help to identify special issues or problems with a
given drug. In later development, the profile of the
product must be investigated more in depth in those
areas that previously might have given rise to atten-
tion (e.g. hepatic issues, gastric bleedings or other
special issues a drug might present during initial
clinical trials). The pharmacovigilance plan aimsat
outlining the risk management procedures planned
and will usually contain a series of planned studies
or observations, preclinical or chemical test pro-
grams aimed at characterizing the drug further and
help to understand the true risk–benefit profile of
the medicinal product.
Post-marketing authorization
Pharmacovigilance in the post-marketing authori-
zation period is tightly regulated. As in North
America and Japan, Europe has adopted the ICH
guidelines with a few, relatively minor additions.
The MA holder must have systems and qualified
personnel in place to fulfill all his obligations
for the monitoring of the safety of its medicinal
products.
Similarly to the QP for GMP, MAH is required
to identify to the authorities an individual to take
the role of the QP for pharmacovigilance. The QP
must be fully versed in all aspects of pharmacov-
igilance and carries personal responsibility for
compliance with all applicable regulations. The
QP is therefore responsible to ensure that the
MAH is diligently collecting safety information
on all its marketed products and adheres to obli-
gations taken with the regulatory authorities (e.g.
commitments made in the pharmacovigilance
plan at time of MA). Regular surveillance over
many different sources of information must be
maintained (e.g. medical journals, spontaneously
reported cases, ‘Yellow Card’ schemes, etc.) and
reportable information identified and processed in
a timely fashion.
The competent national authorities have
received the power of inspection of the pharma-
covigilance system of any MAH, similarly to the
long-standing GMP or newly introduced GCP
inspectorate, and are now equipped with consider-
able power extending to MA suspension and crim-
inal prosecution of the QP, if critical findings are
made and not sufficiently addressed. Pharmacov-
igilance inspections particularly focus on the sys-
tems employedto ensure comprehensive collection
of any serious adverse drug reactions and the
adherence to reporting obligations and timelines.
Companies are expected to audit the pharmacov-
igilance procedures internally and create a record
of compliance.
Inaddition to the periodic reports (see above), all
serious adverse drug reactions reported sponta-
neously, identified in the worldwide scientific lit-
erature or through post-marketing safety studies
have to be reported in an expedited fashion.
Again, fatal or life-threatening reactions have to
be reported within eight calendar days and other
serious reactions within fifteen days if emanating
within the EU. For cases arising from outside the
EU, only the unexpected serious ones must be
reported in an expedited fashion.
Companies with co-licensing agreements have
to prepare detailed contracts about exchange of
safety information and reporting responsibilities,
as duplication of reports are unacceptable to the
regulatory authorities.Periodic safety update reports
As described earlier in this chapter, the MAH is
required to submit regular safety updates to the
competent authorities for each licensed product.
Combination products can either be submitted as
separate PSURs or enclosed in one PSUR cover-
ing all indications, strengths and license variations
of a given medicinal product. The PSUR reports
licensing and marketing status of the product,
estimates exposure during the reporting period
and cumulatively since the first launch of a pro-
duct. Any regulatory action or changes to the Core
Company Safety information on the compound
(CCSI) must be listed in detail. All reported
adverse reactions from any source are listed, ser-
ious and nonserious, reactions of special interest
for a given compound, overdoses, congenital
abnormalities, interactions and newly received
clinical trial data must be presented in detail and
discussed.480 CH34 MEDICINES REGULATION IN THE EUROPEAN UNION