1. New drug development. Preclinical and clinical trials. Prof. M. Kršiak Department of Pharmacology, Third Faculty of Medicine, Charles University in Prague Charles University in Prague, Third Faculty of Medicine Cycle II, Subject: General Pharmacology Lecture: 18th October 2011 8:00-9:30 Jonas Hall, Ruská 87, Prague syllabus : http://vyuka.lf3.cuni.cz

2. 1.HISTORY OF DRUG DISCOVERY 2.SYSTEM OF EVALUATION OF EFFICACY AND SAFETY IN NEW DRUGS 3.STRATEGY, COSTS AND RISKS IN DISCOVERY AND DEVELOPMENT OF NEW DRUGS AT PRESENT 4.PHARMACEUTICAL COMPANIES 5.DRUG REGULATORY AGENCIES 6.SUMMARY

3. 1. HISTORY OF DRUG DISCOVERY Drugs/medicines of plant origin poppy - opium willow – bark Hippokrates 400 p.n.l. 1829 – salicin > 1853 sodium salicylate > 1899 acetylsalicylic acid ASPIRIN ADVANCES IN CHEMISTRY

4. Felix Hoffmann ASPIRIN Bayer 1899

5. 1905 FIRST CZECH TEXTBOOK OF PHARMACOLOGY 1905 there was: aspirin, digitalis, ether, cocaine, bromide, saccharin 1905 did not exist: drugs e.g. For hypertension, diabetes, asthma, antibacterial drugs, lipid- lowering drugs, psychotropic drugs emika, etc 1905 ignorance of neurotransmitters molecular targets of drug

6. + Advances in pharmacology 1963 propranolol – betablockers – hypertension, angina pectoris 1972 cimetidin – H 2 antagonists – peptic ulcer disease Sir James W. Black Nobel price 1988

7. GREAT SUCCESSES …BUT REGRETTABLY… DRUGS CAN SIGNIFICANTLY INCREASE LIFE EXPECTANCY AND QUALITY OF LIFE

8. DRUGS CAN CAUSE DISASTERS THALIDOMIDE 1956 – 1961 about 10 000 children affected, not in USA [FDA]

9. 2. SYSTEM OF EVALUATION OF EFFICACY AND SAFETY IN NEW DRUGS - BEFORE DRUGS CAN BE APPROVED FOR USE - AFTER DRUGS ARE APPROVED FOR USE

10. SYSTEM OF EVALUATION OF EFFICACY AND SAFETY IN NEW DRUGS PRECLINICAL DEVELOPMENT CLINICAL TRIALS REGISTRATION POSTMARKETING SURVEILLANCE SAFETY - PHARMACOVIGILANCE

11. PRE-CLINICAL DEVELOPMENT EVALUATION PHARMACOLOGICAL (pharmacodynamics, pharmacokinetics) TOXICOLOGICAL (toxicity acute, chronic, special toxicity tests e.g. – embryotoxicity,teratogenity, mutagenity, cancerogenity PHARMACEUTICAL (e.g. identity, formulation, stability) GOOD LABORATORY PRACTICE - GLP

12. CLINICAL TRIALS GCP (Good Clinical Practice) selection of probands, randomization, control group, double- blind experiment, randomized controlled trials (RCT), placebo, bias, informed consent, Declaration of Helsinski, ethical committees …

13. PHASES I.healthy volunteers a small (20-100) group – first evaluation of tolerability, kinetics II.first patients larger groups (100-300) - first evaluation of therapeutic efficacy III.randomized controlled multicenter trials on large patient groups (300–3,000 or more) - the definitive assessment of how effective the drug is IV.Postmarketing surveillance after drug receives permission to be sold - the safety surveillance CLINICAL TRIALS - cont

14. NEW DRUGS NOVEL TYPE OF ACTION NEW CHEMICAL/ MOLECULAR ENTITY (NCE/NME) „MEE-TOO“ GENERICS (actually copies of the original drug once the patent expires) 3. STRATEGY IN DISCOVERY AND DEVELOPMENT OF NEW DRUGS Known type of action, but NCE/NME [additional betablockers, H 2 antagonists, PPIs, statins, triptans etc…] first betablocker, H 2 antagonist, PPI, statin, triptan … bioequivalence „Blockbuster“

15. 3. RISKS IN DISCOVERY AND DEVELOPMENT OF NEW DRUGS -NME Preziosi 2004

16. 3. COSTS IN DISCOVERY AND DEVELOPMENT OF NEW DRUGS - NME

17. NEW DRUGS NOVEL TYPE OF ACTION NEW CHEMICAL/ MOLECULAR ENTITY (NCE/NME) „MEE-TOO“ GENERICS (actually copies of the original drug once the patent expires) 3. STRATEGY IN DISCOVERY AND DEVELOPMENT OF NEW DRUGS Known type of action, but NCE/NME [additional betablockers, H 2 antagonists, PPIs, statins, triptans etc…] first betablocker, H 2 antagonist, PPI, statin, triptan … bioequivalence „Blockbuster“

18. 4. PHARMACEUTICAL COMPANIES Pfizer, AstraZeneca, Eli Lilly, Merck, Novartis, Abbot, GlaxoSmithKline, Bristol-Myers, Sanofi-Synthelabo, Janssen-Cilag, etc.

19. 1951 -1990 (1999) VÝZKUMNÝ ÚSTAV PRO FARMACII A BIOCHEMII (VÚFB) AJATIN liq., tct. DITHIADEN tbl., inj. VALETOL tbl PROTHIADEN tbl. MESOCAIN inj., gel. TRIMEPRANOL tbl., inj. KINEDRYL aj., aj. New drug discovery and development in Czech republic - history MEE-TOO DRUGS

20. PROTHIADEN (dosulepin) Domestic (SPOFA) Exported (Boots) 1968-19940,5 bilions Kčs 23 bilions Kčs Dr. M. Protiva, DrSc. prof.MUDr. Z. Votava, DrSc. RNDr. PhMr. J. Metyšová,CSc. VÚFB antidepressant

21. TRIMEPRANOL (metipranolol) Domestic (SPOFA) Exported (Boehringer- Ingelheim) 1971-19931.460 bilions Kčs 11.2 bil. Kčs Doc. MUDr. Václav TRČKA, DrSc. VÚFB betablocker

22. NCE/NME Antivirals New drug discovery and development in Czech republic - at present ZENTIVA Good Manufacturing Practice GENERICS Prof. RNDr. Antonín Holý, DrSc., Dr.h.c. Institute of Organic Chemistry and Biochemistry Academy of the Sciences of the Czech Republic Prague

23. 5. DRUG REGULATORY AGENCIES EUROPEAN MEDICINES AGENCY (EMEA) Committee for Medicinal Products for Human Use (CHMP) Státní ústav pro kontrolu léčiv (SÚKL) Medicines and Healthcare products Regulatory Agency Bundesinstitut für Arzneimittel und Medizinprodukte FOOD AND DRUG ADMINISTRATION (FDA) → www.ema.europa.eu

24. 6. SUMMARY DRUGS CAN SIGNIFICANTLY INCREASE LIFE EXPECTANCY AND QUALITY OF LIFE DISCOVERY AND DEVELOPMENT OF NEW DRUGS IS DIFFICULT, COSTY AND RISKY A SOFISTICATED SYSTEM FOR EVALUATION OF EFFICACY AND SAFETY OF DRUGS HAS BEEN DEVELOPED