12 INTRODUCTION TO NEW DRUG DEVELOPMENT-1.ppt

© 2007 Chettinad Hospital & Research Institute
• New drug developments have revolutionized the
practice of medicine,coverting many once fatal or
debilitating diseases into almost routine therapeutic
exercises
• In most countries, the testing of therapeutic agents is
now regulated by legislation and closely monitored by
governmental agencies

• In addition to in vitro studies, most of the biologic
effects of the molecule must be characterized in
animals before human drug trials can be started.
Human testing must then go forward in three
conventional phases before the drug can be considered
for approval for general use. A fourth phase of data
gathering and safety monitoring follows after approval
for general use

DRUG DISCOVERY
• Most of the drug candidates are launched through one or
more of five approaches :
1.Identification or elucidation of a new drug target
2.Rational drug design based on an understanding of biologic
mechanisms, drug receptor structure, and drug structure
3.Chemical modification of a known molecule

DRUG DISCOVERY (Contd…)
4.Screening for biologic activity of large numbers of natural
products; banks of previously discovered chemical entities;
and large libraries of peptides, nucleic acids, and other
organic molecules
5.Biotechnology and cloning using genes to produce larger
peptides and proteins. Moreover, automation,
miniaturization and informatics have facilitated the process
known as “high through-put screening,” which permits
millions of assays per month.

• Major attention is now being given to the discovery of
entirely new targets for drug therapy. These targets
are emerging from studies with genomics, proteomics,
and molecular pharmacology and are expected to
increase the number of useful biologic or disease
targets ten-fold and thus be a positive driver for new
and improved drugs

• Testing involves a sequence of experimentation and
characterization called drug screening
• The type and number of initial screening tests depend
on the pharmacologic goal
• The selection of molecules for further study is most
efficiently conducted in animal models of human
disease
THE DRUG SCREENING

In vitro
studies
Animal
testing
Clinical
testing
Marketing
Generics
become
available
Biologic
Products
Lead compound
Efficacy
Selectivity
mechanism
Chemical
synthesis
Phase 1
Phase 2
(Is it safe,
Pharmacokinetics?)
(Does it work
In patients?)
Phase 3
(Does it work
Double blind?)
Phase 4
Drug metabolism, safety assessment
0 2 4 8 - 9 20
Yeas (average)
IND NDA
(Investigational New Drug) (New Drug Application)
(Patent expires
20 years after filing
Of application
(Postmarketing
Surveillance)

The goals of preclinical toxicity studies include: Identifying
all potential human toxicities; designing tests to further
define the toxic mechanisms; and predicting the specific
and the most relevant toxicities to be monitored in clinical
trials. The major kinds of information needed from
preclinical toxicity studies are
1.Acute toxicity-effects of large single doses up to the lethal
level
2.Subacute and chronic toxicity-effects of multiple doses,
which are especially important if the drug is intended for
prolonged use in humans
3.Effects on reproductive functions, including teratogenicity
and postnatal development
GOAL

4.Carcinogenicity
5.Mutagenicity
6.Investigative toxicology
GOAL (Contd…)

1.Toxicity testing is time consuming and expensive.
Two to 5 years may be required to collect and analyze
data before the drug can be considered ready for
testing in humans.
2.Large numbers of animals are needed to obtain valid
preclinical data.
3.Extrapolation of toxicity data from animals to humans
is not completely reliable
LIMITATIONS OF PRE CLINICAL TESTING

Type of Test Approach Comment
Acute toxicity Acute dose that is lethal in
approximately 50% of animals
and the maximum tolerated
dose. Usually two species,
two routes, single dose.
Compare with
therapeutic dose
Subacute-
toxicity
Three doses, two species. 4
weeks to 3 months may be
necessary prior to clinical
trial. The longer the duration
of expected clinical use, the
longer the subacute test
Clinical chemistry,
physiologic signs,
autopsy studies,
hematology,
histology, electron
microscopy
studies, Identify
target organs of
toxicity

Chronic
toxicity
Rodent and non-
rodent species. 6
months or longer.
Required when
drug is intended to
be used in humans
for prolonged
periods. Usually
run concurrently
with clinical trial
Goals of subacute
and chronic tests
are to shown which
organs are
susceptible to drug
toxcity. Tests as
noted above for
subacute. 3 dose
levels plus controls.

Type of
Test
Approach Comment
Effect on
reprodu-
ctive
perfor-
mance
Effects on animal
mating behavior,
reproduction,
parturition, progeny,
birth defects,
postnatal development
Examines fertility, teratology,
perinatal and postnatal effects
lactation
Carcinog-
enic
potenti-
al
Two years, two
species. Required
when drug is intended
to be used in humans
for prolonged periods
Hematology, histology, autopsy
studies. Tests in transgenic
mice for shorter periods may be
permitted as one species.

Mutagenic
potential
Effects on genetic
stability and
mutations in
bacteria (Ames test
) or mammalian
cells in culture;
dominant lethal
test and
clastogenicity in
mice
Increasing interest in
this potential
problem

Investigative
toxicology
Determine
Sequence and
Mechanism of toxic
action. Discover the
genes, proteins,
pathways involved.
Develop New
methods for
assessing toxicity
May allow rational
and earlier design
and identification
of safer drugs.
Possibly run at
higher compound
throughput.

• For statistical reasons, rare adverse effects are unlikely
to be detected

• The design and execution of a good clinical trial
requires the efforts of clinician – Scientists or clinical
pharmacologists, statisticians, and frequently other
professionals as well. Then need for careful design and
execution is based on three major confoounding factors
inherent in the study of any therapeutic measure –
pharmacologic or nonpharmacologic – in humans.
EVALUATION IN HUMANS

• Once a drug is judged ready to be studied in humans ,
a Notice of Claimed Investigational Exemption for a
New Drug (IND) must be filed with the FDA The IND
includes
1.Information on the composition and source of the
drug
2.Manufacturing information
3.All data from animal studies
4.Clinical plans and protocols
5.The names and credentials of physicians who will
conduct the clinical trials
CLINICAL TRIALS

• Often requires 4 – 6 years of clinical testing to
accumulate all required data. Testing in humans is
begun after sufficient acute and subacute animal
toxicity studies have been completed. Chronic safety
testing in animals is usually done concurrently with
clinical trials
• Three formal phases of clinical trials
CLINICAL TRIALS (Contd…)

• The effects of the drug as a function of dosage are
established in a small number ( 25 – 50) of healthy
volunteers.
• Phase 1 trials are done to determine whether
humans and animals show significantly different
responses to the drug and to establish the probable
limits of the safe clinical dosage range. These trials
are nonblind or “open, “ ie, both the investigators
and the subjects know what is being given. Many
predictable toxicities are detected in this phase.
PHASE 1

Pharmacokinetic measurements of absorption, half
life,and metablism are often done in phase 1. Phase 1
studies are usually performed in research centres by
specially trained clinical pharmacologists.
PHASE 1 (Contd…)

• The drug is studied for the first time in patients with
the target disease to determine its efficacy. A small
number of patients (100 – 200) are studied in great
detail. A single – blind design is often used, with an
inert placebo medication and an older active drug
(positive control) in addition to the investigational
agent. Phase 2 trials are usually done in special clinical
centers (Eg. University hospitals). A broader range of
toxicities may be detected in this phase.
PHASE 2

• The drug is evaluated in much larger numbers of
patients – sometimes thousands – to further establish
safety and efficacy
• Double-blind and crossover techniques are frequently
used
• Phase 3 are usually expensive because of the large
numbers of patients involved and the masses of data
that must be collected and analytzed.
PHASE 3

• If phase 3 results meet expectations, application will
be made for permission to market the new agent. The
process of applying for marketing approval requires
submission of a New Drug Application (NDA) to the
FDA.
NEW DRUG APPLICATION (NDA)

• Once approval to market a drug has been obtained, phase
4 begins. This constitutes monitoring the safety of the
new drug under actual conditions of use in large numbers
of patients.
• Phase 4 has no fixed duration
• The time from the filing of a patent application to
approval for marketing of a new drug may be 5 years or
considerably longer
PHASE 4

12 INTRODUCTION TO NEW DRUG DEVELOPMENT-1.ppt

More Related Content

Similar to 12 INTRODUCTION TO NEW DRUG DEVELOPMENT-1.ppt (20)

More from prakash801438 (20)

Recently uploaded (20)

12 INTRODUCTION TO NEW DRUG DEVELOPMENT-1.ppt

Editor's Notes