A drug is any chemical that affects the way body works when consumed

ahemhootBiotechnology

Dec 5, 2012 (4 years and 8 months ago)

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1.0

INTRODUCTION


1.1


Definition



A drug is any chemical

that affects the way body works

when consumed
.
In

pharmacology
, a drug is
a

chemical

substance used in the treatment, cure,
prevention, or diagnosis of disease or used to otherwise enhance physical or mental
well
-
being.

Drugs may be prescribed for a limited duration
, or on a regular basis
for

chronic disorders
.
The idea that effect of drug in human body are mediated by
specific interactions of the drug molecule with biological mac
romolecules, (proteins
or nucleic acids in most cases) led scientists to the conclusion that individual
chemicals are required for
the biological activity of the drug. This made

up

the
beginning of the modern era in pharmacology, as pure chemicals, instead

of crude
extracts, became the standard drugs
.

1.2

History of drug discovery and development

Drug discovery and develop
ment has a long history in the practice of
medicine and can be dated back to early days of human civilization. The early source
of medicines were derived mainly from botanical species and supplemented by
animal materials and also minerals.
These drugs were

mostly discovered and
developed based on trial and error experimentation and from obser
v
ation of reactions
of human and animal after ingestion of the products. Chinese medicine, Egyptian
medicine, Indian medicine, Greek medicine and roman medicine shows e
vidence of
drug use of natural origin at the early centuries with the discovery of various
pharmacopeias or recipes for medicine which contains writings and list of ingredients
of herbs and formulations used for various treatment purpose
.

Then, in the
middle ages which is around AD 400 to 1500, plagues and
epidemics affect many parts of the world particularly in Europe. During that time,
due to activities of trades with many regions, medical knowledge of Arabians started
to
flourish and contributed in t
he knowledge of medical preparations and distillation
methods. The church, on the other hand, preserived and transcribed the Greek
medical manuscripts and allow the preservation of knowledge developed in the
ancient times which is later used in Renaissance

period and consequently laid
foundation for the modern era drug discovery and development.
During the
Renaissance period, many advances were made in medical discipline in the aspects of
anatomy, physiology, surgery and medical treatments. Examples of adva
nces made in
pharmaceutical aspects were invention of vaccines ag
ainst some infectious diseases
namely the smallpox inoculation invented by Edward Jenner in 1796
; discovery of
microorganisms as causative agents for diseases by Louis Pasteur(1864) and the
s
ubsequent development of vaccination against rabies using attenuated rabies virus;
the introduction of digitalis which is extracted from the plant foxglove for treatment
of cardiac problem a
nd also prescription of Vitamin

C in the form of lemon juice as a
treatment for scurvy.

From the early 1900s, more systematic research is then being
performed for the purpose of drug discovery. In 1928,
Penicillium
mold were
discovered to be active against staphylococcus bacteria by Alexander Fleming. Ten
years later
, us
e

of
Penicillum

mold

is rediscovered by Ernst Chain and Howard
Florey. Large
-
scale production of penicillin is then available, and this work marks the
beginning of application of biotechnology in drug development where
microorganisms were used to develop drug products.



Dev
elopment of synthetic drugs via chemical methods started to flourish at the
beginning of the 1900s which is also the starting point of foundation of pharmaceutical
industry and many drugs which are used for therapeutic purposes are researched and
manufactu
red. From the early 1930s, the main focus of drug discovery is on isolation
of active ingredients via screening of natural products for treating diseases. The active
ingredients is then developed into the synthetic version

(analogs)

of the natural
products

and is termed the new chemical entities (NCEs).
Development of synthetic
drugs offers solution to the issue of development of resistance to natural
penicillin

by
the bacteria which are solved by the ability of preparation of analogs that have the
similar
activity

on the resistant
strains.

Tests

to ensure the safety,
effectiv
eness

and
potency of the NCE are initiated in the pharmaceutical industry.

In the late 1970s, biotechnology industry began to commence in the
pharmaceutical industry with the developme
nt of recombinant DNA products.
In
1980s, w
ith the commercial availability of powerful instruments such as spectrometers
( namely NMR and MS) and also separation techniques (HPLC), pharmaceutical
researches are further empowered as the techniques and instr
uments allow swifter and
more precise determination of structures biologically active natural products which are
often at minute quantities.

Then, in the following
decade
, pharmaceutical industry
starts to shift away from random searches of active natural

products to a new, more
“rational” computational
archetype

for dug discovery, namely, the computer
-
aided
drug design. This shift was driven by the increase in computer technology and also by
concurrent advances in knowledge of structural biology particula
rly in protein
crystallography which provide continuous stream of information on new protein
structures which can be used for computational drug design studies. Also, between the
1960s and 1980s, application of biotechnology and bioinformatics in pharmaceu
tical
discipline increases.

Then further, with the advances made in gene therapy and better understanding of
mechanisms of causes of various diseases and also research results of genetic makeup
of

opened up vast opportunity and possibility for developme
nt of drugs that are more
specific at targeting specific diseases.



1.3

History

perspective

of

regulation

of

drug

development


The pharmaceutical industry was dominated by German and Swiss chemical
companies after the Second World War. Medicines were
developed

in large scale

during
the war to assist the soldiers in coping with war
-
related diseases. Penicillin was mass
produced and antibiotics were immediately available. However, as drugs were mass
produced, drug regulations and safety were overlooked and became liberal, espec
ially in
the free market.


In the 19
th

century, marketing of medicines was not regulated, and corruption,
exp
loitation and fraud were uncontrolled
. Concerns about safety of medicine
and food
then led to
the passing of the Food and Drug Administration Act o
f 1996 which required
drugs to meet official standards of strength and purity, defined the terms of
adulterated
and
misbranded
, and prohibited the shipment of misbranded and adulterated foods,
drinks, and drugs. However, this act did not provide FDA with m
uch power over the issue
and an incident where
due to lack of regulation in the existing law that require the
manufacturers of drugs to demonstrate the drug’s safety, a drug marketed as “
elixir

sulfanilamide” caused deaths of 107 persons in 1
937 due to the toxicity of die
t
h
ylene
glycol which is a component used in the drug. Consequently, the Federal Food, Drug and
Cosmetic Act of 1938 was enacted which commenced the start of the modern FDA. This
act required the manufacturer to be responsible

at proving the safety of a drug before the
drug is marketed, authorized the factory inspections, and also
established penalties

for
false claims and misleading branding on the products. Following this act, FDA distributed
public notices (termed the trade
correspondences) to the industry addressing the issue of
labeling and dispensing of the drugs. With these notices, all drugs are required to carry a
label with adequate information for consumer use or a caution label which warned
consumers about the specif
ic drug that should be used only with prescription. In 1961,
cases of increment of fetal malformations cause by the hypnotic drug thalidomide was
reported by William McBride, an Australian obstetrician. This incident alerted the need
for amendment of more

stringent laws and led to passing of the Kefauver
-
Harris
Amendment in 1962 which
required manufacturers to prove safety of a drug and also to
provide evidence that the product fit the claims made in the labeling through
investigations made by qualified re
searchers. In the late 1970s, guidelines for good
laboratory practices and clinical trials are established by FDA to assure the quality and
integrity of the research data filed with FDA. These guidelines were later developed into
regulations.


1.4

Regulatory
bodies of drug development in Malaysia

In Malaysia, a
ll medicines marketed in the country are required to be registered by
the Drug Control Authority (DCA) of the Ministry of Health.
Practice

of drug registration
commenced at Malaysia since 1986.
All
manufacturers, importers and wholesalers are
required to

be

licensed by the DCA.

The
registrations of prescription and over
-
the
-
counter (OTC) medicines, require

proof of efficacy, quality and safety, and are subjected
to stringent screening and testing as
well as regular and random post
-
marketing
surveillance and testing.

In addition, a
ll manufacturers in Malaysia are subjected to
regular and random inspection by DCA inspectors.
There are currently 250 manufacturers
in Malaysia licensed by the Drug Control
Authority.

To be licensed, manufacturers must be in full compliance with the Code of Good
Manufacturing Practice, which is currently based on the


Pharmaceutical Inspection
Convention (
PIC
)

Code as Malaysia is currently a
member of

Pharmaceutical Inspecti
on
Convention and Pharmaceutical Inspection Co
-
operation Scheme (jointly referred to as
PIC/S)
.

On the other hand, m
edicines are regulated under the Poisons Act, the Dangerous
Drugs Act and the Drugs Act. Medicine advertisements require prior approval by
the
Medicines Advertisement Board.

Also,
Malaysia is a member of the
World Trade
Organization

(WTO)
and
are
assent

to the
Trade
-
Related Aspects of Intellectual Property Rights (
TRIPS
)

agreement.
Therefore, p
atents

protection of drugs

that are

registered a
nd copyrights are protected

in
Malaysia
.

2.0

Objective

The objective of this paper is to describe the process of drug development in the
aspect of drug discovery, drug development and the approval process. In addition,
involvement of biotechnology in the
process of drug development is also discussed.

3.0

Process of drug development

3.1

Pre
-

discovery process

(target identification)

In order to discover new potential medicine, understanding of the disease is
essential in order to identify the molecular target ( the

molecular entity which activity
is significant in the disease). The scientists work to understand the disease in the
aspect of underlying cause of the condition, mechanism of genetic alterations, impact
of the alteration on the cellular proteins and inter
actions of the impacted proteins
with each other and , effect imposed by the impacted pro
tein on other living cells
and the mechanism which leads to the manifestation of the disease.

Then, with the understanding of the underlying cause of the disease, a
process
termed target identification will be carried out in which a target molecule will be
selected by the pharmaceutical researchers. This target molecule is generally a single
molecule namely a gene or a protein, which has significant activity in the d
isease.
The critical element in this step is that the target molecule selected should possess
potential to interact with and be affected by a drug molecule.

Subsequently, a process termed target validation wil be carried out by the
scientists to prove th
e involvement of the target molecule in the disease and how the
target molecule can be potentially affected by a drug molecule.


3.2

Preclinical Phase

Preclinical drug development is a drug development stage that begins before
testi
ng the candidate drug in hu
mans. Purposes of preclinical phase is
to collect the
safety and pharmacology data such as pharmacodynamics, pharmacokinetics and
toxicity through animal testing. From the results of preclinical
stage of drug
development
,
toxic effects and therapeutic
effect of the

target organ, dose
depend
ence, relationship to exposure
and potential reversibility
of the drug
can be
obtain
ed. Hence,
researchers are able to estimate a safe starting dose of the candidate
drug for clinical trial in humans.

Data collected f
rom preclinical testing to support clinical trials is addressed in the
International Conference on Harmonization (ICH) Safety guidelines. However, good
results in the preclinical state do not necessarily mean that similar outcome will be
gain in clinical t
rials on humans.


Figure :
Key steps of drug discovery and development.


3.2.1

Lead

Discovery

With the understanding of the disease, scientists and researchers then can search
for a candidate drug, also termed as the “lead compound” which is comprised of small
molecule compounds which can interfere with the effects of the target molecule.
For
exam
ple, if a microorganism is the main cause of a disease, ways to inhibit the growth
on human will be the main characteristic of the lead compound.

Subsequently, these
drug candidates are then tested for their interaction with the target molecule.
Generally,

up to 5000 to 10000 molecules for each potential drug candidate will then
undergo a screening process to confirm the interaction of the drug candidate with the
target molecule. After a very careful review and testing, then one or more lead
compound can be

chosen, the lead compound, are often termed the New Chemical
Entity (NCE).

NCE is defined by FDA as a drug which contains no active moiety
(which

is molecules or ion that are responsible for the physiology or pharmacology
action
of drug substance) that h
as been approved by FDA in any other application
submitted under section 505(b) of the Federal Food, Drug and Cosmetic Act.

A few methods are often used in the process of searching for a lead compound.
Researchers can either seek for lead compound from na
tural substances such as
bacteria found in soil or moldy plants which can interact with the target molecule,
advances in computational power and robotics provi
de researchers with instruments
with high throughput screening facility
which can be able to scre
en and test hundreds
and thousands of compounds against the target molecule to identify the compound
that possess prom
ising potential against the target molecule. Alternatively, res
earchers
also employ techniques of

biotechnology such as genetic

engineeri
ng to modify
living organisms to produce disease
-
fighting biological molecules or create molecules
de novo
.

3.2.2

Early safety test

After the discovery of the NCE, the selected compound will be subjected through
a set of tests in order to provide an early assessment of the safety of the compound.
Properties that are tested are:
Absorption, Distribution
,
Metabolism,

Excre
tion and
Toxic
ology (ADME/ Tox), or the pharmacokinetics of each lead compound.
Therefore,
in this stage, the properties of th
e drugs concern the researchers are the
ability of the drug to

be absorbed into the bloodstream,

capability

of being distributed
to the proper
s
ite of action in the body, ability

to be metabolized efficiently and
effectively, can be successfully excreted from the body and also being demonstrated to
be not toxic. These tests are useful to aid the researchers to identify the lead
compounds which the
y should prioritize

and eliminate false positive drug entity. The
drug entities are ranked according to the properties measured. The studies are
conducted via computational methods on different genetically engineered cell lines
which act as the target org
an of the candidate drug to demonstrate the effect of the
chemical entity during short term administration.

3.2.3

Preformulation testing

In this stage, potency of the new drug is not the main concern but the factors show
as below become more important:



hit se
lectivi
ty



feasibility of chemic
al synthesis and modification



the mechanism of target interaction



modulation pharmacology kinetic, patentability of final drug

Preformulation

testing are aim to develop a dosage form that is absorbed in to
bloodstream when administrated and is stable when store for long periods of time.
The concentration in the blood is an important factor in early development. The
potential new drug must reach

and maintain a level sufficient to sustain its biological
effect.
Techniques use in lead discovery stage include biophysical or biochemical
assays, cell
-
based screens, in
-
silico predictions and many more.

3.2.4

Lead Optimization

Lead compounds that made throu
gh the initial screening then proceed with
optimization.

The relationship between therapeutic effects of a drug and its adverse effects as a
margin of safety (MOS), it means the difference between the effective dose and the
dose that may cause toxicity.
Function of l
ead optimization is to widen the MOS

and
increase the effectiveness of the drug
. Important information that help to widening
MOS are the fundamental understanding of the mechanisms of interaction with the
desired target and off
-
targets.
With t
he understanding, the lead compound can be
modified in a way that different properties that are beneficial can be given to the
compound such as reducing the potential for side effects by altering the compounds by
making the compound less likely to interact

with other
chemical

pathways in the body.

New techniques such as X
-
ray crystallography, magnetic resonance imaging, and
powerful computer modeling capabilities have transformed the ability of researchers in
process of lead optimization by allowing researc
hers better visualize the molecule and
hence to design potentials drugs that are more powerfully bound to the sites of the
target molecule which they can result in most optimal effect. In addition
,
combinatorial chemistry and rapid in
-
vivo screens
which ar
e important in determining

the relationship between structure and activ
ity of molecules, also aid researcher in the
lead optimization process.


Lead derivation and optimization are guided by 3 important factors: efficacy,
specificity and pharmacokinetics. Pharmacokinetic is the study of time taken of drug
absorption, distribution, metabolism and excretion (ADME), and how ADME relate
with therapeut
ic effect and toxic effect of a drug.

3.2.5

Preclinical Testing

Preclinical testing of a new drug can be carry out by several methods depend on
types of developing drug.
When selecting the
method
of
drug
testing, the main
consideration is whether the chosen
method

can tolerate with large amount of
potentially bioactive molecules.

While non
-
animal models generally are based on
nonclinical endpoint, they are useful to filter out poor candidate and weeding ou
t of
false hits

during earlier drug discovery. In
-
vitro and in
-
silicon method involve more
extensive evaluation and preclinical stage in vertebrate animals on a limited number of
potential therapeutic agents.

Table
3.0
: Method
s used in preclinal studies

No

Method

Explanation

1

In
-
Vitro studies





to establish a concentration
-
effect relationship



b
asic instrument used in this study are such as organ
bath and recording devices.

2.

In
-
Vivo Studies




to define dose
-
respond relationship of the adverse
effect observed




testing
new drug on whole living organism or
animals.



usually animals such as rodents are used as models
of human.


3.

Ex Vivo Studies




drug testing
is performed in vivo



organ

of the animals are detached from the body and
replaced once an ex
periment is performed.




The detached organ are
analyzed in vitro.



animal models are kept under observation and
findings was obtained and recorded for a specific
duration.


4.


In
-
Silico St
udies




find out
pharmacokinetic, pharmacodymanic and
toxicological effect
of candidate drug by using
computer program or via computer simulation.


Although there are other more advanced method in studying new drug effect, in
-
vivo studies method
,

generally known as animal testing
is still more preferred. This is
because certain animal models have greater similarity to human in terms of biological
system.
Animal models chosen must have appropriate condition to be investigated and
believed
to be
abl
e to respond in the same way as human to the proposed treatments.
Animal models use in new drug testing must be sensitive and in large population
.
Animal testing helps to provide data about pharmacological and toxicological effect on
animal.


In additio
n, a
nimal pharmacology studies
is also carried out
to determine and
investigate the undesirable
pharmacokinetic and
pharmacodynamic effects of the
candidate drug.

With the animal testing, p
harmacokinetic effect

which shows how the
new drug are been absorbe
d, distributed, metabolized and eliminated from the animal
model can be demonstrated
.

While the

pharmacodymanic effect

demonstrated through
the animal models

can help scientists to monitor

mechanisms of drug action and
relationship between drug concentration and effect that

is exerted on the

animal

models
can be studied
.

On the other hand, a
nimal toxicology studies are

used

to

evaluate
the systemic
exposure achieved in animal and its relat
ionship to dose level and the time course of the
toxicity study. Toxicological findings
h
elp in select
ion of starting doses for phase

I

of
clinical phase and

provide preliminary identification of target organs of toxicity

to avoid

overdosing in humans

duri
ng phase I of clinical testing
.

3.2.6

Report of Preclinical Study to FDA

If result of preclinical stage is positive, this phase is followed by an application to
the FDA as an investigational new drug (IND). IND should include chemical and
manufacturing data, an
imal test results, rationale for testing a new compound in humans,
strategies for protection of human volunteers and plan for clinical testing. IND will be
evaluated by FDA to decide whether the application can be approved or rejected. FDA
might also reque
st for further study before making decision. If the manufacture’s IND
was approved by FDA, the drug manufacturer can proceed to clinical
phases
.

3.3

Clinical Trials




After a drug had undergone preclinical phase, and FDA was satisfy with the
documentation of IND application that is supported by the results, the drug then proceed
to go through clinical trials. Clinical trials comprised of phase 1, 2, and 3, which are
con
ducted by doctors and researchers. Each phase is carried out for different purposes and
to provide detailed information about the new drug.


3.3
.1 Phase 1




The goal of phase 1 clinical trials are to determine to metabolic and
pharmacological effects of d
rug in humans, i.e. how it is absorbed, distributed,
metabolized and excreted. Hence, this phase requires adequate information about the
pharmacokinetics of the drug. Since the purpose of phase 1 clinical trials are to mainly
determine safety profile, the
researchers have to prove that the new drug can be given
safely to people.




There are small numbers of volunteers who participate in this clinical trials,
generally 20


100 people. The volunteers are closely supervised and can be either
healthy individu
als, or patients with the disease in cases where the tested drug are
targeting the specific disease which is severe or life
-
threatening. Since the evaluation of
efficacy is not the specific objective in phase 1 clinical trials, the volunteers’ population i
s
not restricted to only the patient of the specific disease. However, it is necessary to
exclude volunteers with impaired organ function. This is because they may be more prone
to serious toxicity.




During this phase, the dose of the drug being studied
is gradually increased to find
the does that works best with fewest side effects. Therefore, phase 1 is designed as a
dose
-
escalation study to determine the maximum tolerable dosage (MTD). MTD is the
maximum dose associated with an acceptable level of dose
-
limiting toxicity. Low doses
of a drug are given to the first participant. Next administration with higher amount of
drug to other participant will be continued if there are no or few side effects. Meanwhile,
doctors will collect data on the dose, timing,

and safety of the treatment. The highest dose
with least severe effects will be taken.




Phase 1 clinical trials may last several months to a year. Usually, there are only
two thirds of drugs in phase 1 will be found safe enough to progress to phase 2. F
or
example, if there is 100 drugs of investigational NDA are submitted to FDA,
approximately 70 will successfully complete phase 1 and continue with phase 2.


3.
3
.2 Phase 2




Phase 2 clinical trials are controlled study to explore the effectiveness of the

new
drug. This phase is conducted to provide more detailed information about the safety of the
drug, i.e. the common short
-
term side effects and risks associated with the drug, and also
to evaluate how well it works. Moreover, the method of administration
, for instance, oral
or intravenous administration, and the dosing interval are also determined by the
researchers during this phase. Hence, this phase can be divided into two phases : phase 2a
which is conducted to assess the short
-
term safety; and phase
2b which is carried out to
evaluate the dose range of the new drug.



Typically, there are 100
-
300 volunteers enrolled in this phase 2 clinical trials. In contrast
to phase 1 study, the volunteers who participate in phase 2 are the patients who suffer
from

the condition the new drug is intended to treat. They are closely monitored and
assessed continuously. There are not many volunteers involved in this phase because the
researchers have to avoid unnecessarily exposing the volunteers to a harmful substance.

Hence, this phase 2 study is based on an analysis of the fewest volunteers needed to
provide sufficient statistical power to determine efficacy of the new drug.


Phase 2 clinical trials take several months to 2 years to accomplish and progress to further
phases. For the new drug to be further tested in phase 3, it has to work better or at least as
well as the standard drug treatment. There are about 33% of the drugs successfully tested
and go on to phase 3.


3.3
.
3

Phase 3




After the preliminary evidence
suggesting effectiveness of the drug has been
obtained in phase 2, the phase 3 clinical trials are performed to assemble the additional
information about effectiveness. In order to assess the overall benefit
-
risk relationship of
the drug, the extra informa
tion regarding to the drug safety is also collected. Those data
are gathered from larger population, usually range from several hundred to several
thousand people across multiple sites.



Phase 3 clinical trials are generally randomized controlled study, w
hich mean that
patients are given either investigational treatment or the standard treatment in a non
-
ordered way. The volunteers in phase 3 consist of those patients of various ages, races,
and both genders so that the results can be applicable to a large

number of people, even
though they are patients with a specific disease.




In addition, the purpose of phase 3 clinical trials is also to take a new drug that has
shown promising results when used for a small number of patients with a particular
disease
and compare it with the current standard of care for that specific disease. Hence,
at the end of phase 3, a sufficient basis can be provided for extrapolating the result to the
general population and transmitting that information in the physician labeling.




Phase 3 clinical trials are the final step before seeking the FDA approval. These
studies typically last for 1
-
4 years. If there are originally 100 drugs submitted to FDA, for
example, only 25
-
30% of them can pass phase 3.

3.4

Approval process





Upon

completing all three clinical phases, the drug manufacturer will analyze the
data collected from all the preclinical studies as well as clinical phases. If the findings
show that the experimental drug is effective and safe to be used, the drug manufacture
r
has to obtain approval for that particular drug. This can be done by issuing a New Drug
Application (NDA) to the U.S. Food and Drug Administration (FDA) for approval of that
drug. FDA can either approve or reject the request, or they might also request f
or further
study and information before making a decision. After a drug is being accepted, FDA can
request for the drug manufacturer to conduct additional post marketing studies, or also
can be known as Phase IV. This entire process is time consuming where

it takes between
8 to 12 years on average.




In Malaysia, the manufacture and marketing of drugs are heavily controlled and
regulated as well. All marketed drugs and medicines in Malaysia are required to be
registered by the Drug Control Authority (DCA)
of the Ministry of Health.
Moreover
, all
the drug manufacturers, drug importers and drug wholesalers required to be licensed by
the DCA. This help to prevent from abuse of drug usage.





NDA is an important part in order to obtain approval for a drug. The
re are some
information which should be included inside the NDA, such as all the information from
the previous years of work and also the proposals for manufacturing and labeling of the
new drug. Experts from FDA
will
review all the information included in
side the NDA
carefully and determine whether the information
sufficiently
demonstrates the safety and
effectiveness of the drug. Below are the 3 major concerns in which FDA will take into
cons
ideration to approve a new drug:


1.

FDA must det
ermine whether the

benefits of the

drug outweigh the risks, whether
the drug is effective for its proposed use, and also does the drug has an acceptable
and reasonable balance between benefits and risks been achieved?

2.

FDA must decide the information which should be included

in the package insert
in order to guide the physicians and also healthcare professionals in the use of the
new drug

based on its assessment of risk and benefit
.

3.

FDA must assess whether the methods used to manufacture the drug and also
ensure its quality a
re sufficient to preserve the drug's identity, strength and purity.




After reviewing all the information supplied by the drug manufacturer on that
particular drug, FDA can either choose to approve the medicine, send the drug
manufacturer a letter request
ing for more information or studies before approval is given
or deny the approval. Review of an NDA are usually done by these 3 parties, which
include
:

1.

FDA reviewers;

2.

An independent panel of FDA
-
appointed experts who consider data presented by
drug
manufacturer representatives;

3.

An advisory committee.

Voting will be done by these parties

to decide whether FDA should approve an
application, and under what conditions the approval should be given. FDA
are

not
necessarily required to follow the recommenda
tions of the advisory committees, but they
usually does.




The approval process of drug is very important, because there is no drug which is
completely safe and does not have any side effect. If the drug is released into market
before assessing the balanc
e between the risks and benefits of the drug, that drug may
cause adverse effects to their consumers. Consumers are also more confident towards a
certain drug which is approved. Besides, the approval process also able to control the
quality and quantity of

the drugs which are introduced in the market. If there is no
approval process, there are some irresponsible drug manufacturer who may simply create
drugs for their own profit without considering the effects of the drug towards the
consumers. Therefore, it

is crucial for a tested drug to undergo approval process, and
obtain approval eventually from certified organisation, such as FDA.

3.5

Post Marketing Commitment

The fourth phase of drug development involves post
-
approval research and post
-
marketing survei
llance. The procedures of this phase is done after the FDA approves a
particular drug and is introduced in the market

where the drug can start to be used by
patients and healthcare professionals for treatment purposes
.

Function of phase four is to

identify other possible side effects, to evaluate effect
of the drug in new population groups(such as elderly or pediatric patient), to examine the
effectiveness of the drug for additional indications or to assess the long term effects of
the drug. The p
hase four may be issued by FDA or may be initiated by the sponsor.


FDA
may request the post marketing study in order to examine the risks and benefits of the
new drug in a different population or to conduct special monitoring in a high
-
risk
population. On

the other hand, a phase 4 study might also be commenced by the drug
manufacturer without instruction from FDA aimed to assess long term effects of drug
exposure, to optimize the dose for marketing, to evaluate the effects in pediatric patients,
or to exam
ine the effectiveness of the drug for additional indications.
In this process,
effort from
physicians
or patients are required to report

cases of
adverse

complication
cause by the drug to the Med
-
watch, a medical reporting programme set up by FDA to
track
serious adverse effects . Manufacturers are also complied to report adverse drug
reactions at quarterly intervals for the first three years after the approval, a special report
regarding any serious and unexpected adverse reactions have to be submitted by
the
manufacturer to FDA.

Postmarketing surveillance is very essential because both pre
-
clinical trials and
clinical trials, no matter how well
-
designed , are not capable of uncovering every problem
that might occur after the product is widely used. The gro
ups that use the product can be a
population that are not well studied in the clinical trials, such as elderly patients and
paediatric patients, and the adverse effect that the drug may pose towards these specific
groups may not be known.

4.0

Biotechnology an
d drug development

4.1 Definitio
n



Biotechnology is a field of technological activity which combines biochemical,
genetic, microbiological, and engineering techniques to pursue the technical and applied
aspects of research into biological materials, espec
ially the biological processing.
Biotechnology applies manipulation and modification of biological material,processes
and systems, in the development or manufacture of a product or in the technological
solution to a problem. Also, biotechnology is defined
as

'the integration of natural
sciences and engineering sciences in order to achieve the application of organisms, cells,
parts thereof and molecular analogues for products and services by the European
Federation of Biotechnology General Assembly(1989). Biote
chnology has applications in
four major industrial areas: health care (medical), crop production and agriculture,
industrial (non food) uses of crops and other products (e.g. manufacturing of biofuels, and
biodegradable plastics), and environmental uses. T
he branch of biotechnology applied in
the field of pharmaceutical are generally termed as pharmaceutical technology.


4.2
Branches of biotechnology used in drug development



The science of biotechnology can be divided into a several different
branches(sub
discipline), a few branches that are widely used are: bioinformatics, red
biotechnology, white biotechnology, green biotechnology, and blue biotechnology.
Among these branches, red biotechnology and bioinformatics play important role in drug
development.


4.2.1

Bioinformatics

Bioinformatics, also known as

computational biology
, is a field which applies
computational techniques to address biological problems and function to allow rapid
organization and analysis of biological data. Bioinformatics plays an increasingly
important role in drug development in the aspect of drug disco
very, drug assessment and
drug development. Bioinformatics is important due to the ability of usage of
bioinformatics to handle large volumes of data and to predict, analyze and help interpret
clinical and preclinical findings. Bioinformatics resources (i.
e., databases and softwares)
plays an increasingly important role in understanding and predicting metabolism, with
respect to the aspect of ADMET, which stands for Absorption(A), Distribution(D),
Metabolism(M), Excretion(E) and toxicity(T) of the existing
drugs and the potential drug
being developed
.
The current bioinformatics analytical software can be categorized into
four major segments:

4.2.2

Genomics



Bioinformatic tools allows

effective and accurate analysis of an extensive amount
of data gained when conducting

DNA sequencing and gene expression analysis.
Bioinformatic tools provide researchers with softwares that helps to minimalise the time
spent to quantitate and manage data

and hence helps to shorten the drug development
time. Examples of genomic bioinformatic tool are: Rosetta’s Resolver system which is a
gene expression analysis software that translate image data from microarray instruments
into a quantitative format, Vect
or NTI Advance which is a software used for sequence
analysis and that enables users to conduct DNA analysis and offers efficient data
management.

4.2.3
Cheminformatics



Cheminformatics tools functions to manage high throughput screening(a method
for scie
ntific

experimentation

by using

robotics
, data processing and control software,
liquid handling devices, and sensitive detectors and quickly conduct millions of chemical,
genetic or pharmacological tests. Through this process one can rapidly identify active
compounds, antibodies or genes which m
odulate a particular biomolecular pathway. The
results of these experiments provide starting points for drug design and for understanding
the interaction or role of a particular biochemical process in biology.) and compound
chemistry data. Cheminformatics
is used to in creation of small molecule libraries known
as the virtual compound library. Screening of protein targets against compounds in these
libraries via biochemical assays allows identification and selection of target lead
compounds for therapeutic
development. This techniques have been used to facilitate the
drug development process since 2009 and is believed to be able reduced the development
time needed for preclinical drug discovery up to 50%.


Examples for cheminformatics technology are: the Che
mSpace technology which can
screen up to two trillion compound per hour to select biologicallt relevant compounds,
and also the Accelrys’ Discovery Studio products which enables in silico(i.e. performed
on

computer

or via

computer simulation
) Absorption, Distribution, Metabolism and
Excretion (ADME)/ Toxicology (T) pre
-
screening of drugs candidates hence allow
investigation and testing of h
ypothesis before experimental implementation is carried out
.


4.2.4
Proteomics



Protemomic

experiments are used to determine protein structures, protein
-
protein
interactions and disease mechanisms. Proteomic experiments are carried out via 2D gel
electrophoresis, mass spectrometry, and protein microarrays, and the data generated can
be efficien
tly interpret and analyse with bioinformatics software. Analysis of protein
molecules is essential to identify drug targets in drug discovery. Example of proteomic
bioinformatic tool is Ciphergen’s ProteinChup system which aid in analysis mass
spectrometry

data and providing insight into protein structure and expression levels.


4.2.5

Pharmacogenomics.

Pharmagenomics studies provides informations and data which allows better
understanding of how the individual genetic variations impact drug response and di
sease
susceptibility such as via SNP(single nucleotide polymorphisms) analysis. Example of
pharmacogenomics bioinformatic tool is Genaissance’s DecoGen which allows analysis
of pharmacogenomics data collected through proprietary and public databases and as
sist
clients to organize SNP (the genomic sequence differences that occur between
individuals) into haplotype markers that may correlate with drug responsiveness or
specific disease pathways.


4.2.6

Red Biotechnology

Red biotechnology is the branch of biotechno
logy applied to medical processes which
deals with application in human and animal medicine by using organisms to improve
health care. Example of application of red biotechnology includes: designing organisms
to produce antibiotics and vaccines (eg. Geneti
cally altered cowpox used to prevent
influenza, hepatitis and herpesgenetic engineering where genetic cure are found via
manipulation of an organism’s genetic material, development of therapeutic human
proteins via recombinant methods(eg. Human insulin) an
d using stem cells to regenerate
damaged human tissues or organs.

4.3
Application of biotechnology in drug development


Pharmaceutical biotechnology brings a lot of positive impact to the
pharmaceutical industry. Various techniques and technologies developed in this discipline
ovecame many limitations and difficulties faced in the industry and hence allow a more
robust dev
elopment in the pharmaceutical sciences. For instance, a lot of regulatory
protein which are found to have pharmaceutical potential are not widely used in medical
application due to the minute quantities in which they are naturally produced. Usage of
vario
us biotechnologies such as recombinant DNA technology and monoclonal antibody
technology manage to overcome these difficulties. In production of pharmaceutically
important proteins, biotechnologies, especially the recombinant DNA technology, brings
forth t
he following advantages:



The technology helps to overcome the problem of source availability. Various
proteins with therapeutic potential are produced naturally in human body in a tiny
quantities therefore causes it to be impractical to extract them directly from native
source mat
erial to achieve a quantity which will be sufficient enough to meet the
clinical demands. Therefore, recombinant production enable manufacture of these
proteins artificially in any quantity as required at a lower cost.



The technology improves the product s
afety. Direct extraction of
products

from
natural biological source has high risk of causing
transmission

of disease such as
transmission of Creutzfeldt
-
Jakob disease to recipient who received human growth
hormone (hGH) preparations obtained from human pit
uitaries. With manufacture of
the products via biotechnologies, risks of these transmissions are then reduced.



The technology provides an alternative to direct extraction of materials from
dangerous or
inappropriate

source material. Certain therapeutic pro
teins and
molecules are traditionally extracted from sources like human urine( such as follicle
stimulating hormone from urine of post menopausal women, human chorionic
gonadotrophin from urine of pregnant women) and snake venom ( such as Ancroid
which is
a protein that possess anti
-
coagulant activity). Biotechnology provides
alternative by allowing extraction of such materials in the form of recombinant
production.



The technology aids in production of engineered therapeutic proteins which display
more cli
nical advantage as compared to the original protein product. Biotechnology
allow researchers to manipulate the protein’s amino acid sequence by minimal
changes such as deletion, insertion or alteration of a single amino acid residue, or
more significant ch
anges such as by generation of a novel hybrid protein or by
alteration or deletion of a whole domain. These alterations will generate proteins
that are tailored for specific therapeutic purpose.



Application of Pharmacogenomics which is the study of effect
s of genetic
inheritance on individual’s response to drugs

and also the relationship between
pharmaceuticals and genetics allows development of d
rugs that are able to adapt
better to each person’s genetic makeup and hence allow development of tailor
-
made
medicine which can achieve maximum therapeutic effects.

Example of common pharmaceutical biotechnology products include antibodies ,
proteins an
d recombinant DNA product
.
Recombinant DNA are the genetically
engineered DNA created from recombination of fragments of DNA from various
organisms and the products are inclusive of vaccines, drugs, enzymes, growth hormon
e,
insulin, proteins and yeast. Vac
cines produce by means by recombinant DNA are safer,
better, less costly and also with minimal risks of infections as the organisms used are
transformed via genetic engineering.

Advancement in biotechnology is believed to be able to brings significant impa
ct
on stages of drug development. Development in areas such as genomics, proteomics and
high throughput screening impact the initial stages of drug development significantly by
aiding in identification new drug targets for specific diseases by linking chan
ges in gene
or protein exression to various disease states and also facilitates designation of drugs to be
specific to interact with target molecules which causes the disease. Future innovations
such as development of alternative product prodution systems,

alternative methods of
delivery , development of engineered cell
-
based therapies, development of transgenic
-
based production systems are expected to brings impact on pharmaceutical
biotechnology. Also, development of non
-
parenteral routes of administratio
n
(transdermal, nasal, oral and bucal approaches) of therapeutic protein are also being
researched as it is more convenient, less costly and will be able to improve patient
compliance. In future, products of pharmaceutical biotechnology is expected to play

an
even more important role in medical field.

5.0

Conclusion

The process of drug discovery and development is a time consuming and costly
process. An average of 12 years are needed for a drug to be developed from scratch to the
market, and approximately $ 35
9 million will need to be spent by a pharmaceutical
company in order to develop a new drug. Also, the failure rate at developing rate is very
high , estimation of 10% of drugs ( about five in five thousand) that begin in preclinical
testing ever manage to
survive to clinical phases and only one of these five can be
approved to be marketed for human usage.


Globally, process of drug development are tightly regulated and monitored by
various regulatory bodies which plays thre same role t
o ensure production o
f drugs
that are safe, effective, labeled accurately and also marketed responsibly.

Understanding of the processes involved in drug
development is essential for
physician to promote innovation, understanding their role in promoting drug safety by
reporting

the adverse drug events and also provides
equipped the physicians with
information

to educate
patient
s

about clinical trials. Understanding of the drug
developmental process by the public will also raise awareness among the public

Advances in biotechnology are opening up new possibilities in drug development
and future innovations are believed to be able empower pharmaceutical companies
and researchers to develop drugs that are safer and more effective and also
significantly reduce
the failure rate and time taken in drug discovery process.