Q&A: Post-authorisation measures (recommendations, conditions and specific obligations)
Once a veterinary product has received approval from the Commission (the “Commission Decision”) all further procedures connected with the product will fall under “post-authorisation procedures”.
The guidance published under ‘Post-authorisation procedural Q&A’’ provides an overview for different types of post-authorisation procedures that occur frequently and, in each case, addresses a number of questions which marketing authorisation holders (MAHs) may have.
Applicants should use the eSubmission Gateway / Web Client for all veterinary procedural submissions to the Agency. For more information, including links to guidance on registration with the system see the Veterinary eSubmission website.
At the time of finalising a procedure, the CVMP may agree that the applicant/MAH should, post-authorisation, complement the available data with additional data about the safety and, in certain cases, the efficacy or quality of the authorised veterinary medicinal product. Such post-authorisation measures (PAMs) may be aimed at collecting or providing data to enable the assessment of the safety or efficacy of veterinary medicinal products in the post-approval setting.
The existence of such a system of PAMs does not aim at promoting premature approvals of marketing authorisations or post-authorisation procedures. The background and rationale for requesting PAMs will be described in the relevant assessment, which will present the context and nature of the PAM.
PAMs fall within one of the following categories [EMA codes]1:
- specific obligation [SOB]
- annex II condition [ANX]
- recommendation [REC]
Only certain veterinary medicinal products can be subject to specific obligations (see definitions below). PAMs other than specific obligations can be required for any type of authorisation and will be included in the opinion of an initial marketing authorisation or further to the committee’s assessment during post-authorisation.
The wording of the PAM will describe the issue under investigation that has led to the request together with a clear outline of the studies or activities expected to address it and the deadline for its submission. Compliance with these measures it defined by both the submission of the requested data and adherence to the agreed timeline.
1These codes relate to the Agency's product and procedure tracking database called SIAMED and will be used, together with a numbering system, to identify each PAM of a veterinary medicinal product both in the database and in any correspondence of the Agency with the MAH.
Specific obligations can only be imposed on marketing authorisations granted under exceptional circumstances due to limited efficacy and/or safety data available at the time of the CVMP opinion because:
- The indications for which the product in question is intended are encountered so rarely that the applicant cannot reasonably be expected to provide comprehensive data, or
- In the present state of scientific knowledge, comprehensive information cannot be provided, or
- The authorisation of the product is considered necessary on public or animal health grounds, or
- The disease control is subject to Community law and there are restrictions to conduct clinical trials.
The MAH must apply annually for the re-assessment, providing all CVMP members with an update of the outstanding issues. The rapporteur will assess the fulfilment of these SOBs annually and the assessment will result in an annual CVMP opinion until the outstanding issues have been resolved. Continuation of a marketing authorisation under exceptional circumstances will be determined by the MAH’s compliance with the specific obligations, which are checked annually as part of the annual reassessment.
As specific obligations are binding conditions to the marketing authorisation, any modification proposal by the MAH with regards to their description or due date (as described in Annex II of the product information) has to be submitted within an appropriate procedure i.e. either within the annual reassessment or a variation application.
Interim results not impacting on the product information or on the description of the specific obligation can be submitted as a PAM as described below, if they are not part of the annual reassessment.
The European Commission can impose on the marketing authorisation holder (MAH) the obligation to conduct post-authorisation measures. These obligations can be imposed at the time of the granting of the marketing authorisation or later, as conditions to the marketing authorisation. These are conditions to the marketing authorisation included in annex II of the marketing authorisation.
Annex II conditions are post-authorisation measures which, whilst not precluding the approval of a marketing authorisation or other post-authorisation procedures, are considered to be key to the benefit / risk balance of the product. These can consist of post-authorisation safety or efficacy study.
As annex II obligations are binding conditions to the marketing authorisation, any modification proposed by the MAH with regard to their description or due date has to be submitted as a variation application.
Interim results not impacting on the product information or on the description of the condition as stated in the annex II can be submitted as a PAM as described below.
Final results leading to the fulfilment of the annex II condition should be submitted as a variation application.
During the assessment of an application, the committee may issue recommendations for further development of the veterinary medicinal product, e.g. in terms of optimising some quality aspects. Although these recommendations for further development are not binding to the marketing authorisation, they should be seen as important considerations in view of the potential future use of a veterinary medicinal product by the MAH.
This information can be submitted as a PAM as described below. However if data obtained in the framework of a recommendation has an impact on the authorised veterinary medicinal product and its product information, the MAH has the obligation to submit a variation application as appropriate.
As such, the committees will keep an overview of all recommendations made to a marketing authorisation and monitor whether, how and when the MAH has addressed them.
For recommendations, the MAH should submit the PAM data according to the timeframe specified by the CVMP in the assessment agreed at the time of the opinion.
For conditions and specific obligations, the timeframe is highlighted in Annex II of the Commission Decision. Conditions will be reviewed by the rapporteur once the data are submitted. SOBs are to be reviewed by the CVMP at the intervals indicated and at least annually (at the time of the annual reassessment). The data should in principle be submitted on the anniversary date of the Commission Decision granting the MA.
The MAH shall provide data within the agreed timeframe. When requested, the MAHs should propose due dates for the submission of the post-authorisation data that are realistic and proportionate to the uncertainty to be addressed which are then subject to agreement with the CVMP.
If a MAH is unable to provide the required data on time, the Agency should be informed in writing in advance of the due time of submission. The reason for the delay should be justified and a new submission date proposed. In the case of a non-satisfactory or non-justifiable delay, the Committee/Agency may make this information public.
The Agency will check whether the annual re-assessment application for SOBs is correct and complete before start of the procedure (“validation”).
Where considered appropriate and in view of the urgency of the matter, especially for safety issues, MAHs may submit any variation application resulting from the fulfilment of the PAMs and/or Periodic Safety Update Reports (PSURs) at the same time as the fulfilment of the PAM or submission of the PSUR to minimise the processing and review time. In the case of Type II variations, the Agency shall start the procedure in accordance with the starting dates published on the EMA website (see also Recommended submission dates for centralised and maximum-residue-limit procedures
The submission of PAM data should include:
- A cover letter indicating the full title and the reference procedure number of each PAM, i.e. the number of the procedure during which the measure was requested. The letter should also indicate whether the PAM relates to quality, safety or efficacy. Where a variation is submitted to fulfil PAMs, this should clearly be stated in the cover letter.
- All supporting documentation relevant to the fulfilment of the PAMs should be presented in accordance with the appropriate headings and numbering of a dossier as indicated in Vol. 6B of the Notice to Applicants.
Where the deliverable of a PAM is submitted as part of another procedure, the structure of the submission package should follow the requirements of that procedure and the MAH should indicate exactly which PAM is being addressed, including the EMA reference number and the full description of the relevant PAM. The MAH does not need to submit a separate 'stand-alone' submission of the PAM data.
All submissions should be made in accordance with the guideline on e-submissions.
Applicants should use the eSubmission Gateway / Web Client for all veterinary procedural submissions to the Agency. For more information, including links to guidance on registration with the system, see the Veterinary eSubmission website.
All VNeeS submissions for centrally authorised products (CAP) sent to EMA via the eSubmission Gateway/Web Client will be considered delivered to all National Competent Authorities (NCA) representatives, alternates and scientific experts.
Should a variation be requested as a result of the fulfilment of the PAM(s), this should be clearly indicated in the cover letter for that variation when it is submitted. In this case, the usual procedure for the respective variation(s) applies.
This section only applies to submissions of PAM data as a 'stand-alone' submission. PAMs will be evaluated by the CVMP.
For the timeframe of recommendations and conditions, a 60-day timetable will normally apply, however, the Agency may liaise on a case-by-case basis with the rapporteur.
Specific obligations are usually submitted as part of an annual re-assessment, and the relevant timetables are published in the Recommended submission dates for centralised and maximum-residue-limit procedures
- The PAM is fulfilled and no further action is required;
- the PAM is not yet fulfilled, as further clarifications or additional data are required. A request for supplementary information to be addressed by the MAH within a given timeframe will be issued and a follow-on PAM (such as REC 00X.01) created. The PAM will only be considered as fulfilled, once all requests for supplementary information have been addressed by the MAH to the CVMP’s satisfaction;
- PAM is fulfilled but follow-up regulatory action is required, e.g. a request for variation and this will result in a new PAM being issued. The variation submission is normally requested within 60 days after adoption of the CVMP conclusion. If the MAH is unable to submit the variation within this timeframe, it must justify the delay and inform the Agency and propose a new submission date.
- If the fulfilment of a given PAM results in a negative benefit/risk ratio profile of the medicinal product, the CVMP will consider the possibility to recommend a suspension or the withdrawal of the MA or the relevant presentation.
- Recommended submission dates for centralised and maximum-residue-limit procedures
- Centralised Procedure, The Rules governing Medicinal Products in the European Union Notice to Applicants,Volume 6A, Chapter 4
The EPAR (published on the EMA website) will be revised, if appropriate, to implement the CVMP conclusions in relation to the SOBs. SOBs are reflected in Annex II.E of the Commission Decision and revised product information will be required (in all languages).
For recommendations, the outcome is usually not published.
For conditions listed in Annex II of the Commission Decision, following the fulfilment of such condition, Annex II should be revised at the next procedural opportunity (i.e. a renewal or a variation affecting the product information, where and as appropriate).
Outcomes of PAMs are not published in the EPAR 'Procedural steps taken and scientific information after the authorisation'.
The fifth annual re-assessment of veterinary medicinal products authorised under exceptional circumstances will normally be included as part of the renewal procedure. Therefore, it will not initiate a separate procedure and the renewal timetable will be applied to the 5th annual re-assessment procedure.
Guideline on the processing of renewals in the centralised procedure (Volume 6C of the Rules Governing Medicinal Products in the European Union)