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

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:

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, etc

1905 ignorance of

neurotransmitters molecular targets of drugs

+ 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 …

RCT (Randomized Controlled Trial)

randomizedcontrolled: placebo effect, bias double-blind arrangement

RCT is a basis of „Good Clinical Practice“ (GCP)

L. placere : to please, placebo: I will please

PLACEBO is an imitation of the tested drug without specific (biological) activity

PLACEBO

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?

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

STRATEGY, COSTS AND RISKS IN DISCOVERY AND DEVELOPMENT

OF NEW DRUGS AT PRESENT

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“

RISKS IN DISCOVERY AND DEVELOPMENT OF NEW DRUGS - NME

Preziosi 2004

COSTS IN DISCOVERY AND DEVELOPMENT OF NEW DRUGS - NME

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

DRUG REGULATORY AGENCIES

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

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

RCT is a basis of EBM (Evidence Based Medicine)

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)

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

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

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

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)