Drug Development

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 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
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AIMS of Drug Development
To develop drugs with :
Less toxicity
Increased potency & efficacy
Increased palatibility/acceptability

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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

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DRUG DISCOVERY
 Natural products
 Analog Design
 Peptidomimetics
 Targeted discovery
 Random Screening
 Serendipity

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Target Identification
 The key to rational ‘mechanism-based’ drug
discovery is identifying a good target for drug
development
 A target may be already known from the mechanism
of action of existing drugs or natural ligands
 A target may be identified from an understanding of
basic cellular and physiological processes and/or the
disease mechanism
 A target may be identified from mutations or
alterations in specific disease-related genes
 A target may be identified by sequence or structural
homology to known targets
 A target may be identified serendipitously

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Lead Identification
After an appropriate molecular target is
identified,the next major task in the drug
discovery process is generation and
optimization of lead compounds

Identification of lead compounds requires:

– Developing appropriate screening assays
– Screening molecular libraries containing
potential lead compounds

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 Protein-Ligand Docking
GAPDH
D- Glyceraldehyde 3-phosphate
dehydrogenase Active site
Procedure :
• using the structure of the enzyme
• docking molecules from chemical
library
• retrieving the “best 100 ligands“
• vizualizing the 100 complexes
• eliminating duplicates
• propose 25 inhibitor structures
• biological testing

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Pre-Clinical Development
Objectives:
Pharmacological profile
Toxicity profile
•Acute toxicity (LD50)
•Subacute toxicity(<3 months)
•Chronic toxicity (6-18 months)
•Teratogenicity,Mutagenicity,carcinogenicity
Pharmacokinetic profile i.e.ADME studies
Chemical & Pharmaceutical development

survival: of 5000 pre-clinical → 5 INDs

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SPONSOR/FDA Meetings (Pre-IND)
Open discussion
 Testing phases
 Data requirements
 Any scientific issues that may
need to be resolved

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Submission of IND application
IND application contents:
 Descriptive name of the drug,including the chemical name &
structure of NCE
 Complete list of components of the drug
 Quantitative composition of the drug
 Name & address of supplier of any new drug substance and a
description of synthesis of any new drug substance
 Statement of the methods,facilities & controls used for the
manufacture,processing & packaging of the new drug
 Statement covering all information from preclinical
investigations and any clinical studies &experience with the
drug
 Copies of labels for the drugs
 A description of scientific training & experience considered
appropriate by the sponsor to qualify an investigator as a
suitable expert to investigate the drug
 Names and curriculum vitae of all investigators
 An outline of planned methodology to be adopted in clinical
trials

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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
5→4
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 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

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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

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SPONSOR/FDA Meetings
(End of Phase II)
Plan protocols for phase III
Discuss & identify any additional informatio
that may be required to support the
submission of NDA

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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: 100’s - 1000’s
 time: 1-4 years
 survival: 1

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Phase II & III Failures

•infrequent adverse reactions observed

•drug-drug interactions
•drug-disease interactions in ill patients
•genetic
•effectiveness insufficient (20%)
•economic (24%)

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SPONSOR/FDA Meetings(Pre-NDA)
Discussion of presentation of data
(both paper & electronic) in support of
the application
•Uncover any major unresolved problems or
issues
•Identify studies the sponsor is relying on as
adequate in establishing the effectiveness of the
drug
•Help reviewers to become acquainted with
general information to be submitted
•Discuss presentation of data in NDA to facilitate
its review
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Submission of NDA
NDA application contents:
 Detailed reports of preclinical studies
 Detailed reports of clinical studies
 Information on composition & manufacture of drug
and on controls & facilities used in manufacture
 Samples of drug and its labelling
 Full case reports of each person who received drug –
needed only in limited circumstances
 Patent information
 Material previously submitted to FDA in the IND or
in periodic reports must be included by reference in
the NDA

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Responses of FDA
1. Not approvable letter
2. Approvable letter
3. Approval letter

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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

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 Primary Causes of Failure in 348 Terminated NCEs

13%
21%
Safety
Efficacy
Economics
Others
31%

35%

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

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 Drugs in Developmental phases &
Expected Approval Dates

2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015

Moxifloxacin II III NDA

Gatifloxacin II III NDA
Diarylquinoline R207910 I/II III NDA
Otsuka Compound I II II/III NDA
Pyrrole LL3858 I II II/III NDA
Synthase Inhibitor FAS 20013 I II II/III NDA
Nitroimidazole PA-824 I II II/III NDA
Diamine SQ-109 I II II/III NDA
Translocase I Inhibitors I II II/III NDA

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