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Vol. 3 (1) Jan – Mar 2012 www.ijrpbsonline.com 38
International Journal of Research in Pharmaceutical and Biomedical Sciences ISSN: 2229-3701
__________________________________________Review Paper
Introduction to Various Stages in Process of Drug Development
Nitish Chha
a, Seth Bihani GL and Sudeep Bhardwaj
Department of Pharmacology, S.D college of Technical Education, Sriganganagar, Andhra
Pradesh, India.
__________________________________________________________________________________
ABSTRACT
India is a land of diversity where alternative systems of medicine like Ayurved, Unani, Siddha practiced with
equal fervor. Drug discovery is the process of identifying compounds that have the potential to become useful
new therapies. Development of new drug involves two phases namely drug discovery and drug development.
Internationally, India became a member of world trade organization (WTO) in 1995 & agreed to adhere to the
product patent regime by 2005.
INTRODUCTION
India is a land of diversity where alternative
systems of medicine like Ayurved, Unani, Siddha
practiced with equal fervor. Development of new
drug involves two phases namely drug discovery
and drug development. Drug discovery and
development is long, costly and complex process,
equiring coordinated collaboration of a large
number of individuals and groups from different
departments including research, development,
manufacturing, medical, regulatory, marketing and
usiness management. During the development
process these department interact, as appropriate,
with external scientific a medical advisors,
physicians, research nurses and pharmacists in
order to optimize the development of new drug. It
is only the successful interaction and cooperation
of all these professionals that can culminate me the
success full registration and marketing of a new
medicine4.
Drug development is considered as a series of well
defined steps, culmination, if success full, in
market authorization, of the drug. In practice the
process is seldom linear, with many aspects of the
process taking place in parallel, each step of the
process from target identification through to
product registration is designed to answer a specific
question(s)7.
For an average drug, everyday of delay in obtaining
marketing authorization costs approximately $300
to 350 million i.e. about 100 crore in India. In this
era of pharmaceutical R & D the driving forces for
therapeutic preventive and also curative2.
Internationally, India became a member of world
trade organization (WTO) in 1995 & agreed to
adhere to the product patent regime by 2005.A
well-designed and executed study has built-in
provisions to ensure patient rights & safety. In fact,
a patient may be far easier in a clinical trial than in
outine medical care because careful observations
are made in safety (toxicity) and efficacy.
Historical events like sulfanilamide & thalidomide
disasters are required to be avoided with
appropriate clinical trials.
Two conferences were held on 10-12 October
2007in Hyderabad on the titles discovery to
innovation“& “clinical trials in India”. It had
shown that how international & Indian companies
are actively incorporating India as apart of a global
strategy to accelerate drug discovery24.
Top pharma companies like Ranbaxy, Dr. Reddy`S,
Biocon, Nicholas Piramal, Wockhardt, To
ent,
Avesthagen, Dabur have confirmed their R & D
strategies and parternership objectives will be
shared they expand their global initiatives26.
Drug discovery is the process of identifying
compounds that have the potential to become
useful new therapies. The potential must be
sufficient to justify further research and
development. ; a company may choose to
specialize in a particular therapeutic areas, on a
particular approach (i.e. cancer) that will allow
development of compounds across a range of
disease. Larger companies are likely to adopt
several or all of these approaches while a smaller
one are more likely to focus specifically o one
approach.
Vol. 3 (1) Jan – Mar 2012 www.ijrpbsonline.com 39
International Journal of Research in Pharmaceutical and Biomedical Sciences ISSN: 2229-3701
The drug discovery process
Cu
ent m
Methods used in drug discovery process
Screening large compounds and natural
compounds (from plants, animal products or
microorganisms) for the desired activity.
Changing the chemical structures of
existing molecules
a) Combinatorial chemistry consists of
systemically modifying an exciting compound
chemically to act on a selected target. Screening of
multiple compounds sometimes produce clue about
how structural modification alters the action of a
compound. Subsequent chemical modification of a
lead compound can result in a compound with
enhances properties, such as improved absorption,
enhanced safety, longer duration of action or
increased efficacy. Hence, once a lead compound is
developed, chemist will look to optimize the
desirable characteristics of the compound. [15]
Combinatorial Biosynthesis is a technique for
modeling and building li
aries of chemical
compounds for consideration as drug candidates.
Within these li
aries, information systems are
eing designed to link chemical structures with
various biological activities. High density
synthesizers make millions of samples of the moist
promising compounds each year4.
Studying disease processes
a) Identification of novel pathways that is
associated with disease, selection of targets in the
pathway and development of screens.
) Targeted synthesis, i.e. the creation of
original molecules with biological activities that
target particular stages of a disease process.
Researchers design a synthesize molecules that
ind to a particular locus on a target.
Using computers to design new drugs
a) Molecular modeling using powerful
software graphics and simulation programs to
generate 3D structures of target molecules and
model the affinity of different at these targets. (E.g.
CoMFA, CoMSIA)
Serendipity
Observation by chance e.g. penicillin
Other new technologies
a) Medical genetics
Genetic linkage studies are used to sift through the
human genome to link genes with particular
diseases while genetic association studies are used
to look for known gene sequences in unselected
individuals to determine whether they are more
common in one disease than another.
) Robotic high-throughput screening
(RHTS/HTS)
Using miniaturization and fully automated robotic
technology, compounds generated from
combinatorial chemistry are tested in primary
activity screens, identifying lead compounds for
further biological testing and chemical
optimization.
HTS is the process of assaying a large no. of
potential effectors of drug discovery by screening
large li
aries often composed of hundreds of
thousand of compounds at a rate that may exceed
20000 compounds per week23.
Identification &
validation of
iological target
Optimizing hit
compounds to improve
efficacy, safety, stability
Development of assay
and screening of large
compound collections
Selection of final
candidate
High throughput
screening
obotic
high throughput
sc
Safety,
pharmacokinetics
& pharmaceutics Intellectual
property
Inputs from
global markt
Molecular
modelling
Combinatorial
iosynthesis/
chemistry
Application of
genomics
ioinfo
matics
Compound
collection
Vol. 3 (1) Jan – Mar 2012 www.ijrpbsonline.com 40
International Journal of Research in Pharmaceutical and Biomedical Sciences ISSN: 2229-3701
The new drug development process4
3.5-4 yrs. 6 yrs. 2.5 yrs.
Preclinical development clinical development
chemistry
synthesis &
purification
formulation
animal
pharmacology
animal
pharmacokinetics
animal toxicity
(short/long term)
assess safety &
iological activity
in animals
Phase I
Human
pharmacology
Determine
safety and
dosage
Phase II
Therapeutic
exploratory
Evaluate
effectiveness
and look for
side effects
Phase III
Therapeutic
confirmatory
Verify
effectiveness,
monitor
adverse
eactions
from long-
term use
FDA/DCGI
Review
process/approval
Phase IV
Post
marketing
Additional
post
marketing
testing
equired
y FDA
5,000 compounds evaluated 5 enter trials 1 approved
APPLICATIONS
Investigational new drug application (IND)
After completing preclinical testing, the company
files an IN with FDA to begin to test the drug in
human. INDA (investigational new drug
application) is the means through which sponsor
usually the manufactures or potential marketer
obtain a legal status to call its new investigational
molecule as new drug. The IND is not an
application of marketing approval
Manufacturing information – information
pertaining to the composition, manufacturer,
stability and controls used for manufacturing the
drug substance and the drug product, this
information is assessed to ensure that the company
consistently produce and supply consistent batches
of the drug.
Clinical protocols investigator information
– detailed protocols for proposed clinical
Accelerated development
eview
Treatment IND
Parallel track
File IND to
FDA/DCGI
File NDA to
FDA/DCGI
SUCCESS
RATE
TIME
PERIOD
Vol. 3 (1) Jan – Mar 2012 www.ijrpbsonline.com 41
International Journal of Research in Pharmaceutical and Biomedical Sciences ISSN: 2229-3701
studies to assess whether the initial-phase trials will
expose subjects to unnecessary risks. Also,
information on the qualifications of clinical
investigators professionals (generally physicians)
who oversee the administration of the experimental
compound to assess whether they are qualified to
fulfill their clinical trial duties. Finally,
commitments to obtain informed consent from the
esearch subjects, to obtain review of the study by
an institutional review board (IRB), and to adhere
to the investigational new drug regulations.
IND format
Biologics license application (BLA)
It is an alternative to FDA. [19]
New Drug Application (NDA)
Following the completion of all three phases of
clinical trials the company analyses all of the data
& files an NDA to FDA, of the data successfully
demonstrates safety & effectiveness. The NDA
must contain all of the scientific information that
the company has gathered. NDA is typically run 1,
00,000 pages or more. By law FDA is allowed 6
months to review an NDA in almost all cases the
period between first submission of an NDA & final
FDA approval exceeds that limit .The average
NDA review time for new molecular entities
approved in 1992 was 29.9 months.
REGULATION
CODE OF FEDERAL REGULATIONS (CFR)
The final regulations published in the federal
egister (daily published record of proposed rules,
final rules, meeting notices, etc.) are collected in
the CFR. The CFR is divided into 50 titles which
epresent
oad areas subject to federal regulations.
The FDA`s portion of the CFR interprets the
federal food, drug and cosmetic act and related
statues. Section 21 of the CFR contains all
egulations pertaining to food and drugs. The
egulations document all actions of all drugs
sponsors that are required under federal law.
Code of federal regulations - the final regulations
published in the federal register (daily published
ecord of proposed rules final rules, meeting
notices, etc.) are collected in the CFR. The CFR is
divided into 50 titles that represent
oad areas
subject to federal regulations. The FDA`s portion
of the CFR interprets the federal food, drug and
cosmetic act and related statures section 2 of the
CFR contains most regulations pertaining to food
and drugs. The regulations document all actions of
all drug sponsors that are required under federal
law5.
The following regulations apply to the IND application process
21 CFR Part 312 Investigational New Drug Application
21 CFR Part 314 INDA and NDA applications for FDA approval to market a new drug
21 CFR Part 316 Orphan drugs
21 CFR Part 58 Good lab practice for nonclinical laboratory (animal) studies
21 CFR Part 50 Protection of human subjects
21 CFR Part 56 Institutional review boards
21 CFR Part 201 Drug labeling
21 CFR Part 54 Final disclosure by clinical investigators
REGULATORY AGENCIES
--In India, drug controller general of India (DCGI)
Office under central drug standard control
organization (CDSCO).
--In UK, medicines & healthcare products
egulatory agency (MHRA), advised by the
committee on safety of medicines (CSM).
--In USA food & drug administration (FDA).
Recommended adoption of internationally
ecognized ethical quality requirements are
--GCP
--Schedule Y
--Patent protection
--Abolishing the service tax
Transition in regulatory authority capabilities in India26
Before 2005 after 2005
--Process patent law
--Phase II &III only
--Phase lag...