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1st Master Biomedical Sciences
Pharmaceutical Medicine
Exam questions 2013
Questions of which 2 will be part of the examination:
1. Drug discovery and design: which selection criteria determine the choice of a project for the
development of a new compound? (Drug discovery and design: bespreek de selectiecriteria die in
rekening gebracht worden bij de keuze van een project voor de ontwikkeling van een nieuw
geneesmiddel).
strategic: is it desirable to do it? does it have to be done?
unmet medical need:
identification of domains in which there is an absence or lack of good
drugs
look into the future: drug will only be available 20 yrs later
gap analysis: analysis of the gap between reality and ideal
market analysis:
identification of opportunities and threats
current situation > future prospects
company strategy and competencies
balance the strength and weaknesses
what do we want and what can we do?
SWOT analysis
-scientific and technical: is it feasible? can it be done?
scientific opportunity
solid scientific base?
lead for innovation?
competitive advantage
first in class
fast follower
best in class
me too
be better
expected difficulties
acute vs chronic diseases
life threatening vs comfort diseases
curative vs preventive indications
hard vs surrogate end points
patent protection
-operational: can we do it?
necessary resources
staff and expertise
equipment, material
capital
timescale
planning
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 final choice and start: based on all elements, is decided by top management
2. Discuss the role of pharmacochemistry in drug discovery and design. (Bespreek de rol van de
farmacochemie in drug discovery and design).
1)lead finding
either through screening
high troughput systems
big chemical libraries of pharma companies
or chemical librariers of natural products
combinatorial chemistry
synthesis of relatively large number of products
either through de novo design (CADD = computer assisted drug design)
ligand based
endogenous ligand is lead
synthetic ligands
pharmacophore model
quantitative structure activity relationship (QSAR)
target based
x-ray crystallography or NMR spectroscopy of targets
docking of small molecules in 3D model of target
2)lead optimalisation
aim is improving biological activity (selectivity, strength, safety)
variables taken into consideration
pharmacokinetics, chemical stability, chiriality, ease of synthesis,
patent protection, formulation, genotoxicity
the most difficult step in drug discovery and design
iterative adaptations: very dynamic and fast
3. Drug discovery and design: which criteria determine the choice of a candidate drug for further
non-clinical and clinical development? (Drug discovery and design: welke criteria bepalen de
keuze van een kandidaatgeneesmiddel voor verdere niet-klinische en klinische ontwikkeling?)
mostly based on the following criteria:
selectivity and strength vs target
appropriate pharmacokinetics
relevant pharmacological activity
in vitro and in vivo
acceptable safety profile
chemically stable, compatible with expected formulation
large scale production possible
patent protection ok
for example: selection criteria for drug candidates intended for oral use:
chemical:
patentable structure
water soluble
chemically stable
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large scale synthesis feasible
non chiral
no known toxophoric groups
pharmacological
defined potency on target
selectivity for specific target relative to other related targets
pharmacodynamic activity in vitro and in vivo
no adverse effects in standard safety pharmacology tests
active in disease models
pharmacokinetic
cell-permeable in vivo
adequate oral bioavailability
for CNS drugs: penetrates blood brain barrier
appropriate plasma half life
defined metabolism by human liver microsomes
no inhibition or induction of cytochrome p450
toxicological
in vitro genotoxicity tests negative
preliminary in vivo toxicology test showing adequate margin between
expected therapeutic dose and maximum no adverse effect dose
4. Provide an overview of the physicochemical aspects which are part of the pre-formulation phase
of a drug. (Geef een overzicht van de fysicochemische parameters die in de preformulatie fase
van een geneesmiddel bestudeerd worden).
solubility
-selection of dosage form
-determines the formulation strategy for a specific route of administration
BCS (biopharmaceutical classification system) classification based on
solubility and permeability
class I
soluble
permeable
class II
not soluble
permeable
class III
soluble
not permeable
class IV
not soluble
not permeable
-solubility determination: in water, influence of pH, in buffers, influence of
ionic strength, in organic solvents (influences of polarity), in lipophilic
producs (oil)
-influence of products that can increase the solubility
cosolvents (PG, PEG, glycerol)
complexing agents
surfactants, polymers
-analytical technique available: uv, spectroscopy, HPLC (high throughput)
intrinsic dissolution rate
-what is the rate at which a certain API concentration can be obtained for a
given temperature of the dissolution medium and taking ton account the
hydrodynamics
-relevant for oral bioavailability, solid state stability
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dC DA

(C s  C )
dt
Vh
with D = diffusion constant, A = surface area, V = volume dissolution
medium, h = thickness of the diffusion layer, Cs = saturaton,
solubility, C = concentration
ionization behavior
-determination of pKa (potentiometric titration, uv spectroscopy)
-how can we change the pH of a solution to increase the solubility of an API?
-possibility to consider salt formation
-ionisation behavior in vivo: bioavailability
partition coefficient and distribution coefficient
log P, log D (pH dependent)
indicaton of lipophilicity or hydrophobicity
indication of in vivo absorption (passive diffusion)
n-octanol is solvent of choice
partition behaviour is determined by characteristics of partitioning solvent
solid state properties of the API
-is the API crystalline or amorphous (glass)?
crystalline:
3D arrangements of molecules in space
melting point
thermodynamically stable
preferential state of matter
amorphous: chaotic arrangements of molecules, comparable to
liquid
thermodynamically unstable
non equilibrium material
higher chemical reactivity
no melting transition but a glass transition (this is a
transition from a state of low molecular mobility to a
state of high mobility)
no phase transition !!
higher solubility and dissolution rate
-the difference between those two can be determined by use of differential
scanning calorimetry (DSC: quantification of theat produces or taken up by
materials when they are heated or cooled) and x-ray diffraction (bragg
reflections or halo pattern)
-molecules can be ordered in space different ways to form a lattice:
polymorphism
-the different polymorphic modifications have different stability, melting
point, solubility, dissolution rate… but their properties in the liquid and gas
are the same: influence on bioavailability, process ability. Development of
most stable form
-solvent molecules can be incorporated in the crystal lattice:
pseudopolymorphism
-intramolecular interactions between API and solvent dertermine bonding
strength
-the different psuedopolymorphic modifications have different stability,
melting point, solubility, dissolution rate… but their properties in the liquid
and gas state are the same. Influence on bioavailability, process ability.
Development of most stable form
-nernst-brunner equation:
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 extensive investigaton is required
-solids (both crystalline and amorphous) can take up (ad and absorbtion)
significant amounts of water and vapour. Influence on stability. Dynamic
vapour sorption analysis (DVS)
stability of the API
-stability of the solid state: influence of heat, visible light, water
-stability in solution: influence of heat, visible light, pH, extreme acidic, basic,
oxidizing environment
-compatibility with excipients and packaging materials
5. Provide an overview of the biopharmaceutical aspects which are part of the pre-formulation
phase of a drug. (Geef een overzicht van de biofarmaceutische aspecten die in de preformulatie
fase van een geneesmiddel bestudeerd worden).
permeability – absorption potential
API must be absorbed in the system to be active
in vitro, in vivo, in situ methods available
for example: PAMPA (parallel artificial membrane permeation assay)
advantages: no animals
high throughput
relatively inexpensive
different lipid compositioins
disadvantages: only partially predictive
membrane retention of lipophilic compounds
performance is strongly dependent on lipid
composition, pH
for example: CaCo-2 cell culture
human colon adenocarcinoma
spontaneous enterocyt differentiation in culture
confluent monolayer
expression of certain brush border enzymes and phase2 enzymes
no CYP3A4
active transport systemes
advantages: excellent screening model
no bioanalysis
evaluation of transport mechanisms and absorption
strategies
evaluation of toxicity
no animals
human origing
high throughput
disadvantages: no mucus
unstirred water layer
tight monolayer
low expression of certain uptake transporters
static model
6. What kind of compounds (API and excipients) can be part of a tablet? (Welke soorten stoffen (API
en andere) kunnen deel uitmaken van een tablet?).
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filter, diluent:
to install the correct tablet weight
for example: lactose, cellulose
binder:
to keep individual particles together after compression
for example: starch, cellulose derivatives
disintegrant:
disintegration of tablet after contact with GI fluids
for example: cross-linked polymers (crospovidone), starch
flow promoter:
improvement of flow properties (homogeneous dosing)
for example: talc
wetting agent:
improvement of contact between aqueous environment and solid
for example: polysorbate
lubricant:
decrease of friction forces during compression, compaction, ejection
for example: Mg-stearate
7. What does “an oral controlled drug delivery system” refer to? What are the advantages and
disadvantages of these systems? (Wat wordt er bedoeld met een toedieningsvorm met “orale
gecontroleerde vrijstelling”? Bespreek de voor- en nadelen van dergelijke orale
toedieningsvormen met een gecontroleerde vrijstelling).
oral controlled drug delivery systems are systems that enable continuous release of
the API in the GI tract during a specified time. The release kinetics are reproducible
and predictable. It are systems that enable a controlled residence time of the dosage
form or release the API at a specific site of the GI tract to obtain a systemic or local
effect. (system = tablets, capsules containing pellets or granules)
-advantages: reduced intake
improved patient compliance and comfort
reduced side effects
controllable release kinetics: less fluctuations in plasma API levels and
uniform effect
8. What kind of strategies can be used to make oral controlled drug delivery systems? (Welke
strategieën worden gebruikt om geneesmiddelen met een “orale gecontroleerde vrijstelling” te
maken?).
based on dissolution and diffusion
reservoir systems:
insoluble coating
slowly dissolving coating, pH dependent coating
diffusion of dissolved API through coating
layered systems:
bead layering
API + polymer 1
rate controlling polyper membrane
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API + polymer 2
inert core
matrix system:
insoluble matrix:
diffusion of dissolved API through insoluble matrix
erodable or slowly dissolving matrix:
API is released mainly during erosion or dissolution of the
matrix former
based on bioadhesion
buccal tablet:
bioadhesion via cross-linked polyacrylic acid
based on osmosis
osmotically active core
polymeric push compartment
polymer membrane
GI fluid enters dosage form
polymer in push compartiment swells
swollen polymer pushes the API through the orifice
9. Which elements need to be taken into account during the pharmaceutical development of suspensions,
creams and ointments? (Bespreek de elementen die een rol spelen bij de farmaceutische ontwikkeling van
suspensies, crèmes en zalven).
suspensions: is a homogeneous dispersion of a solid in a liquid
is used when a liquid dosage form is desired and API is
insoluble, when low stability of API in solution, when oral,
parenteral or dermal applications are necessary.
homogeneous dosing: patient determines the administered dose
so: homogeneous distribution of API in suspension medium
excipients: wetting agent, viscosity increasing agents
adequate particle size of API: stokes
stability: caking
particles must remain at a certain distance from each other
structured medium
interaction between particles at secondary medium
electrolytes + polymers: electrostatic and sterical
stabilisation
creams: made up of a water phase and oil phase
an emulsion: water in oil or oil in water: stability: use emulsifier
composition: API, aqueous phase, oil phase, emulsifying agent,
viscosity increasing compounds, moisturizers, penetration enhancers,
fragrances, perfumes…
ointments
stability: use emulsifyer
composition: API, ointment base, surfactants (improvement of contact
between lipid base and API) fragrances, perfumes
10. Discuss the principles taken into account when calculating the MRSD for conducting a FIM trial.
The calculation of the starting dose of biological compounds remains a difficult exercise for
each new biological compound. With a classical NCE the no observed adverse effect level
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(NOAEL) approach as proposed by the FDA, is usually sufficient to calculate a safe starting
dose, where additional safety steps can be taken into account if the NCE concerns a novel
structure, a new mode of action or the target is expressed in sensitive organs (e.g. brain). In
case of a new biological entity preclinical models are often not predictive of whatwill happen
in humans because of species specificity or species specific differences. The NOAEL
starting dose calculation for a biological is often oversimplified when scaling to man. A more
careful approach should be taken. An alternative approach may be the use of minimal
anticipated biological effect level (MABEL), based on the observed pharmacological active
dose (PAD) as determined during in vivo PD modelling studies and related to PK of the
compound (PK-PD modelling). In this approach, as stated in the EMA guideline on
strategies to identify and mitigate risks for first-in-human clinical trials with investigational
medicinal products, the starting point is the dose level or minimal exposure that is
anticipated to produce an acceptable biological effect and in which potential differences of
sensitivity for the mode of action of the investigational medicinal product between humans
and animals need to be taken into consideration e.g. derived from in-vitro studies. An
additional safety factor is usually applied to reach a low enough dose (i.e. without
pharmacodynamic effect) for the first administration of the biological to humans. The
calculation of MABEL should utilise all in vitro and in vivo information available from PK/PD
data such as: i) target binding and receptor occupancy studies in vitro in target cells from
human and the relevant animal species; ii) concentration-response curves in vitro in target
cells from human and the relevant animal species and dose/exposure-response in vivo in
the relevant animal species; iii) exposures at the pharmacological doses in the relevant
animal species. Whenever possible, the above data should be integrated in a PK/PD
modelling approach for the determination of MABEL.
11. Phase I and phase II RCTs: discuss. (Fase I en fase II RCTs: bespreek)
Phase I
-Initial safety trial of a new drug, usually performed in healthy male volunteers. An attempt is
made to determine that is tolerated by volunteers for single and multiple doses. Dose range
Sometimes it is performed on critically ill patients or less ill patients when pharmacokinetic issues
are addressed.
Study performed on healthy volunteers or certain types of patients without therapeutic targets
which includes the following aspects: estimation of initial safety and tolerability,
pharmacokinetics, pharmacodynamics, early measurement of drug activity.
* Subject: healthy volunteers (10-100)
except for toxic components
male (possibly female)
* Objectives: security
tolerance (dose range, MTD)
pharmacokinetics
pharmacodynamics
duration: 6 to 12 months
* Types of phase I studies:
first in man, first in human studies
pharmacokinetic studies
single dose / multiple dose
bioequivalence studies
interactions
pharmacokinetic, pharmacodynamic studies
QT interval studies
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 these are considered as the traditional studies
Now there are new developments:
Phase 0 trials: microdosing / PET studies
exploratory clincial trial applicatoins
proof of concept studies
translational models
Phase Ib, IIa studies
Phase II
Pilot clinical trail to evaluate in a selected population of patients with the condition that you want
to treat, diagnose or prevent. The efficacy and safety It is sometimes referred to as pivotal trail
* Subject: target population (100-500)
male (female not pregnant)
* Objectives: efficacy
tolerance (dose range, MTD)
Safety: therapeutic window, therapeutic index
pharmacokinetics
pharmacodynamics
duration: 12 to 24 months
short duration referred to as GM for short duration
long duration referred to as GM for chronic use
there must be a necessity for the drug
eg development of a GM that is better than its competitors
the target selection is based on a high risk or low risk
= high risk speculative research target
start from a new target to validate
maybe it is not working
but if so then first in class (blockbuster)
low risk = innovative improvement
increase potency
increase selectivity
increase safety margin
me too drug
must be in competition with a known drug
target validation is done through proof of principle or proof of concept studies
12. Phase III RCTs: discuss. (Fase III RCTs: bespreek)
trials done in the patient population for which it is intended, after it had been demonstrated efficacy and to
obtain. additional data on safety and efficacy in large numbers of patients
* subject: real life populations (500-5000)
* objectives: efficacy and safety
confirming indications and dosage
duration: 2 to 7 years
high risk populations studies
NDA (new drug application) to serve
Phase IIIa: NDA submission for
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Phase IIIb: After NDA submission and approval of marketing.what should be measured?
surrogate endpoints:
you can not take mortality as an endpoint because then you have a very long wait
therefore surrogate endpoints:
these are predictors of mortality
be substitutes for clinically meaningful endpoints
therapy-induced changes in a surrogate endpoint reflect changes in a clinically meaningful endpoint
but be careful because a surrogate is only a surrogate.
trial design
superiority trial
in order to detect differences between treatments
equivalence trial
to confirm the absence of a difference (show that a drug is the same than what already exists, this is
statistically very difficult)
non-inferiority trial
in order to show that a treatment at least as effective as any other.
to show that the drug is not worse than what already exists.
13. RCT and trial design: cross-over versus parallel group design. Discuss. (RCT studie ontwerp: cross-over
onderzoek versus parallel groep onderzoek. Bespreek.)
14. Discuss “internal” versus “external” validity in the context of clinical trials. (Bespreek “interne” versus
“externe” validiteit” in de context van klinische studies)
15. Why are the elderly a high risk population for the use of drugs? (Waarom zijn bejaarde patiënten een
risicopopulatie voor het gebruik van geneesmiddelen.)
Differences in pharmacokinetics and pharmacodynamics among elderly patients are not the
only thing to take into account. due to co-morbidity and polypharmacy, the risks for
interactions and side effects are increased. In elderly long term treatment for chronic
diseases is administered, problems with therapy adherence caused by forgetfulness and
loss of eyesight occur and the possibility of confusing side effects with symptoms of old age
can occur.
As a result of old age, the function of several organs has altered, which can have an
immediate impact on the pharmacokinetics of drugs. In particular, the clearance of drugs is
decreased in old age, so a lower dose has to be administered in order to avoid side effects.
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Kidney mass decreases in old age (resulting in a reduction of available nephrons), as does
the renal perfusion and the glomerular filtration rate. Nontheless, there is not often a
noticable increase of plasma creatinin, because its source (muscle) is also decreasing with
age. Hepatic clearance is also decreased due to a decrease of liver volume and liver
perfusion. Finally, also factors that can influence the pharmaceutical phase and distribution
of pharmaceuticals, such as stomach acid production (HCl and pepsin) and the total amount
of body water are progressively decreased, resulting in a relative increase of body fat. To
what extent are the pharmacokinetic parameters affected due to these changes?
a) The bioavailability: with aging, a decreased first-pass effect is to be expected. As a result
the bioavailability of high extraction pharmaceuticals (e.g. propranolol, lidocain) is increased.
On the other hand, activation of pro-drugs is delayed (e.g. ACE inhibitors).
b) Distribution: polar pharmaceuticals (with a low partition coefficient) are inclined to have a
smaller distribution volume in the elderly, so a higher plasma concentration is attained than
in young people. (e.g. gentamycin, digoxin, theophylline, ethanol). As a result, loading doses
should be reduced. This will not frequently affect the terminal elimination halflife, as with
distribution volume, clearance is parallel decreased; the final result is an unchanged half-life.
Non-polar pharmaceuticals (with a high partition coefficient) have a higher distribution
volume at the older age, so the half-life is increased.
c) Renal clearance: lower renal function results in a decreased renal clearance of watersoluble pharmaceuticals (e.g. some antibiotics, diuretics, digoxin, lithium and NSAIDs). For
pharmaceuticals with a narrow therapeutic range, this should be taken into account.
d) Hepatic clearance: reduced hepatic perfusion will mostly affect pharmaceuticals with a
high extraction ratio, as their metabolic clearance is perfusion limited (cf. chapter on
distribution). Furthermore, a decrease in biotransformation by phase I reactions is observed,
resulting from a reduction of liver volume.
When it comes to pharmacodynamics, sensitivity to multiple classes of drugs is increased in
the elderly. This is particulary noticable for pharmaceuticals with central depressing effects,
anticholinergic effects and antihypertensive drugs. In particular, these are observed for
drugs
that work in the central nervous system and the cardiovascular system (e.g.
benzodiazepines and antihypertensive drugs because of the reduced reflexes and
homeostatic mechanisms). As a result of these changes, the following precautions when
prescribing to the elderly apply:
(1) start off with a low dose (half of the normal adult dose) and gradually increase the
dosage, based on clinical input (“start low, go slow”)
(2) use simple treatments and try to limit the number of drugs (avoid over- and under dosing.
Beware of polypharmacy).
(3) Pay extra attention to informing the patient and his/her close relatives about the correct
use of the drug.
(4) Reducing the dose or stopping medication in an elderly person can sometimes have
miraculous effects and make inexplicable “complaints” disappear.
16. Discuss the use of drugs during pregnancy and lactation. (Geneesmiddelen tijdens zwangerschap en
lactatie: bespreek.)
Even prior to conception, both men and women should consider the possible negative
effects of pharmaceuticals: irreversible damage to the ova and/or spermatozoa by
cytostatics or reversible side effects such as for example a reduced sperm count due to
salazopyrin.
During pregnancy and lactation three essential questions arise when it comes to
pharmacotherapy: (1) what are the effects of the drug on the fetus, (2) what are the effects
on the neonate and (3) what are the effects on breast milk production/feeding?
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Pregnancy: blastogenesis, embryogenesis and fetogenesis
When a future mother is taking pharmaceuticals, these will to some extent also reach the
fetus. With placenta formation, drugs have but the lipid bilayer to cross. There is very little
knowledge of pathogenesis by pharmaceuticals causing congenital disorders or their effects
on fetal function. These effects depend on the nature of the pharmaceutical, the time when
the pharmaceutical is administered in relation to the duration of the pregnancy and the
concentration in the fetal tissues. During blastogenesis (weeks 1-2), there is virtually no
contact between mother and “child”. However, during embryogenesis (or organogenesis),
this is the first trimester (weeks 2-12) the embryo is highly sensitive to teratogenic effects of
drugs. During fetogenesis, the further growth of the fetus during the 2 nd and 3rd trimester, the
central nervous system remains sensitive to xenobiotics. It wasn't until the 1960's, when
numerous deformed children were born, due to thalidomide use during early pregnancy, that
the dangers of teratogenicity of drugs became obvious.
It is virtually impossible to predict teratogenicity by animal testing. E.g. thalidomide has
teratogenic properties in humans at low doses, while these are not observed in rodents, only
in other primates during a very limited period of pregnancy. On the other hand,
corticosteroids are teratogenic in animals, while these effects are not clearly observed in
humans. Adding to the complexity of teratogenicity, is the fact that some effects only
become obvious many years after the exposure of the fetus (e.g. diethylstilboestrol, DES).
As a result, some pharmaceuticals will only be used during pregnancy (or when pregnancy
is suspected) under strict precautions. Sometimes, risks for the mother are higher than the
exposure risk for the fetus, making therapy necessary for the mother's well-being. In such
cases, drugs that have proven (by clinical experience) to be safe for use during pregnancy
will be used.
Based on clinical experience (combined with animal testing) a classification system was
devised in Sweden, allowing us to make a responsible choice of therapy during pregnancy.
Four categories are defined, ranging from A (presumed safe) to D (certain toxicity). But a
drug from category D, is not always absolutely contraindicated during pregnancy, if there are
no available alternatives (e.g. anti epileptics). The American FDA classification is also used
and very similar to the Swedish model.
In the third trimester, extra care should be given to the use of several drugs, because of the
danger to both mother and child. The NSAIDs, for instance, (1) constitute a threat to the
continuation of the pregnancy and partus; (2) increase the risk for haemorrhage in the
mother, fetus and neonate and (3) may result in a premature closing the fetal ductus
arteriosus.
Lactation
Most drugs can easily reach the breast milk by passive diffusion, however the amount of
drug that reaches the baby is usually not clinically relevant. Only a handful of drugs can
accumulate in the breast milk and are potent enough to cause adverse effects in the child.
The degree by which a drug is found in breast milk, was the basis for the Swedish “lactation
categories”, ranging from I (not traceable) to III (transmitted to breast milk, with possible
effects on the child). Products in category IV lack the necessary information to be well
defined.
Notice that some pharmaceuticals can inhibit lactation and should be avoided in breast
feeding women. These are estrogens, bromocriptine and diuretics. Therefore, the
progestogen-only pill is advised as contraceptive during lactation.
Practical tips for drug use during pregnancy and lactation:
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(1) only use drug if the use is potentially more beneficial for the mother than it is dangerous
to the fetus / neonate;
(2) if possible, use local treatment;
(3) if systemic treatment is necessary, preferably use pharmaceuticals that are known to be
safe for fetus and neonate (cf. classification systems).
17. Discuss the Declaration of Helsinki. (Bespreek de Verklaring van Helsinki.)
The declaration of Helsinki consists of ethical principles which are expected to be followed. It
is a statement of ethical principles for medical research involving human subjects, including
research on identifiable human material and data. It applies to all involved in conduct of
clinical research. It is not a legally binding instrument in international law.
In 2000 there was a controversial update about the use of placebo or no placebo treatment.
This was allowed only if no proven existing method exists. The controversy was around the
question how it was possible to know the real therapeutic gain if no placebo treatments were
allowed when another proven method exists. So then a clarification to that statement was
made so that the use of placebo or no treatment, is acceptable in studies where no current
proven intervention exists or where for compelling and scientifically sound methodological
reasons the use of placebo is necessary to determine the efficacy or safety of an
intervention and the patients who receive placebo or no treatment will not be subject to any
risk of serious or irreversible harm. All patients must have access to the best method at the
end of the study (compassionate use).
Authors, editors and publishers all have ethical obligations with regard to the publication of
the results of research. Negative and inconclusive as wall s positive results should be
published or otherwise made publicly available. This part about publication is legally obliged.
Before a study can be started, the study needs to be registered. It is to avoid a publication
bias (for example: meta-analysis: if only positive results are published and no negative
results, a wrong conclusion will be made by those meta-analysis).
18. Give an historic overview of the most important guidelines, regulations and laws concerning clinical
research / clinical trials. (Plaats de belangrijkste richtlijnen en wetgeving omtrent klinische studies in
historisch perspectief.)
19. Belgian law concerning experiments on the human person: what is the difference between an experiment
and a (clinical) trial? Give an overview of the different kinds of experiments and trials defined within the
Belgian law. (Belgische wet inzake experimenten op de menselijke persoon: bespreek experiment versus
proef? Tussen welke soorten experimenten en proeven maakt de Belgische wet een onderscheid?)
An experiment is a trial, study or investigation, carried out on the human person with the aim
of developing knowledge particular to the exercise of the health care professions.
A non-commercial experiment is defined as an experiment in which the sponsor is a
university, hospital or foundation, in which the patent holder is not involved in the financing,
in which the sponser the intellectual property (IP), concept, execution and results of the
experiment owns, in which the ethical committee needs not to be paid.
A (clinical) trial is any investigation in human persons intended to discover or verify the
clinical, pharmacological and/or other pharmacodynamics effects of one or more
investigational medicinal product (IMP), and/or to identify any adverse reactions. It consists
of a subset of experiments
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A phase I trial is a study performed on healthy volunteers or on certain types of patients
without therapeutic objectives which covers one or more of the following aspects: estimation
of initial safety and tolerability, pharmacokinetics, pharmacodynamics, early measurement of
drug activity.
The Belgian law makes a difference in interventional trials and non-interventional trials.
When only one intervention (for example blood sample) is done this trial becomes an
interventional trial. A non- interventional trial is defined by: no randomization, no extra
procedures, only follow up and the drug is used according to leaflet indication
20. Give an overview of the composition and the responsibilities of the Ethics Committee for clinical research
as defined by the Belgian law. Is this in keeping with the requirements as set forward in the ICH-GCP
guideline? (Bespreek de samenstelling en verantwoordelijkheden van de Ethische commissie voor klinisch
onderzoek zoals beschreven in de Belgische wetgeving. Stemt dit overeen met de vereisten zoals
beschreven in ICH-GCP?)
Ethical Committee (IRB / ERC): independent body, 8-15 members, both sexes, majority medical
doctors, at least one lawyer, recognized by Ministry of Health, at least 20 protocols per year,
already seen member declares a conflict of interest (coi) may not participate in the vote.
In a single center trial: local EC
relevance to the trial
risk / benefit analysis
protocol
suitability of researchers and staff
clinical investigators brochure
quality of facilities
ICF
volunteers fee
insurance
financial agreements, contracts
subject recruitment
In a multicentre trial: single opinion from central EC
leading / central EC
priority for a university EC
selection by sponsor and participate more
local EC
quality of facilities
ICF
suitability of researchers and staff
In the ICH GCP guideline is assigned a key role to the Ethics Committees, which must approve
each study and will play a decisive role in the scientific and ethical assessment. On the other hand
imposes no harmonizing conditions of Ethics Committees, thus once again discussions often arise
in international studies.
21. Belgian law concerning experiments on the human person: what is the scope of this law? To what extent is
this scope comparable to the scope of the European Directive of 2001? (Belgische wet inzake experimenten
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op de menselijke persoon: bespreek het toepassingsgebied van deze wet. In welke mate stemt dit
toepassingsgebied overeen met het toepassingsgebied van de Europese Directieve van 2001?)
Belgian law: scope
The scope of the Belgian law is much wider than the scope of the European Directive
22. Belgian law concerning experiments on the human person: give an overview of the procedure one has to
follow and the approvals / authorizations which are needed prior to conducting an interventional clinical
trial in Belgium. To what extent is this different for a non-interventional clinical trial? (Belgische wet
inzake experimenten op de menselijke persoon: beschrijf de procedure die moet doorlopen worden alvorens
een interventionele proef in België kan gestart worden. In welke mate is deze procedure anders voor een
niet-interventionele proef?)
An experiment is a trial, study or investigation, carried out on the human person with the aim
of developing knowledge particular to the exercise of the health care professions.
A non-commercial experiment is defined as an experiment in which the sponsor is a
university, hospital or foundation, in which the patent holder is not involved in the financing,
in which the sponser the intellectual property (IP), concept, execution and results of the
experiment owns, in which the ethical committee needs not to be paid.
A (clinical) trial is any investigation in human persons intended to discover or verify the
clinical, pharmacological and/or other pharmacodynamics effects of one or more
investigational medicinal product (IMP), and/or to identify any adverse reactions. It consists
of a subset of experiments
A phase I trial is a study performed on healthy volunteers or on certain types of patients
without therapeutic objectives which covers one or more of the following aspects: estimation
of initial safety and tolerability, pharmacokinetics, pharmacodynamics, early measurement of
drug activity.
The Belgian law makes a difference in interventional trials and non-interventional trials.
When only one intervention (for example blood sample) is done this trial becomes an
interventional trial. A non- interventional trial is defined by: no randomization, no extra
procedures, only follow up and the drug is used according to leaflet indication
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23. Belgian law concerning experiments on the human person: discuss the vulnerable populations and the
precautions taken to protect them in the context of clinical research. (Belgische wet inzake experimenten op
de menselijke persoon: bespreek de “kwetsbare populaties” en de voorzorgen die genomen worden in de
context van klinisch onderzoek)
Vulnerable populations are minors and adults incapable of giving consent.
If possible a written ICF (informed consent form) needs to be present. A lack of ICF is
tolerable in case of an emergency.
When dealing with minors, the ICF needs to be given by parents or repetitives. Advice by
two pediatricians is necessary. When dealing with adults incapable of giving consent the ICF
needs to be given by a legal representative, only live threatening situations are allowed and
advice by a knowledgeable person is necessary.
To prevent professional participants and to avoid over-volunteering minimal intervals are
clarified. (interval period depends on which regulation is followed.)
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24. The pharmacokinetics of drugs can be profoundly different between children and adults. Provide an
overview of the factors contributing to these differences. (De farmacokinetiek van geneesmiddelen kan
grondig verschillen tussen kinderen en volwassenen: bespreek de factoren die bijdragen tot deze
verschillen.)
Children should not be seen as miniature adults. As well in pharmacokinetics as in
pharmacodynamics there are distinctions between adults and children.
Children have a higher amount of body water compared to adults: 75% in neonates, 85% in
preterms and 60% in older ages. Lower protein binding results in different drug distribution.
Low metabolic capacity of the liver and a limited glomerular filtration (only 30-40% of adult
capacity) account for the longer half-life and restricted clearance of most pharmaceuticals.
Higher sensitivity in comparison to adults, to a number of drugs (measured in mg/kg) calls
for an thorough adjustment of neonatal dose charts.
At six months renal capacity of children is similar to adults, but metabolic capacity of the liver
is often increased in young children. As a result, sometimes children require a higher dose
compared to adults. Ont hthe other hand, young children show an increased toxicological
sensitivity for antihistamines and benzodiapines (causing paradoxal aggression).
25. Pediatric clinical pharmacology: the metabolism of drugs (i.e. biotransformation) depends on a number of
co-variables. Discuss these variables and give examples. (Pediatrische klinische farmacologie: het
metabolisme van geneesmiddelen (biotransformatie) is afhankelijk van een aantal co-variabelen. Bespreek
deze co-variabelen (geef voorbeelden).)
Delayed maturation of drug-metabolizing enzyme activity may account for the marked
toxicity of drugs in the very young, as exemplified by the cardiovascular collapse associated
with the gray syndrome in newborns treated with chloramphenicol. Important developmental
changes in the biotransformation of drugs prompt the need for age-appropriate dose
regimens for many drugs commonly used in neonates and young infants, such as the
methylxanthines, nafcillin, third-generation cephalosporins, captopril, and morphine. Distinct
patterns of isoform-specific developmental changes in the biotransformation of drugs are
apparent for many phase I (primarily oxidation) and phase II (conjugation) drug-metabolizing
enzymes. Selected examples are summarized below.
development of phase I enzymes
The expression of phase I enzymes such as the P-450 cytochromes (CYPs) changes
markedly during development. CYP3A7, the predominant CYP isoform expressed in fetal
liver, may protect the fetus by detoxifying dehydroepiandrosterone sulphate and potentially
teratogenic derivatives of retinoic acid. The expression of CYP3A7 peaks shortly after birth
and then declines rapidly to levels that are undetectable in most adults. Distinct patterns of
isoform-specific developmental expression of CYPs have been observed postnatally. Within
hours after birth, CYP2E1 activity surges, and CYP2D6 becomes detectable soon
thereafter. CYP3A4 and CYP2C (CYP2C9 and CYP2C19) appear during the first week of
life, whereas CYP1A2 is the last hepatic CYP to appear, at one to three months of life.
Insight into the ontogeny of drug metabolism can also be derived from pharmacokinetic
studies of drugs metabolized by specific CYP isoforms. The clearance of intravenously
administered midazolam from plasma is primarily a function of hepatic CYP3A4 and
CYP3A5 activity, and the level of activity increases from 1.2 to 9 ml per minute per kilogram
of body weight during the first three months of life. The clearance of carbamazepine from
plasma, which is also largely dependent on CYP3A4, is greater in children than in adults,
thereby necessitating higher weight-adjusted doses (i.e., milligrams per kilogram of body
weight) of the drug to achieve therapeutic plasma levels. CYP2C9 and, to a lesser extent,
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CYP2C19 are primarily responsible for the biotransformation of phenytoin. The apparent
half-life of phenytoin isprolonged (to approximately 75 hours) in preterm infants, but it
decreases to approximately 20 hours, in term infants during the first week of life and to
approximately 8 hours after the second week of life. Concentration-dependent metabolism
(i.e., that accounted for by Michaelis–Menten kinetics) does not appear until approximately
10 days of age, demonstrating the developmental acquisition of CYP2C9 activity. The
maximal velocity of phenytoin (which reflects the extent of CYP2C9 activity) declines from
an average value of 14 mg per kilogram per day in infants to 8 mg per kilogram per day in
adolescents, producing a profound corresponding agerelated difference in the daily
therapeutic dose requirement. Caffeine and theophylline, both substrates for CYP1A2, are
commonly prescribed for neonates and young infants. In infants older than four months of
age, the clearance of caffeine from plasma primarily reflects demethylation activity mediated
by CYP1A2 and approaches adult values ; by the time infants are six months of age (as
reflected by theophylline plasma clearance), the rate may exceed that in adults.
Furthermore, the rate of demethylation of caffeine in adolescent girls appears to decline to
levels seen in adults once girls reach Tanner stage 2, whereas it occurs at Tanner stage 4
or 5 in adolescent boys, thus demonstrating an apparent sex based difference in the
ontogeny of CYP1A2.
development of phase ii enzymes
The ontogeny of conjugation reactions (i.e., those involving phase II enzymes) is less well
established than the ontogeny of reactions involving phase I enzymes. Available data
indicate that the individual isoforms of glucuronosyltransferase (UGT) have unique
maturational profiles with pharmacokinetic consequences. For example, the glucuronidation
of acetaminophen (a substrate for UGT1A6 and, to a lesser extent, UGT1A9) is decreased
in newborns and young children as compared with adolescents and adults. Glucuronidation
of morphine (a UGT2B7 substrate) can be detected in premature infants as young as 24
weeks of gestational age. The clearance of morphine from plasma is positively correlated
with post-conceptional age and quadruples between 27 and 40 weeks postconceptual age,
thereby necessitating corresponding increases in the dose of morphine to maintain effective
analgesia. A consistent observation in clinical studies of drugs metabolized in the liver is an
age-dependent increase in plasma clearance in children younger than 10 years of age, as
compared with adults, which necessitates relatively higher weight-based dose requirements.
The mechanisms underlying these agerelated increases in plasma drug clearance are
largely unknown. A single small in vitro study failed to identify developmental differences in
hepatic expression of CYPs. However, a detailed study of the CYP2C9 substrate S-warfariN
confirmed that the clearance of unbound oral S-warfarin was significantly greater among
prepubertal children than among pubertal children or adults after adjustment for total body
weight or body-surface area but not estimated liver weight. However, the clearance of
antipyrine, which is dependent on several CYPs, correlates significantly with age, even after
correction for liver weight. Therefore, it is unlikely that the greater drug clearance in infants
and young children can be attributed solely to a disproportionateincrease in liver mass,
given that the weight of the liver as a percentage of total body mass reaches a maximum
between one and three years of age and declines to adult values during adolescence. This
assertion would appear to be particularly true for drugs metabolized by enzymes with
substantial extrahepatic expression (e.g., CYP3A4, CYP3A5, and isoforms of UGT).
26. What is the objective of the European obligation to make a Pediatric Investigational Plan (PIP) for all new
drugs in development? (Wat is het doel van de Europese Wetgeving die verplicht om een Pediatrisch
Ontwikkelingsplan voor te stellen voor nieuwe geneesmiddelen: the Paediatric Investigational Plan (PIP)?)
Ethical restrictions used to limit the possibilities of clinical trials in children in the past.
Recent changes in the European Regulations (January 2007) oblige the pharmaceutical
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industry to submit a Pediatric Investigational Plan (PIP) to the competent authorities for new
drugs in clinical development.
For drugs which were already on the market prior to this new regulations, there are 3
practical possibilities:
(1) the dose for children is known based on experience: dose in relation to age is looked up
in (preferably standardized) pediatric reference books;
(2) The drug is not suitable for kids: some drugs cannot be prescribed to children because of
age specific side effects or contra-indications (e.g. tetracyclins, quinolones);
(3) There is no available information, nor formal contraindication: dose per body surface
area is the best measurement to use to convert the adult dose to the pediatric dose.
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27. Give an overview of the different kinds of study design which are being used in clinical research and in
pharmaco-epidemiology. What are their respective advantages and disadvantages? (Bespreek de
verschillende soorten opzet (“design”) voor klinische studies zoals gebruikt in de farmaco-epidemiologie
met hun voor- en nadelen.)
in level of evidence: systematic reviews, randomized control trials, cohord studies, casecontrol studies, case series and case reports, editorials and expert opinion
study design = observational and descriptive
case report
reporting about 1 case / observation
frequently a rare/unusual observation
concept is challenge, dechallenge and rechallenge
pro:
cheap
easy
hypothesis generating
con: little evidence for causality
does not allow hypothesis testing
case series
pooling of cases, number of cases
hoe meer ik het observer, hoer meer ik geloof date r een causale relatie is
pro:
estimation of incidence
hypothesis generating
con: little evidence for causality
no control population
no hypothesis testing
study design = observational and analytical
case control
compares cases (positives) with controls (negatives) and looks for differences in
preceeding exposure in the past. the change in risk due to the exposure is expressed
in odds ratio
pro:
rare and late responses can be investigated
multiple exposures can be investigated
easy, quick, cheap
statistiek is mogelijk
con: sensitive to bias (vertekening, afwijking van de waarheid)
selection bias: groep is niet representatief voor de hele populatie
information bias: incomplete informatie
recall bias: de personen herinneren zich niet meer alle informatie,
mensen die meer lijden, zullen het zich waarschijnlijk gemakkelijker
herinneren
confounding/verwarring ivm multiple parameters
cohord
comparison of exposed with non exposed, in case exposed subjects display
higher/lower incidence of a consequence, the possibility exists of an association
between exposure and consequence
pro:
multiple responses can be investigated
rare exposures can be investigated
no historical controls (if prospective)
information about incidence
con: large groups are required
selection bias
long lasting, expensive in case of late or rare responses
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RCT
is a type of scientific research in the life sciences, especially in medicine, which tries to
answer the question whether a particular treatment ('intervention') employed or useful. For
this purpose, a specific method is used, the test treatment is carried out at a test group and
compared with a control group. A control is a similar group of subjects or experimental
animals with the same complaint if the same problem, but those with a placebo or with
another agent is treated. Sometimes, use is made of three or even more groups: for example,
in addition to the test group also groups that received either a placebo, or a similar other
means or in the whole receive no treatment. To ensure that in the classification of the groups
no difference occurs between the groups increasing the likelihood of success of the treatment
may be affected, an additional allocation of subjects or animals to different groups by lot
(random) are determined . This is the meaning of the word 'randomized' in the title.
Otherwise so can be guided. Those who select themselves by unconscious factors
pro: checks for unknown and unmeasurable confounders
most powerful research in statistical terms
con: limited number of participants
limited exposure and follow up on time
Inclusion and exclusion criteria
artificial
expensive
logistically demanding
ethical concerns
study design = meta analysis
a meta-analysis is a systemic review of multiple RCTs
by bringing the results of multiple RCTs together and analyzing them as if it concerned one
large study, conclusions can be drawn and insights can be obtained which could not be
possibly by only taking the results of the individual studies into account.
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pro:
con:
very powerful statistical method
cave publication bials
28. Provide an overview of the production process of biologicals. (Bespreek het productieproces van
biologicals.)
Production of recombinant protein
Unicellularsystem: Bacteria,Yeast,Mammalian
Multicellular system: Transgenic plant, Transgenic animal
gene of interst+ plasmids-> restriction enzymes. after that we use DNA ligase to
do the cloning(usually we have also a selection gene. then we pick the recombinant
cell line. and we do a cell culture. recombinant cells express desire protein
characterization and stability
Cell bank-> Fermentation-> Purification-> Purified protein
29. What are the most important differences between “small molecules” and “biologicals”. (Bespreek de
belangrijkste verschillen tussen “small molecules” en “biologicals”.)
The definition of a biological in a broad sense is that biologicals are medicinal products
derived from a biological (living) system and created by biological processes. They are
usually based on chains of amino acids (e.g. peptides, proteins, antibodies), but can also be
cells and tissue. However, in most cases the term “biologics” is used more restrictively for a
class of medications produced by biological processes involving recombinant DNA
technology. Biological compounds have a unique profile in efficacy but also very specific
safety concerns.
Compared to small molecules, biologics have a high degree of species specificity, are
immunogenic and usually have a long lasting effect. Biologicals are large molecules with a
molecular weight that usually exceeds 5 kilo Daltons. Oral availability is poor and therefore
biologicals needs to be administered by parenteral route (intravenous (IV) or subcutaneous
(SC)). The synthesis of a biological compound normally involves at least partly a living
organism, which makes them more difficult to characterize or control compared to standard
chemically synthesised pharmaceuticals or small molecules. The starting material may be of
human, animal tissue or of microbiological origin.
The volume of distribution of biologicals is usually small and distribution itself can be
targetmediated with a high selectivity and specificity for the selected target. Toxicity most
often relates to on-target mediated exaggerated pharmacology, because the binding of the
biological to its target can result in the onset of a downstream cascade of different
processes. The advantage of biologicals is that hepatic drug interactions rarely happen and
hepatic toxicity is less likely compared to small molecules.
The long-lasting effect is a result of the very long half life (average t½: 21-25 days) due to
slow elimination of biologicals which mostly happens through degradation or intracellular
catabolism in stead of biotransformation or metabolisation. The drawback of elimination
through intracellular catabolism is that capacity is saturable because of finite expression of
the target. Saturation can result in complicated non-linear kinetics, usually with variable
decrease in clearance as dose increases, and dosing intervals which often require several
weeks. As a result, intermittent dosing schedules are used, compared to chronic daily
dosing for small molecules. For biologicals immunogenicity is sometimes observed with the
formation of anti-drug antibodies (ADA’s) against the biological compound. The formation of
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these ADA’s may alter pharmacokinetics and efficacy and pose specific safety issues, a
though the latter is of less concern. Nevertheless, the effects of biologicals on the immune
system may be complex and unpredictable.
The differences between biological compounds and small molecules create specific
challenges with regards to safety, pharmacokinetic (PK) and pharmacodynamic (PD)
evaluation of biologicals when translating the preclinical data to humans. All of the
differences often result in a specific case-by-case approach and specific challenges which
need to be addressed, not only in the preclinical development of the biological compound
itself but also in the early evaluation of biologicals in humans
30. What are “biosimilars”? Why was this concept introduced? What is the difference between a generic (small
molecule) drug and biosimilars? (Wat wordt er bedoeld met “biosimilars” en waarom is dit concept
ingevoerd? Wat is het verschil tussen een generisch product en biosimilars?)
Definition of a biosimilar
A biosimilar is a biological medicinal product which is similar to a reference medicinal product which is
registered in the European Community. Comparative research is necessary to demonstrate that the product
is equivalent in terms of quality, safety and efficacy of the chosen reference product in the European
Community. The EU legislation provides a legal framework for this purpose since 2006. The concept and
methodology of the competition will be further elaborated in the guidelines of the European Medicines
Agency (EMA). These guidelines include general and more specific recommendations, taking into account
the characteristics of the biological medicinal product concerned (see ref. EMA guidelines and Q & A
document). For biosimilars are needed beyond what was required for the original reference product. Less
(non-) clinical data (modules 4 and 5) The requirements relating to administrative (module 1), technical
(module 2) and chemical-biological-pharmaceutical (Module 3) data are identical to those for the biological
reference medicine.
Why a specific approach for biosimilars
Bio (techno) logical medicaments are prepared through the use of live biological systems. Inherent in the
nature of organic products and their manufacturing process is the heterogeneity. Moreover, the process (and
thus the end product) are very sensitive to changes in the production process (Preparation, purification,
formulation, ...). Two independently developed manufacturing processes for the same biological drug can
cause similar, but never identical drugs. A biosimilar will therefore almost always exhibit differences from
the reference product.
Therefore, detailed studies in which the two drugs are compared. These studies included a stepwise process,
in which first the chemical-pharmaceutical quality compared. When this is considered sufficient
comparable, are then also performed studies to assess the safety and efficacy comparison. The number and
size of these studies are smaller than those of the reference medicinal product and should be rather short
term to demonstrate that what the safety and efficacy concerns no significant differences between the
biosimilar and the reference product.
31. What is GCP? Who is GCP for? What are the objectives of implementing ICH-GCP in clinical research and
who benefits from complying with GCP? (Wat is GCP, op wie is het van toepassing, wat is het doel van de
implementatie van GCP en wie heeft er belang bij GCP in klinisch onderzoek?)
GCP stands for Good Clinical Practice, it is a term used for the collection of rules, recommendations
and guidelines on how good clinical research should be performed. When there is compliance with
GCP, the subjects are properly protected, studies are based on good science, study procedures are
properly undertaken and documented, data is complete, accurate and unbiased. When GCP is not
followed, subjects may be exposed to increased risk, subjects rights may be violated, collected data
may be unreliable, the study will be rejected by regulatory agencies. GCP is for everybody working
on a trial: subject, investigator, study staff, ethics committee, sponsor, monitor etc. ICH stands for
International Conference on Harmonization of technical requirements for registration of
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pharmaceuticals for human use. It is a joint tripartite initiative involving both regulatory groups and
industry in partnership to create human research guidelines. The objectives from the ICH are to make
recommendations on ways to achieve grater harmonization, to use economical human, animal and
material resources, to eliminate unnecessary delay in global development and availability of new
medicines and to maintain safeguards on quality, safety and efficacy and regulatory obligations to
protect public health. The ICH definition of GCP is ‘an international ethical and scientific quality
standard for designing, conducting, recording and reporting trials that involve the participation of
human subjects.
32. What is ICH? What are the objectives of it and which topics are covered by ICH? (Wat is ICH? Wat zijn de
doelstellingen ervan en op welke topics heeft het betrekking?)
ICH stands for International Conference on Harmonization of technical requirements for
registration of pharmaceuticals for human use. It is a joint tripartite initiative involving both
regulatory groups and industry in partnership to create human research guidelines. The
objectives from the ICH are to make recommendations on ways to achieve grater
harmonization, to use economical human, animal and material resources, to eliminate
unnecessary delay in global development and availability of new medicines and to maintain
safeguards on quality, safety and efficacy and regulatory obligations to protect public health.
The ICH definition of GCP is ‘an international ethical and scientific quality standard for
designing, conducting, recording and reporting trials that involve the participation of human
subjects.
33. What is an informed consent form? Give an overview of the informed consent process for participation in a
clinical study? What is the historical origin of this procedure? (Bespreek de procedure voor het bekomen
van een geïnformeerde toestemming voor deelname aan een klinische studie (i.e. the “Informed Consent”
proces). Waar vindt deze procedure historisch gezien haar oorsprong?)
ICF stands for Informed Consent Form, it is a document that describes the rights of the
study participants, it includes details about the study and it is designed to begin the IC
process which consists of conversation between the subject and research team. The ICF is
composed of a signature page and subject information pages.
Obtaining the informed consent is the important first step: the subject voluntary confirms
willingness to participate, it must be obtained prior to the subject’s participation in the trial
before any study procedure takes place and in must be signed and dated by each subject.
The informed consent process step by step:
1. Explain: explain pertinent aspects of the study, its purpose and purpose of ICF
2. Use simple words: non-technical, simple and practical language
3. Answer questions: provide the subject with ample time and opportunity to ask any
question, all questions must be answered to subject’s satisfaction
4. Give time: ample time to decide whether or not the subject wants to participate,
without coercion or unduly influence
5. Signature: the subject and person who conducted the informed consent discussion
sign and personally date
6. Provide ICF copy to subject: provide a copy of the singed and dated ICF prior to the
study participation
34. What is an IRB / IEC? What are the functions, composition and responsibilities of this committee? Are
there any differences with respect to function, composition and responsibilities of an IRB between the GCP
guideline and the Belgian law of May 2004? (Wat is een IRB / IEC? Bespreek haar functie, samenstelling
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en verantwoordelijkheden. Zijn er verschillen tussen wat de GCP richtlijn hierover zegt en de Belgische
wet inzake experimenten op de menselijke persoon?)
IRB/IEC stands for Institutional Review Board/Independent Ethics Committee. It is an
independent body constituted of medical, scientific and non-scientific members, whose
responsibility is to ensure the protection of the rights, safety and well-beeing of human
subjects involved in a trial by, among other things, reviewing, approving, and providing
continuing review of trial protocol and amendments and of the methods and materials to be
used in obtaining and documenting informed consent of the trial subjects.
The proper function of IRB/IEC is to be more comfortable about the conduct of a clinical trial
in human, to guarantee that research activities minimize the potential risks to human
subjects and to make a risk-benefit ratio.
The IRB/IEC consists of a reasonable number of members, who collectively have the
qualifications and experience to review and evaluate the science, medical aspects, and
ethics of the proposed trial. At least there has to be a non-scientific member, an independent
member, three IRB members of which one is the chairman. Only members independent of
the investigator of the trial should vote or provide opinion. A list of IRB/IEC members and
qualifications should be maintained.
The IRB/IEC responsibilities are to review a proposed trial and documents, to continue
review the trial to see if there are deviations or changes in the protocol, to see if there is
safety reporting and new safety information, to see if there is study progress and study
completion notification, to pay special attention to trials that may include vulnerable subjects,
to review qualifications of the investigators, to make decisions at announced meetings and
to maintain adequate records and to see if the way that is worked is in a CGP manner.
35. What are the differences between monitoring, auditing and inspection of a clinical study? (Wat is het
verschil tussen: monitoring, auditing en inspectie van een klinische studie?)
The monitor or Clincial Research Associate (CRA) is appointed by the sponsor to monitor
the trial. The CRA ensures adherence to the protocol, informed consent procedure, source
data verification, checks medicinal supply and sample handling, laboratory assessment.
An audit is a systematic and independent examination of trial related activities and
documents to determine whether the evaluated trial related activities were conducted and
the date were recorded, analyzed and accurately reported according to the protocol,
sponsor’s SOPs, GCP and applicable regulatory requirements.
Differences from monitoring are once only look at site, covers entire study to that point,
process focus, observer is independent of conduct of study.
An inspection is the act by a regulatory authority of conducting an official review of
documents, facilities, records and ay other resources that are deemed by the authority to be
related to the clinical trial and that may be located at the site of the trial or at the sponsor’s
facilities. There are several inspection types: pre-approval inspection (follow new product
marketing applications, are part of assessment, are study or project specific: verify if trial
was conducted, data generated, documented an reported with protocol, GCP and sponsor
SOPs), routine GCP inspection (system inspection, evaluate QA/QC systems established by
sponsor to assure that trials are conducted and data generated, recorded and reported in
compliance with protocol, GCP and applicable requirements), triggered, directed, for-cause
inspection (after a complaint, when poor compliance with regulatory requirements). The
focus lays on a routine inspection.
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Difference from audit: an audit is a sponsor quality system, by sponsor’s regulatory
compliance, an inspection is external to the sponsor, it is an official review of regulatory
authorities.
36. Pharmacovigilance (pre-registration): discuss the causality assessment of an adverse event taking place
during a clinical trial. (Farmacovigilantie (pre-registratie): bespreek de causaliteitsbepaling van ongewenste
effecten (inclusief de WHO causaliteitscode).)
An adverse drug reaction is defined as any response to a drug which is noxious, unintended
and occurs at doses normally used in man for prophylaxis, diagnosis or therapy of disease or
for modification of physiological function by the WHO. A synonym is side effect. This
definition can only be used post-registration, because ‘doses normally used’ are not known in
clinical trials. A synonym is side effect. Described in the Belgian law as follows: any
untoward and unintended response to an investigational medicinal product or to an
experiment and, when an investigational product is concerned, related to any dose
administered.
the investigator must perform a causality assessment of the adverse event. This can be based on
global introspection or algorithms. The investigator relies upon experience with the product and
experience with target population, medical history of the participant, properties of the adverse
event, dechallenge/rechallenge/respons to treatment and alternative explanations.
Causality is to determine, in an individual case, if the suspected drug has caused the adverse event.
Verschillende klassificatie systemen zijn mogelijk: WHO, EU, US systeem etc. The complex
interaction between the drug, the participant and external factors must be examined. The causality
assesment has only a limited scientific value. By definition further Top analytical and scientifical
research is Necessary to prove a causal correlation between the adverse event and the drug. The
following may help: time relationship, pharmacological parameters, known correlation with the
drug or drug class, under lying conditions / concomitant diseases, concomitant medication,
dechallenge (what happens when the drug treatment stops put, the reaction is stronger or weaker?
), rechallenge (risk should be estimated), dose-effect relation etc.
37. Pharmacovigilance: what is the difference between an adverse event and an adverse drug
reaction? (take the definitions in the Belgian legislation into account). When will an adverse event
or an adverse drug reaction be considered “serious”? (Farmacovigilantie: wat is het verschil
tussen een “ongewenst voorval” en een “bijwerking”? (vergelijk ook met de definities in de
Belgische wetgeving). Wat maakt dat een “ongewenst voorval” of “bijwerking” als “ernstig”
beschouwd wordt?)
An adverse drug reaction is defined as any response to a drug which is noxious, unintended
and occurs at doses normally used in man for prophylaxis, diagnosis or therapy of disease or
for modification of physiological function by the WHO. A synonym is side effect. This
definition can only be used post-registration, because ‘doses normally used’ are not known in
clinical trials. A synonym is side effect. Described in the Belgian law as follows: any
untoward and unintended response to an investigational medicinal product or to an
experiment and, when an investigational product is concerned, related to any dose
administered.
unexpected adverse reaction: an adverse reaction, the nature or severity of which is not
consistent with the information on the experiment, and, when a clinical trial is concerned,
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with the applicable product information
suspected unexpected serious adverse reaction: a suspected unexpected serious reaction, the
nature or severity of which is not consistent with the information on the experiment and
when a clinical trial is concerned, with the applicable product information.
An adverse drug event is defined as any medical event that occurs during treatment with a
drug, but not necessarily with a causal link with this drug by the WHO. (for example: a drug
can make you less alert, you can fall from the stairs.) Described in the Belgian law as
follows: any untoward medical occurrence in a patient or subject of the treated group during
an experiment, and which does not necessarily have a causal relationship with this treatment.
Serious adverse event is an adverse event which results in death, is life-threatening, requires
hospitalization, prolongs hospitalization, results in persistant or significant disability or
incapacity, is associated with a congenital abnormality or birth defect and this is regardless of
the dose.
38. Discuss: Data Safety Monitoring Board. (Data Safety Monitoring Board: bespreek)
DSMB stands for Data Safety Monitoring Board, it is an officially designated and independent
group consistiong of at least three members, responsible for interim monitoring of accumulating
data of an ongoing study. It is required for each clinical study involving a potential risk for the
participant (large multicenter studies, when the nature of investigational product or intervention is
unclear…)
DSMB function differs from the function of the ethics committee: monitor inclusion rate, detect
protocol violations, edit data safety monitoring plan, check credibility, integrity and validity of
data, detect unexpected high drop out ratios and exclusions, preserve safety of participants, study
of all ADR reports, be available for PI for discussion of ADR.
DSMB composition is based on nature, size and domain of the study, taking into account
expertise, experience (in domain, with studies, with DSMB) and absence of conflict of interest. At
least with expertise or experience in relevant domain, at least one biostatistician, sometimes also
an ethicist, other scientists, representative of patient organization…
Purpose of interim analysis is to do an evaluation of efficacy, linked to stopping rules, evaluation
safety and tolerability, statistical analysis, early detection of possible bias. Data is obviously ver
confidential, it is based on results it will be determined if it is ethical to continue the safety.
Possible decisions are to continue as planned, to stop because of major safety reasons, to stop
because efficacy is proven, to stop because additional data are available and it is no longer ethical
to continue, to stop because the study will probably not prove anything, to adjust design etc.
DSMP stands for Data Safety Monitoring Plan, it describes how the PI plans ensure safety and
wellbeing of the participants, it describes the processes to follow for monitoring of the progression
and the safety of the study, for reporting of non-anticipated problems, for suspension or
termination, it ensures the accuracy of data and compliance to the protocol.
Conclusion is that DSMB plays a key role in a clinical trial, it makes sure decisions are taken
based on clear and predeterminded clinical and statistical grounds, it watches over safety and
wellbeing of the participants, it ensures that the maximum on information can be extracted from a
study and it ensures participants, investigators, ethics committees and public opinion that the study
is conducted in an honest and responsible way.
39. Define some important limitations of the safety evaluation of a drug (i.e. pharmacovigilance)
during (1) the premarketing period and (2) after bringing the drug onto the market? (Bespreek
enkele belangrijke beperkingen van de veiligheidsevaluatie (i.e. farmacovigilantie) van een
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geneesmiddel (i) tijdens de klinische ontwikkelingsfase en (ii) na het commercieel beschikbaar
komen van het geneesmiddel.)
40. What are the objectives of pharmacovigilance and how is the reporting of supposed adverse drug
reactions organized in Belgium? (Wat zijn de doelstellingen van de geneesmiddelenbewaking en
hoe is de melding van vermoedelijke bijwerkingen in België georganiseerd?)
the objectives of pharmacovigilance are:
detection of new ADRs (unknown) and increase the frequency of known ADRs
identification of risk factors and mechanisms that are at the basis of the occurrence of
ADRs
evaluation of continuous reevaluation of the risk-benefit balance of medicines
communication and risk restriction to inform health care professionals and patients about
the safety profile: prevention of ADRs and to limit the consequences
41. Which problems / challenges is post-marketing pharmacovigilance facing? (Farmacovigilantie:
met welke problemen / “uitdagingen” wordt de post-marketing geneesmiddelenbewaking
geconfronteerd?)
*underreporting
depending on the source, only 1-5% ADRs are being reported
less reports from hospitals
only 1% ADRs led to hospitalization are reported
consequences: incomplete databases
underestimation incidence ADRs
late signal detection
difficult for correct evaluation of risk-benefit balance
total number of exposed patients is not exactly known
variable reporting frequency in time
*unbalance in reports
percentage reports directly submitted to BCPH by HCPs is low compared to reports received
from pharmaceutical industry (in Europe it is the opposite)
*incomplete reports
part of the yellow cards is incomplete: report is difficult to evaluate and to encode
important elements are often missing
importance of complete reports to make a qualitative evaluation and encoding
possible, no need to contact notifier so faster, more efficient
*impact of ADRs
human and ecomonical costs
42. Discuss: the nomenclature of drugs. (Bespreek de naamgeving van geneesmiddelen)
The chemical name is based on the molecular structure of the active substance
The generic name (generic name) or INN is internationally accepted and recommended name
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The trade, specialty or brand (specialty name) is the brand name under which the drug is registered and
sold.
ΝΑ ΔΙΑΒΑΣΩ ΠΑΡΑΔΕΙΓΜΑΤΑ
Brand names may differ depending on the country
Same active substance may be registered under several brands
INN: intrenational nonproprietary names
identification of pharmaceutical substances,
unique public name
generic name
requirements for classification of drugs
conditions
easily recognizable names
not too long
minimal risk for error, confusion, mixed with other medicinal
useful in all languages
names in the same drug class usually start or end with the same vowel
sometimes useful
sometimes confusing
the proposed names are published by the WHO
can be criticized, comments are given for 4 months
43. Discuss the difference between “off label” and “unlicensed” use of drugs and illustrate with an
example. (Bespreek het verschil tussen: “off label use” en “unlicensed use” van geneesmiddelen
en geef een voorbeeld).
off label use
use for indications other than those approved (by the FDA, EMA)
for example, the use of intravenous immunoglobulins in Staphyloccus septic shock
eg the use of rituximab in patients with idiopathic thrombocytopenic purpura
eg using enoxaparn as a thrombo-prophylaxis in patients neurochirugische
unlicensed use
the use of a drug in a different patient population, other dose or other route of administration than is
approved by the package insert and without the side effects of the pharmaceutical company to charge
eg the use of lipid complexed amphotericin B as a fungal prophylaxis in lung transplant recipients via
nebulisatie, while only approved for iv injection
44. Discuss the different aspects and the importance of cold chain management. Give a real life
example. (Bespreek de verschillende aspecten en het belang van “cold chain management. Geef
een voorbeeld)
Management of guaranteeing the adequate storage of drugs, even if they have to be kept
at special temperatures. Should be adequate for the …
• Original product (storage in the company, storage during
transportation, storage in the pharmacy and on the wards/at
patient’s home)
• After reconstitution and dissolution
All fridges and freezers are connected with an alarmsystem
Quality of pharmaceutical products is of primary concern
Chemical and physico-chemical stability depends on temperature
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45. What is “polypharmacy”? What are the dangers associated with it? (also explain in the context of
transmural care). (Wat is polyfarmacie? Wat zijn de gevaren die er aan verbonden zijn; bespreek
dit ook in de context van transmurale zorg)
polypharmacy: more than 6 drugs / day
simultaneous use of multiple drugs
Associated factors include older age, multiple pathologies per patient,
associated pathologies, drugs used to side effects of other drugs to solve
risk for drug interactions and decreased adherence. The side effects of
each drug should be charged.
46. What is seamless or transmural care? What are the barriers associated with it, especially in
Belgium? (Wat is “naadloze” of transmurale zorg? Wat zijn de hindernissen die hiermee
gepaard gaan, specifiek in België)
transmural care = seamless care difference between home medicines and hospitalization
Transfer of information is needed
Recording: what the patient takes medicines at home?
prescription drugs without a prescription, vitamins, nutritional supplements etc
dismissal: what drugs should be continued and how?
all drugs should be taken into account for the recording?
drugs which have to be added to the therapy? How and for how long?
important role for communication!
hospital pharmacist may only supply medicines for 3 days after the resignation to bridge the weekend. Then
be gone himself to the home pharmacy
47. Discuss the financial “life cycle” of drugs including the implications for the pharmaceutical
company. (Bespreek de “financiële levenscyclus” van het geneesmiddel inclusief de gevolgen
voor farmaceutische bedrijven)
Who decides on the price of drugs?
• Licence to get a drug launched on the market (VHB)
– Ministry of Health Care (registration and approval of
scientific summary of product characteristics)
• Setting of the price
– Ministry of Economic Affairs
– Reimbursed drugs
After advice from the Prijzencommissie voor de Farmaceutische
specialiteiten
– Non reimbursed drugs or drug not on prescription
After advice from the Bestendig Comité van de Commissie tot
Regeling Der Prijzen
Point of view of the company:
Financing and lifecycle of reimbursed drugs
• Starting from original basis of reimbursement
• After patent:
– If no cheaper drug available (no generic available)
• After 12 yrs reimbursement: - 15 %
• After 15 yrs reimbursement: - 2,35 %
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– If generic available-> price is changed into ‘reference
reimbursement’
• Generic: per definition 30% cheaper than original, original
gets also ‘reference reimbursement’
• Afterwards:
– Reimbursement > 12 jaar: -17 % extra
– Reimbursement > 15 jaar: - 1,19 % extra
Point of view of the company:
Financing and lifecycle of a drugs
• Pricesetting is in the end…
– Reference reimbursement (30% lower than
original pricesetting)
– Extra decreases in function of duration of
availability on the market
-> in the end: price can be > 40 % lower than
original price
48. Give an overview of the reimbursement of drugs for ambulatory patients, depending on the
“category” and “chapter” they are in (provide examples). (Bij de terugbetaling van
geneesmiddelen wordt een onderscheid gemaakt tussen verschillende “categorieën” en
“hoofdstukken” van geneesmiddelen. Bespreek)
three prizes based on the type of patient
for patients in public pharmacy--------public prices
for ambulatory patients in the hospital---------- Ambulatory patients in hospital (day care patients,
e.g. cancer patients receiving chemotherapy in daycare)rates (*)
for hospitalized patients who stay at least one night in hospital-------hospitalized prices (**)
drugs are divided into categories: each category represents a different percentage of repayment
category A
live saving drugs (insulin and antidiabetics, anti-epileptics, cytostats)
category B
important therapeutic drugs (antibiotics, Antihypertensives)
category C, Cs, Cx
drugs for symptomatic use (Acetylcystein, hormonal anticonception)
category D
not reimbursed
deciding which category a drug should be made by the minister of social affairs and health care based
on a proposal and opinion of the CTG.
drugs are categorized into chapters: each chapter represents a different criterion of repayment
49. Give an overview of the existing options in Belgium to make drugs available to patients free of
charge. What are the restrictions and requirements? (Welke mogelijkheden bestaan er in België
om een geneesmiddel gratis ter beschikking te stellen van een patiënt? Wat zijn de beperkingen
en vereisten?)
Drugs disposed for ‘free’
• Compassionate use
• Medical need
• Medical monsters (samples)
To make drugs available, for reasons of
compassion, following a centralized procedure for
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patients suffering from:
– Chronic illnesses
– Life threatening illnesses
For the drug being distributed by CU should
the registration file be submitted or should
the clinical trials be ongoing
Requirements for CU
• Drug not yet approved in any indication
• Drug delivered free to the patient
• Company should inform
– The government (FAGG)
– Ethical committee of the hospital where the
patient is treated
• Treating physician can apply for CU at the
company
Medical Need Program (MNP)
‘Medisch noodprogramma’
• Same definition as for CU
• Same requirements as for CU
• But….
– Product is currently under approval for other indications than
indications used in medical need program
• Product should be labeled with “MNP – can not
be sold”
Medical samples
• Requirements (KB 1 January 1993)
– Only for drugs approved and available on the
market
– Not bigger than smallest package available
– Product should be labeled with ‘Free sample – can
not be sold’
– No samples permitted for:
• Narcotics, psychotropics, drugs containing isotretinoin
Physician
– Written apply by physician
– Max amount of samples per year per physician
(600) and max 8 per drug per prescribing
physicians
• Company: should document
– Number of samples per physician
– Annual report of samples to FAGG
50. Which are the most important procedures available in Europe for the registration of new drugs?
Which are the pros and cons of each procedure? (Geef een overzicht van de procedures die
kunnen gevolgd worden om een geneesmiddel te registreren in Europa, inclusief de voor- en
nadelen van de verschillende procedures.)
REGISTRATION FOR NEW MOLECULES IS PRIMARILY DONE
AT PAN-EUROPEAN LEVEL
1° Centralized Procedure : CP
2° Mutual Recognition Procedure : MRP
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Consists of : single application to the EMA
CENTRALISED PROCEDURE (CP)
EMA : European Medicines Agency)
CHMP : Committee for Human Medicinal Products (2 Members/MSs)
(responsible for preparing the Scientific Opinion on the evaluation of
the product).
� Leads to : single evaluation by the CHMP
single marketing authorisation valid
throughout the EU with unique Tradename
and common Labelling (SmPC/PL)
� Compulsory for all medicines derived from biotechnology or
other high tech processes, as well as for medicines for the
treatment of HIV/AIDS, cancer, diabetes, neurodegenerative
disorders, (auto) immune dysfunctions and viral diseases
one application
one approval for the whole EU
10 years exclusivity in all Countries
Consensus by majority vote
Centralised Procedure: PROS & CONS
CONS
“all or nothing”
Rapporteurs selected by the CHMP
tradename must be the same in all countries
Very limited time for Country organizations to deliver translations
Mutual Recognition Proceudre
The opportunity to choose the Reference Member State
The ability to launch the medicinal product early in the RMS (rare)
The option to withdraw an application in a concerned member state
without jeopardizing the application in the rest of the EC
Possible use of different trademarks
Mutual Recognition : PROS & CONS
CONS
Instead of pure mutual recognition of RMS assessment, all CMSs are
again assessing the registration file, which leads to many
queries/objections
Major objection in one (or more CMS) can lead to withdrawal in those
countries
51. Provide an overview of the tasks of a medical department within a pharmaceutical company.
(Geef een overzicht van de taken van een medisch departement)
Medical department is responsible for research and development: is global, with other countries, regions
regulatory: european is regulated
access (reimbursement) is regulated national
commercialization: national is usually regulated
research and development
role of the medical department of clinical development in this is global
Collect data over the world and use this data
-provide input into the development of the protocol
based on feedback from regulators, access Authorities and specialized centers, personal knowledge.
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-selecting clinical sites for study participation
based on the protocol
it looks at expertise, interests, resources, infrastructure ...
-ensure regular follow-up of clinical sites
fidelity to the protocol, GLP is checked
the further you go in the development, the more your costs go up exponentially
there are low detection ratios but high development failure ratios
reasons of failure:
early safety problems
complicated dosing
interactions
efficiency problems
side effects
lack of medical benefit
impractical to make it
the cost of developing a drug to rise, you could used with a certain sum of money to develop more drugs.
Now costs 1 molecule develops more than one billion U.S. dollars.
the investment is so great and the risk is that it is no longer possible for a small business to these costs and
risks to assume. There is a need for collaborative approaches. Academic results are shared with the
industry. The industry has a reputation as 'the devil' to be academia 'Angel', but there is need full
transparency on both sides.
52. Give an overview of the reimbursement procedure for drugs in Belgium. What is the role of the
commission for the reimbursement of drugs (CTG/CRM) in Belgium? What is the role of the
different ministries? (Geef een overzicht van de terugbetalingsprocedure van geneesmiddelen in
België met bijzondere aandacht voor de rol van de Commissie Tegemoetkoming
Geneesmiddelen. Wat is de rol van de verschillende ministeries?)
1. is the pharmaceutical compound granted access to the market?
= registration of compound
FAGG (federal ministry of health)
effectiveness, safety, quality
generally European registration
2. at what maximal price setting?
ministry of economical affairs
pricing commission for pharmaceutical compounds
3. to be reimbursed by the health care insurance?
ministry of social affairs
commissie tegemoetkoming geneesmiddelen (CTG)
main tasks:
provide a proposal to the minister concerning reimbursement criteria for an individual compound
(indications, reimbursement category, price, based on scientific and pharmaco-economic evaluation)
advice to the minister at his/her demand concerning pharmaceutical reimbursement policy
composition:
academics, sickness funds, physician and pharmacist organizations, industry, experts from RIZIV
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