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EU Pharmacovigilance

Legislation - One Year

Sarah Daniels; Senior Partner
TranScrip Partners LLP

Since July 2012 we have officially been operating under EU legislation

Directive 2010/84/EU amending directive 2001/83/EC for National and
Mutual Recognition processes and Regulation (EU) NO 1235/2010
amending regulation (EC) NO 726/2004 for Centralised processes.
The legislation was accompanied by the Commission implementing
regulation (EU) No 520/2012.
In the following paragraphs I will touch on some of the key changes,
making no apologies for not covering everything as due to the extensive
nature of the new legislation this would be impossible.
The objectives of the new legislation in a nutshell are to increase
transparency and provide better information on medicines, ensure that
the roles and responsibilities of key stakeholders are clearer, rationalise
and simplify Adverse Drug Reaction (ADR) and Periodic Safety Update
Report (PSUR) reporting and reduce duplication/redundancy, while at the
same time engaging both patients and healthcare professionals and
promoting and protecting public health.
A tall order some might say.
Let start with the implementing legislation. This is a new concept.
Previously we all worked to the guidelines provided in Volume 9A; though
as everyone knows these were only ever guidelines and never had the
weight of the law behind them, even though it might have felt like it at
In this brave new world we are exchanging approximately 150 pages of
Volume 9A guidelines for 15 (originally intended to be 16) Good
Pharmacovigilance Practices (GVP) modules enshrined in law; the first 7
prioritised modules were released in July last year, and were swiftly
followed by 4 more already taking up over 350 pages of text even without
annexes. So it seems there will be a GVP module for every eventuality.
The remaining modules XI, XII, XIV and XVI on Public participation in
pharmacovigilance; Continuous pharmacovigilance, on-going benefit-risk
evaluation, regulatory action and planning of public communication;
International cooperation and risk minimisation measures: selection of
tools and effectiveness indicators, respectively, are currently under
development. Modules XI, XII and XIV are scheduled for release for public

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consultation before the end of the year. While the public consultation for
Module XVI has completed.
Be aware that GVP Module XIII incident management (unlucky for
some?) is now to be incorporated into GVP Module XII. The modular
format should make it easier to amend the documents on an on-going
basis as necessary. Indeed at least 2 modules have already been
amended, while revisions to several others are expected.
GVP Module I covers quality systems and includes, though is certainly
not limited to, the roles and responsibilities of the all-important EU
Qualified Person for Pharmacovigilance (QPPV). One thing worthy of note
is that he or she must now both live and work in the EU (or Norway,
Iceland or Liechtenstein), so working in Switzerland while living in France
or Germany is now no longer an option.
GVP Module II which has already been revised once, lays out the
concept of the Pharmacovigilance Systems Master File (PSMF). This
replaces the oft maligned Detailed Description of Pharmacovigilance
Systems. Only a summary of the PSMF is required to accompany
Marketing Authorisations (MA), though the PSMF must be available to the
competent authorities on request. Unlike its predecessor, changes to its
content are not automatically notifiable to the competent authorities. Be
aware however that the PSMF must be available to the competent
authorities on request (the default time period is within 7 days, but
immediate access may also be required!), so complacency is not
advisable. Indeed in large and/ or complex organisations keeping the
PSMF up to date is likely to require an entire team in itself.
GVP Modules III and IV (which were part of the second wave of
released modules), cover inspections and audits from the EU perspective.
For the uninitiated these are useful reference documents, covering pretty
much all one needs to know about these somewhat daunting activities.
GVP Module V covers Risk Management Planning (RMPs). Whats new
here? An RMP describing the risk-minimisation strategy has been
required for all new MA applications from July 2012. However, in certain
circumstances some modules may be omitted unless specifically requested
by the competent authority. In other words the RMPs should be

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developed in proportion to risk. So while there may be more RMPs they

may not all require the same level of detail.
A point worth noting is the requirement to ensure the effectiveness of risk
minimisation measures, which is re-emphasised in the module although
the requirements on exactly HOW to do this are still in development (GVP
Module XVI now closed to public consultation).
Adverse Drug Reporting (ADR) is defined in GVP Module VI, the most
weighty of the GVP modules. In theory this mandates centralised
reporting by industry to the Eudravigilance database (currently, reports go
via the individual national competent authorities). However this will not
actually come into effect until 6 months after Eudravigilance database
functionality is updated, audited and approved. This is somewhat of a
moving target but is currently thought to be somewhere around 2015;
until then transitional measures apply. This means essentially nothing has
changed yet in terms of how ADRs are reported.
The definition of an ADR has changed subtly though;
The text limiting an ADR to one which occurs at doses normally
used in man for the prophylaxis, diagnosis or therapy of disease or
for the restoration, correction or modification of physiological
function has gone.
An ADR is now simply any report where harm has occurred to a
patient or any reaction that is noxious and unintended.
Effectively this widens the definition and means reports of ADRs
that are a result of error, misuse, abuse and off-label use must also
be reported. Furthermore reports from patients must now be
included as valid, reportable ADRs.
Hence in the short term/ transitional period, the ADR reporting
burden on MAHs might be expected to increase rather than
GVP Module VII, another large module, covers Periodic Safety Update
Reports (PSURs). The PSUR now has an alternative name - the Periodic
Benefit-Risk Evaluation Report or PBRER. While it doesnt exactly roll off
the tongue, it does give an indication of what is expected from these new
look PSURs. There are twice as many sections to the new PSUR, with

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additional sections including efficacy data, signal detection and evaluation,

and benefit evaluation. Moreover previously existing sections have been
expanded with new sub-sections. The PSUR now requires input from many
functions previously blissfully unaware that such a document existed and
it is therefore expected to be a much more balanced document allowing
for the conduct of a full benefit-risk analysis. This was something of a
challenge with the old PSURs as they contained data mainly relevant to
risk and not to benefit.
The new PSURs therefore require more evaluation and interpretation and
are less of a data dump. Unsurprisingly they now require more time to
prepare and by way of recognising this, the timelines between data lock
point and submission have been increased slightly, though in practice they
are still challenging. Identifying and assessing base line efficacy for
indications for more mature products can be particularly difficult as much
information may no longer be current or even relevant by todays

Certainly , from a purely resource perspective, these

documents are now more intensive, certainly in the short term.

On the plus side, PSURs will not be required for ALL products in the EU as
the new legislation waives the obligation to submit PSURs routinely for
generic products, well-established use products, homoeopathic products,
and traditional herbal products. Also documents including the PSUR, RMP,
DSURs etc. are now modular in structure with some modules overlapping
one or more documents, allowing for an easier flow of information betwixt
and between documents (in theory at least).
GVP Module VIII outlines requirements for post-authorisation safety
studies (PASS), and the new post-authorisation efficacy studies (PAES).
This is another GVP module that has already been revised once with
various clarifications and editorial corrections.
The new requirements for signal detection are provided in GVP module
IX. You may remember there was no definition for a signal in Volume 9A.
This omission has now been redressed and detailed requirements around
signal detection and management are provided here. The key take home
message is that one size is not expected to fit all and document

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GVP Module X additional monitoring is the most recently released

(April 2013) module and provides the EU requirements for products
requiring additional monitoring. Its not that dissimilar from the MHRA
Additional Monitoring Programme. Affected products, identified by an
inverted black triangle, will be published on the EMA website on a monthly
basis following recommendations by the Pharmacovigilance Risk
Assessment Committee (PRAC).
Finally, last but by no means least, the final currently available module,
GVP Module XV covers all aspects of safety communication, from Dear
Healthcare Professional letters to web based communications.
In conclusion, the new PV legislation was hailed by the EMA as the biggest
change to the regulation of human medicines in the European Union (EU)
since 1995 with significant implications for MAHs, and a year later this
certainly seems to be the case. However it is probably too soon to judge
whether the objectives, in particular to rationalise and simplify ADR and
PSUR reporting and reduce duplication/redundancy will be met. The
coming months and years will definitely be interesting.

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