By Simon Ruini,
London 23 Jan 2014
The Q&A guidance document on Article 31 Referrals addresses a number of questions which marketing authorisation holders (MAHs), may have on referral procedures resulting from the evaluation of data from pharmacovigilance activities. It provides an overview of the Agency’s practical and operational aspects with regards to the handling of Article 31 Pharmacovigilance referral procedures.
An article 31 pharmacovigilance referral is initiated where the interests of the Union are involved as a result from the evaluation of data from pharmacovigilance activities of an authorised medicinal product, without being an urgent Union procedure.
All products affected by the safety concern referred and with a valid marketing authorisation in the Union will be included in the article 31 pharmacovigilance referral. This includes all products affected by the safety concern, regardless if the marketing authorisation was granted nationally (including via the mutual recognition and decentralised procedures) or via the centralised procedure.
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 a therapeutic class (several active substances concerned).
The start of the procedure is announced as part of the PRAC meeting highlights to be published on the Friday of the PRAC meeting during which the matter is considered. The announcement specifies the safety issue under consideration and includes the publication of the following documents on the Agency’s website on the specific procedure webpage:
- summary of the start of the procedure;
- notification triggering the procedure;
- draft list of concerned medicinal products/active substances and MAHs;
- list(s) of questions and timetable(s) adopted by the PRAC;
In addition, all marketing authorisation holders (MAHs) of a product(s) concerned by the article 31 pharmacovigilance referral identified in the published list, should be notified in writing by the Agency. The letter notifying the MAHs of the procedure initiation will include the contact details of the Agency’s Product Team Leader (PTL) from the referral procedures service that will be the primary contact point during the procedure and will include the link to the webpage on the Agency’s website where the relevant documentation is available.
To facilitate the exchange of information during the procedure, the marketing authorisation holders (MAHs) should inform the Agency of the designated contact person (Pharma Design offers this service to it’s clients) for the specific procedure. The designated contact person will receive all correspondence from the Agency regarding the specific procedure. As a general rule, MAHs can be represented by another party and/or grouped with other MAHs provided that the MAH submits a letter of representation.
Marketing authorisation holders (MAHs) concerned by an article 31 pharmacovigilance referral procedure will be invited to submit information relevant for the assessment of the safety concern. The PRAC will, in any case, issue a recommendation applicable to all marketing authorisations concerned by the procedure, independently of whether or not the MAHs presented their explanations to the PRAC.
The safety concern triggering the article 31 pharmacovigilance referral will be substantiated by additional data that could be requested by the PRAC under the format of a list(s) of questions/list of outstanding issues, 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 State(s).
The assessment will result with the PRAC issuing a recommendation on the safety issue reviewed, to be provided for adoption to the Committee for Medicinal Products for Human Use (CHMP).
| Article 31 pharmacovigilance referral – Timetable for the assessment | Day |
| First meeting of the PRAC following receipt of the notification.The PRAC discusses the question(s) referred during the plenary meeting and whether a public hearing, oral explanation(s) are to be held.PRAC (co-) rapporteur appointed.Adoption of the PRAC LoQ to be addressed by the MAHs and timetable; | Day 1 |
| For the MAH(s) to answer to the PRAC LoQ; | Clock Stop |
| Following submission of responses (in accordance with published submission dates); | Clock re-startDay 2 |
| PRAC (co-) rapporteur circulate the assessment report(s) on the written responses from the MAH(s); | Day 20 |
| Comments in writing by PRAC members, CHMP concerned Rapporteur(s) (if at least one CAP(s) is involved), CMD(h) member with leading role (if applicable); | Day 25 |
| Discussion at PRAC:Adoption of the PRAC recommendation, or adoption of PRAC List of Outstanding Issues to be answered in writing and/or in public hearing /non-public hearing, oral explanation; | Day 30 |
| If necessary, for the preparation and submission of written and/or oral explanations and/or public hearing/non-public hearing; | Clock Stop |
| If necessary, following submission of written explanations and/or at the time of oral explanations and/or public hearing/non-public hearing; | Clock re-startDay 31 |
| PRAC Recommendation:• Final discussion is held and the final recommendation is reached | Day 60 |
Please note that the above timelines are provided for guidance purposes only and they refer to active days, i.e. correspond to the real time the PRAC takes to assess the data provided. The PRAC can alter them in order to reflect the particularities of a specific procedure. The PRAC may also extend the time limit of 60 up to 120 days (clock-stop) to allow for the assessment of further data provided as answers to the PRAC list of outstanding issues, oral explanation, public (and non-public).
All marketing authorisation holders (MAHs) with products included in the scope of the article 31 pharmacovigilance referral will be provided with the PRAC (co-) rapporteur’s assessment report(s).
The PRAC may decide whether there are issues that need to also be addressed orally by the MAHs. In such case, the PRAC will take due account of the request and will decide whether the oral explanation will be held. The MAHs will be duly informed in advance on the issues to be addressed during an oral explanation.
The MAHs may also request the PRAC to hold an oral explanation. In such case, the MAHs should send a written request to the PRAC stating the reasons and specifying the issue(s) to be addressed during the oral explanation. 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 here.
The PRAC recommendation will usually be issued on the last day of the PRAC’s plenary meeting.
The PRAC recommendation on the safety matter referred under article 31 may be that:
a) the authorisation should be maintained subject to certain conditions, in view of conditions considered essential for the safe and effective use of the medicinal product including pharmacovigilance; or
b) a marketing authorisation should be suspended, varied or revoked;
Where the recommendation is for the marketing authorisation to be varied, including changes or addition of information in the summary of product characteristics or the labelling or package leaflet:
- the recommendation will include the suggested wording of such changed or added information and state where in the summary of the product characteristics, labelling or package leaflet such wording should be placed.
Where the PRAC recommends that the marketing authorisations should be subject to certain conditions, these can include, but are not limited to, requesting the MAH to conduct a post-authorisation safety study and/or a drug utilisation study and/or to implement other risk minimisation measures.
Simon Ruini, is Managing Director of Pharma Design Limited