Drug Development - An Overview

Dr. Joseph Kamalesh MBBS MD

Associate Vice President
Quest Life Sciences Pvt. Ltd

Drug Development
The average time it takes to bring a drug to market is ~15 yrs
6 years : Drug Discovery & Pre-clinical phase
6-7 years: Clinical Trials
2 years : Approval phase
The average cost to bring a drug to market is ~$800million
70-90% of new chemical entities (NCEs) fail
>60% of terminations: Phases II & III
Steady decline in no. of drugs introduced into the market
1960s : 70-100
1970s : 60-70
1980s : 50
1990s :40

AIMS of Drug Development

To develop drugs with :
Less toxicity
Increased potency & efficacy
Increased palatibility/acceptability

Drug Development Phases

Discovery of NCE (New Chemical Entity)
Preclinical Development
Investigational New Drug Application (IND)
Phase I clinical trials
Phase II clinical trials
Phase III clinical trials
New Drug Application (NDA)
Phase IV clinical trials

Pre-Clinical Development
Objectives:
Pharmacological profile
Toxicity profile
Acute toxicity
Subacute toxicity(<3 months)
Chronic toxicity (6-18 months)
Teratogenicity, Mutagenicity, carcinogenicity

Pharmacokinetic profile
Chemical & Pharmaceutical development
survival: of 5000 pre-clinical 5 INDs

Clinical Trials
PHASE I
Objective: Safety, pk/pd in normals
study size: 20-80
time: 2-3 years
open study
80% proceed to Phase 2
54

Phase I Failures
pre-clinical animal models behavior
in humans
inadequate preclinical data
change in drug formulation between
time of preclinical and clinical testing
pk/pd relationships
poorly designed clinical studies
drug too toxic in humans

Phase II Clinical Studies

objectives: to assess therapeutic efficacy
& safety and to find appropriate dosage
schedule of drug in patients
types of studies: small controlled trials in
patients
limited centres
study size: 100-300
time: months - 2 years
survival: 2 go on to Phase 3

Phase III Clinical Studies

objectives:
Long term toxicity data

Benefit-risk relationship
Dose-response relationships
Assessment of adverse drug reactions

targeted patients
multi-centered
placebo-controlled
double blinded
cross over design
size: 100s - 1000s
time: 1-4 years
survival: 1

Phase II & III Failures

infrequent adverse reactions observed
drug-drug interactions
drug-disease interactions in ill patients
genetic
effectiveness insufficient (20%)
economic (24%)

Phase IV Clinical Trials

(Post Marketing Surveillance)
Drug marketed in limited
centres,closely monitored for
unexpected effects which were never
foreseen
If significant toxic effect-withdrawn
from market
If safe-marketed overall

Primary Causes of Failure in 348 Terminated NCEs

13%

21%
Safety
Efcacy
Economics

31%

Others

35%

Ref: DiMasi, J. Clin Pharmacol Ther (2001) 69;297-307.

Generic Drug: Definition

Same active ingredient (s)

Same route of administration
Same dosage form
Same strength
Same indications
Compares to reference listed drug
(RLD)

Bioequivalence (BE): Definition

the absence of a significant difference in
the rate and extent to which the active in
gredient or active moiety in pharmaceuti
cal equivalents or pharmaceutical alterna
tives becomes available at the site of dru
g action when administered at the same
molar dose under similar conditions in an
appropriately designed study.
CDER U.S. Food & Drug Administration

Bioequivalence