1st Master Biomedical Sciences Pharmaceutical Medicine Exam questions 2013 Questions of which 2 will be part of the examination



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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

 final choice and start: based on all elements, is decided by top management





  1. 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



  1. 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

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


  1. 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

-nernst-brunner equation:

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

 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





  1. 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





  1. 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?).

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


  1. 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





  1. 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

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



  1. 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



  1. 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 (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.





  1. 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
 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


  1. 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
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.


  1. RCT and trial design: cross-over versus parallel group design. Discuss. (RCT studie ontwerp: cross-over onderzoek versus parallel groep onderzoek. Bespreek.)




  1. Discuss “internal” versus “external” validity in the context of clinical trials. (Bespreek “interne” versus “externe” validiteit” in de context van klinische studies)




  1. 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. 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 water-soluble 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.





  1. 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?
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 2nd 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:

(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).




  1. 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).



  1. 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.)




  1. 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
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



  1. 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.




  1. 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 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



  1. 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



  1. 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.)



  1. 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).



  1. 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.



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