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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
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
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
Felix Hoffmann
ASPIRIN Bayer
1899
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
+ Advances in pharmacology
1963 propranolol – betablockers – hypertension, angina pectoris
1972 cimetidin – H2 antagonists – peptic ulcer disease
Sir James W. Black
Nobel price 1988
GREAT SUCCESSES
…BUT REGRETTABLY…
DRUGS CAN SIGNIFICANTLY INCREASE LIFE EXPECTANCY AND QUALITY OF LIFE
DRUGS CAN CAUSE DISASTERS
THALIDOMIDE 1956 – 1961 about 10 000 children affected,
not in USA [FDA]
2. SYSTEM OF EVALUATION OF EFFICACY AND SAFETY IN NEW
DRUGS
- BEFORE DRUGS CAN BE APPROVED FOR USE
- AFTER DRUGS ARE APPROVED FOR USE
SYSTEM OF EVALUATION OF EFFICACY AND SAFETY IN NEW DRUGS
PRECLINICAL DEVELOPMENT
CLINICAL TRIALS
REGISTRATION
POSTMARKETING
SURVEILLANCE
SAFETY -PHARMACOVIGILANCE
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
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 …
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
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, H2 antagonists, PPIs, statins, triptans etc…]
first betablocker, H2 antagonist, PPI, statin, triptan …
bioequivalence
„Blockbuster“
3. RISKS IN DISCOVERY AND DEVELOPMENT OF NEW DRUGS -NME
Preziosi 2004
3. COSTS IN DISCOVERY AND DEVELOPMENT OF NEW DRUGS - NME
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, H2 antagonists, PPIs, statins, triptans etc…]
first betablocker, H2 antagonist, PPI, statin, triptan …
bioequivalence
„Blockbuster“
4. PHARMACEUTICAL COMPANIES
Pfizer, AstraZeneca, Eli Lilly, Merck, Novartis, Abbot, GlaxoSmithKline, Bristol-Myers, Sanofi-Synthelabo, Janssen-Cilag, etc.
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.KINEDRYLaj., aj.
New drug discovery and development in Czech republic - history
MEE-TOO DRUGS
PROTHIADEN
(dosulepin)
Domestic (SPOFA)
Exported (Boots)
1968-1994 0,5 bilions Kčs
23 bilions Kčs
Dr. M. Protiva, DrSc.prof.MUDr. Z. Votava, DrSc.
RNDr. PhMr. J. Metyšová,CSc.
VÚFB
antidepressant
TRIMEPRANOL
(metipranolol)
Domestic (SPOFA)
Exported (Boehringer-Ingelheim)
1971-1993 1.460 bilions Kčs
11.2 bil. Kčs
Doc. MUDr. Václav TRČKA, DrSc.
VÚFB
betablocker
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 BiochemistryAcademy of the Sciences of the Czech Republic Prague
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
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