Chapter 10: Pharmacovigilance
“All substances are poisons; there is none which is not a poison. The right dose differentiates a
poison and a remedy” – Paracelsus (1443 – 1541).
1. Introduction
During registration (European or decentral registration) of a drug, three parameters are being
judged:
1. Quality of the formulation; the purity of the compound or formulation; the stability aspects,
the pH, chemical aspects; etc. (focus on production process)
2. Safety (preclinical as well as clinical)
3. Efficacy (clinical)
Safety is an important aspect of the registration file. After quality, safety is the second most
important focus in the registration process, especially after a few historical incidents (for example the
thalidomide incident). The acceptable risk needs to be proven by tests, in vitro, in animals and in
humans. This is tested together with the efficacy in the benefit/risk ratio. The safety is a relative
concept: We allow more severe side effects for drugs which are very promising on the benefit side of
the ratio! The benefit/risk ratio is a mean ratio of individual risks and efficacies. This will lead to the
overall benefit/risk ratio of a drug (in a population). They will always look at this on a population
level – they will get an idea of the benefit/risk ratio on the studied population. There might be
differences on a patient-individual level (more or less pronounced).
Some definitions
There are different definitions known of pharmacovigilance. The WHO states: “the science and
activities concerning the follow-up, evaluation, understanding and prevalence of side effects or other
(drug-related) problems (= adverse drug events) occurring with a drug”. So, this is not only about the
side effects and the adverse drug reactions, but also about the adverse drug events (other drug
related problems). The FAMHP states: “all processes concerning vigilance and evaluation of side
effects (= adverse drug reactions) of drugs”. So, events are not monitored and followed-up
(medication related incidents), but they only want to know everything about the side effects. The
post-marketing surveillance is the follow-up of a drug after commercialization – the purpose is to
further define or get insight in the benefit/risk ratio. The pharmaco-epidemiology is a branch of
epidemiology (evaluation of drugs in broad scale populations) investigating in drug use and effects of
drugs in broad scale populations. An adverse drug event (ADE) is “every event occurring during drug
treatment; the event should however not be caused in a direct manner by the drug”. The medication
errors or medication related incidents are also included! In the hospital, there is an incident reporting
system. This is made in an electronic tool and can be completed by every health care professional.
Pre- and post-marketing
There also will be a small part of the pharmacovigilance already before a drug comes onto the
market.
Pre-registration – GCP-requirements for pharmacovigilance
The Clinical Trials Directive 2001/20/EC is translated into the Belgian law of 7 May 2004. It contains
guidelines on reporting adverse events during clinical trials. It is based on the Good Clinical Practice
(GCP). Since 31 January 2022, the European Clinical Trials Regulation (No 536/2014) is published. The
goal is harmonization through the CTIS portal and the Eudravigilance database. This will lead to
efficiency and transparency.
When do you start with pharmacovigilance in a clinical trial? You start during the preparatory phase
of a clinical trial, so during the animal toxicity studies and if there are adverse events in other trials
with humans. You can also start within the clinical trials. The ICH stated: “An adverse event is any
untoward medical occurrence in a patient or clinical investigation subject administered a
Pagina 1 van 8
“All substances are poisons; there is none which is not a poison. The right dose differentiates a
poison and a remedy” – Paracelsus (1443 – 1541).
1. Introduction
During registration (European or decentral registration) of a drug, three parameters are being
judged:
1. Quality of the formulation; the purity of the compound or formulation; the stability aspects,
the pH, chemical aspects; etc. (focus on production process)
2. Safety (preclinical as well as clinical)
3. Efficacy (clinical)
Safety is an important aspect of the registration file. After quality, safety is the second most
important focus in the registration process, especially after a few historical incidents (for example the
thalidomide incident). The acceptable risk needs to be proven by tests, in vitro, in animals and in
humans. This is tested together with the efficacy in the benefit/risk ratio. The safety is a relative
concept: We allow more severe side effects for drugs which are very promising on the benefit side of
the ratio! The benefit/risk ratio is a mean ratio of individual risks and efficacies. This will lead to the
overall benefit/risk ratio of a drug (in a population). They will always look at this on a population
level – they will get an idea of the benefit/risk ratio on the studied population. There might be
differences on a patient-individual level (more or less pronounced).
Some definitions
There are different definitions known of pharmacovigilance. The WHO states: “the science and
activities concerning the follow-up, evaluation, understanding and prevalence of side effects or other
(drug-related) problems (= adverse drug events) occurring with a drug”. So, this is not only about the
side effects and the adverse drug reactions, but also about the adverse drug events (other drug
related problems). The FAMHP states: “all processes concerning vigilance and evaluation of side
effects (= adverse drug reactions) of drugs”. So, events are not monitored and followed-up
(medication related incidents), but they only want to know everything about the side effects. The
post-marketing surveillance is the follow-up of a drug after commercialization – the purpose is to
further define or get insight in the benefit/risk ratio. The pharmaco-epidemiology is a branch of
epidemiology (evaluation of drugs in broad scale populations) investigating in drug use and effects of
drugs in broad scale populations. An adverse drug event (ADE) is “every event occurring during drug
treatment; the event should however not be caused in a direct manner by the drug”. The medication
errors or medication related incidents are also included! In the hospital, there is an incident reporting
system. This is made in an electronic tool and can be completed by every health care professional.
Pre- and post-marketing
There also will be a small part of the pharmacovigilance already before a drug comes onto the
market.
Pre-registration – GCP-requirements for pharmacovigilance
The Clinical Trials Directive 2001/20/EC is translated into the Belgian law of 7 May 2004. It contains
guidelines on reporting adverse events during clinical trials. It is based on the Good Clinical Practice
(GCP). Since 31 January 2022, the European Clinical Trials Regulation (No 536/2014) is published. The
goal is harmonization through the CTIS portal and the Eudravigilance database. This will lead to
efficiency and transparency.
When do you start with pharmacovigilance in a clinical trial? You start during the preparatory phase
of a clinical trial, so during the animal toxicity studies and if there are adverse events in other trials
with humans. You can also start within the clinical trials. The ICH stated: “An adverse event is any
untoward medical occurrence in a patient or clinical investigation subject administered a
Pagina 1 van 8
