CMDh and other updates - July 2022

Last updated: 21 September 2022

See list of updates at the end of the post.

Report and minutes from the CMDh meeting held on 19-20 July 2022

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 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 report and minutes from the above meeting include the following items:

1. Nitrosamines: deadline for steps 2 and 3 of call for review exercise for medicines with chemically synthesised active substances i.e. for medicinal products containing chemically synthesised APIs

The deadline for completing the call for review exercise for human medicines containing chemically synthesised APIs (launched in September 2019) is approaching. In consideration of the scientific developments since 2020, specifically in relation to active substance related nitrosamines, the deadline to submit step 3 variations to the marketing authorisations is now extended to 1 October 2023. This extension is intended to allow companies to perform a thorough investigation and establish any required risk mitigating actions. Nevertheless, MAHs are encouraged to submit variation applications as soon as investigations are concluded and therefore in advance of the above deadline. The step 2 confirmatory testing deadline remains 26th September 2022. Nonetheless, it is emphasised that MAHs should only submit complete step 2 outcomes. In summary, the deadlines for Steps 2 and 3 are as follows:

Step 2

Chemical medicinal products: 26 September 2022
Biological medicinal products: 1 July 2023

Step 3

Chemical medicinal products: 1 October 2023
Biological medicinal products: 1 July 2023

The CMDh has 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 to reflect this change. The changes to the document are as follows:

Q 1.9. When in the step 1 template a potential risk for nitrosamines is identified as not all relevant data were available and later on it is clarified that there is actually no risk, may I submit updated templates, i.e. replace the “risk identified” template by a “no risk identified” template?

The response to Q1.9 has been updated to give information that in specific cases, it may be possible to correct a former step 1 outcome from “risk” to “no risk” by using the “Step 2 no nitrosamine detected response template”. This template has been updated (available here) and now contains a tick box for such cases. The possibility to amend the step 1 outcome may only be used in cases where data was missing at the March 2020 deadline and is now available.
In case of necessary changes from a former “no risk” step 1 outcome to a “risk” due to new available data or an update of the EMA Q&As, no change of the step 1 outcome is needed. Instead, the process under step 2/3 has to be followed.

Q 3.1. When should any necessary variations be submitted?

The text in this section has been amended and additional text added as follows:

For products containing chemically synthesised APIs, confirmatory testing activities at Step 2 are expected to be finalised at the latest by 26th September 2022. MAHs should refrain from submitting incomplete step 2 outcomes.
The submission of any changes required to Marketing Authorisations (Step 3), if applicable, is expected at the latest by 1st October 2023. However, variations should be submitted as soon as possible and not be delayed until the end of the deadline.

Here you can view the track changed (June 2022 Rev.17) and clean version (July 2022 Rev.18) of the practical guidance for MAHs.

Questions and answers for marketing authorisation holders/applicants on the CHMP Opinion for the Article 5(3) of Regulation (EC) No 726/2004 referral on nitrosamine impurities in human medicinal products

The above document has also been updated to the version of 29 July 2022 Rev.11. The main change in this document is the response to the following quesytion:

For the ‘call for review’ for chemically synthesised and biological medicinal products, when and how should MAHs report steps 1 and 2 to competent authorities? (UPDATED)

You can view the updated document here.

2. EMA/CMDh explanatory notes on variation application form

The CMDh agreed an update of the EMA/CMDh explanatory notes on the variation application form (human medicinal products only). In the update it has been further specified which previous harmonisation of the product information needs to be declared by the applicant in the application form. The updated document has now been published on the CMDh website under “Procedural Guidance > Variation”. CMDh Best Practice Guide on Variation Worksharin

The document has been updated from the version of December 2021 Rev.8 to the version of
July 2022 Rev.9.

Here, you can view the tracked changed and clean versions of the document.

3. CMDh Best Practice Guide on Variation Worksharing

In May 2022, the CMDh agreed an update of its BPG on variation worksharing (Chapter 7) . To improve the
worksharing procedures, it was agreed that for worksharing procedures which only include quality changes of type IB (or groupings with type IB as the highest type of change), the assessment report can be reduced to the minimum necessary information and that the timetable for type IB variations can be followed (30-30-30 days). In specific cases, the reference authority can extend this to the 60- day type II timetable, if needed.
The update of the BPG is published now as the necessary technical changes to CTS have been
implemented and will be available with the next CTS client release.

The most significant changes to the document are in section 6 Th Procedure and a new flowchart has been just before Annex I under the heading 30 day timetable for quality changes of type IB only or groupings with type IB as the highest variation type.

The BPG has been updated from the version of May 2022 Rev.28 to the version of July 2022 Rev.29. Here you can view the track changed and clean versions of the updated BPG.

The updated document will be published on the CMDh website under “Procedural Guidance >
Variation”.

4. RMS Validation Checklist for Human Medicinal Products in DCP and CMDh Procedural Advice on Validation of MRP/RUP/DCP

The CMDh agreed an update of its RMS validation checklist in DCP. Information on the documents to be provided for the risk evaluation on potential presence of nitrosamines has been included in the list as a non-validation issue (i.e. the RMS can start the procedure although the issues still have not been solved on Day 0). It has further been agreed that non-validation issues need to be rectified by the applicant by day 30 rather than day 50. A corresponding update of the CMDh Procedural Advice on Validation of MRP/RUP/DCP and of the CMS validation checklist in DCP has been agreed.

The updated documents have been published on the CMDh website under “Procedural Guidance > Application for MA”.

You can download the RMS validation checklist in DCP here and the CMS validation checklist for DCP here.

5. CMDh Recommendations on Informed Consent Applications in MRP and DCP

The CMDh has agreed an update of its guidance document “Recommendations on Informed Consent Applications in MRP and DCP”. The document has been updated to make it more reader friendly. Recent CMDh agreements have been included in the document and a new section on maintenance of the dossier following granting of the informed consent marketing authorisation has been added.

The updated document has now been published on the CMDh website under “Procedural Guidance > Application for MA”.

The document has been updated from Rev.4 to Rev.5.

Here you can view the track changed and clean versions of the document.

6. Best Practice Guide on Article 45 and 46 – Paediatric Regulation – EU Worksharing Procedure

The CMDh has agreed an update of its BPG on Article 45 and 46 – Paediatric Worksharing Procedures. With the update it was agreed that the appointed Art. 46 rapporteur will directly request the submission of the relevant data from the MAH (this was previously done by the EMA). The relevant template emails have been included in the BPG as an annex. It has also been clarified that in case the need of new supporting data has been recommended during the worksharing procedure, the submission date of a type II variation will be discussed with the Rapporteur before the procedure is finalised.

The updated document has beenpublished on the CMDh website under “Paediatric Regulation > Guidance documents”.

The document has been updated from the version of Sept 2021 Rev.1 to the version of July 2022 Rev.2.

Here, you can view the track changed and clean versions of the document.

The full list of updated documents in this section can be viewed here.

Source: CMDh – Heads of Medicines Agencies

7. Information for similarity assessment to orphan medicinal products

In order to reduce the burden on regulators without increasing the workload on applicants too
much, the CMDh discussed a proposal for applicants to provide the information on approved
orphan drugs and the applicant’s position on similarity of their product with already
authorised orphan products directly in the similarity AR template for submission in a DCP.

The CMDh agreed that the relevant template should be made available on the CMDh website
for the applicants to be completed. The completed template should then be submitted in word
and PDF format. The RMS could reduce the text proposed by the applicant in the word
document to reduce the length and extensiveness of the summary of the response in the
template.

Several guidance documents will need to be updated to reflect the new approach and to give
sufficient instructions for applicants. The similarity AR report template also would need to
include instructions which parts are for the applicant and which parts are for the RMS to be
filled in. DE and NL, in consultation with the rapporteurs, will review the relevant guidance
documents and will propose updates, as needed, for further discussion in September.

8. Legal basis for enantiomer claiming to be the same active substance
as the racemate

The CMDh discussed the most appropriate legal basis for an enantiomer of a well-established
substance following a national request for scientific/regulatory advice. The enantiomer has
not been authorised before in the EU but has been authorised outside the EU.

According to the reflection paper on the chemical structure and properties criteria to be considered for the evaluation of new active substance (NAS) status of chemical substances (EMA/CHMP/QWP/104223/2015), the enantiomer and the racemic mixture would be considered the same active substance, unless they differ significantly in properties with regard to safety and/or efficacy.
The CMDh agreed that an Article 10(3) application for the enantiomer making reference to racemate, containing a justification that the two substances are to be considered the same, could be validated. During the procedure, it would be assessed whether the two substances can be considered the same and, if not, the application would be rejected, unless the differences are not considered significant and well documented, see below.
If the applicant claims that the enantiomer has a better safety (and/or efficacy) profile, it could lead to the conclusion that the two substances differ significantly (if the criteria in the EMA guideline are fulfilled). Therefore it would not be possible to use the racemic mixture as reference medicinal product. In such scenario, an Art. 8(3) application should be considered instead, with possible (but not automatic) NAS status.
If the claims do not fulfil the EMA criteria “differ significantly”, they may be accepted in the SmPC of a hybrid application, if sufficiently documented.
During the scientific advice, the NCA will also provide advice on the data requirements for such an application.

9. Medical device regulation

Following receipt of a question from a MAH, the CMDh agreed to correct the CMDh February
2022 minutes to clarify that transdermal patches (using passive diffusion) do not fall
under the second subparagraphs of Article 1(8) or (9) of the MDR and therefore do not need
to comply with Section 3.2., point 12, of Annex I of Directive 2001/83/EC, as amended by
Article 117 MDR.

The clarification to the February 2022 minutes has been added to avoid confusion and
contradiction with the MDCG guidance.

10. Digital Application Dataset Integration (DADI) Network Project

The EMA informed the CMDh about the revised go-live scope of the DADI variations form.

In October 2022, the DADI human variations form supporting CAPs only will go live.
The second release, supporting all types of EU variation procedures (CAPs and NAPs) will follow in March 2023.
It was clarified that for mixed CAP/NAP variation worksharing procedures the submission will continue to follow the old format until DADI supports all procedures. Guidance on such cases will be provided.
The EMA is also looking into the issue that for MRP/DCP products variations may be submitted before a national MA is granted (though after the end of the EU phase). This should be solved before the go-live date for NAPs.
Further information will be provided before the go-live for NAP

11. Acceptability of hybrid application with reference to pro-drug

Based on a recent request for a hybrid application for a modified release product with the
pro-drug as reference medicinal product, which was given new active substance (NAS) status
at the time of authorisation, the CMDh discussed if a claim for NAS could be re-assessed in
the context of a hybrid application. It was noted that the data exclusivity period of the RefMP
has elapsed and that new scientific information for the NAS assessment might be available.
There was a majority that considered that such an application could be submitted and validated under Art. 10(3), if a justification is included in the application why both substances
should be considered the same. The justification would then be assessed during the procedure. However, also several MSs raised concerns that they could not validate such an application as the previous decision to grant NAS status to the pro-drug should be respected.

Minutes from the CMDh meeting with representatives of Interested Parties held on 18 May 2022

Among the interest parties at the above meeting were the European Medicines Agency, the EFPIA and Medicines for Europe.

Various items were discussed at this meeting and the meeting minutes include the following:

Multilingual Labelling in MRP

IE informed the participants of the activities of the CMDh Multilingual Packaging Working Group, including an update of the BPG in October and the progress on the pilot on EU reduced harmonised text.

It was announced that a survey on the experience with MLP and the pilot would be sent to Interested Parties in June with a deadline to reply by September. It was requested to provide one response per trade association.

The short presentation is available here.

Renewal of Marketing Authorisations

Medicines for Europe gave a presentation on the divergent approach of MSs to shortened renewal procedures and requested that all MSs should accept shortened renewals without additional information requests and with respecting the timelines.

The CMDh noted that the CMDh Best Practice Guide allows Member States to request additional information, which is needed in some MSs due to national legislation.
While the CMDh is supportive to change legislation in the future, the current EU and national legislation has to be respected.
It was noted that a shortened renewal is still possible, despite requests for additional documentation (a longer validation period is likely in such a case).
Medicines for Europe asked MSs that have legal requirements to consider revising their national legislation.
It was noted that the revision of the EU legislation in the framework of the Pharmaceutical Strategy might need to be awaited.

Improvements in the Repeat Use Procedure (RUP)

Medicines for Europe presented proposals for changes to the repeat-use procedure (RUP) as an opportunity to solve issues and broaden access e.g. currently, there are unpredictable and lengthy timelines to complete a Repeat Use (RUP) application thereby frustrating the ability to quickly respond to patients’ needs (including fast a fast in case of shortages).

The proposals included the following suggestions for improvement to the RUPs for Human medicines:

Improvement 1- Accept End of Procedure of MRP/DCP, instead of RMS Marketing Authorisation as the basis for an RUP
Improvement 2 – Allow Variations IA and IB to run in parallel to a RUP submission
- Variations IA and IB do not influence the AR content
- Variation packages can be made available to new CMS in a submitted pending approval status
Improvement 5 concerned the following suggestions:
- Provide opportunity for Member State to officially make use of a 0-day RUP
- Take all Assessment Report (AR) information as is
- Take dossier as is, including pending variations
- Immediately close a procedure upon administrative start and grant MA within maximum 30 days

In response to the proposals, the CMDh noted that a change in legislation would be needed to accept the End of Procedure of MRP/DCP, instead of an RMS MA, to start the RUP.

The CMDh will look into the possibility of allowing the start of RUP while certain specific smaller type IA/IB variations are ongoing
With regard to 0-day RUPs, the CMDh stressed that these are already possible within the current legislation. Currently MSs allow the use of 0-day procedures in case of urgent need of a certain medicinal product, but it is not mandatory for MSs to accept 0-day procedures. Especially for older products with outdated dossiers, it would be more difficult to accept 0-day procedures.
Companies are encouraged to check with individual MSs if they accept 0-day RUPs. Several MSs have gathered experience with 0-day procedures during the COVID-19 pandemic, which can be applied to other shortage situations. However, a general approach for 0-day procedures was not supported.
The CMDh is looking into further improvements of the RUP, e.g. if updates introduced in the veterinary legislation could also be applicable for human medicinal products, and especially improvements that can be implemented without changes of the legislation. Any updates will be communicated as soon as agreed.

Proposal for mandatory worksharing

The EFPIA asked the CMDh for more information about the proposal for mandatory worksharing as included in the CMDh Multi Annual Work Plan.

The CMDh explained that the proposal is inspired by the new veterinary legislation, and it could be applied in a similar way to human medicinal products.

The CMDh often discusses cases of parallel national variation submissions that could benefit from variation worksharing to save resources at MAH and National Competent Authority level and to ensure a harmonised outcome of the assessment. In these cases, the CMDh often writes to the concerned MAHs, but the MAHs do not always follow the CMDh advice.

On the basis that parallel assessment should be avoided wherever possible due to scarce resources, the CMDh proposes to make variation worksharing mandatory, in a similar way to veterinary medicinal products.

The CMDh further informed the participants that it agreed a simplification/ optimisation of worksharing for minor quality variations with type IB as highest variation, to apply shorter timelines (in line with the type IB timetable). The Assessment Report will be skipped or shortened in these cases. Due to the need for technical amendments, the change will be implemented around the summer break.