Drug Discovery

and Clinical
Research
SK Gupta, Sushma
Srivastava
SECTION 1
DRUG DISCOVERY AND
SECTION 1: DRUG DISCOVERY AND
DEVELOPMENT DEVELOPMENT
 CHAPTER 1: Drug Discovery Process
 CHAPTER 2: Translational Research
 CHAPTER 3: Preclinical In Vitro Screening
Methods To Predict Drug Safety During
Drug Development Process
 CHAPTER 4: Drug Discovery And Development
Of Biologics SECTION OUTLINE
SECTION 2: BASIC PRINCIPLES OF CLINICAL Drug Discovery Process
RESEARCH Translational Research
 CHAPTER 5: Clinical Development Of New Preclinical In Vitro Screening Methods to Predict Drug Safety during Drug Development
Drugs
Process
 CHAPTER 6: Regulations For Conducting
Drug Discovery and Development of Biologics 2
Clinical Trials In India
 CHAPTER 7: International Conference On

 Drug Discovery Process CHAPTER 1

Pravina Koteshwar,
Shubha R,
Diana Francis,
SK Gupta

INTRODUCTION TO DRUG DEVELOPMENT

Drug development is a scientific endeavor which is highly regulated due to public health
concern. A promising new molecule identified in drug discovery has to go through the
complex and time-consuming process of drug development before it becomes available to
patients.

The discovery process begins with an understanding of the disease mechanism(s) or

cause of the disease and discovery (or identification) of genes and/or proteins involved in
causing certain diseases. The identification of genes/proteins responsible for the disease
condition is referred to as target identification. These identified targets (gene/proteins) are
the potential targets for drugs to interact and to bring about a beneficial effect in a patient.
Next step is target validation, where certain studies are performed to confirm that targets
(genes/proteins) are actually involved in the disease. In this stage, along with validation of
the target, ability of the target to bind to a drug is identified.

After target identification and validation, a lead compound needs to be identified. A

lead compound is a substance which has the greatest potential for successful interaction
with the identified target. A lead compound is generally selected from libraries containing
thousands of compounds. This step of the drug discovery process is known as lead
identification. After the lead compound is identified it goes through an optimization
process wherein the structure of the compound may be altered to make it safe and
efficacious. Once this process is completed the compound is tested first in animal models
(such as rats and mice), then in humans to further ascertain its properties.

It takes about ten to twelve years to develop a new drug and the cost is over €800
million, about 60% of which is spent on necessary rigorous clinical trials. For a variety of
reasons, fewer than one or two compounds per ten thousand tested actually make it to the
TOC Index 
 market and are authorized for use in patients. In view of the high cost of the drug
development process, the industry has to be careful and has to look into the factors that
have significant impact on the process and should form basis for allocation of resources.
Drug Discovery
and Clinical The decision to develop a new drug by a pharmaceutical company depends on the
Research various factors and one of the key factors is to review and find out the unmet medical
SK Gupta, Sushma needs in the specific therapeutic area in which the company is interested due to strategic
Srivastava
reasons. In some cases there may be industry—university or industry—government
scientific institutes collaboration that may help to develop a new molecule. New and
interesting findings may also come from university, institutes and the lead may be taken
over by the pharmaceutical companies for further research. 4
SECTION 1: DRUG DISCOVERY AND
DEVELOPMENT
 CHAPTER 1: Drug Discovery Process Table 1.1 Cost and time involved in drug discovery
 CHAPTER 2: Translational Research
Target discovery
 CHAPTER 3: Preclinical In Vitro Screening
Methods To Predict Drug Safety During 2.5 years ↓ 4%
Drug Development Process Lead generation and lead optimization
 CHAPTER 4: Drug Discovery And Development 3.0 years ↓ 15%
Of Biologics
Preclinical development
SECTION 2: BASIC PRINCIPLES OF CLINICAL
RESEARCH 1 year ↓ 10%
 CHAPTER 5: Clinical Development Of New Phase I, II and III clinical trials
Drugs
6 years ↓ 68%
 CHAPTER 6: Regulations For Conducting
Clinical Trials In India FDA review and approval
 CHAPTER 7: International Conference On 1.5 years ↓ 3%
Drug to the market
14 years € 880 million

 The drug discovery and development process is designed to ensure that only those
pharmaceutical products that are both safe and effective are brought to market for the
benefit of the patients (Table 1.1).

DRUG DISCOVERY PROCESS

OVERVIEW OF DRUG DISCOVERY PROCESS

During the last 50 years the philosophy of valuable drugs discovery has evolved from one
that was mostly based around chemistry to one that has more biological approach to treat
a disease. These changes were not only driven by strategic imperative, but are enabled
also by the significant changes in technology that has occurred during the past half
century.

HISTORICAL BACKGROUND

Before the existence of pharmaceutical industry, medicines were discovered by accident,

and their use was passed down by written and verbal tradition. For example, digitalis is an
active principal of a natural product, namely foxglove leaf used to treat dropsy or edema, in
which liquids accumulate in the body and causes swelling of tissues and body cavities.

This remedy was described and used some hundred(s) of years before the isolation of
the active components. In 1776, William Withering, a physician in England treated a lady
who was dying from a disease called dropsy. He left her, expecting her to die shortly, but
he later learned that she had recovered after taking an old cure of a garden plant called
foxglove. For ten years, Withering conducted experiments to demonstrate the uses of
foxglove and discovered that dropsy is actually a symptom of heart disease in which the
heart does not pump hard enough to get rid of urine. He showed that foxglove stimulated
urination by pumping more liquids to the kidneys. He published his results in 1785, but it
was not until the 20th century that the cardiac glycosides, the component of the foxglove
plant, were structurally and pharmacologically described

In 1950s and 1960s, pharmaceutical industries’ success in drug discovery had its
origins in serendipity, i.e. discovery by accident/chance. Lead molecules were found by
TOC Index  chance or from screening the chemical diversity available. These were then optimized by
 medicinal chemists to produce candidates, which were passed to development and
eventually into the market. This method led to discovery of drugs such as Chlorpromazine,
Meprobamate, and Benzodiazepines (Chlordiazepoxide, Diazepam) all of which have gone
Drug Discovery on to become successful medicines.
and Clinical
Research However, this approach at that time suffered from lack of sufficient molecules with
SK Gupta, Sushma high enough structural diversity, and the common use of animal models meant that other
Srivastava
factors such as absorption, metabolism, brain penetration, and pharmacokinetics had
profound effects on the number of active molecules found. In addition, many molecules
that showed activity in the models were of unknown mechanism. This greatly impeded the
development of back-ups when the lead failed due to toxicity or poor pharmacokinetics.
SECTION 1: DRUG DISCOVERY AND
DEVELOPMENT
To combat these problems, a more rational approach was developed based around
 CHAPTER 1: Drug Discovery Process
the structure of the agonist (i.e., hormones and neurotransmitters) and its receptor. This
 CHAPTER 2: Translational Research
 CHAPTER 3: Preclinical In Vitro Screening was set against a background of studying biological/physiological systems in animal
Methods To Predict Drug Safety During tissues. Thus, knowledge around molecular determinants that contribute to affinity and
Drug Development Process
efficacy enabled a generation of specific and potent agonists and antagonists to be
 CHAPTER 4: Drug Discovery And Development
Of Biologics developed.
SECTION 2: BASIC PRINCIPLES OF CLINICAL
RESEARCH
 CHAPTER 5: Clinical Development Of New STEPS IN DRUG DISCOVERY
Drugs
 CHAPTER 6: Regulations For Conducting
Clinical Trials In India The advent of molecular biology, coupled with advances in screening and synthetic
 CHAPTER 7: International Conference On chemistry technologies, has allowed a combination of both knowledge around the
receptor and random screening to be used for drug discovery. 5

Fig. 1.1: Steps in new drug development

The process of drug development is divided into two stages: New lead discovery and
new product development (clinical development) (Fig. 1.1).

TARGET IDENTIFICATION

Before any potential new medicine can be discovered the disease to be treated needs to
be understood, to unravel the underlying cause of the condition. Even with new tools and
insights, research on disease mechanism takes many years of work and, too often, leads
to frustrating dead ends. And even if the research is successful, it will take many more
years of work to turn this basic understanding of what causes a disease into a new
treatment.

The disease mechanism defines the possible cause or causes of a particular disorder,
as well as the path or phenotype of the disease. Understanding the disease mechanism
directs research and formulates a possible treatment to slow or reverse the disease
process. It also predicts a change of the disease pattern and its implications.

Disease mechanisms can be broadly classified into the following groups:

Defects in distinct genes—genetic disorders

Infection by bacteria, fungi, viruses, protozoa or worms.
Immune/autoimmune disease
Trauma and acute disease based on injury or organ failure
Multicausal disease.

TOC Index 
 The identification of new and clinically relevant molecular targets for drug intervention
is of outstanding importance to the discovery of innovative drugs.

Drug Discovery It is estimated that up to 10 genes contribute to multifactorial diseases, which are
and Clinical linked to another 5–10 gene products in physiological and pathophysiological circuits
Research which are also suitable for intervention with drugs. Environmental factors such as diet,
SK Gupta, Sushma exposure to toxins, trauma, stress, and other life experiences are assumed to interact with
Srivastava
genetic susceptible factors to result in disease. Thus, drug targets may include molecular
pathways related to environmental factors.

Current drug therapy is based on less than 500 molecular targets with potential to
SECTION 1: DRUG DISCOVERY AND exploit at least 10 times the number of targets in the future. Targets for therapeutic
DEVELOPMENT
intervention can be broadly classified into these categories:
 CHAPTER 1: Drug Discovery Process
 CHAPTER 2: Translational Research Receptors
 CHAPTER 3: Preclinical In Vitro Screening
Methods To Predict Drug Safety During Proteins and enzymes
Drug Development Process DNA
 CHAPTER 4: Drug Discovery And Development
Of Biologics RNA and ribosomal targets
SECTION 2: BASIC PRINCIPLES OF CLINICAL
RESEARCH Methods used for target identification include classical methods such as cellular and
 CHAPTER 5: Clinical Development Of New molecular biology and newer technique such as genomics and proteomics.
Drugs
 CHAPTER 6: Regulations For Conducting In the classical method, animal and human cell lines are used to identify the potential
Clinical Trials In India
target of drug action. Two key research avenues involve the enzymes that metabolize the
 CHAPTER 7: International Conference On
molecules (drugs) and proteins that act as receptors. 6

The newer methods like genomics and proteomics along with bioinformatics are
aimed at discovering new genes and proteins and quantifying and analyzing gene and
 protein expression between diseased and normal cells.

TARGET VALIDATION

Target validation requires a demonstration that a molecular target (such as an enzyme,

gene or protein) is actually involved in a disease process, and that binding of a drug to the
target is likely to have a curative effect.

The validation of a molecular target in vitro (in an artificial environment) usually

precedes the validation of the therapeutic concept in vivo (in a living organism); together
this defines its clinical potential. Validation involves studies in intact animals or disease-
related cell-based models that can provide information about the integrative response of
an organism to a pharmacological intervention and thereby help to predict the possible
profile of new drugs in patients.

Targets are validated with:

In vitro models: RNA and protein expression analysis and cell based assays for
inhibitors, agonists (substances which activate the target) and antagonists (counteracts
the effect of a target). In vitro assays are more robust and cost-effective, and have fewer
ethical implications than whole-animal experiments. For these reasons they are usually
chosen for high-throughput screening, a process through which active compounds,
antibodies or genes which modify a particular biomolecular pathway can be identified
rapidly.
In vivo models: In vivo testing involves testing in whole animals. It assesses both
pharmacology and biological efficacy in parallel. Animal models that are capable of
mimicking the disease state (e.g. animals mimicking diabetes), by adding/modifying or
deleting certain genes are used. These animal models are referred to as knock-in and
knock-out animal models.

Along with validation of the target it is essential to predict the “druggability” of the
target. The “druggability” of a given target is defined either by how well a therapeutic agent,
such as small drug molecule or antibody, can access the target (i.e. ability of a target to
bind to drug).

Knowledge of three–dimensional structure will help to unravel the physiological roles

of target proteins and contribute to “chemical” target validation and also enable the
prediction of “druggability” of the protein. One of the successfully targeted targets is G-
TOC Index 
 protein coupled receptors (GPCRs), and a sizable number of drugs prescribed today hit
this particular class. Therefore, the GPCR target type is considered druggable.

Drug Discovery In summary, target validation is one of the bottlenecks in drug discovery, as this phase
and Clinical is less adaptable to automation. Careful validation of target not only with respect to
Research relevance to disease but also druggability will reduce the failure rate and increase the
SK Gupta, Sushma efficiency of drug discovery.
Srivastava

LEAD IDENTIFICATION

SECTION 1: DRUG DISCOVERY AND In this phase, compounds which interact with the target protein and modulate its activity
DEVELOPMENT
are identified.
 CHAPTER 1: Drug Discovery Process
 CHAPTER 2: Translational Research
The lead identification process starts with the development of an assay which will be
 CHAPTER 3: Preclinical In Vitro Screening
Methods To Predict Drug Safety During followed by screening of compound libraries. The quality of an assay determines the
Drug Development Process quality of data. The assay used should fulfill these criteria: relevance, reliability,
 CHAPTER 4: Drug Discovery And Development practicability, feasibility, automation and cost effectiveness.
Of Biologics
SECTION 2: BASIC PRINCIPLES OF CLINICAL Primary screens will identify hits. Subsequently, confirmation screens and counter
RESEARCH
screens will identify leads out of the pool of hits. This winnowing process is commonly
 CHAPTER 5: Clinical Development Of New
Drugs referred to as “hits-to-leads.”
 CHAPTER 6: Regulations For Conducting
Clinical Trials In India The success of screening depends on the availability of compounds, as well as their
 CHAPTER 7: International Conference On quality and diversity. Efforts to synthesize, collect, and characterize compounds are an
essential and costly part of drug discovery.

There are several sources for compounds:

 Natural products (NPs) from microbes, plants, or animals. NPs are usually tested as
crude extracts first, followed by isolation and identification of active compounds.
(Random) collections of discreetly synthesized compounds.
Focused libraries around certain pharmacophores. 7

Random libraries exploring “chemical space.”

Combinatorial libraries.

A primary screen is designed to rapidly identify hits from compound libraries. The
goals are to minimize the number of false positives and to maximize the number of
confirmed hits. Depending on the assay, hit rates typically range between 0.1% and 5%.
This number also depends on the cutoff parameters set by the researchers, as well as the
dynamic range of a given assay.

Typically, primary screens are initially run in multiplets of single compound

concentrations. Readouts are expressed as percent activity in comparison to a positive
(100%) and a negative (0%) control. Hits are then retested a second time (or more often,
depending on the assays’ robustness). The retest is usually run independently of the first
assay, on a different day. If a compound exhibits the same activity within a statistically
significant range, it is termed a confirmed hit, which can proceed to dose-response
screening.

Establishing a dose-response relationship is an important step in hit verification. It

typically involves a so-called secondary screen. In the secondary screen, a range of
compound concentrations usually prepared by serial dilution is tested in an assay to
assess the concentration or dose dependence of the assay's readout. Typically, this dose-
response is expressed as an IC50 in enzyme-, protein-, antibody-, or cell-based assays or as
an EC50 in in vivo experiments. IC50 is a measure of the effectiveness of a compound in
inhibiting biological or biochemical function. This quantitative measure indicates how
much of a particular drug is needed to inhibit a given biological process by half. EC50 (half
maximal effective concentration) refers to the concentration of a drug or antibody which
induces a response halfway between the baseline and maximum. The EC50 of a graded
dose response curve therefore represents the concentration of a compound where 50% of
its maximal effect is observed.

Confirmed hits proceed to a series of counterscreens. These assays usually include

drug targets of the same protein or receptor family, for example, panels of GPCRs (G-
protein coupled receptors) or kinases. In cases where selectivity between subtypes is
TOC Index  important, counterscreens might include a panel of homologous enzymes, different
 protein complexes, or heterooligomers. Counterscreens profile the action of a confirmed
hit on a defined spectrum of biological target classes. The number and stringency of
counterscreens can vary widely and depend on the drug target.
Drug Discovery
and Clinical One of the goals throughout the discovery of novel drugs is to establish and confirm
Research the mechanism of action (MOA). In an ideal scenario, the MOA remains consistent from
SK Gupta, Sushma the level of molecular interaction of a drug molecule at the target site through the
Srivastava
physiological response in a disease model, and ultimately in the patient.

The tools used for lead identification are: High throughput screening, in silico/virtual
screening, NMR-based screening and X-ray crystallography.
SECTION 1: DRUG DISCOVERY AND
DEVELOPMENT High-throughput screening (HTS) aims to rapidly assess the activity of a large number
 CHAPTER 1: Drug Discovery Process of compounds or extracts on a given target. Entire in-house compound libraries with
 CHAPTER 2: Translational Research millions of compounds can be screened with a throughput of 10,000 (HTS) up to
 CHAPTER 3: Preclinical In Vitro Screening 100,000 compounds per day (ultra HTS) using robust test assays.
Methods To Predict Drug Safety During
Drug Development Process Virtual (in silico) screening sifts through large numbers of compounds based on a user-
 CHAPTER 4: Drug Discovery And Development defined set of selection criteria. Selection criteria can be as simple as a physical
Of Biologics
molecular property such as molecular weight or charge, a chemical property such as
SECTION 2: BASIC PRINCIPLES OF CLINICAL
RESEARCH number of heteroatoms, number of hydrogen-bond acceptors or donors. Selection
 CHAPTER 5: Clinical Development Of New criteria can be as complex as a three dimensional description of a binding pocket of the
Drugs
target protein, including chemical functionality and solvation parameters. In silico
 CHAPTER 6: Regulations For Conducting
Clinical Trials In India screening can involve simple filtering based on static selection criteria (i.e., molecular
 CHAPTER 7: International Conference On weight) or it can involve actual docking of ligands to a target site, which requires
computer-intensive algorithms for conformational analysis, as well as binding energies.
NMR-based screening fills the gap between HTS and virtual screening. This method
combines the random screening approach with the rational structure-based approach to
 lead discovery.
X-ray crystallography: X-ray crystallography uses X-rays to determine the structure and
functioning of biological molecules. The point at which X-ray crystallography comes into
the drug discovery and development process depends on the purpose for which it is
used. X-ray crystallography is being increasingly used to determine the three-
dimensional structure of a lead compound. The information accumulated during the
process of lead identification by means of X-ray crystallography is essential for the next
stage of drug development which is lead optimization. 8

Following are the criteria for hits to be regarded as leads:

Pharmacodynamic properties: Efficacy, potency and selectivity in vitro and in vivo;

Physicochemical properties: For example, Lipinski's “rule of five”
Pharmacokinetic properties: For example, permeability in the Caco-2 assays
Chemical optimization potential
Patentability.

LEAD OPTIMIZATION

Lead optimization is the complex, nonlinear process of refining the chemical structure of a
confirmed hit to improve its drug characteristics with the goal of producing a preclinical
drug candidate. This stage constitutes the tightest bottleneck in drug discovery.

Lead optimization employs a combination of empirical, combinatorial, and rational

approaches that optimize leads through a continuous, multi-step process based on
knowledge gained at each stage. Typically, one or more confirmed hits are evaluated in
secondary assays, and a set of related compounds, called analogs, are synthesized and
screened.

The testing of analog series results in quantitative information that correlates changes
in chemical structure to biological and pharmacological data generated to establish
structure activity relationships (SAR).

The lead optimization process is highly iterative. Leads are assessed in

pharmacological assays for their “drug-likeness.” Medicinal chemists change the lead
molecules based on these results in order to optimize pharmacological properties such as

TOC Index 
 bioavailability or stability. At that point the new analogs are fed back into the screening
hierarchy for the determination of potency, selectivity, and mechanism of action.

Drug Discovery Pharmacokinetics (PK)/Pharmacodynamics (PD)/Absorption, Distribution,

and Clinical Metabolism, Excretion (ADME) studies are an integral part of lead optimization. They feed
Research back into the medicinal chemistry effort aiming to optimize the physicochemical
SK Gupta, Sushma properties of new leads in terms of minimal toxicity and side effects, as well as of
Srivastava
maximum efficacy toward disease. PK/PD/ADME studies rely heavily on analytical
methods and instrumentation. The recent innovation and progress in mass spectroscopy,
(whole-body) imaging, and chromatography technology (HPLC, LC-MS, MS) have
tremendously increased the quantity and quality of data generated in PK/PD experiments.
SECTION 1: DRUG DISCOVERY AND
DEVELOPMENT
This data is then fed into the next optimization cycle. The lead optimization process
 CHAPTER 1: Drug Discovery Process
continues for as long as it takes to achieve a defined drug profile that warrants testing of
 CHAPTER 2: Translational Research
 CHAPTER 3: Preclinical In Vitro Screening the new drug in humans (Fig. 1.2).
Methods To Predict Drug Safety During
Drug Development Process
 CHAPTER 4: Drug Discovery And Development
Of Biologics
LEAD OPTIMIZATION: FORMULATION AND DELIVERY
SECTION 2: BASIC PRINCIPLES OF CLINICAL
RESEARCH Formulation development: It is the process of turning an active compound into a form and
 CHAPTER 5: Clinical Development Of New strength suitable for human use.
Drugs
 CHAPTER 6: Regulations For Conducting Formulation and delivery of drugs is an integral part of the drug discovery and
Clinical Trials In India
development process. Indeed, formulation problems and solutions influence the design of
 CHAPTER 7: International Conference On
the lead molecules; they feed back into the iterative lead optimization cycle, as well as the
preclinical and clinical evaluations.

If formulation substances are not generally recognized as safe (GRAS), they become
 part of the safety assessment and their PK/PD/ADME behavior, as well as toxicity profile,
needs to be documented in the IND (investigational new drug) application. In fact, side
effects such as local irritation or allergic reactions are often attributable to drug
formulation, not the active pharmaceutical ingredient (API).

Formulation substances might exhibit different biological activity than the actual drug.

Indeed, a sizable number of drug discovery and development programs in the

pharmaceutical and biotech industry are centered on new ways of formulating already
known and even marketed drugs to increase their efficacy or safety profiles. 9

Fig. 1.2: Depicts use of In-Silico technology in various stages of selection of a drug candidateSource: [Link]-
[Link]/Image/[Link]

STAKEHOLDERS IN NEW DRUG DEVELOPMENT

Expertise involved to achieve goal of new drug development are numerous, once the
management team sets therapeutic targets, budgets and resources, departments involved
in drug discovery include:

Research and development: It is responsible for finding new compounds and assuring
that they are safe enough to test in humans.
TOC Index 
 Medicinal chemists: Whose responsibilities are to prepare new chemical entities which
can be screened for biological activity and to prepare compounds which have been
found to be active (new leads) in quantities sufficient for advanced testing.
Drug Discovery Pharmacology/molecularbiology/screening: Examines each New Chemical Entity (NCE)
and Clinical
in a set of high throughput screens.
Research
SK Gupta, Sushma Safety evaluation: Demonstrates that the NCE and its metabolites do not accumulate
Srivastava and do not cause harm during short-term administration.
Formulations research: Develop a dosage form that is absorbed into the bloodstream
when administered and is stable when stored for long periods of time. The
concentration in the blood is an important factor in early development. The potential
SECTION 1: DRUG DISCOVERY AND
DEVELOPMENT new drug must reach and maintain a level sufficient to sustain its biological effect;
 CHAPTER 1: Drug Discovery Process these studies are initially conducted in animals, to establish the doses for human
 CHAPTER 2: Translational Research studies.
 CHAPTER 3: Preclinical In Vitro Screening
Methods To Predict Drug Safety During Process research: Manufacture the NCE in sufficient quantity for advanced testing,
Drug Development Process dosage form development.
 CHAPTER 4: Drug Discovery And Development
Of Biologics
Legal affairs: Writes and files the patents necessary to protect a company's inventions.
SECTION 2: BASIC PRINCIPLES OF CLINICAL Research administration: Collects the material generated by all of the departments and
RESEARCH
formats it into a request for exemption so that the NCE can be tested in humans. This
 CHAPTER 5: Clinical Development Of New
submission is the Investigational New Drug (IND). 10
Drugs
 CHAPTER 6: Regulations For Conducting
Clinical Trials In India
 CHAPTER 7: International Conference On
NEED FOR SYSTEMATIC APPROACH IN NEW DRUG DISCOVERY

The pharmaceutical industry is operating in a world where medicines have to add real
value in an environment in which costs are under constant pressure. This high cost is

causing the evolution of the drug discovery process so that high percentages of efficient
pipeline molecules are delivered to market quickly. The following needs to be considered
to have a systematic approach in drug discovery:

UNMET MEDICAL NEEDS

A constant driver for developing new medicines has always been the unmet medical need.
However, there are now strong pressures to treat the underlying cause of the disease
rather than provide symptomatic relief alone. This is reinventing the biological systems
approach, but using humans rather than animals. In order to accomplish this, the
investment that has already been initiated in technologies such as noninvasive imaging,
clinical genetics and genomics will increase. This is now assured with the publication of
the human genome.

The lack of disease models in animals in some therapeutic areas is a major driver to
understand the human pathology. This is particularly relevant in the central nervous
system (such as depression, bipolar disorder, schizophrenia) area. In these diseases, with
no simple ways to validate the targets in the complex intact system, option left is targeting
components such as receptor or biochemical systems. In these cases, the scientist is
constrained to collecting a logical series of evidence that associates the target with the
disease. Along with the existing imaging methods such as positron emission tomography
(PET) and functional magnetic resonance imaging (fMRI), application of technologies like
clinical genetics and genomics will strengthen the understanding of the correlation
between disease and specific receptors.

Clinical genetics networks are being put into place to allow sufficient information on
probands (proband denotes a particular subject (person or animal) first affected with
genetics disorder) to be collected, such that associations between particular gene(s) and
disease (target validation) can be made and eventually resulting in identification of a lead
compound.

The advent of the human genome's publication now offers a great opportunity for the
understanding of the genetic make-up of disease and will furnish specific gene products
and/or pathways as new targets that would not have been previously identified.
Importantly, they will be born out of human data, so again adding to the level of confidence
in the validity of the target.

TOC Index 
 ATTRITION

Drug Discovery Attrition is another driver for systematic approach in drug discovery for overall success
and Clinical rate. Attrition has remained static despite the investment in the new technologies. This
Research reflects the fact that good molecules need more than potency and selectivity to be
SK Gupta, Sushma
successful, and it is in these areas where technology has been concentrating in the last
Srivastava
few years. The challenges ahead lie in reducing the risk of not obtaining efficacy in
humans, and in increasing the developability of the molecules.

Efficacy: Many new mechanisms fail when they get into humans through lack of efficacy.
SECTION 1: DRUG DISCOVERY AND
DEVELOPMENT This is one of the risks that the industry takes when developing such molecules. One way
 CHAPTER 1: Drug Discovery Process to diminish risk is to get better validation in humans (proof-of-concept i.e. proof of
 CHAPTER 2: Translational Research efficacy) as soon as possible. The use of imaging, genetics, and genomics has already
 CHAPTER 3: Preclinical In Vitro Screening been discussed earlier as a way to help build early confidence in the target.
Methods To Predict Drug Safety During
Drug Development Process
It is now recognized that fast decision making saves money and allows resources to
 CHAPTER 4: Drug Discovery And Development
Of Biologics be more effectively used. Proof-of-concept is generally obtained in phase III. Killing
SECTION 2: BASIC PRINCIPLES OF CLINICAL compounds in Phase III is extremely costly; therefore it is a disadvantage to obtain proof
RESEARCH of concept at such a late stage. Thus, simple proof-of-concept (POC) studies are being
 CHAPTER 5: Clinical Development Of New
Drugs
sought in phase I or phase II. If POC were to be obtained during phase I and phase II
 CHAPTER 6: Regulations For Conducting instead of phase III it will provide sponsors with sufficient evidence which can be used to
Clinical Trials In India assess the clinical and commercial potential of the drug and in turn eliminate potential
 CHAPTER 7: International Conference On failures from the drug discovery pipeline. 11

In addition, diagnostics will play a greater role in helping to choose patient

populations, at least initially to show that the mechanism works. This will see greater use
 of imaging, proteomics and genetics in helping to identify the right patient group.

In the meantime, a better balance of novel molecules and those that are precedented
will be seen in the drug discovery portfolio. This will mean that a higher proportion of
molecules will not fail for efficacy. However, this strategy creates its own problems in that
to be successful in the marketplace the molecule will need to be differentiated from those
already present. To do this in the clinic will add to the cost and to the overall cycle time,
thus these problems will need to be addressed much earlier in the process.

Developability: A large proportion of molecules fail due to of lack of developability. Prentis

et al. suggest that this proportion is as high as 69%, broken down as toxicity (22%), poor
biopharmaceutical properties (41%) and market reasons (6%). This is not a new revelation,
and efforts have been actively followed to automate and miniaturize methods to measure
solubility, stability, pKa (value which describes the acid and basic properties of a
substance), bioavailability, brain penetration, and various toxicity. These methods
(combinatorial lead optimization) are being applied to leads during optimization, but need
to be developed further and applied even earlier to maximize their impact. This is
particularly true for toxicity screens, where it can be predicted that a great deal of effort
will be done in the next few years.

Great extent of work is being done in the field of predictive algorithms, and Pfizer has
developed tool known as the “rule of 5”. This is an awareness tool for medicinal chemists
that suggest that there will be poor absorption if a molecule has two or more of the
following: more than 5 H-bond donors; a molecular weight >500; c log P >5; the sum of Ns
and Os (a rough measure of H-bond acceptors) >10.

While it is inherently costly to try to fix poor developability by formulation,

pharmaceutical development will become more actively engaged in alternative
formulations and delivery systems during the lead optimization phase. The trend toward
higher potency compounds, that reduces cost of goods, also allows, due to the smaller
dose, alternative delivery systems such as inhalation, nasal, buccal and sublingual
absorption.

CYCLE TIMES

The need to speedup the delivery of molecules to the market is another driver to have
systematic approach in drug discovery. The regulatory environment and the growing
complexity of drug development affect the time taken for a drug to reach the market.
TOC Index 
 Screening automation and combinatorial chemistry have greatly reduced the time to
candidate selection. This will almost certainly decrease again by further application of
techniques like chemoinformatics to aid library design, both for those to be used for
Drug Discovery random screening and those within the process of lead optimization. As mentioned above,
and Clinical continual automation of developability criteria will also speed up the process by selecting
Research compounds with a high probability of succeeding. This raises the concept that speed in
SK Gupta, Sushma
Srivastava each phase should not always be the major driver. A candidate for development goes
forward with all of its associated baggage. Fixing problems becomes costly and may lead
to a suboptimal product that cannot fulfill its medical and commercial potential. Thus,
spending time choosing the right candidate will have major benefits downstream, both in
SECTION 1: DRUG DISCOVERY AND terms of speed and value. The same concept applies to development candidates in phase
DEVELOPMENT III. Differentiation may not be obvious if the mechanism is precedented with another
 CHAPTER 1: Drug Discovery Process
marketed product. Thus, differentiation will become a challenge, which potentially will
 CHAPTER 2: Translational Research
increase the time in phase III. To aid in this process and help in choosing which
 CHAPTER 3: Preclinical In Vitro Screening
Methods To Predict Drug Safety During differentiators to pursue, this problem will need to be addressed much earlier. This might
Drug Development Process stimulate automated assays for common side effects of drugs as part of the candidate
 CHAPTER 4: Drug Discovery And Development
Of Biologics
selection criteria during the lead optimization stage.
SECTION 2: BASIC PRINCIPLES OF CLINICAL
RESEARCH
 CHAPTER 5: Clinical Development Of New ECONOMIC VALUE
Drugs
 CHAPTER 6: Regulations For Conducting
Clinical Trials In India
There is growing internal pressure to increase productivity while controlling costs. This
 CHAPTER 7: International Conference On has led to the drive for high-value molecules in diseases with high unmet need. An
extension of this concept is the “blockbuster” approach where projects that deliver
medicines with potential peak sales greater than 1 billion pounds are given the highest
priority. This means that portfolio management will become even more important with an
 associated greater interaction between R&D and the commercial functions. 12

Thus, new portfolio tools will also be major contributors to the future process of drug
development. The real value of medicines to the health of society is only now beginning to
be recognized. It has taken many years of persuasion that medicines can have profound
economic benefit.

The push to raise health, economic, and quality-of-life issues has produced a counter
response from some regulators that the industry demonstrates added value in its novel
medicines. Thus, committees like National Institute for Clinical Excellence (NICE) in the UK
will put pressure on the process to produce medicines that have significant value for
society. This will mean that in the future more outcome studies will be needed to
demonstrate quality-of-life and economic benefit.

PRECLINICAL DRUG DEVELOPMENT

INTRODUCTION

Preclinical drug development is a stage that begins before clinical trials (testing in
humans) during which important safety and pharmacology data is collected. Clinicians
and regulators need to be reassured that information concerning all of these different
aspects is available to enable clinical trials to progress and ultimately to support
regulatory decisions on whether a new drug can be approved for marketing. Most
regulatory toxicity studies are conducted in animals to identify possible hazards from
which an assessment of risk to humans is made by extrapolation. Regulatory agencies
request studies in a rodent (e.g. rat) and a non rodent (e.g. dog). The choice of animal
species is made based on the similarities of its metabolism to humans or the applicability
of desired pharmacological properties to humans. It is not possible or ethical to use
animals in large numbers, to compensate for the same it is assumed that increasing the
dose and prolonging the duration of exposure will improve both sensitivity and predictivity
of the tests.

Preclinical research includes synthesis, purification and animal testing which is done
to measure the biological activity and safety of an investigational drug or device.
Preclinical research is conducted by pharmaceutical companies early in the process of
new drug development. This research takes place in either the part or whole animal to
TOC Index 
 determine important information, including: therapeutic effects the drug may have,
potential side effects and toxicities and metabolism and clearance of the drug in the body.
Good results in the preclinical or animal stage do not necessarily mean that similar results
Drug Discovery will be found when the drug is given to healthy volunteers or patients.
and Clinical
Research The main goals of preclinical studies are to determine a drug's pharmacodynamics
SK Gupta, Sushma (PD), pharmacokinetics (PK) and toxicity through animal testing. This data allows
Srivastava
researchers to estimate a safe starting dose of the drug for clinical trials in humans.

The goals of the nonclinical safety evaluation include:

Categorization of toxic effects with respect to target organs, dose dependence,

SECTION 1: DRUG DISCOVERY AND
DEVELOPMENT relationship to exposure, and potential reversibility. This information is important for the
 CHAPTER 1: Drug Discovery Process estimation of an initial safe starting dose for the human trials
 CHAPTER 2: Translational Research The identification of specific parameters for clinical monitoring for potential adverse
 CHAPTER 3: Preclinical In Vitro Screening
Methods To Predict Drug Safety During effects.
Drug Development Process The nonclinical safety studies, although limited at the beginning of clinical development,
 CHAPTER 4: Drug Discovery And Development
Of Biologics
should be adequate to characterize potential toxic effects.
SECTION 2: BASIC PRINCIPLES OF CLINICAL
RESEARCH The need for nonclinical information including toxicology, pharmacology and
 CHAPTER 5: Clinical Development Of New pharmacokinetics to support clinical trials is addressed in the ICH (International
Drugs Conference on Harmonization) Safety guidelines. Typically, both in vitro and in vivo tests
 CHAPTER 6: Regulations For Conducting will be performed. Studies of a drug's toxicity on organs targeted by that drug, as well as
Clinical Trials In India
 CHAPTER 7: International Conference On
any long-term carcinogenic effects or toxic effects on mammalian reproduction will be
estimated in preclinical studies. 13

 TYPES OF PRECLINICAL STUDIES

In vitro studies
In vivo studies
Ex vivo studies.

IN VITRO STUDIES

In vitro studies are done for testing of a drug or chemical's effect on a specific isolated
tissue or organ maintaining its body functions. Basic instruments used for isolated tissue
experiments are organ baths, recording devices.

Few examples of in vitro studies include:

Langendorff's heart preparation: The objective is to study the effect of drugs—

noradrenaline, acetylcholine and isoprenaline on the coronary blood flow and heart rate
and force of contraction using rat isolated heart.

Ileum preparation: The objective is to record the effect of drugs—histamine and

antihistamine by using segment of ileal portion of Guinea pig.
Rectus abdominus muscle preparation: The objective is to record the effect of drugs d-
tubocurarine by using rectus abdominis muscle of frog.

IN VIVO STUDIES

It is a Latin term meaning (with) “in the living”. It indicates the use of a whole
organism/animals (for an experiment). Researchers use laboratory animals as models of
humans or some other target species to achieve long-term objective, such as developing a
new drug for a particular disease, screening a particular compound for human toxicity,
studying a gene or mutation found in both animals and human; to achieve short-term
objective to find out how the animal responds to the treatment. If it is a faithful model of
humans, then humans should respond in the same way. Animals, and other models, are
used because the research cannot be done on humans for practical or ethical reasons.

Purpose of models: A specific model is chosen because it is believed to be appropriate to

the condition being investigated and is thought likely to respond in the same way as
TOC Index  humans to the proposed treatment(s) for the character being investigated.
 Having chosen the model it is essential that any experiments in which it is used are
well designed, i.e. are capable of demonstrating a response to a treatment. If the model
happens to be insensitive or the experiments are badly designed so that they are incapable
Drug Discovery of distinguishing between treated and control groups, say as a result of using too few
and Clinical animals, then the model is not appropriate to its purpose
Research
SK Gupta, Sushma Animal models are used to define a new molecule's:
Srivastava
Therapeutic potential
Toxicity potential
Pharmaceutical properties and metabolic pathways
SECTION 1: DRUG DISCOVERY AND
DEVELOPMENT Mechanism and specificity of action (lead molecules).
 CHAPTER 1: Drug Discovery Process
In vivo studies are preferred over in vitro studies for the following reasons:
 CHAPTER 2: Translational Research
 CHAPTER 3: Preclinical In Vitro Screening Greater similarity to human studies when compared to in vitro screening
Methods To Predict Drug Safety During
Drug Development Process Drug effects modified by physiological mechanisms can be studied
 CHAPTER 4: Drug Discovery And Development
ADME of drugs that modifies drug effects are also factored
Of Biologics
SECTION 2: BASIC PRINCIPLES OF CLINICAL Most animal systems are similar to human systems
RESEARCH
Effect of drug is studied on complete systems rather than tissues and organs
 CHAPTER 5: Clinical Development Of New
Drugs Drugs acting on central nervous system, cardiovascular system, gastrointestinal
 CHAPTER 6: Regulations For Conducting system, and other systems can be studied
Clinical Trials In India
 CHAPTER 7: International Conference On Results easier to interpret and extrapolate

Some of the examples of in vivo studies are:

Non-invasive method—rat tail cuff method

 Invasive methods—BP recording in anesthetized dog or cat

Transgenic animal models: Partly due to the low speed and high cost of conventional
animal models (typically rodents) and the relatively high number of preliminary hits from
HTS (High Throughput Screening), alternative small-animal models have emerged. The
small size, high utility, and experimental tractability (i.e. easy to manage) of these animals
enable cost-effective and rapid screening of numerous compounds. Technologies for 14
engineering the mouse genome have made it possible to create various disease models
for use in screening corresponding therapeutic compounds. Knockout mouse models have
been shown to be highly predictive of the effects of drugs that act on target specific gene-
sequence alterations or manipulate the levels and patterns of target-gene expression.
Using these techniques, researchers can generate specific disease models to validate
targets as therapeutic intervention points and screen drug candidates. Transgenic
technology represents an attractive approach to reduce the attrition rate of compounds
entering clinical trials by increasing the quality of the target and compound combinations
making the transition from discovery into development. Some of the transgenic animal
models are Obese Zucker rats for testing obesity related hypertension, genetically epilepsy
prone rats for testing antiepileptic drugs.

EX VIVO STUDIES

In ex vivo, experiment is performed in vivo and then analyzed in vitro. The organs of the
animals are detached from the body and replaced once an experiment is performed. Then
the animals are kept under observation and findings recorded for a set duration.

General requirements for conducting preclinical studies are:

Toxicity studies should comply with Good Laboratory Practice (GLP).

These studies should be performed by suitably trained and qualified staff employing
properly calibrated and standardized equipment, done as per written protocols.
Standard operating procedures (SOPs) should be followed.
Test substances and test systems (in vitro or in vivo) should be properly characterized
and standardized.
All documents belonging to each study, including its approved protocol, raw data, draft
report, final report, and histology slides and paraffin tissue blocks should be preserved
for a minimum of 5 years after marketing of the drug.
TOC Index 
 ANIMAL PHARMACOLOGY STUDIES

Drug Discovery Safety pharmacology studies are studies that investigate potential undesirable
and Clinical pharmacodynamic effects of a substance on physiological functions in relation to
Research exposure within the therapeutic range or above. Specific pharmacological actions are
SK Gupta, Sushma
those which demonstrate the therapeutic potential for humans.
Srivastava

Based on the individual properties and intended uses of an investigational drug,

specific studies that need to be conducted and their design will vary. Only scientifically
validated methods should be used.
SECTION 1: DRUG DISCOVERY AND
DEVELOPMENT
The essential safety pharmacology is to study the effects of the test drug on vital
 CHAPTER 1: Drug Discovery Process
functions. Vital organ systems such as cardiovascular, respiratory and central nervous
 CHAPTER 2: Translational Research
 CHAPTER 3: Preclinical In Vitro Screening
systems should be studied.
Methods To Predict Drug Safety During
Drug Development Process In addition to the essential safety pharmacological studies, additional supplemental
 CHAPTER 4: Drug Discovery And Development and follow-up safety pharmacology studies may need to be conducted as appropriate.
Of Biologics
These depend on the pharmacological properties or chemical class of the test substance,
SECTION 2: BASIC PRINCIPLES OF CLINICAL
RESEARCH and the data generated from safety pharmacology studies
 CHAPTER 5: Clinical Development Of New
Drugs Specific and essential pharmacological studies should be conducted to support use of
 CHAPTER 6: Regulations For Conducting therapeutics in humans. Essential safety pharmacology studies may be excluded or
Clinical Trials In India
supplemented based on scientific rationale. Also, the exclusion of certain test(s) or
 CHAPTER 7: International Conference On
exploration(s) of certain organs, systems or functions should be scientifically justified.
Supplemental Safety Pharmacology Studies are required to investigate the possible
adverse pharmacological effects that are not assessed in the essential safety

 pharmacological studies and are a cause for concern.

The following factors are to be considered when specific tests are to be conducted:

Mechanism of action
Class specific effects
Ligand binding or enzyme assay suggesting a potential for adverse events

Safety pharmacology studies are usually not required when:

Product is to be used for local application, e.g. dermal or ocular,

The pharmacology of the investigational drug is well known, and/or 15

Systemic absorption from the site of application is low.

Safety pharmacology testing is also not necessary, in case of a new derivative having
similar pharmacokinetics and pharmacodynamics. For biotechnology-derived products
that achieve highly specific receptor targeting, it is often sufficient to evaluate safety
pharmacology endpoints as a part of toxicology and/or pharmacodynamic studies;
therefore, safety pharmacology studies can be reduced or eliminated for these products.
For biotechnology-derived products that represent a novel therapeutic class and/or those
products that do not achieve highly specific receptor targeting, a more extensive
evaluation by safety pharmacology studies should be considered.

In vivo safety pharmacology studies should be designed to define the dose-response

relationship of the adverse effect observed. When feasible the time course (e.g. onset and
duration of response) of the adverse effect should be investigated.

In vitro studies should be designed to establish a concentration-effect relationship.

The range of concentrations used should be selected to increase the likelihood of
detecting an effect on the test system. The upper limit of this range may be influenced by
physicochemical properties of the test substance and other assay specific factors (Figs
1.3A And B).

ANIMAL TOXICITY STUDIES

Toxicokinetic studies should be conducted to assess the systemic exposure achieved in

animals and its relationship to dose level and the time course of the toxicity study. Other
objectives of toxicokinetic studies include:

To relate the toxicological findings to clinical safety.

TOC Index 
 To support in selecting species, treatment regimen and designing subsequent non-
clinical toxicity studies.

Drug Discovery Several toxicity studies need to done before a drug goes into the clinical phase. They
and Clinical are:
Research
SK Gupta, Sushma
Srivastava SYSTEMIC TOXICITY STUDIES

Single dose study (acute toxicity studies): Single dose studies in animals are essential for
any pharmaceutical product intended for human use. The information obtained from these
SECTION 1: DRUG DISCOVERY AND studies is useful in choosing doses for repeat-dose studies, providing preliminary
DEVELOPMENT
identification of target organs of toxicity, and occasionally, revealing delayed toxicity. Acute
 CHAPTER 1: Drug Discovery Process
 CHAPTER 2: Translational Research
toxicity studies may also aid in the selection of starting doses for phase I human studies,
 CHAPTER 3: Preclinical In Vitro Screening and provide information relevant to acute overdosing in humans.
Methods To Predict Drug Safety During
Drug Development Process Repeated-dose systemic toxicity studies: The primary goal of repeated dose toxicity
 CHAPTER 4: Drug Discovery And Development studies is to characterize the toxicological profile of the test compound following repeated
Of Biologics
SECTION 2: BASIC PRINCIPLES OF CLINICAL
administration. This includes identification of potential target organs of toxicity and
RESEARCH exposure/response relationships, and may include the potential reversibility of toxic
 CHAPTER 5: Clinical Development Of New effects. This information should be part of the safety assessment to support the conduct
Drugs
of human clinical trials and the approval of a marketing authorization.
 CHAPTER 6: Regulations For Conducting
Clinical Trials In India
 CHAPTER 7: International Conference On

Figs 1.3A and B: A researcher studies a rat being used in medical experiment
16

TOC Index 
 Drug Discovery
and Clinical
Research
SK Gupta, Sushma
Srivastava

SECTION 1: DRUG DISCOVERY AND

DEVELOPMENT
 CHAPTER 1: Drug Discovery Process
 CHAPTER 2: Translational Research
 CHAPTER 3: Preclinical In Vitro Screening
Methods To Predict Drug Safety During
Drug Development Process
 CHAPTER 4: Drug Discovery And Development
Of Biologics
SECTION 2: BASIC PRINCIPLES OF CLINICAL
RESEARCH
 CHAPTER 5: Clinical Development Of New
Drugs
 CHAPTER 6: Regulations For Conducting
Clinical Trials In India
 CHAPTER 7: International Conference On

Figs 1.4A and B: Reproductive studies done on rats

The decision whether a developmental toxicity study needs to be performed should be

 made on a case-by-case basis taking into consideration historical use, product features,
intended target population and intended clinical use.

MALE FERTILITY STUDIES

Male fertility studies are designed to provide general information concerning the effects of
a test substance on male reproductive system such as gonadal function.

FEMALE REPRODUCTION AND DEVELOPMENTAL TOXICITY STUDIES

Female fertility studies are designed to provide general information concerning the effects
of a test substance on female reproductive system such as ovary function and lactation.
These studies need to be carried out for all drugs proposed to be studied or used in
women of child-bearing age (Figs 1.4A And B).

TERATOGENICITY STUDY

The drug should be administered throughout the period of organogenesis in animals if the
test drug is intended for women of child-bearing age and if women of child-bearing age are
to be included as subjects in the clinical trial stage.

PERINATAL STUDY

This study is specially recommended if the drug is to be given to pregnant or nursing

mothers for long periods or where there are indications of possible adverse effects on
fetal development.

TOC Index 
 Drug Discovery
and Clinical
Research
SK Gupta, Sushma
Srivastava

SECTION 1: DRUG DISCOVERY AND

DEVELOPMENT
 CHAPTER 1: Drug Discovery Process
 CHAPTER 2: Translational Research Fig. 1.5: Rabbits kept ready for ocular tests
 CHAPTER 3: Preclinical In Vitro Screening
Methods To Predict Drug Safety During
Drug Development Process
LOCAL TOXICITY
 CHAPTER 4: Drug Discovery And Development
Of Biologics
SECTION 2: BASIC PRINCIPLES OF CLINICAL These studies are required when the new drug is proposed to be used by some special
RESEARCH route (other than oral) in humans. The drug should be applied to an appropriate site (e.g.
 CHAPTER 5: Clinical Development Of New skin or vaginal mucous membrane) to determine local effects in a suitable species. If the
Drugs
 CHAPTER 6: Regulations For Conducting
drug is absorbed from the site of application, appropriate systemic toxicity studies will
Clinical Trials In India also be required. Examples of Local Toxicity are Dermal Toxicity Study, Vaginal Toxicity
 CHAPTER 7: International Conference On Study, Photo-Allergy, Rectal Tolerance Test, Ocular Toxicity Studies, Inhalational Toxicity
Studies, Hypersensitivity (Fig. 1.5).

 GENOTOXICITY

Genotoxicity refers to potentially harmful effects on genetic material (DNA) which may
occur directly through the induction of permanent transmissible changes (mutations) in 17
the amount or structure of the DNA within cells. In vitro (artificial environment) and in vivo
(in living organisms) genotoxicity tests are conducted to detect compounds which induce
genetic damage directly or indirectly. These tests should enable hazard identification with
respect to damage to DNA and its fixation. Damage to DNA can occur at three levels:

Point mutations
Chromosomal mutations
Genomic mutations

The following standard test battery is generally expected to be conducted:

A test for gene mutation in bacteria (Ames Test).

An in vitro test with cytogenetic evaluation of chromosomal damage with mammalian
cells or an in vitro mouse lymphoma assay.
An in vivo test for chromosomal damage using rodent hematopoietic cells.

CARCINOGENICITY

Studies should be performed for all drugs that are expected to be clinically used for six
months or more than six month as well as for drugs used frequently in an intermittent
manner in the treatment of chronic or recurrent condition (Figs 1.6 and 1.7).

LIMITATIONS OF PRECLINICAL STUDIES

The purpose of preclinical work (animal pharmacology/toxicology testing) is to develop

adequate data to undergird a decision that it is reasonably safe to proceed with human
trials of the drug. Mice and rats are the most widely used host species for preclinical drug
development for a variety of important reasons. First, rodents have a comparatively short
life cycle. Rodent research studies can be time-compressed to evaluate disease
progression with or without therapeutic intervention. The short life cycle has also lent itself
to the development of many unique inbred strains. In addition, rodents, especially mice,
have been thoroughly characterized genetically and were the first animal species to be
TOC Index 
 genetically modified by transgenic and gene knock-out methods. The microbiology of rats
and mice has been extensively studied. Sophisticated husbandry, biosecurity practices,
and diagnostic testing effectively control environmental conditions and adventitious
Drug Discovery infections with pathogenic microorganisms that might cloud the interpretation of
and Clinical experimental findings.
Research
SK Gupta, Sushma
Srivastava

SECTION 1: DRUG DISCOVERY AND

DEVELOPMENT
 CHAPTER 1: Drug Discovery Process
 CHAPTER 2: Translational Research
 CHAPTER 3: Preclinical In Vitro Screening
Methods To Predict Drug Safety During
Drug Development Process
 CHAPTER 4: Drug Discovery And Development
Of Biologics
SECTION 2: BASIC PRINCIPLES OF CLINICAL
RESEARCH
 CHAPTER 5: Clinical Development Of New
Drugs Fig. 1.6: Carcinogenicity test done on mice

 CHAPTER 6: Regulations For Conducting

Clinical Trials In India
 CHAPTER 7: International Conference On

Fig. 1.7: Lab mice showing one with a tumor, the other treated with toxin cancer drug

Because genetic, environmental, and microbiological variables can be

comprehensively defined and carefully controlled, data from studies using rodents are
invaluable for characterizing disease conditions and therapies. Also, research reagents are
more widely available for biochemical testing of rodents then for testing other laboratory
animal species.

However, animal studies have certain limitations:

Not reliably predictive of human responses due to species variation and extrapolation,
Poor disease models, confounding effects of laboratory confinement, stress,
environment and food. 18

Repeatability/reproducibility is difficult
Expensive, time-consuming, and not amenable to high throughput. Toxicity studies are
costly in terms of animals and resources. For a product developed for chronic oral
therapy approximately 4,000 rats, 1300 mice, 100 rabbits, 50 guinea pigs and 160 dogs,
a total of nearly 5,000 animals are used. If the fetus and offspring from the reproductive
toxicity studies are included, the number doubles.
Attempting to translate research from animals to humans not as efficient as studying
humans directly—92% of drugs that pass preclinical testing, almost all in vivo animal-
based, fail in clinical trials.
Ethical issues in using animal for studies.

Predictive software and advanced in vitro technologies, have improved both the
efficiency of laboratory animal experiments and the quality of data to make decisions
about dosing with New Chemical Entity. It is very clear that animals are not the way to
explore libraries of 1 million or even 25,000 compounds. On the other hand, much can be
done when the number that survives the in silico and in vitro process reaches 1000 or
TOC Index  fewer. There are several very compelling new technologies now available that include:
 whole-body imaging, protein biomarkers monitoring by multichannel immunoassays, flow
cytometry of blood components, metabonomic component monitoring using in vivo
microdialysis and in vivo ultrafiltration, automated blood sampling for awake, freely-
Drug Discovery moving animals [pharmacokinetics (PK) and biomarkers] and parallel monitoring of
and Clinical physiological and electrocardiogram and psychological parameters. While not all of these
Research data sources can be enabled simultaneously, many of them can be accomplished
SK Gupta, Sushma
Srivastava automatically, raising the quality of information available from animal models dramatically.

FDA REQUIREMENTS FOR PRECLINICAL STUDIES

SECTION 1: DRUG DISCOVERY AND
DEVELOPMENT It is essential to ensure the quality and reliability of safety studies and this can be achieved
 CHAPTER 1: Drug Discovery Process by adhering to Good Laboratory Practices (GLP). The purpose of GLP is to obtain data on
 CHAPTER 2: Translational Research properties and safety of these substances with respect to human health and environment,
 CHAPTER 3: Preclinical In Vitro Screening to promote development of quality test data, such comparable data forms the basis of
Methods To Predict Drug Safety During
Drug Development Process mutual acceptance across organizations/countries, confidence in and reliability of data
 CHAPTER 4: Drug Discovery And Development from different countries will prevent duplicating tests, saves time, energy and resources.
Of Biologics
SECTION 2: BASIC PRINCIPLES OF CLINICAL For every 5000 drug compounds that enter preclinical testing in the United States, only
RESEARCH
about 5 will eventually be considered acceptable to test in humans. Of those final 5, only 1
 CHAPTER 5: Clinical Development Of New
Drugs drug may actually receive approval for use in patient care.
 CHAPTER 6: Regulations For Conducting
Clinical Trials In India Under FDA requirements, a sponsor must first submit data showing that the drug is
 CHAPTER 7: International Conference On reasonably safe for use in initial, small-scale clinical studies.

Depending on whether the compound has been studied or marketed previously, the
sponsor may have several options for fulfilling this requirement:
 Compiling existing nonclinical data from past in vitro laboratory or animal studies on the
compound
Compiling data from previous clinical testing or marketing of the drug in the United
States or another country whose population is relevant to the US population or
Undertaking new preclinical studies designed to provide the evidence necessary to
support the safety of administering the compound to humans.

At the preclinical stage, the FDA will generally ask, at a minimum that sponsors:

Develop a pharmacological profile of the drug;

Determine the acute toxicity of the drug in at least two species of animals
Conduct short-term toxicity studies ranging from 2 weeks to 3 months, depending on
the proposed duration of use of the substance in the proposed clinical studies.

Organization of Economic Cooperation and Development (OECD) framed guidelines

known as Good Laboratory Practice (GLP). GLP gives guidelines for animal testing facility
(Fig. 1.8), housing the animals, responsibilities and duties of personnel conducting the
animal studies, equipment, quality control, etc.

In India, the Committee for the Purpose of Control and Supervision for Experiments on
Animals (CPCSEA) ensures that the animal facilities are well maintained and experiments
are conducted as per internationally accepted norms. Organizations or individuals that use
animals for research, testing and teaching are required to have a code of ethical conduct
which sets out the policies and procedures which must be followed when using animals
for research, testing or teaching 19

TOC Index 
 Drug Discovery
and Clinical
Research
SK Gupta, Sushma
Srivastava

SECTION 1: DRUG DISCOVERY AND

DEVELOPMENT
 CHAPTER 1: Drug Discovery Process
 CHAPTER 2: Translational Research
 CHAPTER 3: Preclinical In Vitro Screening
Methods To Predict Drug Safety During Fig. 1.8: Animal testing facility according to good laboratory practice (GLP) requirements
Drug Development Process
It needs to specify provisions for compliance monitoring, the collection and
 CHAPTER 4: Drug Discovery And Development
Of Biologics maintenance of information on projects involving animals and animal management
SECTION 2: BASIC PRINCIPLES OF CLINICAL practices and facilities, and allow the fair and prompt handlings of complaints from any
RESEARCH
member of the animal ethics committee An Institutional Animal Ethical Committee (IAEC)
 CHAPTER 5: Clinical Development Of New
Drugs must be established by an institution (or group of organizations) which has an approved
 CHAPTER 6: Regulations For Conducting code of ethical conduct.
Clinical Trials In India
 CHAPTER 7: International Conference On A final report shall be prepared for each non clinical laboratory study and shall include:

Name and address of the facility performing the study and the dates on which the study
was initiated and completed.

 Objectives and procedures stated in the approved protocol, including any changes in the
original protocol.
Statistical methods employed for analyzing the data.
The test and control articles identified by name, chemical abstracts number or code
number, strength, purity, and composition or other appropriate characteristics.
Stability of the test and control articles under the conditions of administration.
A description of the methods used.
A description of the test system used. Where applicable, the final report shall include
the number of animals used, sex, body weight range, source of supply, species, strain
and sub strain, age, and procedure used for identification.
A description of the dosage, dosage regimen, route of administration, and duration.
A description of all circumstances that may have affected the quality or integrity of the
data.
The name of the study director, the names of other scientists or professionals, and the
names of all supervisory personnel, involved in the study.
A description of the transformations, calculations, or operations performed on the data,
a summary and analysis of the data, and a statement of the conclusions drawn from the
analysis.
The signed and dated reports of each of the individual scientists or other professionals
involved in the study.
The locations where all specimens, raw data, and the final report are to be stored.
A statement prepared and signed by the quality assurance unit and the final report
signed and dated by the study director.

CONCLUSION

Drug discovery and drug development is being revolutionized due to changes in

technology. Technologies like genomics, proteomics, high throughput screening and
structure-based design have enabled the process of drug discovery to evolve into a system
where new lead molecules can be rapidly found against novel, and difficult targets.
Preclinical testing of pharmaceuticals in animals has been instrumental in the
development of modern therapeutic regimens. Unquestionably, human quality of life (and
life expectancy) has flourished as a result of preclinical testing of drugs in animals.
However, drug development remains extremely challenging, with numerous obstacles to
TOC Index 
 overcome. The transition from activity in vitro (cell culture) to activity in vivo (animal
model) can be especially challenging. Obtaining pharmacokinetic behavior consistent with
the desired reactivity can be very difficult and the use of animals in toxicity testing has not
Drug Discovery progressed without controversy. Objections to animal testing have emphasized that the
and Clinical results obtained from animal tests do not always correlate well with human experience. 20
Research
SK Gupta, Sushma Attrition rates remain high, and generally only one out of ten thousand drugs tested
Srivastava
will enter clinical development and make it all the way to regulatory approval and find a
place in the market. Drugs most frequently fail in the clinic because of poor
pharmacokinetics or toxicity.

SECTION 1: DRUG DISCOVERY AND Despite the fact that drug development remains a long and arduous journey, the
DEVELOPMENT
prospect of genome-targeted individualization of therapy remains an extremely exciting
 CHAPTER 1: Drug Discovery Process
one. The possibility of personalized treatments (right drug for the right patient) based on
 CHAPTER 2: Translational Research
 CHAPTER 3: Preclinical In Vitro Screening the genomic or proteomic readout of the particular patient is now becoming a reality.
Methods To Predict Drug Safety During
Drug Development Process It is envisaged that more and more strategic alliances will be formed between
 CHAPTER 4: Drug Discovery And Development biotechnology and small pharmaceutical companies to make the most of all of the
Of Biologics
opportunities like human genome data (Fig. 1.9).
SECTION 2: BASIC PRINCIPLES OF CLINICAL
RESEARCH
During a new drug's early preclinical development, the sponsor's primary goal is to
 CHAPTER 5: Clinical Development Of New
Drugs determine that the product is reasonably safe for initial use in humans and that compound
 CHAPTER 6: Regulations For Conducting exhibits pharmacological activity that justifies commercial development. When a product
Clinical Trials In India
is identified as a viable candidate for further development, the sponsor then focuses on
 CHAPTER 7: International Conference On
collecting the data and information necessary to establish that the product will not expose
humans to unreasonable risks when used in limited, early-stage clinical studies.

FDA's role in the development of a new drug begins when the drug's sponsor (usually
 the manufacturer or potential marketer) having screened the new molecule for
pharmacological activity and acute toxicity potential in animals, wants to test its
diagnostic or therapeutic potential in humans. At that point, the molecule changes in legal
status under the Federal Food, Drug, and Cosmetic Act and becomes a new drug subject
to specific requirements of the drug regulatory system.

Before the sponsor proceeds to study a new drug in human, approval has to be
obtained by through Investigational New Drug Application.

Fig. 1.9: The drug discovery process

21

INVESTIGATIONAL NEW DRUG APPLICATION

An Investigational New Drug (IND) application is to provide the data showing that it is
reasonable to begin tests of a new drug on humans. In many ways, the IND application is
the result of a successful preclinical development program. The IND application is also the
vehicle through which a sponsor advances to the next stage of drug development known
as clinical trials (human trials). Current Federal law requires that a drug be the subject of
an approved marketing application before it is transported or distributed across state
lines. Because a sponsor will probably want to ship the investigational drug to clinical
investigators in many states, it must seek an exemption from that legal requirement. The
IND application is the means through which the sponsor technically obtains this
exemption from the FDA. The IND application shows results of previous experiments, how,
TOC Index 
 where and by whom the new studies will be conducted, the chemical structure of the
compound; how the compound is manufactured and any toxic effects in the animal
studies.
Drug Discovery
and Clinical There are two IND application categories:
Research 1. Commercial
SK Gupta, Sushma
Srivastava 2. Research (noncommercial)
There are three IND application types:

1. An investigator IND application: It is submitted by a physician who both initiates and

conducts an investigation, and under whose immediate direction the investigational
SECTION 1: DRUG DISCOVERY AND
DEVELOPMENT drug is administered or dispensed. A physician might submit a research IND
 CHAPTER 1: Drug Discovery Process application to propose studying an unapproved drug, or an approved product for a
 CHAPTER 2: Translational Research new indication or in a new patient population.
 CHAPTER 3: Preclinical In Vitro Screening
Methods To Predict Drug Safety During 2. Emergency use IND application: It allows the FDA to authorize use of an experimental
Drug Development Process drug in an emergency situation that does not allow time for submission of an IND
 CHAPTER 4: Drug Discovery And Development application. It is also used for patients who do not meet the criteria of an existing
Of Biologics
study protocol, or if an approved study protocol does not exist. In such a case, FDA
SECTION 2: BASIC PRINCIPLES OF CLINICAL
RESEARCH may authorize shipment of the drug for a specified use in advance of submission of
 CHAPTER 5: Clinical Development Of New an IND application.
Drugs
3. Treatment IND application: It is submitted for experimental drugs showing promise in
 CHAPTER 6: Regulations For Conducting
Clinical Trials In India clinical testing for serious or immediately life-threatening conditions while the final
 CHAPTER 7: International Conference On clinical work is conducted and the FDA review takes place. A drug that is not
approved for marketing may be under clinical investigation for a serious or
immediately life-threatening disease condition in patients for whom no comparable
or satisfactory alternative drug or other therapy is available. The purpose is to
 facilitate the availability of promising new drugs to desperately ill patients as early in
the drug development process as possible, before general marketing begins, and to
obtain additional data on the drug's safety and effectiveness. In the case of a serious
disease, a drug ordinarily may be made available for treatment use during phase III
investigations or after all clinical trials have been completed. In the case of an
immediately life-threatening disease, a drug may be made available for treatment use
earlier than phase III, but ordinarily not earlier than phase II.

The IND application must contain information in three broad areas:

Animal pharmacology and toxicology studies: Preclinical data to permit an assessment
as to whether the product is reasonably safe for initial testing in humans.
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 can adequately produce and
supply consistent batches of the drug.
Clinical protocols and investigator information: Detailed protocols for proposed clinical
studies to assess whether the initial-phase trials will expose subjects to unnecessary
risks. Also, information on the qualifications of clinical investigators 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
research subjects, to obtain review of the study by an institutional review board (IRB),
and to adhere to the investigational new drug regulations. 22

Sponsor files the IND application in Form 1571 to the FDA for review once successful
series of preclinical studies are completed.

Along with the IND application, the sponsor submits the statement of the Investigator
(Investigator's undertaking) in Form 1572.

Once the IND application is submitted, the sponsor must wait 30 calendar days before
initiating any clinical trials. If the sponsor hears nothing from CDER (Center for Drug
Evaluation and Research), then on day 31 after submission of IND application, the study
may proceed as submitted. The CDER is a division of the FDA that reviews New Drug
Applications to ensure that the drugs are safe and effective.

During this time, FDA has an opportunity to review the IND application for safety to
assure that research subjects will not be subjected to unreasonable risk.

TOC Index 
 Medical review: During the IND application review process, the medical reviewer
evaluates the clinical trial protocol to determine: (1) if the participants will be protected
from unnecessary risks; and (2) if the study design will provide data relevant to the
Drug Discovery safety and effectiveness of the drug. Under Federal regulations, proposed phase I
and Clinical studies are evaluated almost exclusively for safety reasons. Since the late 1980's, FDA
Research reviewers have been instructed to provide drug sponsors with greater freedom during
SK Gupta, Sushma
Srivastava phase I, as long as the investigations do not expose participants to undue risks. In
evaluating phase II and III investigations, however, FDA reviewers also must ensure that
these studies are of sufficient scientific quality to be capable of yielding data that can
support marketing approval.
SECTION 1: DRUG DISCOVERY AND Chemistry reviewers: They address issues related to drug identity, manufacturing
DEVELOPMENT
control, and analysis. The reviewing chemist evaluates the manufacturing and
 CHAPTER 1: Drug Discovery Process
processing procedures for a drug to ensure that the compound is adequately
 CHAPTER 2: Translational Research
 CHAPTER 3: Preclinical In Vitro Screening reproducible and stable. At the beginning of the chemistry and manufacturing section,
Methods To Predict Drug Safety During the drug sponsor should state whether it believes the chemistry of either the drug
Drug Development Process
substance or the drug product, or the manufacturing of either the drug substance or the
 CHAPTER 4: Drug Discovery And Development
Of Biologics drug product, present any signals of potential human risk. If so, these signals should be
SECTION 2: BASIC PRINCIPLES OF CLINICAL discussed, with steps proposed to monitor for such risks. In addition, sponsors should
RESEARCH
describe any chemistry and manufacturing differences between the drug product
 CHAPTER 5: Clinical Development Of New
Drugs proposed for clinical use and the drug product used in the animal toxicology trials that
 CHAPTER 6: Regulations For Conducting formed the basis for the sponsor's conclusion that it was safe to proceed with the
Clinical Trials In India proposed clinical study.
 CHAPTER 7: International Conference On
Pharmacology/toxicology review: This team is staffed by pharmacologists and
toxicologists who evaluate the results of animal testing and attempt to relate animal
drug effects to potential effects in humans. This section of the application should
 contain, if known:
A description of the pharmacologic effects and mechanism(s) of action of the drug in
animals
Information on the absorption, distribution, metabolism, and excretion of the drug.
The regulations do not further describe the presentation of these data, in contrast to
the more detailed description of how to submit toxicology data. A summary report,
without individual animal records or individual study results, usually suffices. An
integrated summary of the toxicology effects of the drug in animals and in vitro the
particular studies needed depend on the nature of the drug and the phase of human
investigation. When species specificity, immunogenicity, or other considerations
appear to make many or all toxicological models irrelevant, sponsors are encouraged
to contact the agency to discuss toxicological testing.

Statistical analysis: The purpose of these evaluations is to give the medical officers a
better idea of the power of the findings to be extrapolated to the larger patient
population in the country.
Safety review: Following review of an initial IND application submission, CDER (Center
for Drug Evaluation and Research) has 30 calendar days in which to decide if a clinical
hold is necessary (i.e., if patients would be at an unacceptable risk or if CDER does not
have the data to make such a determination) (Flow Chart 1.1).

Generally, drug review divisions do not contact the sponsor if no concerns arise with
drug safety and the proposed clinical trials. If the sponsor hears nothing from CDER
(Center for Drug Evaluation and Research), then on day 31 after submission of the IND
application, the study may proceed as submitted. The sponsor is notified about the
deficiencies through a clinical hold. A clinical hold is issued by the FDA to the sponsor to
delay a proposed clinical Investigation or to suspend a clinical Investigation. 23

TOC Index 
 Drug Discovery
and Clinical
Research
SK Gupta, Sushma
Srivastava

SECTION 1: DRUG DISCOVERY AND

DEVELOPMENT
 CHAPTER 1: Drug Discovery Process
 CHAPTER 2: Translational Research
 CHAPTER 3: Preclinical In Vitro Screening
Methods To Predict Drug Safety During
Drug Development Process
 CHAPTER 4: Drug Discovery And Development
Of Biologics
SECTION 2: BASIC PRINCIPLES OF CLINICAL
RESEARCH
 CHAPTER 5: Clinical Development Of New
Drugs
 CHAPTER 6: Regulations For Conducting
Clinical Trials In India
Flow chart 1.1: IND Application Review Process*While sponsor answers any deficiencies
 CHAPTER 7: International Conference On

SPONSOR NOTIFICATION
 Once a clinical hold is placed on a commercial IND application, the sponsor will be notified
immediately by telephone by the division director. For both individual and commercial IND
applications, the division is required to send a letter within five working days following the
telephone call. The letter should describe the reasons for the clinical hold, and must bear
the signature of the division director (or acting division director).

The grounds for imposition of Clinical Hold are as follows:

Human subjects are or would be exposed to an unreasonable and significant risk of

illness or injury.
Clinical investigators named in IND application are not qualified.
Investigator brochure is misleading, erroneous or materially incomplete.
IND does not contain sufficient information to assess risks.
Protocol is deficient to meet objective of trial.
Mechanism that CDER uses when it does not believe, or cannot confirm that the study
can be conducted.
CDER will contact sponsor within 30 days initial review period.

The sponsor may then respond to CDER by sending an “IND CLINICAL HOLD
RESPONSE” letter to the division. To expedite processing, the letter must be clearly
identified as an “IND CLINICAL HOLD RESPONSE” letter. 24

The division then reviews the sponsor's response and decides within 30 days as to
whether the hold should be lifted. If the division does not reply to the clinical hold response
within 30 calendar days, the division director will telephone the sponsor and discuss what
is being done to facilitate completion of the review.

If it is decided that the hold will not be lifted, the hold decision is automatically sent to
the office director for review. The office director must decide within 14 calendar days
whether or not to sustain the division's decision to maintain the clinical hold. If the
decision is made to lift the hold, the division telephones the sponsor, informs them of the
decision, and sends a letter confirming that the hold has been lifted. The letter will be sent
within 5 working days of the telephone call. However, the trial may begin once the decision
has been relayed to the sponsor by telephone.

SPONSOR WILL BE NOTIFIED

TOC Index 
 If other deficiencies are found in an IND application that the review division determines are
not serious enough to justify delaying clinical studies, the division may either telephone or
forward a deficiency letter to the sponsor. In either case, the division informs the sponsor
Drug Discovery that it may proceed with the planned clinical trials, but that additional information is
and Clinical necessary to complete or correct the IND application file.
Research
SK Gupta, Sushma
Srivastava
STUDY ONGOING

Once the CDER's 30-day initial review period expires, clinical studies can be initiated,
unless a clinical hold has been placed. Beyond the 30-day review period for an IND
SECTION 1: DRUG DISCOVERY AND
DEVELOPMENT application, subsequent clinical trials may begin immediately upon submission of the
 CHAPTER 1: Drug Discovery Process clinical protocol to the IND application (i.e., there is no 30-day waiting period for
 CHAPTER 2: Translational Research subsequent clinical trials after the submission of the first clinical trial protocol). If the
 CHAPTER 3: Preclinical In Vitro Screening sponsor was notified of deficiencies that were not serious enough to warrant a clinical
Methods To Predict Drug Safety During
Drug Development Process hold, the sponsor addresses these deficiencies while the study proceeds.
 CHAPTER 4: Drug Discovery And Development
Of Biologics
SECTION 2: BASIC PRINCIPLES OF CLINICAL EXPLORATORY INVESTIGATIONAL NEW DRUG STUDIES
RESEARCH
 CHAPTER 5: Clinical Development Of New
Drugs Exploratory IND studies are intended to provide clinical information for a new drug
 CHAPTER 6: Regulations For Conducting candidate at a much earlier phase of drug development. These studies help to identify the
Clinical Trials In India
best candidates for continued development and eliminate those lacking promise. These
 CHAPTER 7: International Conference On
clinical trials occur very early in phase I, involve very limited human exposure, and have no
therapeutic intent. Exploratory IND studies are conducted prior to the traditional dose
escalation, safety, and tolerance studies and provide important information on
 pharmacokinetics (PK) and bioavailability of a candidate drug.

In April 2005, the FDA released a draft guidance for Exploratory IND studies that
clarifies preclinical and clinical approaches that should be considered when planning
exploratory IND studies in humans. As part of FDA's “Critical Path Initiative”, this process is
a new tool available to the industry that enables a faster, more cost-effective path to early
clinical development.

BIBLIOGRAPHY
1. Abbreviated New Drug Application (ANDA) Process for Generic Drugs

Http://[Link]/Cder/Regulatory/Applications/[Link]. (Accessed on 20/07/2008).

2. Bianca Piachand. 2002. Challenges facing the pharmaceutical industry. Http://[Link]/

3. CDER Manual of Policies and Procedures (MaPP). Http://[Link]/Cder/[Link]. (Accessed on

23/07/2008).

4. Code of Federal Regulations (CFR). Http://[Link]/Cfr/[Link]. (Accessed on 22/07/2008).

5. Dimasi JA. Risks in new drug development: Approval success rates for investigational drugs. Clin Pharmacol

Ther. 2001;69:297–307.

6. EMEA. Eudravigilance data analysis system. 2006. [Link]

7. EMEA. Transitional measures for submission of PSURs for centrally authorized medicinal products for

human and veterinary use. 2005. [Link].

8. FDA. Reporting adverse experience to FDA. 2007. [Link]/Medwatch/How/Htm.

9. Genevieve D, Buyse M. Clinical research after drug approval. What is needed and what is not. Drug

Information. 1999;33:627–34. 25

10. Giersiefen H, Hilgenfeld R, Hillisch A. Modern methods of drug discovery: An introduction. In: Modern

methods of drug discovery. Ed. Hilgenfeld R and Hillisch A; 2004. pp. 1–18.

11. ICH Guidance for Industry, S7A Safety Pharmacology Studies for Human Pharmaceuticals. Available on

Http://[Link]/Cber/Gdlns/[Link] (Accessed on 30/07/2008).

12. IND Forms and Instructions

Http://[Link]/Cder/Regulatory/Applications/Ind_page_1.Htm#IND%20Forms. (Accessed on

20/07/2008).

13. Investigational New Drug (IND) Application Process,

Http://[Link]/Cder/Regulatory/Applications/Ind_page_1.Htm. (Accessed on 23/07/2008).

TOC Index 
 14. Jens Eckstein. ISOA/ARF Drug Development Tutorial. Available on

Http://[Link]/Drg/Tut/[Link] (Accessed on 30/07/2008).

15. Lindquist M. Data quality management in pharmacovigilance In: Rosie Stather (Ed). Drug Safety, 2005.
Drug Discovery
and Clinical 16. Mant T. Early phase studies, pharmacokinetics and adverse drug reactions. In: Giovanna ID, Hayes G (Eds).
Research Principles of Clinical Research; 2001. pp. 117–60.
SK Gupta, Sushma
Srivastava 17. Michelle DG, Mike IW, McDonald E, Ian Judson, Paul Workman. The contemporary drug development

process: advances and challenges in preclinical and clinical development. Progress in Cell Cycle Research.

2003;5:145–58.

18. Ministry of Health and Family Welfare (n.d.) National pharmacovigilance program. [Link]
SECTION 1: DRUG DISCOVERY AND
DEVELOPMENT 19. Mishra SK. Drug development and discovery. In: Gupta SK (Ed). Basic Principles of Clinical Research and
 CHAPTER 1: Drug Discovery Process Methodology, 2007.
 CHAPTER 2: Translational Research
 CHAPTER 3: Preclinical In Vitro Screening 20. Naidu MUR, Usharani P. Drug development and discovery. In: Gupta SK (Ed). Basic Principles of Clinical
Methods To Predict Drug Safety During Research and Methodology, 2007.
Drug Development Process
 CHAPTER 4: Drug Discovery And Development 21. New Drug Application (NDA) Process. Http://[Link]/Cder/Regulatory/Applications/[Link].
Of Biologics
(Accessed on 23/07/2008).
SECTION 2: BASIC PRINCIPLES OF CLINICAL
RESEARCH 22. Posner J. Exploratory development. In: Griffin JP, O'Grady J (Eds). The Textbook of Pharmaceutical Medicine;
 CHAPTER 5: Clinical Development Of New
2005. pp. 170–213.
Drugs
 CHAPTER 6: Regulations For Conducting 23. Ratti E, Trist D. Continuing evolution of the drug discovery process in the pharmaceutical industry. Pure Appl
Clinical Trials In India
Chem. 2001;73(1):67–75.
 CHAPTER 7: International Conference On
24. Rolan P. Clinical pharmacokinetics. In: Griffin JP, O'Grady J (Eds). The Textbook of Pharmaceutical Medicine;

2005. pp. 214–46.

 25. Ross Tonkens. An overview of the drug development process. 2005. The Physician executive.

26. Schedule Y (Amended Version)-CDSCO, Appendix III of Schedule Y, Animal Toxicity. Available on

Http://[Link]/Html/Schedule-Y%20(Amended%20Version-2005)%[Link]. (Accessed on

23/07/2008).

27. Schedule Y (Amended Version)-CDSCO, Appendix IV of Schedule Y, Animal Pharmacology. Available on

Http://[Link]/Html/Schedule-Y%20(Amended%20Version-2005)%[Link]. Accessed on

27/07/2008).

28. Spilker B. Classification and description of phases I, II, III Designs. In: Williams L, Wilkins (Eds). Guide to

Clinical Trials; 1991. pp. 27–43.

29. Spilker B. Classification and description of phases IV post marketing study designs. In: Williams L and

Wilkins (Eds). Guide to Clinical Trials; 1991. pp. 44–58.

30. The process of Drug Development. Available on Http://[Link]/Courseware/Drugs/[Link]

(Accessed on 25/07/2008).

31. Tweats DJ, Scales MDC. Toxicity testing. In: Griffin JP and O'Grady J (Eds). The Textbook of Pharmaceutical

Medicine; 2005. pp. 128–69.

32. Workflow driven Pharmacovigilance software. Http://[Link]/[Link]. Downloaded

on 20th August 2008.

TOC Index 