new drug development. preclinical and clinical trials. placebo. ebm prof. m. kršiak department of...
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New drug development. Preclinical and clinical trials. Placebo. EBM
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
teaching unit ID9240 http://vyuka.lf3.cuni.cz
2013-2014
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1. HISTORY OF DRUG DISCOVERY
2. SYSTEM OF EVALUATION OF EFFICACY AND SAFETY IN NEW DRUGS
3. RCT, PLACEBO
4. STRATEGY, COSTS AND RISKS IN DISCOVERY AND DEVELOPMENT OF NEW DRUGS AT PRESENT
5. DRUG REGULATORY AGENCIES
6. EBM
7. FOOD (DIETARY) SUPPLEMENTS
8. SUMMARY
Outline:
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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
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Felix Hoffmann
ASPIRIN Bayer
1899
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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, etc
1905 ignorance of
neurotransmitters molecular targets of drugs
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+ Advances in pharmacology
1963 propranolol – betablockers – hypertension, angina pectoris
1972 cimetidin – H2 antagonists – peptic ulcer disease
Sir James W. Black
Nobel price 1988
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GREAT SUCCESSES
…BUT REGRETTABLY…
DRUGS CAN SIGNIFICANTLY INCREASE LIFE EXPECTANCY AND QUALITY OF LIFE
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DRUGS CAN CAUSE DISASTERS
THALIDOMIDE 1956 – 1961 about 10 000 children affected,
not in USA [FDA]
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2. SYSTEM OF EVALUATION OF EFFICACY AND SAFETY IN NEW
DRUGS
- BEFORE DRUGS CAN BE APPROVED FOR USE
- AFTER DRUGS ARE APPROVED FOR USE
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SYSTEM OF EVALUATION OF EFFICACY AND SAFETY IN NEW DRUGS
PRECLINICAL DEVELOPMENT
CLINICAL TRIALS
REGISTRATION
POSTMARKETING
SURVEILLANCE
SAFETY -PHARMACOVIGILANCE
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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
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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 …
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RCT (Randomized Controlled Trial)
randomizedcontrolled: placebo effect, bias double-blind arrangement
RCT is a basis of „Good Clinical Practice“ (GCP)
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L. placere : to please, placebo: I will please
PLACEBO is an imitation of the tested drug without specific (biological) activity
PLACEBO
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Distinguish:
Placebo – imitation of drug (or of treatment) for separating proper biological effect of the drug (treatment) from a psychological effectPlacebo is used practically only in research, should not be used in clinical practice
Placebo effect – psychological effect resulting from positive expectations, trust, good faith in a drug, treatment, doctor, healer, hospital ….
Placebo effect should be utilized in clinical practice
„Your faith has healed you.” – is it only a placebo (=psychological) effect?
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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
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STRATEGY, COSTS AND RISKS IN DISCOVERY AND DEVELOPMENT
OF NEW DRUGS AT PRESENT
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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)
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“
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RISKS IN DISCOVERY AND DEVELOPMENT OF NEW DRUGS - NME
Preziosi 2004
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COSTS IN DISCOVERY AND DEVELOPMENT OF NEW DRUGS - NME
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PRECLINICAL DEVELOPMENT
CLINICAL TRIALS
REGISTRATION
POSTMARKETING
SURVEILLANCE
SAFETY -PHARMACOVIGILANCE
~ 1.5 years ~ 5 years ~2 years ~ 5 years and more
DISCOVERY AND DEVELOPMENT OF NEW DRUGS – NME IS LENGTHY
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DRUG REGULATORY AGENCIES
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DRUG REGULATORY AGENCIES
EUROPEAN MEDICINES AGENCY (EMA)
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
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EBM
(Evidence Based Medicine)
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Levels of EBM:
A Meta-analyses of numerous RCT
B RCTs less numerous
C Case studies with comparable case studies, preferably prospective
D Expert opinion
RCT is a basis of EBM (Evidence Based Medicine)
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Strengths of EBMEBM separates the chaff from the wheat
Weakness of current EBM● current EBM is focused on average, not on the
individuum• EBM mostly evaluates effects under specific
conditions (e.g. RCTs…) which may be rather remote to real conditions of common life
Distinguishing
EFFECTIVENESS (therapeutic success/acceptability in a broader sense)from
EFFICACY (biological effects)
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Additional limits of EBM:
EBM can ascertain only effects (phenomena) which can be evoked experimentally,
not effects (phenomena) which cannot be evoked experimentally
The problem is that there are phenomena which cannot be evoked experimentally, which occur spontaneously and which may have a great importance subjectively , which can be adequately known only personally, which defy objective testing, knowledge from outside …
phenomena in the self (e. g. ideas, meaning of one‘s own life, romantic love, knowledge of one‘s own beeing) …. spiritual phenomena?
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FOOD (DIETARY) SUPPLEMENTS
Effects of most of these products have not been determined in randomized clinical trials and manufacturing is lightly regulated
Supplements as generally understood include vitamins, minerals, fiber, fatty acids, or amino acids
There are more than 50,000 dietary supplements available
They mimic regular drugs, but mostly produce only placebo effect
BIG BUSSINESS
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Comment:1.Type-I collagen is striped, mostly found in fibrous tissues such as tendons, not in articular cartilage, while the basis for articular cartilage is netlike Type-II collagen
2. No evidence of efficacy complying with principles of EBM
Contains Type-I collagen indicated for joints
Example: COLAFIT firmy Dacom
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Example: COLAFIT firmy Dacom
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SUMMARY
• 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
• THIS RIGOROUS EVALUATION SYSTEM IS REQUIRED FOR REGULAR DRUGS NOT FOR FOOD SUPPLEMENTS (which mostly mimic regular drugs)
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