1st Master Biomedical Sciences Pharmaceutical Medicine Exam questions 2014 Questions of which 2 will be part of the examination: Ch1. Drug Design and Discovery – J. Thomas 1. Drug discovery and design: which selection criteria determine the choice of a project for the development of a new compound? Strategic: Is it desirable to do it? Does it have to be done? Will we profit? Market prediction (future prospects, opportunities and threats) unmet medical need (Gap between ideal and reality, look in the future) company strategy and competencies (strengths and weaknesses) Scientific and technical: Can it be done? Is it feasible? Available proteins, assays, animal models, … Scientific opportunity: scientific base, room for innovation? Competitive advantage: First-in-class, Fast follower, me too, … Expected difficulties: endpoints? Acute or chronic? Life threatening? Patent protection Operational: Can we do it? Work with other company? Necessary resources: Staff and expertise, facilities, capital, equipment, …. Timescale & planning? Decision by management based on all elements 2. Discuss the role of pharmacochemistry in drug discovery and design. - Lead finding Screening HTS of chemical libraries Combinatorial chemistry (combining (protein) building blocks) De Novo design = Computer Assisted Drug Design (CADD) Ligand based improvements of endogenous L development of synthetic L: Pharmacophore model (hydrophilic + hydrophobic) Target Based: Docking of small molecules in 3D structure of target (X-ray Christalography or NMR spectroscopy) - Lead optimization: Improve the biological activity: selectivity, strength, safety Variables: PK, stability,Patents, formulations, genotoxicity, chirality, ease of synthesis, … 3. Drug discovery and design: which criteria determine the choice of a candidate drug for further non-clinical and clinical development? - Selectivity and strength for Target - Appropriate PK (ADME) - Pharmacological activity (in vivo and In Vitro functioning - Safety profile - Chemically stable (in formulation) - Large scale production and patent protection possible? 1 Ch2. Pharmaceutical Development – G. Van den Mooter API = Active Pharmeceutical Ingredient – Drug Substance Drug Product = API + excipients Excipient = inactive compounds that allow administration and formulation, Bulk formation (core+coating) 4. Provide an overview of the physicochemical aspects which are part of the pre-formulation phase of a drug. - Solubility => BCS classification Determines the formulation strategy, Poor solubility can still have good bioavailability Influences of pH, buffers, organic solvents, ionic strength -> High-throughput analysis Increasing solubility: Cosolvents, complexing agents (cyclodextrins encapsule non-soluble parts), surfactants & polymers - Intrinsic Dissolution rate = Absortion window Rate at which an API can be obtained -> Bioavailability and stability =ΔC. (D.A/V.d) - Ionisation => effect on bioavailability Determine pKa -> change pH to improve solubility or salt formation - Partition Coefficient = LogP Indication of Lipophilicity/hydrophobicity => absorption (80% by passive diffusion) Partitioning solvent changes LogP (mostly n-Octanol) - Solid state properties Crystaline = preferential 3D arrangement, thermodynamically stable (melting point), phase transition Amorphous = chaotic arrangement and unstable, glass transition –> change in baseline of thermogram, higher solubility and dissolution rate Differential Scanning Calorimetry = Quantification of heat production and uptake -> Thermogram (dq/dt) C -> uptake of heat; A -> shift in baseline X-ray diffraction: C -> Bragg reflections (positive interference), A -> Halo Pattern Polymorphisms (different lattice) in solid state: conformational or stacking Pseudopolymorphisms (solvents in lattice) => intermolecular interactions determine bondings strength change physicochemical properties => most stable form needed! Dynamic Vapour Sorption analysis: uptake off water can influence stability - Stability is influenced by: Solid state : Heat, light and water Solution: Heat, light, pH and extreme acidic, basic or oxidizing environment Compatibility with excipients and packaging 5. Provide an overview of the biopharmaceutical aspects which are part of the pre-formulation phase of a drug. Permeability – absorption potential - Parallel artificial membrane permeation assay (multi-well) No animals, HT, inexpensive Only passive diffusion, dependent on pH and lipid composition - CaCo cultures: Human colon adenomacarcinoma Erythrocyte Monolayer with TJ, Active transports, brush border enzymes Human, evaluation of toxicity, transport and observation No mucus and static model 2 6. What kind of compounds (API and excipients) can be part of a tablet? - API Filler/diluents: reach correct weight ex cellulose Binder: keep everything together ex. starch Desintegrant: desintegration at correct location (contact with GI fluids) ex. Cross-linked polymers Flow promotor: for homogenous dosing ex. Colloidal SiO2 Wetting agent: improve contact between aqueous environment and compound ex polysorbate-80 Lubricant: decrease friction during manufacturing ex Mg-Stearate 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. Release kinetics are reliable and reproducible. Systems that enable a controlled residence time of the dosage form or release at a specific site in the GI tract to obtain a specific or local effect. + reduced intake and side effects + better compliance and comfort + less fluctuation 8. What kind of strategies can be used to make oral controlled drug delivery systems? Reservoir systems: - Polymer coating (insoluble, slowly dissolving or pH-dependent) ex. Ethylcellulose => rate controlling membrane - Layered system: API 1 - polymer - API 2 (slow release) - inert core - Pulsed release: 3 layers of API released at different time points Matrix Systems - Insoluble matrix: diffusion of API - Erodable or slowly dissolving: API is released because of erosion Hydrophilic matrix ex. Cellulose Acetate Pallidium Lipophilic matrix ex. Glycerylmonostearate Bioadhesion: Buccal tablet stays on gingiva and is slowly absorbed <-> gels Osmosis: Osmotically active core, push compartment and membrane with hole. API is pushed out when polymer swells 9. Which elements need to be taken into account during the pharmaceutical development of suspensions, creams and ointments? Suspenisons = Solid dispersed in liquid - For insoluble or instable APIs, when liquid is desired - Difficult homogenous dosing: wetting agent, increasing viscosity, adequate particle size - Stability: Caking = interaction at secondary minimum -> structured medium, electrostatic and sterical stabilisation Creams = water and oil phase - Emulsifiers to maintain stability, viscosity increasing, moisturizers, penetration enhancers - Production by applying energy Ointments = No water - Ointment base (ex. vaseline) - Surfactant, fragrances, perfumes 3 Ch3. Clinical Drug Development – J. de Hoon Clinical research = improve knowledge of disease or treatment, scientifically sound and ethically acceptable, in humans Clinical Trial = evaluate efficiency and safety of medicinal products IND file = Investigational new drug file: all data obtained for molecule in non-clinical test Mode Of Action , safety, … IB = Investigators brochure, IND + info from clinical trials RCT: Randomized Controlled Trial Clinical Endpoint: describes how a patient feels, functions, survives Hard vs Soft ; Primary vs Secondary Needed for approval Surrogate Endpoint: as predictor for Clinical endpoint, Therapy induced changes Biomarker: objectively measured characteristic for therapy induced changes and response Benefit vs risk 10. Discuss the principles taken into account when calculating the MRSD for conducting a FIM trial. MRSD = Maximal Recommended Starting Dose FIM trial = First-in-Man or Phase I trial NO(A)EL = No Observed (Adverse) Effects Level HED = Human Equivalent Dose MABEL = Minimal Anticipated Biological Effect Level (NOEL) MED = Minimal Effective Dose PAD = Pharmacological Active Dose Toxicological approach NOAEL based on animal studies (mg/kg) => convert to Human Equivalent Dose Small animals: more efficient metabolism, larger body surface HED from most appropriate/sensitive species Divide by safety factor (default = 10) -> MRSD Conservative approach MABEL: Lowering the dose even further when Biological effect is expected 11. Phase I and phase II RCTs: discuss. Phase I: Initial safety trial - in healthy male volunteers (exceptionaly on patients, ex oncology) - without therapeutic objectives: Safety, tolerance and PK, 6-12m - Single/multiple ascending dose (PK) - After phase II: Bio-equivalence, interaction & QT studied - Alternatives: microdosing, Proof-of-Concept, eCTA, translational models - Small groups: descriptive statistics Phase II: First into target population - Evaluate efficacy and safety in small group of patients, no intent to treat - Tolerance, PK & PD, 12-24 months, male and female - Target validation: Proof-of-Concept/Principle 12. Phase III RCTs: discuss. - Confirming efficacy and safety in a larger patient population New Drug Application => while waiting for Approval 4 - Confirm indications and dosing, 2-7y Investigate High risk population Superiority Trial: to detect a difference between treatments Equivalence Trial: to confirm the absence of a difference Non-inferiority trial: to show that the new treatment is at least as effective as... 13. RCT and trial design: cross-over versus parallel group design. Discuss. Golden standard but expensive, prospective - Patients randomly assigned in active and control group - Controls: Placebo, best available treatment, nothing, dose-response, historical data, … Parallel group - Progress together in time Cross-over study - After wash-out period -> Patients change groups - All patients receive both treatments - Less variation, less subjects - Not for fast evolving diseases, might not go back to baseline 14. Discuss “internal” versus “external” validity in the context of clinical trials. Internal validity - Was the trial executed in a scientifically correct way? Prevention of bias and confounding: Randomization, Blinding (single,double, triple,…), Placebo vs Nocebo Best available treatment External validity - Can results be extrapolated to all patients in the “real” world? - Selection criteria limit the sample -> artificial CH 4 Biologicals and Biosimilars – P. Declerck 15. Provide an overview of the production process of biological - Cloning: plasmid and DNA strand ligated -> transfection - Cell line expansion: cell cultures or bioreactors -> monitor conditions - Protein expression: recovery through centrifugation and filtration - Purification, characterization and stability - Controls: check for mutations, correct configuration - Back-up: Sample in liquid Nitrogen 16. What are the most important differences between “small molecules” and “biologicals”. Small molecules - Chemical synthesis - Defined structure - Relatively stable - Less sensitive to changes in process - Not immunogenic Biological - Produced by living system, cell cultures - complex biomolecule: Heterogenous structure <- cell type and culture/external conditions - Variable, sensitive to conditions - Extremely sensitive to changes - Immunogenic: also dependent on production process, handling, … 5 17. What are “biosimilars”? Why was this concept introduced? What is the difference between a generic (small molecule) drug and biosimilars? Biosimilar: Copy of an already authorized biological product claimed to be similar in quality, safety and efficacy, Comparability exercises and guidelines (quality and clinical) (since 2006) Why? New product developed -> approved and Patented Patent expires: several companies start to produce same protein -> never identical Physicochemical properties, impurities and clinical properties Centralized procedure for assessment by EMA (CHMP) WHO: Naming of drugs -> International Non-proprietary Names Difference? Small molecules will always be the same independent of production process. Even pure protein will still contain many variants (glycosylation, oxidization, deamination,…) Interchangeability needs to be proven, Diverge over time, biosimilars not compared to eachother CH 5 Study design 18. 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? Observational - Descriptive - Case Report: challenge – dechallenge – rechallenge (only if mildly toxic) 1 unusual observation -> hypothesis generating Cheap and easy but little causality, and no hypothesis testing - Case series: pooling of cases -> estimate incidence (No control!) Observational - Analytical - Case-Control Trial – Retrospective Select cases and controls => Look for previous exposures => Odds ratio Multiple exposures, rare and late responses Sensitice to bias and confounders - Cohort study – Prospective, retrospective and ambispective Follow an exposed group over time => Incidence/hazard ratio Multiple responses and rare events Large groups and Bias, long duration Experimental – Analytical - RCT Powerful statistics and control for confounders Many limitations: nr of patiets, exposure, follow up time Ethical issues, expensive, External validity Registering before start -> Ethical approval - Meta-analysis Systematic review of several studies of same drug -> Publication bias Large Power! CH 6 High Risk Populations - J. de Hoon 19. Why are the elderly a high risk population for the use of drugs? High risk and also more drug use Slow metabolism, Los of functional units: Alveoli, nefrons, hepatocytes 6 Absorption - Decrease stomach fluids – decreased acidity – decreased solubility - Decreased first-pass metabolism: larger bioavailability or less activation Distribution - Decreased Extravascular fluids o Polar drugs: smaller Vd -> lower Dose o Non-polar drugs: larger Vd -> Longer T1/2 Reduced clearance - Liver: high extraction ratio - increased sensitivity - Kidney; water soluble drugs – effect on Liver Cl 20. Discuss the use of drugs during pregnancy and lactation. Chronic illness - Attention needed as soon as there is the intention of pregnancy - influences on fertility (reversible) - Men and women - Counseling: Infertility, birth defects, danger to the mother, … - Mostly dangerous during embryogenesis Pregnancy - should not use Drugs - Adjust treatment: Historically safe - Mother comes first, try not to risk the baby Lactation - Less risks – only small amounts go to baby - Except hypnotics & sedatives CH 7 Pediatric Clinical Development – K. Allegaert 21. The pharmacokinetics of drugs can be profoundly different between children and adults. Provide an overview of the factors contributing to these differences. - - - - Bodycomposition = age depedent Large head, growth of lymphoid mass < age 10 and of genitalia during puberty Body water and Vd decrease till age 2 for hydrophilic drugs Metabolic capacity – hepatic maturation Biotransformation phase 1 or 2 -> drugs more hydrophilic : absent in neonates No renal clearance -> acculmulation CYP3A7: fetal enzyme -> CYP3A4 most prominent in adults Strong increase in Clearance <6m Allometrics (caloric intake): Higher in small animals -> higher dose <2y GI function: Route dependent bioavailability Rectal: low conc, large variability, repeated admin -> noise increases Oral: conc decreases Integumentary development -> physical bariers Anaesthesia at early age limits brain development Maturation of renal function: Cox2-inhibitors -> nephrotoxic Pharmacogenetics, tailored to children: still need to grow into phenotype, some fetal markers Ontogeny (changes during maturation), i.e. age related drug metabolims 22. Pediatric clinical pharmacology: the metabolism of drugs (i.e. biotransformation) depends on a number of co-variables. Discuss these variables and give examples. 7 Co- variates of metabolism - Age (ontogeny) -> adjust for enzyme development, but not for size Cyp-enzymes change: CYP3A7: fetal enzyme & Lung; CYP3A4 most prominent in adults - - - Dextromethorphan: o-demethylation -> N-demethylation different metabolites: Dextrorphan acculumates -> Sudden Infant Death Syndrome Glucuronidation weight Polymorphisms: CYP-enzymes Change in receptor efficiency drug metabolism: maturation -> WT become fast metabolisers; can stay slow metabolizers Co-morbidity: type of surgery Morphine clearance and CYP450 metabolism Xantine Oxidase, CYP1A2/2C6, NAT2 Environmental: maternal smoking, drinking, comedication 23. What is the objective of the European obligation to make a Pediatric Investigational Plan (PIP) for all new drugs in development? Improving the health of children by: - fascilitating the development and availability of medicines for children - ensuring that the medicines for use in children are of high quality, ethically researched and authorised appropriately - improving the availability of information on the use of medicines in children Without; - subjecting the children to unncecessary trials - delaying the authorisation of medicinal products for adults CH 8 Guidelines and Regulations – J. Dehoon 24. Discuss the Declaration of Helsinki. - Informed consent and IND file already excisted WMA 1964: ethical principles for Medical Research involving human subjects Revisions have been made over the years: changing environment For everyone involved: guidelines, not legally binding -> applied to national law 2000: placebo only if no treatment available Acces of all patients to the best available method (compasionate use) all results need to be reported 2013: also for storage of human material 25. Give an historic overview of the most important guidelines, regulations and laws concerning clinical research / clinical trials. - 1947: Nurenberg Code: Voluntary Informed Consent No experiments where death or injury is expected, ecept when physician is also at risk 10 basic principles -> basis of curent guidelines and regulations - 1961: Thalidomide disaster - 1962: Kefhauver-Harris amendment: IND file needs to be present before going to humans: Protocol, safety data, efficacy results, side effects, Informed Consent form - 1964: Declaration of Helsinki: Statement of ethical principles for medical research involving Human subjects - 1997: GCP guidelines: Tripartite: Japan, USA and EU o Technical requirements for registration of pharmaceuticals for human use. 8 - - april 2001: European clinical Trial Directive: guidelines become National law o Clinical trials involving medicinal products according to GCP may 2004: Belgian Law concerning experiments on the human person o all experiments on humans 26. 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 = 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 o non-commercial exp: sponsor is university, hospital or foundation, owns IP, concept, execution and results Clinical trial = any investigation in the human person intended to discover or verify a clinical, pharmacological and/or pharmacodynamics effects of one or more IMP, and /or to identify any adverse effects o non-interventional: normal clinical practice -> extra information o phase I: Healthy volunteers, without any therapeutic objective o approval from Competent Authorities 27. 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? Composition - institutional review board/ ethical review committee - 8-15 independent members: 1 lawyer + doctors - fully recognized: 20 protocols a year - declare COI -> no voting - single center: local EC - multi-center: fully recognized -> chosen by sponsor Responsibilities - Relevance of the trial, Risk / benefit analysis - Protocol; Clinical Investigator Brochure - Suitability of investigators and staff; Quality of facilities - Informed Consent Form (ICF); Volunteer payment; Subject recruitment - Insurance; Financial agreements / contract; quality criteria according to ICH-GCP -> fully recognized EC 28. 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? - for all involved insurance: no fault needed, causal relationship is sufficient vulnerable populations prevent over-volunteering: minimal interval for BE, US and UK, not in EU or GCP responsibilities of the sponsor: pay EC and CA, insurance, chose EC, apply to CA o manufacturing, import and distribution of IMP 9 29. 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? Interventional trial - EudraCT number: on every CTA - Investigator: submit to local and leading EC -> one written opinion - sponsor: submit CTA to CA -> Tacit approval o quality and toxicology - start trial: reporting safety, amendment, end of trial, Synopsis CSR non-interventional: no application to CA and smaller payment to EC 30. 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 - Always written ICF minors: ICF by parents -> 2 paediatricians in EC incapable of giving consent: legal representative -> EC: knowledgeable person emergency: no ICF CH9 Good Clinical Practice – B. Van der Taelen 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? - - Quality system: A term used for the collection of rules, recommendations and guidelines on how good clinical research should be performed Tracability (what), accountability (who) and documentation Everyone: Principal investigator, staff, subject sponsor and Ethical comitee ICH Regulatory groups and industry in US, EU and Japan -> guideline E6: GCP o Safeguard Safety, efficacy and quality o Allow global acceptance o Reduce number of humans and animals used o Allow rapis approval and availability Everyone: Subject (safety), investigator (credibility) and sponsor (international approval, valid data, quality assurance), public reassurance 32. What is ICH? What are the objectives of it and which topics are covered by ICH? - - International Conference on Harmonization Regulatory groups and industry from US, EU and Japan Objectives Safety: Safeguard Safety, efficacy and quality Globalisation: Allow global acceptance Economy: Reduce number of humans and animals used Timeline: Allow rapis approval and availability Topics: o Quality: Chemical and Pharmaceutical Quality Assurance o Safety: in-vitro and in-vivo pre-clinical testing o Efficacy (GCP) o Multidisciplinary: electronical standards, standardization of medical terminology 10 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 - Information pages : Describes the rights of a study participant: details about the study to start the communication signature page: subject and informer, personally date Voluntary, Before any study has taken place Explain study, use simple words, answer questions, give time, sign, provide copy of ICF Origin: post-world war II crime trials for unethical medical experimentation in Nurenberg 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? - - Institutional review board / Independent ethics committee Protection of rights, safety and well being of human subjects involved in the trial, continuously review Functions: minimize risks and follow-up conduct of trial Composition: Indepentent from investigator with sufficient qualifications and experience 3 IRB members, non-scientific member and independent member drom institution Responsibilities: o Review a proposed trial and continue review o Review Investigator o Especially when involving vulnerable subjects o Announced meetings and adequate records IRB according too Belgial Law May 2004 o Experiments (not just trials) on humans: drugs, surgery devices, … o Approved by IRB or IEC o Composition: independent body 8-15 members: doctors, min 1 lawyer, declare COI 35. What are the differences between monitoring, auditing and inspection of a clinical study? - Quality assurance: planned and systematic actions to confirm compliance with GCP, based on SOP - Audit: retroactive quality assurance -> ensure quality of product and process = A systematic and independent examination of trial related activities and documents to determine whether the evaluated trial related activities were conducted, and the data wererecorded, analysed and accurately reported according to the protocol, sponsor’s SOPs,GCP and the applicable regulatory requirement(s). - Monitoring: independent observer covers entire study up to that point (once) - Inspection: official review of documents, facilities and records by regulatory authorities Chapter 10: Drugs and society – I. Spriet Pharmacopeia: Official handbook with standards for analysis of drugs, all products should comply, mentioned on leaflet Unmet Medical need: No alternative available 11 Ex tempore preparations: Is prepared according to receipt in a pharmacy for an individual patient Completely individual, standardized or mixture of commercially available products All products should fulfill quality standards Physician (prescription & receipt -> Pharmacist (preparation and distribution) 36. Discuss: the nomenclature of drugs. - - - Chemicale name: based on chemical structure o Para-acetoaminophepol or Acety-salisylic acid Generic name: international nonproprietary name (refers to API) o Paracetamol or Asprin o Easy to recognize: minimanl risk of mistakes, not too long, valid in different languages o Often refer to the pharmavological class (-mab, -pril, …) Trade name: different names within and between countries o Daphalgan or Aspro o Publishes in WHO Bulletin Anatomic Therapeutic Chemical Classification: 5 Levels by WHO o Associated with daily defined dose o Based on functioning (anti-infectives -> antibacterial -> penicilins) 37. Discuss the difference between “off label” and “unlicensed” use of drugs and illustrate with an example. - OFF label: used in other indications then approved: o IV Ig in Staphylococal septic Shock o Retuximab (anti-CD20) in idiopathic thrombocytopenia purpura - Unlicensed: use in different patient population, different dose, other routes of administration without taking into account any CI o E.g. use of enoxaparin (LMWH) as thrombo-prophylaxisin neurosurgical patients despite contra-indication (becauseof risk of bleeding) in package insert Why? Use in children, registration not attractive for company, application not researched, sometimes standard practice - 38. 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 Original product: production, transport and storage Alarm system ( on fridge, freezers) emergency electrical supply After reconstitution and dissolution o Antibiotics and injectable drugs (stability and sterility) 39. What is “polypharmacy”? What are the dangers associated with it? (also explain in the context of transmural care). - Concomitant use of multiple therapies (>5) Old age, associated/multiple pathologies, prescribing cascade Interactions and less compliance 12 40. What is seamless or transmural care? What are the barriers associated with it, especially in Belgium? - Efficient transfer of information associated with hospitalization Admission: Adequate drug history Discharge: which should be continued, added, … Hospital pharmacy: up to 3 days after discharge 41. Discuss the financial “life cycle” of drugs including the implications for the pharmaceutical company? Company: Price setting - Licensing (ministry of health care) - Original Price setting (ministry of economic affairs) - Basis for Reimbursement - Expiry of patent o No generic: decrease with 15% after 12y o Generic available: decrease with 30%, after 2, 4 and 12 years even further decrease -> reference reimbursement - Eventually >40% lower Government: reimbursement - Annual review of budget - Clawback and sparefunding from Pharmaceutical companies - Private insurance and Society funded Patient - Non-reimbursed vs reimbursed - Personal contribution 42. Give an overview of the reimbursement of drugs for ambulatory patients, depending on the “category” and “chapter” they are in (provide examples) - - Category: percentage of reimbursement based on importance A. Lifesaving 100% ex Insulin, cytostatics B. Therapeutic Important drugs 75% ex antibiotics, antiHT C. Symptomatic treatment 50-40-20% ex anti-conception, ASA D. Not reimbursed o Ministry of Health Care and Social Affairs (advice from committee of reimbursement) Chapter: criteria for reimbursement based on indication I. For all indications ex Antibiotics, Insulin all cat II. Indications based on IBM ex PPI, lipid lowering drugs cat B & C III. Infusion fluids ex parenteral nutrition cat B IV. Specific indications ex certain cytostatics and antifungals o A priori control: after approval by mutuality o Bis: drugs available abroad cat A & B 43. Give an overview of the existing options in Belgium to make drugs available to patients free of charge. What are the restrictions and requirements? - Compassionate use o Chronical or life threatening illness o Centralized procedure, if no alternative approved in Be o Ongoing registration or Clinical Trial o Company should inform Government and local EC o Physician can apply for CU 13 - - Medical Need Program o Same principles as CU o Under approval for other indications o Labeled as “MNP – Can not be sold” Medical Samples o Under approval and available o At most smallest package available o Labeled as “free sample – Can not be sold” o Not for narcotics, psychotropic, or it containing isotretinoin o Physician: max amount, should apply o Company: document and annual report Chapter 11: Registration and reimbursement – M Casteels FAGG: Federal Agency for Medicines and Health products, ensure quality, safety and efficacy MAA: Market Authorization Application CMA: conditional marketing authorization CHMP: committee for Medicinal Products for Human use EPAR: European Public Assessment Report SmPC: Summary of Product Characteristics: Definitive description including properties, chemical, pharmacological and pharmaceutical data and clinical use CTG: comité voor tegemoetkoming van Geneesmiddelen 44. Which are the most important procedures available in Europe for the registration of new drugs? Which are the pros and cons of each procedure? European medicines Agency - Central procedure o 1 application to EMA evaluation by CHMP (2 MS) -> EPAR -> gives final SmPC commitments, follow-up questions, outstanding issues, RMP 1 MA, 1 Tradename o Compulsory: Advenced technologies, Diabetes, HIV, Autoimmune diseases,devices, Orphan drugs… o Pro: 1 application, 1 approval, consensus and 10y exclusivity o Con: All-or-nothing, 1 tradename, limited time for translation, rapporteurs selected by CHMP (2 Member states) - MRP: mutual recognition procedure o National phase: application -> MA -> Assessment report o Mutual recognition: validation -> recognition -> National authorization o Pro: choose the reference MS, earlier commercialization , different Trade names, withdraw in one MS if concerns, still valid in others o Con: individual evaluation per MS (more objections), not all countries accept - DCP: decentralized procedure 45. 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? - Reimbursement after MA by Sponsor (within SmPC) Sponsor asks to admit, modify or cancel reimbursement Maximum price (M. of Economic Affairs) Apply for reimbursement with CTG -> motivated advice based on Motivation File 14 - - Reimbursement (M. Social Affairs) based on Class and Chapter o positive decision: inform Inspector of Finances and Ministry of Budget o Company notified within 180 Days o Transparency: Declare COI Integrate Evidence Based Medicine: safety, efficacy, added value, pharmacoeconomic arguments Possibility for revision: Follow-up, Group or individual Change of reference reimbursement after patent expires does not take into account: Real-life data, Rare AE, competitors, benefit/risk Chapter 12: the medical department – D. Vander Mijnsbrugge Attrition: High developmental failure, low discovery yield -> Interactions, manufactureing, side effects, efficacy, safety, dosing, lack of benefit. 46. Provide an overview of the tasks of a medical department within a pharmaceutical company. Research and Development – Global o Input on protocol development based on regulatory feedback Endpoints, design, comparators, feasibility, … - Select clinical sites : Infrastructure, knowledge, Interest, potential, … o follow up: compliance with GCP and protocol - Regulatory – European o Centralized procedure o Mutual Recognition Procedure o Coordinate local activities: answer questions, timely applications to Reg.Auth. - Access – Local o Reimbursement after registration o Maximum price (M. of Economic Affairs) o Apply for reimbursement with CTG -> motivated advice Individual revision: CTG decides when and what elements o Reimbursement (M. Social Affairs) o Evidence based: safety, efficacy, added value, pharmacoeconomic arguments - Commercialization o Life cycle of drugs: New Indications, dosing, formulations,.. o Maintain registration: renewal, Pharmacovigilance, keeping registration up-to-date Periodic safety update reports by Rapporteur MS o Maintain reimbursement: observational studies, post reimbursement commitment , monitor available evidence and present when needed o Medical information: strictly regulated -> Label, Scientifically accurate - Chapter 13: pharmacovigilance Pharmacovigilance: monitor safety, reduce risks and increase benefits of medicinal products RMP: Risk Management Plan PSUR: Periodic Safety Update report 47. Pharmacovigilance (pre-registration): discuss the causality assessment of an adverse event taking place during a clinical trial. - Determine the likelihood that the treatment is the cause of the ADE (case study) Important to determine Benefit/Risk ratio 15 - - - Is it possible? (previous knowledge) Dit it cause the AE? (assessment) o Global introspection: Based on clinical judgement o Algorithms: calculate likelihood based on soecific questions and scoring (rare) o Bayesian approach: probability based on prior knowledge or specific data (posterior) Multicausal: Drug (dose, interactions,…), person (age, sex, diseases,…), external factors Limited scientific value -> need for further research Important parameters o Time of reaction: reaction follows administration o Positive dechalenge: improvement in reaction when drug is withdrawn Not for irreversible reactions o Positive rechalenge: Event reoccurs, mostly accidental, when AE is objectifiable Benefit needs to outweigh the risks Performed by PI, can include DSMB 48. 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”? - ADR: all untoward and unintended responses to an IMP or to an experiment and, when an investigational product is concerned, related to any dose administered ADE: 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: Death, life-threatening, hospitalisation, disability or congenital abnormality Unexpected: when nature or severity is not consistent with existing information Suspected unexpected: 49. Discuss: Data Safety Monitoring Board. DSMB - Independent experts that follow-up Safety, progress and efficacy endpoints o Clinicians, Biostatistition, other experts: scientist, EC, parents,… - Gives advice on modifications, continuation and termination - When? In potential risk: large multicentre trials, severe morbidity as endpoint, … - What? Safeguard safety, study ADR, follow-up inclusion criteria, detect protocol violations, edit DSMP, detect high rates of drop out or exclusion, … - Interim analysis of potential risks, unblended o Evaluate efficacy, safety, detect potential bias, statistical analysis Data safety monitoring plan - Contains process to be followed to guarantee safety and well-being of participants - Monitor progression and safety, report any AE, ensure accuracy and conpliance 50. 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 Premarketing Period - Rechallenge and causality assessment not always possible - Very rare side effects are difficult to detect in a short time frame - The selection of subjects sample is very restricted: limited view contrast with the real situation (where everybody uses it with other medication) 16 Postmarketing Period - collecting data: sufficient information needs le reach company and authority o mutual responsibility - no RCT possible, mostly case studies (observational) - difficult to prove causal relationship 51. What are the objectives of pharmacovigilance and how is the reporting of supposed adverse drug reactions organized in Belgium? - - Guard safety and well-being of participants EudraVigilance: registration of all products and collect ADR o Detect ADR, learn about relevance and seriousness o EU: bigger database and harmonization, faster detection of signals Report ADR -> EMA and national Adjust RMP o Obligatory for registration -> Qualified person o Overview of all planned actions to prevent or reduce the risks o Part1: Risk profile and pharmacovigilance plan o Part2: Risk minimisation plan: Education, communication ,… PSUR’s o Interim report per substance o Standard obligation for registration -> by MAH 52. Which problems / challenges is post-marketing pharmacovigilance facing? Postmarketing Period - collecting data: sufficient information needs le reach company and authority o mutual responsibility - no RCT possible, mostly case studies (observational) - difficult to prove causal relationship 17