Last updated on 26 September 2023
See updates at the end of the post.
Guidance for the transition of clinical trials from the Clinical Trials Directive to the Clinical Trials Regulation
The European Commission recently published guidance on the transition of clinical trials, i.e. the implementation of EU Regulation 536/2014.
The transition of clinical trials from the Clinical Trials Directive (CTD) is an administrative process following which the assessment by Member States is reduced to the minimum required to ensure compliance with the CTR rules (i.e. transparency, trial category). To facilitate that process, sponsors are encouraged to register their clinical trials under CTIS at their
earliest convenience taking into account the time needed for the approval of the applications.
The guidance in Q & A format provides information on:
- the type of clinical trials that sponsors have to transfer to CTIS
- the timeline
- the content of the application for mono- and multinational trials.
Clinical trials will be considered regulated by CTR when they are authorised under the CTR by the first Member State on the basis of a transition application.
Only clinical trials authorised under the CTD with at least one active site in the EU on 30 January 2025 need to be transitioned.
Fimea, the Finnish regulatory authority has also published key points based upon the EMA guidance.
Sources: European Commission; Fimea
Guidance to applicants /Marketing Authorisation Holders (MAHs) on oral explanations at EMA
Revision 2 (August 2023) of this guidance has now been published. You can view it here.
Update to the European Medicines Agency post-authorisation procedural advice for users of the centralised procedure
Rev 104 (31 July 2023) of the above document has now been published. Here, you can view the track changed (5 July 2023) and clean (31 July 2023) versions of the document. There are updates to the following Q&As in July 2023:
- 1.4. How shall I present and submit my Type IA/ IAIN Variation(s)?
- 1.10. What changes will trigger new EU number(s) (additional presentation(s))?
- 1.11. How to obtain new EU sub-numbers for Type IAIN variation concerning an additional presentation (e.g. new pack-size)?
- 1.15. Who should I contact if I have a question when preparing my Type 1A variation application or during the procedure?
- 2.12. How to obtain new EU sub-numbers for a Type IB variation concerning an additional presentation (e.g. new pack-size)
- 2.14. Who should I contact if I have a question when preparing my Type IB variation application or during the procedure?
- 3.11. How shall my Type II application be handled (timetable)?
- 3.27. Who is my contact at the European Medicines Agency during a type II variation, including extension of indications?
- 3.28. Whom should I contact if I have a pre-submission question when preparing my type II variation application (non-clinical/clinical/RMP)?
- 6.7. How will variation applications under worksharing be handled (timetable)? What will be the outcome of the evaluation of a variation application under worksharing?
- 8.2. How should I send queries to the pre-submission queries service?
- 19.15. Who should I contact if I have a question when preparing my MAH Transfer application or during the procedure?
- 22.1. What are Article 61(3) Notifications?
- 22.3. When can I submit my 61(3) Notification?
Source: EMA
Report and minutes from the CMDh meeting held on 18-20 July 2023
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:
1a. Call for review for chemically synthesised and biological medicinal products regarding nitrosamine impurities –Update to the Q&A document
The CMDh in liaison with EMA and CHMP has agreed an update of the Questions and Answers for MAHs/applicants on the CHMP Opinion for the Article 5(3) of Regulation (EC) No 726/2004 referral on nitrosamine impurities in human medicinal products.
- Q&A 10 has been amended to include the Carcinogenic Potency Categorisation Approach (CPCA) and the enhanced Ames test (EAT) for establishing Acceptable Intakes (AIs) for N-nitrosamines. The list of nitrosamines for which AIs have been established by the Non-clinical Working Party (NcWP) has been moved to a new Appendix 1, which includes new AIs for N-nitrosamines determined using the CPCA. Annex 2 and 3 have been added to further describe the CPCA and the EAT conditions.
- A further update of Q&A 20 and 21 has been included to remove the universal temporary AI (t-AI), while a formal AI is established, as it is no longer considered necessary.
- Q&A 22 on the approach to control presence of N-nitrosamine exceeding the AI while CAPAs are being implemented, has been amended to extend the scope to authorised products for chronic use and clarify the applicable limits and exemptions.
- You can view the updated Q&A document here. Although Q&A 10 has been updated (see above), it appears not to be shown as ‘updated’ in the document.
b. Updated – Template for the notification of Step 2 confirmatory testing outcome: confirmation of nitrosamine detected
The CMDh and EMA have further updated the template for the notification of step 2 confirmatory testing outcome: confirmation of nitrosamine detected, to reflect the new approaches. You can download the updated template here.
c. MAH concerned by particular nitrosamines with new and revised Acceptable Intakes (AIs) requested to resubmit their step 2 response
As new and revised Acceptable Intakes (AIs) have been published for some nitrosamines, MAHs of products concerned by those nitrosamines are requested to resubmit their step 2 response in the updated template to (re-) confirm under which scenario their products should be classified under the newly published AIs. This is particularly important in case a step 2 scenario A or D response was submitted.
d. Update to Practical Guidance for MAHs of nationally authorised products (incl. MRP/DCP) in relation to the Art. 5(3) Referral on Nitrosamines
The CMDh agreed an update of its Practical Guidance for MAHs of nationally authorised
products (incl. MRP/DCP) in relation to the Art. 5(3) Referral on Nitrosamines.
- As the process for handling nitrosamines is now well-established and Acceptable Intakes (AIs) can be determined in a timely manner with the CPCA, the CMDh does not consider it necessary anymore to keep procedures in clock-stop due to missing data on nitrosamines.
- Any outstanding issues related to nitrosamines would have to be addressed before Day 210 of the DCP without the possibility for post-approval commitments.
Here, you can view the track changed (April 2023) and clean (July 2023) versions of the updated practical guidance document. The changes to the document are in the following sections:
- 1.6. What is the approach for new and ongoing marketing authorisation applications (MAA)?, subsection During the MA evaluation procedure:
- 1.7. How to deal with pending or newly submitted MRPs or RUPs or line extensions?
- 3.1. When should any necessary variations be submitted?
2. Regulation (EC) No 1234/2008 on variations – update of Chapters 4, 5, 7 and 9 of its Best Practice Guides (BPGs)
- The CMDh agreed an update of Chapters 4, 5, 7 and 9 of its Best Practice Guides (BPGs) for the Submission and Processing of Variations in the Mutual Recognition Procedure.
- A statement has been included in the chapters that the applicant should keep data synchronisation between modules 3-5 and module 1.2 during the procedures and submit an updated application form, each time the dossier information is modified in the context of response submissions.
- This is in line with the guidance given for new marketing authorisation applications.
The updated documents have been published on the CMDh website under “Procedural Guidance > Variations”. You can view them at the links provided below:
Chapter 4 : CMDh BPG for the processing of Type IB Minor Variations (Notifications) in the Mutual Recognition Procedure
Here you can view the track changed (December 2022) and clean (July 2023) versions of the document.
There are changes in the following section of the document:
- 2.4. The Evaluation Process (Day 0 to Day 30)
Chapter 5 – CMDh Best Practice Guide for the handling of Type II variations in the Mutual Recognition Procedure
Here you can view the track changed (December 2022) and clean (July 2023) versions of the document.
There are changes in the following section of the document:
- 7. Evaluation
Chapter 7 – CMDh Best Practice Guide on Variation Worksharing
Here you can view the track changed (January 2023) and clean (July 2023) versions of the document.
There are changes in the following section of the document:
- 6. The Procedure
Chapter 9 – CMDh Best Practice Guide on fast track procedure for the annual update of human influenza vaccines
Here you can view the track changed (March 2023) and clean (July 2023) versions of the document.
There are changes in the following section of the document:
- 4.2. Second step – Submission of additional data (if requested)
Clinical Data Publication (CDP) – Q&A on the External Guidance on the implementation of the European Medicines Agency policy on the publication of clinical data for medicinal products for human use (Policy 0070)
Revision 3 (26 July 2023) of this document has been published. The aim of the document is to provide Applicants/MAHs with the information they need to navigate the CDP process – to identify, redact/anonymise and submit documents. The document:
- addresses key questions on the CDP process and provides a compilation of, and references to, relevant guidance, recommendations and supportive documentation to facilitate the submission of documents in the context of CDP.
- will be revised regularly as more information becomes available. New or revised questions will be marked with ‘New’ or ‘Rev’ together with the relevant date.
3. Blister packs with empty cavities – risk for potential medication errors / patient non-compliance
The CMDh agreed by majority with the wording proposed to be included in the QRD stylistic
matters guide to address the issue of empty cavities in blister packs. However, the CMDh
requested QRD to strengthen the wording that the foil of the blister should indicate which
pockets are empty. This was not considered to be an issue with multi-lingual packs as a
simple symbol could be used. The CMDh request will be further discussed by QRD.
4. Bridging requirements for well-established use applications
The Netherlands presented the outcome of a questionnaire to Member States on data requirements for well-established use applications, in particular, which bridging studies are needed.
- Survey responses showed a different interpretation / implementation of the requirements mentioned in Annex I Part II of Directive 2001/83/EC (“The non-clinical and/or clinical overviews must explain the relevance of any data submitted which concern a product different from the product intended for marketing.
- A judgement must be made whether the product studied can be considered as similar to the product, for which application for a marketing authorisation has been made in spite of the existing differences”) by MSs.
- The CMDh agreed to consult MWP in order to establish a consistent approach among Member States, preferably via guidance.
- Questions to MWP will be prepared for further discussion in September.
- The CMDh also stresses to applicants that well-established use applications are strongly discouraged in case a RefMP is available on the market. In such cases, generic applications should be submitted.
Updates
| Date | Update(s) |
|---|---|
| 26 Sep 2023 | Link added to minutes rom the CMDh meeting held on 18-20 July 2023. ALso, Items no 3 and 4 added under the heading Report and minutes from the CMDh meeting held on 18-20 July 2023 |
| 8 Aug 2023 | The following sections were added: i) Guidance to applicants /Marketing Authorisation Holders (MAHs) on oral explanations at EMA ii) Update to the European Medicines Agency post-authorisation procedural advice for users of the centralised procedure |