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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