF)” prepared by the Working Group on ASMF procedures.
- The document has been revised based on the experience gained since the implementation of the procedure.
- The main change is to allow already approved ASMFs (with an assessment history of at least 2 years) to step into the ASMF worksharing procedure under certain conditions.
- The EU ASMF number request form will be updated accordingly.
- The procedural guidance document has now been adopted by all relevant groups and has been published on the CMDh website under “CMD Working Parties/Working Groups > WG on ASMF procedures”. Here, you can view the track changed and clean (May 2024) versions of the document. This is a substantial update.
5. Questions and answers on implementation of the medical devices and in vitro diagnostic medical devices Regulations ((EU) 2017/745 and (EU) 2017/746)
The CMDh in liaison with the EMA and the European Commission has agreed an update of the joint EMA/CMDh Questions & Answers for applicants, marketing authorisation holders of medicinal products and notified bodies with respect to the implementation of the Regulations on medical devices and in vitro diagnostic medical devices (Regulations (EU) 2017/745 and (EU) 2017/746).
- The main objectives of this update are to reflect the experience gained from the MDR implementation (particularly Article 117) and IVDR implementation.
- The updated Q&A document has been published on the EMA website and linked from the CMDh website under “Questions and Answers”.
Here, you can view the track changed and clean versions (Rev.4 May 2024) of the document. You can read more about this topic in this blog post.
6. GMP documentation in MRP/RUP
Following the update of the template for request for Mutual Recognition and Repeated Use
Procedures in April, the CMDh discussed a proposal for the process for confirmation of GMP
compliance in MRP/RUP.
- The CMDh agreed by majority that the RMS should actively (re)assess the validity of the submitted GMP documentation in connection with the preparation of the updated AR.
- It was noted that, although the product is already authorised in the RMS, it concerns a new application for the proposed CMS(s).
- In addition, it is expected to streamline the procedure by avoiding further CMS comments concerning GMP.
- Consideration will be given to whether the request form and other documents need to be updated.
7. Acceptance of GMP certificates issued by MHRA
The CMDh discussed the process for use of GMP certificates issued by MHRA for UK and 3rd
country manufacturing sites post-Brexit.
- It was discussed if the current agreement as published in the September 2023 CMDh minutes is still applicable, i.e. valid GMP certificates issued by UK authorities after the end of the transition period can continue to be considered for the purposes of verifying GMP compliance.
- The process for acceptance of GMP certificates issued by MHRA will be further discussed in next meetings
8. Submission of a single ASMF for co-crystal, complex, or a mixture containing more than one active substance
The CMDh rediscussed the submission of a single ASMF for a co-crystal, a complex, or a mixture containing more than one active substance. The discussion was triggered in relation to a specific case of a generic application.
- Malta raised a few questions to the CMDh in relation to co-crystals, complexes or mixtures consisting of two or more APIs, whether these can be considered as a single API and, if so, whether they could be considered as a new active substance (NAS).
- It would be expected that a generic of a fixed-dose combination reference medicinal product would contain the same qualitative and quantitative composition in active substances, therefore, more than one active substance. It was also noted that an ASMF should contain the information related to one well established active substance only.
- There was a general agreement that, for the specific case under discussion, and consistently with the strategy chosen by the applicant, the co-crystal contains more than one active substance, hence it would not be possible to have a single ASMF for the co-crystal. It was therefore agreed that two separate ASMFs are required for similar applications and that the submission of a single ASMF should henceforth be considered as a validation issue by member states preventing the start of the procedure
- In general, most MSs mentioned that the submission of one single ASMF would depend on whether it is accepted to view the specific co-crystal or complex as one well-defined active substance. There was also an agreement that for mixtures containing more than one active substance separate ASMFs are expected for each individual API.
- Finally, there was a question, for the case where separate ASMFs are required, on where the information regarding the formation of the co-crystal, complex or mixture should be included.
- There were divergent views on whether the information could be included in the restricted part, applicant’s part (3.2.S) or section 3.2.P.3. of the dossier.
- Nevertheless, a case-by-case decision should be considered depending on the differences in the manufacturing steps/process of forming the co-crystal, complex or mixture.
9. Medical Device Regulation
NL presented a case of a hybrid application, consisting of a solution that is supplied in a tube
with a long tip for rectal administration.
- The CMDh discussed whether micro-enemas with a long nozzle should be classified as medical device or container closure system.
- The advice from the CMDh/EMA MDR subgroup was that it can be considered as a container closure system.
- Some MSs were in favour of its classification as medical device and will provide their arguments for further discussion on the next steps and which groups/bodies could be consulted (Action: MSs)
10. Data exclusivity of Art. 10a dossier when generic product is already authorised under the same GMA
The CMDh discussed the feedback provided by the EC following a question on the potential
data exclusivity of a medicinal product authorised under Article 10a of Directive 2001/83/EC
(well-established use (WEU)) when a generic product is already authorised under the same
global marketing authorisation (GMA) and the reference medicinal product disappeared due to
Brexit.
- It was clarified by the Commission, that in such a scenario, a WEU MA can be used as a reference medicinal product (as per the Olainfarm judgment- C-104/13)).
- In addition, it was confirmed that the WEU MA would not trigger a new start of regulatory data protection when there is already a generic authorised under the same GMA.
- In any case, the 8-year period for its use as a Reference Medicinal Product (RefMP) must be observed, starting from the date of the MA of the generic product.
- The specificity of this post-Brexit scenario was also stressed by the EC, and the fact that it is more a theoretical example.
- The CMDh agreed to send a follow-up question to the EC on the remaining open issues
11. Pilot project on submission of bioequivalence study data in CDISC format
Denmark provided an update to the CMDh on the ongoing pilot project on submission of
bioequivalence study data in CDISC format.
- DK presented the feedback from the companies participating in the project.
- The pilot has been extended in order to gather more experience to decide whether the use of clinical data in CDISC format should be used routinely in connection with the assessment of marketing authorisation applications.
12. Bioequivalence studies for two strengths with different RefMPs
Spain informed the CMDh of a marketing authorisation application under Article 10(1) of
Directive 2001/83/EC, which is currently in clock-stop.
- In this application different reference medicinal products (RefMPs), belonging to different global marketing authorisations (GMAs), have been chosen by the applicant for each of the strengths.
- For each of the strengths a separate bioequivalence study was submitted per each corresponding RefMP.
- The CMDh discussed whether the notion of GMA is fulfilled in the above-mentioned MAA or if only one RefMP from one GMA can be used for both strengths when submitted within the same procedure (same procedure number).
- It was noted that, in this case, the handling of the product information could be complex as there are separate RefMP SmPCs.
- Some MSs reported that they would request the submission of a separate procedure per RefMP.
- The CMDh agreed to consult the EC on whether the concept of GMA is correctly applied in this situation and, if not, what would be the possible legal basis to refuse one of the strengths
- Spain will draft the question for written agreement
Data requested for New Applications in the MRP/DCP which are not stated in the current EU legislation and/or in Volume 2B, Presentation and format of the dossier Common Technical Document (CTD) and/or in the EEA approved Guidelines/Recommendation papers
The document with the above title has been updated substantially. Here, you can view the track changed and clean versions.
Source: HMA
The Worksharing Procedure for the Assessment of Active Substance Master File (ASMF)
The document with the above title has been updated quite substantially. Here, you can view the track changed and clean versions.
Source: HMA
Procedural advice on paediatric applications
This guidance has been updated to Rev. 9.0 4 June 2024. You can view it here.
Source: EMA
User guide for micro, small and medium-sized enterprises
This user guide was updated in March 2024, specifically Section 4.4. Clinical trial applications and their management – reflecting changes in Clinical Trials Regulation. The update was made available recently. You can view it here.
Source: EMA
Simultaneous National Scientific Advice (SNSA)
For the above, the list of participating NCAs and contact information was updated in June 2024. You can view the updated list here.
Source: HMA