CMDh and other EU updates-September 2023

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Last updated: 19 October 2023

See updates at the end of the post.

Clinical Trials Regulation (EU) No 536/2014 Questions and Answers

The Q & A document has been updated to Version 6.6 of September 2023. You can view it here. The changes to the document are as follows:

  • Review of point 102.
  • New Q&A 7.51
  • Review Q&A 9.4
  • Annex II: NL (fields of the application form) ; SK, EE, LV (patient facing documents)
  • Annex III : LU contact points for part I and II.

Source: European Commission

Report and minutes from the CMDh meeting held on 12-13 September 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:

1. Overview of outcome of EU safety assessments

MAHs are responsible to keep their product information up-to-date and in line with the current scientific knowledge or recommendations. MAHs are responsible for regularly monitoring relevant sources of new information and recommendations.

To facilitate this task, the CMDh has agreed an update of the CMDh website.

  • Under the heading “Product information”, the CMDh will provide an overview of outcome of EU safety assessments via various procedures.
  • This part of the CMDh website will provide a compilation of links where to find recommendations and outcomes resulting in amendment of the product information.

2. Update of eAF at the end of procedure (MRP/DCP)

In December 2020, the CMDh agreed that the Electronic Application Form (eAF) should be the leading document and should be updated with every applicant’s response if the information on manufacturers is changed during the procedure. The information should be synchronised with module 1.2 and module 3.

For the end of procedure (EoP) only the final information in Module 1.2 with Annex 5.8 will be considered. The “Applicant’s response document in MRP and DCP for MAAs” has been updated accordingly at the time.

  • However, the CMDh noted that in many cases the applicants still do not synchronise the information on manufacturers in the eAF with module 3 during the procedure and up to the EoP, resulting in an increased workload during the national phase.
  • The RMS and CMS will keep alerting applicants to keep the eAF up to date until the EoP. However, the CMDh has now agreed that when discrepancies between Module 3 and Module 1.2 are identified after EoP, a variation will be requested to include/correct the information on the manufacturer. The variation has to be submitted according to the relevant category of the classification guideline, including all relevant documentation. At the EoP, the MA will be issued based on the information available in the latest version of the eAF at EoP.
  • The Applicant’s response document in MRP and DCP for MAAs and the user guide for the eAF for a MA have been updated accordingly. A tick box has been included in the Applicant’s response template in DCP to confirm that data between module 3 and module 1.2 has been synchronised.
  • The updated documents have now been published be published on the CMDh website under “Procedural Guidance > Applicant’s Response”, “Procedural Guidance > Application for MA” and “Templates > Assessment reports > DCP (AR/Comments)”, respectively

Here, you can view the track changed (December 2021) and clean (September 2023) versions of the User Guide for the electronic application form for a Marketing Authorisation

Here, you can view the track changed (September 2022) and clean (September 2023) versions of the Applicant’s response document in MRP and DCP for MAAs

3. Regulation (EC) No 1234/2008 on variations

The CMDh agreed an update of its Questions and Answers on Variations. A new Q&A (3.31) has been added on how to submit new or updated environmental risk assessment. Reference is made to the EMA post-authorisation guidance on (non-)clinical changes (question 3.2), as the CMDh agreed to follow the same approach.

The updated document has now been published on the CMDh website under “Questions & Answers”.

Here, you can view the track changed (May 2023) and clean (September 2023) versions of the document.

The WP Chair informed the group about the discussions on how to improve the handling of Worksharing (WS) variations. Upon identification of parallel submissions of the same variation and product in other MSs, the WP agreed that a WS should be requested for all cases of safety-relevant changes, indications and posology (not all cases need to be brought to the CMDh, only when a CMDh letter is requested).

It was agreed to perform a systematic check (every 6 months) of the submission of WS variations after being request by the CMDh.

In addition, a questionnaire will be circulated to collect the different NCAs approaches with the aim to better understand the challenges posed by safety/clinical WS variations and to propose plausible solutions to make these procedures more efficient and therefore attractive for use by most MAHs.

The CMDh was informed of a proposal to submit type IA-A1 variations only for the RMS and CMS affected by the change in MAH information. This proposal was not accepted, as simultaneous submission to CMS is a legal requirement.

4. Practical guidance for procedures related to Brexit for medicinal products for human use approved via MRP/DCP

In May 2023, the CMDh agreed a new Q&A on variations (Q3.30) giving guidance on the submission of variations for generics/hybrid medicinal products in cases when the Reference Medicinal Product (RefMP) from the initial MA has ceased to be valid. As similar information is given in the practical guidance for procedures related to Brexit (Q39), the CMDh agreed to simplify the information given in the Brexit guidance and to cross refer to the Q&A on variations instead.

The updated document has now been published on the CMDh website under “Brexit”.

Here, you can view the track changed (May 2022) and clean (September 2023) versions of the document.

5. Timetables for MRP/DCP applications referred to the CMDh in accordance with Article 29(1) of Directive 2001/83/EC

The CMDh has adopted an updated guidance document with the timetables for MRP/DCP applications referred to the CMDh for the 60-days referral procedure in 2024. The updated guidance document will be published on the CMDh website under “CMDh referrals”.

You can view the updated document (September 2023) here.

6. Acceptance of GMP certificates issued by MHRA

In light of the EU-UK Trade and Cooperation Agreement (TCA) with regards to GMP certificates for third countries issued by the MHRA and the related guidance published by the EMA, as well as the GMDP IWG position statement on risk-based approach for use of GMP certificates issued by UK authorities for UK and 3rd country manufacturing sites post-Brexit, the CMDh agreed to apply the principles as included in the IWG position statement:

  • As of the end of the transition period, manufacturing sites with a GMP certificate issued by an UK authority before the end of the transition period can be considered EU GMP compliant for the validity period of that GMP certificate, provided that subsequently no EU/EEA competent authority raised a GMP non-compliance statement regarding the manufacturing site.
  • Valid GMP certificates for sites located in the UK and in 3rd countries issued by UK authorities after the end of the transition period, can continue to be considered for the purposes of verifying GMP compliance in the context of regulatory submissions and/or importation requirements without prejudice to national legislation in the EU/EEA, provided that:
    • the scope of the UK GMP certificate encompasses the facilities, dosage forms and/or manufacturing processes for which it is being relied upon in the EU/EEA
    • an inspection by an EU/EEA authority is not possible due to limited resources or
      travel restrictions
    • MHRA and VMD keep on providing information about GMP compliance and noncompliance and participation as PIC/S members to the Rapid Alert Network system

7. TiO2 (E171) used as excipient

The CMDh was informed of a letter sent by the EC to EMA requesting an updated analysis of the feasibility of alternatives to replace TiO2, without negatively impacting the quality, safety and efficacy of medicines and, if the feasibility is confirmed, the impact on the availability of medicinal products. The request follows Art. 3 of Regulation (EU) 2022/63, which foresees a re-evaluation of the situation within 3 years after the date of entering into force of the Regulation.

The EMA informed the CMDh of the next steps. A drafting group will work on the analysis. A meeting with industry representatives is being organised.

8. Medical Device Regulation

Repeat Use Procedures

The CMDh discussed the handling of Repeat Use Procedures (RUPs) in relation to the MDR. The EMA/CMDh Q&A states that MRP/RUP is a new MA in the concerned MS and the dossier must comply with the regulatory requirements applicable at the time of the MRP/RUP application. However, the EC Q&As regarding the transition period for medical devices already on the market give options for devices that can benefit from the extended transitional period, provided that the conditions as laid down in Article 120(3c) MDR are fulfilled.

It was agreed that a proposal will be prepared for a potential update of the EMA/CMDh Q&As for further discussion in the MDR small group. The proposal will then also be discussed with the EC.

Missing information from Notified bodies

There was also a discussion if missing information from notified bodies should be a validation or assessment issue, and if handled during assessment, if the missing information would prevent the granting of the MA or if commitments to provide the information could be accepted. It was agreed that missing information from notified bodies should not be a validation issue, but the handling of missing information at the EoP needs further reflection.

9. Legal basis for combination pack for an ongoing procedure

Due to different opinions during validation of an ongoing procedure, the CMDh discussed the most appropriate legal basis for a combination pack of tablets and film-coated tablets containing two different active substances. The application was submitted under Art. 8(3) and consists mainly of literature data and a BE study for one of the components.

It was noted that the Notice to Applicants (NtA) specifies that, in very exceptional circumstances, which must be considered on a case-by-case basis, the marketing of distinct medicinal products in the same package may be indispensable for public health reasons. Such reasons cannot be related to convenience or commercial purposes.

  • MSs expressed different views on what could be a potential acceptable legal basis for the application.
  • No consensus view could be reached in the CMDh.
  • The RMS will proceed with the assessment of the justification for the combination pack and, if applicable, with the application based on a consensus of the CMS involved in the procedure.
  • The RMS will keep the CMDh informed of the procedure.

10. Possibility of having different shelf-life per pack size or primary packaging

The CMDh discussed if all pack sizes with the same primary packaging in one marketing authorisation should have the same shelf-life and if the shelf-life can differ if the primary packaging material is different.

  • There was a majority of MSs agreeing that all pack sizes with the same primary packaging in one marketing authorisation should have the same shelf-life and that shelf-life can differ for different primary packaging materials.
  • However, a number of MSs considered that for certain types of packaging, different pack sizes could also have a different shelf-life.
  • As the question was raised in the framework of the implementation of SPOR and ideally there should be a consensus view, the CMDh advised to consult the QWP on the question.

11. Definition of Member State (MS) of source in comparative studies for generics

Based on the validation of a currently ongoing application, the CMDh discussed the meaning of MS of source in comparative studies for generics.

  • In the application, the applicant uses a product bought in the UK in 2022 from a batch that was released in the EU in 2019 (before the end of the Brexit transition period) for in vitro dissolution studies to support a biowaiver.
  • With reference to the guidance on Brexit, the CMDh agreed that a study performed after Brexit with a Reference Medicinal Product (RefMP) sourced (purchased) in the UK in 2022 cannot be accepted, even if the batch was released in an EU MS before the end of the Brexit transition period.
  • A proposal will be worked upon to update the user guide on the eAF to clarify that the MS where the product was purchased should be mentioned in section 1.4.2 Member State of source
First rollout of Regulatory Procedure Management for Product Lifecycle Management (PLM) on IRIS

As of November 2023, the EMA will do a first rollout of product lifecycle management (PLM) via IRIS, initially for around 110 selected Human and Veterinary products authorised via the centralised procedure which have a simple lifecycle associated changes e.g. Article 61.3 notifications and/or marketing authorisation transfer procedures.

On 15 September, the EMA held a webinar to share more about the above. You can view the webinar here.

The new Health Technology Assessment (HTA) Regulation

The Regulation on Health Technology Assessment (EU) 2021/228 which entered into force in January 2022 and applies as of January 2025, will govern the European cooperation between medicine regulators and HTA bodies.

  • Under the new framework, the EMA and HTA bodies will collaborate in the context of joint clinical assessments, joint scientific consultations, and the identification of emerging health technologies.
  • While aiming to improve the availability of innovative medicines and certain medical devices for patients in the EU, it will also ensure efficient use of resources and enhance the quality of health technology assessment in the EU by ensuring the sustainability of European cooperation.
  • The establishment of the Member State Coordination Group on Health Technology Assessment, as provided by the regulation, and of a stakeholder network, will give a transparent and inclusive framework to facilitate continued collaboration between partners and reduce duplication of efforts for national HTA authorities and industry.
Transition period to 2025

EMA and HTA organisations have established a new framework for Parallel EMA/HTA Scientific Advice for the period September 2023 until January 2025, when the HTA Regulation applies.

Preparations are also continuing at the EMA to pave the way for the implementation of the Regulation.

  • The Agency has identified a number of priorities and opportunities for the next 15 months.
  • These include defining a single evidence plan to facilitate development programmes, harmonising views on the strength of the evidence, and involving patients, clinical experts and other relevant experts in decision-making.

Source: EMA

Guidance on paediatric submissions (Via Syncplicity Web Client)

Revision 6 of the above guidance has been published. You can view it here

Updates
DateUpdate(s)
19 Oct 2023The heading Report from the CMDh meeting held on 12-13 September 2023 was updated to Report and minutes from the CMDh meeting held on 12-13 September 2023. Under this heading, the following changes were made:
1) Four new paragraphs were added to Item 3
2) Item no 6 Acceptance of GMP certificates issued by MHRA was added.
3) Item no 7 TiO2 (E171) used as excipient was added.
4) Item no 8. Medical Device Regulation was added.
5) Item no 9. Legal basis for combination pack for an ongoing procedure was added.
6) Item no 10. Possibility of having different shelf-life per pack size or primary packaging was added.
7) Item no 11. Definition of Member State (MS) of source in comparative studies for generics was added.
29 Sep 2023Heading Updated document – Questions & Answers : Clinical Trials Regulation (EU) No 536/2014 and relevant content added.
27 Sep 2023Links have been provided to the documents mentioned in points no 3 and 3 under the heading Report from the CMDh meeting held on 12-13 September 2023
26 Sep 2023Links have been provided to the documents mentioned in points no 2 and 5 under the heading Report from the CMDh meeting held on 12-13 September 2023
21 Sep 2023Heading Report from the CMDh meeting held on 12-13 September 2023 plus relevant content added.
20 Sep 2023Added link to webinar on First rollout of Regulatory Procedure Management for Product Lifecycle Management (PLM) on IRIS