1st Licentie Biomedische Wetenschappenwikimedica.medica.be/wiki/images/4/4a/Pharmaceutical_medicine… · Web viewTo ensure that in the classification of the groups no difference

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 doneunmet 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 latergap analysis analysis of the gap between reality and ideal

market analysis identification of opportunities and threatscurrent situation gt future prospects

company strategy and competenciesbalance the strength and weaknesses

what do we want and what can we doSWOT analysis

-scientific and technical is it feasible can it be donescientific opportunity

solid scientific baselead for innovation

competitive advantagefirst in classfast followerbest in classme toobe better

expected difficultiesacute vs chronic diseaseslife threatening vs comfort diseasescurative vs preventive indicationshard vs surrogate end points

patent protection-operational can we do it

necessary resourcesstaff and expertiseequipment materialcapital

timescaleplanning

1ste Master Biomedical Sciences Pharmaceutical Medicine questions version 21 May 2013 1

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 findingeither through screening

high troughput systemsbig chemical libraries of pharma companiesor chemical librariers of natural products

combinatorial chemistrysynthesis of relatively large number of products

either through de novo design (CADD = computer assisted drug design)ligand based

endogenous ligand is leadsynthetic ligands

pharmacophore modelquantitative structure activity relationship (QSAR)

target basedx-ray crystallography or NMR spectroscopy of targetsdocking of small molecules in 3D model of target

2)lead optimalisationaim 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 designiterative 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 criteriaselectivity and strength vs targetappropriate pharmacokineticsrelevant pharmacological activity

in vitro and in vivoacceptable safety profilechemically stable compatible with expected formulationlarge scale production possiblepatent protection ok

for example selection criteria for drug candidates intended for oral usechemical

patentable structurewater solublechemically stable


large scale synthesis feasiblenon chiralno known toxophoric groups

pharmacologicaldefined potency on targetselectivity for specific target relative to other related targetspharmacodynamic activity in vitro and in vivono adverse effects in standard safety pharmacology testsactive in disease models

pharmacokineticcell-permeable in vivoadequate oral bioavailabilityfor CNS drugs penetrates blood brain barrierappropriate plasma half lifedefined metabolism by human liver microsomesno inhibition or induction of cytochrome p450

toxicologicalin vitro genotoxicity tests negativepreliminary 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 permeableclass II not soluble permeableclass III soluble not permeableclass 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 agentssurfactants 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 coefficientlog P log D (pH dependent)indicaton of lipophilicity or hydrophobicityindication of in vivo absorption (passive diffusion)n-octanol is solvent of choicepartition 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 spacemelting pointthermodynamically stablepreferential state of matter

amorphous chaotic arrangements of molecules comparable to liquid

thermodynamically unstablenon equilibrium materialhigher chemical reactivityno 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 ratehellip 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 ratehellip 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

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 ndash absorption potentialAPI must be absorbed in the system to be active

in vitro in vivo in situ methods availablefor example PAMPA (parallel artificial membrane permeation assay)

advantages no animalshigh throughputrelatively inexpensivedifferent lipid compositioins

disadvantagesonly partially predictivemembrane retention of lipophilic compoundsperformance is strongly dependent on lipid

composition pHfor example CaCo-2 cell culture

human colon adenocarcinomaspontaneous enterocyt differentiation in cultureconfluent monolayerexpression of certain brush border enzymes and phase2 enzymesno CYP3A4active transport systemesadvantages excellent screening model

no bioanalysisevaluation of transport mechanisms and absorption

strategiesevaluation of toxicityno animalshuman originghigh throughput

disadvantagesno mucusunstirred water layertight monolayerlow expression of certain uptake transportersstatic 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)


filter diluentto install the correct tablet weightfor example lactose cellulose

binderto keep individual particles together after compressionfor example starch cellulose derivatives

disintegrantdisintegration of tablet after contact with GI fluidsfor example cross-linked polymers (crospovidone) starch

flow promoterimprovement of flow properties (homogeneous dosing)

for example talcwetting agent

improvement of contact between aqueous environment and solidfor example polysorbate

lubricantdecrease of friction forces during compression compaction ejectionfor example Mg-stearate

7 What does ldquoan oral controlled drug delivery systemrdquo refer to What are the advantages and disadvantages of these systems (Wat wordt er bedoeld met een toedieningsvorm met ldquoorale gecontroleerde vrijstellingrdquo 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 comfortreduced side effectscontrollable 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 strategieeumln worden gebruikt om geneesmiddelen met een ldquoorale gecontroleerde vrijstellingrdquo te maken)

based on dissolution and diffusionreservoir systems

insoluble coatingslowly dissolving coating pH dependent coatingdiffusion of dissolved API through coating

layered systemsbead layering

API + polymer 1rate controlling polyper membrane


API + polymer 2inert core

matrix system insoluble matrix

diffusion of dissolved API through insoluble matrixerodable or slowly dissolving matrix

API is released mainly during erosion or dissolution of the matrix former

based on bioadhesionbuccal tablet

bioadhesion via cross-linked polyacrylic acidbased on osmosis

osmotically active corepolymeric push compartmentpolymer membrane

GI fluid enters dosage formpolymer in push compartiment swellsswollen 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 cregravemes en zalven)

suspensions is a homogeneous dispersion of a solid in a liquidis 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 doseso homogeneous distribution of API in suspension medium

excipients wetting agent viscosity increasing agentsadequate particle size of API stokes

stability cakingparticles must remain at a certain distance from each other

structured mediuminteraction between particles at secondary medium

electrolytes + polymers electrostatic and sterical stabilisationcreams made up of a water phase and oil phase

an emulsion water in oil or oil in water stability use emulsifiercomposition API aqueous phase oil phase emulsifying agent viscosity increasing compounds moisturizers penetration enhancers fragrances perfumeshellip

ointmentsstability use emulsifyercomposition 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


(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 (eg 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 eg derived from in-vitro studies An additional safety factor is usually applied to reach a low enough dose (ie 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 PKPD 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 doseexposure-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 PKPD 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 addressedStudy 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 componentsmale (possibly female) Objectives securitytolerance (dose range MTD)pharmacokineticspharmacodynamicsduration 6 to 12 months Types of phase I studiesfirst in man first in human studiespharmacokinetic studiessingle dose multiple dosebioequivalence studiesinteractionspharmacokinetic pharmacodynamic studiesQT interval studies


these are considered as the traditional studiesNow there are new developmentsPhase 0 trials microdosing PET studiesexploratory clincial trial applicatoinsproof of concept studiestranslational modelsPhase Ib IIa studies

Phase IIPilot 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 efficacytolerance (dose range MTD)Safety therapeutic window therapeutic indexpharmacokineticspharmacodynamicsduration 12 to 24 monthsshort duration referred to as GM for short durationlong duration referred to as GM for chronic usethere must be a necessity for the drugeg development of a GM that is better than its competitorsthe target selection is based on a high risk or low risk= high risk speculative research targetstart from a new target to validatemaybe it is not workingbut if so then first in class (blockbuster)low risk = innovative improvementincrease potencyincrease selectivityincrease safety marginme too drugmust be in competition with a known drugtarget 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 safetyconfirming indications and dosageduration 2 to 7 yearshigh risk populations studiesNDA (new drug application) to servePhase IIIa NDA submission for


Phase IIIb After NDA submission and approval of marketingwhat should be measured

surrogate endpointsyou can not take mortality as an endpoint because then you have a very long waittherefore surrogate endpointsthese are predictors of mortalitybe substitutes for clinically meaningful endpointstherapy-induced changes in a surrogate endpoint reflect changes in a clinically meaningful endpointbut be careful because a surrogate is only a surrogatetrial designsuperiority trialin order to detect differences between treatmentsequivalence trialto confirm the absence of a difference (show that a drug is the same than what already exists this is statistically very difficult)non-inferiority trialin order to show that a treatment at least as effective as any otherto 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 ldquointernalrdquo versus ldquoexternalrdquo validity in the context of clinical trials (Bespreek ldquointernerdquo versus ldquoexternerdquo validiteitrdquo in de context van klinische studies)

15 Why are the elderly a high risk population for the use of drugs (Waarom zijn bejaarde patieumlnten 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 changesa) The bioavailability with aging a decreased first-pass effect is to be expected As a result the bioavailability of high extraction pharmaceuticals (eg propranolol lidocain) is increased On the other hand activation of pro-drugs is delayed (eg 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 (eg 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 increasedc) Renal clearance lower renal function results in a decreased renal clearance of water-soluble pharmaceuticals (eg some antibiotics diuretics digoxin lithium and NSAIDs) For pharmaceuticals with a narrow therapeutic range this should be taken into accountd) 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 drugsthat work in the central nervous system and the cardiovascular system (eg 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 (ldquostart low go slowrdquo)(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 hisher 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 ldquocomplaintsrdquo 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 andor spermatozoa by cytostatics or reversible side effects such as for example a reduced sperm count due to salazopyrinDuring 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 productionfeeding


Pregnancy blastogenesis embryogenesis and fetogenesisWhen 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 ldquochildrdquo 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 wasnt until the 1960s 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 Eg 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 (eg 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 mothers 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 (eg 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

LactationMost 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 ldquolactation categoriesrdquo 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)

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 andor other pharmacodynamics effects of one or more investigational medicinal product (IMP) andor 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

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 ECrelevance to the trialrisk benefit analysisprotocolsuitability of researchers and staffclinical investigators brochurequality of facilitiesICFvolunteers feeinsurancefinancial agreements contractssubject recruitment

In a multicentre trial single opinion from central ECleading central ECpriority for a university ECselection by sponsor and participate morelocal ECquality of facilitiesICFsuitability 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


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 Belgieuml kan gestart worden In welke mate is deze procedure anders voor een niet-interventionele proef)







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 ldquokwetsbare populatiesrdquo 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)


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 mgkg) 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 (ie 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 enzymesThe 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 12 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 (ie milligrams per kilogram of body weight) of the drug to achieve therapeutic plasma levels CYP2C9 and to a lesser extent


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 (ie that accounted for by MichaelisndashMenten 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 enzymesThe ontogeny of conjugation reactions (ie 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 (eg 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


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 (eg 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


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 (ldquodesignrdquo) 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 case-control studies case series and case reports editorials and expert opinion

study design = observational and descriptivecase report

reporting about 1 case observationfrequently a rareunusual observationconcept is challenge dechallenge and rechallengepro cheap

easyhypothesis generating

con little evidence for causalitydoes not allow hypothesis testing

case seriespooling of cases number of caseshoe meer ik het observer hoer meer ik geloof date r een causale relatie ispro estimation of incidence

hypothesis generatingcon little evidence for causality

no control populationno hypothesis testing

study design = observational and analyticalcase 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 ratiopro rare and late responses can be investigated

multiple exposures can be investigatedeasy quick cheapstatistiek is mogelijk

con sensitive to bias (vertekening afwijking van de waarheid)selection bias groep is niet representatief voor de hele populatieinformation bias incomplete informatierecall bias de personen herinneren zich niet meer alle informatie mensen die meer lijden zullen het zich waarschijnlijk gemakkelijker herinneren

confoundingverwarring ivm multiple parameters cohord

comparison of exposed with non exposed in case exposed subjects display higherlower incidence of a consequence the possibility exists of an association between exposure and consequencepro multiple responses can be investigated

rare exposures can be investigatedno historical controls (if prospective)information about incidence

con large groups are requiredselection biaslong lasting expensive in case of late or rare responses


RCTis 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 confoundersmost powerful research in statistical terms

con limited number of participantslimited exposure and follow up on timeInclusion and exclusion criteriaartificialexpensivelogistically demandingethical concerns

study design = meta analysisa meta-analysis is a systemic review of multiple RCTsby 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

pro very powerful statistical method


con cave publication bials

28 Provide an overview of the production process of biologicals (Bespreek het productieproces van biologicals)

Production of recombinant proteinUnicellularsystem BacteriaYeastMammalianMulticellular system Transgenic plant Transgenic animal

gene of interst+ plasmids-gt restriction enzymes after that we use DNA ligase to do the cloning(usually we have also a selection gene then we pick the recombinantcell line and we do a cell culture recombinant cells express desire protein

characterization and stabilityCell bank-gt Fermentation-gt Purification-gt Purified protein

29 What are the most important differences between ldquosmall moleculesrdquo and ldquobiologicalsrdquo (Bespreek de belangrijkste verschillen tussen ldquosmall moleculesrdquo en ldquobiologicalsrdquo)

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 (eg peptides proteins antibodies) but can also be cells and tissue However in most cases the term ldquobiologicsrdquo 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 tfrac12 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 (ADArsquos) against the biological compound The formation of these ADArsquos 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 ldquobiosimilarsrdquo Why was this concept introduced What is the difference between a generic (small molecule) drug and biosimilars (Wat wordt er bedoeld met ldquobiosimilarsrdquo 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 amp 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 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 lsquoan 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 lsquoan 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 geiumlnformeerde toestemming voor deelname aan een klinische studie (ie the ldquoInformed Consentrdquo 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 subjectrsquos 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 ICF2 Use simple words non-technical simple and practical language3 Answer questions provide the subject with ample time and opportunity to ask any

question all questions must be answered to subjectrsquos satisfaction4 Give time ample time to decide whether or not the subject wants to participate

without coercion or unduly influence5 Signature the subject and person who conducted the informed consent discussion

sign and personally date6 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


en verantwoordelijkheden Zijn er verschillen tussen wat de GCP richtlijn hierover zegt en de Belgische wet inzake experimenten op de menselijke persoon)

IRBIEC stands for Institutional Review BoardIndependent 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 IRBIEC 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 IRBIEC 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 IRBIEC members and qualifications should be maintained

The IRBIEC 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 sponsorrsquos 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 sponsorrsquos 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 QAQC 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


Difference from audit an audit is a sponsor quality system by sponsorrsquos 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 lsquodoses normally usedrsquo 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 dechallengerechallengerespons 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 ldquoseriousrdquo (Farmacovigilantie wat is het verschil tussen een ldquoongewenst voorvalrdquo en een ldquobijwerkingrdquo (vergelijk ook met de definities in de Belgische wetgeving) Wat maakt dat een ldquoongewenst voorvalrdquo of ldquobijwerkingrdquo als ldquoernstigrdquo 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 lsquodoses normally usedrsquo 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 administeredunexpected 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


with the applicable product informationsuspected 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 informationAn 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 treatmentSerious 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 unclearhellip)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 organizationhellipPurpose 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 etcDSMP 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 protocolConclusion 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 (ie pharmacovigilance) during (1) the premarketing period and (2) after bringing the drug onto the market (Bespreek enkele belangrijke beperkingen van de veiligheidsevaluatie (ie farmacovigilantie) van een


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 Belgieuml georganiseerd)

the objectives of pharmacovigilance aredetection of new ADRs (unknown) and increase the frequency of known ADRsidentification of risk factors and mechanisms that are at the basis of the occurrence of

ADRsevaluation of continuous reevaluation of the risk-benefit balance of medicinescommunication 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 ldquouitdagingenrdquo wordt de post-marketing geneesmiddelenbewaking geconfronteerd)

underreportingdepending on the source only 1-5 ADRs are being reportedless reports from hospitalsonly 1 ADRs led to hospitalization are reported

consequences incomplete databasesunderestimation incidence ADRslate signal detectiondifficult for correct evaluation of risk-benefit balance

total number of exposed patients is not exactly knownvariable reporting frequency in time

unbalance in reportspercentage reports directly submitted to BCPH by HCPs is low compared to reports received from pharmaceutical industry (in Europe it is the opposite)

incomplete reportspart of the yellow cards is incomplete report is difficult to evaluate and to encodeimportant 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 ADRshuman 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


The trade specialty or brand (specialty name) is the brand name under which the drug is registered and soldΝΑ ΔΙΑΒΑΣΩ ΠΑΡΑΔΕΙΓΜΑΤΑ

Brand names may differ depending on the country

Same active substance may be registered under several brands

INN intrenational nonproprietary namesidentification of pharmaceutical substancesunique public namegeneric name

requirements for classification of drugsconditionseasily recognizable namesnot too longminimal risk for error confusion mixed with other medicinaluseful in all languagesnames in the same drug class usually start or end with the same vowelsometimes usefulsometimes confusingthe proposed names are published by the WHOcan be criticized comments are given for 4 months

43 Discuss the difference between ldquooff labelrdquo and ldquounlicensedrdquo use of drugs and illustrate with an example (Bespreek het verschil tussen ldquooff label userdquo en ldquounlicensed userdquo van geneesmiddelen en geef een voorbeeld)

off label useuse for indications other than those approved (by the FDA EMA)for example the use of intravenous immunoglobulins in Staphyloccus septic shockeg the use of rituximab in patients with idiopathic thrombocytopenic purpuraeg using enoxaparn as a thrombo-prophylaxis in patients neurochirugische

unlicensed usethe 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 chargeeg 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 ldquocold chain management Geef een voorbeeld)

Management of guaranteeing the adequate storage of drugs even if they have to be keptat special temperatures Should be adequate for the hellipbull Original product (storage in the company storage duringtransportation storage in the pharmacy and on the wardsatpatientrsquos home)bull After reconstitution and dissolution

All fridges and freezers are connected with an alarmsystemQuality of pharmaceutical products is of primary concern Chemical and physico-chemical stability depends on temperature


45 What is ldquopolypharmacyrdquo 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 daysimultaneous use of multiple drugsAssociated 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 ldquonaadlozerdquo of transmurale zorg Wat zijn de hindernissen die hiermee gepaard gaan specifiek in Belgieuml)

transmural care = seamless care difference between home medicines and hospitalization

Transfer of information is neededRecording what the patient takes medicines at homeprescription drugs without a prescription vitamins nutritional supplements etcdismissal what drugs should be continued and howall drugs should be taken into account for the recordingdrugs which have to be added to the therapy How and for how longimportant role for communicationhospital 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 ldquolife cyclerdquo of drugs including the implications for the pharmaceutical company (Bespreek de ldquofinancieumlle levenscyclusrdquo van het geneesmiddel inclusief de gevolgen voor farmaceutische bedrijven)

Who decides on the price of drugsbull Licence to get a drug launched on the market (VHB)ndash Ministry of Health Care (registration and approval ofscientific summary of product characteristics)bull Setting of the pricendash Ministry of Economic Affairsndash Reimbursed drugsAfter advice from the Prijzencommissie voor de Farmaceutischespecialiteitenndash Non reimbursed drugs or drug not on prescriptionAfter advice from the Bestendig Comiteacute van de Commissie totRegeling Der Prijzen

Point of view of the companyFinancing and lifecycle of reimbursed drugsbull Starting from original basis of reimbursementbull After patentndash If no cheaper drug available (no generic available)bull After 12 yrs reimbursement - 15 bull After 15 yrs reimbursement - 235


ndash If generic available-gt price is changed into lsquoreferencereimbursementrsquobull Generic per definition 30 cheaper than original originalgets also lsquoreference reimbursementrsquobull Afterwardsndash Reimbursement gt 12 jaar -17 extrandash Reimbursement gt 15 jaar - 119 extra

Point of view of the companyFinancing and lifecycle of a drugsbull Pricesetting is in the endhellipndash Reference reimbursement (30 lower thanoriginal pricesetting)ndash Extra decreases in function of duration ofavailability on the market-gt in the end price can be gt 40 lower thanoriginal price

48 Give an overview of the reimbursement of drugs for ambulatory patients depending on the ldquocategoryrdquo and ldquochapterrdquo they are in (provide examples) (Bij de terugbetaling van geneesmiddelen wordt een onderscheid gemaakt tussen verschillende ldquocategorieeumlnrdquo en ldquohoofdstukkenrdquo van geneesmiddelen Bespreek)

three prizes based on the type of patientfor patients in public pharmacy--------public pricesfor ambulatory patients in the hospital---------- Ambulatory patients in hospital (day care patientseg 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 repaymentcategory Alive saving drugs (insulin and antidiabetics anti-epileptics cytostats)category Bimportant therapeutic drugs (antibiotics Antihypertensives)category C Cs Cxdrugs for symptomatic use (Acetylcystein hormonal anticonception)category Dnot reimburseddeciding 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 Belgieuml om een geneesmiddel gratis ter beschikking te stellen van een patieumlnt Wat zijn de beperkingen en vereisten)

Drugs disposed for lsquofreersquobull Compassionate usebull Medical needbull Medical monsters (samples)

To make drugs available for reasons of


compassion following a centralized procedure forpatients suffering fromndash Chronic illnessesndash Life threatening illnessesFor the drug being distributed by CU shouldthe registration file be submitted or shouldthe clinical trials be ongoing

Requirements for CUbull Drug not yet approved in any indicationbull Drug delivered free to the patientbull Company should informndash The government (FAGG)ndash Ethical committee of the hospital where thepatient is treatedbull Treating physician can apply for CU at thecompany

Medical Need Program (MNP)lsquoMedisch noodprogrammarsquobull Same definition as for CUbull Same requirements as for CUbull Buthellipndash Product is currently under approval for other indications thanindications used in medical need programbull Product should be labeled with ldquoMNP ndash can notbe soldrdquo

Medical samplesbull Requirements (KB 1 January 1993)ndash Only for drugs approved and available on themarketndash Not bigger than smallest package availablendash Product should be labeled with lsquoFree sample ndash cannot be soldrsquondash No samples permitted forbull Narcotics psychotropics drugs containing isotretinoinPhysicianndash Written apply by physicianndash Max amount of samples per year per physician(600) and max 8 per drug per prescribingphysiciansbull Company should documentndash Number of samples per physicianndash 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 DONEAT PAN-EUROPEAN LEVEL1deg Centralized Procedure CP2deg Mutual Recognition Procedure MRP


Consists of single application to the EMACENTRALISED PROCEDURE (CP)EMA European Medicines Agency)CHMP Committee for Human Medicinal Products (2 MembersMSs)(responsible for preparing the Scientific Opinion on the evaluation ofthe product)1048766 Leads to single evaluation by the CHMPsingle marketing authorisation validthroughout the EU with unique Tradenameand common Labelling (SmPCPL)1048766 Compulsory for all medicines derived from biotechnology orother high tech processes as well as for medicines for thetreatment of HIVAIDS cancer diabetes neurodegenerativedisorders (auto) immune dysfunctions and viral diseases

one application one approval for the whole EU 10 years exclusivity in all Countries Consensus by majority voteCentralised Procedure PROS amp CONSCONS ldquoall or nothingrdquo 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 statewithout jeopardizing the application in the rest of the EC Possible use of different trademarksMutual Recognition PROS amp CONSCONS Instead of pure mutual recognition of RMS assessment all CMSs areagain assessing the registration file which leads to manyqueriesobjections Major objection in one (or more CMS) can lead to withdrawal in thosecountries

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 regionsregulatory european is regulatedaccess (reimbursement) is regulated nationalcommercialization national is usually regulated

research and developmentrole of the medical department of clinical development in this is globalCollect 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-selecting clinical sites for study participationbased on the protocolit looks at expertise interests resources infrastructure -ensure regular follow-up of clinical sitesfidelity to the protocol GLP is checkedthe further you go in the development the more your costs go up exponentially

there are low detection ratios but high development failure ratiosreasons of failure early safety problemscomplicated dosinginteractionsefficiency problemsside effectslack of medical benefitimpractical 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 US 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 (CTGCRM) in Belgium What is the role of the different ministries (Geef een overzicht van de terugbetalingsprocedure van geneesmiddelen in Belgieuml 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 compoundFAGG (federal ministry of health)effectiveness safety qualitygenerally European registration

2 at what maximal price settingministry of economical affairspricing commission for pharmaceutical compounds

3 to be reimbursed by the health care insuranceministry of social affairscommissie tegemoetkoming geneesmiddelen (CTG)

main tasksprovide 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 hisher demand concerning pharmaceutical reimbursement policy

compositionacademics sickness funds physician and pharmacist organizations industry experts from RIZIV


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 findingeither through screening

high troughput systemsbig chemical libraries of pharma companiesor chemical librariers of natural products

combinatorial chemistrysynthesis of relatively large number of products

either through de novo design (CADD = computer assisted drug design)ligand based

endogenous ligand is leadsynthetic ligands

pharmacophore modelquantitative structure activity relationship (QSAR)

target basedx-ray crystallography or NMR spectroscopy of targetsdocking of small molecules in 3D model of target

2)lead optimalisationaim 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 designiterative 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 criteriaselectivity and strength vs targetappropriate pharmacokineticsrelevant pharmacological activity

in vitro and in vivoacceptable safety profilechemically stable compatible with expected formulationlarge scale production possiblepatent protection ok

for example selection criteria for drug candidates intended for oral usechemical

patentable structurewater solublechemically stable































































































































Belgian law scope




















































































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Belgian law scope




















































































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Belgian law scope




















































































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Belgian law scope




















































































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Belgian law scope




















































































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Belgian law scope




















































































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Belgian law scope




















































































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Belgian law scope




















































































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Belgian law scope




















































































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Belgian law scope




















































































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Belgian law scope




















































































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Belgian law scope




















































































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study participation








































































































































































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Documents

1st Licentie Biomedische Wetenschappenwikimedica.medica.be/wiki/images/4/4a/Pharmaceutical_medicine… · Web viewTo ensure that in the classification of the groups no difference