Questions and answers: Article 29(4) referral procedures
HumanRegulatory and procedural guidanceReferrals
This page lists questions that stakeholders, particularly marketing authorisation holders (MAHs)/applicants, may have on Article 29(4) referral procedures.
It provides an overview of the European medicines Agency's practical and operational aspects with regards to handling of Article 29(4) referral procedures. Revised topics are marked 'New' or 'Rev.' with the relevant date upon publication.
A PDF version of these questions and answers is available:
These questions and answers are for guidance only, and should be read in conjunction with the rules governing medicinal products in the European Union, Volume 2A, chapter 3, notice to applicants. Marketing authorisation holders (MAHs)/applicants must in all cases comply with the requirement of EU legislation.
Initiation of Article 29(4) referral procedure
An Article 29(4) referral procedure follows the provisions of Article 29(4) of Directive 2001/83/EC.
It applies when, during the co-ordination group procedure of Article 29(1) to (3) of Directive 2001/83/EC, the Member States fail to reach an agreement on an application for mutual recognition of a marketing authorisation or on an application in the decentralised procedure (DCP), on the grounds of a potential serious risk to public health.
The procedure for an Article 29(4) referral is laid down in Articles 32, 33 and 34 of Directive 2001/83/EC.
References:
- Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use
- Notice to Applicants, volume 2A Procedures for marketing authorisation, Chapter 3 Union Referral Procedures
- Guideline on the definition of a potential serious risk to public health in the context of Article 29(1) and (2) of Directive 2001/83/EC
An Article 29(4) referral procedure should be initiated on the grounds of potential serious risks to public health, where no agreement has been reached by the Member States during the 60-day co-ordination group procedure carried out by the Co-ordination Group for Mutual Recognition and Decentralised Procedures (CMDh). The reasons for the disagreement can relate to aspects detailed in the assessment report (e.g. related to the efficacy, safety or quality data), the summary of product characteristics (SmPC), the labelling or the package leaflet (PL) proposed by the reference Member State (RMS) in the context of a mutual recognition or a decentralised procedure. In such a case the RMS will refer the matter to the Agency.
In cases of repeat use of the mutual recognition procedure, the new concerned Member States can raise issues that they consider to be grounds for potential serious risks to public health (provided that these grounds were not already covered in an earlier referral procedure, if any). In case such grounds are raised, they will lead to a new discussion in the coordination group and, possibly, to an Article 29(4) referral procedure.
A potential serious risk to public health concern can only be raised by the concerned Member States (CMS) in case of a positive assessment by the RMS.
For the definition of 'potential serious risk to public health', the Commission has adopted a guideline and annex of examples (please refer to guideline on the definition of a potential serious risk to public health and annex).
References:
An Article 29(4) referral procedure must be initiated by the reference Member State (RMS) when its assessment is positive but that Member States do not reach agreement in the co-ordination group procedure on the grounds of a 'potential serious risk to public health'.
The RMS shall provide the notification form for a referral procedure to the Committee for Medicinal Products for Human Use (CHMP)/Agency, which will include a detailed statement of the matter(s) on which the Member States concerned have been unable to reach agreement and the reasons for the disagreement based on potential serious risk to public health grounds.
References:
An application for mutual recognition of a marketing authorisation or an application in the decentralised procedure may be withdrawn by the marketing authorisation holder (MAH)/applicant at any time in any Member State.
However after a potential serious risk to public health has been raised in accordance with Article 29(1) by a concerned Member State, a withdrawal of the application in some of the Member States will not stop the matter from being discussed within the Co-ordination Group for Mutual Recognition and Decentralised Procedures (CMDh) and, eventually, from a referral procedure being initiated.
The referral procedure can only be stopped if the MAH/applicant withdraws the application/marketing authorisation in the European Economic Area (EEA) Member States.
For Article 29(4) referral procedures, only the concerned medicinal product in the mutual recognition or a decentralised procedure will be the subject of the referral.
The marketing authorisation holder (MAH)/applicant will be requested to provide a list of the (invented) names of the medicinal product, the name of the MAH/applicant to whom the product will be/is authorised, the strength(s), pharmaceutical form(s), route of administration(s), content (as applicable) in the respective Member States (MSs). This will be checked with the national competent authorities (NCAs) of the MSs.
To facilitate the exchange of information prior to the start and during the procedure, the marketing authorisation holder (MAH)/applicant should confirm the designated contact person for the Article 29(4) referral procedure.
The MAH/applicant may if they wish, be represented by another party (e.g. a consultant), who will be the contact person for the procedure. In this case it must inform the procedure manager identified in the letter notifying the procedure initiation.
All documentation concerning the Article 29(4) referral procedure will be sent to the contact person only. The contact details of the person should be clearly stated (name, address, phone and fax number and email address) in the letter of representation.
It is the responsibility of the MAH/applicant to notify the Agency of any change that might affect the validity of the letter of representation as soon as possible (e.g. in case of a change of the contact person), and to provide a revised letter of representation.
All documentation concerning the Article 29(4) referral procedure will be sent to the contact person only.
A brief summary of the issue will be discussed at the upcoming Committee for Medicinal Products for Human Use (CHMP) plenary meeting and will be included in the agenda published at the beginning of the meeting.
The start of the procedure will be announced as part of the CHMP meeting highlights, which will be published on the next working day following the CHMP meeting during which the matter is considered.
The announcement will specify the concern under consideration.
Reference:
The public announcement on the Agency's website will include information related to the start of procedure.
The letter notifying the marketing authorisation holder(s) (MAHs)/applicants of the procedure initiation will include:
- the name and contact details of the Agency's dedicated procedure manager who will be the primary contact point during the procedure, and the e-mail address of the product-shared mailbox, which should always be copied in all correspondence with the Agency;
- the notification triggering the procedure;
- the timetable and the list of questions (if applicable) adopted by the Committee for Medicinal Products for Human Use (CHMP).
No fees are payable for referral procedures under Article 29(4) of Directive 2001/83/EC.
As soon as the marketing authorisation holder (MAH)/applicant is/are informed that the matter concerning a potential serious risk to public health has been referred to the Agency, the MAH/applicant must forward to the Agency a copy of the application submitted to the competent authorities of the Member States concerned, containing the information and documents referred to in Articles 8, 10, 10a, 10b or 10c and 11 of Directive 2001/83/EC, as relevant.
During the Article 29(4) procedure, the MAH/applicant will in most cases be requested to submit further information relevant for the assessment, in response to a list of question adopted by the Committee for Medicinal Products for Human Use (CHMP).
This is an opportunity for the MAH/applicant to present written or oral explanations to the CHMP within a time limit(s) as specified in the procedure timetable before an opinion is issued by the CHMP.
The MAH/applicant will be informed of the start of the procedure and during the procedure on how and when to submit data (please refer to Questions 8, 11 and 14).
Regardless of whether or not the MAH/applicant present their explanations to the CHMP, an opinion will be issued by the CHMP, applicable to the MAH/applicant concerned by the procedure.
At the start of the procedure the data considered to be necessary for the assessment will be identified in a list of questions for submission within the specified deadline as indicated in the timetable (please refer to Questions 8, 14 and 15).
In certain cases, the procedure may begin with the assessment of the data already submitted to the competent authorities of the Member States concerned, containing the information and documents referred to in Articles 8, 10, 10a, 10b or 10c and 11 of Directive 2001/83/EC (please refer to Question 10).
The Committee for Medicinal Products for Human Use (CHMP) may also collect additional data through a list of outstanding issues and/or in an oral explanation.
The assessment of data within the Article 29(4) referral procedure is the responsibility of the Committee for Medicinal Products for Human Use (CHMP). At the start of the procedure, the CHMP Chairperson appoints a rapporteur and a co-rapporteur who will perform the assessment of all data collected within the agreed timelines.
The assessment of all the available data will result in the CHMP adopting an opinion on the issue reviewed.
The Committee for Medicinal Products for Human Use (CHMP) (co-)rapporteurs for an Article 29(4) referral procedure is appointed by the CHMP Chairperson from amongst the members or alternates, as soon as the Article 29(4) referral procedure has been triggered by the reference Member State (RMS).
The CHMP Chairperson will appoint (co-)rapporteurs to represent the RMS (rapporteur) and the objecting concerned Member State(s) (co-rapporteur).
Reference:
During the assessment
The marketing authorisation holder (MAH)/applicant is requested to submit to the Agency and all Committee for Medicinal Products for Human Use (CHMP) members all available evidence to support the Article 29(4) referral procedure.
Referrals procedures starting with a list of questions (LoQ)
For these referrals, the MAH/applicant should submit their responses to the list of questions (LoQ) as follows:
- The data should be presented electronically according to the electronic Common Technical Document (eCTD)/CTD format and accompanied by a signed cover letter and a written summary of each question.
- The must make clear reference to the procedure number and the Agency's Procedure Manager should always be put in copy.
- The written summary answering each question should follow the numbering as per the CHMP list of questions/CHMP list of outstanding issues. Please note that supportive data to the responses submitted (e.g. new analyses, study reports, literature data) are expected to be provided together with a summary of those data as per the modular structure of the CTD format.
It is left to the MAH/applicant's discretion to submit the relevant documentation necessary for the evaluation of the matter referred.
Referral procedures starting with the assessment of the data already available
- In these referral procedures, the evaluation starts with the data which has already been made available by the MAH/applicant at the start of the procedure (please refer to Question 10).
It should be noted that the responsibility for the quality of the submitted documentation lies with the MAH/applicant and is crucial to the overall assessment. All submissions are expected to be submitted in English and electronically only (please refer to Question 15).
Responses from the marketing authorisation holder (MAH) should be submitted to the Agency within the timeline specified in timetable enclosed to the letter notifying the MAH of the procedure initiation.
All submissions for referral procedures should be sent via the eSubmission Gateway or eSubmission Web Client. These portals send automated acknowledgement of receipt of submission, or of failed submission if an error occurred. The Agency no longer accepts submissions on CD-ROM or DVD.
Please note that submissions for nationally authorised products (NAPs), are not available via the Common Repository and should be sent separately to each NCA. For all referral submissions related to NAPs, the Agency strongly recommends using the electronic Common Technical Document (eCTD) or Non-eCTD electronic Submissions (Nees) formats.
For all types of submissions, responses should be presented in the modular format.
Documentation - Recommended folder structure
Documentation can be included in respective modules following the CTD location as referenced in the above folder structure – e.g. as following:
- Root folder should be 4 digits (between 0000-9999), e.g. 'submission 0000'. See screenshot below
Any working documents (for example: documents in Word format) should be outside the root submission folder, e.g. as following:
More information on the required naming conventions and file formats can be found in detailed examples of filenames for different application types and in the eSubmission gateway web client - guidance for applicants. For more information please refer to eSubmission website.
There is no need to send any separate paper cover letters for these submissions, as the cover letter will be in the relevant part of eCTD/CTD module 1 in PDF format.
Should you have any questions regarding your submission, please contact us via email: referralsubmission@ema.europa.eu, for any technical issues contact esubmission@ema.europa.eu.
Submissions from the marketing authorisation holder (MAH)/applicant should be provided directly to the Committee for Medicinal Products for Human Use (CHMP) (co-)rapporteurs to be considered in their assessment.
All information gathered will be assessed within an agreed timeframe (please refer to Question 17). The assessment report(s) prepared by the CHMP (co-)rapporteurs will reflect all data reviewed and considered relevant for the assessment.
The CHMP may in some cases require input from individual experts to advise it on specific questions in relation to the assessment.
The CHMP (co-)rapporteur's assessment report(s) will be circulated to the CHMP members for comments.
Please note that the timelines below are provided for guidance purposes only and they refer to active days, which correspond to the time the Committee for Medicinal Products for Human Use (CHMP) takes to assess the data provided.
The timetable for the Article 29(4) referral procedure is as follows:
Article 29(4) referral procedure starting with a list of questions (LoQ)- Timetable for the assessment | Day |
|---|---|
Notification of a referral procedure to the CHMP/Agency Secretariat | Day 0 |
Discussion at the first meeting of the CHMP following receipt of the notification:
| Day 1 |
Preparation and submission of written explanations by the MAH/applicant in response to the CHMP list of questions | Clock Stop |
Re-start of the procedure following submission of written explanations (in accordance with procedural timetables) | Clock re-start |
Circulation of the CHMP (co-)rapporteur's assessment report(s) on the MAH's/applicant's written responses and the proposed SmPC/labelling/PL, if applicable | Day 20 |
Comments in writing from CHMP members on the CHMP (co-)rapporteur's assessment reports and proposed SmPC/labelling/PL, if applicable | Day 25 |
Discussion at the CHMP meeting:
| Day 30 |
If the CHMP adopts a LoOI:
Preparation and submission of written and/or of oral explanations the MAH/applicant in response to the CHMP list of questions | Clock Stop |
Re-start of the procedure following submission of written explanations (in accordance with the procedural timetables) or at the time of oral explanations | Clock re-start Day 31 |
Circulation of the CHMP (co-)rapporteur's assessment report(s) on the MAH's/applicant's written responses and the proposed SmPC/labelling/PL, if applicable | Day 51 |
Comments in writing from CHMP members on the CHMP (co-)rapporteur's assessment reports and proposed SmPC/labelling/PL, if applicable | Day 55 |
Discussion at the CHMP meeting
| Day 60 |
Alternatively, an Article 29(4) starting with the assessment of the data already available may also be considered following the first discussion at CHMP, and the timetable in such a situation is as follows:
For an Article 29(4)referral procedure starting with the assessment of the data already available - Timetable for the assessment | Day |
Notification of a referral procedure to the CHMP/Agency Secretariat Submission of the relevant documentation by the MAH/applicant to the CHMP/Agency secretariat. | Day 0 |
Discussion at the first meeting of the CHMP following receipt of the notification (provided that the relevant documentation has been submitted by the MAH/applicant in advance of the start of the procedure):
| Day 1 |
Circulation of the CHMP (co-)rapporteur's assessment reports on the MAH/applicant's submitted documentation and the proposed SmPC/labelling/PL, if applicable | Day 20 |
Comments in writing from CHMP members on the CHMP (co-)rapporteur's assessment reports and proposed SmPC/labelling/PL, if applicable | Day 25 |
Discussion at the CHMP meeting:
| Day 30 |
If the CHMP adopts a LoQ:
Preparation and submission of written explanations by the MAH/applicant in response to the CHMP list of questions | Clock Stop |
Re-start of the procedure following submission of written explanations (in accordance with the procedural timetables) | Clock re-start Day 31 |
Circulation of the CHMP (co-)rapporteur's assessment report(s) on the MAH's/applicant's written responses and the proposed SmPC/labelling/PL, if applicable | Day 51 |
Comments in writing from CHMP members on the CHMP (co-)rapporteur's assessment reports and proposed SmPC/labelling/PL, if applicable | Day 55 |
Discussion at the CHMP meeting:
| Day 60 |
The dates to be followed in accordance to the above timetable for each month can be found in procedural timetables.
As a general rule, a clock-stop of up to one month will apply. For an extension of the clock-stop adopted by the CHMP, the MAH/applicant should send a justified request to the Agency for agreement by the CHMP. The letter specifying the length of the requested extension should be addressed to the CHMP Chairperson, signed and sent electronically to the EMA procedure manager. In preparing the justification, the MAH should consider the issue under consideration and the impact the extension may have. The CHMP will consider the request, and if agreed, an extended timetable may be adopted.
The marketing authorisation holder (MAH)/applicant will be provided with the Committee for Medicinal Products for Human Use (CHMP) (co-)rapporteur's assessment report(s) electronically via Eudralink.
The Committee for Medicinal Products for Human Use (CHMP) may decide whether there are issues that also need to be addressed orally by the marketing authorisation holder (MAH)/applicant. The MAH/applicant will be duly informed in advance of the issues to be addressed during an oral explanation.
The MAH/applicant may also make a request to the CHMP to attend an oral explanation. In such a case, the MAH/applicant should send a written request to the CHMP stating the reason(s) and specifying the issue(s) to be addressed during the oral explanation. The CHMP will take due account of the request and will decide whether the oral explanation should be held.
The oral explanation should take place during the assessment phase and after the receipt of the CHMP (co-)rapporteur's assessment report(s). See further detailed information on Guidance to applicants/marketing authorisation holders on oral explanations at European Medicines Agency.
If the marketing authorisation (MA) is withdrawn or transferred during the referral procedure, the former marketing authorisation holder (MAH) should inform the Agency. The Agency will then liaise with the national competent authority (NCA) of the Members State (MS) concerned.
Following confirmation by the NCA of the withdrawal of the MA, the Agency will inform the former MAH that the specific product will no longer be included in the ongoing referral procedure. If the product is withdrawn in all European Economic Area (EEA) Member States, the Article 29(4) procedure ends.
Following confirmation by the NCA of the transfer of a MA, the Agency will inform the transferee that they are included in the referral procedure, and will request the submission of an updated letter of representation.
If the name of the product or the name and/or address of a marketing authorisation holder (MAH)/applicant changes during the referral procedure, the MAH/applicant should inform the Agency. The Agency will then liaise with the national competent authority (NCA) of the Member State (MS) concerned. Following confirmation by the NCA of the change, the Agency will inform the MAH/applicant that the change has been noted.
Committee for Medicinal Products for Human Use (CHMP) opinion
The Committee for Medicinal Products for Human Use (CHMP) will issue an opinion on the matter referred under Article 29(4)within 60 days of the start date of the procedure. The CHMP opinion will usually be adopted on the last day of the CHMP's plenary meeting.
The Committee for Medicinal Products for Human Use (CHMP) opinion on an Article 29(4)referral procedure may be that:
- the application does not satisfy the criteria for authorisation;
- the summary of the product characteristics (SmPC) proposed by the applicant should be amended;
- the marketing authorisation(s) (MA) should be granted subject to certain conditions if applicable;
- already granted MA(s) should either be (subject to certain conditions if applicable) maintained, varied, suspended or revoked, as applicable.
In the case of a positive outcome of the referral procedure resulting in the granting of MAs, an amended summary of product characteristics (SmPC), labelling and the package leaflet (PL) will be annexed to the CHMP opinion, if applicable. It is also possible that the assessment of the CHMP concludes that no modifications of the final versions of the summary of product characteristics, labelling and package leaflet achieved during the co-ordination group procedure are needed, in which case the CHMP opinion shall reflect that conclusion.
In cases where the assessment of the CHMP is restricted to limited parts of the SmPC, labelling and PL, only those parts which were subject to amendment during the referral procedure will be annexed to the CHMP opinion, together with a statement that for the remaining parts, the summary of product characteristics, labelling and package leaflet are the final versions achieved during the coordination group procedure.
Where the MA should be subject to certain conditions or is to be suspended with the condition(s) for lifting the suspension of the marketing authorisation(s), these will be clearly stated in the CHMP opinion. These can include, but are not limited to, requesting the marketing authorisation holder to conduct a post-authorisation study and/or a non-interventional study. The assessment of the fulfilment of the condition(s) will be the responsibility of the Member States, coordinated by the reference Member State unless otherwise stated.
The CHMP opinion can be adopted by consensus or by majority vote. In the event of an adoption by majority vote, the divergent positions of the relevant CHMP members will be appended to the opinion.
The Committee for Medicinal Products for Human Use (CHMP) opinion will include:
- a cover page in which the adopted opinion is outlined together with the voting outcome of CHMP;
- a listing of all products/applications concerned, including the names of all identified products involved in the procedure, their respective marketing authorisation holders (MAHs)/applicants in each Member State;
- the scientific grounds and explanations for the CHMP opinion;
- the summary of product characteristics and/or the labelling or package leaflet, or those parts which were subject to amendment during the referral procedure, if applicable;
- the conditions or restrictions imposed on the marketing authorisation(s), if applicable;
- the conditions for lifting the suspension of the marketing authorisation(s), if applicable;
- the CHMP members' divergent views, in case the opinion is adopted by majority;
- the CHMP assessment report on the evaluation performed and the conclusion of the CHMP that led to the adoption of the opinion, based on all the data gathered.
A brief outcome of the Committee for Medicinal Products for Human Use (CHMP) opinion will be included in the CHMP meeting highlights that are released on the Friday of the CHMP plenary meeting week, together with a summary of the CHMP conclusions in the format of a Question & Answers document, together with adopted product information, if applicable.
The CHMP opinion will be published on the procedure webpage following the adoption of the European Commission Decision (please refer to Question 30).
Reference:
The designated contact person representing the marketing authorisation holder (MAH)/applicant (please refer to Question 6) identified at the start of the procedure, will receive the Committee for Medicinal Products for Human Use (CHMP) opinion and assessment report during the week following the adoption of the CHMP opinion.
The marketing authorisation holder (MAH)/applicant may, within 15 calendar days of the receipt of the Committee for Medicinal Products for Human Use (CHMP) opinion, notify the Agency in writing of its intention to request a re-examination of the CHMP opinion.
After these 15 calendar days, if the MAH/applicant has not requested a re-examination, the CHMP opinion is considered final and will be sent to the European Commission (EC) for the initiation of the decision-making process.
Re-examination
If, within the 15 days after the receipt of the CHMP Opinion, the MAH/applicant has notified the Agency in writing of its intention to request a Procedural advice on the re-examination of CHMP opinions, the Agency will inform the CHMP of the letter of intent received.
The detailed grounds for the re-examination requested should be sent to the Agency within 60 calendar days of receipt of the CHMP opinion. The detailed grounds submitted will determine the scope of the re-examination procedure and may encompass all aspects set out in the CHMP opinion or only certain aspects of it. However, no new data can be presented at this stage of the procedure.
The re-examination procedure will only deal with the aspects of the CHMP opinion identified by the MAH/applicant in the detailed grounds for re-examination. The MAH/applicant may request that the CHMP consults a scientific advisory group (SAG) or ad-hoc expert group during the re-examination procedure. In such a case, this request should be made as early as possible, and should be no later than the submission date of the detailed grounds.
New rapporteurs will be appointed for the re-examination, and within 60 calendar days of receipt of the detailed grounds for re-examination, the CHMP will conclude its assessment of the detailed grounds and adopts a final opinion.
The CHMP final opinion following re-examination will be sent to the EC for the initiation of the decision-making process.
The marketing authorisation holder (MAH)/Applicant will have to provide translations in all EU languages (including Icelandic and Norwegian) of the following annexes to the Committee for Medicinal Products for Human Use (CHMP) opinion:
- listing of nationally authorised products concerned by the procedure;
- the harmonised summary of product characteristics (SmPC) and/or the labelling and/or package leaflet (PL), if applicable
The Agency will contact the MAH/applicant as early as possible to ensure the smooth running of the process. The translations will have to be provided to the Member States contact points for linguistic check by Day +5 (i.e. 5 days after adoption of the opinion) and copied to the Agency. Member states may send linguistic comments until Day +19. The MAH should send the translations amended accordingly together with the completed Practical information on translations for referral procedures (human) to the Agency by Day +22.
See detailed information on the Practical information on translations for referral procedures (human).
Following the adoption of the Committee for Medicinal Products for Human Use (CHMP) opinion, the Agency together with the marketing authorisation holder (MAH) and national competent authorities (NCAs) in the Member States (MSs) will finalise the translations and will send these to the European Commission (EC).
The EC will then start the decision-making process leading to the adoption of a binding decision addressed to the MSs and notified to the MAH/applicant.
See detailed information on the decision-making process.
See the Co-ordination Group for Mutual Recognition and Decentralised Procedures (CMDh) recommendation for implementation of Commission Decisions.
Around one week following the adoption of the European Commission (EC) decision, the Committee for Medicinal Products for Human Use (CHMP) assessment report, in English only, will be published on the procedure webpage. Within four weeks of the adoption of the EC decision, the CHMP opinion with its annexes and the Question & Answers document in all EU languages will also be published on procedure webpage on the Agency's website, which will be updated to reflect the date of the EC decision.
Reference: