Clinical research unit 1

DRUG DEVELOPMENT PROCESS
D R . S P S R I N I V A S N A Y A K
A S S I S T A N T P R O F E S S O R , P I P R
P A R U L U N I V E R S I T Y .

DEFINITION
Drug development is the process of bringing a new pharmaceutical drug to
the market once a lead compound has been identified through the process
of drug discovery. It includes preclinical research on microorganisms and
animals, filing for regulatory status, such as via the United States Food and
Drug Administration for an investigational new drug to initiate clinical trials
on humans, and may include the step of obtaining regulatory approval with
a new drug application to market the drug
Drug development is considered as a series of well defined steps,
culminating, if successful, in market authorization, of the drug
D R S P N A Y A K - P A R U L U N I V E R S I T Y 2

Various Steps Involved in Drug Development
Process
 New drug discovery
 Preclinical testing
 Investigational New Drug Application (IND)
 Clinical Trials (phase I,II,II trails)
 New Drug Application (NDA)
 Post Marketing Surveillance / phase IV clinical trials

New Drug Discovery
Definition : Drug discovery is the process of identifying compounds that
have the
potential to become useful new therapies
Common ways of developing new drugs
1. From natural products e.g. plants and animals
2. changing the chemical structure of existing molecules
3. Studying disease process
4. Using computers to design new drugs
5. Serendipity : observation by chance e.g. penicillin

NEW DRUG DISCOVERY (CONT.)
The first phase, target selection, involves choosing a disease to treat and
then developing a model for that disease AND target validation
The second phase, drug selection(Lead identification), is a process that
involves finding a drug or group of drugs that work within that model
system and Lead optimization
The third phase, product development, is a process that involves
discovering a biological target such as a particular enzyme, receptor or
ion channel that the scientific team believes may be linked to a
pathologic process D R S P N A Y A K - P A R U L U N I V E R S I T Y 6

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1. Identification
and validation
of biological
target
2. Development of
assay and
screening of large
compound
collections
3. Optimizing hit
compounds to
improve efficacy,
safety, stability etc.
Robotic high
throughput screening
Safety,
pharmacokinetics and
pharmaceutics
Intellectual
property
Application of
Genomics/
Bioinformatics
Compound
collection
Combinatoria
l
biosynthesis/
chemistry
Inputs from the
global
market/busines
s
4. Selection of final
candidate(s)
Molecular
modelling
Figure : The Drug Discovery
Process

Current Methods Used In Drug Discovery Process
This includes -
1. Identification of novel pathways that are associated with disease,
selection of target in the pathway and development of screens
2. Screening large compounds and natural compounds (from plants,
animal products or microorganisms) for the desired activity
3. Molecular modelling using powerful software graphics and stimulation
programs to generate 3D structures of target molecules and model the
affinity of different molecules at these targets

CURRENT METHODS USED IN DRUG DISCOVERY PROCESS
4. Targeted synthesis, i,e. the creation of original molecules with
biological activities that target particular stages of disease process.
Researchers design and synthesize molecules that bind to particular
locus on a target
5. Combinatorial chemistry consists of systematically modifying and
existing 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
enhanced properties, such as improved absorption, enhanced safety,

New technologies that are pivotal to the drug discovery and
development
 Medical genetics : genetic linkage studies are used to sift through the
human genome to link genes with particular disease, while genetic
association studies are used to look for gene sequences in unselected
individuals to determine whether they are more common in one disease than
another
 Combinatorial biosynthesis : it is a technique for modelling and building
libraries of chemical compounds for consideration as drug candidates
• Within these libraries, information system are being designed to link
chemical structures with various biological activities

NEW TECHNOLOGIES THAT ARE PIVOTAL TO THE DRUG DISCOVERY
AND DEVELOPMENT (CONT.)
 Robotic high-throughput screening : using miniaturization and fully
automated robotic technology, compounds generated from
combinatorial chemistry are tested in primary activity screens,
identifying lead compound for further biological testing and chemical
optimization
 Bioinformatics : information systems developed for analysis of
biological, particularly genomic data. Bioinformatics is used for gene
identification and mapping, comparing sequence data in search of
similarities, linking genes with their associated proteins and biological
functions. Ultimately , it is used to identify and validate new targets and

Preclinical Testing
Preclinical tests are performed in laboratory, using a wide array of chemical
and biochemical assays, cell culture and animal models. The pharmacological
activity of every new compound is carefully analyzed
Preclinical testing involves :
• Pharmacology testing
• Toxicology testing
• Animal Pharmacokinetics testing

PHARMACOLOGY TESTING
These are the studies to explore the pharmacological activity and therapeutic
potential of compounds. These tests involve the use of animals, isolated cell
cultures and tissues, enzymes and cloned receptor sites as well as computer
models
If the results of the test suggest potential beneficial activity, related compounds
(each a unique structural modification of the original) are tested to see which
version of the molecule produces the highest level of pharmacological activity
and demonstrates the most therapeutic promise, with the smallest number of
potentially harmful biological properties

PHARMACOLOGY TESTING (CONT.)
Animal pharmacology studies allow the effects of the lead compound on
the disease process (pharmacodynamics) to be corelated with the
concentration of compound needed to achieve these effects
(pharmacokinetics)
Animal pharmacology testing is performed in animal models of human
disease. Animal model of human disease may occur :
1. Naturally i.e, squirrel monkeys develop dementia in old age that is
behaviorally and histologically similar to Alzheimer's disease in humans

PHARMACOLOGY TESTING (CONT.)
2. By introduction of genetic defect in germ cells of an animal strain so
that its reproduction produces off springs with the disease of interest. For
example, introducing a mutation that prevents the serotonin 2C receptor
from functioning results in animals that exhibit anxiety
3. Using toxins that selectively destroy a particular type of cells. Eg:
administrating the neurotoxin MPTP selectively destroys dopaminergic
neurons in the brain, producing Parkinson's like disease state

Toxicological testing
• Toxicological studies will be carried out in both in vitro and on animal species
known to have drug metabolism and disposition parameters (the fate of the
drug in the body) resembling those in humans, although the pharmaceutical
industry is always striving to replace animal experiments with meaningful In
vitro studies (such as the Ames test)
• Toxicology and safety testing determine the potential risk a compound poses to
man and the environment
• Generally, two or more species ( one rodent, one non-rodent) are tested
because a drug may effect one species differently from another

Toxicity studies are done to calculate :
 Maximum tolerated dose
 Gross pathology to indicate target organs
 Satisfactory therapeutic with regard to animal efficacy studies
They are conducted to :
 Select or reject lead candidate
 General indication of suitability
 Dose selection and guidance to clinician
Toxicological testing (cont.)

Types of Toxicology Investigations
Toxicity Studies Required for Complete Preclinical Development of the Drug
Types Duration of the study
Acute toxicity • 2 week studies in 3-4 species to determine
maximum tolerated dose
Sub- acute toxicity • 6 month studies in 2 species
Chronic toxicity • Up to 12 month studies in rats and a non rodent
to determine If adverse effects occur with
repeated daily dosing
• Oncology studies- at least 18 months in mice
- 2 years in rat

Types Duration of the study
Reproductive Up to 9 month studies in 2 species to determine
effects of drug on fertility and reproduction and
expose any teratogenic effects
Mutagenic 18-24 month in vitro and in vivo studies
Types of Toxicology Investigations cont.
Toxicity Studies Required for Complete Preclinical Development of the Drug

If the results of these toxicity studies indicate that the range between biological
activity and toxicity is acceptable, the company will apply to the relevant
regulatory body for permission to continue development (example: if the
regulatory body is the FDA, an Investigational New Drug (IND) application can
be filed at this stage)
Acceptable Toxicity
Extensive toxicity studies ensure that drugs causing serious toxicity do not
reach the market- unless of course, the agent concerned has a potentially life
saving role in treating a disease and where no other more suitable drugs are
available
(cont.)

At present, HIV infection represents such a serious threat to life it is considered
acceptable to use drugs to treat it which are rather toxic to human body
Animal Pharmacokinetics testing
Pharmacokinetic studies are used to measure how much of a drug is absorbed
into the blood (drug absorption), how it is broken down chemically in the body, the
toxicity of the drug, its breakdown products (metabolites), and how quickly the
drug and its metabolites are excreted from the body (excretion)
If the compound is successful and continues its progression through the
development process, the studies will be repeated in humans
(cont.)

Investigational New Drug Application (IND)
After completing preclinical testing, the company files an IND with FDA or
DCGI in India to begin to test the drug in human
INDA (Investigational New Drug Application) is the means through which
sponsor (manufacturer or potential marketer) obtain a legal status to call its
new investigational molecule as new drug

INVESTIGATIONAL NEW DRUG APPLICATION (IND) (CONT.)
The IND is not an application for marketing approval
A sponsor will probably want to ship the investigational drug to clinical
investigators in many states, it must seek an exemption from the legal
requirement
The IND is the means through which the sponsor technically obtains this
exemption from the FDA
However, its main purpose is to detail the data that provide documentation to
proceed with certain human trails with the drug
The IND becomes effective if FDA does not disapprove it within 30 days

INVESTIGATIONAL NEW DRUG (CONT.)
Drug developers, or sponsors, must submit an Investigational New Drug
(IND) application to FDA before beginning clinical research
In the IND application, developers must include:
Animal study data and toxicity (side effects that cause great harm) data
Manufacturing information
Clinical protocols (study plans) for studies to be conducted
Data from any prior human research
Information about the investigator

Asking for FDA Assistance
Drug developers are free to ask for help from FDA at any point in the drug
development process, including:
Pre-IND application, to review FDA guidance documents and get answers
to questions that may help enhance their research
After Phase 2, to obtain guidance on the design of large Phase 3 studies
Any time during the process, to obtain an assessment of the IND
application

Even though FDA offers extensive technical assistance, drug
developers are not required to take FDA’s suggestions
As long as clinical trials are thoughtfully designed, reflect what
developers know about a product, safeguard participants, and
otherwise meet Federal standards, FDA allows wide latitude in
clinical trial design

FDA IND Review Team
The review team consists of a group of specialists in different scientific
fields. Each member has different responsibilities
Project Manager: Coordinates the team’s activities throughout the review
process, and is the primary contact for the sponsor
Medical Officer: Reviews all clinical study information and data before,
during, and after the trial is complete

Statistician: Interprets clinical trial designs and data, and works closely
with the medical officer to evaluate protocols and safety and efficacy
data
Pharmacologist: Reviews preclinical studies
Pharmakineticist: Focuses on the drug’s absorption, distribution,
metabolism, and excretion processes. Interprets blood-level data at
different time intervals from clinical trials, as a way to assess drug
dosages and administration schedules

Chemist: Evaluates a drug’s chemical compounds. Analyzes how a drug
was made and its stability, quality control, continuity, the presence of
impurities
Microbiologist: Reviews the data submitted, if the product is an
antimicrobial product, to assess response across different classes of
microbes

The FDA review team has 30 days to review the original IND submission.
The process protects volunteers who participate in clinical trials from
unreasonable and significant risk in clinical trials
FDA responds to IND applications in one of two ways: Approval to begin
clinical trials and clinical hold to delay or stop the investigation. FDA
can place a clinical hold for specific reasons, including:
Participants are exposed to unreasonable or significant risk
Investigators are not qualified
Materials for the volunteer participants are misleading
The IND application does not include enough information about the trial’s risks

If FDA is satisfied that the trial meets Federal standards, the applicant is
allowed to proceed with the proposed study
The developer is responsible for informing the review team about new
protocols, as well as serious side effects seen during the trial. After the
trial ends, researchers must submit study reports
This process continues until the developer decides to end clinical trials or
files a marketing application. Before filing a marketing application, a
developer must have adequate data from two large, controlled clinical
trials D R S P N A Y A K - P A R U L U N I V E R S I T Y 31
Investigational New Drug (cont.)

Clinical trials/ Clinical Development of Drug
The clinical development plan
The safety and toxicity data generated from preclinical studies enables the drug
company to safely initiate clinical trials
Clinical trials on patients in different countries are approved and monitored by
different regulatory agencies like:
1. In India, Drug Controller General of India (DCGI) office under Central Drug
Standard Control Organization (CDSCO)

CLINICAL TRIALS/ CLINICAL DEVELOPMENT OF DRUG
(CONT.)
2. In UK, Medicines and Healthcare products Regulatory Agency
(MHRA) , advised by the Committee on Safety of Medicines (CSM)
3. In USA , Food and Drug Administration (FDA)

Phases of clinical trials
• Clinical research is done in four phases (I,II,III and IV), each designed to
address different questions
• The knowledge gained from one phase is assessed before progressing to
the next phase
• However, research in a particular phase may continue after the drug has
progressed to further stages of development

PHASES OF CLINICAL TRIALS (CONT.)
Based on the data gathered from the preclinical trials/ animal
testing, the sponsor has some estimation of:
 The drug’s therapeutic effect and dose levels
 Toxicity profile and dose levels
This information is used in the design of phase I clinical trials

PHASE 1
The first question in drug research is to find out the safety of drug in
humans. Phase I studies, sometimes called as “first in man”, starts to
answer this question by testing the investigational product in healthy
volunteers
If the drug has the potential for toxic adverse events, it may be given only
to subjects with the targeted condition to reduce risks to healthy
subjects (example: anticancer drugs are never tested in healthy
volunteers)

PHASE 1 (CONT.)
The main purpose of the initial phase I studies is to establish a safe
dosage range
During the phase I studies, sufficient information about the drug’s
pharmacokinetics (ADME) and pharmacological effects should be
obtained to permit the design of well-controlled, scientifically valid,
phase II studies
Phase 1 studies also evaluate drug metabolism, structure activity
relationships, and the mechanism of action in humans

PHASE 1 (CONT.)
These are generally conducted on 20-80 healthy human volunteers and typically
lasts for 3-6 months
Initially, a single small dose is administered to each volunteer in a hospital –
type setting ( perhaps a purpose- built unit within/outside the drug company’s
premises) so that the effects of the drug can be closely monitored
In phase I studies, regulatory bodies (FDA) can impose a clinical hold ( i,e,
prohibit the study from proceeding or stop a trial that has started) for reasons
of safety, or because of a sponsor’s failure to accurately disclose the risk of
study to investigators

PHASE 1 (CONT.)
Phase I trials address:
 How rapidly the drug is absorbed ?
 Where is the drug distributed in the body?
 Which organs or organ systems are involved in metabolism of the
drug?
 How quickly is the drug eliminated from the body?
Only about 70% of experimental drugs passes Phase I clinical trials

PHASE 2
Phase I clinical trials gives valuable information about any adverse reactions and
fate of the drug in the healthy human body, these parameters may be different in
patients suffering from the disease which the drug under test is designed to treat
For example: some antibiotics like benzylpenicillin only penetrate into the CSF if
the meninges are inflamed whereas penetration is poor in healthy individuals
Phase II clinical trials are conducted on patients. The main question asked by
Phase II studies is: “ what is the most effective dosage range and is the drug safe
within that range?”

PHASE 2 (CONT.)
Phase II studies enroll small number of subjects, typically 100 to
300 and the trial may last from 6 months to 2 years
The primary aims of Phase II clinical trials are to establish clinical
efficacy, determine the incidence of ADRs, define the optimum
therapeutic dosage and provide detailed pharmacokinetic and
pharmacological data to substantiate the adequate trial of the
drug

PHASE 2 (CONT.)
Trials on patients may be conducted in an open (non-blind) manner, where the
patients know whether they are receiving the drug or whether they are
receiving a placebo (an inactive material serving as a negative control) and
also as blind trials
In single blind trials, only the patients do not know whether they are receiving the
drug or the placebo
In double blind trials, both the patient and the clinical investigators do not know
which agent the patient is receiving

PHASE 2 (CONT.)
Phase II trial address:
 What is the minimum effective dose?
 What is the maximum tolerated effective dose?
 Is the drug effective in mild, moderate, and severe cases of the disease or
condition?
 Is the drug effective for all expected indications?
Only about 35% of experimental drugs passes Phase II clinical trials

PHASE 3
Phase III studies are expanded controlled and uncontrolled trials
They are performed after preliminary evidence suggesting effectiveness
of drug has been obtained in Phase II, and are intended to gather the
additional information about effectiveness and safety that is needed to
evaluate the overall benefit- risk relationship of the drug
Phase III clinical trials may involve several hundreds to several thousand
patients and lasts for 1-5 years

PHASE 3 (CONT.)
The main aim of this phase is to verify the drug’s effectiveness and any ADRs in
a large group of patients over a longer period of exposure, to establish the
safety and efficacy of the drug
Very often Phase III trials involve different patient sub- groups, such as children,
the elderly, and perhaps those with impairments in kidney and liver function
Once the Phase III has been completed satisfactorily, the drug company is in a
position to apply the marketing application to the regulatory authorities to market
the drug

PHASE 3 (CONT.)
Phase III trials address:
 Overall risk-benefit relationship
 Adverse reactions in large group of patients over a longer period of
exposure
 The ideal dosage regimen
 Is the drug allowed to be marketed?
Only about 25% of experimental drugs passes Phase III clinical trials

New Drug Application (NDA)
• Following the completion of all three phases of clinical trials, the company
analyzes all of the data and files an New Drug Application (NDA) with FDA, if
the data successfully demonstrate safety and effectiveness
• The NDA must contain all of the scientific information that the company has
gathered
• NDAs typically run 100,000 pages or more. By law, FDA is allowed six
months to review an NDA

NEW DRUG APPLICATION (NDA) (CONT.)
In almost all cases, the period between the first submission of an NDA and
final FDA approval exceeds that limit; the average NDA review time for
new molecular entities approved in 1992 was 29.9 months
Submitting an Application
Submission of a Marketing Authorization Application (i.e NDA to FDA) to a
Regulatory Authority requires extensive documentation since it covers
every aspect of the product development from its initial chemical
characterization to its claimed efficacy

The main section of a typical new drug application to the regulatory
authorities are:
1. Dossier summary
Administrative data; summary of the product characteristics; expert
reports on chemical; pharmaceutical and clinical documentation
2. Chemical, Pharmaceutical and Biological Documentation Composition;
method of preparation; control of starting materials; control tests on
intermediate products; control tests on the finished product; stability

3. Pharmaco-Toxicological Documentation
Single and repeated dose toxicity; reproductive studies; mutagenic potential;
oncogenic/carcinogenic potential; pharmacodynamics; pharmacokinetics; local
tolerance
4. Clinical Documentation
Clinical pharmacology; clinical experience
5. Special Particulars
Dosage form; samples; manufacturers authorization; marketing authorization

NEW DUG APPLICATION (NDA) (CONT.)
Successful Application
Assuming that the Regulatory Authority grants a product license, the
product can be marketed in the relevant countries
Product Registration
To be marketed, medicines needs to receive approval from the appropriate
Regulatory Authorities

For example: In India, DCGI is the final authority for approval of a new
drug for marketing
FDA is the final authority for approval of a new drug for marketing in
United States
Only 1 in every 3 drugs which reach the market recoups its development
costs
Product manufacture
Considerations about the large-scale manufacture of the drug molecules
and the dosage forms takes place at an early stage in the development
process

The full- scale production of the drug involves a large number of people of
different scientific disciplines (such as chemists, process engineers, plant
designers etc)
The life of a patent for a new drug is 20 years
If it takes 10-14 years to develop the product and clinically test it before
permission is granted by the regulatory authorities to market it, the drug
company will wish to manufacture it as soon as it can to claim as much of the
patent life as possible
Once the patent has expired, other manufacturers can produce the product
(called a Generic version) and sell it at lower cost

POST MARKETING SURVEILLANCE / PHASE IV CLINICAL
TRIALS
Sometimes adverse drug reactions only come into light after the drug
has been in the market for a while and has been used by very large
number of patients. Phase IV Clinical Trials identifies such problems
Withdrawal of drug from the market is not an uncommon occurrence,
one notorious case in the 1960’s involved the drug Thalidomide
Phase IV Clinical Trials are done after a drug has been shown to work
and has been granted a license

POST MARKETING SURVEILLANCE / PHASE IV CLINICAL
TRIALS
(CONT.)
Phase IV clinical trials address :
 More about the side effects and safety of the drug?
 What the long term risks and benefits of the drug are?
 How well the drug works when it’s used more widely than in clinical
trials?

Dosage forms
Pre- formulation:
• Before a drug can be formulated into a medicine (a dosage form) which
can be administered to a patient, something must be known about its
physio-chemical properties and behavior (e.g. its solubility, its crystal
structure)
• These will dictate, to a certain extent, the dosage form(s) in which the
medicine will be marketed and the dosage form(s) which can be used
during drug development investigations
• Such data are gathered in pre-formulation studies and these play an
important part in anticipating formulation problems later on

DOSAGE FORMS (CONT.)
For example: aspirin can be satisfactorily formulated as a tablet but is too
unstable in aqueous solution to be formulated as a liquid dosage form
Although soluble or dispersible aspirin tablets are designed to be added to
water, this is only satisfactory if the resulting solution or suspension is taken
immediately
As a second example, benzylpenicillin is inactivated by gastric acid so is
available as an injection, rather than as a preparation which can be taken
orally
It is manufactured as the sodium or potassium salt to make it dissolve readily in
water prior to injection
Its packed in vials as a powder because it is susceptible to hydrolysis if stored

Drug characterization
Spectroscopy To produce a simple method for analysis of the drug
Solubility For identifying the best salt to develop and for producing
liquid dosage forms
Melting point Which reflects, for example, crystalline solubility
Assay development Necessary for drug stability studies and perhaps
employing thin layer or high pressure liquid
chromatography

Stability In solution and in the solid state
Microscopy To determine crystal morphology and particle size
Powder flow and
compression
properties
Necessary data for capsule and tablet formation
Excipient
compatibility
To ensure that dosage forms perform correctly
Drug characterization (cont.)

Types of Drug dosage forms
Tablets and capsules Convenient and commonest dosage forms but likely to
be no good if the drug cannot be absorbed in the
alimentary tract of if the patient ( for e.g. child) cannot
swallow them
Injections and
infusions
Rapid action but impractical for treating chronic (long
term) illnesses
Pessaries and
suppositories
Can deliver the drug to local area where required but
have limited general use
Solutions,
suspensions and
elixirs
Useful for children and elders but bulky and less useful
if the drug is unpalatable or unstable in the presence of
water D R S P N A Y A K - P A R U L U N I V E R S I T Y 60

Ointments, creams
and paints
Use in restricted to topical application
Aerosols and dry
powder inhalations
Good for drugs required in the large but can be
difficult to administer the dose correctly
Transdermal
patches
Convenient if the dose needs to be released over a
long period ( for example: hormone replacement
therapy) but can cause irritation
Types of Drug dosage forms (cont.)

EXAMPLES FOR DOSAGE FORMS
Therapeutic considerations play an important role in deciding the dosage
form to formulate
Some examples include
A tablet is not suitable dosage form if the drug cannot be absorbed in the
alimentary tract – unless, of course, it is required to treat an ailment in
the tract itself ( such as gut infection)
Instead of a tablet, an injection might be suitable alternative

EXAMPLES FOR DOSAGE FORMS CONT.
Even if the drug can be absorbed in the alimentary tract (example:
intestine), a simple tablet will still be unsatisfactory if the drug is
destroyed by the stomach acid
In such a case the tablet might be enteric coated to prevent drug
destruction while the tablet is passing through the stomach
By the time the tablet reaches the intestine the coating has dissolved
liberating the drug for absorption through the intestinal wall

Drugs which need to act immediately (example: bronchodilator drugs for
treating asthmatic attacks where the airways suddenly become so
constricted that the patient has difficulty in breathing) are best
delivered by inhalation directly to the lungs where they can rapidly
dilate the airways, rather than being swallowed in the form of tablet
with the consequent delay in action while the drug is absorbed and
delivered to the lungs
Examples for dosage forms cont.

BIOPHARMACEUTICS
The study of pharmaceutical factors which affect the fate of the drug after
administration is called biopharmaceutics and these factors will need to
be evaluated in the development of the new drug
To be effective, a drug must reach in desired concentration to the part of
the body where it is required to act and, ideally, must be maintained at
concentration for the appropriate period of time

BIOPHARMACEUTICS CONT.
This goal is influenced by the key interactions which take place between the drug
and the body after the drug has been administered
These are :
Absorption
Distribution
Metabolism
Elimination

PRODUCT STABILITY
After the dosage forms of the medicine have been chooses, stability
studies must be undertaken because manufacturers needs to know how
long their product remains therapeutically active in the packaging
material they intend to use
Any pharmaceutical product can be subject to chemical or
microbiological deterioration and the regulatory authorities will need to
be shown the manufacturer’s experimental evidence for their claimed
shelf-life of the product
If, for example, the medicine is principally going to be used in the tropics,
it should be able to withstand climatic conditions there for the duration

THANK YOU
ALL THE BEST..!

Clinical research unit 1

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Clinical research unit 1