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The EMA issued a six page document in late April on “Guidelines on Good PV Practices (GVP)”. This is a revision of its earlier guidelines on GVP.

This document that summarizes where the EMA is on GVP.  It covers the history of GVP, objectives, roles, legalities, scope and, most importantly, maintenance and further develop and the structure of GVP in the European Union.

As you may have been following in the news, there is much operational and financial turmoil in the EU in terms of Greece requiring bailouts of their financial and banking system from the EU, Great Britain threatening (softly) to leave the EU and issues of stability of the Euro currency.  In addition, there is a long and on-going debate, both on a theoretical and practical level, of how much power and authority should be centered in the EU (in our pharmaceutical world in the EMA) versus how much should be left in each of the 28 member states (e.g. the MHRA for the UK).  The tendency has been to bring more power into Brussels (the EU) and away from each of the individual countries.

This consolidation of power has occurred in the EMA.  Since 2012, the EMA has redefined PV and issued the Good PV Practices modules which created new mechanisms and institutions for PV (e.g. the Pharmacovigilance and Risk Assessment Committee – PRAC) as well as clarifying the requirements that each member state’s health/drug authority must follow.

So what we have seen, primarily since 2012, is a major change in PV in the EU, particularly for marketed drugs.  This document gives the philosophy behind these changes as well as a rough roadmap for the future.  Here is a brief summary.


The first seven PV modules were published in early 2012 and came into force in July 2012.  Additional modules were released individually later in 2012, 2013 and 2014.

However, even though all the modules had not yet been issued, some of the already-issued ones were revised in 2013 and 2014.  Some modules already had a revision 2 issued. In April 2015 a draft addendum on module XVI (educational materials) was issued.  Other modules and revisions are due for release in 2015.  Module XIII (incident management) is no longer under development and those topics are now in Module XII.

The modules, their original dates and latest revisions, can be found on a very complex and messy page at the EMA’s website.

To get the latest version of each module along with its timeline and dates of earlier versions, you click on the hyperlink for each module.  Module VIII has both the guideline itself (Post-Authorisation Safety Studies) as well as a separate guideline entitled: Module VIII Addendum I –Member States’ requirements for transmission of information on non-interventional post-authorisation safety studies (Rev 1).

Comment: It is not easy to navigate these modules and find out what is required and what is the latest revision, what is no longer in force and what is new.  It is hard to know if one is following the requirements in the latest version, addendum, revision etc.  There is also a massive amount of detail.  This is largely in contrast to the US FDA where there is nowhere near the detail seen in the EU PV modules nor are there such frequent revisions in requirements. Not a lot of harmonization anymore.


These are the obvious ones: public health, prevent harm etc.  See the document for more detail.

Roles of Different Actors

The standard roles of the “actors” (The EMA’s word; an interesting choice or wording) are noted with no surprises.  The most interesting point is that the EMA has increased the role of health care professionals and patients.  The new framework for patient reporting of “suspected AEs”, the PRAC, public hearings, risk-benefit matters involving all stakeholders are noted.

Comment: Input from patients and health care practitioners is somewhat new for the EMA compared to the US and Canada.  Patient-reported AEs have been standard for decades.  The EU used to want “medical confirmation” before using or analyzing patient reports.  This view has moved closer to the US view now.

Maintenance and Further Development of GVP

The EMA notes that proposals for corrections, revisions, additions, new GVP chapters etc. may be made by any stakeholder including the public.  The FDA accepts citizen petitions and other mechanisms to change the regulatory requirements in the US.  The EMA notes: “There may not be an immediate, individual response, but all proposals will be reviewed regularly and prioritised…”.

Comment: This promises to keep the PV modules dynamic and ever-changing.  Whether this is good or bad remains to be seen.  Are all of these changes helping public health?  Has anyone measured this?  Is it even possible to measure?

Structure of GVP

This is a brief section in the document but is quite complex.  First the EMA notes that PV activities are organized by processes and each module is one major PV practice. Each module has three basic sections: A: the legal, technical and scientific context; B: guidance on scientific and regulatory “approaches” and C: specifics of the approaches, formats and standards.

Another complex paragraph states: “While the development of GVP is ongoing, some guidelines developed under the previous legislation remain valid in principle (unless any aspect is not compatible with the new legislation) until they are revised at a later point in time for inclusion in GVP. They are published on the Agency’s GVP webpage under GVP Annex III.”

Comment: This is a bit troublesome to parse to put it mildly.  GVP development is ongoing.  That is fine.  Some older guidelines from previous legislation remain “valid in principle (unless any aspect is not compatible with the new legislation)”.  That is unclear.  If they are valid, they are valid; if not valid, they are not valid.  It is not clear what the “in principle” wording means.  This is not defined.  So they are still valid until revised at a later point.  They are published in GVP Annex III.  This seems to be the section on the referenced webpage entitled “Final GVP annex III-Other PV Guidance”.  This is midway down the webpage and includes Guidelines, notes for guidance, overviews for guidance, draft notes for guidance and actual guidelines.  The latest is from 2011 and some date from 2005.  So you have to go into the annex to see what’s valid in the guidelines?  This makes it very hard to actually understand what is in place and clearly to be followed, what is out of date, what is valid but only in principle, etc.  This should be made far, far more user-friendly.

The comparison to the now sunset Volume 9A is striking.  That document, though long, was clear, indexed (or searchable in pdf form) and the rules rather straightforward and available.  Changes were generally made in large scale rather than the bit by bit changes we now see.  It was a workable document and a fine source of the rules of the game.

Practical Advice for the Public Consultation

Here the EMA indicates that public comments must be submitted using specific templates for each chapter and the Definition or Template Annex as appropriate.  Comments will only be processed if “submitted as completed templates in open word format”.  Comments should not comment on the underlying legal requirements as these cannot be altered by this process.  This is very bureaucratic.  A little more flexibility would be appreciated.

Overall Comments

This document that was just released is a very bureaucratic guideline that attempts to explain the reasons for the transition from Volume 9A to the very complex and continually changing modules, templates, annexes, guidelines and draft PV guidelines.  This makes the entire process rather opaque and difficult to interpret.  It is not clear what is valid, valid in principle, required or merely suggested.

Unlike the US, where guidances represent FDA’s latest and best thinking on a matter, but are not necessarily required, the EU guidelines (all the modules are called guidelines but are required) are not the same.

The upshot of all of this is that doing PV, at least for those of us in the global pharma industry where we deal with multiple countries and health authorities, has become cumbersome, difficult to understand, track and follow. Requirements which had been harmonized are less so now (e.g. clinical trial SUSAR reporting in the US vs the EMA on causality).  The goals of ICH, which included standardization, harmonization and (perhaps) simplification, seem to have peaked about five years ago and are now badly fraying.

Perhaps the most important question is really whether all of these major changes are making PV better? Are we understanding a drug’s safety profile more easily, more quickly and more transparently? Are we harmonizing the public health to better use our limited resources to do better drug safety, signaling and PV?  Are we really helping the public health or are we simply making employment opportunities for PV folks better?  Nothing wrong with the latter but the real goal is the former.

Unless we actually measure this in some controlled way, we cannot answer these questions.  There is a presumption all these changes are good and will make PV better but we can’t really know unless we look and measure.

What To Do

For those of us in industry doing PV, we would like, as always, clarity, consistency, harmonization and simplicity with infrequent changes and updates.  We will probably not see this.  So the best I think that we can hope for would be two changes that do not require wholesale redoing of EU PV:

  1. The EMA PV Website: What would be useful and probably practical would be a revamping of the GVP module website to make clear what is current, when things have changed and clear statements of what we need to do. Make it easier for us to find what we need asap.
  1. A summary document: Create a single book or document summarizing these complex requirements – “one stop shopping” again. It should be indexed and searchable (as a pdf).  Perhaps an EU version of the Good PV Practice Guide that the MHRA put forth several years ago would be worthwhile (and would probably also produce some nice income for the EMA).


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