Transcript EBM

Charles University in Prague, Third Faculty of Medicine
Cycle II, Subject: General
Pharmacology
2013-2014
New drug development. Preclinical and
clinical trials. Placebo. EBM
Prof. M. Kršiak
Department of Pharmacology, Third Faculty of Medicine, Charles University
in Prague
teaching unit ID9240
http://vyuka.lf3.cuni.cz
Outline:
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
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
1899
ASPIRIN Bayer
1905 FIRST CZECH TEXTBOOK OF PHARMACOLOGY
1905 there was:
1905 did not exist:
aspirin, digitalis, ether,
cocaine, bromide,
saccharin
drugs e.g. for hypertension, diabetes,
asthma, antibacterial drugs, lipidlowering drugs, psychotropic drugs, etc
1905 ignorance of
neurotransmitters
molecular targets of drugs
1963 propranolol – betablockers
– hypertension, angina pectoris
+ Advances in
pharmacology
1972 cimetidin – H2 antagonists
– peptic ulcer disease
Sir James W. Black
Nobel price 1988
GREAT
SUCCESSES
DRUGS CAN SIGNIFICANTLY INCREASE LIFE
EXPECTANCY AND QUALITY OF LIFE
…BUT REGRETTABLY…
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
POSTMARKETING
REGISTRATION
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, doubleblind experiment, randomized controlled trials (RCT),
placebo, bias, informed consent, Declaration of Helsinski,
ethical committees …
RCT is a basis of „Good Clinical Practice“ (GCP)
RCT (Randomized Controlled Trial)
randomized
controlled: placebo effect, bias
double-blind arrangement
PLACEBO
PLACEBO is an imitation of the tested drug without
specific (biological) activity
L. placere : to please, placebo: I will please
Distinguish:
Placebo – imitation of drug (or of treatment) for separating
proper biological effect of the drug (treatment) from a
psychological effect
Placebo 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?
CLINICAL TRIALS - cont
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
STRATEGY, COSTS AND RISKS IN
DISCOVERY AND DEVELOPMENT
OF NEW DRUGS AT PRESENT
STRATEGY IN DISCOVERY AND DEVELOPMENT OF
NEW DRUGS
first betablocker, H2 antagonist, PPI, statin, triptan …
NOVEL TYPE OF ACTION
„Blockbuster“
NEW CHEMICAL/
MOLECULAR
ENTITY (NCE/NME)
„MEE-TOO“
NEW DRUGS
Known type of action, but NCE/NME
[additional betablockers, H2 antagonists, PPIs, statins, triptans etc…]
GENERICS
(actually copies of the original drug once the patent expires)
bioequivalence
RISKS
IN DISCOVERY AND DEVELOPMENT OF NEW DRUGS - NME
Preziosi 2004
COSTS IN DISCOVERY AND DEVELOPMENT OF NEW DRUGS - NME
DISCOVERY AND DEVELOPMENT OF NEW DRUGS – NME IS LENGTHY
PRECLINICAL
DEVELOPMENT
CLINICAL
TRIALS
POSTMARKETING
REGISTRATION
SURVEILLANCE
SAFETY PHARMACOVIGILANCE
~ 1.5 years
~ 5 years
~2 years
~ 5 years and more
DRUG REGULATORY AGENCIES
DRUG REGULATORY AGENCIES
EUROPEAN MEDICINES AGENCY (EMA)
www.ema.europa.eu
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)
EBM
(Evidence Based Medicine)
RCT is a basis of EBM (Evidence Based Medicine)
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
Strengths of EBM
EBM 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)
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?
FOOD (DIETARY) SUPPLEMENTS
Supplements as generally understood include vitamins, minerals,
fiber, fatty acids, or amino acids
There are more than 50,000 dietary supplements available
Effects of most of these products have not been
determined in randomized clinical trials and
manufacturing is lightly regulated
They mimic regular drugs, but mostly
produce only placebo effect
BIG BUSSINESS
Example: COLAFIT firmy Dacom
Contains Type-I collagen indicated for joints
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
Example: COLAFIT firmy Dacom
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)