Drug Discovery and

Development
How are drugs discovered and developed?

Overview
Outline here the fundamental concepts and processes of drug
discovery
Drug discovery
Pre clinical study
Investigational New Drug
Clinical research
New Drug Approval Process
Marketing

Drug Discovery and

Development

IND

NDA

Drug Discovery Process

Number of years:
2-3
1-2

2-3

5-8

Cost
$1
Billion

Number of subjects:
Ph I
<50

Ph II
<500

Ph III
<5-5000

Ph IV
100s- 1000s

Process for Successful Molecule

Phase 1
5-10,000
Molecule
Phase 2
250 Molecule
Phase 3
5 Molecule
NDA

1
Molecule

Drug Discovery Process

Identify disease

Human clinical
trials
(2-10 years)

le

Formulation

ND

Fi
IN le
D

Preclinical testing
(1-3 years)

Fi

Isolate protein
involved in
disease (2-5 years)

Find a drug effective

against disease protein
(2-5 years)
Scale-up

FDA approval
(2-3 years)

The Steps Involved In Drug

Discovery

Choosing a Disease
Number of deaths

Causes of death in
developed countries

Number of deaths

HIV-AIDS

2,678,000

Ischaemic heart
disease

3,512,000

Lower respiratory
infections

2,643,000

Cerebrovascular
disease

3,346,000

Ischaemic heart
disease

2,484,000

Chronic obstructive
pulmonary disease

1,829,000

Diarrhea

1,793,000

Lower respiratory
infections

1,180,000

Cerebrovascular
disease

1,381,000

Lung cancer

938,000

Malaria

1,103,000

Stomach cancer

657,000

Tuberculosis

1,021,000

Hypertensive heart
disease

635,000

Chronic obstructive
pulmonary disease

748,000

Tuberculosis

571,000

What factors?

Medical

Economic

Geographical

Target Identification
Most of the drugs act on the cellular receptor or biological molecules in the body, which are associated with
disease, is known as Targets.
Various methods are used to identify target.
Interactions and role of target in disease are studied.

Drug targets fall into one of three

main classes

Most current drugs are aimed at protein targets. However,

current existing therapies only hit about 400 different drug targets
out of an estimated pool ten times this size.

Potential Drug Targets

AgonistNa

Agonist

Agonist

Agonist

Potential Drug Targets

Na

Phosphorylation of

G- Protein Tyrosines on key signaling

Activation Molecules
Transport to the
Nucleus

Activation of
conductance
Generation of
Second
Messenger
Activation
of cell
signaling

Activation of cell
Signaling
Activation of
transcription and
translation

Target Validation

Lead molecule
- A molecule
that is believed
to have
potential to
treat disease.

Scientists
Lead
compare Identification
Leads are

standard drug
in the specific
disease with
new molecule
to determine
the successful
action.

developed as
collections ,
libraries,
individual
molecules etc.

Evaluation is
done to confirm
its effect on
the target.

Lead Identification

Lead Identification -Process

1.Comput
er-aided
5.Assay
Drug
3.Synthe
Develop
Design
2..Virtual
sis And
4.IN
ment
(CADD)
(In-silico)
Combinat
SILICO
HTS
And
Screenin
orial
Predictiv Leads to
Structure g Leads
Chemistr e Toxicity
LEAD
-based
to HITS
y
Compoun
Drug
d
Design
(SBDD)

Tools for Drug Discovery

1.Computer-aided Drug Design (CADD)

And Structure-based Drug Design (SBDD)
IN SILICO SCREENING
SCREENING THROUGH CADD/SBDD
HITS
HITS
COMBINATORIAL
COMBINATORIAL CHEMISTRY
CHEMISTRY
HIGH
HIGH THROUGHPUT
THROUGHPUT SCREENING
SCREENING
LEADS

2.Virtual (in-silico) screening

3.Hits to Synthesis and

Combinatorial Chemistry
1

Hits to Synthesis and Combinatorial Chemistry

New Compounds are supplied by chemist

New compounds are converted to large amount of
precursor

By rule of thumb, one chemist synthesizes, purifies,

and characterizes about 100 novel compounds per
year
Which give 10,000 compound to develop one drug

4.IN SILICO Predictive

Toxicity
Mutagenicity
Carcinogenicity
Reproductive Toxicity

Computational programs
ultimately fulfill the
requirement for determining
liabilities at the early stages
of discovery

Primary screens
will identify Hits
Confirmation
screens and
counter screens
will identify leads
out of the pool of
hits

High-throughput
screening (HTS)
aims to quickly
review the
goings-on of a
large number of
compounds.

5.Assay DevelopmentHTS

Development of
Assay
Screening of
compounds

 Quantitativ
e structure
activity
relationshi
Leadp (QSAR)
Optimizatio
n

Structure
Activity
Relationshi
p
Lead
Optimizatio
n

Animal
PK/PD
Lead
Optimizati
on

Lead Optimization

Toxicity

Lead
Optimizatio
n

Formulatio
n and
Delivery
Lead
Optimization

1.Quantitative structure
activity relationship (QSAR)Lead Optimization

Reflects
the
property
of binding
cavity on
protein
target.

Derive a
functional
group
that links
biological
activity
The
derived
function
group is
used as a
guide to
select
best
candidate
for drug
design.

Quantitative
Structure Activity
Relationship (QSAR)

2.Structure Activity Relationship

Lead Optimization
Pharmacological
assay for lead
assessment

Data into next

optimization
cycle

Optimization
of
pharmacologic
al properties

Determination
of Potency,
selectivity
and MOA

3.Animal PK/PD-Lead
Optimization
Animal pharmacokinetics (ADME)
and pharmacodynamics (PD) assess
the general pharmacology and
mechanisms of action of drugs..
Lead molecules are administered via
different routes: intravenous (iv),
intraperitoneal (ip), subcutaneous
(sc), intramuscular (im), rectal,
intranasal (IN), inhalational, oral ,
trans dermal, topical, etc
The main models used are rodents
including mouse and rat, but larger
animals such as dogs, pigs, and,
more rarely, monkeys, are also used
under certain circumstances.

3.Animal PK/PD-Parameters
PK/PD studies rely heavily on
analytical methods and instrumentation.
The recent innovation and progress in mass
spectroscopy, (whole-body) imaging, and
chromatography technology (HPLC, LC-MS,
GC-MS) have tremendously increased the
quantity and quality of data generated in
PK/PD experiments.
A large number of parameters is assessed.
Here is a partial list:
(ADME); bioavailability (F) and protein
binding; stability and half-life (t1/2);
maximum serum concentration (Cmax); total
exposure or area under the curve (AUC);
clearance (Cl); volume of distribution (Vd);
drug drug interactions; onset of drug action;
multicompartmental analysis of blood, liver,
and other tissues.

Principles and applications

of LC-MS in new drug
discovery

4.Toxicity-Lead Optimization

Formulation and Delivery

Formulation and Delivery

Preclinical
Studies

Pre-Clinical Studies

Once the drug is designed it have to be

tested
In vitro [ in laboratory conditions-glass
wares].

In vivo [in animals (rodents and non

rodents, lab models)].

Difference between In Vivo

And In Vitro

Objective of Preclinical
Studies

Importance Of
Pharmacokinetic Studies
Research and
selection of a
promising
molecules

Formulation

Dosage

Toxicology and
safety assessment

Dosing
recommendation for
age groups and
subgroup
population

Effect of meals and

dosing

Importance of Toxicokinetic
Studies

Toxicokinetic Studies
Genotox
Single Repeated
Reproducti
ic
Carcinogeni
dose
-dose
ve toxicity potentia
city
Toxicity toxicity
l

Safety
pharmacolo
gy.

Coordination of preclinical
and clinical studies.

Coordination of
preclinical and
clinical studies

Drug information journal Vol. 35, pp. 321336,2001

Investigational
New Drug
Application
(INDA)

Sponsors

IND

What is an INDA?

FDA

To initiate the
conduct of
clinical trials

Contents of INDA

Table of
content
Additional
Information

Previous
Human
Experience

Cover
Letter

Introductory
Statement
and General
Investigation
al Plan

IND
A

Pharmacolog
y and
Toxicology
Information

Investigator
s Brochure

Chemistry
Manufacturin
g and
Controls
Information

Clinical
Protocol

Clinical Trials

Phase I:Studies in
normal
healthy
volunteers to
understand
pharmacokine
tics

Phase II: Dose

ranging
efficacy safety
studies to
determine the
optimal dose
for a
particular
indication

Phase III:Large
scale
multicentre
comparative
studies to
assess
efficacy safety
of the study
drug v/s
currently
accepted
treatment.

Phase IV: Post

Marketing
Studies.

Clinical Trial Phase I

Types of Phase I Trial:

SAD (Single
Ascending Dose )
studies

MAD (Multiple
Ascending Dose)
studies

Small l group of people

receives single dose.

.In these studies, a group of

patients receives multiple
low doses of the drug

Adverse Event Nil,

Escalation of dose

The dose is subsequently

escalated for further groups,
up to a predetermined level.

Continued till intolerable

side effects start showing

Continued till intolerable

side effects start showing .

Phase II
Rigid and
wellcontrolled
Pharmacokin
etic and
other
pharmacologi
cal studies
are done.

Efficacy and
safety are
evaluated.

small
population
between
100-300.
Phase 2

Double blind
studies using
placebo or
standard
treatment
are done.

Types of Phase II Studies

Phase 2 Trials

Phase IIA

Phase IIB

is specifically
designed to
assess dosing
requirements
(how much drug
should be
given).

is specifically
designed to
study efficacy
(how well the
drug works at
the prescribed
dose(s)).

Phase III

Pharmaco
kinetics
with
others
drugs and
Quality of
life
(depends)
are
evaluated.

Done in a
large
population
- above
300

Compariso
n with
other
standard
drugs.

Phase 3

Evaluation
of efficacy
and safety
profile
(initial risk
benefit
assessme
nt)

Identificati
on of the
disease
sub types
for which
drug is
effective.

Types of Phase III

Done while the New Drug Application (NDA) is
submitted to FDA.
Studies which start pre-launch but which are
not intended to form part of Regulatory
dossier are referred to as Phase III-b.
The data of this study also submitted to FDA.

Difference between Phase

I,II and III Trials

Phase 1
Safety
Dose Ranging

Phase 2

Safety
Efficacy
Dose
Route

Phase3
Efficacy vs.
standard
Defined
endpoints

New Drug
Application
(NDA)
The formal request to be allowed
to market a drug.
Sponsor submit NDA to FDA after
phase III trials are competed.
Have to submit everything that is
known about the drug to date, all
protocols, case report forms.
Regulation for NDA are found in 21
CFR 314.

New Drug Application (NDA)

IND

Large scale
studies with
diseased
individuals

NDA

FDA

Phase IV

Population
S.No

Phases

No of People

Group

Safety/Efficacy

Goal

The main goal of a Phase 1 trial is

to discover if the drug is safe in
humans. Researchers look at the
pharmacokinetics
of a drug. How is it absorbed? How
is it metabolized and eliminated
from the body?

They also study the drugs

Pharmacodynamic: Does it
cause side effects? Does it produce
desired effects?

Healthy
1 Phase I

20-100

Individuals

Safety

Dose ranging studies

,Safety Studies
In Phase 2 trials researchers
evaluate the candidate drugs
effectiveness
Examine the possible short-term
side effects (adverse events) and
risks associated with the drug.

Diseased

Researchers also analyze optimal

dose strength and schedules for

Population
S.No

Phases

No of People

Group

Safety/Efficacy

Goal

This phase of research is key in

determining whether the drug is
safe and effective.

It also provides the basis for

labeling instructions to help

3 Phase III

1000-5000

Safety and efficacy

ensure proper use of the drug (e.g.,

Diseased

and benefit-risk

information on potential

Individuals

relationship

interactions with other medicines).

These trials can be set up to

evaluate long-term safety or how

4 Phase IV

>5000

Ongoing

the new

Real Life

monitoring of

medicine affects a specific

Population

safety of drug

subgroup of patients.