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Prescription (legal) status

Prescription (legal) status. Categories vary country by country NP („OTC”) POM Subcategories. Prescription. 1. EU Directive. Main categories NP POM  renewable/non-renewable prescr iptions  special medical prescr.

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Prescription (legal) status

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  1. Prescription (legal) status Categories vary country by country • NP („OTC”) • POM • Subcategories Prescription 1

  2. EU Directive Main categories • NP • POM renewable/non-renewable prescriptions  special medical prescr.  restricted medical prescr., reservedfor use in spec. areas 2

  3. EU Directive A medicinal product is NP, if it does not meet the criteria of POM (Very important!) (In many countries just the opposite is applied) 3

  4. EU Directive When POM? • danger, even used correctly, if without medical supervision • frequently used incorrectly presenting danger • APIs with activity/ADRs still be studied • parenterals 4

  5. EU Directive POM, sub-category specialist’sprescription • narcotic/psychotropic substance • if used incorrectly, abuse/misuse • novel active principle, precautionary 5

  6. EU Directive POM, sub-category restricted use • can be used in hospitals only • can be diagnosed in hospitals only • specialist’s supervision (e.g. ADRs) 6

  7. EU Directive (SUB)CATEGORIZATION • Taking into account single and max. daily doses, strength, dosage-form, pack unit • Annually updated published list of POM (sub)categories 7

  8. EU Guideline Goal: To help MAHs when applying to change the classification (i.e., to harmonize the swithches!) • POM/NP criteria • switch application criteria 8

  9. Guideline NP or POM? Direct danger: even if used correctly • Toxicity • Serious and existing less serious ADRs • Interactions with commonly used drugs 9

  10. Guideline NP or POM? Indirect danger: • Masking conditions that would require medical attention. NP: time-limit must be set • Wider use increase resistance, particularly in general population 10

  11. Guideline NP or POM? Risk and consequences of incorrect use • If used according to indications (too many contra-indications, precautions, warnings, etc. May lead to incorrect use • If the opposite: off-label or longer use 11

  12. Guideline NP or POM? Self-assessment/diagnosis • Symptoms can be correctly assessed by patients (may vary country by country!) • Natural course of disease, duration or re-occurrence of symptoms may be self-assessed • Contraindications, etc. can be understood by the consumer 12

  13. Guideline NP or POM? • The way patient info is written • „If not POM, must be less dangerous” • Layman’s terms used? • Explanation of use? • Explanation when should not be used? 13

  14. Good question - who is „Patient”? 14

  15. Summarising the legal status Ailment Treatm. ADR Dr’s diagn. Med.Att. Status Minor any NS none no NP Major single NS yes no NP/POM Major long NS yes rare NP/POM Major long S yes rare NP1/POM Major any any yes yes NP2/POM 1if the patient can be informed… 2the smallest pack size 15

  16. In case of rigid systems... The NP/POM choice may cease to exist! Rigid systems: • Drugs are officially classified either NP or POM (NP may be prescribed but not vice versa!) • If NP no reimbursement 16

  17. Professional switches? • It must be realised: this is a semi-political matter! • If no consensus between reimbursement-policy makers and DRAs, affordability problems may occur! 17

  18. The second issue: OTC distribution channels in the country and/or 18

  19. The third issue: Patients, their perception to medication, knowledge on drugs, etc. (Average patient does not exist!) 19

  20. Back to the registration: Accompanying sheets • SmPC (Summary of Product Characteristics = Data Sheet) for professionals • PIL for patients • Label • (Assessment Report written by the DRA) Medi cine 20

  21. Issuance of the MA • Civil Service authoritative text (what is contained is binding!) • The Accompanying Sheets annexed STAMP 21

  22. Actual marketing (in many countries)? Pricing and reimbursement negotiations! • MA: risk/benefit • Pricing, reimbursement: cost/benefit 22

  23. MA withdrawn (deletion from the Register) • Applies to „the product”! • Who may initiate: • MAH - without specifying any reason (!) • Medical Boards, DRA - with good reason (risk/benefit) • Civil Service authoritative decision 23

  24. Withdrawal/Recall from the market • It applies to a given batchof the medicine! • Decided by the DRA, MAH may initiate it • In Hungary: DRA informs by telefax the Nat. Publ. Health Serv., and central health-care organs • Then “info-cascade” in the counties 24

  25. European Union • The present marketing authorisation rules and procedures 25

  26. Certain EU terms • Sources of law:  Regulation  Directive • Brussels: Commission, DGs DG Enterprise, DG SANCO • London: European Medicines Agency (EMA) 26

  27. EMA • Established in 1995 • Both 2 DGs pharmacists until now • Task: centralised MA procedure, ADR monitoring, guidance, appeal procedures • Committees (one per member state) 27

  28. EMA Committees • C’ttee of Human Medicinal Prodcts CHMP • C’ttee of Veterinary Medicinal Products CVMP • C’ttee of Orphan Medicinal Products COMP • Herbal Medicinal Products C’ttee HMPC • Pediatric Committee PDCO • C’ttee of Advanced Therapy Medicinal Products CAT 28

  29. MA procedures in the EU Procedures • Centralised CP • Decentralised DP • Mutual recognition MRP • National 29

  30. Centralised MA procedure • Mandatory: biotech substances, HIV/AIDS, cancer, diabetes, neurodegenerative diseases, orphan drugs (5:100,000), somatic cell- and tissue therapy medicinal products • Possible:  new active substances “high-tech products”  new, “important” indication  blood products 30

  31. Centralised procedure • One single application to EMA • CHMP-assessment (2 rapporteurs from MSs) • 210 days dead-line, then EMA issues Accompanying Sheets (SmPC, PIL) and Assessment Report in all languages • MSs: 15-day possibility for „serious risk to public health” appeal • Then signature by the Commission in Brussels: MA valid for the whole EU • If negative: banned for the whole EU! 31

  32. Decentralised procedure • Possible: any product for which CP is not mandatory • “Referens MS (DRA)”, RMS where the first application is submitted (“lead market”) and • Concerned MS (DRA) CMS where to submit later 32

  33. Decentralised procedure • Application dossiers sent to RMS and CMSs, validation • RMS: preliminary MA issued (time-frame!), Accompanying Sheets and Assessment Report (also in English) • Discussion with to CMSs = final MA = national MAs in RMS and CMSs • Opposing opinions: appeal (see CP) • Any changes: similar procedure 33

  34. Mutual recognition • (When the MA has already been issued in one MS) • The Firm requests an AR (in English) from the national competent authority (it is the RMS then) • It, together with the full documentation submitted to CMSs asking a „recognition” of the AR (time-frames!) • Opposing opinions: appeal (see CP, the decision is binding) • Any changes: similar procedure 34

  35. EU registration collaborations • Many Working Groups and Committees under EMEA and Commission • EMEA CHMP Q, S, E, Herbal Medicines, Pharmacovigilance, Heads of Agencies, etc. Working Parties • Commission Pharmaceutical Committee 35

  36. Back to the general regulatory affairs concerning registered drugs on the market

  37. Post-marketing surveillance • GMP (manufacturers), GDP (wholesalers), GCP (CT sites), GLP (safety study laboratories) • Drug Adverse effect monitoring (Pharmacovigilance) • Mandatory Quality defect reporting national system 37

  38. Pharmacovigilance Doctors and Marketing Authorisation Holders must report (to the DRA) • serious • unexpected (not listed in the information for professionals) side effects (=adverse drug reactions, ADRs), level of seriousness, time-frames may be specified in the law 38

  39. A little story: what happens to these ADR reports? • ADR Data Banks at national, regional (e.g. European Union) and global (e.g. WHO ADR Monitoring Centre in Uppsala, Sweden) • All ADR data put into the Banks • From time-to-time, professionals review similar data • If the connection between taking a drug and the ADR is possible: it is called a signal and national ADR centres, professional societies, etc. signalised: monitor this ADRs of this drug strictly • If the connection becomes proven (many cases!): it comes to the information material of the drug

  40. A signal generation story (WHO Uppsala Monitoring Centre) • Spontaneous reports ot the Data Bank • Data „mining” with softwares • Signal generation review • If causality probable: signal message to the National Monitoring Centres • If proven later: part of the information material of that drug

  41. Signal to the hydroalcoholic extract of a medicinal plant: Teucrium chamaedrys

  42. Signal generation example 1 • Teucrium chamaedrys: the hydroalcoholic (alcohol-water) extracts of the herb are extremely bitter. It is frequent component of reductant (anti-obesity) tees • There were more than 20 data on hepatic adverse reactions (jaundice, hepatitis) in the WHO database • In cases when the patients, after recovery, drank the tee again, the same symptoms were recurring very quickly (in 2 days, the note at the registration was: rarely possible!)

  43. Signal generation example 2 • How to start the review? • If the quick recurrence is true, that would mean an immunological mechanism • Literature search: can liver damage be caused via immunological mechanism? • Answer: yes! • Literature search: the main components of the plant are diterpenoids and fenyl-ethanoid glycosides, they are free radical scavengers

  44. Signal generation example 3 • But these are small molecules, too small for an immune response. Could they modify human proteins by binding on them? (E.g. an alkylating mechanism)? • Literature search: • the tsructure of the plant components: there is no alkílating agent among them • but, if free radical scavengers, they perhaps will be metabolised via oxidation • Literature search: what could be oxidised metabolites of these components? There is a furane ring on the side chain of one of the triterpenoids (the tecurin-A)

  45. Signal generation example 4 • Literature search: the oxidative metabolism of the furane ring is: • Irodalmazás: this epoxid can alkylate the human epoxid hydrolaseenzyme, the resulting modified protein is „foreign”, there will be antibody formation against it… CYP450 O O O

  46. Signal generation example 5 • But the extracts of the plant are widely used in various products as amarum. If this is the basis of the adverse effect, why is it so rare? • The place of oxidative metabolisms is the liver. Perhaps is there something in the liver to react with the epoxide, other that the mentioned enzyme? • Literature search: the epoxidesaz epoxidok prefer reaction with „soft” (according to the Pearson classification) nucleofils • Is there such compound in the liver? Yes! The γ-L-glutamyl-L-cysteinil-glycin (glutathion) -HN-CH-CO-NH- CH2-SH

  47. Signal generation example 6 • Now we already know why only the anti-obesity tees caused the (relatively high number of the) adverse effects • Glutathion: extreme diurnal changes in the organism! When fasting, its level goes almost to zero! And people whi take anti-obesity tees are fasting… • The signal is ready! WHO Signal, March 2006, pp. 8-17

  48. National mandatory quality defect reporting system • Wholesalers, marketing authorisation holders must report to the DRA drug quality defects, pharmacies even suspected ones • Prerequisite: at least organoleptic checking of incoming drugs mandatory 48

  49. You may say that no quality defect can never be identified by organoleptic checking – is it true? 49

  50. „the same” tablets in the same package unit 50

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