DRUG DEVELOPMENT PROCESS

Drugs are perhaps the most important therapeutic interventions in modern

health care. Development of new drug is always a prime concern for
research based pharmaceutical industries.The new drugs may be discovered
from a variety of natural sources or synthesized in laboratory. Genetic
engineering and biotechnological advancement provides new platform for
drug development process. The process and time course from drug
discovery to marketing is a lengthy and tedious process.

APPROACHES TO DRUG DISCOVERY

The drug discovery begins generally by identifying a promising molecule (a

lead compound) that could become a drug. A lead compound is a
prototype chemical compound that has a fundamental desired biologic and
pharmacologic activity. The lead compound may not contain all desired
features of a successful drug. Thus they are modified to produce
analogue with additional or different functional chemical groups, altered ring
structure or different clinical configuration. The lead compounds go through
a series of tests to provide an early assessment of the safety with lead
compounds.The pharmacokinetic and toxicity studies of each lead
compound are performed in living cells, animals or via compartment
models. Nowadays much emphasis is on identifying the cause and
process of a disease and designing molecules capable of interfering with
that process. Most diseases arise from a biochemical imbalance, an
abnormal proliferation cells, an endogenous deficiency or an exogenous
chemical toxin or invasive pathogen.
SIX BASIC APPRHOACHES TO DRUG DEVELOPMENT

1. Identification of new drug target: a target is usually a single

gene, gene product or molecular mechanism that has been
identified on the basis of genetic analysis or biological
observations. The completion of human genome project has
resulted in identifying as many as 700 targets.
 2. Drug design based on biological mechanisms, drug receptor
structure and drug structure.
3. Chemical modification of known drug.
4. Screening of known products: natural products, peptides, nucleic
acids are exploited.
5. Biotechnology and cloning
6. Combination of known drugs either to improve therapeutic
efficacy or reduce toxicity or reduce the incidence of resistance
or repositioning a known drug for new indication.

With one or more optimized compounds in hand, it is necessary now to

test them extensively for safety and efficacy both in living cell cultures
and animal model. This phase of evaluation is known as preclinical
studies. The preclinical testing results are the foundation for clinical testing
on human beings.

PRECLINICAL TESTINGS

The primary aim of pre-clinical (animal) testing is to obtain basic

information on the drug’s effects that may be used to predict safe and
effective use in humans. Unfortunately, useful animal models are not
available for every human disease. There are specific difference between
humans and animals too. Hence it is essential that the drugs needs
testing in humans beings too before being approved for marketing (general
use). Accordingly, the objective of animal testing is to generate all data
that satisfy all the requirement before a new compound is deemed fit to
be tested for the first time in humans.This pre-clinical testing can be
divided into two broad categories: Pharmacological testing including
pharmacological kinetic testing and toxicological testing.

Pharmacological screening
The prospective drug substances are tested for biological activity to assess
their potential for developing as drugs. The work basically involves
pharmacological and toxicological screening of substance to determine
whether the substance has effectiveness and reasonable safety profile. A
stepwise progress through increasingly sophisticated evaluation based on
test compounds success in prior studies is followed
Molecular level study: The prospective substance is studied for its
selectivity (affinity) for various receptors and its activity against selective
enzyme systems. Cell membrane fractions from organs or cultured cells,
cloned receptors, sympathetic nerve, adrenal glands, purified enzymes, liver
etc. are used. Example: Receptor binding study can be performed in cell
membrane fractions from organs or cultured cells.
Cellular level study; the use of cell and tissue culture and computer
programmes that simulate human and animal system are increasingly used
to assess the pharmacological action. Testing through these systems has
reduced the dependence on the use of animals. Isolated tissues are also
equally helpful in identifying the substance’s activity and selectivity. Isolated
tissues like blood vessels, heart, lung, ileum of rat or guinea pig are
used. The study of antibacterial agent in bacterial culture, effect on
vascular contraction and relaxation in isolated tissues and effect on other
smooth muscles in isolated tissues are few examples.

Whole animal study:Whole animal studies are generally necessary to

determine the effect of prospective substance on organ systems and
disease models. These studies are generally reserved for testing
substances that have demonstrated reasonable potential in vitro testing. A
number of animal models are available to mimic certain human diseases
and are effectively used in screening.The pharmacological testing also
ensures that the drug does not produce any potential hazardous or
serious unwanted effects like bronchoconstriction, change in blood pressure
etc.
The pharmacokinetic testing is done to determine

 The extent and rate of absorption from various routes of

administration, including the one intended for human use
 The rate of distribution of the drug through the body and site and
duration of drug’s residence
  The primary and secondary rate, site ,mechanism of drug metabolism
in the body ,chemistry and pharmacology of any metabolites
 The proportion of administered dose eliminated from the body and
its rate and route of elimination

Toxicological evaluation:Toxicity is the most difficult drug property to

adequately evaluate, because it could be species specific, organ specific,
and cold involve multiple host factors and chronic dosing regimens and all
of which cannot be adequately modeled experimentally.. though toxicity
data of animals cannot be extrapolated to humans because of reasons
like species variation, different dose response relationship, immunological
differences etc., it is necessary to test the drug first in several species of
animals. The greater the number of animals species tested that
demonstrate a toxic effect, the greater the chance the effect will be seen
in humans.
The toxicity studies are undertaken to determine the test drug’s

 Potential for toxicity with short term and long term use
 Potential for specific organ toxicity
 Mode, site and degree of toxicity
 Dose response relationship for low, high and intermediate doses over
a specified time
 Gender, reproductive or teratogenic toxicities
 Potential for carcinogenic and genotoxicity

Most animal testing is done on small animals, usually rodents.however in

final studies, two or more animal species are used.

Acute Studies: Acute toxicity studies look at the effects of one or

more doses administered over a period of up to 24 hours. The
goal is to determine toxic dose levels and observe clinical
indications of toxicity. Usually, at least two mammalian species are
tested. Data from acute toxicity studies helps determine doses for
repeated dose studies in animals and Phase I studies in humans.
Subacute(subchronic) Studies:This involves giving the prospective drug
substance daily for minimum period of two weeks at three or more
dosage levels to two animal species. This is useful generating
evidence to support initial administration of a single dose in human
clinical testing.

Chronic toxicity studies:the animal studies of three to six months is

required if the tested drug is intended to be given for one week or
more in humans. For drugs intended to be given for chronic illness,
animal studies for one year or longer is required.

Genotoxicity Studies(mutagenicity):These studies assess the likelihood

that the drug compound is mutagenic or carcinogenic. Procedures
such as the Ames test (conducted in bacteria) detect genetic
changes. DNA damage is assessed in tests using mammalian cells
such as the Mouse Micronucleus Test. The Chromosomal Aberration
Test and similar procedures detect damage at the chromosomal
level.

Reproductive Toxicity Studies:Segment I reproductive toxicity studies

look at the effects of the drug on fertility. Segment II and III
studies detect effects on embryonic and post-natal development. In
general, reproductive toxicity studies must be completed before a
drug can be administered to women of child-bearing age.

Carcinogenicity Studies:Carcinogenicity studies are usually needed only

for drugs intended for chronic or recurring conditions. They are time
consuming and expensive, andmust be planned for early in the
preclinical testing process. The studies are carried out in a limited
number of rat and mouse strains for which there is reasonable
information on spontaneous tumor incidence. The high dose to be
used for the study should be maximum tolerated dose to elicit signs
of minimal toxicity without significantly altering the animal’s normal
life span by effects other than carcinogenicity.

DEVELOPMENT OF CHEMICAL AND PHARMACEUTICAL

INFORMATION
The appendix 1 of drug and cosmetic rules Y specifies the data
under chemical and pharmaceutical information subheading required to
be submitted with the application to conduct clinical trials.Once the
prospective drug substance crossed the pharmacologic and toxicology
evaluation in animals, it becomes necessary to generate data on
chemical and physical properties that are useful developing stable
and effective pharmaceutical formulation. This part of study id
intended generating information relating to composition, manufacture,
stability and controls used for manufacturing the drug substance nd
the product.
This information is assessed to ensure that the sponsor or the
company has the ability to produce and supply consistence batches
of the drug substance. If the drug is either unstable or not
reproducible, then validity of any clinical testing would be
undermined because one would not know what was really being
used in the patients.

1. Information on active ingredients: the drug substance is

basically a chemical and is identified by several names. The
following names are most important: chemical name and
generic name ( or INN).
2. Physiochemical data:
Chemical name and structure: empirical formula and molecular
weight
Physical properties: description, solubility, rotation, partition
coefficient ,dissociation constant.
3. Analytical data: elemental analysis, mass spectrum, NMR
spectra, IR spectra, UV spectra, polymorphic identification.
4. Complete monograph specification including identification, identity/
quantification of impurities, enantiomeric purity, assay
5. Validation: assay methods, impurity estimation method, and
residual solvent/ other volatile impurities estimation method.
6. Stability studies: final release specification, reference standard
characterization, material safety data sheet.
7. Data on formulation

INVESTIGATIONAL NEW DRUG APPLICATION: The INDA is

required to be submitted to Drug Regulatory Authority before
initiation of clinical trial. The INDA can be submitted by the sponsor
but may employ CRO to conduct the actual studies. The appendix
1 of schedule Y of drugs and cosmetic rules specifies the data
required to be submitted along with the application to conduct
clinical trials.

The INDA can be submitted for one or more phases of clinical

investigation. The INDA is reviewed to ensure the protection of
rights and safety of the human subjects and that the
investigational plan is sound and allows evaluation of safety and
effectiveness on approval.
CONTENTS OF INDA

 Name, address, and telephone number of the sponsor of the

drug.
 Name and titles of the person responsible for monitoring the
conduct and progress of the investigation.
 Name and titles of the persons responsible for the review
and evaluation of information relevant to safety of the drug.
 Name and address of any CRO involved in the study.
 identification of phase or phases of clinical investigation to be
conducted.
 Introductory statement and general investigational plan.
 Description of the investigational plan.
 Brief summary of previous human experience with the drug,
including the reasons if the drug has been withdrawn from
any other investigation and/ or marketing.
 Chemistry, manufacturing and control information.
 Pharmacologic and toxicology information.
 If the new drug is the combination of previously investigated
components, a complete preclinical and clinical summary of
these components when administered singly and any data or
expectations relating to the effect when combined.
 Clinical protocol of each planned study.
 Commitment that an Institutional Review Board has approved
the clinical study and will continue to review and monitor the
investigation.
  Investigator Brochure.
 Commitment not to begin clinical investigation until te IND is
approved, signature of the sponsor or authorized
representative, and the date of signed application.

Clinical testing:On successful completion of the pre-clinical testing of

the potential molecule, the clinical testing can be initiated after
obtaining the regulatory approval based on the investigational new
drug(IND) application.

The clinical trial must comply with ethical and legal requirements of
the country. It requires that all studies be approved by the
Institutional Review Board(IRB)/ Institutional Ethics Committee (IEC) at
the institutions where trials will take place.

Phase 0:A recently introduced (FDA) phase where micro-dosing of candidates is used to
determine distribution (PK and PD) related information in man.
Phase I:Phase I trials are the first stage of testing in human subjects. Normally, a small (20-80)
group of healthy volunteers will be selected. This phase includes trials designed to assess the
safety, tolerability pharmacokinetics and pharmacodynamics of a drug.
Phase II:Once the initial safety of the study drug has been confirmed in Phase I trials, Phase II
trials are performed on larger groups (20-300) and are designed to assess how well the drug
works, as well as to continue Phase I safety assessments in a larger group of volunteers and
patients.
Phase III:Phase III studies are randomized controlled multicenter trials on large patient groups
(300–3,000 or more depending upon the disease/medical condition studied) and are aimed at
being the definitive assessment of how effective the drug is, in comparison with current 'gold
standard' treatment. Because of their size and comparatively long duration, Phase III trials are the
most expensive, time-consuming and difficult trials to design and run, especially in therapies for
chronic medical conditions.
Phase IV:Phase IV trial is also known as Post Marketing Surveillance Trial. Phase IV trials
involve the safety surveillance and ongoing technical support of a drug after it receives
permission to be sold. In larger patient populations issues such as rare side effects or interactions
with other prescribed drugs are identified

REFERENCES

1. Textbook on clinical research:a guide for aspiring professionals and professionals,

byguru Prasad mohanta,page no;-6-24
2. http://www1.imperial.ac.uk/medicine/research/institutes/drugdiscoverycentre/guide/
clinicaldevelopment/