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Elke Claerhout Pharmaceutical Medicine 1e M Klinische BMW

1. Drug discovery and design: which selection criteria determine the choice of a project for the development of a new compound?

- Strategic elements: is there an unmet need? Will the need still be there in 15 years? Market analysis: is it desirable to do it? The company needs to balance its strengths and weaknesses. What do we want to do and can we do it?

- Scientific and technical elements: o Scientific opportunity; lead for innovation?o Competitive advantage; first in class, fast follower or best in class.o Expected difficulties; acute vs chronic disease, life threatening vs comfort disease,

curative vs preventive, hard vs surrogate endpoints.o Patent protection

- Operational elements: can we do it? Do we have the necessary resources, how about the timescale and planning? This is why the final decision is made by top management and not by researchers.

2. Discuss the role of pharmacochemistry in drug discovery and design.

Main goal: lead finding and lead optimization.

- Lead finding: through screening. In high-throughput systems or by combinatorial chemistry.- Lead finding: through de novo design (CADD in 3D); ligand based (analyse the endogenous

ligand and reinvent a new one) or target based (use the target 3D structure to find a ligand).Don’t forget Lipinski’s rule of 5.

- Lead optimization: improve the biological activity of the one lead we have selected/created. Many variables need to be taken into account, this makes it the hardest step of DDD. Variables: PK, stability, chirality, ease of synthesis, patent protection, formulation, genotoxicity,… make iterative adaptations.

3. Drug discovery and design: which criteria determine the choice of a candidate drug of further non-clinical and clinical development?

The product selected for further non-clinical and clinical development is chosen based on following criteria:

- selectivity and strength vs target- appropriate PK- relevant pharmacological activity (in vitro and in vivo)- acceptable safety profile- chemically stable and drugable- large-scale production is possible- patent protection is okay- microdose studies in humans (phase 0)

Very early on there is a multidisciplinary (chemists, pharmacologists, pharmacokinetics, toxicologists) approach needed. If drugs fail, they need to fail early.

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4. Provide an overview of the physicochemical aspects which are part of the pre-formulation phase of a drug.

- Solubility (eg. can be enhanced by cyclodextrines), determines the route of administration and formulation strategy.

- Intrinsic dissolution rate (= a constant for each API), relevant for oral intake drugs.- Ionisation behaviour (determined by pKa), influences the bioavailability in vivo.- Partition coefficient (hydrophilic or lipophilic), affects the absorption potential.- Solid state properties of the API (crystalline/amorphous, influences the characteristics of the

substance, can be measured by DSC or X-ray diffraction) (polymorphous, pseudopolymorphous)

- Stability of the API (in solid state or solution and compatibility with excipients)

5. Provide an overview of the biopharmaceutical aspects which are part of the pre-formulation phase of a drug.

Permeability and the absorption potential, one is dependent on the other. This can be measured in vitro through PAMPA or Caco-2 cell culture. PAMPA is a Parallel Artificial Membrane Permeation Assay. The Caco-2 cell line are human colon adenocarcinoma cells which spontaneously differentiate into enterocytes.

6. What kind of compounds (API and excipients) can be part of a tablet?- Filler diluent: to install the correct tablet weight- Binder: to keep individual particles together after compression- Disintegrant: helps disintegration of tablet after contact with GI fluids- Flow promotor: improvement of flow properties (homogenous dosing)- Wetting agent: improvement of contact between aqueous environment and solid particles- Lubricant: decrease of friction during compression- API

7. What does ‘an oral controlled drug delivery system’ refer to? What are the advantages and disadvantages of these systems?

= systems that enable continuous release of the API in the GI tract during a specified time. (Reproducible and predictable kinetics.)

= systems that enable a controlled residence time of the dosage form or release the API at a specific site in the GI tract.

Advantages: reduced intake needed (when low t1/2), this leads to improved patient compliance and comfort. Reduces side effects due to less fluctuations in plasma concentration of the API (controllable release kinetics).

Disadvantages: more expensive; larger first pass-effect which leads to lower F; once a patient has taken it, there’s no way back (no way to correct the dose); if there is a production mistake, there can be dose dumping.

Examples of systems: see question 8.

8. What kind of strategies can be used to make oral controlled drug delivery systems?- Based on dissolution and diffusion:

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Reservoir systems: insoluble polymer coating (the API dissolves through the coating)Layered systems: bead layering (multiple layers/doses of API can be released with the help of internal rate controlling polymer membranes)Matrix systems: insoluble matrix (based on diffusion of dissolved API through the matrix), erodible matrix (API is released during erosion of the matrix)

- Bioadhesion (buccal tablet, via cross-linked poly-acrylic acid)- Osmosis (osmotically active core + polymeric push compartment)

9. Which elements need to be taken into account during the pharmaceutical development of suspensions, creams and ointments?

A suspension is used when a liquid dosage form is required, but the API is insoluble or the API has low stability in solution. Wetting agents and viscosity increasing agents are needed, plus an adequate particle size of the API. The patients choose the administered dose. Downside: particles need to remain a certain distance from each other to prevent caking. Polymers on the surface can help with this.

Creams are made up of water and oil, so an emulsifier is needed. How do you make it? You apply heat to a thermodynamically instable system. Composition: API, aqueous phase, oil phase, emulsifying agent, moisturizers, penetration enhancers, viscosity enhancers, perfume, …

Ointments contain no water. Surfactants can improve contact between lipid base and API. Composition: API, ointment base (lipids), surfactants, perfumes, …

10. Discuss the principles taken into account when calculating the MRSD for conducting a FIM trial.

MRSD = maximal recommended starting dose

The pharmacological approach:

First you look at the NOAEL measured/observed in animals. Then you check how you should convert this number into a HED (human equivalent dose). Sometimes you just calculate the mg/kg, sometimes you take the body surface area into account and you consult a schedule with conversion numbers per animal. After doing this for both species, you take the lowest HED. A safety factor of x10 is usually used to decrease this number a bit more, to be on the safe side.

The pharmaceutical approach:

We should not forget to take MABEL (minimal anticipated biological effect level) into account. If our corrected factor is still above the dose we get by looking at MABEL, the lower dose should be taken. (Often needed when there is a huge gap between MED (minimal effective dose) and NOAEL. If we correct only by factor 10, it is possible that this dose still falls in the plateau-phase of the drug (PK), which would give maximal therapeutic effect at first-in-men administration.)

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11. Phase I and phase II RCTs. Discuss.

Phase I studies are often conducted in healthy volunteers. Only when AE are unacceptable in healthy persons, patients are used, eg. cytostatics. These studies are safety studies and do not have any therapeutic objectives. People are paid for these trials, as an incentive, because they have nothing (therapeutically or otherwise) to gain from them. Tolerance (toxicity), dose range (MTD), PK,… are endpoints of a phase I trial.

Objective: safety, tolerance (dose range, MTD), PK, no formal statistics. Duration: 6-12 months

Phase II trials are in larger groups of patients. These patients are the intended-to-treat population. Here, showing efficacy is the most important endpoint. After phase II a go/no-go decision needs to be made. This is when we leave the exploratory phases to go to the confirmatory phases (phase III). Also safety and other parameters are being monitored.

Objectives: efficacy, tolerance (MED vs MTD), safety (therapeutic window), PK, PDDuration: 12-24 months

RCT = randomized controlled trial. This means that there will always be a comparison of at least two groups of people. One group will be treated while the other will be the control-group. ‘Placebo’ given to the control group can mean many things: no treatment, standard of care, different dosage, …

12. Phase III RCTs. Discuss.

These are trials done to confirm safety and efficacy established during phase I and II trials. These are large scale and are supposed to be in a population that resembles the real-world population (external validity). (Because there are still many in- and exclusion criteria, this sometimes is not the case and limitations will be mentioned on the label after approval.) After phase III, a file is made to apply for market authorisation; NDA (new drug application).

Objectives: establish efficacy and safety, confirm indications and dosing, investigate high risk populationsDuration: 2-7 years

13. RCT and trail design: cross-over versus parallel group design. Discuss.

RCT = randomized controlled trial. This means that you divide you patients/subjects into different groups in a completely* random way. This corrects for unpredictable and unmeasurable confounding factors. Controlled means that there is one group which gets the treatment you want to investigate, and one group which gets placebo (or standard care). This way it is possible to conclude that associations you find have a causal relationship to your intervention.

Parallel groups: One group gets placebo, the other one the treatment. This remains the same throughout the whole duration of the study.

Cross-over: one group starts as placebo, but after a wash-out period it switches to the treatment arm. This cannot be done for progressive diseases nor for diseases that are lethal in the short run.

- Benefits: less people needed to get more significant statistical results, less interindividual variability (smaller groups needed), each patient gets compared to himself.

- Disadvantages: carry-over effect (washout period is not long enough, patients don’t go back to baseline), period effect (the intensity of the disease might be different in two periods)

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*stratification is allowed, to make sure you don’t put all young women in one group and all old men in the other. You gather several critical parameters about you subjects and randomize them while taking these parameters into account.

14. Discuss internal versus external validity in the context of clinical trials.

Internal: To minimize bias and confounding: randomized, blinded, controlled. Is the clinical trial executed in the correct way? Are we following GLP guidelines?

External: is our patient selection a representative sample. Can we extrapolate the results to the whole population? This can be a problem because of in- and exclusion criteria. (The sample population is artificial and there’s a chance that the sample doesn’t resemble the real population anymore.) Randomisation solves the problem of unknown confounding factors, this helps external validity.

15. Why are the elderly a risk population for the use of drugs?- There’s a big variability within the elderly population- they use many drugs (co-morbidities) –> more chance of interactions- they are older so they have lost functional units: nefrons, alveoli, neurons, … and loss of

regulatory processes.- changes in PK:

Absorption: less first pass metabolism (many drug doses need to be reduced)Distribution: polar drugs have a smaller Vd, non-polar drugs have a larger Vd and a larger half-life. (because of clearance decrease Vd/Cl=t1/2)Renal clearance decreases (TDM is necessary)Hepatic clearance decreases of high ER drugs.

- Their sensitivity increases, on top of everything.

16. Discuss the use of drugs during pregnancy and lactation.

3 phases of pregnancy:- blastogenesis: 1-2w, there’s virtually no contact between mother and foetus. Drugs will not be passed on to the baby, which is a good thing, because the mother doesn’t know she’s pregnant yet.

- embryogenesis: 1st semester, the embryo is very sensitive to all sorts of (chemo)stimulae. The mother should not take any drugs at all. Unless when absolutely necessary. Then the benefit for the mother might outweigh the risk for the baby (eg. anti-epileptics). When necessary, drugs which are known to be safe(st) should be chosen. (See classification system).

- fetogenesis: 2nd en 3rd semester, the baby is less prone to develop deformations because of pharmalogical stimulae. But PD effects must be taken into account. Eg. NSAIDs can close the ductus Botalli prematurely.

Lactation: drugs can accumulate in the breastmilk (even though there usually is no clinical effect in the baby at these doses). Caution when taking drugs. It is best to avoid them.

17. The pharmacokinetics of drugs can be profoundly different between children and adults. Provide an overview of the factors contributing to these differences.

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Because of changes in body form and proportions, each age group should be considered as a special population. There is also great variability among same aged children (much bigger than seen in adults).

- Absorptiono Neutral gastric pH at birth. acidic values at 2y.o Prolonged gastric emptying in new-borns.o Poor bile secretion the first 2-3 weeks.o High intestinal permeability at birth. decreases during first week.o Active transporters are expressed according to the need of the child.o Passive and active transport are matured by 4 months.o Orifice rejection, crying, …o Percutaneous absorption is increased. Toxicity!

- Distributiono Dependent upon body composition (amount of (extracellular) water, fat).o Plasma protein binding; unbound fraction determines pharmacological activity. New-

borns have less plasma proteins. Higher unbound fraction in children.o Children have larger Vd.

- Metabolism and elimination o Microsomal protein content increases with age. However, …o Hepatic clearance can be higher due to higher blood flow to the liver (relatively

larger liver size).o Differences in enzyme expression and activity.o Production of metabolites which are not seen in adults.o Different bacterial colonization in the gut adult like when 1-4 years oldo Immaturity of renal function adult values when 1 year oldo Larger relative size of kidney, high elimination capacity in young childreno Urinary pH is lower (accumulation of weak bases)

18. Paediatric clinical pharmacology: the metabolism of drugs (i.e. biotransformation) depends on a number of co-variables. Discuss these variables and give examples.

a. Microsomal protein content increases with age. Eg. CYP3A4 activity is only complete from the age of 1. Lower doses metabolized by CYP3A4 are needed for younger children.

b. Differences in enzyme expression and activity result in an altered metabolism. Eg. Paracetamol

c. Production of metabolites which are not seen in adults.Eg. Theophylline turns to caffeine in new-borns.

d. Different bacterial colonization of the intestine, changes with age and diet. adult-like when 1-4 years old. Eg. Plays a role when entero-hepatic circulation is needed.

19. What is the objective of the European obligation to make a Paediatric Investigational Plan (PIP) for all new drugs in development?

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Children are not just small adults. Calculation doses for children from adult doses by using age, body weight, body surface, etc. is not a good idea. Also, there is not a single dosing algorithm appropriate for all age ranges.

In 1998 people realized that off-label treatment is more likely to be harmful than well-conducted studies about medicines that are likely to be beneficial. Therefore, they invented the PIP. The PIP must cover all age groups and comes with a reward (longer patent life, funding).

General aim:

- To develop medicines as efficiently and quickly as possible, particularly for serious conditions affecting children

- To support dosing recommendations- To support formulation development

When is PIP mandatory? For new unauthorised drugs under development, for variations of patented authorised medicines and for excipients.

20. Give an overview of the different kinds of study design which are being used in clinical research and pharmaco-epidemiology.

1. Meta-analysis2. RCT3. Cohort study (select people with certain exposures and wait for events)4. Case-control study (select cases and controls and ask what their exposure has been)5. Case-report or case-series6. Editorial, expert opinion

These are written in order of statistical strength (1 is the strongest for which assiociation is most likely causality).

21. Provide an overview of the production process of biologicals.

Overview: you put the desired cDNA sequence in a plasmid. You put the plasmid in a cell (transformation) and produce the desired cell line. The selected cells express the desired protein.

- cell expansion- cell production in bioreactors- recover through filtration or centrifugation- purification through chromatography- characterization and stability

It is very important to keep all the production parameters constant. When these change, the characteristics of the product will change. At different stages, many different quality control analyses need to be done.

22. What are the most important differences between “small molecules” and “biologicals”?

Small molecule Biological Small chemical entity Large, complex biological molecule

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Not or less immunogenic Immunogenic (depends on the production process)

Not or less influenced by production process changes

Extremely sensitive to changes (eg. Temperature influences the glycosylation pattern)

Relatively stable Variable, sensitive to conditions Chemical synthesis Cell culturesDefined structure Heterogeneous structures (many PTM)

23. What are biosimilars? Why was this concept introduced? What is the difference between a generic (small molecule) drug and biosimilars?

What? Biosimilar = a biological medicinal product that contains a version of the active substance of an already authorised original biological medicinal product.

Why? Changes in manufacturing process imply changes in properties (immunogenicity, biological activity, pharmacological properties).

(But even with in the exact same circumstances, there will always be product variants present. Even in a 100% pure solution, there will be a number of variants of the same molecule. Because of the many possibilities of PTM, and because of the extreme sensitivity to environmental influences, there are a very large number of variants possible.)

After the ending of the patent-protected period, other companies can buy your product, analyse it and try to remake it. They can extract the genetic information, but they can’t know your exact production parameters/process. Because different production processes deliver similar biologicals, but not exactly the same molecules, pharmacological similarity needs to be proven.

Generic drug biosimilarWhen A = B and A = C, B = C This is not true for biosimilars. The

equivalence/similarity of B and C needs to be tested.

Identical to reference chemical compound Similar compound, with comparable pharmacological characteristics

Interchangeable (If no TDM) Not interchangeable, needs to be proven separately

Stays the same Divergence over time from the reference product

24. What is the general goal of vaccination and which immunological processes are important to achieve this goal? Discuss.

Purpose: To develop protection against infectious diseases in healthy persons, by means of an irreversible immunological reaction.

How: The innate immunity with its fagocyting, antigen presenting cells + the adaptive immunity with its (memory) B and T cells. B cells produce IgM’s at first contact. After a maturation period of 4 months, the more specific and higher quality IgG’s are produced. Maturation happens with the help of T cells.

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Immune process:

1) interaction with innate immunity. Ag preparation for adaptive immune response2) interaction with adaptive immune system. Ag-specific B cell differentiation. And Ag-

specific T cell response (CD4+ and CD8+).3) Final response of adaptive immune system. plasma cells and memory B cells + Ag specific

T cell memory response.

25. Which are the 4 obstacles in vaccine design related to the antigen? Discuss each obstacle.1) Choice of the Ag: most crucial to detect the correct Ag which leads to neutralisation of

pathogen. This can be done through HTproteomicS technologies or through sequence based computational approach. The Ag can be an animal pathogen (cowpox), human pathogen (extracts, attenuated), toxoids, sub-unit vaccines, etc.

2) Overcoming host diversity: some MO have no or only a little genetic variability through time. Others, mostly the ones who are transmitted to or from animals, have a much larger genetic evolution. For example: influenza with its genetic shift and drift every year. This makes it much harder to select the correct antigens to put in the vaccine.

3) Correlate of protection: what is necessary to protect humans against a specific disease? Ab, T cells, memory cells, innate immunity,…? This can be measured with ELISA, cytokine production, etc. For many vaccines no correlate of protection is known. Efficacy is based on other endpoints.

4) Delivery of Ag to immune system: current vaccines Ag presented to the innate immune system. Preparation of Ag by DC and marcophages (APC’s) and the modified Ag is presented to B and T cells. Vaccines in development DNA vaccines and viral vectors.

26. Which are the two main animal models used in preclinical studies of vaccines? Discuss.

Mouse (dominant animal model) and non-human primate.

Mouse is preferred because:

- similar immune system compared to humans. (human orthologues with similar/identical functions)

- Capacity to manipulate mice genetically. (transgenic mice, KO mice, wild-type mice)- capacity to develop molecular tools to analyse T and B cell responses. (Qualitatively: amount

of Ab, quantitatively: quality of Ab)- challenge studies can be done (immunize and then present with MO sick yes or no?)

Non-human primates are used because they have a close relationship to humans. Their immune system resembles ours. Challenge studies can be done. They are especially important for HIV, Ebola, TBC.

27. What are the different steps in the production process of vaccines? Discuss the upstream processes.

1) Generation of the Ag.

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The Ag is crucial to trigger the immune response. Viruses: master cell bank, master viral seed. Bacteria: grown in bioreactors. Recombinant proteins generated in yeast, bacteria or cell culture.

2) Release and isolation of the antigen.Release as much virus, bacteria or Ag as possible and separate it from the cells. Isolate it from proteins and other parts of growth medium.

3) Purification.4) Addition of other compounds.5) Packaging

28. What are the different steps in the production process of vaccines? Discuss the downstream processes.

1) Generation of the Ag. 2) Release and isolation of the antigen.3) Purification.

Removal of impurities. But be careful to preserve the structure of the Ag! There are several separation steps according to differences in protein size, physicochemical properties, binding affinities and biological activity.

4) Addition of other compounds.Addition of adjuvant to enhance the immune response. Addition of stabilizer to prolong shelf-life. Addition of preservatives to use in multi-dose vials, to prevent bacterial contamination. This way the vaccine needs to stay stable for 2 years in refrigerated state.

5) Packaging.Vaccine is put in recipient vessel in highly controlled environment.

29. Discuss the importance and requirements of phase IV vaccine clinical trials.

After approval and licensure of the vaccine. The main purpose of phase IV trial is:

- safety: determine rare side effects- efficacy: is the disease reduction in the real life situation? Are there changes in epidemiology

of the pathogen?- special populations: immuno-compromised, chronic conditions, other age groups, other

gender,…

Because vaccines are given to healthy people, often children, safety is a very important issue. Monitoring for (late) AE therefore is also very important.

30. Discuss the declaration of Helsinki.

The declaration of Helsinki is a set of ethical principles for medical research involving human subjects. Since it is a guideline, it is not legally binding, but many national laws refer to ‘the latest version of the declaration of Helsinki’. It mostly relates to good clinical practice, for example, voluntary informed consent is always obliged, placebo can only be used when no proven-benefit alternative exists.

Examples of subjects that are discussed:

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- Placebo use- Compassionate use- Informed consent- Publication of results

31. Give a historic overview of the most important guidelines, regulations and laws concerning clinical research/clinical trials.

- Nuremberg code (after medical malpractices in WWII), 10 rules which are the historical basis of our GCP guidelines today.

- (Thalidomide disaster, resulted in DART studies)- (IND required -> FDA)- Declaration of Helsinki- ICH-GCP guideline (harmonisation of rules between EU, USA and Japan)- European clinical trial directive (European rules that need to be implemented in national

laws, poging to harmonisatie binnen EU)- Belgian law 7th of May 2004, on CT but also on many other experiments on the human

person.- EU regulation…

32. 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.

Experiment: more broad. Every trial, study or investigation carried out on the human person with the aim of developing knowledge particular to the exercise of the health care profession.

Clinical trial: relates to an IMP. It is one form of an interventional experiment. Any investigation in human persons intended to discover or verify the clinical, pharmacological and or other pharmacodynamics effects on one or more IMPs and or to identify any adverse reactions.

Overview:

- Experiment (which falls under the Belgian law)o Trial

Interventional (clinical trial) Non-interventional

o Experiments with medical deviceso Research with surgical procedureso Epidemiological prospective research

(The law on experiments does not concern: embryos in vitro, corpses, human biological material separated from the human body, retrospective research.)

33. Give an overview of the composition and the responsibilities of the EC for clinical research as defined by the Belgian law. Is this in keeping with the requirements as set forward in the ICH-GCP guideline?

Responsibilities: To comment/give advice on

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- Suitability of staff/PI- Quality of the facilities- The protocol- The ICF- The CIB (preclinical data)- Insurance- Volunteer fee- Financial aspects/contract- Biobank supervision- Relevance of the trial- Risk/benefit analysis- Subject recruitment

To declare COI when necessary, and refrain from voting.

To be an independent body.

Composition: 8-15 people, both genders

- 2 nurses- 1 psychologist- 1 philosopher/expert in medical ethics- 1 GP- 1 hospital pharmacist- 1 expert in methodology of clinical research- 1 expert in pharmacology, PK, pharmacotherapy- 1 lawyer

34. 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?

Belgian law = LEH. Law concerning experiments on human people. This means every experiment, and not just Clinical Trials. The European Directive only covers Clinical Trails.

Experiment: more broad. Every trial, study or investigation carried out on the human person with the aim of developing knowledge particular to the exercise of the health care profession.

Clinical trial: relates to an IMP. It is one form of an interventional experiment. Any investigation in human persons intended to discover or verify the clinical, pharmacological and or other pharmacodynamics effects on one or more IMPs and or to identify any adverse reactions.

Overview:

- Experiment (which falls under the Belgian law)o Trial

Interventional (clinical trial -> European Directive) Non-interventional

o Experiments with medical deviceso Research with surgical procedureso Epidemiological prospective research

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(The Belgian law on experiments does not concern: embryos in vitro, corpses, human biological material separated from the human body, retrospective research.)

35. Belgian law concerning experiments on the human person: give an overview of the procedure one has to follow and the approvals/authorisations which are needed prior to conducting an interventional clinical trial in Belgium. To what extent is this different for a non-interventional clinical trial?

First you need a EudraCT number (EMA supplies these). Once you have this, you put it on the right documents and you (the PI) apply for authorisation by an ethics committee (ERC/IRB). For an interventional trial you also need to apply for approval with the competent authorities, on the same day. In Belgium this is the FAGG/FAMHP. The latter is the responsibility of the sponsor.

Waiting for approval from the competent authorities (CA) lasts maximum 28 days (only 15 for a phase I trial). After that you can assume that your trial has been approved (= tacit approval), but usually you get written confirmation.

On the contrary to approval from the CA, written approval from the ethics committee is obliged. You need their stamp on your letter in order to move forward with the trial. What does the EC approve/comment on:

- ICF- CIB- Relevance of the trial- Suitability of the investigators- Risk/benefit ratio- Protocol- Quality of facilities- Volunteer payment- Insurance- Financial agreements- Subject recruitment- Biobank supervision

What do the CA do:

- Evaluate the quality of the IMP (IMPD)- Evaluate the pre-clinical toxicology data (CIB)- (they don’t look at the ethics)

A non-interventional trial only needs approval from the ERC, no CA are involved.

36. 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.

The Belgian law contains special clauses about vulnerable populations. But if it is at all possible, one should always foresee a signed ICF.

- Minors: ICF signed by parents of legal representative. An ICF on the level of the child should be provided. EC needs the advice of two paediatricians.

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- Adults not capable of giving consent: ICF signed by legal representative. Witness needed to see if representative is properly informed. The experiment needs to relate directly to a life threatening situation or a debilitating clinical condition. EC needs advice from a knowledgeable person.(eg. dementia, mental retardation, …)

- Lack of ICF in case of emergency. Only very exceptionally. The ICF is signed by two independent physicians.

The EC always evaluates risk-benefit beforehand, on population level.

37. Explain the principle of herd immunity and discuss an example.

Herd immunity is obtained when you vaccinate >90-95% of the population. It means that because of the high vaccination percentage, not only the vaccinated people are protected, but everyone is, also the people who can’t build up an immune response for themselves. It’s a principle of solidarity.

Through herd immunity it is possible to eradicate a disease. For example, small pox. Through very intensive vaccination programs and actively looking for the last communities in which small pox was still ‘alive’, people succeeded to eradicate the disease completely. (Immediate contacts and ring of households needed to be vaccinated.)

38. Which elements need to be taken into account when a new vaccine is introduced in a vaccination program? Explain briefly.

1) Define if burden of disease is substantial enough to incorporate new vaccine. (Check epidemiology, mathematical models)

2) Define your target group per vaccine. (infants, children, elderly)3) Can you reach your target group? (How and which health care structures already exist which

you can use?)4) Can you reach high vaccination coverage rates? (>90%)5) Can you sustain high coverage rates? (Resources, till infinity?)

39. How can a vaccination program be evaluated? Explain briefly.- vaccination coverage studies

This is necessary to know if high vaccination coverage is obtained. Then if there is an outbreak, you have something to fall back on.

- seroprevalence studiesThis is important to check how well the population is vaccinated. Older people lose their Ab over time… All age groups should be sampled. You need to define which critical infectious diseases need to be monitored.It is a reliable source of info to estimate risk of infectious disease of different age groups.

- epidemiology of vaccine preventable disease (pre- and post-vaccine era)pre-vaccine: monitor reported cases of infectious diseases. Determine the burden of disease, determine which age groups are affected most, determine how epidemics are moving, determine cost-effectiveness.Post-vaccine: monitor reported cases of vaccine-preventable diseases. Important to measure the impact of vaccine recommendations, to detect outbreaks and to monitor these

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outbreaks. Difficulties are that there is less recognition of the disease and it depends on the willingness of the doctors to report.

- vaccinovigilance: adverse events reportingThere is an AEFI surveillance system. Any AE should be reported.Three steps: signal detection, development of causality hypothesis, testing of causality hypothesis.

40. 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?

What? Good clinical practice = a term used for the collection of rules, recommendations and guidelines on how good clinical research should be performed.

Who is it for? For everyone involved in clinical research. Study staff, sponsor, subjects, etc.

Objectives? To ensure a product is safe and meets its intended use. To ensure safety of the participants of clinical experiments.

Who benefits?

- The subjects because they are properly protected. - The sponsor because the data are complete, accurate and unbiased and will not be rejected

by regulatory agencies. If efficacy is proven; international regulatory approval. Quality compliance and consistency.

- The investigator will gain scientific credibility.

41. What is ICH? What are the objectives of it and which topics are covered by ICH?

International conference on harmonisation of technical requirements for registration of pharmaceuticals for human use. It is a partnership between USA, EU and Japan involving both regulatory groups and industry.

Objectives:

- safety: maintain safeguards on quality, safety and efficacy to protect public health- globalisation: recommend ways to achieve better global acceptance of CT submissions- economic: reduction in number of animals/humans required to show efficacy- timeliness: facilitation of rapid (but safe) approval and availability of new drugs

Topics:

- quality: chemical and pharmaceutical quality assurance- safety: pre-clinical testing- efficacy: CT in human subjects, dose response studies- multidisciplinary: electronic standardisation for transfer of regulatory info and documents,

medical terminology, non-clinical safety studies, etc.

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42. 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?

An informed consent form is a form used to start the informed consent process with. It contains details on the trial, the participant’s rights and a signature page. It is very important that the ICF is signed voluntarily (no pressure from anyone, what so ever) and that this is done before any trial related procedure is done. The voluntary part is very important. The ICF came to play after WWII. During which unethical medical procedures were tested on prisoners, mentally ill, etc. It is essential that the subject always freely decides whether or not to participate in a medicinal experiment.

Informed consent process:

1. explain the experiment2. use simple words3. answer all questions4. give time to think about it5. do not pressure, it must be a free decision6. sign ICF, both patient and person who conducted the IC process7. give copy of ICF to participant

43. 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?

IRB = institutional review boardIEC = independent ethical committee

Function: to give advice on:

- Relevance of the trial- Suitability of the investigators- Quality of the facilities- Insurance- Payment of the volunteer- Financial agreements- ICF- CIB- Biobank supervision- Subject recruitment- Protocol- Risk/benefit ratio

Composition: independent body with the following members:

- 8-15 members- Both genders- Members declare conflict of interest (COI), no participation in voting- Majority of medical doctors, in addition:

2 nurses 1 hospital pharmacist

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1 expert in methodology of clinical research 1 expert in pharmacology, pharmacotherapy, PK 1 psychologist 1 gp 1 lawyer 1 philosopher or expert in medical ethics

44. What are the differences between monitoring, auditing and inspection of a clinical study?

Auditing Monitoring InspectionBy external person (sponsor’s regulatory compliance), commissioned by sponsor= independent

By external person, chosen by sponsor.CRA (clinical research associate) = monitor= not idependent

By regulatory agencies (government!), official review,

- One time.- Covers the entire study

to that point. - Process focus.

Continuously, throughout the whole trial.

One time, reasons: - Pre-approval- Routine GCP- Triggered

A systematic and independent examination of trial related activities and documents to determine whether everything was recorded, analysed and accurately reported according to protocol, sponsor’s SOPs, GCP and applicable regulatory requirements.

The CRA trains the CTA’s, checks their work, finds mistakes and tags them, gives feedback and evaluates. The monitor is there to continuously follow up the trial and to make sure the rules are followed.

Review of documents, facilities, records and any other resources that are deemed by the CA related to the CT

Audit is commissioned by the sponsor and is a one-time evaluation of and independent person, to check if everything happens according to the rules.

A CRA is a monitor who reviews the trial continuously and who guides the people conducting the trial.

Inspection is also a one-time evaluation, but this time commissioned by the government. It’s an official evaluation, needed for approval/MA.

45. Pharmacovigilance (pre-registration): discuss the causality assessment of an adverse event taking place during a clinical trial.

Causality assessment = the evaluation of the likelihood that a particular treatment is the cause of an observed AE. (Did the patient bring the problem to the product or did the product bring the problem to the patient?)

It is an important component of the evaluation of the benefit/harm profiles of drugs. Though, it has only a limited scientific value. More research will be necessary to prove any real causal relationship.

2 important questions need to be asked:

1) Is it possible that the medicinal product caused this AE?Based on everything that is known about the product (SmPC, literature, …)

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2) Did the medicinal product cause the AE?Real assessment

There are several methods for evaluation:

- Global introspection (clinical judgement)- Algorithms (questions and scores)- Bayesian approaches (prior estimate and posterior estimate)

What can help the assessment?

- Time relationship (immediate anaphylactic shock)- Pharmacological properties- Known association with the medicinal product or the class (rhabdomyolysis for statins)- Underlying disease- Concomitant medication- Dechallenge, rechallenge- Dose-effect relationship- Localisation of the AR (injection site)

After the assessment you’ll never be a 100% sure and you’ll never be able to quantify. There rarely is only one cause, often the relationship is multi-causal.

You determine the causality to be in of these categories: Certain, Probably/Likely, Possible, Unlikely, Conditional, Unassessable.

46. Pharmacovigilance: what is the difference between an adverse event and an adverse reaction? (take the Belgian legislation into account). When will and adverse event or an adverse drug reaction be considered “serious”?

Adverse event = any untoward medical reaction in a patient participating in an experiment, not necessarily causally linked to the experiment/IMP.

Adverse reaction = all untoward and unintended reactions to an IMP/experiment, at any dose.

When is it serious? Any untoward medical occurrence or effect that:

- Results in death- Is life threatening- Requires hospitalisation or prolongs hospitalisation- Results in persistent or significant disability or incapacity- Is a congenital anomaly or birth defect

And this, when it’s a CT, at any dose.

47. Discuss: Data Safety Monitoring Board.

DMC = Data monitoring committee. =

DSMB = independent group of experts, external to the CT, assessing the progress, safety data and critical efficacy endpoints of a CT. A DSMB may unblind and perform interim analysis.

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It is required for each CT implicating a potential risk to the participant (= pretty much every CT). They play a very important role before and during the CT. Ensures that decisions are taken on clear and upfront decided clinical and statistical grounds. Safeguards that a maximum of info is extracted from the study.

A DSMB differs from an IEC as such:

- Follow up of inclusion rates- Detection of protocol violations- Edition of DSMP (plan how the sponsor/PI are planning to ensure safety and well-being of

the participants.- Control on credibility, integrity, validity of the data- Detection of unexpected high rates of drop-out- Safeguard the safety of the participants- Detection of unexpected rates of exclusion- Study of AR reports- Being available for the PI to discuss an AE

(An IEC doesn’t do these things, it isn’t up to date all the time)

Composition: based on sort, size and clinical domain of study. There has to be at least 1 biostatistician.

Aim of interim analysis: evaluation of safety and efficacy, statistical analysis and early detection of possible bias. possible decisions: continue, stop, adapt design.

48. 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.

(1) Premarketing is the fictive life of the drug. It’s not released into the real world yet.

Limitations of clinical trials:

- Too fewNot enough participants

- Too simpleToo many inclusion and exclusion criteria, limited dose range, only limited number of concomitant diseases allowed, …

- Too median-agedUnderrepresentation of extremer age groups

- Too narrowClinical indications, concomitant diseases, …

- Too shortDuration of treatment and follow-up

(2) All these limitations make the evaluation/prediction of safety in the real world, post-marketing, difficult. Sometimes rare but severe side effects are discovered after marketing authorisations, through reporting’s of physicians and patients. Also:

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- There is the uncertainty of the causality assessment.- There’s a problem of reporting. Most doctors don’t bother to report serious AR.- Bias in the AR-reports. When people see that there this kind of AR is reported, suddenly

everyone has it. - Comparison of drugs can be very hard.

49. Discuss: the nomenclature of drugs.

- Chemical name (eg. acetoaminophenol)- Generic name or INN (international non-proprietary name) (eg. paracetamol)- Brand name (eg. dafalgan)

Nomenclature can be very confusing: brand names might differ among countries, same active substances can have different brand names, sound-alike’s, etc.

The INN is an identification of the pharmaceutical substance/the active ingredient. It is unique and public. Conditions: easily recognisable, not too long, minimal risk for confusion, useful in many languages. (Same drug class often same ending or beginning.)

Brand names need to be published in WHO bulletin. Anyone can formulate remarks within 4 months.

50. Discuss the difference between “off label” and “unlicensed” use of drugs and illustrate with an example.

Off label Unlicensed When drug is used for a different indication than the approved ones by the FDA/EMA.

When drug is used in different:- Population- Route of administration- Dosage

Use of rituximab (anti-CD20) in patients with ITP (idiopathic thrombocytopenia purpura), normally it is used to treat cancer.

Injectable Phenergan (anti-histaminic) is only approved for IM injection, but is also used IV in haematological patients.

51. Discuss the different aspects and the importance of cold chain management. Give a real life example.

= management of guaranteeing the adequate storage of drugs, even if they have to be kept at special temperatures.

This should be adequate for the original product and also after reconstitution and dissolution.

- Room temperature 15-25°C- Fridge 2-8°C, preferably 4°C- Freezer -15°C

All fridges and freezers are foreseen with alarm systems connected with phones and are provided by the emergency electricity network. TempTales can be used to give alerts. To check whether at any point in time the temperature has been off.

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I can be complicated sometimes: in fridge before reconstitution, at room temperature after.

For injectable drugs the lower temperatures can help with maintaining microbiological durability (sterile) and chemical durability (stable).

Example: when vaccines are shipped to Africa, it can be a real struggle to keep them at low enough temperatures. When an outbreak of a preventable disease happens in a vaccinated population, we must check whether the cold chain of the vaccines was maintained the entire time. If it has been too high, there’s a high probability of denaturation of the protein.

52. What is “polypharmacy”? What are the dangers associated with it? (also explain in the context of transmural care).

53. What is seamless or transmural care? What are the barriers associated with it, especially in Belgium?

54. Discuss the financial “life cycle” of drugs including the implications for het pharmaceutical company.

It starts with an approved drug. This has a certain price, as long as the patent stands. When the patent expires there are two possibilities.

1) There is no generic/cheaper drug available: after 12 years of reimbursement, the price will go down 15%. After 15 years -2.35%.

2) There is a generic available: the price (basis for reimbursement) goes down by 30%. This is now the reference reimbursement. When you buy the generic or the original product, you get the same amount reimbursed, even when the original product is still more expensive.After 12 years there’s an additional decrease of 17%, after 15 years -1.19%.

In the end (after years and years), the price can be more than 40% lower than the original price. But the original pharmaceutical company often has no choice but to lower the price. If the generic product is much lower, people will start buying that one. Companies can also decide to stop the production of this particular drug (as long it doesn’t leave an unmet medical need behind).

55. Give an overview of the reimbursement of drugs for ambulatory patients, depending on the ‘category’ and ‘chapter’ they are in (provide examples).

(There are three different prices based on the type of patient: public, ambulatory or hospital.)

Drugs are divided into categories. Each category stands for another percentage of reimbursement.

Category Type of drugs % of reimbursementA Lifesaving drugs (insulin) 100%B Therapeutically important drugs (antibiotics) 75%

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C, Cs, Cx Drugs for symptomatic use (hormonal anticonception) 50-40-20%D The rest: sedatives, anxiolytics, analgesics, …

(paracetamol)0%

Drugs are divided into chapters. Each chapter stand for other criteria for reimbursement.

Chapter I Reimbursement for all approved indications, no special conditions (antibiotics, insulin)

A, B, C, Cs, Cx

Chapter II Indications based on EBM (statins, PPI) – a posteriori control

B, C

Chapter III Infusion fluids BChapter IV Limited indications based on specific

indications or budget restrictions (expensive tuberculostatics) – a priori control

A, B, C

Chapter IV bis Drugs only available abroad A, B

56. Give an overview of the existing options in Belgium to make drugs available to patients free of charge. What are the restrictions and requirements?

1) Compassionate use:- To make drugs available, for reasons of compassion, following centralized procedure for

patients suffering from;- a chronic disease or a life-threatening illness.- The registration file of the drug must be submitted or the CT must be ongoing- The drug can’t be approved yet for any indication- The drug is delivered free to the patient- The company should inform the FAGG and EC- It is the physician who applies

2) Medical need program:- Same definition and requirements as CU, but the drug is under investigation for another

indication.- Label: MNP – cannot be sold.

3) Medicinal samples:- Only for approved and available drugs- Not bigger than the smallest package available. - Label: free sample – cannot be sold- Not for narcotics, psychotropics, drugs containing isotretinoin- Written apply by physician- Company should document

57. Which are the most important procedures available in Europe for the registration of new drugs? Which are the pros and cons of each procedure?

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Centralised procedureYou submit a single registration application file to EMA. The CHMP picks two reference countries (rapporteurs) to do full research on it. These two countries give advice to the whole CHMP committee. All 28 countries vote, and if there is a majority, this is the decision.

+ one application procedure+ one approval for the whole EU+ 10 years of exclusivity in all EU countries+ consensus by majority vote (even if 5 of them said no, still approval in these countries)-all or nothing-only one trade name, for all countries the same-rapporteurs are selected by the CHMP-very limited time for country organisations to deliver translations

Mutually recognised procedure (MRP)You submit your registration application file in one country. This country becomes the reference member state. It does a full check-up and publishes an authorisation report. The other member states have 10 days to validate the report and then have 90 days to do their own research (or just read the report) and decide whether or not they recognize the medicinal product in their country (= mutual recognition).+ you choose your own reference country+ you can choose different trade names in different countries+ there’s a possibility to launch the product early in the reference member state+ you have the option to withdraw an application in 1 member state, without jeopardizing the application in the rest of the member states-Major objection in one or more member states can lead to withdrawal in these states-Instead of pure mutual recognition, many member states assess the registration file all over again, which leads to many queries/objections.

58. Provide an overview of the tasks of a medical department within a pharmaceutical company.

- Provide input into protocol developmentDesign, endpoints, comparators, etc. Based on personal experience and feed-back for regulators. (Access to authorities and specialized centres.)

- Select clinical sites for study participation- Ensure regular follow up of clinical sites

Protocol and GCP compliance- Apply for CP or MRP- Coordinate local activities

Address questions of CA, ensure all submissions are timely done, etc.- Building and evidence based file for reimbursement.

Safety and efficacy evidence, added value vs. existing treatments, outcomes research, etc.- Life cycle management

New indications, new dosing regiments, new formulations, …- Maintain registration

Pharmacovigilance, maintain the registered data up-to-date (new indications, labelling), renewal is 5-yearly.

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- Maintain reimbursementPost-reimbursement commitment, observational studies, real world data, monitoring of available evidence and present it where needed.

59. 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?

Every EU member state has its own reimbursement procedure. In Belgium the CTG/CRM-procedure is at the federal level.

The aim of the reimbursement procedure is to speed up the procedures and to make them more transparent, to integrate EBM and to have to possibility of revision of reimbursement.

The commission provides a positive list of reimbursed medicinal products. They can approve reimbursement for every or for selected indications of the SmPC. A temporary contract for new medicines is a possibility.

What do they evaluate?

- Quality, safety, efficacy + effectiveness, +convenience, + other things.- Relative therapeutic value as compared to alternatives- Relative economic value as compared to alternatives

Belgium:

- Marketing authorisation: National procedure minister of public healthEuropean procedures European commission

- Price: minister of economic affairs- Reimbursement: minister of social affairs/minister of budget

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