PHARMACOVIGILANCE
Traceability and
pharmacovigilance
An important requirement for the safety monitoring of all biologics (including biosimilars) is the need
for awareness of adverse events, and product and batch traceability during clinical use and at all
levels in the supply chain
Alain Astier PharmD PhD
Vice-President ESOP;
Honorary Head of the
Department of Pharmacy.
Member of the French
Academy of Pharmacy,
Henri Mondor University
Hospitals, School of
Medicine, Paris, France
Pharmacovigilance is defined as the practice
of monitoring the effects of licensed drugs,
especially in order to identify and evaluate
previously unreported adverse reactions. 1 To do this,
it is crucial to ascertain if the adverse event is
actually caused by a drug and, in the case of
polytherapy, to identify which drug might be
responsible. The batch must also be identified,
because a specific impurity or degradation product
present in a specific batch could be involved. Thus,
for a proper pharmacovigilance, the traceability of
the drug (knowing the batch reference, its history,
storage conditions, identification of the patient who
received it, etc) is mandatory.
Traceability and risk management
Traceability is a key element in monitoring the
safety of biologics by enabling pharmacovigilance
measures. Real life conditions, such as risks of drug–
drug or drug–food interactions are not accurately
evaluated by clinical trials. Thus, long-term follow-
up is essential to establish a risk management plan
(RMP). The aim of risk management is to address
uncertainties in the safety profile at different
points in the lifecycle, and to plan accordingly.
This procedure was put in place in 2005 as part
FIGURE 1
Risk management plan
Risk management plan
Marketing authorisation
Safety specification
Pharmacovigilance
planning
Risk minimisation
planning
Adverse drug reactions
Reporting
Epidemiological
studies
Regulatory decisions
of European pharmacovigilance legislation and
comprises part of the marketing authorisation
application of a drug. 2
RMPs include plans for pharmacovigilance
activities designed to gain greater knowledge and
explain how risks will be minimised in patients, and
how those efforts will be measured (see Figure 1).
An RMP is required for all drugs containing
a new active substance. The RMP might also be
implemented after the product has been marketed
if significant changes occur (for example, new
indication, new dosage, new route of administration,
new manufacturing process) or if a significant risk
has been identified after the drug has reached the
market. The RMP is also required for biosimilar
products registered in the EU. The World Health
Organization has published guidance on scientific
principles for regulatory risk assessment of
biotherapeutic products, including RMPs. 3
For a biosimilar, as for any biologic, variability
between products from different manufacturers
with the same active substance and batches of the
same product from the same manufacturer need to
be considered. 4 Moreover, numerous changes in the
production process during the life of the biologic
might induce large modifications in its composition,
as demonstrated, for example, for rituximab
originator. 5 Thus for each physicochemical or
biological parameter, a biosimilar must fall in the
range of variability observed for the originator. 3,6
Through the extensive comparability exercise for
the originator drug and its biosimilar candidate,
including a Phase III clinical trial, the tolerance
and the classical side effects can be demonstrated
as identical for both originator and biosimilar.
However, immunological side effects remain a key,
even controversial, issue, and are frequently cited
by opponents of the use of biosimilars, particularly
with regards to switching, interchangeability and
extrapolation procedures. 5,6 Thus, it is paramount
to verify whether a biosimilar has more or fewer
immunological side effects compared with the
reference drug.
For biologics that are the subject of a suspected
adverse event, it is of particular importance that
the batch number, in addition to the brand names
or name of the manufacturer, is reported. 7 Some
immunological side effects, such as the presence
of neutralising antibodies, are due to factors
not directly related to the drug. For example,
the production of neutralising antibodies for
a biologic is not only related to the drug itself (that
is, specific antigenic sequences, presence of foreign
proteins and aggregates) but also to the patient’s
characteristics, co-medications and pathology. 8,9
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