EMA GPVP Module V – Risk Management: Draft Revision 2

Apr 20, 2016
Bart Cobert

Pharmacovigilance, Drug Safety and Regulatory Affairs Author & Expert

On February 29, 2016 the EMA released a cover letter reviewing the objectives of the PV Modules released over the last 5 years, as well as a draft of the revisions for the new version of Module V on Risk Management.

The cover letter runs 6 pages and goes over the background for Good PV Practices (GVP), the history of the modules, the objective of PV, the roles of the different actors (their word) in PV in the EU, the legal basis, scope and process for GVP, maintenance and development GVP, the structure of GVP in the EU and comments on public consultation.

The revised module V itself runs 41 pages and is, as is the original version, a complicated document covering PV structures and processes, the Risk Management Plan (RMP), risk management and how the EU network operates. This draft is significantly revised from the original. The good news, I guess, is that this document is about 20 pages shorter than the original version.

There are major revisions throughout the document in this draft and cover:

  • Clarification of what RMPs should focus on in relation to an important identified or important potential risk and missing information
  • Removal of duplication within GVP Module V and in other guidance documents
  • Guidance on the expected changes in the RMP during the life cycle of the product
  • Updated requirements for different types of initial marketing authorisation applications, with the aim to create risk-proportionate, fit for purpose RMPs
  • An amended RMP template for initial marketing authorisation application
  • The EMA asks four specific and very technical questions for public feedback (page 2)

Since the changes are not noted or marked within the new document, one must open the old one and the new one and compare them side by side. This is very hard to do. It is clear, when doing this, that there are significant changes. I will highlight some of the more important ones.


The first section is terminology.  There are important changes here. Identified Risk is redefined. The new definition is for an Identified Risk in the RMP:

  • Old: An untoward occurrence for which there is adequate evidence of an association with the medicinal product of interest.
  • New: An undesirable outcome for which there is sufficient scientific evidence that it is caused by the medicinal product.
  • Comment: This is a change and now it appears that there needs to be sufficient evidence for causality rather than association. This is stronger and may imply that there will be fewer “identified risks.” In the new version, the examples given previously are gone and there is more detail on comparators. See page 6 of the document.

Potential Risk  Here too there are important changes. Again this is now referred to as a Potential Risk in the RMP.

  • Old: An untoward occurrence for which there is some basis for suspicion of an association with the medicinal product of interest but where this association has not been confirmed.
  • New: An undesirable outcome for which there is a scientific basis for supposition of a causal relation with the medicinal product (e.g. a signal, a class effect plausible also for the new product, findings from (non-) clinical studies) but where there is insufficient support to conclude that there is a causal association.
  • Comment: The definition changes from an unconfirmed association to a supposition for a causal basis but insufficient support. Again, the move is away from “association” and towards “causality.”

Whether these definition changes will change how signals/risks are categorized remains to be seen. The distinction is still between risks which are identified (have some solid evidence) and potential (some data but nothing conclusive) remains the same.

There are also other changes in the definitions of Missing Information (in the RMP), Important Identified Risk and Important Potential Risk (in the RMP and Safety Concern which change the nuance but do not change the concepts presented in the earlier version.

If your SOPs and other procedural documents carry these definitions verbatim from the Module, you should consider changing them if and when this document is finalized.

Principles of Risk Management

There is a revised discussion of these principles in the draft document. The concepts are similar to the earlier document though it has been rewritten somewhat. The key concepts are that the MAH/applicant must have an appropriate risk management system in place and that the knowledge and understanding continuously gained following the use of the product are critically reviewed and the risk management system is updated as appropriate.

The format of the RMP, as well as its mapping to the eCTD, are presented in the next section.  These documents are modular and it is the intent of the guidance that modules can be used in either document (with little or no change as appropriate). This is similar to the original document.

The RMP is discussed in great detail. The sections are largely unchanged from the original document but there are some significant differences and changes. The mapping between the RMP modules and the eCTD are also unchanged.

Next there are many pages going through the details of each RMP section. Those of you who prepare RMPs should review this new document (presuming it will be finalized and put into effect by the EMA) to see what changes you should make in your template and methodology for RMP preparation.

Many of the changes are small. For example, in the RMP Part I Product Overview the new draft does not ask for the date and country of first worldwide authorization and launch in this section as it did before.

There are also many new references to the eCTD (e.g. the eCTD link to the currently approved PI) which did not appear in the 2011 Module V version. These are fairly numerous and will need to be updated in your RMPs.

Safety Specifications

This section has also been totally revised and includes some additional elements not mentioned in the earlier version including: environmental impact and “exceptionally, quality aspects relevant in relation to the safety of the product and not adequately addressed at time of MA.”

There are new sections covering Generics and Advanced Therapy Medicinal Products that should be reviewed when preparing RMPs for such products.

The epidemiology section on the indications and target populations has been expanded.  There are changes in the Clinical Trial Exposure and Populations Not Studied sections with a significant shortening of the latter section details.

The Post-Authorisation Experience section has been shortened from 2-1/2 pages to four paragraphs.

The very important section SVII on Identified and Potential Risks has been greatly expanded with types of risks now specified including risks resulting from or relating to: medication errors, transmission of infectious agents, off-label use, PK and PD interactions, pregnant and lactating women using the product, fertility and others.  There is a section on advanced therapy medicinal products which discusses risks to living donors and to patients related to quality issues, storage and distribution, administrative procedures and more.

Comment: This section has been thoroughly revised.  Many of the requirements have moved or been updated. Some new things have been added and old requirements altered.

Part III PV Plan & Activities

These sections have been rewritten somewhat but do not appear to have major changes.

The “Summary table of additional PV activities” has been modified with the removal of the category currently entitled “Stated.” Thus the three remaining categories (Imposed PASS, Specific Obligation and Required) remain.

The Risk Minimisation Activities section has also been somewhat revised though the actual actions for risk minimization remain similar.


With the use of the eCTD the annexes have changed somewhat.  Annex 1 is now the structured electronic representation of the EU RMP. Other annexes have also changed.

My Overall Comments:

The changes in the new draft are many and complex.  Some are very substantial and some less so. Some are primarily format. Some relate to the eCTD and the move away from paper documentation. Advanced therapeutic products and generics are addressed in more detail.

This document, especially when finalized, must be read and scrutinized very carefully as major changes have been made. The level of detail and complexity have increased.

Unfortunately, the numbering of the sections of the new document does not always correspond to the numbering of the sections in the older document making section by section comparisons very difficult. An annotated list of changes, subtractions and additions would be useful (in effect, the MS Word tracking and review version of the document).

One virtue of the change, however, is that the new document is only 41 pages long whereas the older version was 60 pages.


MAHs should review this new document and be ready to make changes to their preparation of RMPs when the new version is finalized. Of course, the final version may or may not reflect all the changes seen in this draft. Pharmacovigilance is becoming more and more detailed, complex and bureaucratic.

My final comment is, as always, will these changes improve public health and drug safety or simply add to the bureaucratic requirements? The answer is unclear.



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