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