Renewal and annual re-assessment of marketing authorisation

In accordance with Article 14 (1-3) of Regulation (EC) No 726/2004, a marketing authorisation (MA) is valid for five years from the date of notification of the Commission Decision to the marketing authorisation holder (MAH), and is renewable upon application by the MAH.

Notification dates of the Commission Decision are published in the Official Journal and can also be found in the EC Pharmaceuticals - Union Register for each product. Once renewed, the MA will be valid for an unlimited period, unless the Competent Authority decides, on justified grounds relating to pharmacovigilance (e.g. exposure of an insufficient number of patients to the medicinal product concerned), to mandate one additional five-year renewal.

MAs under exceptional circumstances granted under Article 14(8) of Regulation (EC) No 726/2004 are also valid for 5 years.

Conditional MAs granted under Article 14-a of Regulation (EC) No 726/2004 do not fall under the above provisions. They are valid for 1 year and should therefore be renewed annually. For further information on the ‘conditional’ MAs, see Q&A of the pre-submission procedural guidance  'Could my application qualify for a conditional marketing authorisation?').

References

• Article 14 (1-3) of Regulation (EC) No 726/2004
• Article 24 of Directive 2001/83/EC
• Guideline on the processing of renewals in the centralised procedure (EMEA/CHMP/2990/00 Rev. 5)

In order to remain valid, the renewal of the MA is required within five years of its granting. A renewal application must be submitted to the Agency at the latest 9 months before the expiry date of the MA. A renewal application should also be submitted for suspended MA. If a MAH does not submit the renewal application, the MA will expire on the last day of its validity.

The MA validity period is calculated from the date of notification of the Commission Decision to the MAH.

To ensure that the Commission Decision on the renewal application is issued before expiry of the MA, when planning for their renewal submission, MAHs should take into account the following principles:

• The renewal application must be submitted at least 9 months before the MA expiry date. Any anticipation in the submission of the renewal application by more than 2 months (i.e. earlier than 11 months before the MA expiry) will not be accepted by the Agency.
• The start of the evaluation process will be the nearest possible starting date to the submission of a valid dossier, as published by the EMA in the “Human Medicines – Procedural Timetables / Submission dates”).
• The PRAC/ CHMP assessment process can take up to 120 days of active time.

References

• Article 14(2) of Regulation (EC) No 726/2004
• Guideline on the processing of renewals in the centralised procedure (EMEA/CHMP/2990/00 Rev. 5)
• Union Register of medicinal product : website of the European Commission

Renewal applications should be submitted in eCTD format and have to contain the documents listed in the Annex 2 of the Guideline on the processing of renewals in the centralised procedure (EMEA/CHMP/2990/00 Rev.5) and which are listed below:

Module 1:      

1.0       Cover letter. The cover letter should be signed by the person designated as MAH contact with the EMA. (NB: the Renewal application is not an opportunity to notify the Agency of changes in contact person) In order to facilitate the registration of the submission, marketing authorisation holders are required to fill in all the submission attributes through the eSubmission delivery file.

1.2       Renewal Application form. The electronic EU Renewal application form (eAF) should be signed by the person designated as MAH contact with the EMA and completed with the following annexes (the form is available on the EMA public website):

• List of all authorised product presentations for which renewal is sought in tabular format (following the template for Annex A to CHMP Opinion)

The MAH should complete and sign the renewal application form, appending a list of all authorised strengths, pharmaceutical forms and presentations of the product concerned for which renewal is sought. In cases where the MAH does not wish to renew certain product presentations (e.g. a certain pharmaceutical form, strength or pack-size), this should be clearly indicated in the cover letter and the concerned presentations should not be included in the appended list.

• Details of contact persons:
  • Qualified person in the EEA for pharmacovigilance
  • Contact person in the EEA with the overall responsibility for product defects and recalls
  • Contact person for scientific service in the EEA in charge of information about the medicinal product

Note: The Renewal application is not an opportunity to notify the Agency of changes in contact persons. More information is available on ‘Contacting EMA: post-authorisation’.

• List of EU Member states/Norway/Iceland where the product is on the market and indicating for each country which presentations are marketed and the launch date
• Chronological list of all post-authorisation submission since granting the MA or since the last renewal: a list of all approved or pending Type IA/IB and Type II variations, Extensions, Art 61(3) Notifications, USR, and PSURs, giving the procedure number (where applicable), date of submission, date of approval (if approved) and brief description of the change.
• Chronological list of conditions and Specific Obligations submitted since the granting of marketing authorisation or the last renewal indicating scope, status, date of submission and date the condition/ obligation was fulfilled (where applicable)
• Revised list of all remaining conditions and Specific Obligations (where applicable)
• A statement, or when available, a certificate of GMP compliance, not more than three years old, for the manufacturer(s) of the medicinal product listed in the application issued by an EEA competent authority or MRA partner authority. A reference to the Union EudraGMP database, if available will suffice.  
• For manufacturing sites of the medicinal product not located in the EEA or in the territory of an MRA partner, a list of the most recent GMP inspections carried out indicating the date, the inspection team(s) and outcome of the inspection(s)
• In accordance with Article 46(f) of Directive 2001/83/EC manufacturing authorisation holders are required to use as starting materials only active substances which have been manufactured in accordance with the detailed guidelines on good manufacturing practice for starting materials as adopted by the Union. 

The following declarations are required:

• A declaration by the Qualified Person (QP) of each of the manufacturing authorisation holders (i.e. located in the EEA) listed in the application form where the active substance is used as a starting material.
• A declaration by the Qualified Person (QP) of the manufacturing authorisation holder(s) listed in the application as responsible for batch release.
• These declarations should state that all the active substance manufacturer(s) referred to in the application form operate in compliance with the detailed guidelines on good manufacturing practice for starting materials.

1.3.1   Summary of Product Characteristics, Labelling and Package Leaflet

• If no changes to the PI (SmPC, Annex II, outer/ inner labelling and Package Leaflet) are proposed by the MAH, a ‘clean’ version of the latest PI in English has to be provided (in Word format). This document is needed for the QRD review of the Product Information.
• If changes to the PI are proposed as part of the Renewal dossier, a version of the PI in English, highlighting the changes proposed by the MAH should be provided in Word format. In addition, a ‘clean’ version of the PI should be provided in the eCDT and Word.
• Note: All other language versions are only to be submitted after adoption of the opinion (See also “When do I have to submit revised product information? In all languages?”).

1.4       Information about the Experts

1.4.1   Information about the Expert – Quality (incl. Signature + CV)

1.4.2   Information about the Expert – Non-Clinical (incl. Signature + CV) – if applicable

1.4.3   Information about the Expert – Clinical (incl. Signature + CV)

1.8.2 Risk Management Plan:

An RMP is not systematically required as part of the renewal application. Three scenarios are possible:

• Where the MAH considers that no update to the RMP needs to be implemented, no RMP should be included in section 1.8.2 of the Renewal dossier. In this case, the MAH should specify this in the cover letter and provide a declaration in the clinical overview, confirming that the current approved RMP remains unchanged and applicable. Alternatively, if applicable, the MAH can state that an RMP update is being assessed in a procedure ongoing in parallel RMP changes are considered warranted.
• If an update of the RMP is proposed by the MAH with the Renewal application, section 1.8.2 should contain the updated RMP (‘clean’ version). In this case, in addition, a version of the RMP, highlighting the changes proposed by the MAH should be provided in Word format.
• Where there is no RMP for the medicinal product, this should be stated in the cover letter.

Module 2:

2.3       Addendum to Quality Overall Summary

The Addendum should include a declaration of compliance with Article 16(1) of Regulation (EC) No 726/2004, which obliges the MAH “…to take account of technical and scientific progress and introduce any changes that may be required to enable the medicinal product to be manufactured and checked by means of generally accepted scientific methods”.

The Addendum to the Quality Overall Summary should also include:

• Confirmation that all changes relating to the quality of the product has been made following applications for variations and that the product conforms to current CHMP Quality guidelines.
• Currently authorised specifications for the active substance and the finished product (with date of latest approval and procedure number)
• Qualitative and quantitative composition in terms of the active substance(s) and the excipient(s) (with date of latest approval and procedure number)

2.4       Addendum to Non-clinical Overview

An Addendum to the non-clinical Overview is not systematically required as part of the renewal application.

When new data are submitted in the non-clinical Addendum, a critical discussion must be submitted as part of the renewal application supporting the risk-benefit balance re-evaluation for the product taking into account any new non-clinical data accumulated since the initial MA or the last renewal, or any relevant new information in the public domain.

In case no new non-clinical data have been gathered since the initial MAA or since the last renewal, this should be stated in the Addendum to the Clinical Overview.

2.5       Addendum to Clinical Overview

A critical discussion should be provided within the Addendum to the Clinical Overview. It should address the benefit/risk balance for the product at the time of the Renewal, on the basis of the Periodic Safety Update Reports (PSUR) submitted and safety/efficacy data accumulated since the granting of the MA or since the last renewal, making reference to relevant new information in the public domain. The discussion should clearly reflect the data previously included in the PSURs and the new data that have emerged since the DLP of the last PSUR up to the DLP of the renewal. The DLP of the renewal should not exceed 90 days prior to the renewal submission.

Note: MAHs are advised to consider the Good Vigilance Practice Module VII on PSUR as guidance for the preparation of the sections of the clinical overview described below.

The Addendum to the Clinical Overview should contain the following information:

• History of pharmacovigilance system inspections (date, inspecting authority, site inspected, type of inspection and if the inspection is product specific, the list of products concerned) and an analysis of the impact of the findings overall on the benefit/risk balance of the medicinal product.
• Worldwide MA status: overview of number of countries where the product has been approved and marketed worldwide.
• Actions taken for safety reasons during the period covered since the initial MA or since the last renewal until to the DLP of the renewal: description of all significant actions related to safety that had a potential influence on the benefit/risk balance of the approved medicinal product (e.g. suspension, withdrawal, temporary halt or premature ending of clinical trial for safety reasons, issue requiring communication to healthcare professionals…). Actions taken from the DLP of the last PSUR up to the DLP of the renewal should be clearly identified and highlighted.
• Significant changes made to the Reference Information (RI) during the period covered since the initial MA or since the last renewal. In this section, new changes made from the DLP of the last PSUR up to the DLP of the renewal should be clearly highlighted.
• Estimated exposure and used patterns: data on cumulative exposure of subjects in clinical trials as well as of patients from marketing exposure for EU and non-EU regions. If the MAH becomes aware of a pattern of use of the medicinal product considered relevant for the implementation of the safety data, a brief description should be provided; such patterns may include in particular off-label use.
• Data in summary tabulations: Summary tabulations of serious adverse events from clinical trials as well as summary tabulations of adverse reactions from post-marketing data sources reported during the period covered since the initial MA or since the last renewal until to the DLP of the renewal.
• Summaries of significant safety and efficacy findings from clinical trials and non-interventional studies during the period covered by the renewal: description of any significant safety findings that had an impact on the conduct of clinical trials or non-interventional studies. It should also address whether milestones from post-authorisation safety studies, post-authorisation efficacy studies, studies included in the pharmacovigilance plan of the RMP and studies conducted as condition or specific obligations of the MA, have been reached in accordance with agreed timeframes. New data since the DLP of the last PSUR up to the DLP of the renewal should be highlighted.
• Overview of signals: High level overview of signals for which evaluation was completed during the period covered by the renewal and any action taken or planned; and high-level overview of ongoing signals (i.e. that are undergoing evaluation at the DLP of the renewal application) should be provided. The information should be provided in tabular format.
• Signal and risk evaluation: the MAH should summarise signals for which evaluation was completed during the reporting period of the renewal. For signals that became important identified or potential risks or are related to a known risk, a characterisation of the risk should be provided. Evaluation of signals completed from the DLP of the last PSUR to the DLP of the renewal should be clearly highlighted. The MAH should discuss whether any changes are considered necessary to the existing safety concerns and whether any additional risk minimisation activities for the product are warranted, considering the data collected during the period covered by the renewal.
• Relevant information on patterns of medication errors and potential medication errors (even when not associated with adverse outcomes) during the period covered by the renewal. Such information may be relevant to the interpretation of safety data or the overall benefit/risk balance evaluation.
• Literature: review of important literature references published during the period covered since the initial MA or since the last renewal until the DLP of the renewal that had a potential impact on the benefit/risk balance of the medicinal product.
• Benefit evaluation: the MAH should summarise important efficacy and effectiveness information (including information on lack of efficacy) for the period covered since the initial MA or since the last renewal until the DLP of the renewal.
• Benefit/risk balance: a discussion on the benefit/risk balance for the approved indication should be presented, based on the above information.
• Late-breaking information: The MAH should summarise the potentially important safety, efficacy and effectiveness findings that arise after the DLP of the renewal but during the period of preparation of the addendum to the clinical overview.

The Clinical Expert Statement should:

• Confirm that no new clinical data are available which change or result in a new benefit-risk balance evaluation.
• Confirm that the product can be safely renewed at the end of a 5-year period for an unlimited period, or any action recommended or initiated should be specified and justified.
• Confirm that the authorities have been kept informed of any additional data significant for the assessment of the benefit/risk balance of the product concerned.
• Confirm that the product information is up to date with the current scientific knowledge including the conclusions of the assessments and recommendations made publicly available on the European medicines web-portal.

It should be noted that the responsibility for the quality of the submitted documentation lies with the MAH and is crucial to the overall process. For queries relating to the application, please contact the Product Lead responsible for the product.

In order to ensure that renewal applications are complete and correct before submitting them to the Agency, it is strongly recommended using the pre-submission checklist for 5-year renewal applications.

References

• Guideline on the processing of renewals in the centralised procedure (EMEA/CHMP/2990/00 Rev. 5)
• Electronic Renewal application form

How: The requirements for the submission of applications related to the centralised procedure are provided on the EMA website. Information is available on ‘Submitting a post-authorisation application'. 

To whom: To the EMA, CHMP, PRAC and CAT (when involved) members, submissions via the Common Repository only.

The MAH must apply for a renewal no later than 9 months before the expiry date of the MA. The recommended submission dates published on the EMA website will apply in order to determine the start of the procedure.

The Agency will acknowledge receipt of a valid renewal application and shall start the procedure in accordance with the recommended starting dates published on the EMA website. The MAH will be informed of the adopted timetable at the start of the procedure.

The timetable for the scientific evaluation by the PRAC and the CHMP will be set in order to allow the Commission Decision to be adopted before the expiry date of the MA. Please refer to Annex 1 of the Guideline on the processing of renewals in the centralised procedure (EMEA/CHMP/2990/00 Rev. 5) .

Full procedural detailed timetables are published as a generic calendar on the EMA website (see: submission deadlines and full procedural timetables).

The published timetables identify the start and finish dates of the procedures as well as other interim dates/milestones that occur during the procedure.

The renewal procedure will involve the CHMP Rapporteur and the PRAC Rapporteur appointed for the medicinal product.

Re-examination

Article 9(2) of Regulation (EC) No 726/2004 applies to CHMP Opinions adopted for renewal applications. The MAH may therefore notify the EMA/CHMP of their intention to request a re-examination of the opinion within 15 days of receipt of the opinion; if such a request is not made within these 15 days, the opinion becomes final.

The detailed grounds for the request must be forwarded to the EMA within 60 days of receipt of the opinion. If the MAH wishes to appear before the CHMP for an oral explanation, the request should also be sent at this stage.

A new CHMP Rapporteur, CAT Rapporteur as applicable, and a new PRAC Rapporteur, different from those for the initial opinion will be appointed to co-ordinate the re-examination procedure, accompanied, if necessary, by additional experts.

References

• Guideline on the processing of renewals in the centralised procedure (EMEA/CHMP/2990/00 Rev. 5)

For information about fees and fee payment in the Centralised Procedure, please refer to the Explanatory note on fees payable to the European Medicines Agency

In case an inspection is required, please note that in addition to the renewal fee, an inspection fee will be requested (see alsoInspections).

References

• Fees payable to the European Medicines Agency

None of the changes introduced at renewal should substitute for the MAH's obligation to update the MA throughout the life of the product as data emerge.

Besides, major changes to the product, such as the introduction of a new indication and quality changes such as an extension of shelf life, should not be modified as part of the renewal procedure but have to be submitted and assessed through the appropriate variation procedure.

Where there are adequate and objective reasons not to renew the MA in its existing terms and changes are necessary to the SmPC, labelling and package leaflet arising from the renewal evaluation, the MAH may submit additional information and/or change the product information as part of the renewal process to address the concerns raised. Such changes will not initiate a separate variation procedure.

Other issues arising from assessment and changes due to the revision of the SmPC guideline, other relevant guidelines impacting on the product information, or EMA/QRD Product Information Templates should be considered within the renewal procedure.

The section “present/proposed” in the application form should clearly list any changes introduced to the product information (including any minor linguistic amendment introduced for each language). Alternatively, such listing may be provided as a separate document attached to the application form. Any changes not listed will not be considered as part of the renewal application.

References

• Guideline on the processing of renewals in the centralised procedure (EMEA/CHMP/2990/00 Rev. 5)

MAHs are advised to plan, when possible, the submission of variation applications outside the period of the submission of the renewal application and the renewal assessment procedure. However, where the need for a variation of the MA has been identified, in particular in the context of safety concerns, the MAH is advised to contact the Agency in advance of the submission of the variation application to agree on the procedural aspects for handling these parallel applications.

In case an ongoing variation (Type IA/IB or Type II) affecting the product information is not yet finalised at the time of the submission of the renewal application, the last product information adopted/accepted by the EC/CHMP/EMA should be used for the submission of the renewal application.

If a variation procedure is finalised before or upon finalisation of the renewal procedure, the accepted/adopted variation changes should be reflected in the product information adopted with the CHMP Renewal opinion.

In cases where any ongoing procedure may affect the product information, the MAH is advised to contact the Agency in advance of the submission or finalisation of the procedure(s) concerned.

The MAHs are reminded of the requirement to submit specimens at the time of the 5-year Renewal Application. These are to be submitted by post to the Agency.

For further information concerning submission of mock-ups and specimens in the framework of post-authorisation procedures, please refer to the document ' Checking process of mock-ups and specimens of outer/immediate labelling and package leaflet of human medicinal products in the centralised procedure .

References

• The checking process of mock-Ups and specimens of outer/immediate labelling and package leaflets of human medicinal products in the centralised procedure

Where no amendments to the product information are proposed by the MAH, only a copy of the latest approved product information (full set of Annexes, 'clean') in English must be submitted to the Agency in Word format.

In case the renewal application includes proposals for changes to the SmPC, Annex II, labelling and/or package leaflet, the product information must be submitted as follows:

At submission

English language (only): complete set of Annexes within the eCTD sequence and in Word format (both clean and highlighted showing the changes proposed as part of the Renewal).

If changes are approved as part of the Renewal, the following steps will apply:

After CXMP Opinion (Day +5)

All EU languages (incl. EN, NO and IS): complete set of annexes in Word format (highlighted)

After Linguistic check (Day +25)

All EU languages (incl. EN, NO and IS): complete set of annexes in Word format (highlighted) and in PDF (clean)

Translations of the adopted product information in all EU languages (incl. EN, NO and IS) are to be provided electronically (in one Eudralink package) to the Member States Contact Points for Translations by Day +5 with a copy to the EMA Procedure Assistant and to the EMA Product Shared Mailbox.

The 'full set of Annexes' consists of Annex I, II, IIIA, IIIB and, if applicable, IV and 127a as appropriate.

Annexes must be presented sequentially (i.e. Annex I, II, IIIA, IIIB, and if applicable, IV) as one Word document for each official EU language. Annex 127a (when applicable) must be presented as a separate PDF document with “127a” removed from the title page together with the Word files highlighted with tracked changes. All translations should be numbered as ONE document, starting with "1" (bottom, centre) on the title page of Annex I and Annex (127a) when applicable. The ' QRD Convention ' published on the EMA website defines format and layout of the PI. The PDF user guide should also be followed as it provides guidance on how to correctly prepare the PDF versions. When submitting the full set of Annexes in PDF format, this should be accompanied by the completed checklist. Highlighted changes should be indicated via 'Tools – Track changes'. Clean versions should have all changes 'accepted'.

The revised Annex A, where applicable, is to be provided to the Agency as a separate Word document in all EU languages (see point 1.12 below) and in PDF (clean).

The Annexes provided should only reflect the changes introduced by the Renewal. However, in exceptional cases where MAHs take the opportunity to introduce minor linguistic amendments to the texts (e.g. further to a specimen check), this should be clearly mentioned in the cover letter.

In addition, the section “present/proposed” in the application form should clearly list the minor linguistic amendments introduced for each language.

Alternatively, such listing may be provided as a separate document attached to the application form. Any changes not listed will not be considered as part of the renewal application.

Please be reminded that in accordance with Union data protection requirements, no personal data should be included in the annotated product information annexes. This applies to the English version submitted at the time of opinion, the draft translations submitted at Day+5 and the final translations submitted at Day+25. Please submit annotated product information annexes in an anonymised format (i.e. names of the reviewers removed from the track-changes). If you do not wish to do so, please ensure that the individuals whose data is included consented to its sharing with EMA and its further sharing by EMA with third parties such as other marketing authorisation applicants, marketing authorisation holders and National Competent Authorities, as relevant. EMA expressly disclaims any liability or accountability for the presence of unnecessary personal data in the annotated product information annexes submitted by the marketing authorisation holder.

References

• Guideline on the processing of renewals in the centralised procedure (EMEA/CHMP/2990/00 Rev. 5)
• The new Linguistic Review Process of Product Information in the Centralised Procedure (EMEA/5542/02 Rev. 5 )

During the scientific renewal assessment, a detailed pre-opinion review of the English (EN) version of the product information will be performed by the Agency, the QRD (Quality Review Document) members and representatives of Patients' and Consumers' Organisations. Technical Labelling Review comments will be sent to the MAH by day 75. When providing a revised EN version for adoption of the opinion, applicants should inform the Agency if and why certain Technical Labelling Review comments are not taken into account.

Translations of the adopted product information in all other EU languages (including IS and NO) are to be provided electronically (in one Eudralink package) to the Member States Contact Points for Translations by Day +5 with a copy to the EMA Procedure Assistant and to the EMA Product Shared Mailbox.

The following checks post-opinion will apply:

Comments will be sent directly by the Member States to the MAH at the latest by Day +19, with a copy to the EMA Product Shared Mailbox.

The MAH will send the final translations with tracked changes, incorporating the Member States' comments in Word format, as well as in PDF format (clean), electronically (in one Eudralink package) to the EMA Procedure Assistant with a copy to the EMA Product Shared Mailbox by Day +25. The Eudralink package should be presented in compliance with the Checklist for the submission of Day +25 (235) final product information annexes

The Agency will check if all Member States' comments have been implemented before sending the final translations to the Commission. In order to facilitate and accelerate the check of the implementation of the Member States' comments, the applicant should indicate in QRD Form 2 for each language if all comments have been implemented or not. In the latter case, a justification as why certain comments are not reflected in the final texts should be provided for the appropriate language(s). Such justification(s) and/or alternative proposals should be discussed and agreed with the relevant Member State(s) before submitting final translations to the Agency.

In case the Renewal affects only the Annex II, no or a shorter post-opinion translation timetable may be considered by the Agency on a case-by-case basis.

Following receipt of the final translations from the EMA, the Commission will start the 22-day Standing Committee consultation, addressing only legal and public health matters (which means in principle no further linguistic review).

The Commission Decision on the renewal will be issued after consultation of the Standing Committee, by Day +67.

Please be reminded that in accordance with Union data protection requirements, no personal data should be included in the annotated product information annexes. This applies to the English version submitted at the time of opinion, the draft translations submitted at Day+5 and the final translations submitted at Day+25. Please submit annotated product information annexes in an anonymised format (i.e. names of the reviewers removed from the track-changes). If you do not wish to do so, please ensure that the individuals whose data is included consented to its sharing with EMA and its further sharing by EMA with third parties such as other marketing authorisation applicants, marketing authorisation holders and National Competent Authorities, as relevant. EMA expressly disclaims any liability or accountability for the presence of unnecessary personal data in the annotated product information annexes submitted by the marketing authorisation holder.

References

• Guideline on the processing of renewals in the centralised procedure (EMEA/CHMP/2990/00 Rev. 5)
• SOP/EMEA/0046: PIQ/QRD Pre-opinion Review of Product Information for Renewal Procedures
• Procedure for review of information on medicinal products by Patient's/Consumers Organisations (PCOs) (EMA/174255/2010 Rev. 2)
• SOP/EMEA/0048: QRD Post-opinion Review of Product Information for post-authorisation procedures affecting the annexes, excluding Annex II applications

MAHs should only complete the renewal application form for those presentations which they would like to renew. In cases where the MAH does not wish to renew certain product presentations (e.g. a certain pharmaceutical form, strength or pack-size) this should be clearly indicated in the cover letter (see also “How shall I present my renewal application”).

In case the MAH does not wish to renew the entire MA (i.e. all authorised presentations) a letter to this effect should be addressed to the rapporteur, Product Lead, EMA product shared mailbox and the contact point at the European Commission, at the latest 9 months prior to the expiry of the concerned MA, clearly stating the reasons for not requesting the renewal of the MA.

This is without prejudice of the MAH obligation to notify such action to the Agency according to the provisions set out in Article 14 (b) of Regulation (EU) No 726/2004. Please refer to the EMA questions and answers on Withdrawn product notification.

References

• Article 14(b) of Regulation (EC) No 726/2004
• Directive 2001/83/EC

The EPAR (published on the EMA website) will be revised to implement the CHMP conclusions in relation to the renewal procedure.

Besides, the CHMP meeting highlights following each CHMP meeting give information in its Annex on opinions in relation to renewal applications. This information includes the invented name of the product, its INN and the name of the MAH.

In case of an unfavourable opinion, recommending the suspension or the non-renewal of the MA, a Question and Answer (Q&A) document will be published by the Agency. This will include information and reasons for such opinion. The information will be provided in lay language, so that it can be understandable for the general public.

References

• CHMP: Agendas, minutes and highlights

If you cannot find the answer to your question in the Question and Answer (Q&A) when preparing your application or during the procedure, please contact the Product Lead responsible for your product.

In accordance with Article 14-a of Regulation (EC) No 726/2004, a conditional marketing authorisation (MA) is valid for one year from the date of notification of the Commission Decision to the marketing authorisation holder (MAH), and is renewable, annually, upon application by the MAH.

The conditional MA validity period is expressed in Commission Decisions, as follows:

• Initial MA: by reference to the date of notification of the Commission Decision to the MAH. Notification dates of the Commission Decision are published in the Official Journal and can also be found for each product in the Union Register published by the European Commission.
• Renewal: By reference to the previous MA expiry date.

In order for a conditional marketing authorisation to remain valid, a renewal application has to be made annually (irrespective of whether the marketing authorisation is suspended).

The renewal decision will usually refer to the expiry date of the preceding marketing authorisation so that the renewed authorisation will be valid from the date of the previous expiry.

For further information on the 'conditional' marketing authorisations, see Q&A of the pre-submission procedural guidance question "Could my application qualify for a conditional marketing authorisation?".

References

• Article 14-a of Regulation (EC) No 726/2004
• Commission Regulation (EC) No 507/2006

According to the legislation, MAHs must apply for an annual renewal at least six months before the expiry date of the conditional MA.

In case a MAH does not submit a renewal application, the conditional MA will expire automatically.

Once a renewal application has been submitted within this deadline, the conditional marketing authorisation shall remain valid until a decision is adopted by the Commission in accordance with Article 10 of Regulation (EC) No 726/2004.

In order to ensure that the Commission Decision on the renewal application can be issued ideally before expiry of the conditional MA, MAHs should take into account the following principles when planning for their renewal submission:

• The annual renewal application must be submitted at least 6 months before the MA expiry date. A submission of the annual renewal application more than 1 month in advance of the submission due date will not be accepted by the Agency.
• The DLP of the annual renewal should not exceed 70 days prior to the submission.
• The start of the evaluation process will be the nearest possible starting date, as published by the EMA in the "Human Medicines – Procedural Timetables / Submission dates".
• The CHMP assessment process can take up to 90 days.
• The Decision-Making Process (incl. Standing Committee consultation) for renewal procedures is 67 days.

In addition, as the quality of the annual renewal application will be key to ensure a timely start and finalisation of the annual renewal procedure, a pre-submission dialogue between MAHs and the Agency may be considered, approximately nine months in advance of MA expiry.

References

• Article 6 of Commission Regulation (EC) No 507/2006
• Union Register of medicinal product : website of the European Commission

In order to allow the CHMP to confirm the benefit-risk balance of the medicinal product and to review the specific obligations and their timeframes for completion, annual renewal applications should be presented as indicated below, in accordance with the appropriate headings and numbering of the EU-eCTD format.

In order to ensure that annual renewal applications are complete and correct before submitting them to the Agency, it is strongly recommended to use the pre-submission checklist for annual renewal of conditional marketing authorisation applications.

Module 1        

1.0       Cover letter[1] with the following documents attached

• List of all authorised product presentations for which renewal is sought in tabular format (following the template for Annex A to CHMP Opinion)

Note: In cases where the MAH does not wish to renew certain product presentations (e.g. a certain pharmaceutical form, strength or pack-size), this should be clearly indicated in the cover letter and they should not be included in the appended list.

• Chronological summary table of the Specific obligations (SOBs) and other conditions to the MA stating the following for each: description (scope), reference number (preferably SIAMED number), due date indicated in Annex II of the Product Information, date of submission and procedure within which the SOB was submitted (if appropriate), date when the obligation or condition has been resolved (if applicable), and the current status.
• A present/proposed table listing any changes introduced to the product information (incl. any minor linguistic amendment introduced for each language), if applicable
• Advice provided by the Pre-submission query service and or Product Lead, if applicable

The submission should also contain a duly completed eSubmission delivery file in order to facilitate registration of the submission.

[1] Please note that there is no application form available for annual renewals and that the application form for standard 5-year renewals available on the eSubmission website is not applicable to annual renewals of conditional marketing authorisations and therefore cannot be used

Note: The Cover Letter should be signed by the person designated as MAH contact with the EMA. The Annual Renewal application is not an opportunity to notify the Agency of changes in contact person, which should be notified separately. More information is available on ‘Contacting EMA: post-authorisation’.

1.3 Product Information (PI):

1.3.1 Summary of Product Characteristics, Labelling and Package Leaflet

• If no changes to the PI (SmPC, Annex II, outer/ inner labelling and Package Leaflet) are proposed by the MAH clear reference to it should be made in the cover letter. In addition, a 'clean' version of the latest PI in English has to be provided in Word format.
• If changes to the PI are proposed as part of the Annual Renewal dossier, a version of the PI in English, highlighting the changes proposed by the MAH should be provided in the eCTD and in Word format. In addition, a 'clean' version of the PI should be provided as Word format.

Note: All other language versions are only to be submitted after adoption of the opinion (See also, “When do I have to submit revised product information? In all languages?”).

The Annexes submitted should only reflect the changes introduced by the Annual Renewal data. Any updates to the product information not resulting from data submitted as part of the Annual Renewal should be submitted by use of the appropriate procedure (see question 1.7). However, minor linguistic amendments to the texts could be accepted in addition to changes introduced based on the annual renewal data, but this should be clearly mentioned in the cover letter and list of such changes provided as an attachment to the cover letter.

1.4 Information about the Expert

1.4.1 Information about the Expert – Quality (incl. signature + CV) – if applicable

1.4.2 Information about the Expert – Non-Clinical (incl. signature + CV) – if applicable

1.4.3 Information about the Expert – Clinical (incl. Signature + CV)

1.8.2 Risk Management Plan

An RMP is not systematically required as part of the Annual renewal application. Two scenarios are possible:

• If an update of the RMP is proposed by the MAH with the Annual renewal application, section 1.8.2 should contain the updated RMP ('clean' version). In this case, a version of the RMP, highlighting the changes proposed by the MAH should be provided in Word format.
• Where no update to the RMP is to be implemented, an RMP update should not be included in the Annual renewal submission. In this case, the MAH should specify this in the cover letter and declare in the clinical overview that the current approved RMP does not require changes. Alternatively, if applicable, the MAH can state that an RMP update is being assessed in a procedure ongoing in parallel and no additional RMP changes are considered warranted.

Module 2

2.3Addendum toQuality Overall Summary

An Addendum to the Quality Overview is not systematically required as part of the annual renewal application. It should be provided only in case important new pharmaceutical data are available.

2.4 Addendum to Non-Clinical Overview

An Addendum to the Non-clinical Overview is not systematically required as part of the annual renewal application. It should be provided only in case important new non-clinical data are available.

2.5 Addendum to Clinical Overview

A critical discussion should be provided within the Addendum to the Clinical Overview. It should address the current benefit/risk balance for the product on the basis of the data generated in SOBs and taking into account any other safety/efficacy data (including PSUR data) accumulated since the granting of the MA.

An Interim Report on the specific obligations should be included in a separate section in the clinical overview addendum, reflecting the situation as close as possible to the submission date. The interim report on the fulfilment of the specific obligations should include details for each specific obligation. The aim of this report is to inform about the status of fulfilment of specific obligationsand the impact of data generated on the benefit risk-balance of the product. If data from a specific obligation is due at the time of annual renewal submission and have not been yet submitted, it can be included in the annual renewal submission dossier. Final reporting of clinical trials should follow the conventional format of study reports (see ICH Topic E3 Note for guidance on structure and content of clinical study reports, CHMP/ICH/137/95). Clinical Summaries and Clinical Study Reports should not be included in section 2.5, but in the respective dedicated eCTD Sections, see below. One single report should be submitted for the product including all remaining specific obligations. The structure and contents of the interim report will vary depending on the type of study and available data. For further guidance on the contents of interim report on the specific obligations, please refer to the &quot CHMP guideline on the scientific application and the practical arrangements necessary to implement Commission Regulation (EC) No 507/2006 on the conditional marketing authorisation for medicinal products for human use falling within the scope of Regulation (EC) No 726/2004

2.7 Clinical Summaries

Clinical summaries will generally need to be updated, as appropriate, when new clinical study reports are submitted.

Module 5

5.3.5 Reports of Efficacy and Safety Studies (as appropriate) submitted to fulfil SOBs:

5.3.5.1 Study Reports of Controlled Clinical Studies Pertinent to the Claimed Indication

5.3.5.2 Study Reports of Uncontrolled Clinical Studies

5.3.5.3 Reports of Analyses of Data from More Than One Study

5.3.5.4 Other Clinical Study Reports

¹Please note that there is no application form available for annual renewals and that the application form for standard 5 year renewals available on the eSubmission web site is not applicable to annual renewals of conditional marketing authorisations and therefore cannot be used.

How: The requirements for the submission of applications related to the centralised procedure are provided on the EMA website. Information is available on ‘Submitting a post-authorisation application’.

To whom: To the EMA, CHMP, PRAC and CAT (when involved) members, submissions via the Common Repository only.

The MAH should submit the annual renewal application by the recommended submission dates published on the EMA website and, in any case, no later than 6 months before the MA ceases to be valid.

The Agency will acknowledge receipt of a valid annual renewal application and shall start the procedure in accordance with the recommended starting dates published on the EMA website. The MAH will be informed of the adopted timetable at the start of the procedure.

The timetable for the scientific evaluation by the CHMP will be set in order to ideally allow the Commission Decision to be adopted before the expiry date of the marketing authorisation.

Full procedural detailed timetables are published as a generic calendar on the EMA website (see: submission deadlines and full procedural timetables).

The published timetables identify the start and finish dates of the procedures as well as other interim dates/milestones that occur during the procedure.

The renewal procedure will involve the CHMP Rapporteur as well as the PRAC Rapporteur who have been appointed for the medicinal product. In case of an advanced therapy medicinal product additional steps will be included to accommodate the lead assessment by Committee for Advanced Therapies.

There is no fee payable for the annual renewal of a conditional marketing authorisation.

References

• Fees payable to the European Medicines Agency

None of the changes introduced at renewal should substitute for the MAH's obligation to update the marketing authorisation throughout the life of the product as data emerge.

In particular major changes to the product, such as the introduction of a new indication and quality changes such as an extension of shelf life, should not be modified through the annual renewal procedure but have to be submitted and assessed through the appropriate variation procedure.

Where there are adequate and objective reasons not to renew the marketing authorisation in its existing terms and changes are necessary to the SmPC, labelling and package leaflet arising from the renewal evaluation, the Marketing Authorisation Holder may submit additional information and/or change the product information as part of the annual renewal process to address the concerns raised. Such changes will not require a separate variation procedure.

Other issues arising from assessment of data required for the annual renewal and changes due to the revision of the product information in line with SmPC guideline, other relevant guidelines, or EMA/QRD Product Information Templates can be considered within the annual renewal procedure.

A present/proposed table clearly listing any changes introduced to the product information (incl. any minor linguistic amendment introduced for each language) should be attached to the cover letter.

Although MAHs are advised to avoid other procedures at the time of annual renewal, such situations cannot be excluded.

In case that an ongoing variation (Type IA/IB or Type II) affects the product information and is not yet finalised at the time of the submission of the annual renewal application, the last product information adopted/accepted by the EC/CHMP/EMA should be used in the submission of the annual renewal application.

If the variation procedure is finalised before or upon finalisation of the annual renewal procedure, the accepted/adopted variation changes should be reflected in the annual renewal product information.

In cases where any other ongoing procedure may affect the product information, the MAH is advised to contact the Agency in advance of the submission or finalisation of the procedure(s) concerned.

No mock-ups or specimens are required for the annual renewal of a conditional marketing authorisation. For details of when to submit mock-ups and specimens in the post-authorisation phase of your medicinal product, please refer to the revised checking process of mock-up and specimens information on the EMA web.

References

• Checking process of mock-ups and specimens of outer/immediate labelling and package leaflet of human medicinal products in the centralised procedure (EMA/305821/2006/Rev. 2) .

In case the renewal application affects SmPC, Annex II, labelling and/or package leaflet, the revised product information Annexes must be submitted as follows:

At submission

English language (only): complete set of Annexes within the eCTD sequence and in Word format (clean and highlighted showing the changes proposed as part of the Annual Renewal).

Where no amendments to the product information are proposed by the MAH, only an electronic copy of the latest approved product information (full set of Annexes, 'clean') in English must be submitted to the Agency in Word format.

If changes are approved as part of the Annual Renewal, the following steps will apply:

After CHMP Opinion (Day +5)

In case the annual renewal results in changes to the SmPC, Annex II, labelling and/or package leaflet, the revised complete set of Annexes must be submitted as follows:

All EU languages (incl. EN, NO and IS): complete set of Annexes in Word format (highlighted).

After Linguistic check (Day +25)

In case the annual renewal results in changes to the SmPC, Annex II, labelling and/or package leaflet, the revised complete set of Annexes must be submitted as follows:

All EU languages (incl. EN, NO and IS): complete set of Annexes in Word format (highlighted) and in PDF (clean).

Translations of the adopted product information in all EU languages (including English, Icelandic and Norwegian) are to be provided electronically (in one Eudralink package) to the Member States Contact Points for Translations by Day +5 with a copy to the EMA Product Shared Mailbox.

The revised Annex A, where applicable, is to be provided to the Agency as a separate word document in all EU languages (see point 1.12 below) and in pdf (clean).

Please be reminded that in accordance with Union data protection requirements, no personal data should be included in the annotated product information annexes. This applies to the English version submitted at the time of opinion, the draft translations submitted at Day +5 and the final translations submitted at Day +25. Please submit annotated product information annexes in an anonymised format (i.e. names of the reviewers removed from the track-changes). If you do not wish to do so, please ensure that the individuals whose data is included consented to its sharing with EMA and its further sharing by EMA with third parties such as other marketing authorisation applicants, marketing authorisation holders and National Competent Authorities, as relevant. EMA expressly disclaims any liability or accountability for the presence of unnecessary personal data in the annotated product information annexes submitted by the marketing authorisation holder.

References

• Guideline on the processing of renewals in the centralised procedure (EMEA/CPMP/2990/00 Rev. 4)
• The new Linguistic Review Process of Product Information in the Centralised Procedure (EMEA/5542/02 Rev. 4.2 )

Translations of the adopted product information in all other EU languages (Including Icelandic and Norwegian) are to be provided electronically (in one Eudralink package) to the Member States Contact Points for Translations ( list of members states contact points for translation ) by Day +5 and copied to the EMA Procedure Assistant.

The following checks post-opinion will apply:

Comments will be sent directly by the Member States to the MAH at the latest by Day +19, with a copy to the EMA Procedure Assistant.

The MAH will send the final translations with tracked changes, incorporating the Member States’ comments, electronically to the Product Lead secretary by Day +25.

The Agency will check if all Member States' comments have been implemented before sending the final translations to the Commission. In order to facilitate and accelerate the check of the implementation of the Member States' comments, the applicant should indicate in QRD Form 2 for each language if all comments have been implemented or not. In the latter case, a justification should be provided for the appropriate language(s) stating why certain comments are not reflected in the final texts.

In case the Renewal affects only the Annex II, no or a shorter post-opinion translation timetable may be considered by the Agency on a case-by-case basis.

Following receipt of the final translations from the EMA, the Commission will start the 22-day Standing Committee consultation, addressing only legal and public health matters (which means in principle no further linguistic review).

The Commission Decision on the renewal will be issued after consultation of the Standing Committee, by Day +67.

Please be reminded that in accordance with Union data protection requirements, no personal data should be included in the annotated product information annexes. This applies to the English version submitted at the time of opinion, the draft translations submitted at Day +5 and the final translations submitted at Day +25. Please submit annotated product information annexes in an anonymised format (i.e. names of the reviewers removed from the track-changes). If you do not wish to do so, please ensure that the individuals whose data is included consented to its sharing with EMA and its further sharing by EMA with third parties such as other marketing authorisation applicants, marketing authorisation holders and National Competent Authorities, as relevant. EMA expressly disclaims any liability or accountability for the presence of unnecessary personal data in the annotated product information annexes submitted by the marketing authorisation holder.

References

• The new Linguistic Review Process of Product Information in the Centralised Procedure (EMEA/5542/02 Rev. 4.2 )
• SOP/EMEA/0046: PIQ/QRD Pre-opinion Review of Product Information for Renewal Procedures
• Procedure for review of information on medicinal products by Patient's/Consumers Organisations (PCOs)(EMA/174255/2010 Rev. 2)
• SOP/EMEA/0048: QRD Post-opinion Review of Product Information for Renewal Applications, Annual Reassessments, Type II Variations (60/90 Days) and Referrals .

In cases where the MAH does not wish to renew certain product presentations (e.g. a certain pharmaceutical form, strength or pack-size) this should be clearly indicated in the cover letter (See also “How shall I present my renewal application”).

In case the MAH does not wish to renew the entire Marketing Authorisation (i.e. all presentations) a letter to this effect should be addressed to the Agency and the European Commission at the latest 6 months prior to the expiry of the concerned Marketing Authorisation, clearly and in detail stating if the marketing authorisation is surrendered for any reasons beyond purely commercial ones.

This is without prejudice of the MAH obligation to notify such action to the Agency according to the provisions set out in Article 14 (b) of Regulation (EU) No 726/2004. Please refer to the EMA questions and answers on Withdrawn product notification.

References

• Article 14(b) of Regulation (EC) No 726/2004
• Directive 2001/83/EC

Once the specific obligations have been fulfilled, the Committee may, following an application by the marketing authorisation holder, at any time adopt a recommendation for the granting of a marketing authorisation no longer subject to specific obligations and valid for five years. MAHs who consider that all Specific Obligations have been fulfilled should indicate this in the cover letter of the submission, in which final data from the last outstanding specific obligation is being submitted. This could be either within an annual renewal application or a variation, whichever is appropriate. 

References

• Article 14-a(8) of Regulation (EC) No 726/2004
• Article 7 of Commission Regulation (EC) No 507/2006

The EPAR (published on the EMA website) will be revised to implement the CHMP conclusions in relation to the renewal procedure.

Besides, the CHMP meeting highlights following each CHMP meeting gives information in its Annex on opinions in relation to renewal applications.

In case of an unfavourable opinion, recommending suspension or non-renewal of the MA, a Question and Answer (Q&A) document will be published by the Agency. This will include information and reasons for such an opinion. The information will be provided in lay language, so that it can be understandable for the general public.

References

• CHMP meeting highlights
• EPARs

If you cannot find the answer to your question in the Question and Answer (Q&A) when preparing your application or during the procedure, please contact the Product Lead responsible for your product.

In exceptional circumstances and following consultation with the applicant, an authorisation may be granted subject to certain conditions, so called specific obligations (SOBs), in particular relating to the safety of the medicinal product, notification to the national competent authorities of any incident relating to its use, and action to be taken.

Such a marketing authorisation may only be granted when the applicant can show that they are unable to provide comprehensive data on the efficacy and safety of the medicinal product under normal conditions of use and must be based on one of the grounds set out in Annex I of Directive 2001/83/EC (rarity of the condition, state of scientific knowledge, ethical grounds).

Continuation of such a marketing authorisation shall be linked to the annual re-assessment of the conditions mentioned above. The SOB(s) may include an identified programme of studies to be conducted within a specified time period and aim at the provision of additional safety and efficacy data, e.g. a registry or an observational cohort study, where data is collected and reported annually based on an agreed protocol.

The outcome of the annual re-assessment will reflect the status of fulfilment of the SOB(s) and the impact of the SOB data on the benefit / risk profile of the medicinal product and will conclude on whether the marketing authorisation should be maintained, varied or suspended based on the review of these two elements.

References

• Directive 2001/83/EC, Article 22 and its Annex I, Part II.6
• Regulation (EC) No 726/2004, Article 14(8)
• Guideline on procedures for the granting of a marketing authorisation under exceptional circumstances

The CHMP Co-Rapporteur is not systematically involved in the evaluation of the annual re-assessment application. The PRAC is systematically involved in the assessment and will focus on the assessment of the SOB data and any methodological aspects of the generation of these data in case they are falling within the definition of a non-interventional post-authorisation safety study (PASS). In this case the PRAC provides its expertise to the CHMP in terms of the assessmentof the non-interventional PASSs and any potential changes to additional pharmacovigilance and risk minimisation activities proposed in the Risk Management Plan.

Note: For ATMP products, the CAT is the lead committee for the assessment of this type of products. References to the CHMP should be understood as CAT for ATMPs.

Annual re-assessment applications should be presented as indicated below, in accordance with the appropriate headings and numbering of the EU-eCTD format.

In order to ensure that annual re-assessment applications are complete and correct before submitting them to the Agency, it is strongly recommended to use the pre-submission checklist for annual re-assessment of an MA under exceptional circumstances applications.

Module 1:       1.0       Cover letter with the following documents attached:

• A chronological tabulated summary table of the SOBs stating the following for each: description, reference number (preferably SIAMED number), due date indicated in Annex II of the Product Information, date of submission and procedure within which the SOB was submitted (if appropriate), and status. 
• Revised list of pending SOBs (where applicable).
• A present/proposed table listing any changes introduced to the product information (incl. any minor linguistic amendment introduced for each language), if applicable.

The cover letter should indicate the time period covered by the annual re-assessment application.

 In order to facilitate the registration of the submission, marketing authorisation holders are required to fill in all the submission attributes through the eSubmission delivery file UI.

Note: The Cover Letter should be signed by the person designated as MAH contact with the EMA. The Annual Re-Assessment application is not an opportunity to notify the Agency of changes in contact person, which should be notified separately. More information is available on ‘Contacting EMA: post-authorisation’.

                        1.3       Product Information

 1.3.1 Summary of Product Characteristics, Labelling and Package Leaflet

• If no changes to the PI (SmPC, Annex II, outer/inner labelling and Package Leaflet) are proposed by the MAH, clear reference to it should be made in the cover letter.
• If changes to the PI are proposed as part of the Annual Re-Assessment, a version of the PI in English, highlighting the changes proposed by the MAH should be provided in the eCTD and Word format. In addition, a ‘clean’ version of the PI should be provided in the eCTD and in Word format.
• Note: All other language versions are only to be submitted after adoption of the opinion (See also question - “When do I have to submit (revised) product information? In all languages?”)

The Annexes provided should only reflect the changes introduced by the Annual Re-Assessment. However, if the PI update is already warranted by the annual re-assessment data, the MAH can also take the opportunity to implement changes due to the revision of the SmPC guideline, other relevant guidelines impacting on the product information, or EMA/QRD product information templates and minor linguistic amendments.  This should be clearly mentioned in the cover letter and list of such changes provided as an attachment to the cover letter. Any changes not listed will not be considered as part of the application.

            1.4       Information about the Expert

            1.4.3    Information about the Expert – Clinical (incl. Signature + CV)

           1.8.2    Risk Management Plan

If an update of the RMP is proposed by the MAH as a consequence of SOB data submitted with the annual re-assessment application, section 1.8.2 should contain the updated RMP (‘clean’ version).  A version of the RMP, highlighting the changes proposed by the MAH should also be provided in Word format.

Module 2:       2.5       Addendum to Clinical Overview

The Expert report addressing the data as well as the status of fulfilment of the SOBs and their impact on the overall benefit/risk balance of the medicinal product, in the form of a Clinical Overview update or addendum, based on the following structure (headings):

• Summary of information previously submitted to address ongoing SOBs
• Data submitted with the annual re-assessment to address outstanding SOBs
• Critical evaluation of status of fulfilment of each pending SOB

Clinical summaries and clinical study reports should not be included in section 2.5 but in the respective dedicated eCTD sections; see below.

2.7       Clinical Summaries

Clinical summaries will generally need to be updated, as appropriate, when new clinical study reports are submitted.

Module 5:       5.3.5 Reports of Efficacy and Safety Studies (as appropriate) submitted to fulfil SOBs:

5.3.5.1 Study Reports of Controlled Clinical Studies Pertinent to the Claimed Indication

5.3.5.2 Study Reports of Uncontrolled Clinical Studies

5.3.5.3 Reports of Analyses of Data from More Than One Study

5.3.5.4 Other Clinical Study Reports

References

• Directive 2001/83/EC, Article 22 and its Annex I, Part II.6
• Regulation (EC) No 726/2004, Article 14(8)

A PSUR cannot be submitted as part of an annual re-assessment procedure (see also Q&A 'PSURs').

If SOB data submitted with the annual re-assessment warrant an RMP update, an updated RMP should be submitted. In such cases, it is recommended to liaise with the Agency in advance of the planned submission to agree on the details of such an update. When updates to the RMP are not warranted by newly submitted SOB data, an RMP should not be submitted within the annual re-assessment application.

If an updated RMP is already warranted as a consequence of the annual re-assessment data provided, some additional changes to the RMP may also be included in that RMP update (for further guidance please see question “Which changes can be included in an RMP update without the need for an additional variation?”).

When: The annual re-assessment application should be submitted on the anniversary date of the Commission decision granting the marketing authorisation. Flexibility in the submission date could however be envisaged, in order to synchronise the annual re-assessment submission with the submission of data from the SOBs. The annual re-assessment application submission could be adjusted within a maximum of +/- 2 months in such cases. The DLP of the annual re-assessment should not exceed 70 days prior to the submission.

Marketing authorisation holders (MAHs) are therefore advised to discuss and agree the annual re-assessment submission date with the Agency and the Rapporteur well in advance of the submission.

The MAH shall submit the annual re-assessment application at the latest by the recommended submission dates published on the EMA website. See also Human Medicines – Procedural Timetables / Submission dates).

How and to whom:More information is available on ‘Submitting a post-authorisation application’.

Identical annual re-assessment applications for multiple marketing authorisations must be submitted separately. Each marketing authorisation is considered to be a stand-alone dossier. For this reason no cross-references will be accepted and applications must be submitted for each concerned product as a complete and stand-alone document.

The EMA will acknowledge receipt of a valid application of an annual re-assessment and shall start the procedure in accordance with the recommended starting dates published on the EMA website.

The submission deadlines and full procedural detailed timetables are published as a generic calendar on the EMA website (see: submission deadlines and full procedural timetables).

The published timetables identify the submission, start and finish dates of the procedures as well as other interim dates/milestones that occur during the procedure.

The annual re-assessment procedure will involve the CHMP and the PRAC.

The following 90-day timetable shall normally apply:

Note: For Advanced Therapy Medicinal Products (ATMPs), the CAT is the lead committee for the assessment of this type of products (see: Timetable: Annual reassessment – ATMP).

Depending on the assessment, one of the following outcomes can be envisaged:

• Maintenance of the MA considering that:
  • SOBs remain in place unchanged
  • Data from the SOBs do not require changes to the MA (e.g. changes to benefit risk profile of medicinal product and product information)

All SOBs will be reviewed again at the time of the following annual re-assessment together with their impact on the benefit/risk profile of the medicinal product.

• Variation of the MA considering that:
  • SOBs need to be modified; and/or
  • Data from the SOBs warrant changes to the MA (e.g. changes to benefit risk profile of medicinal product and/or product information)

All SOBs will be reviewed again at the time of the following annual re-assessment together with their impact on the benefit/risk profile of the medicinal product.

• Suspension/revocation of the MA considering that:
  • Data from the SOBs affect the benefit/risk profile of the medicinal product to the extent it warrants the suspension/revocation of the MA for the medicinal product

or

• • The status of compliance with the SOBs is unsatisfactory and it is therefore considered that conditions to the marketing authorisation have not been fulfilled.
• Exceptionally, the CHMP may consider that all specific obligations have been fulfilled and comprehensive data on the efficacy and safety of the product is available. In such cases the CHMP may recommend granting a Marketing Authorisation not subject to specific obligations.

The Agency will subsequently forward the opinion to the European Commission, the Member States, Norway and Iceland and the Marketing Authorisation Holder together with the CHMP assessment report. The Decision-Making Process of the European Commission starts once the opinion with annexes in all official EU languages has been received.

When the annexes to the Marketing Authorisation have not been affected by the annual re-assessment, no Commission Decision will be issued.

References

• Directive 2001/83/EC
• Annex I to Directive 2001/83/EC, Part II.6
• Regulation (EC) 726/2004

The annual re-assessment of medicinal products authorised under exceptional circumstances cannot be part of the 5-year renewal procedure, as their scope is different.

References

• Guideline on the processing of renewals in the centralised procedure (EMEA/CPMP/2990/00) Rev.4

There is no fee payable for the annual re-assessment.

References

• Fees payable to the European Medicines Agency

In case that an ongoing variation(Type IA/IB or Type II) affects the product information and is not yet finalised at the time of the submission of the annual re-assessment application, the last product information adopted/accepted by the EC/CHMP/EMA should be used in the submission of the annual re-assessment application by the MAH.

If the variation procedure is finalised (notification of a Type IA/IB or opinion of the Type II) before or upon finalisation of the annual re-assessment procedure, the accepted/adopted variation changes should be used in the product information adopted with the annual re-assessment.

MAHs are advised to contact the Agency in order to discuss how to optimally handle the above situations.

No mock-ups or specimens are required for the annual re-assessment of a marketing authorisation under exceptional circumstances.

Proposals for changes to the Annexes prompted by data submitted with the annual re-assessment application may be submitted as part of the annual re-assessment procedure. In such cases, the revised product information will be considered in the annual re-assessment opinion and implementation of changes will not initiate a separate variation procedure (see also Question “How shall I present my annual re-assessment application?”, Section 1.3.1).

At submission

In case the annual re-assessment affects the SmPC, Annex II, labelling and/or package leaflet, the revised product information Annexes must be submitted as follows:

English language (only): complete set of Annexes within the eCTD sequence and in Word format (clean and highlighted showing the changes proposed as part of the Annual Re-Assessment).

In case the annual re-assessment results in changes to the SmPC, Annex II, labelling and/or package leaflet, the revised complete set of Annexes must be submitted as follows:

After CHMP Opinion (Day +5)

All EU languages (incl. EN, NO and IS): complete set of Annexes in Word format (highlighted) and in PDF (clean).

After Linguistic check (Day +25)

All EU languages (incl. EN, NO and IS): complete set of Annexes in Word format (highlighted) and in PDF (clean)

Translations of the adopted product information in all EU languages (incl. EN, NO and IS) are to be provided electronically (in one Eudralink package) to the Member States Contact Points for Translations by Day +5 and copied to the EMA procedure assistant.

The 'complete set of Annexes' consists of Annex, I, II, IIIA and IIIB i.e. all SmPC, labelling and PL texts for all strengths and pharmaceutical forms of the product concerned and Annex related to the Art. 127a if appropriate.

Annexes must be presented sequentially (i.e. Annex I, II, IIIA, IIIB, and if applicable, Annex related to the Art, 127a) as one Word document for each official EU language. Annex related to the 127a (when applicable) must be presented as a separate PDF document with “127a” removed from the title page together with the Word files highlighted with tracked changes. All translations should be numbered as one document, starting with "1" (bottom, centre) on the title page of Annex I and Annex (127a) when applicable. The 'QRD convention' published on the EMA website defines format and layout of the PI. The PDF user guide should also be followed as it provides guidance on how to correctly prepare the PDF versions.. When submitting the full set of Annexes in PDF format, this should be accompanied by the completed Day +25 checklist. Highlighted changes should be indicated via 'Tools – Track changes'. Clean versions should have all changes 'accepted'.

The revised Annex A, where applicable, is to be provided to the Agency as a separate Word document in all EU languages. See point 1.12 below.

The Decision-Making Process of the European Commission starts once the opinion with Annexes in all official EU languages, as appropriate, has been received. When the Annexes to the Marketing Authorisation have not been affected by the annual re-assessment, no European Commission Decision will be issued.

Note: Please be reminded that in accordance with Union data protection requirements, no personal data should be included in the annotated product information annexes. This applies to the English version submitted at the time of opinion, the draft translations submitted at Day +5 and the final translations submitted at Day +25. Please submit annotated product information annexes in an anonymised format (i.e. names of the reviewers removed from the track-changes). If you do not wish to do so, please ensure that the individuals whose data is included consented to its sharing with EMA and its further sharing by EMA with third parties such as other marketing authorisation applicants, marketing authorisation holders and National Competent Authorities, as relevant. EMA expressly disclaims any liability or accountability for the presence of unnecessary personal data in the annotated product information annexes submitted by the marketing authorisation holder.

Reference

• The new Linguistic Review Process of Product Information in the Centralised Procedure (EMEA/5542/02 Rev. 5 )

The EPAR (published on the EMA website) will be revised to reflect the CHMP conclusions in relation to the annual re-assessment procedure.

The CHMP meeting highlights published following each CHMP meeting gives information in its Annex on opinions in relation to annual re-assessment applications. This information includes the invented name of the product, its INN, the name of the MAH and the procedure outcome.

In case of an unfavourable opinion, recommending suspension or revocation of the MA, a Question and Answer (Q&A) document will be published by the Agency. This will include information and reasons for such an opinion. The information will be provided in lay language, so that it can be understandable for the general public.

References

• CHMP meeting highlights
• EPARs

If you cannot find the answer to your question in the Q&A when preparing your application or during the procedure, please contact the Product Lead responsible for your product.