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 1960’s : 70-100 1970’s : 60-70 1980’s : 50 1990’s :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

Objectives: Pharmacological profile Toxicity profile

Pharmacokinetic profileChemical & Pharmaceutical development

survival: of 5000 pre-clinical → 5 INDs

•Acute toxicity

•Subacute toxicity(<3 months)

•Chronic toxicity (6-18 months)

•Teratogenicity, Mutagenicity, carcinogenicity

Pre-Clinical Development

Clinical Trials

PHASE IObjective: Safety, pk/pd in “normals”

study size: 20-80

time: 2-3 years

open study

80% proceed to Phase 2

5 → 4

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:

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

Long term toxicity data

Benefit-risk relationship

Dose-response relationships

Assessment of adverse drug reactions

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

21%13%

31%

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 ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study.”

•CDER U.S. Food & Drug Administration

Bioequivalence

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