product complaints which need to be thoroughly
investigated.
In order to allow effective tracking of products,
record keeping of product distribution is necessary.
Sufficient information on wholesalers and/or
directly supplied customers with precise batch
numbers and quantities supplied together with con-
tact numbers and addresses must be available and
up to date. The process of the recall must be
recorded including reconciliation between deliv-
ered and returned quantities of the products.
A designated person in the company needs to
be responsible for execution and coordination of
product recalls. This person should be indepen-
dent from the sales and marketing personnel. The
QP of the company must be made aware of the
product recall. Furthermore, it is required to
inform the regulatory authorities of any recall
action.
34.14 Safety reporting and
pharmacovigilanceThe assessment of safety in the use of medicinal
products starts before the first administration to
humans and continues throughout the development
of the medicine to the MA for the lifetime of the
drug. It is governed by a set of comprehensive
rules, which are published in Volume 9 of the
rules governing the use of medicinal products in
the EU, notice to applicants (see boxed item
above). These rules have seen several major
updates in the time since the first publication in
1986, and a comprehensive review is currently
ongoing. The nonclinical aspects of product safety
are discussed elsewhere in this book.
Directive 2001/20 had a major impact on phar-
macovigilance in Europe because it demanded the
creation of a pan-European safety database for all
medicinal products in the market and extending to
IMPs. The system was named EudraVigilance.
The EuDRACT system (clinical trials registration,
see above) was created as part of it. The detailed
guidance about reporting of adverse reactions to
IMPs, whether licensed or not, was issued in April
2004.
Safety monitoring in clinical trials
The sponsor of an IMP or the MA holder in the case
ofaclinicaltrialusingalicensedmedicineisrespon-
sible for the ongoing safety assessment, compliance
with reporting timelines and distribution of reports
to all concerned parties. Furthermore, the sponsor of
a trial now also has the responsibility to report
serious adverse drug reactions occurring in the use
of active comparator products, evenifthe sponsor of
the trial is not its MA holder. The guidelines recom-
mend that the sponsor also inform the MA holder
about the reported case.
An AE is defined as: any untoward medical
occurrence in a subject or clinical investigation
subject administered a pharmaceutical product
and which does not necessarily have to have a
causal relationship with this treatment.
An AE can therefore be any unfavorable and
unintended sign (including an abnormal laboratory
finding, for example), symptom or disease tempo-
rally associated with the use of a medicinal pro-
duct, whether or not considered related to the
medicinal product.
A serious adverse event (SAE) is defined as any
untoward medical occurrence that at any dose:results indeath;islife threatening;requires inpatienthospitalizationor prolonga-
tion of existing hospitalization;results in persistent or significantdisability/inca-
pacity;is acongenital anomaly/birth defect;is animportant medical eventthat may require
intervention to prevent the above five conditions
or may expose the subject to danger, even though
the event is not immediately life threatening or
fatal or does not result in hospitalization.
*The term ‘life threatening’ refers to an event in which the
patient was at risk of death at the time of the event; it does not
refer to an event that hypothetically might have caused death
if it were more severe.34.14 SAFETY REPORTING AND PHARMACOVIGILANCE 477