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National Drug Quality Assurance • Regulated introduction of new drugs • National Drug QA laboratory • Inspection of the drug supply chain (GMP) • Organised recall if quality defects 1 Regulated introduction of new drugs WHO: 3 levels •„Registration”: assessment of submitted dossier + certain own tests •„Authorisation” on the basis of foreign registration + WHO Certification Scheme •„Notification” (simple listing) 2 Notification • In the less developed countries: only „to know, what is on the market” • If drugs imorted in ahigher quantity or donated: their data (name, API, origin, etc.) must be notified (e.g. MoH) • MoH has/issues the actual list 3 Authorisation • Moderately developed countries: select countries the drug authorisation of which is recognised, publish it + WHO Certificate from these countries’ authorities needed • No (or minimal) local assessment, data put into the Register 4 Registration • Submission of formal dossiers (quality, safety, efficacy, both animal and human studies) requested • (at least some parts of the) dossier assessed locally (e.g. quality, bioequivalence), some own tests (e.g. physico-chemical and chemical quality control, in vitro dissolution) • Suitable also for registration of locally manufactured drugs 5 Further on, we speak about full Drug Registration (Bee careful, the EU and WHO/USA English may differ!) I use registration = marketing authorisation 6 Why is it important? The pharmacist always should speak about medicines. It were a pity not to know how they are assessed and authorised... 7 Moreover... There are always inventors Natural products in fashion Physicians’ or pharmacists’ new combinations The patient heard something (Internet!) 8 Medicine (assessment for) registration = = very complex (and interesting!) in nature, it is better to know it! 9 Medicine registration = marketing authorisation (EU terminology) Medicine Act: only authorised medicines may be used Marketing authorisation: the most frequent one 10 Other kinds of authorisation? • Individual import or compassionate use (rare diseases, to a named patient or to a hospital) • Donation (to hospital, pharmacist’s supervision advisable!) • Clinical trial samples 11 Medicine registration Legal side (both the regulatory authority and the Firm are concerned) Pharmaceutical/medical (professional) side (assessment: suitable to be medicine or not?) 12 Registration? • Product categorisation is it medicine? • Professional side is it suitable to be medicine? • Legal side civil service step with consequences 13 Professional side Assessment of the documentation (sample) submitted • Quality (substances and preparation) • Relative safety • Efficacy (risk/benefit) 14 Registration: professional side • Application — Assessment of • Quality and its guarantee (Manufacture and ? process validation, Quality Specification and method validation, Pharmaceutical development) • Safety (animal and clinical toxicology) • Efficacy (experimental and clinical pharmacology) • Authorisation with info material 15 Before detailing the drug registration: • Intellectual Property rights (IP): Patent protection • Data exclusivity 16 Patent protection • After synthesis (etc.), new innovations (e.g. drug entities) may be patented • As a rule, 20 years • („Bolar provision” permits the same drug development, clinical trials, registration underpatent protection, but not marketing!) 17 Data exclusivity, 1 • Generic route of registration: patent expired, other manufacturer may produce similar drug with the same API • No animal experiments and human clinical trials performed, only the „equivalence” to the innovator product proven… 18 Data exclusivity, 2 • …as if it said „I do not know what is in the innovator’s pre-clinical and clinical dossier submitted, however, for I Have proven the equivalence, take as I had submitted the same dossiers” • =reference to the innovator’s data 19 Data exclusivity, 3 • DE is to forbid the regulatory authorities to accept any reference to the innovator’s data for a specified period of time after the registration (10 years in the EU at present, from the first registration in any of the member states) 20 PP and DE • Patent: 20 years from filing the patent protection request (the drug still in early development phase) • DE: 10 years from the first registration! 21 Patent/DE issues during registration • As a rule, DRAs are not empowered to clarify patent/DE issues when new drug applications are submitted (however, in Canada, the MA is on hold and issued only after patent issues are checked) • Moreover, it would require enormous resources • Advisable solution: Applicant’s declaration required that IP/DE rules were clarified and no violation found 22 Doha declaration • November 2001 • Permits development and export of a generic product, still under PP in the country of manufacture, to developing countries • as a rule, the brand patent holder’s (BPH) consent needed • BPH is given also royalty 23 Doha arrengement • e.g. Canada, European Union signed • Labelling that would hinder re-export • e.g. HIV/AIDS medicines concerned 24 The art of medicine registration and assessment Documentation Expert Reports 25 In drug assessment • Work interdisciplinary • Everything must be evaluated from every angle! • (A fulsih exampleon the next slide) 26 „Everything must be evaluated form every angle”! Do you like this girl? See it upside down. Do you still like her? 27 Common Technical Document • An ICH Guideline • International Conference on Harmonisation of technical requirements for registration of pharmaceuticals for human use: EU, USA, Japan - DRA and Industry • „Soft law” 28 CTD M1 Regional administrative info Quality M2 Not part of CTD Nonclinical overview Clinical overview Nonclinical summary Clinical summary overall summary M3 M4 M5 Quality Nonclinical study reports Clinical study reports CTD 29 Structure and terms Structure for all parts: • Introduction • Overview: short description • Overall summary: written tabulated • Original study/trial reports E X P E R T R E P O R T S 30 Expert reports • EU phylosophy: an evaluated documentation should be submitted for authorisation • DRA review: comparison of the review done by the Company expert with that done by the regulatory one • Never „to try to find out” why something was (not) done 31 Quality Overall Summary • 40 pages + tables, figures • Evaluates the quality module, emphasising critical key parameters, justifies when guidelines are not followed, reference to other modules (e.g. toxicological qualification of impurities) 32 Quality module, 1 DRUG SUBSTANCE (API) • General info (nomenclature, structure, general properties) • Manufacture (flow diagram, catalysators, solvents, temp., yields, etc.) • QC of starting materials (standards and justification of the grade) • Critical steps (identification and control) 33 Structure elucidation of new APIs – see the 3D structure! paroxetin SO2NH 2 Cl furosemid HOOC NH-CH2 O 34 Structure elicidation of new APIs paroxetin SO2NH 2 Cl furosemid HOOC NH-CH2 O 35 3D structure • Elucidation (abs. and rel.) – but not enough! • Assessment: other structure also present impurity characterisation • Racemate or one single? (issue, PK, PD) corporate decision: reveal it – hide it until PP expires? citalopram – escitalopram • Stereochem. stability – If rapid interconversion: in vivo also possible metabolism – If slow interconversion: take it into consideration at PD and PK for the other form may have different action or at the toxicity studies (3 months + peri- és postnatal, minimum in 1 dose), 36 as well as at planning human clinical trials Physical structure • Particle size (issue: dosage-form, significance?) – Dissolution, bioavailability? (PK) Coated tablets under electron– During the processing? microscope – Stability? – Content Uniformity (API-content in dosageform units)? – appearance? 37 Quality module, 2 DRUG SUBSTANCE • Process validation (plans, limits, operational parameters, etc.) • Manufacturing process development (description, discussion, changes) • Characterisation (impurities, reference to their toxicity, specification, test methods and validation, batch analyses, reference standards) 38 „Impurity rule”, ICH • Unknown impurity should be noted: max. daily dose 1 g: 0.1%; 1 g: 0.05% • Impurity should be identified: max. daily dose 1 mg: 1%; 1-10 mg: 0,5%; 10 mg2 g: 0.2%; 2 g: 0.1% • Impusity must be toxicologically characterised: max. daily dose 1 mg: 1%; 1-100 mg: 0.5%; 100 mg-2 g: 0.2%; 2 g: 0.15% genotox. (in vitro mutagen. + kromoszóma-aberráció), egyszeri dózis, ismételt dózis 1-3 hó 39 Quality evaluation Drug analysis! Toxic degradation products, 1) • Acetilsalicylic acid (everobody knows?) • cefalosporins • oxitetracyclin • PAS • Fat emulsions... 40 Tetracyclin and its one toxic degradation product H3C OH HO CH3 N-CH3 O HO O O H tetracyklin H3C CH3 N-CH3 OH OH CONH2 CONH2 HO OH O O O H epi-anhidro-tetracyclin Renal complaints, tubular necrosis, reverzible Fanconisyndrome 41 Quality evaluation 2) Anaphylactoid reactions of degradation products • corticosteroids • penicillins The ampicillin story Studies in a Swiss hospital pharmacy 42 Corticosteroid-protein interaction CH2-OH C=O cortikosteroid HC=O ox. C=O H2N H2N CH- arginin-reziduum of human proteins The new modified protein is taken as „foreign” by the human immune system and antibody formation starts 43 The ampicillin-story • Hungary, the early 80’s. The Paediatric Clinic (Budapest) notifies the regulatory authority: after administration of the (Bulgarian) Ampicillin injection there was a temperature elevation in children. It never occurred formerly when British Ampicillin injection was used • ? • HPLC-analyses, withdrawal from the market. International debate (won!), etc. • What happened? 44 Amino-penicillin decomposition product as eliciting antigen • Beta-lactam of one penisicllin molecule reacts the amino group on the side chain of an other penicillin molecule, the beta-lactam of which reacts another side chain amino group, etc. • oligomers (n = 4-8) formed this way) -CO-NH-, i.e. peptide! • (With which bonds) • These are still small molecules for antibody formation, however, may react with existing penicillin antibodies giving rise to clinical manifestation of an anaphylactoid reaction (no clinical manifestation would occur in case of intect penicillin!) • One of the symptom of the anaphlactoid reaction is: fever! 45 Swiss hospital pharmacy study • Comparison of penicillin infusion treatment • Two groups – Penicillin injection into a large volume (1 litre) infusion solution („inject the patient only once”), preparation the day before, stored in refrigerator – Penicillin injection as bolus or in rapid infusion • Significantly more hyeprsensitivity reactions in the first group! 46 Solvent residues, ICH 3 solvent classes: 1. To be avoided! benzene, chloro-ethanes… 2. To be limited chloro-methanes, methanol, ethylene glycol, acetonitrile… 3. Less toxic • Limits everywhere, depending on the single and daily dose, but there are also absolute limits such as for acetonitrile 410 ppm 47 Solvent residues, examples • Benzene (class 1!) e.g. may be sideproduct of a Grignard-reaction (Ph-Mghalogenide, hydrolysis of its excess) • The API is mesylate and the dosage-form has ethanol residues: ethyl mesylate is formed later (mutagenic)! (Methanesulfonate = mesulyte) • In an application: loss on drying of an API”: 99.2% ethanol, 0.1% water. What can be the remaining part? Wasis absolute ethanol, the benzene is possible? 48 Quality module, 3 DRUG SUBSTANCE • Container and closure system (choice of primary packaging, quality, dimensions, description of secondary) • Stability (pre-approval forced degradation: types of studies, their justification; post-approval study plans, data and evaluation) 49 Quality module, 4 DRUG PRODUCT • Description and composition (all constituents, their functions and qualities) • Pharmaceutical development (compatibility of API with excipients, rationale, formulation development, manufacturing process development, container and closure, microbiological attributes, if appropriate) 50 Just a word: are the excipients „inactive” regarding therapy, and safe? The CJD story 51 Terms • Creutzfeld-Jacob Disease = CJD = fatal neurodegenerative condition. Patients develop a rapidly progressive dementia associated with multifocal neurologic signs • Sporadic CJD = sCJD, 1-2 cases per million people per year. Its cause is unknown. (continued) 52 Terms (continued) • Variant CJD = vCJD = caused by prion (see BSE!) or iatrogenic way by contaminated human pituitaryderived growth hormone, gonadotropin, corneal transplants, etc. • The casual link between vCJD and BSE is based on epidemiological, biochemical and transmission (animal) studies (continued) 53 Terms (continued) • Bovine Spongiform Encephalopathy = BSE. Identified first in British cattle. Attacks the brain of the animal. The disease originated from the use of feed supplements contained meat contaminated with a TSE agent (mammalian derived protein) • TSE = Transmissible Spongiform Encephalopathy = BSE, scrapie (in sheeps, goats) (continued) 54 Risk • Human blood products exclusion criteria for donation: - CJD - transfusion - pituitary gland hormon therapy • Vaccines produced in animals • Bovine, etc. derived materials used in drug production 55 Measures to minimise risk to humans from vaccines produced in animals • Selection of source countries: GBR Geographic BSE Risk (World Organization for Animal Health) • Use of well-monitored herds 56 Measures to minimise risk to humans from excipients from animal sources • Lactose from milk – appeared to be less/non infectious • Gelatin (!) from bovine bone, skin… (Animal, human) Tissue infecticity categories 57 High-infectivity tissues High-infectivity tissues brain, spinal cord, retina, pituitary gland… Lower-infectivity tissues lymph nodes, large intestine, lung, perhaps blood Tissues with no detected infectivity placenta fluids, bone, skin, milk 58 Gelatin • Skin gelatin: less dangerous than bone gelatin • Bone gelatin: brain, spinal cord must be excluded from source bone! • Alkaline hydrolysis better than acidic treatment alone • Also: source country and noninfected herd selection, certification (gelatin deliveries should be followed back to the source) 59 Quality module, 5 DRUG PRODUCT • Manufacture (each steps, batch formula, process and IPC description, critical steps and their control, process validation, excipient control and its validation) • Product control (specifications, justification, test methods, validation batch analyses, reference standards) • Container and closure system 60 Importance of dosage-form characteristics (such as dissolution) • …and the presentation of the dosage-form development in the application dossier • The nitroglycerol sublingual tablet story in Hungary 61 Nitroglycerol 0.5 mg sublingual tablets • Angina pectoris attack – treatment – prevention (according to the personal experience, to be used before/starting the provocation of the attack) • Adjuvant therapy of acute asthma cardiale in urgent cases • In acute myocardial infarct… 62 angina pectoris and nitroglycerol… 63 Nitroglycerol 0.5 mg sublingual tablets • Hungary, early 80’s: the nitroglycerol API production temporarily blocked • The Ministry of Health, to avoid shortages, imported „similar” tablets without prior checks or registration (that time it was possible) • They appeared to be not „similar”! 64 The NG story • The most of the complaints received to the „Soviet” tablet. There were two kinds of complaints – No therapeutic action – Too rapid and strong action • The API content was in order • The regulatory authority developed a special dissolution test (small volume dissolution media + HPLC) 65 NG 0.5 mg sublingual tablets 100 80 Dissolv- 60 ed % Soviet Polish Hungarian Roman 40 20 Soviet 5 4 3 2 Roman 1 0 0 time (min) Well, which of the is „good”? 66 The question was wrong! • Any of them can be „good”! • But you can toke take any according to the another’s instructions! • Hungarian tablets: „when you feel the attack is coming, place one tablet under your tongue. When the signs of the attack are over, take the remaining part of the tablet out of your mouth” 67 NG 0.5 mg sublingual tablets • The Soviet one was a „pastille”, it disintegrated completely at once in the mouth by releasing all the NG. Then – If the patient swallowed it: the absorption from the stomach is slower = „no action” – If not, all the active principle absorbed from under the tongue at once: „too strong action” • Remember to one of the former class hours: „Drug = product + information”! 68 Quality module, 6 DRUG PRODUCT • Stability (pre-approval forced degradation: types of studies, their justification; post-approval study plans, data and evaluation) • Literature references 69 Nonclinical overview • 30 pages. Critical evaluation. Comments on GLP status. Association with quality module (impurity pharmacology and toxicology) • The structure follows that of the nonclinical written summaries 70 Nonclinical written summary, 1 GENERAL GUIDANCE • Age- and gender-related effects should be discussed • Animal exposure discussed in relation to that in humans • Species sequence (mouse-rat-hamster-rabbitdog-primates-other) • Route of administration sequence oraliv-im-ip-sc-inhal-topical) 71 Nonclinical written summary, 2 PHARMACOLOGY • • • • • • Primary pharmacodynamics Secondary pharmacodinamics Safety pharmacology Pharmacodynamic drug interactions Discussion, conclusions Tables, Figures 72 Pharmacology evaluation Experimental pharmacology on animals • What is the action? the pain test story 73 Hot plate test • Hot-plate test: rat placed on a plate, itis warmed, the time (or temperature) when the rat licks its legs or jumps (indicating the warmth of the plate has been recognised) is recorded • The better is the pain-killing effect the later (at a higher temperature) is the record 74 The hot plate test story • Hungarian inventor: new substance, with a morphine-like pain-killing result • Authority assessor: dose too close to LD50 • Assessment: the rat became sick with the high dose, if so: recognised the warmth later, but it is not a painkilling effect! 75 The hot plate test story • Pharmacology results can not be evaluated without taking the toxicology data into account! • In general: all different data needed for the final evaluation! 76 Nonclinical written summary, 3 PHARMACOKINETICS • • • • • • • Methods of analysis Absorption Distribution Metabolism Excretion Pharmacokinetic drug interactions Discussion, Tables, Figures 77 Nonclinical written summary, 4 TOXICOLOGY • Rationale for the programme • Single-dose tox., Repeat-dose tox. (various from 1 to 9 months), Genotox., Carcinogenecity, Reproductive tox., Studies in juvenile animals, others (e.g. dependence). • Discussion, Tables, Figures 78 Other nonclinical part • Nonclinical tabulated summaries • Nonclinical study reports 79 Clinical overview • 30 pages. Critical evaluation. Comments on GCP status. Association with safety module (toxic symptoms, interactions) • The structure follows that of the nonclinical written summaries 80 Clinical written summary, 1 • 50 to 400 pages BIOPHARMACEUTIC studies • Development, in vitro-in vivo, dissolution to develop bioavailability, anal. methods • Summary of individual studies, comparison accross studies (possible effect of food…) 81 Clinical written summary, 2 CLINICAL PHARMACOLOGY • Human PK, PD, in vitro studies on human cells (dose-response, metabolism, dosage-ranging, single and repeated-dose PK, population PK) • Immunogenecity (for proteins, e.g. vaccines) • Clinical microbiology (if relevant) 82 Clinical written summary, 3 CLINICAL EFFICACY • The programme of controlled (and any other) studies, design, comparative efficacy, long-term efficacy • Individual studies, comparison of results across studies (population, baseline characteristics, drop-outs, etc.) 83 Clinical written summary, 4 CLINICAL SAFETY • Extent of exposure to the drug (population, concomitant illness, etc.) • Adverse events (common, serious, deaths, by organ and syndrome) • Clinical Lab evaluations • Special groups and situations (ethnic, alcohol-food, pregnancy and lactation, overdose, abuse, withdrawal, driving 84 Clinical written summary, 5 CLINICAL SAFETY • Post-marketing data (ADR reporting if it does exist in the country. Spontaneous or mandatory reporting) 85 Proof for safe use of a drug • I.e. acceptable therapeutic effect/health risk ratio • How it was established: we speak about different „levels of proof” 86 Levels of proof: I. Meta-analysis of randomised, controlled clinical trials Ib. At least one randomised, controlled clinical trial IIa. At least one controlled, non/randomised clinical trial IIb. At least one open clinical trial III. Documented data on individual treatments, evaluated by scientific methods IV. Expert/regulatory Committees published standpoint on the basis of evaluated literature data 87 Terms used • Meta-analysis: statistical method to „pool” data generated in different clinical trials • „Randomised”, „controlled”, „open”: see the lecture on clinical trials • Level I. gives the highest, level IV. the lowest acceptable proof • As a rule, minimum level Ib. is needed for the registration of a new drug in the Developed World. Herbal drugs: see later 88 Complete application (new medicine) • (ten)thousands of pages • hundredMios of USD 89 Application types Not only „completely new”: • Registered in another country • Line-extension • Generic 90 Line extension • New strength, dosage-form... • It is advisable to use the template of the complete application and explain what is missing and why 91 Generics “it shall not be required to provide results of toxicological and pharmacological tests and/or clinical trials if it is demonstrated that the product is essentially similar to a medicinal product authorised in the Member State concerned…” 92 Generics • PP and DE expired • Equivalence proven instead of pharmacotoxicology and CTs: bio-, farmacodynamic, clinical, evidence, in vitro • cheaper! C time 93 „Pharmaceutical equivalence” • identical API • comparable (administration) dosageform • strength? only the same strength two 50 mg tablets = one 100 mg tablet ½ 100 mg tablet = one 50 mg tablet? 94 Bioequivalence • Equivalence established by pharmacokinetic (PK) method • After administration of two (pharmaceutically equivalent) drug products: comparison of blood level – time curves • Area under curve (AUC), the maximum concentration (cmax)and the time belonging to cmax (tmax) are compared, the maximu permitted differences specified 95 Pharmacodinamic equivalence • Not only blood level could be measured for comparison in some cases, but e.g. blood pressure, body temperature… • Rarely used 96 Equivalence by comparative clinical trials • When no blood level or pharmacodynamic data could be measured • E.g. comparing the two pharmaceutically equivalent drugs by treating 100-100 patients 97 Equivalence based on „evidence” • E.g. two aqueous i.v. injections are, by definition, bioequivalent (shot into the vein: the drug is there!) • Also, as a rule, oral aqueous solutions 98 Equivalence established by in vitro data • Limited value! (Can the LADME be modelled by L exclusively?) • Can be used e.g. for oral immediate release dosage-forms with an API that is highly soluble and permeable (see the Biopharmaceutical Classification System, BCS) 99 Medicine assessment • surely multidisciplinary business • experts writing the summaries must emphasise the logics of the product development, preclinical study and CT strategy 100