TRULY SITORUS

Depart. of Pharmacology & Therapy Medical Faculty Padjadjaran University

LIFE OF A DRUG
Drug marketing & Line extension Drug Development Period
* Launch * PMS * New indication * New dosage forms * Clinical Trial IV

Drug Discovery
Period
* Idea
* Synthesis * Test

* Preclinical

* Clinical trial I-III

* IND

* NDA

DRUG DISCOVERY
1)

2)

3) 4)

Chemical modification of unknown molecule Random screening for biologic activity of natural product Rational drug design Biotechnology and cloning

WHAT IS NEEDED TO START CLINICAL STUDIES GENERAL REQUIREMENTS (I)

Preclinical information - Acute/ subacute toxicity mutagenicity partial antigenicity - Reproductive toxicity - Preliminary ADME

WHAT IS NEEDED TO START CLINICAL STUDIES GENERAL REQUIREMENTS (II)

General information on discovery Data on physiochemical properties, standard and test methods Data on stability of formulations Data on pharmacological activity

CLINICAL TRIALS
Any systematic study on medicinal products in human subjects whether in patients or non patient volunteers in order to discover or verify the effects of and/or to study their absorption, distribution, metabolism and excretion in order to ascertain the efficacy and safety on the products. * Include : therapeutic procedures

THE GOAL OF DISCOVERY DEVELOPMENT DRUG

Efficacy Adverse Drug Reaction Dosage Regimen

EXAMPLES ANTIHISTAMINES
CHLORPHENIRAMINE (CTM) TERFENADIN

antiallergy 1st generation AHI sedation dry mouth 3 dd I

antiallergy 2nd generation AH2 non sedation dry mouth (-) 1 dd I

CLINICAL TRIALS
4 Phase Phase I Phase Phase II III Phase IV
Post marketing trials

Pre NDA trials

PHASE I
Normal/ healthy volunteers. Number 20 80 The Goal : SAFETY PHARMACOKINETICS DATA

PHASE I
single dose in men multiple dose in men Pharmacokinetics data Adverse reaction profile Max. tolerated dose Dose range and route of administration established

PHASE II

Restricted patients Number 10 200 A single blind design Pre post design Controlled studies (placebo)

The Goal : EFFICACY SAFETY

PHASE II
Dose ranging pilot studies in diseased men (wide dose range) II A Pre eliminary evidence of efficacy Pharmacodynamic/ effects in patients. Effective range of dose decision yes no

PHASE III

Extended clinical trials in large patient Number > 1OO More general population Long term duration

The Goal :

PHASE III

Controlled studies Positive control (standard) or placebo

Confirmation of efficacy Establishment of complete safety profile Base for regulatory information (labeling) Assessment of risk/ benefit yes Preparation of NDA

PHASE IV
(Post marketing drug surveillance)

Retrospective Epidemiology survey

ADR Chronic SE Efficacy in severe, multiple disease Geriatry, Pediatri New indication New drug interaction

EXAMPLE ANTIHISTAMINE
CHLORPHENIRAMINE TERFENADINE AZTEMIZOLE

CI : Erythromycin Itraconozole Ketoconazole

GOOD CLINICAL PRACTICE (GCP)

A standard by which clinical trials are designed. Implemented and reported
The data are credible, and that the right, integrity and confidentiality of subjects are protected.

I. AIMS

The Principles of Clinical Trials

I.
II. III. IV. V.

VI.

The aims of the trials Its design The drugs to be tested The subjects to be studied The analysis and interpretation of the results Ethical considerations

I. BASIC DESIGN
A. DESIGN
1. GROUP COMPARISION I T 2. MATCHED PAIRS I II S II

T S 3. CROSS OVER DESIGN I II

T I S S II T

B.

BLINDNESS 1. Single blind 2. Double blind NUMBER OF CENTRES PROSPEKTIVE OR RETROSPECTIVE

C. D.

II. SUBJECTS

Numbers Criteria for selection or exclusion * Inclusion criteria * Exclusion criteria Disease characteristics (severe duration) In patients or out patients Age and sex Race * Failure to respond to other treatment

III. DRUG USED

Placebo Run in periods Wash out periods Dosage regimens (Dose, frequency of administration of treatment, and total duration of treatment) Compliance Other therapy