It provides an overview of the European Medicines Agency's (the Agency) practical and operational aspects with regards to the handling of Article 20 pharmacovigilance procedures. Revised topics are marked 'New' or 'Rev.' on publication.
A PDF version of these questions and answers is available below:
These questions and answers are for guidance only, without prejudice to legal and regulatory interpretation that might be provided in future updates of the rules governing medicinal products in the European Union, volume 2, notice to applicants.
These questions and answers should be read in conjunction with the Regulation (EC) No 726/2004 of the European Parliament and of the Council of 31 March 2004 laying down Union procedures for the authorisation and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency. Marketing authorisation holders (MAHs) must in all cases comply with the requirement of EU legislation.
Links to documents referred to in the below questions and answers can be found under Referral procedures: regulatory and procedural guidance.
An Article 20 pharmacovigilance procedure follows the provisions of Article 20 of Regulation (EC) 726/2004.
It applies when the procedure is initiated as a result of the evaluation of data relating to pharmacovigilance of medicinal product(s)* authorised via the centralised procedure only.
References:
*When the procedure is initiated as a result of the evaluation of data that do not result from pharmacovigilance activities, for example relating to the quality or efficacy of centrally authorised medicinal product(s), the Article 20 non-pharmacovigilance procedure will apply, and in such cases the matter should be referred to the Committee for Medicinal Products for Human Use (CHMP). Please refer to theQuestions and answers: Article 20 non-pharmacovigilance procedures.
An Article 20 pharmacovigilance procedure should be initiated in case a Member State (MS) or the European Commission (EC), as a result of the evaluation of data relating to pharmacovigilance, considers that at least one of the measures envisaged under title IX (Pharmacovigilance) or XI (Supervision and sanctions) of Directive 2001/83/EC must be applied for centrally authorised medicinal products.
References:
An Article 20 pharmacovigilance procedure can only be initiated by the European Commission (EC). A marketing authorisation holder cannot trigger this procedure.
The EC refers the safety matter to the Agency, by circulating a notification to the Agency and to all Member States, requesting an opinion by the Committee for Medicinal Products for Human Use (CHMP) to be adopted on the basis of a recommendation from the Pharmacovigilance Risk Assessment Committee (PRAC).
The notification will identify the safety concern including a detailed explanation of the issue raised and the need for any regulatory action to be considered.
The notification will be publicly available at the start of the procedure (please refer to Question 6).
A Member State (MS) may on its own initiative or at the European Commission’s (EC) request, where urgent action is essential to protect public health, suspend the use of a centrally authorised medicinal product in its territory until a definitive decision is adopted.
When it does so on its own initiative, the MS should inform the EC and the Agency of the reasons for its action at the latest on the next working day following the suspension.
The Agency will inform all other MSs without delay, and the EC will immediately initiate an Article 20 pharmacovigilance procedure, if not already ongoing.
An Article 20 pharmacovigilance procedure is initiated where only centrally authorised medicinal products (CAPs) are concerned by the safety issue.
The procedure may concern a specific medicinal product, all medicinal products containing the same active substance (range of medicinal products) or all medicinal products belonging to the same therapeutic class (several active substances concerned). If the safety concern referred relates to a range of medicinal products or therapeutic class involving not only CAPs but also nationally authorised medicinal products (including products authorised via the mutual recognition and decentralised procedures), then an Article 31 pharmacovigilance procedure1 or an Article 107i procedure2, as appropriate, will be initiated including all medicinal products affected.
1 Please refer to Questions and answers: Article 31 pharmacovigilance referrals
2 Please refer to Questions and answers: Urgent Union procedures (Article 107i)
Once the Article 20 pharmacovigilance procedure is triggered, the safety issue will be discussed at the upcoming Pharmacovigilance Risk Assessment Committee (PRAC) plenary meeting and a brief summary will be included in the agenda published at the beginning of the PRAC meeting.
The start of the procedure will be announced as part of the PRAC highlights, which will be published on the next working day following the PRAC meeting during which the matter is considered.
In certain cases, depending on the urgency of the matter the announcement may take place earlier.
The announcement will specify the safety issue under consideration, the medicinal product(s) concerned and will include the publication of the following documents on the Agency’s website on a page created specifically for the procedure:
The announcement on the Agency’s website will also be linked to the European public assessment report (EPAR) of the centrally authorised medicinal product(s) concerned by the Article 20 pharmacovigilance procedure.
Reference:
Whenever possible, MAHs will be informed on the Wednesday before the PRAC meeting of new pharmacovigilance Article 20 procedure(s) that the PRAC will consider the following week. This communication will be provided for information only.
Following the PRAC meeting, a public announcement on the Agency’s website will include all information related to the start of procedure. In addition, all qualified persons for pharmacovigilance (QPPV) of the medicinal product(s) concerned by the Article 20 pharmacovigilance procedure will be notified electronically (via email/Eudralink) by the Agency. The notification of the procedure initiation to the QPPV will include:
The Agency may release updated information on the website during the procedure and therefore marketing authorisation holder(s) should continuously check the Agency’s website for any relevant updates (please refer to Question 27, Question 33, and Question 36).
The qualified person for pharmacovigilance (QPPV) will, by default, be the contact person and will receive all correspondence from the Agency regarding this procedure.
The QPPV may if they wish to, either designate a different contact person within the organisation of the MAH or designate another party to represent the MAH for the Article 20 pharmacovigilance procedure. In this case they must inform the EMA procedure assistant via email.
All documentation concerning the Article 20 pharmacovigilance procedure will be sent to the contact person only.
Receipt of any documents by the contact person will be considered to constitute effective receipt by the MAH inter alia for the purposes of calculating the procedural timelines.
All communications with the Agency should be channelled via the contact person only.
The marketing authorisation holder(s) (MAHs) can form a group for the purpose of the procedure (irrespective of group/company affiliation) in order to provide a single consolidated response and/or oral explanations to the questions raised by the Pharmacovigilance Risk Assessment Committee (PRAC) during the procedure. In this case the cover letter accompanying the single consolidated response and/or request for oral explanation should clearly identify the parties responsible for the submission/request.
The Agency will levy a fee for a pharmacovigilance procedure under Article 20 of Regulation (EC) 726/2004.
The share payable by each marketing authorisation holder (MAH) will be calculated by the Agency based on information recorded in the Article 57 database. An advice note will be sent after the start of procedure, to the relevant qualified person(s) for pharmacovigilance (QPPV) in order to ensure the accurate identification of the chargeable units for the medicinal products involved in the procedure. Following the advice note, an invoice will be sent to each MAH.
For MAHs already qualified as a micro-, small or medium-sized enterprise (SME) by the Agency, or those that send a SME declaration within 30 days of the invoice date, the fee will be reduced (small- or medium-sized enterprise) or waived (micro-sized enterprise).
References:
The marketing authorisation holder(s) (MAHs) concerned by an Article 20 pharmacovigilance procedure will be requested to submit information relevant for the assessment of the safety concern.
The MAHs can present written or oral explanations to the Pharmacovigilance Risk Assessment Committee (PRAC) within the time limit as specified in the procedure timetable, and before a recommendation is issued by the PRAC.
For detailed information on how and when to submit data please refer to Question 15 and Question 17.
Regardless of whether or not the MAHs present written or oral explanations to the PRAC, a recommendation applicable to all marketing authorisation(s) concerned by the procedure will be issued by the PRAC.
The safety concern triggering the Article 20 pharmacovigilance procedure will be substantiated by additional data that could be requested by the Pharmacovigilance Risk Assessment Committee (PRAC) in the format of a list of questions, comments on the scientific background supporting the triggering of the procedure or by using data sources available to the Agency and/or to the national competent authorities (NCAs) of the Member States.
This data may be gathered from several different sources (i.e. from concerned marketing authorisation holders (MAHs), healthcare professionals, patients’ organisations, Eudravigilance data, data available to the NCAs, etc).
The need for specific data to be collected is identified by the PRAC at the start of the procedure.
The data to be considered for the assessment will have to be submitted within the specified deadline as published in the announcement of the start of the procedure (please refer to Question 6).
Notwithstanding the above, the PRAC may also collect additional data through a further list of outstanding issues, a public hearing and/or an oral explanation in accordance with an extended timetable, which will be made publicly available (please refer to Question 19 and Question 21).
The assessment of data within the Article 20 pharmacovigilance procedure is led by the Pharmacovigilance Risk Assessment Committee (PRAC). At the start of the procedure, the PRAC Chairperson appoints a PRAC rapporteur and PRAC co-rapporteur(s) who will perform the assessment of all data collected within the agreed timelines.
The assessment will result in the PRAC adopting a recommendation on the safety issue reviewed, which will be forwarded to the Committee for Medicinal Products for Human Use (CHMP) (please refer to Question 2).
Even though the assessment of the Article 20 pharmacovigilance procedure will be performed by the PRAC, there will be a close collaboration between the PRAC (co)- rapporteurs and the CHMP (co)- rapporteurs.
The Pharmacovigilance Risk Assessment Committee (PRAC) (co-)rapporteurs for an Article 20 pharmacovigilance procedure should be appointed by the PRAC Chairperson from amongst its members or alternates (hereafter referred to as PRAC members). Priority is given to the PRAC (co?)rapporteurs already nominated for the centrally authorised medicinal products (CAPs).
In case of an Article 20 procedure concerning several active substances belonging to the same therapeutic class, or where several issues are to be assessed, a lead rapporteur and several co-rapporteurs may be appointed.
The PRAC Chairperson will endeavour to apply the criteria of best available expertise to be taken into account for the appointment of the PRAC (co-)rapporteurs for each procedure.
Reference:
Marketing authorisation holder(s) (MAHs) should submit to the Agency and all Pharmacovigilance Risk Assessment Committee (PRAC) members all available evidence to support the assessment of the impact of the safety concern being reviewed in the procedure in response to the list of questions and as per the timelines published on the Article 20 pharmacovigilance procedure page.
MAHs of medicinal products concerned by the procedure should submit their responses as follows:
Published data can be presented as supportive documentation in response to a specific question if no other data is available.
In case some questions (e.g. on a specific pharmaceutical form) are not applicable/relevant to all medicinal product(s) concerned by the procedure, or to the medicinal product(s) of the represented group, the response should be “not applicable” with a short explanation.
It should be noted that the responsibility for the quality of the submitted documentation lies with the MAHs and is crucial to the overall assessment. The data presented in the submissions should be intended exclusively for the purposes of the concerned procedure. The information and data contained in the individual submissions will be assessed and reflected in the assessment reports related to the concerned procedure. As a general rule, such information and data will not be redacted from the assessment reports with respect to individual products prior to sharing them with all concerned MAHs. Indeed for transparency reasons and in order to respect the right of defence of the MAHs concerned by the procedure, the Agency will share all the information and data relevant for the scientific assessment with all concerned MAHs. Moreover in general, it is not expected that individual submissions by the MAHs will include commercially confidential information.
It should be noted that neither the Agency nor the MAHs can use the information and data contained in the submissions for any other purposes than those related to the concerned procedure.
All submissions are expected to be submitted in English and electronically only (please refer to Question 17).
Submission of responses should also follow the Dossier requirements for centrally authorised products (please refer to Question 17).
In case MAHs formed a group (please refer to Question 9), the cover letter accompanying the single consolidated response and/or request for oral explanation should clearly identify the parties responsible for the submission/request.
In case the answers to the Pharmacovigilance Risk Assessment Committee (PRAC) require changes to the product information, the marketing authorisation holders (MAHs) must submit the revised product information annexes as part of the responses. Only the English language version (highlighted version) of a relevant example of the full set of product information annexes (i.e. Annex I, II, IIIA and IIIB) is required during the assessment.
Responses from marketing authorisation holder(s) (MAH) should be submitted to the Agency within the timeline specified on the procedure page. All submissions should be sent using the electronic Common Technical Document (eCTD) format and via the eSubmission Gateway or the Web Client. These portals send automated acknowledgement of receipt of submission, or of failed submission if an error occurred. Responses submitted via these portals are available in the common repository and will be considered delivered to all Committee members and alternates. The Agency no longer accepts submissions on CD or DVD. Additional copies of submissions should not be sent directly to the NCAs on CD/DVD or via common European submission portal (CESP) as this might cause delays in processing the submissions.
It is not possible to submit a standalone joint eCTD for the CAPs concerned. Responses should always be submitted individually as the next sequence in each CAP product lifecycle.
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.
For advanced therapy medicinal product (ATMP), additional submission requirements apply. Please refer to the Dossier requirements for centrally authorised products.
Submissions from marketing authorisation holder(s) (MAHs) are directly available in the common repository to the Pharmacovigilance Risk Assessment Committee (PRAC) (co-)rapporteurs to be considered for the assessment.
All information gathered will be assessed within an agreed timeframe as published on the Article 20 pharmacovigilance procedure page. The assessment report(s) prepared by the PRAC (co-)rapporteur will reflect all data submitted and considered for the review.
The PRAC (co-)rapporteur’s assessment report(s) will be circulated to the PRAC members for comments. These will also be shared with the Committee for Medicinal Products for Human Use (CHMP) (co?)rapporteur(s) 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 Pharmacovigilance Risk Assessment Committee (PRAC) takes to assess the data provided.
The timelines following a 30 day assessment period are as follows:
|
Article 20 pharmacovigilance procedure – Timetable for the assessment |
Active day |
|
Notification of an article 20 pharmacovigilance procedure to the PRAC/Agency secretariat; |
Day 0
|
|
Discussion at the first meeting of the PRAC following receipt of the notification:
|
Day 1 |
|
Preparation and submission of written explanations by the MAH(s) in response to the PRAC list of questions; |
Clock Stop |
|
Re-start of the procedure following submission of the responses in accordance with published submission dates |
Clock re-start
|
|
Circulation of the PRAC (co)-rapporteurs assessment report(s) on the MAH(s)' written responses; |
Day 20 |
|
Comments in writing from PRAC members, Committee for Medicinal Products for Human Use (CHMP) concerned Rapporteur(s) on the PRAC (co)-rapporteurs assessment report(s) |
Day 25 |
|
Discussion at the PRAC meeting:
|
Day 30 |
The dates to be followed in accordance with the above timetable by the PRAC for each month can be found in Procedural timetables
The PRAC may extend the time limit to allow for the assessment of further data provided as answers to the PRAC list of outstanding issues, oral explanation, public (and non-public) hearing and/ or in case the PRAC requires input from a scientific advisory group (SAG) or from an ad-hoc expert group to support the PRAC recommendation.
As a general rule, a clock-stop of up to one month will apply. For an extension of the clock-stop adopted by the PRAC, the MAH should send a justified request to the Agency for agreement by the PRAC. The letter specifying the length of the requested extension should be addressed to the PRAC Chairperson, signed and sent electronically to the EMA procedure manager. In preparing the justification, the MAH should consider the seriousness and urgency of the issue under consideration and the impact the extension may have on public health. The PRAC will consider the request, and if agreed, an extended timetable will be adopted. All MAHs involved in the procedure will be informed of the PRAC outcome.
The PRAC assessment of responses to the list of outstanding issues will take up to 30 or, in exceptional cases, 60 days depending on the complexity and amount of data provided by the MAH(s).
All marketing authorisation holder(s) with medicinal products included in the scope of the Article 20 pharmacovigilance procedure will be provided with the Pharmacovigilance Risk Assessment Committee (PRAC) (co-)rapporteur's assessment report(s) electronically via email/Eudralink.
The Pharmacovigilance Risk Assessment Committee (PRAC) may decide that issues need to be addressed orally by the marketing authorisation holder(s) (MAHs). In such a case, the MAH(s) will be duly informed in advance of the issues to be addressed during the oral explanation.
The MAH(s) may also request to the PRAC to present their views in an oral explanation. In such a case, the MAH(s) should send to the EMA procedure manager a request addressed to the PRAC stating the reason(s) and specifying the issue(s) to be addressed during the oral explanation. The PRAC will take due account of the request and will decide whether the oral explanation will be held.
Oral explanation(s) should take place during the assessment phase and after the receipt of the PRAC (co-)rapporteur’s assessment report(s). Further detailed information on organisational aspects of the oral explanation can be found in .
The MAH(s) can provide the oral explanation on their own behalf or on behalf of the group of MAHs whom they represent.
Where the urgency of the matter permits, the PRAC may hold public hearings, on justified grounds, particularly with regard to the extent and seriousness of the safety concern.
When the PRAC is of the opinion that a public hearing should be convened, the hearing shall be held in accordance with the modalities and rules specified by the Agency and will be announced on the Agency’s website. The announcement will also specify the modalities of participation. Further information can be found in Public hearings.
In case the PRAC has decided to hold a public hearing, a MAH or another person intending to submit confidential data relevant to the subject matter of the procedure may request permission to present that data to the PRAC in a non-public hearing. Such request should be duly justified on the grounds of confidentiality of the data to be presented. A non-public hearing can only be held whenever the PRAC has decided to hold a public hearing.
If during the procedure, the marketing authorisation (MA) for a centrally authorised product is withdrawn or transferred, the former marketing authorisation holder (MAH) should inform the EMA procedure manager and the appropriate procedure should be followed (please refer to Transfer of marketing authorisation: questions and answers and Withdrawn product notification: questions and answers).
If during the procedure, the name of the medicinal product changes, or the name and/or address of a marketing authorisation holder (MAH) changes or if the contact person changes, the MAH should inform the EMA procedure manager and the appropriate procedure should be followed (please refer to Changing the (invented) name of a centrally authorised medicine: questions and answers and Other post-authorisation activities: questions and answers.
The Pharmacovigilance Risk Assessment Committee (PRAC) will issue a recommendation on the safety concern referred under Article 20 in accordance with the timetable adopted at the start date of the procedure. The PRAC may extend the initial timetable to take into account the views of the marketing authorisation holder(s), in case a public (and non-public) hearing is held and/ or an ad-hoc expert/scientific advisory group (SAG) meeting is needed.
The PRAC recommendation will usually be adopted on the last day of the PRAC's plenary meeting.
The Pharmacovigilance Risk Assessment Committee (PRAC) recommendation on the safety issue referred under Article 20 shall include any or a combination of the following:
Where the recommendation is for the MA(s) to be varied, including changes to the information in the summary of product characteristics (SmPC), labelling and/or package leaflet (PL), the recommendation will include the suggested wording of such amendments.
With regards to point (b), the recommendation will specify any conditions or restrictions to which the MA should be made subject. Conditions for the safe and effective use of the product(s) can include, but are not limited to, requesting the marketing authorisation holder(s) to conduct a post-authorisation safety study and/or to implement additional risk minimisation measures.
The PRAC recommendation can be adopted by consensus or by majority vote. In the event of adoption by majority, the divergent positions of the concerned PRAC members and the grounds on which they are based will be appended to the recommendation issued by the PRAC.
References:
The Pharmacovigilance Risk Assessment Committee (PRAC) recommendation will include:
The outcome of the Pharmacovigilance Risk Assessment Committee (PRAC) recommendation will be included in the PRAC meeting highlights that are released on the next working day following the PRAC plenary meeting together with a summary of the PRAC recommendation.
The PRAC assessment report detailing the PRAC recommendation will be published on the procedure page around one week following the adoption of the European Commission Decision (please refer to Question 37).
Reference:
The marketing authorisation holder(s) (MAHs) of medicinal products concerned and identified at the start of the procedure, will receive the Pharmacovigilance Risk Assessment Committee (PRAC) recommendation electronically via email/Eudralink during the week following the PRAC meeting when the recommendation was adopted.
The Pharmacovigilance Risk Assessment Committee (PRAC) recommendation is sent during the week following its adoption to the Committee for Medicinal Products for Human Use (CHMP), for adoption of an opinion.
The CHMP will consider the PRAC recommendation at their following plenary meeting and will agree on the timeframe needed to issue an opinion. This timeframe should not exceed 30 days after receipt of the PRAC recommendation (please refer to Question 31).
Following the receipt of the Pharmacovigilance Risk Assessment Committee (PRAC) recommendation, the Committee for Medicinal Products for Human Use (CHMP) will consider it at their plenary meeting. As a general rule, the aim will be to adopt the CHMP opinion at their next plenary meeting following the receipt of the PRAC recommendation.
However in some cases, the CHMP may agree on the need to further consider the PRAC recommendation. In such cases, the CHMP opinion will be adopted within 30 days after receipt of the PRAC recommendation.
This decision will be reflected in the CHMP meeting highlights published on the next working day following the plenary meetings.
The Committee for Medicinal Products for Human Use (CHMP) will consider the Pharmacovigilance Risk Assessment Committee (PRAC) recommendation and assessment report and will adopt by consensus or by majority vote, a CHMP opinion on the maintenance, variation, suspension or revocation of the marketing authorisations (MAs) concerned (please refer to Question 26).
Exceptionally, an oral explanation may be held in front of the CHMP. he CHMP decides whether the oral explanation will be held.
Where the CHMP opinion differs from the recommendation of the PRAC, the CHMP will attach to its opinion an explanation of the scientific grounds for the differences.
The Committee for Medicinal Products for Human Use (CHMP) opinion will include:
A brief outcome of the Committee for Medicinal Products for Human Use (CHMP) opinion will be included in the meeting highlights that are released on the next working day following the plenary meeting, together with an EMA public health communication (including a summary of the CHMP opinion and targeted information for healthcare professional and patients) and, if applicable, the wording changes to be applied to the product information.
The CHMP opinion will be published on the procedure page following the adoption of the European Commission Decision (please refer to Question 37).
References:
The marketing authorisation holder(s) of medicinal products concerned and identified at the start of the procedure will receive the Committee for Medicinal Products for Human Use (CHMP) opinion during the week following the CHMP plenary meeting when the opinion was adopted.
The marketing authorisation holder(s) of centrally authorised products involved in the procedure will have to provide the full product information in all EU languages by Day +5 (i.e. 5 days after adoption of the opinion) to the Member States’ contact points for linguistic check and copied to the Agency. Member states may send linguistic comments until Day +19. The MAH(s) should send the translations amended accordingly together with the completed Practical information on translations for referral procedures (human) to the Agency by Day+25.
Further detailed information on the translation process of Committee for Medicinal Products for Human Use (CHMP) opinion can be found in Practical information on translations for referral procedures (human).
After the adoption of the Committee for Medicinal Products for Human Use (CHMP) opinion, the Agency together with the concerned marketing authorisation holder(s) (MAHs) and national competent authorities in the Member States 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 MAH(s).
Detailed information on the decision-making process can be found here.
The MAHs need to submit an eCTD closing sequence with the final documents within 5 days following the EC decision.
The PRAC assessment report will be published on the procedure page, in English only, around one week following the adoption of the European Commission (EC) decision,. Within four weeks of the adoption of the EC decision the Committee for Medicinal Products for Human Use (CHMP) Opinion with its annexes in all EU languages will also be published on the procedure page, which will be updated to reflect the date of the EC decision.
Reference: