TRULY SITORUSDepart. of Pharmacology & Therapy

Medical Faculty – Padjadjaran University

“LIFE” OF A DRUGDrug marketing &Line extension Drug * Launch Development * PMS Period * New indicationDrug * Preclinical * New dosage formsDiscovery * Clinical trial I-III * Clinical Trial IV

Period * IND * Idea * NDA * Synthesis

* Test

DRUG DISCOVERY1) Chemical modification of

unknown molecule2) Random screening for biologic

activity of natural product3) Rational drug design4) 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

EfficacyAdverse Drug ReactionDosage Regimen

EXAMPLES ANTIHISTAMINES

CHLORPHENIRAMINE (CTM) TERFENADIN antiallergy antiallergy 1st generation AHI 2nd generation

AH2 sedation non sedation

dry mouth dry mouth (-) 3 dd I 1 dd I

CLINICAL TRIALS 4 Phase Phase Phase Phase Phase

I II III IV

Pre NDA trials Postmarketingtrials

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 no

yes

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 efficacyEstablishment of complete safety profileBase 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

CI :• Erythromycin • Itraconozole • Ketoconazole

CHLORPHENIRAMINE TERFENADINEAZTEMIZOLE

GOOD CLINICAL PRACTICE (GCP)A standard by which clinical trials

are designed.Implemented and reported

The data are credible,and that the right, integrity andconfidentiality of subjects are protected.

I. AIMS

The Principles of Clinical Trials

I. The aims of the trialsII. Its designIII. The drugs to be testedIV. The subjects to be studiedV. The analysis and interpretation

of the resultsVI. Ethical considerations

I. BASIC DESIGN A. DESIGN

1. GROUP COMPARISIONI IIT S

2. MATCHED PAIRSI IIT S

3. CROSS OVER DESIGNI IIT S

I IIS T

B. BLINDNESS1. Single blind2. Double blind

C. NUMBER OF CENTRESD. PROSPEKTIVE OR

RETROSPECTIVE

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