DRUG DEVELOPMENT PROCESS

INTRODUCTION:

Drugs are perhaps the most important therapeutic interventions in modern

healthcare.
Development of new drugs is always a prime concern for research based
pharmaceutical industries.
Many drug discoveries in the past were empirical, i.e., they were based on
observations of certain phenomena.
The observations by William withering (1741 to 1799) that a decoction of
foxglove treated dropsy, i.e., congestive cardiac failure (CCF) was one such
discovery.

DEFINITION:

"Drug development process is defined as a series of well defined steps, for drugs of
new, safe and effective treatment to increase health and quality of life"

STEPS INVOLVED IN DRUG DISCOVERY:

TARGET SELECTION

LEAD IDENTIFICATION

LEAD OPTIMIZATION

PRODUCT DEVELOPMENT

1) TARGET SELECTION:
 1)TARGET SELECTION:
Tage
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Before discovery of drug

Disease to be treated needs to be understood, to identify the

"underlying cause of the same"

Study of disease mechanism

Helps improper research

Helps to formulate a possible tip to slow/reverse the disease progress

TARGET FOR THERAPEUTIC INTERVENTIONS INCLUDE:

Receptors
Proteins

Enzymes
DNA
RNA
Ribosomal targets

METHODS USED FORTARGET IDENTIFICATION INCLUDE:

Cellular biology
CLASSICAL METHODS
Molecular biology

Genomics
NEWER METHODS
Proteomics

TARGET VALIDATION:
 is required to prove that:
In target validation, demonstration
involved in disease process.
a) Identified molecule target is
produces curative effect.
b) Binding of drug to the target

PROCESS INVOLVED IN VALIDATION:

IN-VITRO PHASE

IN-VIVO FACE
RESULT

DEFINES CLINICAL POTENTIAL OF TARGET

" It's also important to determine "druggability of target"

drug.
Druggability of target is defined as the ability of a target to bind to a

2) LEAD IDENTIFICATION:
In lead identification process

Compounds that interact with the target protein is identified

SOURCES OF COMPOUNDS INCLUDE:

a) Natural products from microbes, plants (or) animals.

b) Compound libraries:
1° screening

Identifies Hits from compound libraries

Hits are retested

Retest is done independently of 1" assay (or) on a different day

 Compound

Exhibits some activity within a statistically significant range

It is termed as "confirmed Hit

Proceeds to dose response screening

3) LEAD OPTIMIZATION:
In lead optimization process

The chemical structure of a confirmed hit is defined

Helps to improve drug characteristics

Helps to produce preclinical drug candidate

Different parts of lead optimization include:

Kinetic studies
Dynamic studies
Absorption studies
Distribution studies
Metabolism studies
Excretion studies

4) PRODUCT DEVELOPMENT:
"Then the final product was developed."

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 VARIOUS APPR0ACHES TODRUG DISCOVERY

Approaches to drug discovery

Pre-clinical testing Clinical testing

Pharmacological Toxicological
testing testing
IND application Drug Dosage form
characterization

PRECLINICAL TESTING/EVALUATION:
The primary aim of preclinical testing is to obtain basic information on the drug
effects that may be used to predict safe and effective use in humans.
There are species difference between humans and animals. Hence drugs needed
testing in humans before marketing.
Preclinical testing can be divided into two broad categories. They are:
1) Pharmacological testing
2) Toxicological testing

PHARMACOLOGICAL TESTING
These tests are to determine whether the substance has effectiveness and a
reasonable safety profile.
Components of pharmacological testing/evaluation include:
a) Selectivity testing
b) Pharmacological profiling
c) Testing in animal models of disease
d) Safety pharmacology

a) SELECTIVITY TESTING:
It involves two stages:
1) Screening of selectivity
2) Binding assays
 1)sCREENING OF SELECTIVITY:
The selectivity of a compound for a chosen molecular target needs to be assessed,
because it determines the potency of the drugs.

2) BINDING ASSAYS:
Binding assays needed to determine the dissociation constant of the test component
as a measure of affinity to the receptor.

b) PHARMACOLOGICAL PROFILING:
Pharmacological profiling refers to determining the pharmaco-dynamic effects of
a new compound.
Pharmacological profiling may be as:
1) Invitro models
2) Invivo models

1)INVITRO MODELS:
It involves the studies on isolated tissues.

In vitro profiling is applicable to studies on smooth muscles, cardiac muscles,

brain slices.
Mostly tissue is obtained from a freshly killed (or) anaesthetized animal and
suspended in warmed oxygenated physiological fluids solution.
2) INVIVO MODELS:
It involves testing on normal animal models.
These invivo profiling are time consuming and very expensive.

c) TESTING IN ANIMAL MODELS OF DISEASE:

Animal models of disease can be divided into three models:
1) Acute physiological and pharmacological models.
2) Chronic physiological and pharmacological models.
3) Genetic models.

1) ACUTE PHYSIOLOGICAL AND PHARMACOLOGICAL MODELS:

These models are intended to mimic certain aspects of clinical disorder.
Example: Hot plate for analgesic drugs as a model of pain.
 Electrical stimulation of brain to induce seizures as a model of epilepsy.

2) CHRONICPHYSIOL0GICAL. AND PHARMACOLOGICAL MODELS:

These models involve the use of drugs (or) physical interventions to induce an
ongoing abnormality similar to clinical condition.
Example: self administration of opiates, nicotinic drugs as a model of drug
dependence.
3) GENETIC MODELS:

These are transgenic animals provided by (or) over expression of specific genes
deletion, to show abnormnalities, resembling the human disease.
The development of transgenic technology has allowed inbred stains to be
produced with the gene abnormality to be present throughout the animal life.

d) SAFETY PHARMACOLOGY:
Safety pharmacology is the evaluation and safety of potentially life threatening
pharmacological effects of a potential drug which is unrelated to the desired
therapeutic effect and may present a hazard.
Safety pharmacology seeks to identify unanticipated effects of new drugs on
major organ functions.
To detect possible, undesirable,(or) dangerous effects of exposure of their drug in
the therapeutic doses.

Pharmacological evaluation/testing/screening involves three levels of study:

1) Molecular level studies
2) Cellular level study
3) Whole animals

1)MOLECULAR LEVEL STUDY:

" In this, drug is studied for its selectivity for various receptors and its activity
against selective enzyme systems.
Cell membrane fractions from organs (or) glands etc. are used.
2) CELLULAR LEVEL STUDY:
By using cell and tissue culture &computer programs, the pharmacological action,
is assessed to stimulate human and animal system.
 Isolated tissues like blood vessels, heart, lungs, ileum of rat (or) guinea pig are
used.

3) WHOLE ANIMAL STUDY:

This is to determine the effect of drugs(or) substances on organ systems and
disease models.

Example: Study of anti-hypertensive effects in hypertensive rats.

Pharmacological testing ensures that the drug does not produce any potential
hazardness (or) serious unwanted effects.

TOXICOLOGICAL TESTING/EVALUATION
All drugs are toxic at some dose i.e. no drug is safe at all doses.
Toxicity data on animals cannot be completely extrapolated to humans because of
reason like species,variation, etc. But it is necessary to test the drug first in
several species of animals.
Toxicity studies are undertaken to determine the test drugs potential for toxicity
with short term, long term use etc.
Test drugs are studied at various dose levels to determine effects, potency and
toxicity.

TOXICITY STUDIES:
Various toxicity studies are recommended by regulatory authorities, as follows:
1) Acute toxicity studies
2) Sub acute toxicity studies,
3) Chronic toxicity studies
4) Reproduction studies
5) Carcinogenic studies
6) Geno-toxicity studies

1) ACUTE (SHORT TERM) TOXICITY STUDIES:

In this one drug (or) substance is administered at various dose levels to find the
largest single dose that will not produce a toxiceffect.
 In this test animals are compared with control for eating and drinking habits,
weight change, toxic effects and any untoward effects, usually over a 30 days post
dosing period.
Biological samples are tested to detect changes in clinical chemistry, and any
other changes that could indicate toxicity.
2) SUB ACUTE TOXICITY STUDIES:

In thisdrug (or) substance is given daily for a minimum period of two weeks at
three (or) more dosage levels to two animal species.
The study is useful in generating evidence to support the initial administration of
a single dose and human clinical testing.
Generally, 1/10th of the highest non-toxic dose in mg per kg(mg/kg) bodyweight
is the initial dose in human.

3) CHRONIC TOXICITY STUDIES:

In this, animal studies of three to six months are required. If the tested drug (or)
substance is intended to be given for one week (or) mnore in humans.
For chronic illness, animal studies for one year (or) longer is required.
The comparative data of test &control during sub-chronic and chronic studies are
to be generated.
Ex: body weight, hematology, clinical chemistry, urine analysis etc.
4) REPRODUCTION STUDIES:
In this, drug/substance effects in reproductive performance and studies in
mammalian species to assess fertility and mating behavior.
The maternal parents, fetus, neonates, and wearing offspring are evaluated for
anatomic abnormalities, growth and development.
5) CARCINOGENICITY STUDIES:
These studies are usually carried out in a limited number of rats and mouse
strains for which there is reasonable information on spontaneous tumor
incidence.
Dose used for the studies should be minimum tolerated dose to elicit signs of
minimal toxicity without significantly altering the animal's normal life by effects,
other than carcinogenicity.
 In this survivor animals are killed, and studied at different time & data on causes
of death, tumor incidence, type and sight, and findings of necropsy.

6) GENOTOXICITY (MUTAGENICITY) STUDIES:

These studies are performed to determine the effects of drug on genetic stability
and mutations in bacteria (or) mammalian cells in culture, dominant lethal tests.
Apart from the above toxicological studies, some quantitative estimates are
desirable.
Some invitro methods are used, because to avoid excess animal in animal studies,
but the predictive value in-vitro methods are limited.

INDA (INVESTIGATIONAL NEW DRUG APPLICATION)

Investigational new drug (IND) application is defined as the petition, through
which a drug sponsor requests the FDA to allow human testing of its drug
product.
INDA is required to be submitted to drug regulatory authority before initiation of
clinical trial.
" The INDAcan be submitted by the sponsor, but may employ CRO to conduct the
actual studies.
IND application provides the FDA with the data necessary to decide whether the
new drug and the proposed clinical trials pose a reasonable risk to the human
subjects participating in the study.

INDICATIONS:

INDAis needed, when you want to conduct a clinical trial of an unapproved drug.
It is needed when any drug, the composition of which is not generally recognized
as safe and effective for use under the conditions prescribed, recommended (or)
suggested in the labeling.

TYPES OF IND:

There are four types of IND, they are:

1) Investigational INDs
2) Commercial INDS
3) Emergency use INDs
 4) Treatment IND

1) INVESTIGATOR IND'S:
These are submitted by physician, who both initiates and conducts an investigation
and under whose immediate direction, the Investigation drug is administered (or)
dispensed.

2) COMMERCIAL IND'S:
There are submitted by companies to obtain marketing approval for a new product.

3) EMERGENCY USE IND:

This IND allows the FDA to authorize use of an experimental drug in an emergency
situation.

4) TREATMENT IND:

It is submitted for experimental drugs, showing promise in clinical testing of serious

(or) immediately life threatening conditions.

DATA TO BE SUBMITTED ALONG WITH APPLICATION TO CONDUCT

CLINICAL TRIALS:

Data to be submitted along with application to conduct clinical trial of new drugs for
marketing are as follows:
1) Animal pharmacology and toxicology studies
2) Manufacturing information
3) Clinical protocols and investigator information
1) ANIMAL PHARMACOLOGY AND TOXICOLOGY STUDIES:
Preclinical data to permit an assessment as to whether the product is reasonably safe
for initial testing in humans

2) MANUFACTURING INFORMATION:
Includes composition, manufacturer, stability and controls, used for manufacturing
the drug substance and the drug product.

3)CLINICAL PROTOCOLS AND INVESTIGATORS INFORMATION:

 Detailed protocols and clinical studies to assess whether the initial phase trials
will be exposed subjects to unnecessary risks.
Investigators information contains administration of experimental compound to
assess whether they qualified clinical trials.

FORMAT& CONTENT OF IND:

A. Cover sheet (from FDA-1571)
a) Name, address, telephone number of sponsor
b) Identification of phases
c) Commitment not to begin clinical trials and till IND approval
d) Commitment by IRB form-56
e) Commitment for conducting clinical trials
f) Name, title - monitor
g) Name, title - person
h) Name, Address of CRO
i) Signature of sponsor
B. Table of Contents

C. Investigators brochure
D. Study protocol
E. Investigator facilities and IRB data
F. Chemistry, manufacturing and control data
G. Previous human experience.

OUTCOMES FROM IND:

" 30 days after an IND is submitted to the FDA, if the sponsor has not heard
anything from the FDA, it can be assumed that the drug is not on a clinical hold
and clinical trials may be started.
Investigator brochure will be used during that important first clinical study and in
every clinical study acts as the approved labeling for the drug, while it is under an
IND.

DRUG CHARACTERIZATION

Drug characterization involves finding of biological and physio -chemical properties

of potential drug molecules.
 1)Biological characterization:
Interaction of drug molecules with biological systems.
Ex: Receptor binding, Enzyme inhibition.
2) Physio-chemical characterization:
Physical and chemical characterization of potential drugs.
Ex: Solubility, Pka X- ray, NMR, IR, UV-visible, MS, PET.

1) BIOLOGICAL CHARACTERIZATION:
It is needed to assess whether the molecule will likely to work in humans.

GOALS:

1, To find efficacy
2. Assess toxic effects

Further divided into:

(a) Biochemical assay
(b) Cellular assay
(c) System/whole animal assay.

(a) BI0-CHEMICAL ASSAY:

" Mechanism of action at molecular level.
Receptor binding assays (affinity and selectivity)
Metabolic processing.

(b) CELLULAR ASSAY:

" Cellular cultures: cell penetration, receptor, activity, transport.
Isolated tissues: effects on specific tissues, possible toxicity.
Liver tissues: Drug metabolism, Drug interaction.

(c)SYSTEM/WHOLE ANIMAL ASSAY:

Rat, mouse: Toxicity, LD50, organ-specific efficacy.
Dog, rabbit, Guinea pig, monkey: Pharmacokinetic/Pharmacodynamic,
bioavailability, toxicity.
Lab animal models for disease: efficacy and toxicity.
2) PHYSI0-CHEMICAL CHARACTERIZATION:
Physical and chemical properties of a drug are critical for knowing how it can be
formulated (or) stored, (or) administered.
a) Solubility
b) Pka
c) Partition coefficient: octanol: water
d) Stability
e) Chemical structure: Mass spectroscopy, NMR, X-ray, crystallography.
f) Impurities: TLC, HPLC, GC, Mass spectroscopy.
g) Polymorphism

DOSAGE FORM
At some stage, a decision needs to be mnade about the dosage form(s) for the
delivery of the drug (Ex: tablet (or) capsule, (or) induction).
The factors that determine which dosage forms are to be used are many &
involved marketing considerations apart from scientific considerations.

DOSAGE FORM COMMENTS

Convenient & commonest dosage forms
1) Tablet &capsule But likely to be no good, if drug can't be absorbed
in GI tract (or) if patient can't swallow them.
2) Injection &infusions Rapid action
Impractical for treating chronic illness.

3) Pessaries &suppositories
Can deliver the drug to local area, where required.
Have limited general use.
Useful for children &elderly.
4) Solutions, suspensions & elixirs But are bulky &less useful, if drug is unpalatable
(or) unstable in the presence of water.

5) Ointments, crams and paints Use is restricted to topical application.

Good for drugs required in the lungs.

6) Aerosols &drug powder inhalations Difficult to administer dose correctly.
Convenient, if the dose needs to be released over a
7) Trans-dermal patches long period.
Cause irritation.
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Therapeutic considerations play an important role in deciding the dosage form to

formulate.

EXAMPLE:
Even tablet that absorbs in alimentary tract (i.e. intestine) is unsatisfactory, if
that drug is destroyed by stomach acids.
Tablet is not suitable,if it can't absorb in alimentary tract. Instead of tablet,
an injection is suggested as an alternative.