EMA Post-Marketing Regulations Q&A March 2013

May 08, 2013
Bart Cobert

Pharmacovigilance, Drug Safety and Regulatory Affairs Author & Expert

European Medicines Agency Post-Authorisation Procedural Advice for Users of the Centralised Procedure


In March the EMA released a Q&A document on many of the aspects of post-approval/marketing regulatory rules.  In particular it covers some of the new pharmacovigilance (PV) rules that went into effect in January of this year.  This Q&A document is 195 pages long(!).  It covers many regulatory issues.  Some of these are new and some old.  This is a consolidated view of questions on the website in various areas.  We will briefly(!) summarize the PV related points.  Not every Q&A is noted here and the more arcane details are omitted.  Refer to the document for the full detail.

Post Authorization Safety Studies (PASS) – a new section dated March 2013

A PASS is any study relating to an authorised medicinal product conducted with the aim of identifying, characterising or quantifying a safety hazard, confirming the safety profile of the medicinal product, or of measuring the effectiveness of risk management measures.  They may be voluntary on the part of the Marketing Authorization Holder (MAH) or the competent authority (CA).

Systemic reviews and meta-analyses imposed by the CA are considered non-interventional PASS.

Any CA imposed non-interventional study will be supervised and assessed by the PRAC.  The protocol should be approved (“endorsed”) by the PRAC and also submitted to the member state where it is to be done.  If the PRAC determines that the trial is, in fact, an interventional trial it must be handled as a clinical trial and not as a non-interventional PASS.  Amendments must also be so approved.  The final study report will be assessed by the PRAC.  Results of a non-interventional PASS may lead to a type II variation and/or a safety variation.

PSURs – a new section dated March 2013

There is a discussion of the “EU Single Assessment” which is a PSUR for multiple different Marketing Authorizations (MAs) held by one or more MAHs in which there is the same active substance or same combination of active substances and for which there is a harmonized frequency and submission date in the Union Reference List.  This could include centrally approved, mutual recognition and decentralized approvals.

Next there is a long discussion of the European Union Reference Dates (EURD) List which came into force April 1, 2013.  This is a list of active substances (or combinations) telling the MAHs the frequency and reference (reporting) dates for PSURs.  This list was created to harmonize data lock points and submission frequency and to allow a single assessment in the EU.  The EMA notes that this is a living document and can be amended when considered necessary should new information warrant a change.  This list overrules the “routine” submission schedule used in the past as well as the frequency listed in the MA.

PSURs must be submitted on all approved products even if they are not marketed.

PSURs, PSUR addenda, Summary Bridging Reports and line listings are no longer submitted as part of the renewal application.

An interesting question asks why some data lock points are so far in the future.  The response is that this is the determination based on the risk-benefit profile but the dates are “likely to be amended on a monthly basis to take into account any need to re-evaluate the risk-benefit profile…in case of emergence of any PV concerns.”  So the MAH should check the EURD every month to see if its products’ time lines have changed.

If a company’s product is not on the list they should follow the old schedule of every 6 months, yearly then every 3 years.  Some generics, homeopathics and traditional use products do not have to submit PSURs.  The MAH may request a change in the EURD list for its products for public health reasons, to avoid duplicate submissions and to achieve harmonization of dates.

Single CA PSUR assessments: This has come into effect for centrally approved products.  Nationally approved products are not yet under the single assessment system and will not be until further notice.  The procedures are complex:

  • For a single centrally approved products and for several centrally approved products with the same active substance or combination and where the submission dates are harmonized all PSURs must use the new GVP Module VII requirements (PBRERs) involving the PRAC.
  • For the same substance or combination where there is a mix of centrally and nationally approved drugs, the new single assessment will be done.
  • Nationally approved products may fall under the single assessment if they already participate in the “worksharing” scheme.  If not, the PSUR assessment remains at the national level for now.
  • Single member state approvals remain at the member state level for PSUR assessment and are not covered by the single assessment legislation.

Line listings are no longer required in the PSURs though the EMA or CA may request them.

Timing is 70 calendar days from the data lock point for PSURs covering up to and including 12 months.  PSURs covering intervals greater than 12 months are submitted within 90 days of data lock point.  There is much detail on the format and mechanism of submitting a CR0ROM or DVD.   See the Q&A for full details.

Generics, in general, do not have to submit PSURs if they are not included in the EURD list and there are no conditions in the MA.  Hybrid products must submit PSURs.

The timeline for the handling of the PSUR is as follows:

Day 0 Start of the procedure
Day 60 PRAC Rapporteur’s preliminary assessment report
Day 90 MAH & PRAC members’ comments
Day 105 PRAC Rapporteur’s updated assessment report (if necessary)
Day 120 PRAC recommendation adoption with the final PRAC assessment report
Day 134 CHMP opinion/CMDh position

The outcome of the PSUR assessment results in a legally binding decision (e.g. to vary, suspend, revoke an MA).  PRAC assessments go to the CHMP for PSURs if at least one centrally approved product is involved and the the CMDh if the PSUR only covers nationally approved products.

PV System Summary/PV System Master File (PSMF)

The MAH must have a PSMF which is a detailed description of the PV system used by the MAH.  This is not part of the MA and is maintained separately.  It must be permanently available and produced with 7 days upon CA request.  It must be located in the EU where the main PV work is done or where the QPPV works.  The QPPV must live and work in the EU.

Applicants are required, at the time of initial MA application, to have in place a description of the PV system that describes the system that will be in place and functioning at the time of the granting of the MA and marketing of the product.  A PV system must be in place at the time of the MA approval.  The PSMF may be requested during the MA review.

The MAH may subcontract some PV activities to third parties but the full responsibility for the PSMF remains with the MAH.  There must be a written list of subcontracts with third parties and detailed written agreements describing the roles and responsibilities for the performance of PV and for the PSMF with vendors.

The PSMF is submitted at the time of renewal of the application, at the time of the submission of the annual renewal application for a conditional MA or by July 2, 2015 whichever is earliest.  There is detailed information on the submission of a type IAIN variation and numbering.


This is a highly detailed and complex document summarizing certain issues involving the regulatory requirements in the EU for centralized products with some comments on national approvals too.  Clearly the EU system has become incredibly complex and arcane if not byzantine.  The regulatory requirements are very specific and detailed and must cover multiple approval routes as well as exceptions and waivers.

The new PV requirements that came into effect in 2013 (and some coming into force later) are similarly complex.  Since not all member states are ready to handle the new requirements, there are interim requirements (stated to a degree in this Q&A) which will change over the course of the next several years.  EudraVigilance will be changing and multiple other things will change over the course of time.  The transition to the new rules will take years (e.g. PSMFs may not fully be in place till mid-2015) necessitating all sorts of work-arounds and one-offs.

As always, we ask the question: will this improve public health?