Minutes for the meeting on 22-23 June 2021

21 July 2021

EMA/CMDh/422444/2021 Corr. 1 Human Medicines Division

Coordination Group for Mutual Recognition and Decentralised Procedures - Human (CMDh)

Minutes for the meeting on 22-23 June 2021

Chair: Kora Doorduyn-van der Stoep – Vice-Chair: Susanne Winterscheid 22 June 2021, 09:00 – 17:00, Teleconference

23 June 2021, 09:00 – 17:00, Teleconference CTS Working Group

21 June 2021, 09:30 – 12:00, Teleconference Chair: Dino Soumpasis

Joint CMDh/EMA Working Party on Paediatric Regulation 21 June 2021, 10:30 – 12:00, Teleconference

Chair: Siri Wang

Disclaimers

Some of the information contained in this set of minutes is considered commercially confidential and therefore not disclosed. Ongoing procedures discussed by the CMDh are considered confidential.

Of note, this set of minutes is a working document primarily designed for CMDh members and the work the Committee undertakes.

Note on access to documents

Some documents mentioned in this set of minutes cannot be released at present following a request for access to documents within the framework of Regulation (EC) No 1049/2001 as they are subject to on-going procedures for which a final decision has not yet been adopted. They will become public when adopted or considered public according to the principles stated in the Agency policy on access to documents (EMA/127362/2006).

Table of contents

1. Introduction 5

1.1. Welcome and declarations of interest of members, alternates and experts ... 5

1.2. CMDh membership ... 5

1.3. Adoption of agenda... 5

1.4. Adoption of the minutes ... 5

2. Organisational issues/Reports from other meetings 5

2.1.1. CMDh/EMA Working Party on Paediatric Regulation / WP Chair (NO) ... 6

2.1.2. Multilingual packaging Working Group / IE ... 6

2.1.3. Working Party on Pharmacovigilance Procedures Worksharing / WP Chair (IT) ... 6

2.1.4. CTS Working Group / WG Chair (DE) ... 7

2.1.5. Joint GCP IWG/CMDh Working Party / IE ... 7

2.2. Brexit ... 7

2.3. Multi-Annual Workplan / Chair ... 7

2.4. Presidency meetings... 8

2.4.1. Portuguese Presidency meeting / PT ... 8

2.4.2. Slovenian Presidency meeting / SI ... 8

2.5. Meeting with Interested Parties / Chair ... 8

2.6. International Pharmaceutical Regulators Programme (IPRP) / Chair ... 8

2.7. HMA meeting / Chair ... 8

3. General items 8

3.1.1. Request form for RMS in a DCP / SE ... 8

3.1.2. Template for new agenda topic / EMA ... 9

3.2. Variations ... 9

3.2.1. Requests for worksharing procedures on Variations ... 9

3.2.2. Requests for recommendations on unforeseen Variation under Art. 5 of Variation Regulation ... 9

3.2.3. Submission of parallel national variations / FI ... 9

3.3. GMP ... 9

3.4. GCP ... 9

3.5. COVID-19 ... 9

3.6. Medical Device Regulation / EMA ... 9

3.7. PEG laxatives and interaction with starch-based thickeners / IE ... 10

3.8. Submission of changes to PMS not classified as a variation / DE, Chair... 11

3.9. Informed consent applications in eCTD / PL ... 11

4. Generic/hybrid marketing authorisations 11

4.1. Acceptability of BE waiver for an oily parenteral (i.m.) solution / IT ... 11

4.2. Reliability of software for calculation of the 90% CI of f2 / IT ... 11

4.3. Court cases ... 11

4.3.1. Court judgement on applications for generics of Tecfidera (dimethylfumarate) / Chair, EMA ... 11

4.3.2. Discontinuation of court case on dexmedetomidine / DK, EC ... 12

4.4. Collaboration between CMDh/RMS and EMA on generics and hybrids / EMA ... 12

4.5. Generics containing pirfenidone / DE ... 12

4.6. Non-acceptability of a US reference product for a BE study in case the same batch is marketed in the EU / ES ... 12

4.7. . ... 12

5. Referrals 12

5.1.1. Art. 29/13 referrals for discussion at CMDh ... 13

5.1.2. List of questions ... 13

5.2. Referrals to PRAC (pursuant to Art. 31 or 107i of Directive 2001/83/EC) ... 13

5.2.1. Referral timetables ... 13

5.2.2. Started referral procedures at PRAC ... 13

5.2.3. Information on ongoing referral procedures ... 13

5.2.4. PRAC recommendations for CMDh position ... 13

5.3. Outcome of referrals to CHMP... 13

5.4. Other topics related to referrals ... 13

5.4.1. Presence of nitrosamine impurities in human medicinal products containing chemically synthesised active pharmaceutical ingredients / Chair, EMA, IE ... 13

5.4.2. Angiotensin-II-receptor antagonists (sartans) containing a tetrazole group (Art. 31) / NL . 14 5.4.3. Hydroxyethyl starch (HES) (Art. 31) / DE ... 15

6. Pharmacovigilance 15

6.2. Periodic Safety Update Reports (PSUR) ... 15

6.2.1. PRAC recommendations on PSUSAs for CMDh position ... 15

6.2.2. Information on PRAC recommendations for PSUSAs for maintenance ... 17

6.2.3. Information on PRAC recommendations for PSUSAs for CAPs/NAPs or CAPs ... 19

6.2.4. Outcomes of informal PSUR work sharing procedures / Chair ... 20

6.2.5. PSUSA Lead Member State appointment ... 20

6.2.6. PSUSA Follow-up procedures ... 20

6.3. Results of post-authorisation safety studies (PASS) imposed in the MA (in accordance with Art. 107q) ... 20

6.4. Lists ... 20

6.4.1. Union Reference Date list ... 20

6.4.2. List of medicinal products under additional monitoring ... 20

6.5. Information from Member States on actions for nationally authorised products related to safety ... 20

6.6. Other topics related to pharmacovigilance ... 20

7. Break-out sessions and CMDh scientific input to applications 20

7.2. Mykronor 5 microgram/ml, solution for injection/infusion (NL/H/5186/001/DC) / NL ... 21

8. Miscellaneous 21

8.2. June 2021 CMDh Press Release ... 21

8.3. A.O.B. ... 21

8.3.1. Quality defect of the secondary package / PL ... 21

8.3.2. . ... 21

8.3.3. Interaction between rosuvastatin and ticagrelor / CZ ... 21

8.3.4. Change in address of MAH for UK(NI) located in the UK(GB) / DE ... 22

8.3.5. New indication in a generic product / IE ... 22

9. Other topics and dates for next meeting 22

List of participants ... 23

1. Introduction

1.1. Welcome and declarations of interest of members, alternates and experts

In accordance with the Agency’s policy on handling of declarations of interests of scientific Committees’ members and experts, based on the declarations of interest submitted by the Committee members, alternates and experts and based on the topics in the agenda of the current meeting, the Committee Secretariat announced the restricted involvement of some meeting participants in upcoming discussions as included in the pre-meeting list of

participants and restrictions.

Participants in this meeting were asked to declare any changes, omissions or errors to their declared interests and/or additional restrictions concerning the matters for discussion. No new or additional interests or restrictions were declared.

Discussions, deliberations and voting took place in full respect of the restricted involvement of Committee members and experts in line with the relevant provisions of the Rules of

Procedure and as included in the list of participants. All decisions taken at this meeting were made in the presence of a quorum of members.

The Chairperson opened the meeting by welcoming all participants. Due to the current coronavirus (COVID-19) outbreak, and the associated EMA Business Continuity Plan (BCP), the meeting was held remotely.

1.2. CMDh membership

The CMDh welcomed Marina Fetita Popescu as new CMDh alternate for Romania and Zuzana Fliegerová as new CMDh alternate for Czechia.

1.3. Adoption of agenda

The agenda of the meeting was adopted with the following topics under A.O.B:

- Quality defect of the secondary package - Interaction between rosuvastatin and ticagrelor

- Change in address of MAH for UK(NI) located in the UK(GB) - New indication in a generic product

1.4. Adoption of the minutes

The minutes of the May 2021 meeting, including the comments received and discussed at the meeting, were adopted and will be published on the CMDh website (Action: EMA).

2. Organisational issues/Reports from other meetings

2.1. CMDh Working Groups/Working Parties/Task Force

Report from the June 2021 meeting

The WP chair reported from the June 2021 meeting of the WP.

The WP discussed the ongoing project to clean up ongoing Art. 45 procedures in the

published Art. 45 list. The ongoing Art. 45 procedures were classified per status. The criteria for prioritisation of outstanding procedures and next actions were further discussed. MSs were encouraged to send input on the criteria for prioritisation or Art. 45 studies assessment (Action: MSs). The Rapporteurs were reminded to give a status update on their 45

procedures (Action: MSs). A reminder to progress with the procedures will be sent to those MSs with PAR under preparation (Action: EMA)

The WP discussed, amongst others, the proposed further interaction with EMA/PDCO and an update on the ongoing Art. 45 WS procedures for vaccines and blood products. A call will be circulated for two outstanding guidance documents for which rapporteurs have to be

appointed (Action: EMA).

Public PdARs for paed. studies acc. Art. 45 None

Public PdARs for paed. studies acc. Art. 46 None

Art. 46 worksharing None

2.1.2. Multilingual packaging Working Group / IE

Update on progress on the pilot.

The WG Chair gave an update to the CMDh on the work undertaken and the status of the ongoing pilot on multilingual labelling. As result of the survey, the instructions to the RMS for the pilot were updated and further discussions are ongoing to incorporate the results from the survey in the BPG. The WP discussed the possibility to create a list of contact points for national derogations and for communication on mock-ups.

2.1.3. Working Party on Pharmacovigilance Procedures Worksharing / WP Chair (IT) The WP Chair gave a report from the June WP meeting including feedback from the HaRP group. The WP discussed the update of the EURD list, the outcome of the EU tool survey and the conclusions agreed. The group discussed various proposals on how to optimise/rationalise the CMDh LoSC Excel list. The WG will revise its mandate and consider whether an update is needed.

The CMDh was informed of an ongoing follow-up for PSUSA for NAPs (PSUFU) procedure with a parallel LEG for Fentanyl (transmucosal route of administration) for which some MAHs did not submit the requested data during the PSUFU procedure. In addition, some MAHs had already submitted variations following the PSUSA procedure. The CMDh agreed to delay the start or keep the variation in clock-stop as the PSUFU outcome was still awaited. If the variation has been finalised the company may need to submit new variations depending on the PSUFU outcome. (Action: MSs)

The CMDh would like to remind MAHs that the recommendation to initiate a PSUFU procedure will be reflected in the final PSUSA AR. In addition, the decision to initiate a PSUFU procedure will be published in the CMDh press release including the PSUFU procedure number to be used for the submission of documentation by the MAH(s). For further information on the PSUFU MAHs can refer to the CMDh Guidance on the Informal Work-Sharing procedure for follow-up for PSUSA for NAPs published on the CMDh website.

The CMDh adopted the SmAR Edarclor (azilsartan medoxomil chlorthalidone) and it will be published on the CMDh website (Action: EMA).

2.1.4. CTS Working Group / WG Chair (DE)

The WG chair gave a report from the May 2021 WG meeting.

The WG discussed among others the CTS client development, change requests (including changes related to the NI protocol), the SPOR integration to improve data exchange and CTS interaction with UPD.

MSs were encouraged to join the HMA Risk Management Tool Working Group to develop post- marketing module (Action: MSs).

2.1.5. Joint GCP IWG/CMDh Working Party / IE

The WP chair reported from the June WP meeting.

The WP discussed, amongst others, the CROs of interest, the 2021 CROs Inspection Programme, the WHO-EMA-EU MSs collaboration, statistical issues on bioequivalence

inspections. MSs were invited to send topic proposals for the 2021 BE Forum taking place on 25^th October (Action: MSs).

2.2. Brexit

The CMDh discussed a topic included under 8.3 A.O.B., with regards to a change in address of MAH for UK(NI) located in the UK(GB). The change is submitted as a type IA variation to change the MAH address from and to a site within UK(GB). The CMDh agreed that the RMS will exceptionally validate this variation as this concerns only the UK(NI) MAH and this is a change to be dealt with at a national level by the UK(NI) competent authority.

The CMDh agreed to stop having Brexit as standing topic on the agenda and include it only when there is a specific topic to be discussed.

2.3. Multi-Annual Workplan / Chair

The Chair gave an update on the ongoing discussions on the multi-annual workplan. Following the PT Presidency meeting the topic leaders have drafted proposals and a summary for each topic. The MAWP drafting group will meet in June to discuss and agreed on the proposal to be presented to CMDh in July.

2.4. Presidency meetings

2.4.1. Portuguese Presidency meeting / PT

The minutes from the Portuguese presidency meeting were adopted including comments from MSs. The June 2021 CMDh meeting was the last one under the Portuguese Presidency of the Council of the European Union.

2.4.2. Slovenian Presidency meeting / SI

Slovenia will take over the Presidency in July 2021. Mrs Marjeta Jordan will be the appointed Presidency vice-chairperson of the CMDh during the Slovenian Presidency of the Council of the European Union. The CMDh was informed that SI Presidency meeting will be held remotely on 22 September 2021. MSs were requested to send feedback, propose topics and volunteer as topic leads before the next July meeting (Action: MSs). The first draft agenda will be presented next month.

2.5. Meeting with Interested Parties / Chair

The minutes of the meeting with Interested Parties were agreed. The minutes will be forwarded to Interested Parties for comments for further discussion in July, if needed (Action: EMA).

2.6. International Pharmaceutical Regulators Programme (IPRP) / Chair

The CMDh was pleased to propose for nomination Katalina Mettke as representative for the IPRP Bioequivalence WG (BEWGG). The proposals will be communicated to the EC/EMA IPRP MC members (Action: EMA).

2.7. HMA meeting / Chair

The Chair reported from the virtual HMA meeting and the joint meeting of HMA and CAMD held on 8 June 2021.

3. General items

3.1. CMDh guidance documents

The CMDh discussed and agreed an update of the template for requests for RMS in a DCP for medicinal products for human use. Applicants are now also asked to provide the proposed indication(s) of the product to be applied for and to indicate if ASMF worksharing will be used in case of an ASMF. Further minor editorial changes have been included. The updated

document will be published on the CMDh website (Action: EMA).

3.1.2. Template for new agenda topic / EMA

The CMDh discussed and agreed an update of the template for new topics to be included in the CMDh agenda. MSs are now also asked to provide information on the MAH(s), the MRP/DCP procedure number, CMSs and the INN concerned by a topic, as applicable. The additional information will help MSs to prepare for the CMDh discussion and will further facilitate identifying potential conflicts of interests of participants.

It was noted that for topics on newly identified nitrosamines MSs should provide the CAS number. This will however not be included in the general topic template.

The updated template was adopted and will be made available in MMD (Action: EMA).

3.2. Variations

3.2.1. Requests for worksharing procedures on Variations

The MSs chosen by the CMDh, based on the recommendations of MAHs, agreed to be reference authorities for the procedures.

3.2.2. Requests for recommendations on unforeseen Variation under Art. 5 of Variation Regulation

None

3.2.3. Submission of parallel national variations / FI

The CMDh discussed the parallel submission of purely national variations .

3.3. GMP

None

3.4. GCP

None

3.5. COVID-19

The CMDh was informed that the addendum to the variation guidelines related to changes to the active substance of a vaccine against human coronavirus has been published.

The CMDh agreed to stop having COVID-19 as standing topic on the agenda and include it only when there is a specific topic to be discussed.

3.6. Medical Device Regulation / EMA

The EMA presented the final versions of the update of the Q&As and application forms (new MAA and variations) for the implementation of Medical Device and In Vitro Diagnostics Regulations (MDR/IVDR). The updates have been prepared in collaboration with the EC.

With regard to the consultation procedure for ancillary substances in medical devices, it was specified in the Q&As that the given guidance is only applicable to the EMA consultation. For NCA consultation, applicants should consult the national guidance or liaise with the NCA.

Other minor changes to the AFs, that have been agreed in the past (not related to the MDR), have been included in the update.

The updated Q&As were adopted by the CMDh. The document will be published shortly after the CMDh meeting. The AFs will be forwarded to the NtA for written adoption. They will then be converted into the eAF within 2-3 months, before release.

The EC informed the CMDh that a response to the CMDh question on Art. 117 with respect to MRP/RUP is being prepared. The related Q&A can be updated, as needed, once a feedback from the EC is received.

In preparation of the update of the eAFs, the rapporteurs of related CMDh guidance documents (e.g. RMS validation check list and the user guide for the eAF) were asked to review the documents and prepare an update as needed (Action: BE, FR).

3.7. PEG laxatives and interaction with starch-based thickeners / IE

The CMDh was informed of a discussed the reported interaction on /“liquefying-effect” of PEG (Macrogol) -based laxatives with starch-based thickeners and the potential for aspiration pneumonia with concomitant use in patients with dysphagia.

Patients with dysphagia often need to use starch-based food thickeners to enhance an appropriate intake and may therefore deviate from SmPC advice on mixing the PEG product.

As warnings have been recently approved for Section 4.4 and 4.5 of the SmPC in variation procedure SE/H/1799/01-07/II/195, it was therefore agreed that MAHs for Polyethylene Glycol (PEG) laxatives should review their current product information wording and submit a variation to update sections 4.4 and 4.5 of the SmPC and consequentially the package leaflet in line with wording agreed in procedure SE/H/1799/01-07/II/195, if necessary. This wording is included below for reference, and the applicant is recommended to align their product information promptly, for example by submitting a Type IB variation within 3 months:

The CMDh agreed a common wording to be implemented by MAHs of PEG-based laxatives, in case a similar wording is not already present:

Summary of Product Characteristics Section 4.4

In patients with swallowing problems, who need the addition of a thickener to solutions to enhance an appropriate intake, interactions should be considered, see section 4.5.

Section 4.5

[Product] may result in a potential interactive effect if used with starch-based food

thickeners. The macrogol ingredient counteracts the thickening effect of starch, effectively liquefying preparations that need to remain thick for people with swallowing problems.

Package leaflet

Section 2. What you need to know before you take [Product]

Other medicines and [Product]

If you need to thicken fluids in order to swallow them safely, [Product] may counteract the effect of the thickener.

3.8. Submission of changes to PMS not classified as a variation / DE, Chair

Information related to this section cannot be released at the present time as it is deemed to contain commercially confidential information.

3.9. Informed consent applications in eCTD / PL

The CMDh was informed that the Human Harmonisation Group (HHG) is currently working on an update of the Harmonised Technical Guidance for eCTD Submissions in the EU. As part of the update a new section concerning informed consent applications was prepared on the basis of the CMDh document “Recommendations on Informed Consent Applications in MRP/DCP”.

The CMDh was consulted if the information in the CMDh guidance document is still up to date.

The CMDh confirmed that the information in the CMDh guidance is correct. Module 1 always has to be submitted by the applicant including a letter of consent to modules 3-5, as

applicable. Modules 2- 5, if provided due to national requirements, must be identical with the reference product dossier. MSs that only require Module 1 accept the submission of Modules 1-5, in case other CMS in the procedure have this as national requirement. The CMDh further confirmed that after granting of the MA, the product authorised under informed consent can develop independently. However, all necessary data needs to be submitted for variations. The Rapporteur of the CMDh guidance document will review it to see if more information on the submission of variations after granting of the MA needs to be added (Action: DK).

The CMDh feedback will be further discussed in the HHG for the update of the eCTD technical guidance.

4. Generic/hybrid marketing authorisations

4.1. Acceptability of BE waiver for an oily parenteral (i.m.) solution / IT

Following the discussion in May, the CMDh agreed to send a question to CHMP (PKWP) on the requirements for a biowaiver for oily parenteral solutions. The question will be sent after the meeting (Action: EMA).

4.2. Reliability of software for calculation of the 90% CI of f2 / IT

Following the discussion in May, the CMDh was informed that PKWP is working on a Q&A on software to be used for calculation of the 90% CI of f2 by means of bootstrapping for the comparison of highly variable dissolution profiles. As the question raised in the May meeting will be addressed in this Q&A, the CMDh agreed that there was no need to send the proposed question to PKWP.

4.3. Court cases

4.3.1. Court judgement on applications for generics of Tecfidera (dimethylfumarate) / Chair, EMA

The CMDh discussed the Judgment of the General Court of 5 May 2021 in Case T-611/18, Pharmaceutical Works Polpharma v European Medicines Agency. Based on a reading of the Judgment, the CMDh agreed that Member States that have received marketing authorisation applications for generics of Tecfidera (dimethyl fumarate) can currently not validate such applications until the role of monoethyl fumarate salts within Fumaderm has been assessed by the Committee for Medicinal Products for Human Use. These applications will therefore be held in validation until this assessment is finalised.

4.3.2. Discontinuation of court case on dexmedetomidine / DK, EC

The CMDh was informed that the court case between Orion and DKMA on dexmedetomidine has been discontinued.

4.4. Collaboration between CMDh/RMS and EMA on generics and hybrids / EMA

The EMA proposed to simplify the communication on safety changes of centrally authorised reference medicinal products. Instead of the circulation of emails, it is proposed to only table the information in MMD on a monthly basis. The CMDh agreed with the proposed approach.

The EMA will be looking into updating the best practice guidance on the common principle for collaboration between CMDh/RMS and EMA on generics and hybrids, as needed (Action:

EMA).

4.5. Generics containing pirfenidone / DE

The CMDh discussed and agreed to send questions on the BE requirement for generics of pirfenidone to the CHMP (PKWP). The question will be sent after the CMDh meeting (Action:

EMA).

4.6. Non-acceptability of a US reference product for a BE study in case the same batch is marketed in the EU / ES

The CMDh discussed if a bioequivalence study using a RefMP authorised in the US can be accepted in a MAA for a generic in the EU, in case the product belongs to the same manufacturing batch of a medicinal product marketed in the EU.

It has previously been discussed that a US product cannot be used as RefMP in generic applications in the EU.

Reference was made to the user guide on the eAF and Chapter 1 of the NtA. The CMDh agreed that from a legal point of view the RefMP in the BE study has to be authorised in the EU/EEA and should be sourced from the EU/EEA. The CMDh will consider clarifying this situation in a future revision of the NtA.

4.7.

Information related to this section cannot be released at the present time as it is deemed to contain commercially confidential information.

5. Referrals

5.1. Referrals to CMDh (pursuant to Art. 29(1) of Directive 2001/83/EC or Art. 13 of Regulation (EC) No 1234/2008)

5.1.1. Art. 29/13 referrals for discussion at CMDh

5.1.1.1. Deferasirox Alembic (EE/H/0314/001-003/DC) / EE

The RMS gave an overview of the procedure. The referral was positively finalised before the CMDh meeting based on an additional BE study in fed (low fat, light meal) conditions submitted by the applicant to address the raised PSRPH.

5.1.2. List of questions

None

5.2. Referrals to PRAC (pursuant to Art. 31 or 107i of Directive 2001/83/EC)

5.2.1. Referral timetables

Tabled for information.

5.2.2. Started referral procedures at PRAC

None

5.2.3. Information on ongoing referral procedures

5.2.3.1. Amfepramone (Art. 31)

Tabled for information.

5.2.4. PRAC recommendations for CMDh position

None

5.3. Outcome of referrals to CHMP

None

5.4. Other topics related to referrals

5.4.1. Presence of nitrosamine impurities in human medicinal products containing chemically synthesised active pharmaceutical ingredients / Chair, EMA, IE

The CMDh discussed and agreed an update of the joint EMA/CMDh Q&As 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. The approach for manufacturers not actively used in supply has been clarified in the document and limits for acceptable intake of

newly identified nitrosamines have been added. The updated document will be published on the EMA website. A link will be provided from the CMDh website (Action: EMA).

The CMDh also 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. Following the meeting with Interested Parties in May, further clarifications on step 2 submissions

(confirmatory testing) have been added, especially in which cases these submissions can be grouped. The updated document will be published on the CMDh website (Action: EMA).

The CMDh also agreed an update of the template for the notification of step 2 confirmatory testing outcome: confirmation of nitrosamine detected, to further clarify the submission requirements. The updated template will be published on the CMDh website. The text on the website on when to use the template will also be clarified (Action: EMA).

5.4.1.1.

Information related to this section cannot be released at the present time as it is deemed to contain commercially confidential information.

5.4.1.2.

Information related to this section cannot be released at the present time as it is deemed to contain commercially confidential information.

5.4.1.3.

Information related to this section cannot be released at the present time as it is deemed to contain commercially confidential information.

5.4.2. Angiotensin-II-receptor antagonists (sartans) containing a tetrazole group (Art. 31) / NL

The CMDh reminds MAHs of medicinal products concerned by the Art. 31 referral on angiotensin-II-receptor antagonists (sartans) containing a tetrazole group to submit the necessary variations to implement the new Commission Decision (EMEA/H/A-31/1471 – EC decision 19/02/2021). The new conditions in the marketing authorisations should be

implemented via a type IAIN C.I.11.a variation. The deadline for implementation of condition D (introduction of NDMA and NDEA limit in finished product specification) is 30 June 2021.

Both variation applications should be submitted as a matter of priority in order to avoid regulatory action being taken by National Competent Authorities. MAHs should take into account the guidance provided by the CMDh.

The CMDh discussed and agreed responses to questions sent by Medicines for Europe after the meeting with Interested Parties in May. The agreed responses will be sent to Medicines for Europe (Action: EMA).

The CMDh agreed an update of the Q&A document on the implementation of the outcome of the Art. 31 referral on angiotensin-II-receptor antagonists (sartans) containing a tetrazole group, in line with the responses given to Medicines for Europe. The information related to the conditions imposed by the referral and the lifting thereof has been further clarified. The updated document will be published on the CMDh website (Action: EMA).

The CMDh also discussed if a date should be given until when the MAH has to submit a new type IB B.II.d.1.g variation to lift condition D if the previous variation or the variation to apply

for omission from the specification has been refused. The majority of the CMDh considered that the variation has to be submitted as soon as possible, but in the Q&A the date of 31 December 2021 should be mentioned.

The CMDh further agreed that, in cases where a product is not marketed, the submission of a single type IA variation (C.I.11.a) to provide a written confirmation that the necessary variation will be submitted before the product is launched (delay in fulfilment of conditions B and D) is sufficient. Grouping of two variations is not necessary when both conditions are delayed.

Finally, with regard to requests for extension of the deadline of condition D (30 June 2021), the CMDh agreed that MAH should be reminded that the requested variation should be submitted as soon as possible (without granting an extension).

5.4.3. Hydroxyethyl starch (HES) (Art. 31) / DE

The CMDh discussed an extension of the deadline for the submission of the final study results of the studies agreed as condition of the Art. 31 referral on hydroxyethyl starch (HES). The MAHs have requested an extension for both PHOENICS and TETHYS studies until 28 February 2023.

The CMDh remained extremely concerned about the slow progress of the recruitment and requested the MAHs again to take all the additional measures necessary to compensate the delays accrued. Nevertheless, the CMDh agreed by majority to a final extension of the submission deadline of the final study reports of both PHOENICS and TETHYS studies until 28 February 2023 at the latest.

As it is expected that the final study report of the PHOENICS study will be available before that date, it should be submitted as soon as it is available.

Additionally, in order to further closely monitor the progress of these studies, the CMDh requested the MAHs to continue submitting studies progress reports on a 6-monthly basis to the concerned Member States via worksharing variation applications.

6. Pharmacovigilance

6.1. Report from the June 2021 PRAC meeting

The EMA reported from the PRAC meeting held from 7 to 10 June 2021.

6.2. Periodic Safety Update Reports (PSUR)

6.2.1.1. Baclofen (oral) - PSUSA/00000294/202009

The CMDh, having considered the PSUR on the basis of the PRAC recommendation and the PRAC assessment report, agreed by consensus on the variation of the marketing

authorisations of medicinal products containing baclofen (oral).

1 Subject to adoption via written procedure in advance of the meeting. For discussion/adoption at the plenary if comments are received during written procedure.

6.2.1.2. Hydroxyzine chloride / hydroxyzine pamoate and all fixed combination, hydroxyzine - PSUSA/00001696/202011

The CMDh, having considered the PSUR on the basis of the PRAC recommendation and the PRAC assessment report, agreed by consensus on the variation of the marketing

authorisations of medicinal products containing hydroxyzine chloride / hydroxyzine pamoate and all fixed combination, hydroxyzine.

PRAC noted that information related to the risk of hypotonia, movement disorders including extrapyramidal disorders, clonic movements, CNS depression, neonatal hypoxic conditions, and urinary retention in neonates whose mothers received hydroxyzine during late

pregnancy and/or labour is not always included in sections 4.6 of the Summary of Product Characteristics and the corresponding PL section of hydroxyzine containing medicinal products.

Therefore, PRAC recommends that the following wording is included in product information of hydroxyzine containing products, if similar information is not already included in their product information:

Summary of Product Characteristics Section 4.6

In neonates whose mothers received <product> during late pregnancy and/or labour, the following events were observed immediately or only a few hours after birth: hypotonia, movement disorders including extrapyramidal disorders, clonic movements, CNS depression, neonatal hypoxic conditions, or urinary retention.

Package leaflet Section 2

The following symptoms may occur in newborn babies of mothers that have used

<product> during late pregnancy and/or labour, they were observed immediately or only a few hours after birth: shaking, muscle stiffness and/or weakness, breathing problems and urinary retention (withholding/retaining urine).

The MAHs should submit a variation to the relevant national competent authorities within 2 months to update their product information as proposed above, if similar information is not already included in their product information.

6.2.1.3. Perindopril - PSUSA/00002354/202010

The CMDh, having considered the PSUR on the basis of the PRAC recommendation and the PRAC assessment report, agreed by consensus on the variation of the marketing

authorisations of medicinal products containing perindopril.

In the framework of the PSUSA on perindopril, the PRAC noted that perindopril is also authorised in fixed dose combination (FDC) products. The PRAC considered that the risk of Syndrome of Inappropriate Anti Diuretic Hormone secretion (SIADH), depression, flushing, anuria and oliguria as well as a change in frequency for acute renal failure in patients with hypertension, stable coronary artery disease or symptomatic heart failure, would also be relevant to be included in fixed dose combinations of perindopril as these FDCs have the same pharmaceutical form, strengths and similar indications of perindopril as single

substance. The adverse reactions should be included in the SmPC section 4.8 for perindopril even if already included for another active substance in the same FDC product.

The same timelines as for the present PSUSA on perindopril would apply in accordance with the CMDh guidance on implementing variations.

6.2.1.4. Polystyrene sulfonate - PSUSA/00002472/202010

The CMDh, having considered the PSUR on the basis of the PRAC recommendation and the PRAC assessment report, agreed by consensus on the variation of the marketing

authorisations of medicinal products containing polystyrene sulfonate.

As part of the PSUSA, the frequency of PSUR submission has been revised from 8 years to 1 year. The MAHs of products referred to in Articles 10(1), 10a, 14, 16a of Directive

2001/83/EC as amended are going to be included in the next PSUSA and are asked to provide in the next PSUR a thorough and critical benefit/risk evaluation, considering available efficacy evidence and up-to date evidence of serious gastrointestinal risks associated with the use of polystyrene sulfonate products together with the evaluation of the effectiveness of current routine risk minimisation measures in place. Discussion about accuracy of information presented in the PI with respect to the target population (indication, contraindication, dosage recommendation, treatment duration, recommendation for

electrolytes monitoring, etc.) should be provided and PI update should be proposed if needed.

6.2.2. Information on PRAC recommendations for PSUSAs for maintenance

6.2.2.1. Desogestrel / ethinylestradiol - PSUSA/00000967/202009

In the framework of the PSUSA on desogestrel / ethinylestradiol, the PRAC noted that inconsistent information related with angioedema is included in section(s) 4.4 and 4.8 of the Summary of Product Characteristics and in sections 2 and 4 of the Package Leaflet of all ethinylestradiol containing medicinal products (single agent and in fixed dose

combinations).

Therefore, PRAC recommends that the following is included in the product information of all ethinylestradiol containing medicinal products:

Summary of product characteristics A warning should be added/revised as follows:

Section 4.4

Exogenous estrogens may induce or exacerbate symptoms of hereditary and acquired angioedema.

Section 4.8

Text in the tabulated list of adverse reactions in the SOC Immune system disorders should be added/revised as follows:

Exacerbation of symptoms of hereditary and acquired angioedema. (Frequency

‘Unknown’) Package leaflet

2. What you need to know before you use [brand name]

Tell your doctor if any of the following conditions apply to you.

If the condition develops or gets worse while you use [trade name], you should also tell your doctor.

- If you experience symptoms of angioedema such as swollen face, tongue and/or throat and/or difficulty swallowing or hives potentially with difficulty breathing contact a doctor immediately. Products containing estrogens may cause or worsen the symptoms of hereditary and acquired angioedema.

4. Possible side effects Serious side effects

Contact a doctor immediately if you experience any of the following symptoms of angioedema: swollen face, tongue and/or throat and/or difficulty swallowing or hives potentially with difficulty breathing (see also section “Warnings and precautions”).

6.2.2.2. Tetrabenazine - PSUSA/00002911/202010

In the framework of the PSUSA on tetrabenazine, the PRAC noted that inconsistent information related to the risk of depression and suicidality and overdose is included in sections 4.4, 4.8 and 4.9 of the Summary of Product Characteristics and in sections 2, 3 and 4 of the Package Leaflet of tetrabenazine containing medicinal products.

Therefore, PRAC recommends that the following is included in all product information of concerned products:

Summary of Product Characteristics Section 4.4

Depression/Suicidality

Tetrabenazine may cause depression or worsen pre-existing depression. Cases of suicidal ideation and behaviour have been reported in patients taking the product. Particular caution should be exercised in treating patients with a history of depression or prior suicide

attempts or ideation (see also section 4.3).

Patients should be closely monitored for the emergence of such adverse events and patients and their caregivers should be informed of the risks and instructed to report any concerns to their doctor immediately.

If depression or suicidal ideation occurs it may be controlled by reducing the dose of tetrabenazine and/or initiating antidepressant therapy. If depression suicidal ideation is profound, or persists, discontinuation of tetrabenazine and initiation of antidepressant therapy should be considered.

Section 4.8

The following adverse reactions should be added under the SOC Psychiatric disorders with a frequency of very rare:

- Suicidal ideation - Suicide attempt Section 4.9

Symptoms associated with overdoses of tetrabenazine may include acute dystonia, oculogyric crisis, nausea, vomiting, diarrhoea, sweating, hypotension, confusion, hallucinations, hypothermia, sedation, rubor and tremor.

Treatment should consist of those general measures employed in the management of overdosage with any CNS-active drug. General supportive and symptomatic measures are recommended. Cardiac rhythm and vital signs should be monitored. In managing

overdosage, the possibility of multiple drug involvement should always be considered. The physician should consider contacting a poison control centre on the treatment of any overdose.

Package Leaflet

Section 2. What you need to know before you take [Product]

Warnings and precautions

Talk to your doctor or pharmacist before taking [Product]

• If you have been diagnosed with depression or have thought about or tried to commit suicide.

• If you have ever had depression Section 3. How to take [Product]

If you take more [Product] than you should

If you take too many tablets or someone else accidentally takes your medicine, contact your doctor, pharmacist, or nearest hospital straight away. Symptoms of overdose include

uncontrollable muscle spasms affecting the eyes, head, neck and body, uncontrolled rolling of the eyes, excessive eye blinking, nausea, vomiting, diarrhoea, sweating, dizziness, feeling cold, confusion, hallucinations, drowsiness, redness/inflammation, and tremor.

Section 4. Possible side-effects

Please seek advice immediately or go to your emergency department if you experience the following side effects:

Very Common (may affect more than 1 in 10 people)

• [Product] can cause depression, which can, in some people, lead to thoughts of committing suicide. If you feel down or very sad you may be starting to become depressed and you should tell your doctor about this change.

Very Rare (may affect up to 1 in 10,000 people)

• If you have tried to commit suicide.

• If you have intentionally hurt yourself or if you have started to think about intentionally hurting yourself.

Affected MAHs are requested to submit the appropriate variations to the relevant national competent authorities within 2 months.

6.2.3. Information on PRAC recommendations for PSUSAs for CAPs/NAPs or CAPs None

6.2.4. Outcomes of informal PSUR work sharing procedures / Chair

The CMDh adopted the outcome of the informal PSUR work sharing procedure on Edarclor (azilsartan medoxomil/chlortalidone).

The SmAR will be published on the CMDh website (Action: EMA).

6.2.5. PSUSA Lead Member State appointment

The CMDh appointed the lead Member States for single assessment of PSURs for NAPs to be started in June 2022. The appointed lead member states will be published in the EURD list.

6.2.6. PSUSA Follow-up procedures

None

6.3. Results of post-authorisation safety studies (PASS) imposed in the MA (in accordance with Art. 107q)

6.3.1. PRAC recommendations on PASS results for CMDh position

None

6.4. Lists

6.4.1. Union Reference Date list

The CMDh noted the update of the Union Reference Date list.

6.4.2. List of medicinal products under additional monitoring

The CMDh noted the update of the list of medicinal products under additional monitoring.

6.5. Information from Member States on actions for nationally authorised products related to safety

None

6.6. Other topics related to pharmacovigilance

None

7. Break-out sessions and CMDh scientific input to applications

2 Subject to adoption via written procedure in advance of the meeting. For discussion/adoption at the plenary if comments are received during written procedure.

7.1. .

Information related to this section cannot be released at the present time as it is deemed to contain commercially confidential information

7.2. Mykronor 5 microgram/ml, solution for injection/infusion (NL/H/5186/001/DC) / NL

NL informed the CMDh about the break-out session held for Mykronor 5 microgram/ml, solution for injection/infusion (NL/H/5186/001/DC). The major objections have been

addressed by the applicant after the BOS and the RMS is currently positive in the procedure.

The procedure will end after the CMDh meeting.

8. Miscellaneous

8.1. Report from the June CMDv meeting

The CMDv secretariat reported from the June CMDv meeting.

8.2. June 2021 CMDh Press Release

The CMDh press release will be circulated for written agreement (Action: EMA).

8.3. A.O.B.

8.3.1. Quality defect of the secondary package / PL

The CMDh discussed if it is necessary to add a secondary packing site in EU to the

registration dossier of imported finished medicinal products when the product needs to be repacked in EU because of a quality defect of the secondary package and if it necessary to add to the registration dossier a manufacturing site where the batch control and batch release manufacturer takes place (points 1.1.3 and 1.6 GMP), considering that there is already a secondary packaging site in the EU.

The CMDh concluded that quality defects of the secondary packaging should be an exceptional circumstance and the questions should be handled by inspectorates.

8.3.2. .

Information related to this section cannot be released at the present time as it is deemed to contain commercially confidential information.

8.3.3. Interaction between rosuvastatin and ticagrelor / CZ

The CMDh was informed that following the publication of the May CMDh press release many questions have been received with regard to the implementation of the interaction between rosuvastatin and ticagrelor.

It was agreed to update the information in the May press release to clarify that the

implementation of the interaction between rosuvastatin and ticagrelor should be put on hold

until the outcome of the assessment of the PSUSA on ticagrelor is available. This concerns MAHs of products containing ticagrelor and rosuvastatin (as mono-component or in fixed- dose combination). The implementation of the other conclusions of the PSUSA on

ezetimibe&rosuvastatin (related to DRESS), for products containing rosuvastatin as mono- component or in fixed-dose combination, should not be delayed by this decision. As mentioned before, the CMDh will further communication on the implementation after the finalisation of the PSUSA on ticagrelor.

8.3.4. Change in address of MAH for UK(NI) located in the UK(GB) / DE

See topic 2.2

8.3.5. New indication in a generic product / IE

The CMDh discussed if a generic product can apply for a new indication by way of a variation based solely on bibliographic data.

It has been discussed previously and reflected in the NtA that regardless of the legal basis of the initial MA, a MAH can submit variation applications in relation to further developments or uses of its medicinal product, including new therapeutic indications.

Such variations need to be based on data, which can be bibliographic data only. However, a bridge between the bibliographic data and the product needs to be established. The data (including possible reference to off-label use) are then subject to assessment.

9. Other topics and dates for next meeting

9.1. Draft meeting schedule and draft time schedule for referrals

The meeting schedule for July 2021 was tabled for information.

 More information about acronyms and abbreviations used in this document can be found on the CMDh website: http://www.hma.eu/457.html

List of participants

List of participants including any restrictions with respect to involvement of members / alternates / experts following evaluation of declared interests for the 22-23 June 2021 meeting

Name Role Member

State or affiliation

Outcome restriction following evaluation of e-DoI

Kora Doorduyn-van der

Stoep Chair Netherlands No interests declared

Jascha Johann Hörnisch Member Austria No interests declared

Sophie Colyn Member Belgium No interests declared

Lyudmil Antonov Member Bulgaria No interests declared Teodor Nikolov Alternate Bulgaria No interests declared Sabina Uzeirbegović Member Croatia No interests declared Gorana Perina Lakoš Alternate Croatia No interests declared Emilia Mavrokordatou Member Cyprus No interests declared Jitka Vokrouhlická Member Czechia No interests declared Zuzana Fliegerova Alternate Czechia No interests declared Katrine Damkjær Madsen Member Denmark No interests declared

Anne Kristine Hejlesen Alternate Denmark No restrictions applicable to this meeting

Margit Plakso Member Estonia No interests declared

Pauliina Ikäheimo Alternate Finland No interests declared

Glenn Lastennet Member France No interests declared

Mathilde Geynet-Kovacs Alternate France No interests declared Susanne Winterscheid Member Germany No interests declared

Georgia Bouziou Member Greece No interests declared

Magdolna Nemeth Member Hungary No interests declared Orn Gudmundsson Member Iceland No interests declared Nicole Kavanagh Member Ireland No interests declared

Laura Galatti Member Italy No interests declared

Marco Franceschin Alternate Italy No interests declared

Maija Cirkina Member Latvia No interests declared

Iveta Eglite Alternate Latvia No interests declared

Žydrūnas Martinėnas Member Lithuania No restrictions applicable to this meeting

Mylene Ferrier Member Luxembourg No restrictions applicable to this meeting

Helen Vella Member Malta No interests declared

Paula Cardona Xuereb Alternate Malta No interests declared Priscilla Schoondermark Member Netherlands No interests declared Inger Mulder-van Dam Alternate Netherlands No interests declared

Suzanne Gordon Member Norway No restrictions applicable to this meeting

Cathrine Rolfsen Alternate Norway No interests declared Andrzej Czeslawski Member Poland No interests declared Marta Marcelino Member Portugal No interests declared Rui Pedro da Costa Vilar Alternate Portugal No interests declared Cristian Dan Georgescu Member Romania No interests declared Marina Popescu Alternate Romania No interests declared

Mária Skodova (Pollakova) Member Slovakia No interests declared Marjeta Jordan Member Slovenia No interests declared

Elisa Sulleiro Member Spain No restrictions applicable to this meeting

Veronica Garcia Morales Alternate Spain No interests declared Christin Olofsson Member Sweden No interests declared Adam Andersson Alternate Sweden No interests declared Dino Soumpasis Chair of CTS

WG Germany No interests declared

Martin Huber Chair of Non-

Prescription MPs TF

Germany No interests declared

Maria Luisa Casini Chair of the PhV

WS WP Italy No interests declared

Jayne Crowe Chair of GCP

Inspectors Working Group/CMDh Working Party

Ireland No interests declared

Siri Wang Chair of CMDh

WP on Paediatric Regulation

Norway No interests declared

Representatives from the European Commission attended the meeting Ad hoc experts* attended the meeting

Meeting run with support from relevant EMA staff

*Experts were evaluated against the product(s) they have been invited to talk about