New Drug Development

4/10/2020 JaypeeDigital | eBook Reader
Drug Discovery
and Clinical
Research
SK Gupta
New Drug Development CHAPTER 1

 CHAPTER 1: New Drug Development
INTRODUCTION TO DRUG DEVELOPMENT
 DRUG DISCOVERY PROCESS

 PRECLINICAL DRUG DEVELOPMENT
 CLINICAL DEVELOPMENT
 PHARMACOVIGILANCE
 REGULATORY APPROVALS FOR
REGISTRATION OF DRUGS Drug development is a scienti c endeavor which is highly regulated due to public
 CLINICAL DATA MANAGEMENT health concern. A promising new molecule identi ed in drug discovery has to go
 CHAPTER 2: Drug Discovery And Developmen
through the complex and time-consuming process of drug development before it
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Of Biologics Index 
 CHAPTER 3: Clinical Development Of New
becomes available to patients.
Drugs
 CHAPTER 4: Phase 0 Trials In Cancer Drug The discovery process begins with an understanding of the disease
Development mechanism(s) or cause of the disease and discovery (or identi cation) of genes
 CHAPTER 5: Bioethics In Clinical Research and/or proteins involved in causing certain diseases. The identi cation of
genes/proteins responsible for the disease condition is referred to as target
 identi cation. These identi ed targets (gene/proteins) are the potential targets
for drugs to interact and to bring about a bene cial effect in a patient. Next step
is target validation, where certain studies are performed to con rm 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 identi ed.
After target identi cation and validation, a lead compound needs to be

identi ed. A lead compound is a substance which has the greatest potential for
successful interaction with the identi ed target. A lead compound is generally
selected from libraries containing thousands of compounds. This step of the
drug discovery process is known as lead identi cation. After the lead compound
is identi ed it goes through an optimization process wherein the structure of the
compound may be altered to make it safe and e cacious. Once this process is
completed the compound is tested rst 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 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 in to the factors that have signi cant impact on the
process and should form basis for allocation of resources.
The decision to develop a new drug by a pharmaceutical company depends

on the various factors and one of the key factors is to review and nd out the
unmet medical needs in the speci c therapeutic area in which the company is
interested due to strategic reasons. In some cases there may be industry –
university or industry – government scienti c institutes collaboration that may
help to develop a new molecule. 2
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Table 1.1 Cost and time involved in drug discovery

Target Discovery
Drug Discovery 2.5 years ↓ 4%

and Clinical
Research Lead generation and lead optimization
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3.0 years ↓ 15%
Preclinical development
1.0 year ↓ 10%

Phase I, II and III clinical trials

6.0 years ↓ 68%
 CLINICAL DEVELOPMENT FDA review and approval
 REGULATORY APPROVALS FOR 1.5 years ↓ 3%
REGISTRATION OF DRUGS
 CLINICAL DATA MANAGEMENT Drug to the market 14 years ↓
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Of Biologics Index  ₠ 880 million
Drugs Source: PAREXEL. Parexel's Pharmaceutical R & D Statistical Sourcebook, 2001; p.96
 CHAPTER 4: Phase 0 Trials In Cancer Drug
Development
New and interesting ndings may also come from university, institutes and the
 CHAPTER 5: Bioethics In Clinical Research
lead may be taken over by the pharmaceutical companies for further research.
 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 bene t 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 signi cant 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 of 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 3
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 their origins in serendipity, i.e. discovery by accident/chance. Lead
molecules were found by chance or from screening the chemical diversity
Drug Discovery available. These were then optimized by medicinal chemists to produce
and Clinical candidates, which were passed to development and eventually into the market.
Research
This method led to discovery of drugs such as chlorpromazine, meprobamate,
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and benzodiazepines (chlordiazepoxide, diazepam) all of which have gone on to
become successful medicines.
However, this approach suffered from lack of su cient molecules with high
enough structural diversity, and the common use of animal models meant that
INTRODUCTION TO DRUG DEVELOPMENT other factors such as absorption, metabolism, brain penetration, and
 DRUG DISCOVERY PROCESS pharmacokinetics had profound effects on the number of active molecules
 PRECLINICAL DRUG DEVELOPMENT found. In addition, many molecules that showed activity in the models were of
 CLINICAL DEVELOPMENT unknown mechanism. This greatly impeded the development of back-ups when
 PHARMACOVIGILANCE the lead failed due to toxicity or poor pharmacokinetics.
To combat these problems, a more rational approach was developed based
 CLINICAL DATA MANAGEMENT
around the structure of the agonist (i.e. hormones and neurotransmitters) and its
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Of Biologics Index  receptor. This was set against a background of studying biological/physiological
 CHAPTER 3: Clinical Development Of New systems in animal tissues. Thus, knowledge around molecular determinants that
Drugs
contribute to a nity and e cacy enabled a generation of speci c and potent
Development
agonists and antagonists to be developed.

STEPS IN DRUG DISCOVERY


The advent of molecular biology, coupled with advances in screening and
synthetic chemistry technologies, has allowed a combination of both knowledge
around the receptor and random screening to be used for drug discovery.
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 is 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 takes many more years of work to turn this basic understanding of
what causes a disease into a new treatment.
The disease mechanism de nes 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. 4
Fig. 1.1: Steps in new drug development
It also predicts a change of the disease pattern and its implications.
Disease mechanisms can be broadly classi ed into the following groups:
Defects in distinct genes—genetic disorders
Drug Discovery Infection by bacteria, fungi, viruses, protozoa or worms

and Clinical Immune/autoimmune disease
Research
Trauma and acute disease based on injury or organ failure
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Multicausal disease
The identi cation of new and clinically relevant molecular targets for drug
intervention is of outstanding importance to the discovery of innovative drugs.

It is estimated that up to 10 genes contribute to multifactorial diseases,
which are linked to another 5 to 10 gene products in physiological and
 PRECLINICAL DRUG DEVELOPMENT pathophysiological circuits which are also suitable for intervention with drugs.
 CLINICAL DEVELOPMENT Environmental factors such as diet, exposure to toxins, trauma, stress, and other
 PHARMACOVIGILANCE life experiences are assumed to interact with genetic susceptible factors to
 REGULATORY APPROVALS FOR 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
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 CHAPTER 3: Clinical Development Of New potential to exploit at least 10 times the number of targets in the future. Targets
Drugs for therapeutic intervention can be broadly classi ed into these categories:
Development Receptors
 CHAPTER 5: Bioethics In Clinical Research Proteins and enzymes
DNA
 RNA and ribosomal targets.
Methods used for target identi cation include classical methods such as
cellular and molecular biology and newer technique such as genomics and
proteomics. 5
In the classical method, animal and human cell lines are used to identify the
potential target of drug action. Two key research avenues involve the enzymes
that metabolize the molecules (drugs) and proteins that act as receptors.
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 arti cial environment)

usually precedes the validation of the therapeutic concept in vivo (in a living
organism); together this de nes 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 pro le 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 identi ed rapidly.
In vivo models: In vivo testing involves testing in whole animals. It assesses

both pharmacology and biological e cacy in parallel. Animal models that are
capable of mimicking the disease state (e.g. animals mimicking diabetes), by
Drug Discovery adding/ modifying or deleting certain genes are used. These animal models
and Clinical are referred to as knock-in and knock-out animal models.
Research
SK Gupta Along with validation of the target it is essential to predict the “druggability”
of the target. The “druggability” of a given target is de ned 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).
 CHAPTER 1: New Drug Development 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-protein coupled receptors (GPCRs), and a
 PHARMACOVIGILANCE sizable number of drugs prescribed today hit this particular class. Therefore, the
 REGULATORY APPROVALS FOR GPCR target type is considered druggable. 6
 CLINICAL DATA MANAGEMENT In summary, target validation is one of the bottlenecks in drug discovery, as
 CHAPTER 2: Drug Discovery And Developmen this phase is less adaptable to automation. Careful validation of target not only
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with respect to relevance to disease but also druggability will reduce the failure
Drugs rate and increase the e ciency of drug discovery.
Development
 CHAPTER 5: Bioethics In Clinical Research LEAD IDENTIFICATION
 In this phase, compounds which interact with the target protein and modulate its
activity are identi ed.
The lead identi cation process starts with the development of an assay
which will be followed by screening of compound libraries. The quality of an
assay determines the quality of data. The assay used should ful ll these criteria:
relevance, reliability, practicability, feasibility, automation and cost-effectiveness.
Primary screens will identify hits. Subsequently, con rmation screens and
counter screens will identify leads out of the pool of hits. This winnowing
process is commonly referred to as “hits-to-leads.”
The success of screening depends on the availability of compounds, as well

as their 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 rst, followed by isolation and identi cation of active
compounds
Collections (Random) of discreetly synthesized compounds
Focused libraries around certain pharmacophores
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 con rmed hits. Depending on the assay, hit rates
typically range between 0.1 and 5 percent. 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 rst assay, on a different day. If a compound exhibits
the same activity within a statistically signi cant range, it is termed a con rmed
hit, which can proceed to dose-response screening.
Drug Discovery Establishing a dose-response relationship is an important step in hit

and Clinical veri cation. It typically involves a so-called secondary screen. In the secondary
Research screen, a range of compound concentrations usually prepared by serial dilution 7
SK Gupta 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
INTRODUCTION TO DRUG DEVELOPMENT particular drug is needed to inhibit a given biological process by half. EC50 (Half
 DRUG DISCOVERY PROCESS maximal effective concentration) refers to the concentration of a drug or
 PRECLINICAL DRUG DEVELOPMENT antibody which induces a response halfway between the baseline and
 CLINICAL DEVELOPMENT maximum. The EC50 of a graded dose response curve therefore represents the
 PHARMACOVIGILANCE concentration of a compound where 50% of its maximal effect is observed.
Con rmed hits proceed to a series of counterscreens. These assays usually
include drug targets of the same protein or receptor family; for example, panels
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Of Biologics Index  of GPCRs (G-protein coupled receptors,) or kinases. In cases where selectivity
 CHAPTER 3: Clinical Development Of New between subtypes is important, counterscreens might include a panel of
Drugs
homologous enzymes, different protein complexes, or heterooligomers.
Development
Counterscreens pro le the action of a con rmed hit on a de ned spectrum of
 CHAPTER 5: Bioethics In Clinical Research biological target classes. The number and stringency of counterscreens can vary
widely and depend on the drug target.
 One of the goals throughout the discovery of novel drugs is to establish and
con rm the mechanism of action (MOA). In an ideal scenario, the MOA remains
consistent from the level of molecular interaction of a drug molecule at the
target site through the physiological response in a disease model, and ultimately
in the patient.
The tools used for lead identi cation are: High throughput screening, in-
silico/virtual screening, NMR-based screening and X-ray crystallography.
High-throughput screening (HTS) aims to rapidly assess the activity of a large

number of compounds or extracts on a given target. Entire in-house
compound libraries with millions of compounds can be screened with a
throughput of 10,000 (HTS) up to 100,000 compounds per day (ultra-HTS)
using robust test assays.
Virtual (in-silico) screening sifts through large numbers of compounds based
on a user-de ned set of selection criteria. Selection criteria can be as simple
as a physical molecular property such as molecular weight or charge, a
chemical property such as number of heteroatoms, number of hydrogen-bond
acceptors or donors. Selection criteria can be as complex as a three-
dimensional description of a binding pocket of the target protein, including
chemical functionality and solvation parameters. In-silico screening can
involve simple ltering based on static selection criteria (i.e. molecular
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 lls the gap between HTS and virtual screening. This
method combines the random screening approach with the rational structure-
based approach to lead discovery. 8
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 identi cation by means of X-ray
crystallography is essential for the next stage of drug development which is
lead optimization.
Following are the criteria for hits to be regarded as leads:
Pharmacodynamic properties, e.g. e cacy, potency and selectivity in vitro and

in vivo
Drug Discovery
and Clinical Physicochemical properties, e.g. Lipinski's “rule of ve”
Research Pharmacokinetic properties, e.g. permeability in the Caco-2 assays
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Chemical optimization potential
Patentability.
 CHAPTER 1: New Drug Development LEAD OPTIMIZATION

Lead optimization is a complex, non-linear process of re ning the chemical
 CLINICAL DEVELOPMENT structure of a con rmed hit to improve its drug characteristics with the goal of
 PHARMACOVIGILANCE producing a preclinical drug candidate. This stage constitutes the tightest
 REGULATORY APPROVALS FOR bottleneck in drug discovery.
 CLINICAL DATA MANAGEMENT Lead optimization employs a combination of empirical, combinatorial, and
 CHAPTER 2: Drug Discovery And Developmen rational approaches that optimize leads through a continuous, multi-step
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process based on knowledge gained at each stage. Typically, one or more
Drugs con rmed hits are evaluated in secondary assays, and a set of related
 CHAPTER 4: Phase 0 Trials In Cancer Drug compounds, called analogs, are synthesized and screened.
Development
 CHAPTER 5: Bioethics In Clinical Research 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 “druglikeness.” Medicinal chemists change the
lead molecules based on these results in order to optimize pharmacological
properties such as 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.
Pharmacokinetics (PK)/pharmacodynamics (PD)/absorption, distribution,

metabolism, Excretion (ADME) studies are an integral part of lead optimization.
They feedback into the medicinal chemistry effort aiming to optimize the
physicochemical properties of new leads in terms of minimal toxicity and side
effects, as well as of maximum e cacy toward disease. PK/PD/ADME studies
rely heavily on analytical methods and instrumentation. 9
Fig. 1.2: Depicts use of in-silico technology in various stages of selection of a drug
candidateSource:Www.Scfbio-Iitd.Res.In/Image/Insilicodrug.JPG
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.
These data are then fed into the next optimization cycle. The lead
Drug Discovery optimization process continues for as long as it takes to achieve a de ned drug
and Clinical pro le that warrants testing of the new drug in humans (Fig. 1.2).
Research
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LEAD OPTIMIZATION—FORMULATION AND DELIVERY
Formulation development: It is the process of turning an active compound into a

form and strength suitable for human use.
INTRODUCTION TO DRUG DEVELOPMENT Formulation and delivery of drugs is an integral part of the drug discovery
 DRUG DISCOVERY PROCESS and development process. Indeed, formulation problems and solutions in uence
the design of the lead molecules; they feed back into the iterative lead
optimization cycle, as well as the preclinical and clinical evaluations.
 REGULATORY APPROVALS FOR 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
 CHAPTER 2: Drug Discovery And Developmen as toxicity pro le, needs to be documented in the IND (investigational new drug)
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Of Biologics Index  application. In fact, side effects such as local irritation or allergic reactions are
 CHAPTER 3: Clinical Development Of New often attributable to drug formulation, not the active pharmaceutical ingredient
Drugs
(API).
Development
Formulation substances might exhibit different biological activity than the
actual drug. 10
 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 e cacy or
safety pro les.

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: This department is responsible for nding new

compounds and assuring that they are safe enough to test in humans.
Medicinal chemists: Their 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
su cient for advanced testing.
Pharmacology/molecular biology/screening: This department examines each
new chemical entity (NCE) in a set of high throughput screens.
Safety evaluation: It demonstrates that the NCE and its metabolites do not
accumulate and do not cause harm during short-term administration.
Formulations research: It develops 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 new drug must reach and maintain a level
su cient to sustain its biological effect; these studies are initially conducted
on animals to establish the doses for human studies.
Process research: It manufactures the NCE in su cient quantity for advanced
testing, dosage form development.
Legal affairs: It writes and les the patents necessary to protect a company's
inventions.
Research administration: It collects the material generated by all the
departments and formats it into a request for exemption so that the NCE can
be tested in humans. This submission is the investigational new drug (IND).
NEED FOR SYSTEMATIC APPROACH IN NEW DRUG DISCOVERY

Drug Discovery
and Clinical The pharmaceutical industry is operating in a world where medicines have to
Research add real value in an environment in which costs are under constant pressure.
SK Gupta This high cost is causing the evolution of the drug discovery process so that
high percentages of e cient pipeline molecules are delivered to market quickly.
The following needs to be considered to have a systematic approach in drug
discovery. 11

UNMET MEDICAL NEEDS
 CLINICAL DEVELOPMENT A constant driver for developing new medicines has always been the unmet
 PHARMACOVIGILANCE medical need. However, there are now strong pressures to treat the underlying
 REGULATORY APPROVALS FOR cause of the disease rather than to 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
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Of Biologics Index  initiated in technologies such as noninvasive imaging, clinical genetics and
 CHAPTER 3: Clinical Development Of New genomics will increase. This is now assured with the publication of the human
Drugs
genome.
Development
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 PET (Positron emission tomography) and
fMRI (Functional magnetic resonance imaging), application of technologies like
clinical genetics and genomics will strengthen the understanding of the
correlation between disease and speci c receptors.
Clinical genetics networks are being put into place to allow su cient
information on probands (proband denotes a particular subject (person or
animal) rst 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 identi cation 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 speci c gene products and/or pathways as new targets that would not
have been previously identi ed. Importantly, they will be born out of human data,
so again adding to the level of con dence in the validity of the target.

ATTRITION
Attrition is another driver for systematic approach in drug discovery for overall
success rate. Attrition has remained static despite the investment in the new
technologies. This re ects the fact that good molecules need more than potency
and selectivity to be successful, and it is in these areas where technology has
been concentrating in the last few years. The challenges ahead lie in reducing
the risk of not obtaining e cacy in humans, and in increasing the developability
of the molecules.
E cacy: Many new mechanisms fail when they get into humans through lack of
e cacy. This is one of the risks that the industry takes when developing such 12
molecules. One way to diminish risk is to get better validation in humans (proof-
of-concept, i.e. proof of e cacy) as soon as possible. The use of imaging,
genetics, and genomics has already been discussed earlier as a way to help
build early con dence in the target.
Drug Discovery It is now recognized that fast decision making saves money and allows
and Clinical resources to be more effectively used. Proof-of-concept is generally obtained in
Research phase III. Killing compounds in phase III is extremely costly; therefore, it is a
SK Gupta disadvantage to obtain proof of concept at such a late stage. Thus, simple proof-
of-concept studies (POCs) are being sought in phase I or phase II. If POC, were
to be obtained during phase I and phase II instead of phase III, it will provide
sponsors with su cient evidence which can be used to assess the clinical and
commercial potential of the drug and, in turn, eliminate potential failures from
INTRODUCTION TO DRUG DEVELOPMENT the drug discovery pipeline.
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
 PHARMACOVIGILANCE greater use of imaging, proteomics and genetics in helping to identify the right
 REGULATORY APPROVALS FOR patient group.
 CLINICAL DATA MANAGEMENT In the meantime, a better balance of novel molecules and those that are
 CHAPTER 2: Drug Discovery And Developmen precedented will be seen in the drug discovery portfolio. This will mean that a
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higher proportion of molecules will not fail for e cacy. However, this strategy
Drugs creates its own problems in that to be successful in the marketplace the
 CHAPTER 4: Phase 0 Trials In Cancer Drug molecule will need to be differentiated from those already present. To do this in
Development
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 eld of predictive algorithms, and
P zer has developed tool known as the “rule of 5”. This is an awareness tool for
medicinal chemists that suggests 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 x poor developability by formulation,

pharmaceutical development will become more actively engaged in alternative
formulations and delivery systems during the lead optimization phase. The trend 13
towards 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 speed up 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.
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 random screening and those within the process of lead
optimization. As mentioned above, continual automation of developability
criteria will also speed up the process by selecting compounds with a high
Drug Discovery probability of succeeding. This raises the concept that speed in each phase
and Clinical should not always be the major driver. A candidate for development goes
Research
forward with all of its associated baggage. Fixing problems become costly and
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may lead to a suboptimal product that cannot ful ll its medical and commercial
potential. Thus, spending time choosing the right candidate will have major
bene ts downstream, both in terms of speed and value. The same concept
applies to development candidates in phase III. Differentiation may not be
 CHAPTER 1: New Drug Development obvious if the mechanism is precedented with another marketed product. Thus,
INTRODUCTION TO DRUG DEVELOPMENT differentiation will become a challenge, which potentially will increase the time in
phase III. To aid in this process and help in choosing which differentiators to
pursue, this problem will need to be addressed much earlier. This might
stimulate automated assays for common side effects of drugs as part of the
 REGULATORY APPROVALS FOR candidate selection criteria during the lead optimization stage.
 CHAPTER 2: Drug Discovery And Developmen ECONOMIC VALUE
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Drugs There is growing internal pressure to increase productivity while controlling
 CHAPTER 4: Phase 0 Trials In Cancer Drug costs. This has led to the drive for high-value molecules in diseases with high
Development
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.
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 bene t.
The push to raise health, economic and quality-of-life issues has produced a
counter response from some regulators that the industry demonstrates added 14
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 signi cant value for society. This will mean that in the future
more outcome studies will be needed to demonstrate quality-of-life and
economic bene t.

PRECLINICAL DRUG DEVELOPMENT
INTRODUCTION TO PRECLINICAL DRUG DEVELOPMENT
Preclinical drug development is a stage that begins before clinical trials (testing
in humans) during which important safety and pharmacology data are 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 nonrodent (e.g. dog). The choice of animal species is
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, puri cation 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
Drug Discovery early in the process of new drug development. This research takes place in
and Clinical either the part or whole animal to determine important information, including
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therapeutic effects the drug may have, potential side effects and toxicities and
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metabolism and clearance of the drug in the body. Good results in the preclinical
or animal stage do not necessarily mean that similar results will be found when
the drug is given to healthy volunteers or patients.
The main goals of preclinical studies are to determine a drug's

INTRODUCTION TO DRUG DEVELOPMENT pharmacodynamics (PD), pharmacokinetics (PK) and toxicity through animal
 DRUG DISCOVERY PROCESS testing. These data allow researchers to estimate a safe starting dose of the
 PRECLINICAL DRUG DEVELOPMENT drug for clinical trials in humans.
 PHARMACOVIGILANCE The goals of the nonclinical safety evaluation include:
Categorization of toxic effects with respect to target organs, dose
 CLINICAL DATA MANAGEMENT dependence, relationship to exposure, and potential reversibility. This
 CHAPTER 2: Drug Discovery And Developmen information is important for the estimation of an initial safe starting dose for
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Of Biologics Index  the human trials
Drugs The identi cation of speci c parameters for clinical monitoring for potential
 CHAPTER 4: Phase 0 Trials In Cancer Drug adverse effects 15
Development
The nonclinical safety studies, although limited at the beginning of clinical
development, should be adequate to characterize potential toxic effects.
 The need for nonclinical information including toxicology, pharmacology and

pharmacokinetics to support clinical trials is addressed in the ICH (International
Conference on Harmonization) Safety guidelines. Typically, both in vitro and in
vivo tests will be performed. Studies of a drug's toxicity on organs targeted by
that drug, as well as any long-term carcinogenic effects or toxic effects on
mammalian reproduction will be estimated in preclinical studies.

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 speci c
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:
Langendroff's heart preparation: The objective is to study the effect of drugs like
noradrenaline, acetylcholine and isoprenaline on the coronary blood ow and
heart rate and force of contraction using rat isolated heart.
Ileum preparation: The objective is to record the effect of drugs like 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 like d-tubocurarine by using rectus abdominus muscle of frog.

IN VIVO STUDIES
In in vivo studies, in vivo 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
Drug Discovery mutation found in both animals and human; to achieve short-term objective to
and Clinical nd out how the animal responds to the treatment. If it is a faithful model of
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humans, then humans should respond in the same way. Animals and other
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models, are used because the research cannot be done on humans for practical
or ethical reasons.
Purpose of models: A speci c model is chosen because it is believed to be

appropriate to the condition being investigated and is thought likely to respond
INTRODUCTION TO DRUG DEVELOPMENT in the same way as humans to the proposed treatment(s) for the character being
 DRUG DISCOVERY PROCESS investigated. 16
Having chosen the model it is essential that any experiments in which it is
 PHARMACOVIGILANCE used are well designed, i.e. are capable of demonstrating a response to a
 REGULATORY APPROVALS FOR treatment. If the model happens to be insensitive or the experiments are badly
designed so that they are incapable of distinguishing between treated and
control groups, say as a result of using too few animals, then the model is not
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Of Biologics Index  appropriate to its purpose.
Drugs Animal models are used to de ne a new molecule's:
Development
Therapeutic potential
 CHAPTER 5: Bioethics In Clinical Research Toxicity potential
Pharmaceutical properties and metabolic pathways
 Mechanism and speci city of action (lead molecules).
In vivo studies are preferred over in vitro studies for the following reasons:
Greater similarity to human studies when compared to in vitro screening

Drug effects modi ed by physiological mechanisms can be studied
ADME of drugs that modi es drug effects are also factored
Most animal systems are similar to human systems
Effect of drug is studied on complete systems rather than tissues and organs
Drugs acting on central nervous system, cardiovascular system, gastro-
intestinal system, and other systems can be studied
Results easier to interpret and extrapolate.
Some of the examples of in vivo studies are:
Noninvasive 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 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 speci c
gene-sequence alterations or manipulate the levels and patterns of target-gene
expression. Using these techniques, researchers can generate speci c 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, etc. 17

EX VIVO STUDIES
Drug Discovery In ex vivo, experiment is performed in vivo and then analyzed in vitro. The organs
and Clinical of the animals are detached from the body and replaced once an experiment is
Research performed. Then the animals are kept under observation and ndings recorded
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for a set duration.

GENERAL REQUIREMENTS FOR CONDUCTING PRECLINICAL

STUDIES
 DRUG DISCOVERY PROCESS Toxicity studies should comply with good laboratory practice (GLP).
 PRECLINICAL DRUG DEVELOPMENT These studies should be performed by suitably trained and quali ed staff
employing properly calibrated and standardized equipment, done as per
written protocols.
REGISTRATION OF DRUGS Standard operating procedures (SOPs) should be followed.
Test substances and test systems (in vitro or in vivo) should be properly
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Of Biologics Index  characterized and standardized.
 CHAPTER 3: Clinical Development Of New All documents belonging to each study, including its approved protocol, raw
Drugs
data, draft report, nal report, and histology slides and para n tissue blocks
Development should be preserved for a minimum of 5 years after marketing of the drug.

 ANIMAL PHARMACOLOGY STUDIES
Safety pharmacology studies are studies that investigate potential undesirable

pharmacodynamic effects of a substance on physiological functions in relation
to exposure within the therapeutic range or above. Speci c pharmacological
actions are those which demonstrate the therapeutic potential for humans.
Based on the individual properties and intended uses of an investigational

drug, speci c studies that need to be conducted and their design will vary. Only
scienti cally validated methods should be used.
The essential safety pharmacology is to study the effects of the test drug on
vital functions. Vital organ systems such as cardiovascular, respiratory and
central nervous systems should be studied.
In addition to the essential safety pharmacological studies, additional

supplemental and follow-up safety pharmacology studies may need to be
conducted as appropriate. These depend on the pharmacological properties or
chemical class of the test substance, and the data generated from safety
pharmacology studies.
Speci c and essential pharmacological studies should be conducted to

support use of therapeutics in humans. Essential safety pharmacology studies
may be excluded or supplemented based on scienti c rationale. Also, the
exclusion of certain test(s) or exploration(s) of certain organs, systems or
functions should be scienti cally justi ed. 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. 18
The following factors are to be considered when speci c tests are to be

conducted:
Mechanism of action
Class-speci c 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
Systemic absorption from the site of application is low.
Drug Discovery
and Clinical Safety pharmacology testing is also not necessary, in case of a new
Research
derivative having similar pharmacokinetics and pharmacodynamics. For
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biotechnology-derived products that achieve highly speci c receptor targeting, it
is often su cient to evaluate safety pharmacology end-points as a part of
toxicology and/or pharmacodynamic studies; therefore, safety pharmacology
studies can be reduced or eliminated for these products. For biotechnology-
 CHAPTER 1: New Drug Development derived products that represent a novel therapeutic class and/or those products
INTRODUCTION TO DRUG DEVELOPMENT that do not achieve highly speci c receptor targeting, a more extensive
evaluation by safety pharmacology studies should be considered.
 CLINICAL DEVELOPMENT In vivo safety pharmacology studies should be designed to de ne the dose-
 PHARMACOVIGILANCE 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
 CLINICAL DATA MANAGEMENT investigated.
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Of Biologics Index  In vitro studies should be designed to establish a concentration-effect
 CHAPTER 3: Clinical Development Of New relationship. The range of concentrations used should be selected to increase
Drugs
the likelihood of detecting an effect on the test system. The upper limit of this
Development
range may be in uenced by physicochemical properties of the test substance
 CHAPTER 5: Bioethics In Clinical Research and other assay speci c factors.

 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 (Figs 1.3A And B). Other objectives of toxicokinetic studies
include:
To relate the toxicological ndings to clinical safety

To support in selecting species, treatment regimen and designing subsequent
nonclinical toxicity studies.
Several toxicity studies need to be done before a drug goes into the clinical
phase. They are as follows.

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 studies is useful in choosing doses for repeat-
dose studies, providing preliminary identi cation of target organs of toxicity, and,
occasionally, revealing delayed toxicity. 19
Figs 1.3A and B: A researcher studies a rat being used in medical experiments
Acute toxicity studies may also aid in the selection of starting doses for phase I
human studies, and provide information relevant to acute overdosing in humans.
Repeated-dose systemic toxicity studies: The primary goal of repeated dose

toxicity studies is to characterize the toxicological pro le of the test compound
following repeated administration. This includes identi cation of potential target
Drug Discovery organs of toxicity and exposure/response relationships, and may include the
and Clinical potential reversibility of toxic effects. This information should be part of the
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safety assessment to support the conduct of human clinical trials and the
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approval of a marketing authorization.
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.

 PRECLINICAL DRUG DEVELOPMENT MALE FERTILITY STUDIES
 PHARMACOVIGILANCE Male fertility studies are designed to provide general information concerning the
 REGULATORY APPROVALS FOR effects of a test substance on male reproductive system such as gonadal
function.

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 CHAPTER 3: Clinical Development Of New FEMALE REPRODUCTION AND DEVELOPMENTAL TOXICITY STUDIES
Drugs
 CHAPTER 4: Phase 0 Trials In Cancer Drug Female fertility studies are designed to provide general information concerning
Development
the effects of a test substance on female reproductive system such as ovary
function and lactation (Figs 1.4A And B). These studies need to be carried out
for all drugs proposed to be studied or used in women of childbearing age. 20

Figs 1.4A and B: Depict reproductive studies done on rats

TERATOGENICITY STUDY
The drug should be administered throughout the period of organogenesis in

animals if the test drug is intended for women of childbearing age and if women
of childbearing 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 foetal development.

LOCAL TOXICITY
These studies are required when the new drug is proposed to be used by some
special route (other than oral) in humans. The drug should be applied to an
appropriate site (e.g. skin or vaginal mucous membrane) to determine local
effects in a suitable species. If the drug is absorbed from the site of application,
appropriate systemic toxicity studies will also be required. Examples of local
toxicity are dermal toxicity study, vaginal toxicity study, photoallergy, rectal
tolerance test, ocular toxicity studies (Fig. 1.5), inhalational toxicity studies, and
hypersensitivity.

GENOTOXICITY
Drug Discovery Genotoxicity refers to potentially harmful effects on genetic material (DNA)
and Clinical which may occur directly through the induction of permanent transmissible
Research changes (mutations) in the amount or structure of the DNA within cells. In vitro
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(arti cial 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 identi cation with respect to
damage to DNA and its xation. Damage to DNA can occur at three levels:
 CHAPTER 1: New Drug Development 1. Point mutations
 DRUG DISCOVERY PROCESS 2. Chromosomal mutations
 PRECLINICAL DRUG DEVELOPMENT 3. Genomic mutations. 21
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Drugs
Development

Fig. 1.5: Depicts rabbits kept ready for ocular tests
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 months 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 rst animal species to be genetically
modi ed 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 infections with pathogenic microorganisms that might cloud the
interpretation of experimental ndings. 22
Drug Discovery
and Clinical
Research
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 CHAPTER 2: Drug Discovery And Developmen Fig. 1.6: Depicts carcinogenicity test done on mice
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Drugs
Development
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 de ned 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
con nement, stress, environment and food
Repeatability/reproducibility is di cult
Expensive, time-consuming and not amenable to high throughput. Toxicity
studies are costly in terms of animals and resources. For a product developed 23
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 e cient 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 e ciency of laboratory animal experiments and the quality of data to make
decisions about dosing with NCE. 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 fewer. There are several very compelling new
Drug Discovery technologies now available that include whole-body imaging, protein biomarkers
and Clinical monitoring by multichannel immunoassays, ow cytometry of blood
Research
components, metabonomic component monitoring using in vivo micro dialysis
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and in vivo ultra ltration, automated blood sampling for awake, freely-moving
animals [pharmacokinetics (PK) and biomarkers] and parallel monitoring of
physiological and electrocardiogram and psychological parameters. While not all
of these data sources can be enabled simultaneously, many of them can be
 CHAPTER 1: New Drug Development accomplished automatically, raising the quality of information available from
INTRODUCTION TO DRUG DEVELOPMENT animal models dramatically.
FDA REQUIREMENTS FOR PRECLINICAL STUDIES
REGISTRATION OF DRUGS It is essential to ensure the quality and reliability of safety studies and this can
 CLINICAL DATA MANAGEMENT be achieved by adhering to good laboratory practices (GLP). The purpose of GLP
 CHAPTER 2: Drug Discovery And Developmen is to obtain data on properties and safety of these substances with respect to
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Of Biologics Index  human health and environment, to promote development of quality test data,
Drugs such comparable data forms the basis of mutual acceptance across
 CHAPTER 4: Phase 0 Trials In Cancer Drug organizations/countries, con dence in and reliability of data from different
Development
countries will prevent duplicating tests, saves time, energy and resources.
For every 5000 drug compounds that enter preclinical testing in the United
States, only about 5 will eventually be considered acceptable to test in humans.

Of those nal 5, only 1 drug may actually receive approval for use in patient care.
Under FDA requirements, a sponsor must rst submit data showing that the
drug is 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 ful lling this requirement:
Compiling existing nonclinical data from past in vitro laboratory or animal

studies on the compound 24
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
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 pro le 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 practices (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.
Drug Discovery
and Clinical
Research
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REGISTRATION OF DRUGS 25
Fig. 1.8: Animal testing facility according to GLP requirements
 CHAPTER 2: Drug Discovery And Developmen It needs to specify provisions for compliance monitoring, the collection and
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Of Biologics Index  maintenance of information on projects involving animals and animal
Drugs
management practices and facilities, and allow the fair and prompt handlings of
 CHAPTER 4: Phase 0 Trials In Cancer Drug complaints from any member of the animal ethics committee. An institutional
Development animal ethical committee (IAEC) must be established by an institution (or group
 CHAPTER 5: Bioethics In Clinical Research of organizations) which has an approved code of ethical conduct.
A nal report shall be prepared for each nonclinical 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 identi ed 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 nal 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 identi cation
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 nal report are to be
stored
A statement prepared and signed by the quality assurance unit and the nal
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 26
and structure-based design have enabled the process of drug discovery to
Drug Discovery evolve into a system where new lead molecules can be rapidly found against
and Clinical novel, and di cult targets. Preclinical testing of pharmaceuticals in animals has
Research
been instrumental in the development of modern therapeutic regimens.
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Unquestionably, human quality of life (and life expectancy) has ourished as a
result of preclinical testing of drugs in animals. However, drug development
remains extremely challenging, with numerous obstacles to overcome. The
transition from activity in vitro (cell culture) to activity in vivo (animal model) can
 CHAPTER 1: New Drug Development be especially challenging. Obtaining pharmacokinetic behavior consistent with
INTRODUCTION TO DRUG DEVELOPMENT the desired reactivity can be very di cult and the use of animals in toxicity
testing has not progressed without controversy. Objections to animal testing
have emphasized that the results obtained from animal tests do not always
correlate well with human experience.
Attrition rates remain high, and generally only one out of ten thousand drugs
 CLINICAL DATA MANAGEMENT tested will enter clinical development and make it all the way to regulatory
 CHAPTER 2: Drug Discovery And Developmen approval and nd a place in the market. Drugs most frequently fail in the clinic
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Of Biologics Index  because of poor pharmacokinetics or toxicity.
Drugs
Despite the fact that drug development remains a long and arduous journey,
Development the prospect of genome-targeted individualization of therapy remains an
 CHAPTER 5: Bioethics In Clinical Research extremely exciting one. The possibility of personalized treatments (“right drug
for the right patient”) based on the genomic or proteomic readout of the
particular patient is now becoming a reality.

It is envisaged that more and more strategic alliances will be formed
between biotechnology and small pharmaceutical companies to make the most
of all of the opportunities like human genome data.
During a new drug's early preclinical development, the sponsor's primary

goal is to determine that the product is reasonably safe for initial use in humans
and that compound exhibits pharmacological activity that justi es commercial
development. When a product is identi ed as a viable candidate for further
development, the sponsor then focuses 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 speci c requirements of the drug
regulatory system (Fig. 1.9).
Before the sponsor proceeds to study a new drug in human, approval has to
be obtained by IND application. 27
Fig. 1.9: The drug discovery process

INVESTIGATIONAL NEW DRUG APPLICATION

Drug Discovery
and Clinical
An investigational new drug (IND) application is to provide the data showing that
Research
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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
 CHAPTER 1: New Drug Development 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
 CLINICAL DEVELOPMENT requirement. The IND application is the means through which the sponsor
 PHARMACOVIGILANCE technically obtains this exemption from the FDA. The IND application shows
 REGULATORY APPROVALS FOR results of previous experiments, how, 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.
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There are two IND application categories:
Drugs
Commercial
Development Research (noncommercial).
There are three types of IND application:
 An Investigator IND application is submitted by a physician who both initiates

and conducts an investigation, and under whose immediate direction the
investigational drug is administered or dispensed. A physician might submit a
research IND application to propose studying an unapproved drug, or an
approved product for a new indication or in a new patient population. 28
Emergency Use IND application allows the FDA to authorize use of an

experimental drug in an emergency situation that does not allow time for
submission of an IND application. It is also used for patients who do not meet
the criteria of an existing study protocol, or if an approved study protocol does
not exist. In such a case, FDA may authorize shipment of the drug for a
speci ed use in advance of submission of an IND application.
Treatment IND application is submitted for experimental drugs showing
promise in clinical testing for serious or immediately life-threatening
conditions while the nal 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 quali cations of
Drug Discovery clinical investigators who oversee the administration of the experimental
and Clinical compound—to assess whether they are quali ed to ful ll their clinical trial
Research
duties. Finally, commitments to obtain informed consent from the research
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subjects, to obtain review of the study by an institutional review board (IRB),
and to adhere to the investigational new drug regulations.
Sponsor les 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. 29
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
REGISTRATION OF DRUGS (Center for Drug Evaluation and Research), then on Day 31 after submission of
 CLINICAL DATA MANAGEMENT IND application, the study may proceed as submitted. The CDER is a division of
 CHAPTER 2: Drug Discovery And Developmen the FDA that reviews New Drug Applications to ensure that the drugs are safe
TOC
and effective.
Drugs
During this time, FDA has an opportunity to review the IND application for
Development safety to assure that research subjects will not be subjected to unreasonable
 CHAPTER 5: Bioethics In Clinical Research risk.
Medical review: During the IND application review process, the medical
 reviewer evaluates the clinical trial protocol to determine (i) if the participants
will be protected from unnecessary risks; and (ii) if the study design will
provide data relevant to the safety and effectiveness of the drug. Under
Federal regulations, proposed phase I studies are evaluated almost
exclusively for safety reasons. Since the late 1980s, FDA reviewers have been
instructed to provide drug sponsors with greater freedom during 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 su cient scienti c quality to be capable of
yielding data that can support marketing approval
Chemistry reviewers: They address issues related to drug identity,
manufacturing control and analysis. The reviewing chemist evaluates the
manufacturing and processing procedures for a drug to ensure that the
compound is adequately reproducible and stable. At the beginning of the
Chemistry and Manufacturing section, the drug sponsor should state whether
it believes the chemistry of either the drug substance or the drug product, or
the manufacturing of either the drug substance or the drug product, present
any signals of potential human risk. If so, these signals should be discussed,
with steps proposed to monitor for such risks. In addition, sponsors should
describe any chemistry and manufacturing differences between the drug
product proposed for clinical use and the drug product used in the animal
toxicology trials that formed the basis for the sponsor's conclusion that it was
safe to proceed with the proposed clinical study
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 30
toxicology data. A summary report, without individual animal records or
individual study results, usually su ces. 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 speci city, immunogenicity, or other
considerations appear to make many or all toxicological models irrelevant,
Drug Discovery sponsors are encouraged to contact the agency to discuss toxicological
and Clinical testing.
Research
SK Gupta Statistical analysis: The purpose of these evaluations is to give the medical
o cers a better idea of the power of the ndings 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
INTRODUCTION TO DRUG DEVELOPMENT decide if a clinical hold is necessary (i.e. if patients would be at an
 DRUG DISCOVERY PROCESS unacceptable risk or if CDER doesn't have the data to make such a
 PRECLINICAL DRUG DEVELOPMENT determination).
 PHARMACOVIGILANCE Generally, drug review divisions do not contact the sponsor if no concerns
 REGULATORY APPROVALS FOR arise with drug safety and the proposed clinical trials. If the sponsor hears
nothing from CDER, then on day 31 after submission of the IND application, the
study may proceed as submitted. The sponsor is noti ed about the de ciencies
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Of Biologics Index  through a clinical hold. A clinical hold is issued by the FDA to the sponsor to
 CHAPTER 3: Clinical Development Of New delay a proposed clinical investigation or to suspend a clinical investigation
Drugs
(Flow Chart 1.1).

Development
SPONSOR NOTIFICATION
 Once a clinical hold is placed on a commercial IND application, the sponsor will
be noti ed immediately by telephone by the division director. For both individual
and commercial IND applications, the division is required to send a letter within
ve 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 signi cant

risk of illness or injury
Clinical Investigators named in IND application are not quali ed
Investigator Brochure is misleading, erroneous or materially incomplete
IND does not contain su cient information to assess risks
Protocol is de cient to meet objective of trial
Mechanism that CDER uses when it does not believe, or cannot con rm that
the study can be conducted
CDER will contact sponsor within 30-day initial review period. 31
Drug Discovery
and Clinical
Research
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TOC
Drugs
Development
Flow chart 1.1: IND application review process

* While sponsor answers any de ciencies
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 identi ed as an “IND CLINICAL HOLD RESPONSE” letter.
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. 32
If it is decided that the hold will not be lifted, the hold decision is
automatically sent to the o ce director for review. The o ce 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
con rming 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
If other de ciencies 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 de ciency letter to the sponsor. In
either case, the division informs the sponsor that it may proceed with the
planned clinical trials, but that additional information is necessary to complete
or correct the IND application le.

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 application, subsequent clinical trials may begin immediately upon
Drug Discovery submission of the clinical protocol to the IND application (i.e. there is no 30-day
and Clinical waiting period for subsequent clinical trials after the submission of the rst
Research
clinical trial protocol). If the sponsor was noti ed of de ciencies that were not
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serious enough to warrant a clinical hold, the sponsor addresses these
de ciencies while the study proceeds.


EXPLORATORY IND STUDIES
 DRUG DISCOVERY PROCESS Exploratory IND studies are intended to provide clinical information for a new
 PRECLINICAL DRUG DEVELOPMENT drug candidate at a much earlier phase of drug development. These studies help
 CLINICAL DEVELOPMENT to identify the best candidates for continued development and eliminate those
lacking promise. These clinical trials occur very early in phase I, involve very
REGISTRATION OF DRUGS limited human exposure and have no therapeutic intent. Exploratory IND studies
 CLINICAL DATA MANAGEMENT are conducted prior to the traditional dose escalation, safety and tolerance
 CHAPTER 2: Drug Discovery And Developmen studies and provide important information on pharmacokinetics (PK) and
Of Biologics
bioavailability of a candidate drug.
Drugs
In April 2005, the FDA released a draft guidance for exploratory IND studies
Development that clari es preclinical and clinical approaches that should be considered when
 CHAPTER 5: Bioethics In Clinical Research 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. 33

MICRODOSING (PHASE 0 CLINICAL TRIALS)
A primary application of an Exploratory IND study is microdosing or phase 0

clinical trials. Microdosing studies permit collection of human pharmacokinetic
(PK) and bioavailability data earlier in the drug development process. This
human data is combined with preclinical data to select the best candidates to
advance to further, more expensive and extensive clinical development.
Distinctive features of phase 0 trials include the administration of single sub-
therapeutic doses of the study drug to a small number of subjects (10–15) to
gather preliminary data on the agent's pharmacokinetics parameters such as
clearance, volume of distribution, t1/2 (half-life), etc.
A microdose is de ned as less than 1/100th of the dose calculated to yield a

pharmacological effect of a test substance and a maximum dose of ≤100
micrograms. Since microdosing studies are designed not to induce
pharmacological effects, the potential risk to human subjects is very limited.
Therefore, these studies can be initiated with less preclinical safety data (i.e.
with single dose study/acute toxicity study), help reduce the number of human
subjects needed and require fewer resources for selecting promising drugs
candidates for further development.
Microdosing is dependent on the availability of ultrasensitive analytical

methods able to measure drug and metabolite concentrations in the low
pictogram to femtogram range. Nuclear physics has been applied to conduct
analyses at these concentrations, viz. Accelerator Mass Spectrometry (AMS)
and Positron Emission Tomography (PET). Both techniques rely on the analysis
of radioisotopes incorporated into the drugs under study. In the case of AMS,
[14C] is the most useful isotope for drug metabolism studies whereas for PET
[11C] is proving to be the most useful isotope.
A typical human microdosing study involves the administration of

microgram quantities of drug candidates, lightly-labelled with Carbon-14 (14C), to
healthy volunteers. Following collection of blood, urine and feces from each
subject, samples are analyzed for 14C content using AMS to determine Cmax, AUC
and the terminal half-life of each compound (Fig. 1.10).
If, during the drug discovery process, a number of molecules are identi ed
which have good pharmacological activity but similar or differing animal PK
(pharmacokinetic), comparative human microdose studies can be conducted to
Drug Discovery establish human PK. Armed with this information, the human PK data can then
and Clinical be used to:
Research
SK Gupta Assist in the candidate selection process
Determine the rst dose for the subsequent phase I study on the selected
candidate
Establish the likely pharmacological dose.

 DRUG DISCOVERY PROCESS ADVANTAGES OF MICRODOSING
Select the best lead compound supported by clinical data
 REGULATORY APPROVALS FOR Save time: Advance lead candidates to clinical development in months not
REGISTRATION OF DRUGS years 34
Of Biologics
Drugs
Development
Fig. 1.10: Microdosing/phase 0 studies
Save money: Signi cantly reduced IND submission requirements and costs
Cost-effective approach to adding value to lead candidate or drug pipeline.
In conclusion, Microdosing is a technique for studying the behavior of

compounds in vivo through the administration of doses so low they are unlikely
to produce whole-body effects, but high enough to allow the cellular response to
be studied. This works on the concept that the best model for man is man. This
allows studying the pharmacokinetics of the drug with almost no risk of side
effects.
Use of the technique has been provisionally endorsed by both the European
Medicines Agency and the Food and Drug Administration. It is expected that by
2010, human microdosing will gain a secure foothold at the discovery-preclinical
interface driven by early measurement of candidate drug behavior in humans
and by irrefutable economic arguments.

CLINICAL DEVELOPMENT
Clinical trial/study is any investigation in human subjects intended to discover or

verify the clinical, pharmacological and/or other pharmacodynamic effects of an
investigational product(s) and/or to identify any adverse reactions to an
investigational product(s) and/or to study absorption, distribution, metabolism
and excretion of an investigational product(s) with the object of ascertaining its
safety and/or e cacy. 35
Clinical trials start after the completion of required preclinical studies and
IND application has been led to the concerned regulatory authority.
The objectives of clinical trials are:
To identify the relationship between dose and plasma(or other) concentration

—Pharmacokinetics
Drug Discovery
and Clinical To de ne the shape and location of the dose/concentration/response curves
Research for both desired and undesired effects—preliminary assessments of
SK Gupta bene t/risk
On the basis of these curves, to identify the range of dosage/concentrations
producing maximum bene t with fewest undesirable effects.

INTRODUCTION TO DRUG DEVELOPMENT KEY PLAYERS IN CLINICAL RESEARCH
Clinical research is an integral part of drug development. Unlike in the past, today
the process has gained a unique position due to the regulatory requirements and
ethical guidelines available globally. Thus designing, conducting, monitoring,
REGISTRATION OF DRUGS appropriate quality assurance and data management determine the success of
 CLINICAL DATA MANAGEMENT the clinical research.
Of Biologics Listed below are the players in clinical research who are responsible for
 CHAPTER 3: Clinical Development Of New these activities:
Drugs
 CHAPTER 4: Phase 0 Trials In Cancer Drug Sponsor/clinical research organization
Development
Medical writing team
Statistician
 Clinical research associate

Principal investigator
Clinical research coordinator
Data management team
Ethics committee
Regulatory authority
Data safety monitoring board
Central laboratory.
INTERNAL KEY PLAYERS
Sponsor: An individual, organization or company, that is responsible for the

initiation, management and/or nancing of a clinical investigation.
The sponsor is responsible for the development of the trial protocol and other
study documents; selection of quali ed investigators, sites and monitors;
allocation of duties and responsibilities; study management, data handling
and record keeping; supply, storage and handling of pharmaceutical product.
It is also the sponsor's responsibility to provide all information needed to
conduct investigation, ensure compliance with regulations, inform regulatory
authority regarding adverse events and safety reporting, perform data
analysis, report ndings and submit the IND to the regulatory authority. 36
Contract research organization (CRO): An organization which is contracted by

a sponsor to perform any or all of the activities normally done by the sponsor.
The sponsor is required to describe in writing exact responsibilities and
obligations transferring to CRO.
Medical writing team: This team is involved in preparing various documents
related to clinical trial, viz. protocol, investigator's brochure, clinical study
report.
Statistician: The statistician is responsible for activities such as determination
of sample size, study design, randomization and analysis of data.
Clinical research associate (CRA): CRA is an individual who works for the
sponsor or a CRO. The CRA is responsible for the overall monitoring of the
clinical trial at the trial site. The responsibilities of a CRA include evaluation of
a site and initiation of the trial; he/she should ensure that regulatory
requirements are met and that site personnel are quali ed, trained and aware
of their obligations. The CRA should monitor data and verify source records or
Drug Discovery in other words the CRA should oversee the progress of the study at site level.
and Clinical
Principal investigator (PI): According to the FDA, principal investigators should
Research
be “quali ed by training and experience to be appropriate to serve as PI for a
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trial”. The PI is the individual who conducts, supervises and is responsible for
all aspects of a clinical trial. It is the responsibility of the investigator to
ensure that regulatory, GCP compliance is maintained during trial conduct. PIs
are also involved in the formulation of a recruitment plan, evaluation and
 CHAPTER 1: New Drug Development treatment of research subjects. The PI should supervise the medical staff
participating in the study and perform timely review of all clinical and
laboratory data. One of the most important responsibilities of PIs is to ensure
proper reporting of all adverse events that takes place.
 PHARMACOVIGILANCE Clinical research coordinator (CRC): The CRC is a vital link between the all
 REGULATORY APPROVALS FOR players and the trial site. CRC is placed at the clinical trial site and works
directly under trial investigator. The CRC is responsible for coordinating all
aspects of the clinical trial and day-to-day operations of the research program.
Of Biologics The CRC should perform a protocol assessment and maintain adherence to
 CHAPTER 3: Clinical Development Of New the protocol and document breaches or violations and communicate the
Drugs
same with sponsor and the ethics committee. The CRC should help develop
Development and maintain the study source documents at the trial site. He/she should also
 CHAPTER 5: Bioethics In Clinical Research document all written and phone correspondence with sponsor, labs, IRB, other
regulatory organizations.
 Data management team: The data management team is responsible in the
management of trial related data obtained from investigative site. Data
management related activities include inputs during CRF (case report form)
designing, data acquisition, validation, coding, integration and quality
assurance.
37

EXTERNAL KEY PLAYERS
For a new drug/device/biologics to be tested in humans, approval from Ethics

committee and regulatory authority is required.
Ethics committee—Institutional Review Board (IRB) or Independent Ethics

Committee (IEC): IRB/IEC is a specially constituted board established to protect
rights, safety and well-being of human subjects by providing review and
oversight. The ethics committee may be a part of an institution or an
independent board. The ethics committee should obtain and review trial
documents such as the trial protocol, informed consent document, investigator's
brochure, etc.
Regulatory authority/Licensing authority: The regulatory authority of each

country is responsible for review and approval of drug applications (IND/NDA),
dissemination of safety information and conducting audits or inspections of any
sector of clinical research including sites, sponsors, or IRBs.
Table 1.2 shows regulatory authorities responsible for approving drug

applications of a few countries.
Data Safety Monitoring Boards (DSMB): An independent committee, composed

of community representatives and clinical research experts, which reviews data
while a clinical trial is in progress to ensure that participants are not exposed to
undue risk. DSMBs are needed when interim analyses of safety and e cacy are
considered essential to ensure the safety of trial participants. A DSMB may
recommend that a trial be stopped if there are safety concerns or if the trial
objectives have been achieved.

EXTERNAL KEY PLAYERS—OTHERS
Drug Discovery Central laboratory: Instead of using small, localized laboratory facilities or
and Clinical multiple specialty laboratories for multicentric trials, a central laboratory is used
Research to avoid data errors, lengthened study timelines and increased study costs.
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Table 1.2 Regulatory authorities

Countries Regulatory Authorities
India DCGI (Drug Controller General of India)

USA FDA (Food and Drug Administration)
 PRECLINICAL DRUG DEVELOPMENT European Union EMEA (European Medicines Agency)
 PHARMACOVIGILANCE United Kingdom MHRA (Medicines and Healthcare products Regulatory Agency)
REGISTRATION OF DRUGS Australia TGA (Therapeutic Goods Administration)
Canada Health Canada
Of Biologics
Japan MHLW (Ministry of Health, Labor and Welfare)
Drugs
China Ministry of Health of the People's Republic of China
Development 38
 CHAPTER 5: Bioethics In Clinical Research The concept of a central laboratory is based on the need for homogenous data
integration to improve submission quality and reduce the timelines for data
 submissions. Central laboratories accomplish this by combining the use of high
throughput technology with e cient internal systems that make for quick and
more combinable collection of lab data.

CLINICAL TRIAL DESIGN
Clinical trial may fail to achieve its aim without a good design. Before a clinical
trial may proceed, it will undergo numerous reviews that will include a review of
the trial design and applicability of the design to the situation. A good trial
design will ensure that the trial is given approval to proceed from regulatory
agencies, from ethics committees and from the investigator. A good design will
ensure that the trial set-up is achievable, that the investigator will recruit subjects
and that the trial will be completed—all within the target timescale. The design of
any given clinical trial will depend on many factors. The fundamental factor
contributing to the design is the disease for which is drug is to be tested (Target
indication). The target indication will in uence the objectives of the trial, the
options for clinical measurement and the circumstances under which the trial
should be carried out.

ELEMENTS TO BE CONSIDERED DURING CLINICAL TRIAL DESIGN
Types of control: The purpose of the control group is to provide a yardstick

against which to measure the e cacy and safety of the drug under investigation
and the control may be an untreated group or a group receiving an active
treatment or a placebo.
The choice of the comparator is in uenced by objective of the study. In

cases where e cacy has not yet established (phase I and phase II) it may be
that a placebo is the most appropriate comparator. Assuming that the
compound has been shown to possess e cacy, the objectives of later studies
(phase III onwards) will be to compare the extent of e cacy and safety with that
of currently used therapies.
Volunteer/subjects selection: It is important to carefully de ne the patient

population from which the study participants will be drawn. In early phase II, the
entry criteria for a study may be restrictive and throughout the development
program these criteria will evolve as the drug's characteristics are discovered.
For example, phase I trials will have healthy volunteers probably with a restricted
Drug Discovery age range, usually between 18 and 45 years. By the end of phase III the studies
and Clinical should include a population that is representative of the wider patient population
Research
who will potentially receive the licensed drug.
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Number of subjects: The size of a trial is in uenced by the disease to be

investigated, the objective of the study and the study endpoints.
Statistical assessments of sample size should be based on:

INTRODUCTION TO DRUG DEVELOPMENT The expected magnitude of the treatment effect
 DRUG DISCOVERY PROCESS The variability of the data 39
The speci ed (small) probability of error
 PHARMACOVIGILANCE The desire for information or subsets of the population or secondary
 REGULATORY APPROVALS FOR endpoints.
 CLINICAL DATA MANAGEMENT In uence of disease indication on trial design: The onset and progression of the
 CHAPTER 2: Drug Discovery And Developmen disease will affect the duration of the trial, the timing of each subject's treatment
Of Biologics
and the number and timing of assessments.
Drugs
Acute conditions will require short treatment period and as these types of
Development disease remit spontaneously within certain time, subjects should be entered into
 CHAPTER 5: Bioethics In Clinical Research the study within one day of onset and assessment to be carried out more
frequently to detect early signs of e cacy.
 In chronic diseases, signs and symptoms of the disease will be stable for
longer periods dictating study of six months or more duration, with monthly
assessments carried out for e cacy.
Randomization: Randomization is a process that assigns research participants

by chance, rather than by choice, to either the investigational group or the control
group. In conducting a controlled trial, randomized allocation is the preferred
means of assuring comparability of test groups and minimizing the possibility of
selection bias. Randomization is done using a computer generated random
number table (Fig. 1.11).
Randomization can be simple randomization or strati ed randomization.

Strati ed randomization (strati cation) is used when there are differences in the
nature of the disease in severity or site and responses to treatment might differ
due to this. For example, in analgesic trial, subjects can be strati ed according to
pain severity into mild, moderate and severe, where the response might differ.
Each stratum can be analyzed separately, if required.

BLINDING
Blinding is an important means of reducing the risk of biased study outcomes. A

trial where the treatment assignment is not known by the study participant is
known as single blind study.
Fig. 1.11: Depicts randomization procedure

40
Drug Discovery
and Clinical
Research
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 DRUG DISCOVERY PROCESS Fig. 1.12: Depicts double-blind study

When both investigator and study participants are unaware of the treatment
assignments, the study is double blind. When investigator, study participants and
the sponsor staff are unaware of the treatment assignment, study is referred to
REGISTRATION OF DRUGS as triple blind. Studies that do not utilize blinding are referred to as open label
 CLINICAL DATA MANAGEMENT studies. Thus, all those concerned with trial are aware of the identity of the
 CHAPTER 2: Drug Discovery And Developmen investigational medicinal product (Fig. 1.12).
Of Biologics
It is essential to maintain blinding throughout the trial to maintain the
Drugs
validity of the trial data. During each monitoring visit, the monitor will verify the
Development maintenance of blind. However, there may be a need for the investigator to know
 CHAPTER 5: Bioethics In Clinical Research the identity of drugs administered, e.g. during emergency due to adverse event.
In such a case, contingency should be provided to know the treatment by
 unblinding for that speci c subject. Another example of requirement of
contingency is, in the event of failure of effect (e.g. increased pain); in such a
case rescue medication should be speci ed that is known not to interact with
either of the blinded treatments, to avoid breaking the blind.
Types of trial design: An appropriate study design should be chosen to provide

the desired information in a research study. Examples of study design include
parallel group, crossover, factorial and dose escalation.
The most frequently used designs are: Parallel study and cross-over study.
In a parallel study, each subject is assigned to receive one or other treatment

and subjects are studied ‘in parallel’. In a crossover study each subject will
receive a course of each of the treatments under study (Figs 1.13 and 1.14).
The choice of one of these two designs over the other demands careful
consideration. Crossover design may be helpful in identifying which treatment is
best for a particular patient as each subject acts as his/her own control.
However, results from this may not be extrapolated to general population. The
choice of comparator for a crossover study must be made carefully to prevent
drug interaction and su cient washout period should be given between two
treatment periods so as to avoid carry-over effect of previous treatment. 41
Fig. 1.13: Depicts parallel study
Drug Discovery
and Clinical
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SK Gupta
Fig. 1.14: Depicts Crossover study
 CHAPTER 1: New Drug Development The crossover design will clearly necessitate more subject visits, thus probability
of subject dropping out or even not entering into trial increases. The crossover
design is appropriate for less prevalent disease, as number of subjects required
in crossover design is relatively less and for relatively stable disease, e.g.
hypertension.
REGISTRATION OF DRUGS Factorial: When patients are being treated with a combination of drugs, as is
 CLINICAL DATA MANAGEMENT current practice for HIV infection, a new drug may be evaluated by testing it in
 CHAPTER 2: Drug Discovery And Developmen combination with other drugs rather than by itself. A factorial design trial may be
Of Biologics
used for this purpose. A simple factorial design would have one group testing
Drugs therapy A, another testing therapy B, a third group testing A and B combined and
 CHAPTER 4: Phase 0 Trials In Cancer Drug a control group testing neither A nor B. Factorial designs are considered an
Development
e cient way to test medicines in combination.
Dose escalation: Also referred to as dose ranging design. The main goal of a
dose escalation study is to estimate the response vs. dose given, so as to

analyze the e cacy and safety of a drug. Thus, in a dose escalation study,
different doses of a drug are tested against each other to establish which dose
works best or is least harmful. Dose ranging design is usually chosen for a
phase I or early phase II clinical trial. Typically, a dose ranging study, will include 42
a placebo group of subjects and a few groups that receive different doses of the
test drug. Information on the maximum tolerated dose is required to design the
groups in a dose escalation study. Therefore, this type of study is usually
designed after the availability of maximum tolerated dose information.
Duration of dosing: Duration of dosing is determined by factors like

pharmacokinetics, mode of action and natural history of the disease being
treated. In early phase II clinical trial, available toxicology data may support only
a limited duration of dosing. A drug development program will include
substantial chronic animal toxicology studies running in parallel with the clinical
phases and results from these studies may extend the permissible duration of
dosing as they become available.
Methods of clinical measurement: The assessment method must be

standardized so that results from all subjects can be pooled from all centers and
therefore the protocol should describe in depth method of assessments and at
what time interval these assessments should be made, to obtain uniformity
between centers.
The method chosen must be validated for accuracy and reproducibility. For a
quantitative measurement such as blood pressure, the use of standardized
equipment, e.g. the sphygmomanometer, is clearly most appropriate. For an
assessment of subjective parameter, validated rating scale should be used, e.g.
Hamilton Depression Rating Scale for depression.
The timing and circumstances of the assessment should be standardized.

Even the quantitative measurement such as blood pressure will be in uenced
unless a standard procedure is speci ed. For example, the subject should be
sitting for 10 minutes before two blood pressure readings and the mean will be
used for analysis. Additionally, the time of day for the measurement may be
standardized to avoid diurnal variation.
In summary, elements such as comparator, disease under study, patient

population, randomization and blinding, duration of dosing and methods of
clinical measurement should be considered while designing clinical study.
Drug Discovery
and Clinical
Research ESSENTIAL DOCUMENTS
SK Gupta
Essential documents are those documents that individually and collectively

evaluate the conduct of a trial and the quality of the data produced. These
documents demonstrate the compliance of the investigator and sponsor with
the standards of Good Clinical Practice (GCP) and all applicable regulatory
INTRODUCTION TO DRUG DEVELOPMENT requirements.
The GCP guidelines lists essential documents required for a clinical trial.
 CLINICAL DEVELOPMENT The documents are grouped in three sections according to the stage of the trial:
1. Before the clinical phase of the trial commences
REGISTRATION OF DRUGS 2. During the clinical conduct of the trial
3. After completion or termination of the trial. 43
Of Biologics
Drugs
BEFORE THE CLINICAL PHASE OF THE TRIAL COMMENCES
Development
 CHAPTER 5: Bioethics In Clinical Research Signed and dated protocol: A document that describes the objective(s),
design, methodology, statistical considerations and organization of a clinical
trial

Protocol amendments: The changes in terms of updates or clari cations
made in the protocol
Sample patient information sheet and informed consent form: This document
provides the subjects with necessary details to participate in the study and
their willingness is recorded by means of signing the document
Investigator's Brochure: The IB contains both clinical and nonclinical data
pertaining to the description of new drug
Sample CRF: Case report form is the tool (a paper or electronic questionnaire)
used by the sponsor of the clinical trial to collect data from each participating
trial site
Advertisement for subject recruitment (if used): The advertisement is the
proposed method of subject recruitment for the trial. It contains a brief
description of the study
Financial agreement (where required): An agreement between the parties who
are involved in conducting the clinical trial
Insurance/letter of indemnity (where required): Insurance or a letter
guaranteeing that contractual provisions will be met, otherwise nancial
reparations will be made
Research agreement (where required): Agreement for the research/study to
be conducted between the key players who are involved in the trial
Communication with sponsor/IRB: The communication between IRB
(Institutional Review Board) and the sponsor should be done before
commencing the trial
IRB approval: The IRB or the Ethics Committee is the independent body who
approves the trial documents (protocol, CRF, ICF, etc.)
IRB composition (if not speci ed in IRB letter of approval): Documents
containing the information of the details of the ethics committee quorum,
name and designations of the ethics committee members
Investigators’ CVs—signed personally and dated: The monitor should collect
the Curriculum Vitae of the investigator(s) involved in conducting the trial and
present to the regulatory body concerned with the trial
Signature sheet and authorization sheet: This document contains the names
and signatures of those who are authorized to make changes to the trial
documents
Reference range of local labs and updates when applicable: This document
will contain the reference (normal) range for various tests which are speci c
Drug Discovery for the instruments available at each lab
and Clinical
Research Certi cation/accreditation of local lab: Accreditation/Certi cation is a
SK Gupta process in which the competency, authority or credibility of a laboratory is
presented. The accreditation must be a current one. The accreditation of 44
testing laboratories and certi cation specialists are permitted to issue o cial
certi cates of compliance with established standards, such as physical,
chemical, forensic, quality and security standards
INTRODUCTION TO DRUG DEVELOPMENT Study procedures (Site SOPs): They provide a written set of instructions
 DRUG DISCOVERY PROCESS documenting (normally in a step by step manner) how a procedure should be
 PRECLINICAL DRUG DEVELOPMENT performed
Shipping records for investigational product (IP): A record or a log is
maintained for the shipping/distribution of the IP at various sites where the
REGISTRATION OF DRUGS trial is conducted
 CLINICAL DATA MANAGEMENT Sample of IP label
Of Biologics Sealed envelope of treatment code: The treatment code is kept in a sealed
 CHAPTER 3: Clinical Development Of New envelop and should be duly checked by trial monitor for any tampering with
Drugs
the seal that might occur leading to unfair conduct of the trial. This envelope
Development
can be opened in case of an emergency
 CHAPTER 5: Bioethics In Clinical Research Emergency unblinding procedures (if not already described in protocol):
Emergency unblinding/decoding procedure is carried out by the investigator
 referring the “Treatment decoding log” depending on the occurrence of the
serious adverse events during a trial
Treatment decoding log (emergency unblinding): A record, “Treatment
decoding log”, for the decoding of the code assigned to the subjects in a trial
is always kept ready for emergency situation which may arise during a trial
Study initiation report: The study initiation report should be prepared by the
monitor after the initiation of a study at a site.
DURING THE CLINICAL CONDUCT OF THE TRIAL
In addition to all documents listed above, the following documents are also
required during the conduct of the trial:
Previously-mentioned document: All previously-mentioned document updates

checked before the clinical phase of the trial commences
Monitoring visit report: A written report from the monitor to the sponsor after
each site visit. It contains all trial related communications according to the
sponsor's SOP
Signed and dated informed consent forms: The informed consent obtained in
a form from the subjects should be duly signed and dated by the investigator
as well as the patient
Source documents: Original documents, data and records (e.g. hospital
records, laboratory notes, subjects’ diaries, recorded data from automated
instruments, copies or transcriptions certi ed after veri cation as being
accurate copies, photographic negatives, magnetic media, X-rays and records
kept at the pharmacy, laboratories and at medico-technical departments, etc.
which are involved in the clinical trial)
Signed, dated and completed CRF copy: The copy of a signed, dated and
completely lled case report form (CRF) is also required during the conduct of
the trial 45
Documentation of CRF correction: A documentation of the corrected CRF is

required to be maintained if the CRF has undergone correction
AE and SAE report: A report containing all the adverse events and serious
adverse events prepared by the investigator should be maintained and
presented to the sponsor and the ethics committee/IRB (Investigational

Review Board)
Sponsor's safety update: It is a document which provides regular and timely
Drug Discovery review, appraisal of safety information. Communication of this information is
and Clinical
critical to risk management during clinical development of drugs
Research
SK Gupta Interim/progress report to IRB/IEC: It is the progress report of the
intermediate results and the evaluation based on analysis performed during
the course of a trial
Subject screening log/screen failure log: It will contain all the details of the
subjects who have been screened. This log will also contain information
INTRODUCTION TO DRUG DEVELOPMENT regarding the subjects who did not meet the eligibility criteria (Screen Failure
 DRUG DISCOVERY PROCESS Log)
 PRECLINICAL DRUG DEVELOPMENT Patient identi cation list: A unique identi er assigned by the investigator to
each trial subject to protect the subject's identity and used in lieu of the
subject's name when the investigator reports adverse events and/or other trial
REGISTRATION OF DRUGS related data
 CLINICAL DATA MANAGEMENT Subject enrolment log: This record is maintained to document the
identi cation of the subject who has been enrolled in the trial
Of Biologics
 CHAPTER 3: Clinical Development Of New IP accountability log: The investigational product usage/accountability should
Drugs
be recorded and maintained properly at the site of the trial conduction
Development Record of retained body uids/tissue sample: To document location and
 CHAPTER 5: Bioethics In Clinical Research identi cation of retained samples if tests need to be repeated.


COMPLETION OR TERMINATION OF THE TRIAL
In addition to all documents listed above, the following documents are also
required during the conduct of the trial:
Audit certi cate (if available): A declaration of con rmation by the auditor that
an audit has taken place
Documentation of IP destruction: The accountability of the investigational
product (IP) usage is recorded and the left out IP is either returned to the
sponsor or destroyed at the site and the process is recorded or documented
Study close-out report: The study close-out report is prepared by the study
monitor after the completion of the trial
Final report by investigators to IRB: The investigator prepares the nal report
to be given to the concerned regulatory body (IRB) involved the trial informing
the closing of the trial
Clinical study report: A written description of a trial/study of any therapeutic,
prophylactic or diagnostic agent conducted in human subjects, in which the 46
clinical and statistical description, presentations and analyses are fully
integrated into a single report (see the ICH Guideline for Structure and Content
of Clinical Study Reports).
PHASES OF CLINICAL TRIALS
Phase I: Human pharmacology

Phase II: Therapeutic exploration
Phase III: Therapeutic con rmation
Phase IV: Postmarketing studies.
PHASE I CLINICAL TRIAL
Phase I trials are the rst stage of testing in human subjects. phase I studies are
also known as Human Pharmacology studies. Normally, a small (20–80) group
of healthy volunteers will be selected to participate in these studies. This phase
Drug Discovery includes trials designed to assess the safety, tolerability, pharmacokinetics and
and Clinical pharmacodynamics of a drug. Volunteers are paid an inconvenience fee for their
Research
time spent in the volunteer center.
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OBJECTIVES OF PHASE I STUDIES
Safety and tolerability—maximum tolerated dose (the highest dose of a drug

INTRODUCTION TO DRUG DEVELOPMENT that does not cause overt toxicity in humans)
 DRUG DISCOVERY PROCESS Pharmacokinetics
Pharmacodynamics.
PREREQUISITES FOR PHASE I TRIALS
Of Biologics Preclinical safety data: Animal toxicity which needs to be completed before
 CHAPTER 3: Clinical Development Of New start of phase I studies are—single dose toxicity studies, repeated dose, safety
Drugs
pharmacology studies, local tolerance studies, pharmacokinetic studies,
Development
mutagenicity studies (in vitro), male reproductive system studies
 CHAPTER 5: Bioethics In Clinical Research Regulatory authority and ethics committee approval: Ethics committee
approval is essential since healthy volunteers are included as subjects in this
 phase.

CONDUCT OF THE TRIAL
Site: These trials are often conducted in a specialized inpatient setting called
as clinical pharmacological unit/clinical trial unit, where the subject can be
observed by full-time staff. The study site should be equipped to monitor all
physiological functions, facilities to handle an emergency or a serious
unexpected adverse event, facilities for processing blood/plasma, etc. and
facilities for estimation of drug levels in biological uids (Fig. 1.15).
PLAYERS
Investigator: usually conducted by clinical pharmacologist. The medical staff,

paramedical staff should be quali ed, skilled to handle emergencies; should
be trained in basic life support and also advanced life support
Subjects: Generally healthy volunteer, sometimes patients can be included. 47
Fig. 1.15: Depicts an ideal site for conducting phase I studies
WHO de nes healthy subject as ‘a person who is free from any abnormality
that would complicate interpretation of data or increase the sensitivity of the
subject to toxic potential of a drug.’ A summary of the main points raised in favor
Drug Discovery of healthy volunteers is as follows:
and Clinical
Research 1. Scienti c bene ts: In healthy volunteers there are no hurdles such as the
SK Gupta unknown parameters of disease condition and concomitant medication.
2. Practical bene ts: In healthy volunteers, physiological processes are well
understood and years of experience in terms of phase I trials has established
a strong infrastructure focused on facilities and healthy volunteer databases.
3. Regulatory bene ts: In terms of regulatory bene ts, guidance is well
INTRODUCTION TO DRUG DEVELOPMENT established and dialogue with regulators is simpler.
 PRECLINICAL DRUG DEVELOPMENT Healthy volunteer studies are well understood and can act as a reference
 CLINICAL DEVELOPMENT point to gain an understanding of a test compound.
 REGULATORY APPROVALS FOR There are a number of advantages for using healthy volunteers in early
REGISTRATION OF DRUGS phase clinical trials and such studies can often provide excellent data, more
 CLINICAL DATA MANAGEMENT quickly and at a lower cost. Healthy volunteers are more accessible, do not have
diseases or take medication that needs to be considered and can remain eligible
Of Biologics
 CHAPTER 3: Clinical Development Of New for similar studies in the future. In patient groups, the disease may not be stable
Drugs over time, there is a spectrum of disease ranging from mild to severe, they are a
 CHAPTER 4: Phase 0 Trials In Cancer Drug less accessible group and most patients would prefer to obtain therapeutic
Development
bene t which is not normally anticipated in phase I studies. It can also take
months to recruit su cient patients with speci c indications. In healthy
volunteers, physiological processes are well understood. Healthy volunteers also
 show an increased acceptance of frequent or complex sampling as well as 48
stricter controls such as diet and activities and there is a lower drop-out rate as
compared to patient groups. Although, not a normal practice, individuals with
mild but stable illness, such as hypertension or arthritis, could be considered for
phase I studies considering USFDA de nition of “normal subject”. FDA has
de ned normal subjects as those “individuals who are free from abnormalities
which could complicate the interpretation of the data from the experiment or
which might increase the sensitivity of the subject to the toxic potential of the
drug”. Thus, according to FDA de nition, subject/volunteers with mild stable
illness are considered healthy if they do not have disease for which drug is being
tested and the existing does not complicate with interpretation of data.
For certain disease conditions such as HIV or cancer, real patients who have
end-stage disease and lack other treatment options can be included in phase I
trials. Also for oncology or HIV trials, inclusion of healthy volunteers is ethically
not acceptable, as these drugs are known to have toxic effects.

DESIGN OF PHASE I STUDIES
Type of control: Phase I studies generally have placebo as control. Placebo as

control is needed to determine variation in adverse event, laboratory value
whether due to investigational agent or other in uencing factor like—subject
psychology (many subjects feel, since they are taking medication they should
show some adverse effect), environment (light, temperature, diet, caffeine)
and to evaluate common placebo symptoms like headache, dry throat,
lethargy, etc.
Subject selection: The healthy subjects are generally recruited based on the
following—
Inclusion criteria:
Healthy subjects
No clinically important abnormal physical ndings.
Normal clinically acceptable ECG, normal BP/heart rate.
Body Mass Index—19 to 29 kg/m2
Able to communicate
Competent and willing to give informed consent.
Drug Discovery Exclusion Criteria:

and Clinical
The subjects who have taken investigational drug in 0 to 45 days from the
Research
start of study
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The subjects who have taken any prescribed medicine for 0 to 30 days/any
over-the-counter drugs (0–5 days) from the start of study
The subjects who have donated or lost blood, 0 to 12 weeks from the start of
study
INTRODUCTION TO DRUG DEVELOPMENT Subjects who are unable to communicate
Subjects who are chronic alcoholics and smokers
Female subjects especially if pregnant or at risk of pregnancy or lactating 49
 PHARMACOVIGILANCE Subjects suffering from asthma, neurological, neuromuscular, renal, cardiac,
 REGULATORY APPROVALS FOR hepatic or psychiatric diseases
 CLINICAL DATA MANAGEMENT Subjects who are hypersensitive to drugs
Of Biologics
Randomization and blinding: The allocation of subjects to either group is
 CHAPTER 3: Clinical Development Of New determined by a formal randomization procedure. The level of blinding could
Drugs be either open labeled, single blinded or double blinded
Development
Type of trial design: Either the parallel or crossover design is used in phase I
 CHAPTER 5: Bioethics In Clinical Research studies. However, crossover designs are less commonly used, due to
carryover effect and need for washout period
 Dosing: The rst dose to be administered in humans needs to be estimated to

safeguard the safety of the volunteers. All available information has to be
taken into consideration for the dose selection and this has to be made on a
case-by-case basis.
Estimation of the rst dose in humans: The starting dose will be determined on
the basis of data from animals (two species), in particular, NOAEL (No observed
adverse effect level) is the highest dose level of drug which does not produce a
signi cant increase in adverse effects). It is determined in nonclinical safety
studies performed in the most sensitive and relevant animal species, adjusted
with allometric factors (various conversion steps to calculate rst human dose,
given by FDA) or on the basis of pharmacokinetics which gives the most
important information. The relevant dose is then reduced/ adjusted by
appropriate safety factors according to the particular aspects of the molecule
and the design of the clinical trials.
For high-risk medicinal products, an additional approach to dose calculation

should be taken. The use of ‘minimal anticipated biological effect level’ (MABEL)
approach is recommended. The MABEL is the anticipated dose level leading to a
minimal biological effect level in humans. Safety factors are usually applied for
the calculation of the rst dose in man from MABEL.
The calculation of MABEL should utilize all relevant in vitro and in vivo
available information from pharmacodynamic/pharmacokinetic data such as:
Receptor binding and receptor occupancy studies in vitro in target cells from
human and the relevant animal(s) species and in vivo in the relevant animal
species
Concentration-response curves in vitro in target cells from human and the
relevant animal(s) species and dose response in vivo in the relevant animal
species
Exposures at pharmacological doses in the relevant species
When the methods of calculation (e.g. NOAEL, MABEL) give different
estimations of the rst dose in man, the lowest dose should be used.
Dose escalation scheme: Phase I trials include dose-ranging, also called dose
escalation studies so that the appropriate dose for therapeutic use can be found.
The tested range of doses will usually be a fraction of the dose that causes harm
in animal testing. 50
Drug Discovery
and Clinical
Research
SK Gupta

INTRODUCTION TO DRUG DEVELOPMENT Fig. 1.16: Single ascending dose (SAD)

The dose ranging studies in phase I studies include—Single ascending dose and
multiple ascending dose ranging studies.
 PHARMACOVIGILANCE Single ascending dose (SAD) studies: Single Ascending Dose studies are
 REGULATORY APPROVALS FOR those in which small groups of subjects are given a single dose of the drug
while they are observed and tested for a period of time. The dose that is
 CHAPTER 2: Drug Discovery And Developmen considered to be safe is about 1 to 2 percent of the maximum tolerated dose
Of Biologics in animals (Fig. 1.16).
 CHAPTER 3: Clinical Development Of New Procedure:
Drugs
The subjects are screened and selected based on the inclusion/exclusion
Development criteria. The subjects are then hospitalized, their blood and urine samples are
 CHAPTER 5: Bioethics In Clinical Research analyzed before drug dosing. The samples obtained before dosing are
referred to as trough samples. Once the subjects are dosed with the drug, the
 blood and urine samples are analyzed every four hours from their rst dose.
ECG is to be monitored for the initial 4 to 6 hours from the rst dose
administered. Dosing should be done at the same time for each dose
increment. The nal samples are collected 24 to 48 hours after dosing. The
subject's posture should be standardized. The subjects before being
discharged would be physically examined, ECGs repeated, blood and urine
samples analyzed and asked to report for follow-up after a period of 4 to 7
days from their rst dose. If they do not exhibit any adverse side effects and
the pharmacokinetic data is roughly in line with predicted safe values, the
dose is escalated and a new group of subjects is then given a higher dose.
This is continued until precalculated pharmacokinetic safety levels are
reached, or intolerable side effects start showing up (at which point the drug
is said to have reached the maximum tolerated dose)
Multiple ascending dose (MAD) studies: Multiple ascending dose studies start
after a successful SAD result is obtained. These studies are done for a period
of 14 days; however the time period can vary, some drugs can be tested for a
period of 5 days or for 4 weeks depending on the indication of use. The
interval between doses would be one half-life.
Procedure:
The screening and selection of subjects is done based on the
inclusion/exclusion criteria and tests conducted are similar to the SAD, but the
trough sample has to be analyzed before the next dose is to be administered. 51
Multiple Ascending Dose studies are conducted to better understand the
pharmacokinetics and pharmacodynamics of multiple doses of the drug. In
these studies, a group of patients receives multiple low doses of the drug,
whilst samples (of blood and other uids) are collected at various time points
and analyzed to understand how the drug is processed within the body. The
dose is subsequently escalated for further groups, up to a predetermined
level.
Pharmacokinetic/Pharmacodynamics: Clinical pharmacokinetics and

pharmacodynamics are indispensable source of information for drug
development.
Pharmacokinetics, the study of drug disposition in the body, is an integral

part of drug development and rational use. Knowledge and application of
pharmacokinetic principles leads to accelerated drug development, cost

effective drug use and a reduced frequency of adverse effects and drug
interactions. They are essential to establish therapeutic schedules, to evaluate
Drug Discovery their relevance or to proceed to dosage adjustments in particular patients. This
and Clinical particularly applies to medicinal products with a narrow therapeutic range and to
Research
those for which a close relation between plasma concentrations and therapeutic
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and/or toxic effects can be demonstrated or expected.
In some instances, pharmacokinetic studies may be impossible or limited,

e.g. where their provision raises insuperable di culties or would create risks for
test subjects; in these cases, the use of medicinal product is partly or completely
INTRODUCTION TO DRUG DEVELOPMENT based upon pharmacodynamic and clinical studies.
This consists of two sections:
Pharmacokinetic factors to be studied which deal with:
 REGULATORY APPROVALS FOR Absorption
Distribution
 CHAPTER 2: Drug Discovery And Developmen Metabolism
Of Biologics
Elimination, as well as with interactions and adverse reactions.
Drugs
Methodology and conditions of study which deals with:
Development
Choice of administration (route, dosage, dosage intervals)
Choice of subject (healthy volunteers, patients with relevant disorders,
patients with other interfering conditions)

Choice of methodology (sampling and analysis, data processing and
statistics).
A precise pharmacokinetic analysis of the entire plasma pro le, including

absorption, distribution and elimination, should be given since these various
steps may be interrelated to a great extent. This applies particularly to special
dosage forms for which delayed release of the active substance or a prolonged
duration of action is claimed. Failing this, at least data on substance
concentration at peak (Cmax), time to reach peak (Tmax) and area under the
concentration/time curve (AUC) should be provided. 52
The elimination rate for the parent compound (e.g. total body clearance,
elimination half-life) should be studied in volunteers with normal elimination
mechanisms. The nature of the main routes of elimination and their relative
importance in regard to total elimination should be known.
The pharmacokinetic parameters of most drugs are not expected to change

when different doses are administered or when the drug is given through
different routes of administration or as single or multiple doses. However, for
some drugs the pharmacokinetic parameters change. Hence, in such cases it is
essential to determine the nonlinear kinetic properties (i.e. properties that
change based on the dose of the drug) of drugs.
Pharmacodynamic studies are done to measure drug concentration related

to response: dose-response relationship and also to get an idea of dosage and
dosage regimen.
The procedure for conducting phase I studies would be:
Subject recruitment
Informed consent
Screening
Recording baseline parameters
Drug administration
Blood sampling
Recording post-treatment parameters
Analysis of biological samples (blood) for drug levels

Data collection, data analysis, statistical analysis and report generation.
Drug Discovery Outcome from phase I studies: At the end of phase I studies the sponsor should
and Clinical be ready with:
Research
Safe dose range (the range which indicates the amount of drug that may be
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prescribed safely within the framework of usual medicine practice)
Bioavailability data depending on Cmax (the maximum concentration of a drug
in the body after dosing), Tmax (the time taken to reach maximum
concentration), AUC (area under curve) is a mathematical calculation to
evaluate the body's total exposure over time to a given drug. AUCs are used as
a guide for dosing schedules and to compare the different drugs’ availability in
 PRECLINICAL DRUG DEVELOPMENT the body), the half-life, metabolic pathway of the drug, metabolites, the route
 CLINICAL DEVELOPMENT and rate of excretion (Fig. 1.17)
 PHARMACOVIGILANCE Nature of adverse drug reactions
REGISTRATION OF DRUGS Secondary objectives like drug activity, potential therapeutic bene ts.

Of Biologics
PHASE I IN INDIA
Drugs
 CHAPTER 4: Phase 0 Trials In Cancer Drug Schedule Y requirements to conduct phase I in India:
Development
 CHAPTER 5: Bioethics In Clinical Research Phase I clinical trials are done to determine the maximum tolerated dose in
humans; pharmacodynamic effects; adverse reactions, if any, with their nature
and intensity; as well as the pharmacokinetic properties of the drug 53

Fig. 1.17: Phase I
At least 2 subjects should be used for each dose. These studies may be
carried out in one or two centers
According to the proposed changes of Schedule Y; apart from Indian
companies, foreign companies that share intellectual property rights with an
Indian based pharmaceutical company can conduct phase I trials for a new
drug.
Advantages and challenges in conducting phase I clinical trial
Advantages:
Pharmacokinetic, pharmacodynamic and safety pro le of a drug is obtained.
Challenges:
Ethical issues arise due to the inclusion of healthy volunteers as study

subjects
Stringent monitoring of the subjects is required, as it is the rst time humans
are exposed to the new drug and unexpected drug reactions can occur.

PHASE II CLINICAL TRIALS
Drug Discovery Once the initial safety of the study drug has been con rmed in phase I trials,
and Clinical phase II trials are performed to assess how well the drug works (e cacy), as
Research well as to continue phase I safety assessments in a large group (20–300) of
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patient volunteers. When the development process for a new drug fails, it is
usually during phase II trials when the drug candidate does not work as intended,
or has toxic effects. If the failure is due to the toxic effects of the drug, the
development of the drug is abandoned. On the other hand, if the failure is 54
 CHAPTER 1: New Drug Development associated with e cacy, the sponsor (R & D department) will perform further
INTRODUCTION TO DRUG DEVELOPMENT research (formulation and basic molecular research) to analyze the unfavorable
 DRUG DISCOVERY PROCESS effects of the drug. The sponsor can reinitiate the trial (from phase I) for the
modi ed drug molecule.
 PHARMACOVIGILANCE Objectives of phase II clinical studies:
REGISTRATION OF DRUGS To explore the therapeutic e cacy and safety of the new medicinal product
Aim at identifying the side effects most commonly associated with the new
Of Biologics medicinal product
 CHAPTER 3: Clinical Development Of New Provide essential risk bene t assessment before more new patients are
Drugs
exposed to the new drug.
Development
Additional objectives are:
Evaluation of potential end points
 Therapeutic regimens
Target populations for further studies in phases II and III.
Prerequisites for phase II trials:
Preclinical safety data: Animal toxicity which needs to be completed before

start of phase II studies along with those completed before phase I are—
repeated dose toxicity studies in two species for a period of time equivalent to
length of phase II studies, pharmacokinetic studies, mutagenicity studies (in
vitro and in vivo)
Early phase clinical trial data: Outcome of phase I studies (preliminary safety)
—generally well tolerated, no signi cant adverse events
Regulatory authority and ethics committee approval.
Types of phase II trial: Phase II studies are sometimes divided into phase IIA and
phase IIB. Early phase II trials use a dosage that has been observed to be safe in
phase I trials to investigate the pharmacological effects of the new medicinal
product and to establish if this is a therapeutically useful intervention or not and
may involve only single doses of the drug. Later phase II trials are conducted in
patients to establish a safe dose regimen.
Some trials combine phase I and phase II and test both e cacy and toxicity.
Conduct of the phase II trial and players in phase II:
Site: Phase II studies are conducted in specialized hospital units and are
closely monitored by trained investigator. There should be standard facilities
to handle an emergency or a serious unexpected adverse event at the site.
The medical staff, paramedical staff should be quali ed, skilled to handle
emergencies; should be trained in basic life support and also advanced life
support. Phase IIa studies are conducted in single site but phase IIb studies
are conducted at more than one center hence they are also known as
multicentric studies
Subjects: In phase II studies around 50 to 300 participants who are patients
will be administered the investigational new drug. Phase II is usually the rst
time that patients rather than healthy volunteers are exposed to the new drug. 55
Trial design: Some phase II trials are designed as case series, demonstrating a
drug's safety and activity in a selected group of patients. Other phase II trials are
designed as randomized controlled clinical trials, where some patients receive
Drug Discovery the drug/device and others receive placebo/standard treatment. Randomized
and Clinical phase II trials have far fewer patients than randomized phase III trials (as it is the
Research
rst time patients are exposed to new drug in phase II, inclusion criteria will be
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narrow/stringent, thus the available patient pool meeting this stringent inclusion
criteria will be less).
Phase IIa design components are pilot, single centric, open labeled studies
conducted on small number of homogenous group of patients. Phase II A is
INTRODUCTION TO DRUG DEVELOPMENT speci cally designed to asses dosing regimens, i.e. how much drug should be
 DRUG DISCOVERY PROCESS given.
‘Pilot studies’ refers to a smaller version of a larger study. Conducting a pilot
 PHARMACOVIGILANCE study does not guarantee success in the main study, but it does increase the
 REGULATORY APPROVALS FOR likelihood, by providing a range of important functions and valuable insights for
other researchers. Thus researchers may start with “qualitative data collection
and analysis on a relatively unexplored topic, using the results to design a
Of Biologics subsequent quantitative phase of the study”.
Drugs Phase IIb studies are pivotal, single or double blind, randomized cross over,
 CHAPTER 4: Phase 0 Trials In Cancer Drug multicentric studies conducted on heterogeneous population. Phase II b is
Development
speci cally designed to study e cacy, i.e. how well the drug works at the
prescribed doses.
 Pivotal studies are those studies which will result in important decisions
being made about the medicine and are crucial to draw an inference on e cacy
and safety. The results of pivotal studies are identi ed by the sponsor for
regulatory authority to judge the e cacy and safety of the drug.
Phase II studies are comparative studies, where the comparator could be the
placebo or the active comparator called the gold standard. Scienti cally,
comparison to a placebo is required to assess the e cacy of the new drug but a
standard drug should be used as comparator if there are ethical issues (e.g. in
case of a severe disease condition patient requires a treatment, as placebo has
no effect it is not justi ed).
Procedure of phase II studies:
Pretrial activities are completed to prepare the site to conduct the trial
Suitable subjects with the target disease are identi ed
Informed consent process is completed
Screening procedures are carried out
After con rming the eligibility criteria suitable subjects are enrolled into the
trial
Randomization procedures are done
Subject is given the study drug
Subject is recalled as per the protocol visit schedule to do the protocol
required lab tests
Data obtained is sent to sponsor entered in Case Report Form
Data collected are analyzed 56
Depending on the data obtained the sponsor decides whether it is worthwhile

to proceed further.
A precise pharmacokinetic analysis of the entire plasma pro le, including

absorption, distribution and elimination would be evaluated. If the results of the
phase II trials show that a new treatment may be as good as the existing
treatment or better, it then moves on to phase III.
Outcome of Phase II trial:
Safe dosage schedule: It can be determined based on the safety (phase I) and
e cacy (phase II) results obtained
Characterization of dose-response curve: The graphical representation of the
Drug Discovery responses to the test drug at different dose levels is obtained
and Clinical
Research Clinical bene t (Placebo/Active control): E cacy of drug is obtained and an
SK Gupta initial comparison of the e cacy of test drug with standard marketed drug is
obtained
Pharmacokinetic characteristics of the drug in patients
Nature of adverse drug reaction: Phase II trials subjects have the disease
condition that is being treated by the test drug. Therefore in this phase the
INTRODUCTION TO DRUG DEVELOPMENT possible adverse drug reactions that can be experienced by patients are
 DRUG DISCOVERY PROCESS identi ed (Fig. 1.18).

PHASE II IN INDIA
 CLINICAL DATA MANAGEMENT Schedule Y requirements to conduct phase II in India:
Of Biologics Phase II clinical trials are done to determine possible therapeutic use,
 CHAPTER 3: Clinical Development Of New effective dose range and to further evaluate safety and pharmacokinetics
Drugs
Normally, 10 to 12 patients should be studied at each dose level. These
Development studies are usually limited to 3 to 4 centers.
If the application is for the conduct of clinical trials as a part of multi-national
clinical development of the drug, the number of sites and patients as well as
 the justi cation for undertaking such trials in India should be provided to
licensing authority along with the application.
Advantages and challenges in conducting phase II clinical trial:
Advantages:
E cacy of test drug is determined. Only if a positive result is obtained in this

phase, the dosing schedule for phase III is designed.
Challenges:
If positive results are not obtained during this phase dosage schedule cannot
be determined for phase III. Most often, drug failure is seen in this phase.
PHASE III CLINICAL TRIALS: (THERAPEUTIC CONFIRMATORY

TRIALS)
Phase III studies are also known as “Therapeutic con rmatory trials”. They are
performed after preliminary evidence suggesting effectiveness of the drug has
been obtained in phase II. 57
Drug Discovery
and Clinical
Research
SK Gupta

Of Biologics
Drugs
Development
Fig. 1.18: Phase II
They are intended to gather additional information about effectiveness and

safety that is needed to evaluate the overall bene t-risk relationship of the drug.
Phase III studies also provide an adequate basis for extrapolating the results to
the general population and transmitting that information in the physician
labeling. Even at this nal stage of drug development, protocol will still exclude
many ‘real world’ patients, e.g. those with other serious medical conditions,
women of child bearing age unless using accepted contraceptive precaution. 58
Phase III studies usually include several hundred to thousand patients.

Because of their size and comparatively long duration, phase III trials are the
most expensive, time-consuming and di cult trials to design and conduct.
Data obtained from phase III is the major component of New Drug
Application. The studies carried out in phase III complete the information
needed to support adequate instructions for use of the drug (prescribing
information). All features should represent regulatory requirements and
proposed clinical use after marketing.
Objective(s) of phase III clinical trial: Primary objective of phase III clinical trial is
to con rm the therapeutic bene t(s). They are designed to con rm the
preliminary evidence accumulated in phase II that a drug is safe and effective for
use in the intended indication and recipient population. In this phase,
investigational product is generally compared with standard treatment.
The other objectives of phase III trial are to:
Determine the optimum dosage schedule for general use, safety and e cacy
of the investigational product in combination with other drug(s)
Identi cation of the disease sub types for which drug is effective
Study on special population such as renal and hepatic insu ciency, lactating
women, elderly population
Special studies like food/liquid interaction, drug-drug interaction
Study on patients of different ethnic groups

Phase III trials can also have HRQL (health related quality of Life) and
pharmacoeconomic studies as secondary objective.
Drug Discovery
and Clinical In HRQL studies, effect of investigational product on quality of life of
Research individuals can be assessed. Pharmacoeconomic studies involve comparison of
SK Gupta cost and outcome of medical intervention.
Prerequisites for phase III trials:
Preclinical safety data: Safety data will be collected throughout the

development process. In the early stages reliance is placed upon
INTRODUCTION TO DRUG DEVELOPMENT understanding the class effect where other drugs belonging to the same class
 DRUG DISCOVERY PROCESS already exist. As development process progresses speci c safety data
 PRECLINICAL DRUG DEVELOPMENT collection becomes vital. Animal toxicity which needs to be completed before
start of phase III studies along with those completed before phases I and II
are chronic toxicity, carcinogenicity, in vivo genotoxicity, segment II
REGISTRATION OF DRUGS reproductive toxicity study(if female of childbearing age to be involved in the
 CLINICAL DATA MANAGEMENT study) and supplemental studies
Of Biologics
Early phase clinical trial data: Outcome of phase I studies (preliminary safety)
 CHAPTER 3: Clinical Development Of New —generally well tolerated, no signi cant adverse events; outcome of phase II
Drugs studies (preliminary e cacy)—dose-response relationship, no signi cant
 CHAPTER 4: Phase 0 Trials In Cancer Drug adverse events
Development
 CHAPTER 5: Bioethics In Clinical Research Regulatory authority and ethics committee approval: Ethics committee
approval may be rate limiting step as approval is required from each of the
participating site.
 59

TYPES OF PHASE III TRIALS
Phase III a—compulsory; regulatory requirement for NDA submission; patient

population in large number or in a special category
Phase III b—Extended trials of IIIa after NDA submission; done before launch
as a marketing need. These are conducted predominantly for marketing
purposes and are sometimes intended as the main support for the required
cost/value arguments. Typically market leader is used as comparator, to
achieve a bene t over and above that of the existing drug, thus enabling the
marketing and sales groups to maximize performance after launch. Explores—
new patient population, new indications, special drug features.
CONDUCT OF THE TRIAL AND PLAYERS IN PHASE III
Site: Multispeciality hospital with adequate patient attendance and laboratory

facilities. Less specialized investigator.
Subjects: Patient population of around 250 to 1000 with broader inclusion
criteria are included.
Clinical trial design: Common clinical trial design in phase III is “multicentric,
randomized, controlled and blinded study”.
Types of control: The objective of phase III will be to compare the extent of
e cacy and safety with that of currently used therapies. Placebo can be used
as comparator in phase III, if there is no standard treatment for the disease or
the standard treatment is ineffective.
When selecting active/standard comparator, countries where the study is to
be carried out, registration status of the potential comparator and dosing
regimens of the potential comparator should be considered.
Control in phase III can also be concurrent control-dose comparison, wherein
different dose regimens of same treatment are compared, e.g. comparison of
200 mg and 400 mg of ibuprofen for pain.
Patient population: Patient population included should be representative of

general patient population. Factors to be considered for inclusion and
exclusion criteria are:
Drug Discovery Nature and history of the disease: Inclusion criteria in the protocol should
and Clinical mention clearly patient with which disease and severity of the disease to be
Research
included, without which there could be variability in the response to treatment.
SK Gupta
For example, for an antihypertensive medication trial, inclusion criteria should
be expressed in terms of diastolic blood pressure between X mm Hg and Y
mm Hg.
Concurrent disease and concomitant medication: Presence of concurrent
 CHAPTER 1: New Drug Development disease and concomitant medication along with target disease may in uence
INTRODUCTION TO DRUG DEVELOPMENT the study drug through metabolic interaction, which might affect the
interpretation of results. As the aim of phase III is to evaluate the treatment in
a situation approximating real life, inclusion of patient with concurrent disease
with/without medication needs to be considered with diligence. 60
 REGULATORY APPROVALS FOR In uence of disease indication on trial design: The duration of the trial, the
timing of each subject's treatment and the number and timing of assessments
will depend on whether disease is an acute condition or of chronic type.
Of Biologics Acute conditions will require a short treatment period and as these types of
 CHAPTER 3: Clinical Development Of New disease remit spontaneously within certain time; subjects should be entered
Drugs
into the study within one day of onset and assessment to be carried out more
Development frequently to detect early signs of e cacy.
 CHAPTER 5: Bioethics In Clinical Research In chronic diseases, signs and symptoms of the disease will be stable for long
periods dictating study of six months or more duration, with monthly
assessments carried out for e cacy. If patients are already receiving

treatment, withdrawal of current therapy must be carefully considered so as
not to destabilize the subject without justi cation. If it, is justi ed, adequate
wash out period must be provided to remove the effect of the previous
therapy and to prevent drug-drug interaction.
When withdrawal of current therapy is not justi able, subjects who are newly
diagnosed with the condition can be included. However, number of subjects
available will be considerably less as compared to total population suffering
from the disease requiring longer time to recruit the subjects.
Need to withdraw current treatment can be avoided by designing a trial where
test treatment is added to the current treatment (add-on trial). This implies
that current therapy is inadequate and that measurable improvement can be
gained, either in terms e cacy or safety by new drug.
Randomization and blinding: In phase III trial, each center acts as strata and
within each center randomization like simple randomization or strati cation is
used. Strati cation is used when there are differences in the nature of the
disease in severity or site and responses to treatment might differ due to this.
For example, in an analgesic trial, subjects can be strati ed according to pain
severity into mild, moderate and severe, where the response might differ. Each
stratum can be analyzed separately if required.
Double-blind is the preferable design in phase III trial. However, single blinding
or open-label design can be used if it is appropriate.
Types of trial design: Either parallel, crossover, or factorial design
Duration of dosing: Duration of dosing is determined by factors like

pharmacokinetics, mode of action and natural history of the disease being
treated. The results from phase II will be the guiding factor in deciding the
dosing schedule.

METHODS OF CLINICAL MEASUREMENT (REFER PAGE 42)
A central laboratory should be used in order to prevent variable results that

may arise due to differences in lab procedures, for studies which have a
laboratory parameter as the main e cacy assessment. 61
Procedure of phase III studies:
Pretrial activities are completed to prepare the site to conduct the trial
Drug Discovery Suitable subjects with the target disease are identi ed
and Clinical Informed consent process is completed
Research
Screening procedures are carried out
SK Gupta
After con rming the eligibility criteria, suitable subjects are enrolled into the
trial
Subjects are randomly allocated to different groups
Subjects are given the study/comparator drug
INTRODUCTION TO DRUG DEVELOPMENT Individual patient in clinical trial is monitored by the investigator which may be
 DRUG DISCOVERY PROCESS equal to or greater than standard of care
Subject is recalled as per the protocol visit schedule to do the protocol
required lab tests
 REGULATORY APPROVALS FOR Periodic monitoring from sponsor's personnel (frequency of which depends
on the trial duration)
Data obtained is sent to sponsor in the form of completed Case Report Form
Of Biologics
Depending on risk involved in the trial there can be interval protocol
Drugs
monitoring by independent monitoring committee
 CHAPTER 4: Phase 0 Trials In Cancer Drug Data collected are analyzed.
Development
 CHAPTER 5: Bioethics In Clinical Research If the results of the phase III trials show that a new treatment may be as
good as the existing treatment or better, the sponsor can apply for marketing
 approval.
Outcome from phase III trial:
The e cacy of the test drug is con rmed in a more realistic population (Fig.
1.19)
The e cacy of test drug in special population (such as children or pregnant
women) is obtained
Fig. 1.19: Phase III 62
Tolerability and safety: In this phase the preliminary results pertaining to

safety, e cacy and dosage schedule obtained during phase I and II are
con rmed
Advantages/disadvantages over standard treatment are obtained.
PHASE III IN INDIA
Schedule Y requirements to conduct phase III in India:
Phase III clinical trials are done to obtain su cient evidence about the
e cacy and safety of the drug in a large number of patients generally in
comparison with a standard drug and/or placebo
If the drug is a new drug discovered in India and/or not marketed in any other
country, data should be generated on at least 500 patients distributed over 10
to 15 centers. In addition, postmarketing surveillance on large number of
Drug Discovery patients is a must for detecting adverse drug reactions
and Clinical
For new drugs approved outside India, phase III studies need to be carried out
Research
primarily to generate evidence of e cacy and safety of the drug in Indian
SK Gupta
patients when used as recommended in the prescribing information. Data
should be generated in at least 100 patients over 3 to 4 centers
Prior to conduct of phase III studies in Indian subjects, licensing authority may
require pharmacokinetic studies to be undertaken to verify that the data
generated in Indian population is in conformity with the data already
generated abroad
 PRECLINICAL DRUG DEVELOPMENT If the application is for the conduct of clinical trials as a part of multi-national
 CLINICAL DEVELOPMENT clinical development of the drug, the number of sites and patients as well as
 PHARMACOVIGILANCE the justi cation for undertaking such trials in India should be provided to
Licensing Authority along with the application.
Advantages and challenges in conducting phase III clinical trial
Of Biologics
Advantages
Drugs
Therapeutic con rmation of the investigational product
Development Due to less stringent inclusion and exclusion criteria, recruitment of subject is
 CHAPTER 5: Bioethics In Clinical Research relatively easy
Simultaneous generation of large data
 Results from phase III trial are generalizable.
Challenges: Phase III trial is conducted at multiple centers with a single protocol.
Thus, the protocol needs to be designed accordingly. Following are the
challenges faced during conduct of phase III trial:
IEC/IRB approval should be obtained for each site/center involved, which

might lead to unexpected delay
Patient recruitment—requires large and heterogeneous population, leading to
longer duration and greater cost
Arranging investigators’ meet
Training of staff and monitoring the trial 63
Clinical trial supplies—to be supplied on time to all centers taking into

consideration the expiry date and stability data of the new drug
Central laboratory—sample supply to laboratory
Centralized data management and analysis
Different study outcomes—di cult to interpret
Drafting of a common nal report and publication issues.
Once a drug has proven to be satisfactory, the trial results are usually
combined into a large document containing a comprehensive description of the
methods and results of human and animal studies, manufacturing procedures,
formulation details and shelf-life. This collection of information makes-up the
“regulatory submission” that is provided for review to the appropriate regulatory
authorities in different countries so they can then grant the sponsor approval to
market the drug.

NDA APPLICATION
NEW DRUG APPLICATION (NDA) REVIEW PROCESS
The NDA application is the vehicle through which drug sponsors formally
propose that the FDA approve a new pharmaceutical for sale and marketing in
the US. The data gathered during animal studies and human clinical trials of an
investigational new drug (IND) becomes part of the NDA. Once the sponsor has
completed phase IIIa successfully and is ready with the clinical study report the
Drug Discovery application to market drugs can be led through an NDA application. Following
and Clinical the completion of all three phases of clinical trials, the company analyses all the
Research
data and les an NDA with FDA in the form of a dossier.
SK Gupta
The clinical study report is a document containing the description of the

trial, this when submitted as part of the NDA must comply with requirements as
given in ICH E3 when sponsor has to make the submission to USFDA, EMEA,
MHLW. The sponsor has to follow the requirements listed in Appendix II of
INTRODUCTION TO DRUG DEVELOPMENT Schedule Y to submit the clinical study reports to the regulatory authority of
 DRUG DISCOVERY PROCESS India. The NDA must contain all the scienti c information, safety and e cacy
 PRECLINICAL DRUG DEVELOPMENT data collected during the trials. The NDAs typically run 100,000 pages or more.
 CLINICAL DEVELOPMENT By law, FDA is allowed to take around six months to review an NDA.
 REGULATORY APPROVALS FOR The ICH M4 guideline is for the organization of Common technical
document (CTD) which refers to the application format—a dossier/research
binder for regulatory submission for marketing approval of a drug. CTD helps the
Of Biologics sponsor as it provides a common format for the preparation of technical
 CHAPTER 3: Clinical Development Of New documentation to support a NDA that will be submitted to the regulatory
Drugs
authorities. CTD also reduces time and resources needed to compile the dossier
Development
for different regulatory submissions.
CTD has 5 modules which are as follows:
1. Administrative and prescribing information


2. Overview and summary of modules 3 to 5 64
3. Quality (pharmaceutical documentation)

4. Safety (toxicology studies)
5. E cacy (clinical studies).
The goals of the NDA are to provide enough information to permit FDA
reviewer to reach the following key decisions:
Whether the drug is safe and effective in its proposed use(s) and whether the
bene ts of the drug outweigh the risks
Whether the drugs proposed labeling (package insert) is appropriate and what
it should contain
Whether the methods used in manufacturing the drug and the controls used
to maintain the drug's quality are adequate to preserve the drug's identity,
strength, quality and purity.
NDA CONTENT AND FORMAT REQUIREMENTS
The documentation required in an NDA is supposed to tell the drug's whole story,
including what happened during the clinical tests, what the ingredients of the
drug are, the results of the animal studies, how the drug behaves in the body and
how it is manufactured, processed and packaged. The following resources
provide summaries on NDA content, format and classi cation, plus the NDA
review process.
As outlined in Form FDA-356h, Application to Market a New Drug for Human

Use or as an Antibiotic Drug for Human Use, NDAs consist of as many as 15
different sections:
1. Index
2. Summary
3. Chemistry, manufacturing and control
4. Samples, methods validation package and labeling
5. Nonclinical pharmacology and toxicology
6. Human pharmacokinetics and bioavailability

7. Microbiology (for antimicrobial drugs only)
8. Clinical data
Drug Discovery
and Clinical 9. Safety update report (typically submitted 120 days after the NDA's
Research submission)
SK Gupta 10. Statistics
11. Case report tabulations
12. Case report forms
13. Patent information
INTRODUCTION TO DRUG DEVELOPMENT 14. Patent certi cation
 DRUG DISCOVERY PROCESS 15. Other information.
 CLINICAL DEVELOPMENT Although the exact requirements are a function of the nature of a speci c
 PHARMACOVIGILANCE drug, the NDA must provide all relevant data and information that a sponsor has
 REGULATORY APPROVALS FOR collected during the product's research and development.
 CLINICAL DATA MANAGEMENT CDER classi es new drug applications with a code that re ects both the
type of drug being submitted and its intended uses. The numbers 1 through 7
Of Biologics
are used to describe the type of drug: 65
Drugs
1. New molecular entity
Development 2. New salt of previously approved drug (not a new molecular entity)
3. New formulation of previously approved drug (not a new salt OR a new
molecular entity)
 4. New vombination of two or more drugs
5. Already marketed drug product-duplication (i.e. new manufacturer)
6. New indication (claim) for already marketed drug (includes switch in
marketing status from prescription to OTC)
7. Already marketed drug product—no previously approved NDA
The following letter codes describe the review priority of the drug:
S—Standard review for drugs similar to currently available drugs.
P—Priority review for drugs that represent signi cant advances over existing
treatments.
After a NDA is received by the agency, it undergoes a technical screening

generally referred to as a completeness review. This evaluation ensures that
su cient data and information have been submitted in each area to justify
“ ling” the application, i.e. justifying initiating CDER's formal review of the NDA.
NDA's that are incomplete become the subject of a formal “refuse-to- le”
action. In such cases, the applicant receives a letter detailing the decision and
the de ciencies that form its basis. This decision must be forwarded to the
sponsor within 60 calendar days after the NDA is initially received by CDER.
Medical reviewers are responsible for evaluating the clinical sections of

submissions, such as the safety of the clinical protocols in an IND or the results
of this testing as submitted in the NDA.
Biopharmaceutical reviewers evaluate the rate and extent to which the drug's
active ingredient is made available to the body and the way it is distributed in,
metabolized by and eliminated from the human body.
Statisticians evaluate the statistical relevance of the data in the NDA with the
main tasks of evaluating the methods used to conduct studies and the various
methods used to analyze the data.
Each review division employs a team of chemists responsible for reviewing

the chemistry and manufacturing control sections of drug applications related to
drug identity, manufacturing control and analysis.
The clinical microbiology information is required only in NDAs for anti-

infective drugs. Since these drugs affect microbial, rather than human
physiology, reports on the drug's in vivo and in vitro effects on the target
Drug Discovery microorganisms are critical for establishing product effectiveness.
and Clinical
Research CDER uses advisory committees to obtain outside advice and opinions from
SK Gupta expert advisors so that nal agency decisions will have the bene t of wider
national expert input. Committee recommendations are not binding on CDER,
but the agency considers them carefully when deciding drug issues. During the
course of reviewing an application, CDER usually communicates often with
sponsors about scienti c, medical and procedural issues that arise during the
INTRODUCTION TO DRUG DEVELOPMENT review process. 66

Of Biologics
Drugs
Development
Flow chart 1.2: NDA review process

Source: Http://Www.Washingtonlifescience.Com/Patient/Drug_develop/Nda.Htm
Communications may take the form of telephone conversations, letters, faxes or

meetings (either face-to-face or via video conferencing) (Flow Chart 1.2).

NOTIFICATION OF EASILY CORRECTABLE DEFICIENCIES
CDER makes every effort to communicate promptly to applicants easily

correctable de ciencies found during the review of an application. CDER also
informs applicants of the need for more data or information, or for technical 67
changes in the application needed to facilitate the agency's review. This type of
early communication would not ordinarily apply to major scienti c issues, which
require consideration of the entire pending application by agency nal decision
makers as well as by reviewing staff. Instead, major scienti c issues are usually
addressed in an action letter at the end of the initial review process.

END OF REVIEW CONFERENCE
At the conclusion of CDER's review of an application, there are three possible

action letters that can be sent to the sponsor:
1. Not approvable letter: lists the de ciencies in the application and explains why
the application cannot be approved.
2. Approvable letter: signals that, ultimately, the drug can be approved. It lists
Drug Discovery
minor de ciencies that can be corrected, often involves labeling changes, and
and Clinical
possibly requests commitment to do postapproval studies.
Research
SK Gupta 3. Approval letter: states that the drug is approved. It may follow an approvable
letter, but can also be issued directly.
In some cases, an applicant may seek to augment the information provided

in the original NDA during the review process. For example, the applicant may
 CHAPTER 1: New Drug Development submit a new analysis of previously submitted data or information needed to
INTRODUCTION TO DRUG DEVELOPMENT address a de ciency in the drug application. Any such information provided for
an unapproved application is considered an NDA amendment. The submission
of a signi cant amendment may result in an extension of FDA's time line for
application review.
When an NDA nears approval, agency reviewers evaluate draft package
 CLINICAL DATA MANAGEMENT labeling for accuracy and consistency with the regulatory requirements for
 CHAPTER 2: Drug Discovery And Developmen applicable prescription or over-the-counter drugs. Each element of the proposed
Of Biologics
labeling, including indications, use instructions, and warnings, is evaluated in
Drugs
terms of conclusions drawn from animal and human testing. All claims,
 CHAPTER 4: Phase 0 Trials In Cancer Drug instructions, and precautions must accurately re ect submitted clinical results.
Development The labeling “negotiation process,” through which a drug's nal approved
 CHAPTER 5: Bioethics In Clinical Research labeling is agreed upon, can take a few weeks to many months. The length of the
process depends upon the number of agency comments and an applicant's
 willingness to reach agreement.
There is also extensive communication between review team members. If a

medical reviewer's reanalysis of clinical data produces results different from
those of the sponsor, e.g. the reviewer is likely to forward this information to the
statistical reviewer with a request for a statistical reanalysis of the data.
Likewise, the pharmacology reviewer may work closely with the statistical
reviewer in evaluating the statistical signi cance of potential cancer-causing
effects of the drug in long-term animal studies.
When the technical reviews are completed, each reviewer develops a written
evaluation of the NDA that presents their conclusions and their
recommendations on the application. The division director or o ce director then
evaluates the reviews and recommendations and decides the action that the
division will take on the application. 68
Table 1.3 Labeling requirement to be met for approved product

Description : Proprietary and established name of drug, dosage form,
ingredients, chemical name, and structural formula.
Drug Discovery
and Clinical Clinical pharmacology : Summary of the actions of the drug in humans, in vitro and in
Research
vivo actions in animals if pertinent to human therapeutics,
SK Gupta
pharmacokinetics.
Indications and usage : Description of use of drug in the treatment, prevention or

diagnosis of a recognized disease or condition.
 CHAPTER 1: New Drug Development Contraindications : Description of situations in which the drug should not be used
INTRODUCTION TO DRUG DEVELOPMENT because the risk of use clearly outweighs any possible bene t.
 PRECLINICAL DRUG DEVELOPMENT Warnings : Description of serious adverse reactions and potential safety
 CLINICAL DEVELOPMENT hazards, subsequent limitation in use and steps that should be
 PHARMACOVIGILANCE taken, if they occur.
REGISTRATION OF DRUGS Precautions : Information regarding any special care to be exercised for the
 CLINICAL DATA MANAGEMENT safe and effective use of the drug. Includes general precautions
Of Biologics
and information for patients on drug interactions,
 CHAPTER 3: Clinical Development Of New carcinogenesis/mutagenesis, pregnancy rating, labor and

Drugs delivery, nursing mothers, and pediatric use.
Development Adverse reactions : Description of undesirable effect(s) reasonably associated with
 CHAPTER 5: Bioethics In Clinical Research the proper use of the drug.
Drug : Description of types of abuse that can occur with the drug and
 abuse/dependence the adverse reactions pertinent to them.
Over dosage : Description of the signs, symptoms and laboratory ndings of

acute overdosage and the general principles of treatment.
Dosage/administration : Recommendation for usage dose, usual dosage range, and, if

appropriate, upper limit beyond which safety and effectiveness
have not been established.
How supplied? : Information on the available dosage forms to which the labeling
applies.
The result is an action letter that provides an approval, approvable or non-

approvable decision and a justi cation for that recommendation. Once the FDA
approves the NDA, the new medicine becomes available for physicians to
prescribe. The company must continue to submit periodic reports to FDA,
including any cases of adverse reactions and appropriate quality control records.
The FDA requires additional studies (phase IV) to evaluate long-term effects
(Table 1.3). 69

ELECTRONIC RECORDS FOR NDA
Regulatory agencies are rapidly moving toward requiring submissions in

electronic format because electronic submissions allow regulatory reviewers to
rapidly and e ciently search and navigate marketing applications and other
submissions, facilitating and potentially shortening the time to approval.
An electronic application for a new chemical entity, i.e. NDA, is submitted as

an archival copy.
The archival copy is divided into ve or six sections containing technical

information. Each technical section of the review copy will go to the reviewer in
charge of that speci c section. Thus, the archival copy is intended to serve as a
reference source for FDA reviewers to locate information not contained in the
section of the review copy assigned to them. After approval, the archival copy is
retained by the FDA and serves as the sole le copy of the approved application.
All documents and datasets for the electronic archival copy should be
placed in a main folder using the NDA number (e.g. N123456) as the folder
name. Sponsor should obtain the NDA number prior to submission. Inside the
Drug Discovery main folder, all of the documents and datasets should be organized by the NDA
and Clinical items described on page 2 of FDA form 356h.
Research
SK Gupta The les and folders in folder N123456 contain the following examples:
1. Folder structure for an NDA submission.

2. Table of contents for the NDA.
3. Table of contents with bookmarks for CMC, nonclinical pharmtox, Clinstat,
CRT, CRT datasets, CRT pro les, CRF.
 DRUG DISCOVERY PROCESS 4. Table of contents for Hpbio and micro (no bookmarks).
 PRECLINICAL DRUG DEVELOPMENT 5. Study report bookmarks (Clinstat/Pneumo/1234.Pdf).
6. Document information elds for labels and CRF, publications (pharmtox and
 REGULATORY APPROVALS FOR Clinstat).
7. Full text index (Crf/Cr ndex.Pdx).
8. Data de nition le for nonclinical data (Pharmtox/Datasets/101/De ne.Pdf).
Of Biologics
9. Dataset for tumors from a carcinogenicity study
Drugs
(Pharmtox/Datasets/101/Tumor.Xpt).
 CHAPTER 4: Phase 0 Trials In Cancer Drug 10. Data de nition le for clinical data (Crt/Datasets/1234/De ne.Pdf).
Development
11. Dataset for e cacy data (Crt/Datasets/1234/E cacy.Xpt).
12. Partial bookmarks for CRF (Crf/101/001/112.Pdf).
 The US FDA and the EMEA currently accept the CTD in electronic format.
The table of contents of the eCTD is consistent with that of the CTD. The eCTD is
not limited to transfer of information alone, it also has provisions for creation,
review, life cycle management and archival of electronic submission.
The eCTD is a message speci cation for the transfer of les from a
submitter to a receiver. The primary technical components are:
A high level folder structure 70
An XML backbone le which consists of a comprehensive table of contents

and provides corresponding navigation aid
PDF les.
The eCTD therefore consists of PDF documents stored in the high level
folder structure, which is accessed through the XML backbone.
In summary, NDA includes an integrated summary of e cacy (ISE) and of

safety (ISS). When evaluating NDAs, regulatory agencies look at:
Validity of pivotal studies

Replicability of pivotal studies (consistency across studies)
Generalizability across populations (demographic groups, concomitant
medications, intercurrent diseases, geographic regions, and even cultural
groups)
Establishment of supportable dosage and dose regimen(s)
Clinical relevance of e cacy results
Clinical seriousness of safety pro le (in context of seriousness of condition
being treated)
Overall usefulness of drug (risk/bene t ratio).
In the US, the FDA does not actually approve the drug itself for sale. It
approves the labeling—the package insert (as given in Figure 1.20, nal outcome
of a new drug application review is the label-package insert. All the information
pertaining to new drug should be reproduced as label/package insert complying
with FDA label requirement (refer Table 1.3 for labeling requirement) and this will
be reviewed and approved by FDA reviewers so that product will carry the
truthfully and accurate information as was submitted along with NDA). United
States law requires truth in labeling, and the FDA assures that a drug claimed to
be safe and effective for treatment of a speci ed disease or condition has, in
fact, been proven to be so. All prescription drugs must have labeling, and without
Drug Discovery proof of the truth (Clinical studies data) of its label, a drug may not be sold in the
and Clinical United States.
Research
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NONARCHIVABLE ELECTRONIC RECORDS FOR NEW DRUG

APPLICATIONS
Center policy is to encourage the submission and review of electronic NDAs as

INTRODUCTION TO DRUG DEVELOPMENT described in the guidance for industry:
It is Center's policy to discourage the submission of records in electronic
formats that are not archivable. The only electronic records that are archivable
are those provided as described in the guidance document ‘Providing
 REGULATORY APPROVALS FOR Regulatory Submissions in Electronic Format – NDA (January 1999)’.
In the case when some records are submitted in electronic formats that are
not archivable, the submission must still be accompanied by an electronic
Of Biologics archivable version containing the same information.
 CHAPTER 3: Clinical Development Of New Requests from center staff for word processing les for the purpose of
Drugs
copying and pasting text, gures or tables on individual pages or portions of
Development pages are not consistent with agency policy. 71
Fig. 1.20: NDA review
In most instances when such functions are needed, they can be adequately
performed with archival les.
If a word processing le is submitted, it cannot be accepted by the Agency in
lieu of the archival electronic record as described in the guidance. In other
words, the Agency cannot accept a record in a word processing le format
unless the record is also provided as recommended by the guidance.
Requests from Center staff for datasets in formats other than that described
in the guidance also are not consistent with Agency policy. In most instances,
staff can use the archival dataset to convert data to desired alternative
formats. 72
If datasets are requested or accepted in a format that is different from that

Drug Discovery
recommended in the guidance, it cannot be accepted in lieu of the archivable
and Clinical
electronic record as outlined in the guidance. The Agency cannot accept
Research
dataset records in a le format not described in the guidance unless the
SK Gupta
record is also provided as recommended in the guidance. For a transition
period beginning in February 1999, the Agency has been making exceptions to
its electronic submissions acceptance policy on a case-by-case basis in
situations when a sponsor is unable to provide electronic submissions as
 CHAPTER 1: New Drug Development described in the guidance.
If a sponsor is asked or offered to provide electronic records that will require
 PRECLINICAL DRUG DEVELOPMENT the installation of hardware or executable software on any component of the
 CLINICAL DEVELOPMENT CDER maintained information technology infrastructure, or if the use of the
 PHARMACOVIGILANCE records requires OIT staff support beyond that needed for the electronic
 REGULATORY APPROVALS FOR submission described in the guidance, advance approval from the O ce of
Information Technology (OIT) will be needed.
Of Biologics
Drugs
ROLE OF REGULATORY BODIES
Development In order to license/register a new chemical entity (NCE), a pharmaceutical
 CHAPTER 5: Bioethics In Clinical Research company should develop a dossier that describes the pharmaceutical quality,
safety (in animals and humans) and e cacy of the product for a speci ed
 indication.
The regulatory requirements for a pharmaceutical product would be

evaluation and assessment of the pharmaceutical quality data, including:
assessing that the manufacturer(s) of all components, including that of the
active pharmaceutical ingredient and the nished product, are certi ed as
meeting the international standards for Good Manufacturing Practices, standard
tests for content and impurities, stability, and packaging labeling to ensure that it
complies with speci ed standards.
Evaluation of animal (preclinical) toxicology studies in relation to acute and

chronic toxicity, genetic toxicity, teratogenicity, carcinogenicity and others,
including whether the studies have been carried out to international standards
ICH safety guidelines, national guidelines (like Schedule Y in India) and whether
the data and interpretation of the results are valid.
Evaluation of human clinical trials (either placebo or active comparator

randomized controlled clinical trials) that have been carried out to de ne the
dose, frequency and duration of treatment that is effective and safe, including
assessing that the design and conduct of the trials meets international
requirements like ICH GCP, that data are valid and have been interpreted
correctly.
Food and drug administration: The US Food and Drug Administration (FDA) is an
agency of the United States Department of Health and Human Services and is
responsible for the safety regulation of drugs, vaccines, biological products and
medical devices. New drugs receive extensive scrutiny before FDA approval in a 73
process called a New Drug Application (NDA). The NDA is the vehicle in the
United States through which drug sponsors formally propose that the FDA
approve a new pharmaceutical for sale and marketing. Recently, the FDA has
mandated that NDAs submitted electronically should be done in the eCTD
format.
European Medicines Agency: The European Medicines Agency (EMEA) is the

regulatory agency for the evaluation of medicinal products in European Union.
EMEA operates as a decentralized scienti c agency. For products eligible for or
requiring central approval, a pharmaceutical company submits an application for
marketing authorization to the EMEA. A single evaluation is carried out through
the Committee for Medicinal Products for Human Use (CHMP) if the Committee
concludes that quality, safety and e cacy of the medicinal product is su ciently
proven, it adopts a positive opinion. This is sent to the European Commission to
Drug Discovery be transformed into a marketing authorization valid for the whole of the
and Clinical European Union. The EMEA's Committee on Orphan Medicinal Products (COMP)
Research
administers the granting of orphan drug status.
SK Gupta
Drugs Controller General of India: The Drugs Controller General of India (DCGI) is
responsible for regulatory approvals of clinical trials in India. This central
authority reviews NDAs (form 44) as per the guidelines of Schedule Y. The DCGI
has now classi ed clinical trials into two categories—A and B. Category A
INTRODUCTION TO DRUG DEVELOPMENT comprises of clinical trials for which a protocol has already been approved in
 DRUG DISCOVERY PROCESS speci c countries such as the US, UK, Japan, Australia. The time frames for
 PRECLINICAL DRUG DEVELOPMENT clearance of these applications are 2 to 4 weeks. All other application fall under
 CLINICAL DEVELOPMENT category B. Their review will take at least 8 to 12 weeks. The DCGI has yet to set
 PHARMACOVIGILANCE up an e-submission procedure.
Therapeutic Goods Administration: Therapeutic Goods Administration (TGA) is
the regulatory authority which carries out a range of assessment and monitoring
Of Biologics activities to ensure therapeutic goods available in Australia are of an acceptable
 CHAPTER 3: Clinical Development Of New standard. Medicines are evaluated by one of three regulatory units of the TGA.
Drugs
Prescription and other speci ed medicines are evaluated by the Drug Safety and
Development
Evaluation Branch (DSEB), OTC Medicines by the OTC Medicines Section (OTC),
 CHAPTER 5: Bioethics In Clinical Research and complementary medicines by the O ce of Complementary Medicines
(OCM). One of these regulatory units evaluates the application submitted and
forwards its recommendation to the Australian Drug Evaluation Committee

(ADEC). The ADEC forwards its recommendation for approval or rejection to the
Minister for Health.

ANDA PROCESS
An Abbreviated New Drug Application (ANDA) contains data which when

submitted to FDA's Center for Drug Evaluation and Research, O ce of Generic
Drugs, provide for the review and ultimate approval of a generic drug product. 74
Once approved, an applicant may manufacture and market the generic drug
product to provide a safe, effective, low cost alternative to the public.
A generic drug product is one that is comparable to an innovator drug

product in dosage form, strength, route of administration, quality, performance
characteristics and intended use. All approved products, both innovator and
generic, are listed in FDA's Approved Drug Products with Therapeutic
Equivalence Evaluations (Orange Book).
Generic drug applications are termed “abbreviated” because they are

generally not required to include preclinical (animal) and clinical (human) data to
establish safety and effectiveness. Instead, generic applicants must
scienti cally demonstrate that their product is bioequivalent (i.e. performs in the
same manner as the innovator drug). One way scientists demonstrate
bioequivalence is to measure the time it takes the generic drug to reach the
bloodstream in 24 to 36 healthy, volunteers. This gives them the rate of
absorption, or bioavailability, of the generic drug, which they can then compare
to that of the innovator drug. The generic version must deliver the same amount
of active ingredients into a patient's bloodstream in the same amount of time as
the innovator drug.
Using bioequivalence as the basis for approving generic copies of drug

products was established by the “Drug Price Competition and Patent Term
Restoration Act of 1984,” also known as the Waxman-Hatch Act. This Act
expedites the availability of less costly generic drugs by permitting FDA to
approve applications to market generic versions of brand-name drugs without
conducting costly and duplicative clinical trials. At the same time, the brand-
name companies can apply for up to ve additional years longer patent
protection for the new medicines they developed to make up for time lost while
their products were going through FDA's approval process. Brand-name drugs
are subject to the same bioequivalence tests as generics upon reformulation.
Drug Discovery
and Clinical An application must contain su cient information to allow a review to be
Research conducted in an e cient and timely manner. Upon receipt of the application a
SK Gupta pre- ling assessment of its completeness and acceptability is performed by a
project manager within the Regulatory Support Branch, O ce of Generic Drugs.
If this initial review documents that the application contains all the necessary
components, an “acknowledgment letter” is sent to the applicant indicating its
acceptability for review and con rming its ling date.
Once the application has been determined to be acceptable for ling, the
Bioequivalence, Chemistry/Microbiology and Labeling reviews may begin. If the
application is missing one or more essential components, a “Refuse to File”
 PHARMACOVIGILANCE letter is sent to the applicant. The letter documents the missing component(s)
 REGULATORY APPROVALS FOR and informs the applicant that the application will not be led until it is complete.
REGISTRATION OF DRUGS 75
No further review of the application occurs until the applicant provides the
requested data and the application is found acceptable and complete.
Of Biologics
The FDA requires an applicant to provide detailed information on a product
Drugs to establish bioequivalency. Applicants may request a waiver from performing in
 CHAPTER 4: Phase 0 Trials In Cancer Drug vivo (testing done in humans) bioequivalence studies for certain drug products
Development
where bioavailability (the rate and extent to which the active ingredient or active
moiety is absorbed from the drug product and becomes available at the site of
action) may be demonstrated by submitting data such as (i) a formulation
 comparison for products whose bioavailability is self evident, for example, oral
solutions, injectables or ophthalmic solutions where the formulations are
identical, or (ii) comparative dissolution. Alternatively, in vivo bioequivalence
testing comparing the rate and extent of absorption of the generic vs the
reference product is required for most tablet and capsule dosage forms.
The Chemistry/Microbiology review process provides assurance that the

generic drug will be manufactured in a reproducible manner under controlled
conditions. Areas such as the applicant's manufacturing procedures, raw
material speci cations and controls, sterilization process, container and closure
systems and accelerated and room temperature stability data are reviewed to
assure that the drug will perform in an acceptable manner. Upon ling an ANDA
an establishment evaluation request is forwarded to the O ce of Compliance to
determine whether or not the product manufacturer, the bulk drug substance
manufacturer and any of the outside testing or packaging facilities are operating
in compliance with current Good Manufacturing Practice (cGMP) regulations.
Each facility listed on the evaluation request is evaluated individually and an
overall evaluation for the entire application is made by the O ce of Compliance.
Furthermore, a preapproval product speci c inspection may be performed on to
assure data integrity of the application (Flow Chart 1.3).
The Labeling review process ensures that the proposed generic drug
labeling (package insert, container, package label and patient information) is
identical to that of the reference listed drug except for differences due to
changes in the manufacturer, distributor, pending exclusivity issues or other
characteristics inherent to the generic drug product (tablet size, shape or color,
etc.). Furthermore, the labeling review serves to identify and resolve issues that
may contribute to medication errors such as similar sounding or appearing drug
names, and the legibility or prominence of the drug name or strength.
If there are de ciencies involved in the Chemistry/Manufacturing/Controls,

Microbiology or Labeling portions of the application, these de ciencies are
communicated to the applicant in a facsimile. The facsimile instructs the
applicant to provide information and data to address the de ciencies and
provides regulatory direction on how to amend the application. 76
Drug Discovery
and Clinical
Research
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Of Biologics
Drugs
Development
Flow chart 1.3: ANDA review processSource:Https://Secure.Pharmacytimes.Com/Lessons/200205–01.Asp
Once the above sections are found to be acceptable, as well as, the preapproval
inspection and bioequivalence portion of the application, then the application
moves toward approval.
After all components of the application are found to be acceptable an

approval or tentative approval letter is issued to the applicant to market the
generic drug product. If the approval occurs prior to the expiration of any patents
or exclusivities accorded to the reference listed drug product, a tentative
approval letter is issued to the applicant which details the circumstances 77
associated with the tentative approval of the generic drug product and delays
nal approval until all patent/exclusivity issues have expired. A tentative
approval does not allow the applicant to market the generic drug product.

DRUG APPLICATION REGULATORY COMPLIANCE
Guidance documents represent the Agency's current thinking on a particular

subject. These documents are prepared for FDA review staff and drug sponsors
to provide guidelines for the processing, content, and evaluation of applications,
and for the design, production, manufacturing, and testing of regulated products.
They also provide consistency in the Agency's regulation, inspection and
enforcement procedures.
Following are the guidance documents available:
1. Current Good Manufacturing Practice (cGMP) regulations: The cGMP

regulations for drugs contain minimum requirements for the methods,
facilities and controls used in manufacturing, processing, and packing of a
drug product. FDA can issue a warning letter or initiate other regulatory
actions against a company that fails to comply with Current Good
Manufacturing Practice regulations.
2. Code of Federal Regulations (CFR): The nal regulations published in the

Federal Register (daily published record of proposed rules, nal rules, meeting
notices, etc.) are collected in the CFR. The CFR is divided into 50 titles which
Drug Discovery represent broad areas subject to Federal regulations. The FDA's portion of the
and Clinical CFR interprets the Federal Food, Drug and Cosmetic Act and related statutes.
Research
Section 21 of the CFR contains most regulations pertaining to food and drugs.
SK Gupta
The regulations document the actions of drug sponsors that are required
under Federal law.
3. MaPPs (Manual of Policies and Procedures) are approved instructions for
internal practices and procedures followed by CDER staff to help standardize
 CHAPTER 1: New Drug Development the new drug review process and other activities. MaPPs de ne external
activities as well. All MaPPs are available for the public to review to get a
better understanding of o ce policies, de nitions, staff responsibilities and
procedures.
 PHARMACOVIGILANCE 4. Compliance Policy Programs and Guidelines
REGISTRATION OF DRUGS Compliance References: This web site from the O ce of Regulatory Affairs
 CLINICAL DATA MANAGEMENT provides links to compliance policy guides, regulatory procedures manuals,
 CHAPTER 2: Drug Discovery And Developmen and other compliance related information.
Of Biologics
 CHAPTER 3: Clinical Development Of New Compliance Program Guidance Manual: These programs and instructions
Drugs are for FDA eld inspectors.
Development
POST-DRUG APPROVAL ACTIVITIES
 A vital part of CDER's mission is to monitor the safety and effectiveness of drugs
that are currently available to the American people. FDA has in place 78
postmarketing programs that monitor marketed human medical products for
unexpected adverse events. These programs alert the Agency to potential
threats to public health. Agency experts then identify the need for preventive
actions, such as changes in product labeling information and, rarely, re-
evaluation of an approval decision.
Post-marketing programs: FDA maintains a system of post-marketing

surveillance and risk assessment programs to identify adverse events that did
not appear during the drug approval process. FDA monitors adverse events such
as adverse reactions and poisonings. The Agency uses this information to
update drug labeling, and, on rare occasions, to re-evaluate the approval or
marketing decision.
The adverse event reporting system (AERS) is a computerized information

database designed to support the FDA's post-marketing safety surveillance
program for all approved drug and therapeutic biologic products. The ultimate
goal of AERS is to improve public health by providing the best available tools
for storing and analyzing safety reports. The reports in AERS are evaluated by
multi disciplinary staff safety evaluators, epidemiologists and other scientists
in the Center for Drug Evaluation and Research's (CDER) O ce of Drug Safety.
The MedWatch program is for health professionals and the public to
voluntarily report serious reactions and problems with medical products, such
as drugs and medical devices. It also ensures that new safety information is
rapidly communicated to the medical community thereby improving patient
care. All data contained on the MedWatch form will be entered into the AERS
database.
The prescription drug advertising and promotional labeling webpage provides
links to an interactive chart illustrating CDER's process for reviewing and
monitoring prescription drug advertising and promotional labeling.
Pharmaceutical industry surveillance: After a drug is approved and marketed,
the FDA uses different mechanisms to assure that (i) rms adhere to the
terms and conditions of approval described in the application and (ii) the drug
is manufactured in a consistent and controlled manner. This is done by
periodic, unannounced inspections of drug production and control facilities by
FDA's eld investigators and analysts. Manufacturers of prescription medical

products are required by regulation to submit adverse event reports to the
FDA. The Med Watch website provides information on mandatory reporting by
Drug Discovery manufacturers. In addition, drug manufacturers must submit either error and
and Clinical accident reports or drug quality reports when deviation from current good
Research
manufacturing practice regulations occurs.
SK Gupta
FDA receives medication error reports on marketed human drugs (including
prescription drugs, generic drugs and over-the-counter drugs) and nonvaccine
biological products and devices. A medication error is “any preventable event 79
that may cause or lead to inappropriate medication use or patient harm while
 CHAPTER 1: New Drug Development the medication is in the control of the health care professional, patient or
consumer. Such events may be related to professional practice, health care
products, procedures, and systems, including prescribing; order
communication; product labeling, packaging and nomenclature;
 PHARMACOVIGILANCE compounding; dispensing; distribution; administration; education; monitoring;
 REGULATORY APPROVALS FOR and use.”
Drug shortages: It is FDA's policy to attempt to prevent or alleviate shortages
of medically necessary products. Drug shortages may arise from varying
Of Biologics causes, such as the unavailability of raw materials or packaging components,
 CHAPTER 3: Clinical Development Of New marketing decisions and enforcement issues.
Drugs
 CHAPTER 4: Phase 0 Trials In Cancer Drug Therapeutic inequivalence reporting: In the past 10 years, FDA's Center for
Development Drug Evaluation and Research has received an increase of reports of drug
 CHAPTER 5: Bioethics In Clinical Research products that fail to work in patients because the product simply has no effect
or is toxic. These problems are usually attributed to switching brands of
 drugs.
The following regulations apply to adverse drug event reporting.
21CFR310.305: Records and reports concerning adverse drug experiences of
marketed prescription drugs for human use without approved new drug
applications
21CFR312.32: Investigational new drug safety reports
21CFR314.80: Post-marketing reporting of adverse drug experiences.
There are guidance documents for: Postmarketing Reporting of Adverse

Drug Experiences, Enforcement of the Postmarketing Adverse Drug Reporting
Regulation, Postmarketing Adverse Experience Reporting for Human Drug and
Licensed Biological Products and the Guidance document for CDER staff is
CDER's Manual of Policies and Procedures (MaPPs).
Even when an NDA is approved unconditionally, regulatory scrutiny of a drug

does not end. In most countries, yearly safety reports must be led with the
applicable regulatory agencies as long as a drug remains on the market, and
these agencies independently monitor drug safety.

POST-MARKETING SURVEILLANCE
New drugs should be closely monitored for their safety once they are marketed.
Thus post-marketing surveillance (PMS), which is systematic detection and
evaluation of adverse reactions, is required for a newly marketed drug when
used in clinical practice. The sponsor should furnish Periodic Safety Update
Report (PSUR) by conducting PMS.
Periodic safety update report (PSUR): A PSUR is intended to provide an update

of the worldwide safety experience of a medicinal product to competent
authorities at de ned time points post-authorization. Marketing authorization
(MA) holders are expected to provide succinct summary information together
with a critical evaluation of the risk-bene t balance of the product in the light
of new or changing information. This evaluation should ascertain whether 80
further investigations need to be carried out and whether changes should be
made to the marketing authorization and product information.
PSURs must be submitted for all registered products regardless of marketing

status. A single report may cover all products containing the same active
substance licensed by one MA holder. The report will usually include all
Drug Discovery dosage forms and formulations, as well as all indications, associated with
and Clinical such an active moiety. Within the PSUR, separate presentations of data for
Research
different dosage forms, indications or populations (for example, children vs.
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adults) may be appropriate, however an overview of the combined data should
also be provided.
PSUR reporting cycle in INDIA, EU and USA
India: Schedule Y recommends that for all new products, PSURs should be
 CHAPTER 1: New Drug Development submitted every 6 months for the initial 2 years and thereafter annually for
the next 2 years to the Drugs Controller General of India. The reporting
cycle requirements in India are similar to that of the requirements of
European Union (EU).
 PHARMACOVIGILANCE European Union: PSURs are required to be submitted every 6 months for the
 REGULATORY APPROVALS FOR rst 2 years, annually for the three following years and every 3 years,
thereafter. In EU, it is generally acceptable to the regulators that the generic
companies skip the 6 monthly cycles of initial 2 years and submit the
Of Biologics PSURs every 3 years from the date of marketing approval.
Drugs
United States of America: Reporting requirements of US FDA are different.
 CHAPTER 4: Phase 0 Trials In Cancer Drug The US regulations require quarterly reports during the rst 3 years and
Development annual reports, thereafter.

 PHASE IV CLINICAL TRIAL
Phase IV clinical studies are de ned as those studies performed with drugs that
have been granted marketing authorization. The term “phase IV” is fairly
standard and covers the vast majority of postregistration clinical study. Phase IV
studies are not considered necessary for the granting of a marketing
authorization but they are often important for optimizing the drug's use.
Phase IV studies are also referred to as “marketing studies” or “experience

studies” to emphasize that they are conducted once the drug is marketed, rather
than prior to its approval by the regulatory authorities. Some other terms, such
as “seeding trials” or “observational studies”, have also been used, but they
usually denote efforts made by marketing departments to encourage physicians
to prescribe the new drug, rather than proper trials.
Phase IV studies differ from post-marketing surveillance which is

observational and interventional intended mainly to monitor the safety of a
marketed drug. Phase IV studies are, in fact, part of this process, but their
objectives include e cacy or effectiveness in addition to safety.
Purposes: The role of Phase IV clinical trials are to extend knowledge about drug
e cacy and to con rm the safety of a new drug in a wider patient population 81
treated in regular medical care after the drug has been approved for marketing.
Effectiveness: While the e cacy of the drug has been demonstrated in a

restricted patient population in phase II and III clinical trials, its effectiveness
in a wider population is still largely unknown when the drug comes to the
market.
Phase III clinical trials performed for regulatory purposes usually include
highly selected patients, and the results obtained do not automatically
translate to the population at large. Phase IV clinical studies, in contrast,
include broader patient populations which more closely re ect the reality of
medical practice. A case in point is the elderly population, which has
historically tended to be excluded from preregistration clinical trial programs
and yet account for a substantial proportion of the patient population that
consume medicines.
Comparison with available treatment: A second purpose of phase IV studies is

to investigate the relative merit of a newly marketed drug as compared to
other available treatments. The role of phase I-III trials is to demonstrate that
Drug Discovery the drug has biological activity and clinical e cacy, hence, the need to
and Clinical compare it, to the extent possible, to a placebo or an untreated control group.
Research
In contrast, the role of phase IV studies is to demonstrate that the drug is
SK Gupta
effective, hence, the need to compare it to alternative treatments for the
disease under consideration. Examples of such comparative studies are
comparing different chemical entities (e.g. methyldopa versus propranolol for
hypertension), medicines within the same pharmaceutical class (e.g. captopril
 CHAPTER 1: New Drug Development versus enalapril) and demonstration of e cacy in different patient groups
INTRODUCTION TO DRUG DEVELOPMENT (e.g. treatment of systolic hypertension in elderly patient).
Test new hypothesis: A third purpose of phase IV studies is to focus on
hypotheses and questions which could not be tested and answered in
 PHARMACOVIGILANCE preregistration trials due to the small number of patients and limited time
 REGULATORY APPROVALS FOR available before ling for marketing authorization. Questions still unanswered
at the phase IV stage can include the following:
Long-term bene t or harm of the drug
Of Biologics Impact of the drug on secondary endpoints
Drugs
Details of drug administration schedules (such as dose fractionations),
 CHAPTER 4: Phase 0 Trials In Cancer Drug Combinations with other drugs, the effect of concomitant medications or
Development
supportive care
Overall cost-effectiveness in routine medical practice
Quality of life

Compliance in routine medical practice.
Phase IV studies can also explore:
New indication for a product: Example, bene ts of beta–blockers in heart

failure was identi ed in a phase IV study (CIBIS II trial) 82
New dosage regimen: Example, phenytoin was initially given three times a day
for epilepsy management but subsequent studies demonstrated once-daily
dosing to be su cient.
New formulations: Example, dry powder inhaler for asthma management
instead of metered-dose inhalers.
Introduce drug into clinical practice: Perhaps the more important purpose of
phase IV studies is to introduce a new drug into routine clinical practice. The
motivation for doing so is not only commercial, it also has a sound scienti c
and ethical basis. Indeed, valuable drugs may be underused, if clinicians are
unconvinced of their merit.
Phase IV studies provide the ideal setting to further document the safety of
a newly marketed drug. Because they are properly controlled (generally, phase IV
studies are compared with the existing treatment or with current best practice,
they are said to be controlled trial) and closely watched, such studies yield a
more reliable safety pro le than any method of spontaneous reporting of
adverse drug reactions (ADRs), such as Yellow Cards, case reports, literature
screening and so forth. In particular, the denominator is known in a prospective
trial and therefore, the true incidence of ADRs can be estimated accurately. This
is especially useful to study unpredictable ADRs. Phase IV trials should aim at
the detection of unpredictable ADRs and should not focus on predictable, non
serious adverse events or abnormal laboratory data that are not clinically
important, since these add no value to what is already known from the
pharmacology of the product and from preregistration trials.
While relatively common adverse events are well documented at the end of
phases I-IV, rare ADRs will require the treatment of a larger number of patients to
be detected.

DESIGN CONSIDERATIONS
Drug Discovery Approach in designing phase IV studies should be to minimize the risk of
and Clinical performing unnecessary trials and to ensure that trial has pragmatic and
Research correctly balanced objectives that meet both company and external needs. It
SK Gupta
must be thoughtfully designed to properly address a serious question of interest
to those health care professional who will be using and paying for the drug.
Randomization: The most crucial aspect of phase IV trials is that they should be
based on a sound statistical design. Claims of effectiveness and/or e ciency
can rarely be made on the basis of nonrandomized studies. Properly randomized
 DRUG DISCOVERY PROCESS studies of su cient size yield a reliable and de nitive answer, even if they are
 PRECLINICAL DRUG DEVELOPMENT ultra-simple. Publication of their results may have a major impact on medical
 CLINICAL DEVELOPMENT practice.
 REGULATORY APPROVALS FOR One objective of phase IV studies is to study the effectiveness of a drug in
current clinical practice. This implies that the number of patients entered in such
 CLINICAL DATA MANAGEMENT 83
studies be large enough so as to answer the questions of interest with
Of Biologics reasonable certainty. In fact, the e cacy of a new drug may be expected to be
 CHAPTER 3: Clinical Development Of New lower in phase IV studies than in phase III trials, because less responsive
Drugs
patients may be included in the trial, the conditions in which the patients are
Development
treated may be less tightly controlled, less experienced clinical investigators may
 CHAPTER 5: Bioethics In Clinical Research be involved, and so on. The sample size of a phase IV study should take all these
factors into account.
 Broad eligibility criteria: One of the main objectives of phase IV studies is to

study the drug in wide patient populations. This implies that the eligibility criteria
in such studies be relaxed as compared to those of preregistration trials. Several
authors have discussed the relative merits of strict versus broad eligibility
criteria. As a general rule, strict criteria seem appropriate for preregistration
clinical trials and broad criteria for phase IV studies. No patients should be
excluded from phase IV studies except, if:
There is a safety concern if they receive the drug or

There is a sound basis for targeting certain subpopulation of patients.
The decision to enroll a patient in phase IV study is best left to the discretion
of the attending physician, rather than regulating the process by means of
lengthy lists of inclusion and exclusion criteria. All patients should be included
unless the physician is uncertain about the bene t of either of the treatments to
the patient, only then can the patient can be excluded.
Active control and equivalence trials: Many new drugs have to be compared to
placebo to be granted marketing authorization even though an active treatment
is known for the disease considered. Yet, the relevant medical question is not to
show that the drug is biologically active as compared to placebo, but rather to
prove that the drug has medical or economical bene ts over the currently
available treatment(s). Thus, there is an important place for phase IV studies
with “active controls,” which are not required for regulatory reasons yet are
essential for medical practice.
When studies use an active control group, it is often of interest to show that
the new drug has the same e cacy as the control group (rather than higher
e cacy), in which case these studies are called “equivalence” studies (or “active
control equivalence” studies). Such trials are needed when a new drug is not
expected to have better e cacy than the standard therapy, but offers a better
safety pro le, is more practicable, or is less expensive than the standard therapy,
and should, therefore, be substituted for it in routine clinical practice. There is
also an important place for phase IV “equivalence” trials with such new drugs.

GCP STANDARDS
ICH-GCP is the standard applied by the vast majority of pharmaceutical

companies for phase I-IV clinical trial programs, without distinction of phase or
purpose of the trials. 84
Drug Discovery
and Clinical Simpli ed standards: The spirit of GCP can be maintained even if its
Research implementation is adapted to the post registration setting. First, the intensive
SK Gupta monitoring and site visit frequencies recommended by the GCP guidelines fall
far beyond the budget of most post-registration programs. Monitoring is among
the most costly aspects of trial management, and if it is required to validate data
submitted to regulatory agencies, it may not be needed for studies to yield
informative answers. If intensive monitoring is imposed on all trials, a well-
INTRODUCTION TO DRUG DEVELOPMENT intended sponsor might be tempted to reduce the number of patients required by
 DRUG DISCOVERY PROCESS a phase IV project (or perhaps to drop the project altogether) rather than to relax
 PRECLINICAL DRUG DEVELOPMENT the GCP requirements so as to keep the budget within reasonable limits. In
 CLINICAL DEVELOPMENT phase IV studies, monitoring could well be limited to an initiation and close out
 PHARMACOVIGILANCE visit, or even in some cases to no visit at all. Second, the collection and ling of
essential documents can be considerably reduced in phase IV clinical trials.
Third, quality control, which also needs to be highly detailed in a new drug
Of Biologics application, may receive much less attention in the post-registration setting
 CHAPTER 3: Clinical Development Of New without impairing the scienti c validity of the trial. For example, checking patient
Drugs
compliance through pill counts would be unfeasible, but also pointless in most
Development situations of public health relevance. No measure of compliance is needed when
 CHAPTER 5: Bioethics In Clinical Research the purpose of the study is to investigate the effect of a drug as actually taken by
the patient rather than as intended by the investigator. Since in phase IV settings
the drugs are used as recommended in the summary of the product

characteristics, no special safety by the investigator concern should arise from
their use.
Phase IV trials must aim at con rming the clinical bene t of a new product
in a wide patient population and this is best achieved through large, simple,
randomized clinical studies with realistic rather than exhaustive quality control.
Phase IV studies have been accepted by many companies as a part of the

drug development process. These studies should still comply with ICH GCP.
However, the level and nature of safety monitoring may differ compared with pre-
authorization studies.
Overview of clinical trial phases is discussed in Table 1.4.

PHARMACOVIGILANCE
The World Health Organization in 2002 de ned pharmacovigilance as‘the

science and activities relating to the detection, assessment, understanding and
prevention of adverse effects or any other drug related problems’. The principle
of identifying and responding to drug safety issues apply equally to pre-
marketing period but the term ‘Pharmacovigilance’ originated in the post-
marketing arena. Pharmacovigilance is seen as a specialist discipline within the
industry and most large pharmaceutical companies have sizable
pharmacovigilance departments. Pharmacovigilance is a shared responsibility
that is performed by doctors, pharmacists and pharmaceutical companies
throughout the product life cycle. 85
Table 1.4 Overview of clinical trial phases

Phase IV
Objectives Determine the Evaluate Obtain Monitor ongoing

metabolic and effectiveness, additional safety in large
pharmacological determine the information populations and
Drug Discovery
actions and the short-term side about the identify additional
and Clinical
maximally tolerated effects and identify effectiveness uses of the agent
Research
dose common risks for a on clinical that might be
SK Gupta
speci c population outcomes and approved by the FDA
and disease evaluate the
overall risk-
bene t ratio in
 CHAPTER 1: New Drug Development a
demographical
diverse
 CLINICAL DEVELOPMENT sample
Factors to • Bioavailability • Bioavailability • Drug-disease • Epidemiological
REGISTRATION OF DRUGS be • Bioequivalence • Drug-disease interactions data
 CLINICAL DATA MANAGEMENT identi ed • Dose interactions • Drug-drug • E cacy and safety
 CHAPTER 2: Drug Discovery And Developmen proportionality • Drug-drug interactions within large, diverse
Of Biologics
• Metabolism interactions • Dosage populations
Drugs • • E cacy at various intervals •
 CHAPTER 4: Phase 0 Trials In Cancer Drug Pharmacodynamics doses • Risk-bene t Pharmacoeconomics
Development
• Pharmacokinetics • information
Pharmacodynamics • E cacy and
• Pharmacokinetics safety for
 • Patient safety subgroups
Data • Vital signs • Dose response • Laboratory • E cacy

focus • Plasma and serum and tolerance data •
levels • Adverse events • E cacy Pharmacoeconomics
• Adverse events • E cacy • Adverse • Epidemiology
events • Adverse events
Design • Single, ascending • Placebo-controlled • Randomized • Uncontrolled

features dose tiers comparisons • Controlled • Observational
• Unblinded • Active controlled • 2–3
• Uncontrolled comparisons treatment
• Well-de ned entry arms
criteria • Broader
eligibility
criteria
Duration Up to 1 month Several months Several years Ongoing (following

FDA approval)
86
Population Healthy volunteers Individuals with Individuals Individuals with

or individuals with target disease with target target disease as
the target disease disease well as new age
(such as cancer or groups, genders, etc.
HIV)
Sample 20 to 80 200 to 300 Hundreds to Thousands

size thousands
Example Study of a single Double-blind study Study of drug Study of economic

dose of drug X in evaluating safety X vs. standard bene t of newly-
normal subjects and e cacy of drug treatment in approved drug X vs.
X vs. placebo in hypertension standard treatment
patients with study for hypertension
hypertension
87
However, post-marketing surveillance is solely a sponsor initiated activity. Post-
marketing surveillance is a component of pharmacovigilance.
TERMINOLOGY
Drug Discovery
and Clinical Adverse drug reaction (ADR): An unintended reaction to a drug taken at doses
Research normally used in man.
SK Gupta
Adverse event (AE): A negative experience encountered by an individual during
the course of a clinical trial, which may or may not be associated with a drug.
If an association between an AE and a drug is established the event is referred
to as an adverse drug reaction.
 CHAPTER 1: New Drug Development Serious adverse event (SAE): Any adverse event is referred to as a serious
adverse event when the event is fatal, life-threatening, permanently disabling,
or which results in hospitalization.
 REGULATORY APPROVALS FOR RATIONALE AND AIMS OF PHARMACOVIGILANCE
Events such as the thalidomide tragedy, which was caused by the drug
Of Biologics thalidomide, taken by mothers during their pregnancy leading to limb deformities
 CHAPTER 3: Clinical Development Of New in newborns highlighted the importance of the need for a pharmacovigilance
Drugs
system. However, the need for a pharmacovigilance system in all countries was
Development
highlighted by the exclusive adverse reaction occurrence to the drug clioquinol in
 CHAPTER 5: Bioethics In Clinical Research Japan.
The main reason to monitor ADR for an approved product is due to limitation
 of pre-marketing clinical studies to identify safety issues. Following are the
reasons why pre-marketing studies are inadequate to cover all aspects of drug
safety:
Relatively small number of patients studied as compared to large number of

patients exposed after marketing.
The frequent exclusion of individuals who may be at greater risk of ADRs e.g.
the elderly, children, pregnant women and patients with signi cant, concurrent
disease and taking other medications.
The structured nature of clinical studies where drugs are given at speci c
doses for limited period with careful monitoring by experienced investigators.
In clinical practice, a drug is unlikely to be used according to the instruction
and there is less monitoring.
Duration of clinical studies is limited and there could be long latent period
between starting the drug and the development of ADR which may not be
detected in clinical studies.
Based on these observations the primary aims of pharmacovigilance

programs are as follows:
To improve patient care and safety in relation to the use of medicines, and all
medical and paramedical interventions
To improve public health and safety in relation to the use of medicines 88
To contribute to the assessment of bene t, harm, effectiveness and risk of

medicines, encouraging their safe, rational and more effective (including cost-
effective) use
To promote understanding, education and clinical training in
pharmacovigilance and its effective communication to health professionals
and the public.
PHARMACOVIGILANCE PROCESS
In many countries, pharmacovigilance is part of governmental drug regulation. In

several countries, it has become mandatory for pharmaceutical companies to
assess case causality in case reports of adverse reactions to their own drugs.
The pharmacovigilance process includes the following steps:
Detecting and reporting an adverse drug reaction
Drug Discovery Data collection and capture

and Clinical Data storage and maintenance
Research
Data selection, retrieval and manipulation
SK Gupta
Pharmacovigilance relies on information gathered from the collection of

individual case safety reports and other pharmacoepidemiological data. For the
detection of new adverse reaction, post-marketing reports by alert individuals is
the main source of information.
INTRODUCTION TO DRUG DEVELOPMENT Reporting of an adverse drug reaction: A paper based, ADR (adverse drug
reaction) form is lled out with patient and reaction details. Such data
recorded on a paper form is later the basis for data entry into a computerized
system. ADR reporting is of two types—spontaneous reporting and mandatory
 REGULATORY APPROVALS FOR reporting.
REGISTRATION OF DRUGS Spontaneous reporting: This is the most common form of ADR reporting
 CLINICAL DATA MANAGEMENT where in healthcare professionals identify and report any suspected
Of Biologics
adverse drug reaction to their national pharmacovigilance centre or to the
 CHAPTER 3: Clinical Development Of New manufacturer. Spontaneous reports are almost always submitted
Drugs voluntarily.
Development Mandatory reporting: Manufacturers are required to submit reports they
 CHAPTER 5: Bioethics In Clinical Research receive from healthcare providers to the national authority, in the form of a
PSUR (Periodic Safety Update Report).
 Data collection and capture: Data collection and capture in a database

management system involves creation, update and transformation of
information.
Data storage and maintenance: Once data have been entered into a database,
it could be assumed to be a static system, in which nothing can change.
However, maintaining the quality of data that has been stored poses its own
challenges. The data must be secured against partial and complete loss. The
integrity of the data must be protected. 89
Data selection, retrieval and manipulation: The production of useful output

involves the transformation of raw data into a re ned representation which
should remain truthful to the source of information and be appropriate for
analysis. The common technique for selection, retrieval and aggregation of
data in a database involves the use of query languages. Query commands can
be executed through specially designed search interfaces.
Once the ADR data are obtained the data are sent to the WHO Uppsala
Monitoring Centre where the data are stored in the central database. Based on
the information in the central database a signal can be generated. The WHO
de nition of a pharmacovigilance signal is “reported information on a possible
causal association between an adverse event and a drug, the relationship being
unclear or incompletely documented previously”. Signal detection is one of the
most important objectives of pharmacovigilance. The whole process of
risk/bene t evaluation depends on effective detection of signals.
The process of signal detection is done by collection of adverse event

reports followed by assessment of individual reports or clusters of reports in
spontaneous reporting systems, observational databases and clinical trials. The
detection of signals requires clinical assessment assisted by epidemiological
and statistical analyses.

WHO AND UPPSALA MONITORING CENTRE (UMC)
The Uppsala Monitoring Centre is the eld-name of the WHO Collaborating

Centre for International Drug Monitoring. The UMC is responsible for the
management of the WHO program for international drug monitoring.
The WHO Program for international drug monitoring provides a forum for
WHO member states to collaborate in the monitoring of drug safety. Within the
program, individual case reports of suspected adverse drug reactions are
Drug Discovery collected and stored in a common database.
and Clinical
Research Functions of the WHO Program for international drug monitoring include:
SK Gupta
Identi cation and analysis of new adverse reaction signals from the case
report information submitted to the National Centres and from them to the
WHO database. A data-mining approach is used at the UMC to support the
clinical analysis made by a panel of signal reviewers
 CHAPTER 1: New Drug Development Information exchange between WHO and National Centres, mainly through
‘Vigimed’, an e-mail information exchange system
 PRECLINICAL DRUG DEVELOPMENT Publication of periodical newsletters, guidelines and books in the
 CLINICAL DEVELOPMENT pharmacovigilance and risk management area
 PHARMACOVIGILANCE Supply of tools for management of clinical information including adverse drug
reaction case reports. The main products are the WHO Drug Dictionary and
the WHO Adverse Reaction Terminology 90
 CHAPTER 2: Drug Discovery And Developmen Provision of training and consultancy support to National Centres and
Of Biologics
countries establishing pharmacovigilance systems
Drugs Computer software for case report management designed to suit the needs of
 CHAPTER 4: Phase 0 Trials In Cancer Drug National Centres (VigiFlow)
Development
 CHAPTER 5: Bioethics In Clinical Research Annual meetings for representatives of National Centres at which scienti c
and organizational matters are discussed
 Methodological research for the development of pharmacovigilance as a

science.
The functions of the UMC are as follows:
To co-ordinate the WHO program for international drug monitoring and its
more than eighty member countries
To collect, assess and communicate information from member countries
about the bene ts, harms and risks of drugs and other substances used in
medicine to improve patient therapy and public health worldwide
To collaborate with member countries in the development and practice of the
science of pharmacovigilance.
PHARMACOVIGILANCE IN INDIA
The Government of India with the assistance of World Bank initiated the National
Pharmacovigilance Programme in 2004. The Central Drugs Standard Control
Organization (CDSCO) coordinates this country-wide pharmacovigilance
program under the aegis of DGHS, Ministry of Health and Family Welfare.
India did not have a formal pharmacovigilance system in the past to detect
adverse reactions of marketed drugs as very few new drugs were discovered in
India. However, due to the increase in the number of new drugs being approved
for marketing in India, there was a need for a vibrant pharmacovigilance system
in the country. The legislative requirements of pharmacovigilance in India are
guided by speci cations of Schedule Y of the Drugs and Cosmetics Act, 1945.
The Schedule Y also deals with regulations relating to preclinical and clinical
studies for development of a new drug as well as clinical trial requirements for
import, manufacture, and obtaining marketing approval for a new drug in India.
The section entitled post-marketing surveillance in this schedule includes the
requirement for submission of periodic safety update reports (PSURs), PSUR
cycle, template for PSUR, and the timelines and conditions for expedited
reporting.
As per the requirements of Schedule Y of the Drugs and Cosmetic Act, 1945,
the reporting of adverse events from the clinical trials is mandatory. Schedule Y
provides details of timelines for reporting adverse events by sponsor,

investigator and ethics committee. These details are listed below (Fig. 1.21).
Drug Discovery Any unexpected serious adverse event occurring during a clinical trial should
and Clinical be communicated by the sponsor to the Licensing authority within 14 calendar
Research days. 91
SK Gupta

Of Biologics
Drugs
Development
Fig. 1.21: Flow of pharmacovigilance data in IndiaSource:Http://Www.Ijp-
Online.Com/Temp/IndianJPharmacol393124-6222353-014342.Pdf
Any unexpected serious adverse event occurring during a clinical trial should
 be communicated by the investigator to the sponsor within 24 hours and to the
ethics committee within 7 working days.

PHARMACOVIGILANCE IN THE UNITED KINGDOM
The primary system for reporting suspected ADRs in the United Kingdom is the
“Yellow Card Scheme” (YCS) which was introduced in 1964 as a result of the
thalidomide tragedy. The YCS is a ‘spontaneous’ reporting system wherein health
professionals voluntarily complete a card at the time a patient presents with a
potential ADR. Completed Yellow Cards are submitted to the Medicine and
Healthcare Products Regulatory Agency. Since 1991, data have been stored on
the adverse drug reactions on-line information tracking system (ADROIT).
Until 2002, Yellow Cards were completed by doctors, dentists, coroners and
pharmacists who suspected that an adverse event (AE) was related to a
particular medication or combination of medications. In 2002, the YCS was
extended so that nurses, midwives and health visitors could also report
suspected ADRs.
EudraVigilance is a data processing network and management system for

reporting and evaluating suspected adverse reactions during the development
and following the marketing authorization of medicinal products in the European
Economic Area (EEA). 92
Fig. 1.22: Components of Eudravigilance analysis

systemSource:Http://Eudravigilance.Emea.Europa.Eu/Human/EVComDataAnalysisSystem.Asp
EudraVigilance supports in particular (Fig. 1.22):
Electronic exchange of suspected adverse reaction reports (referred to as

Individual Case Safety Reports) between the European Medicines Agency
Drug Discovery
(EMEA), national competent authorities, marketing authorization holders, and
and Clinical
Research sponsors of clinical trials in the EEA
SK Gupta Early detection of possible safety signals associated with medicinal products
for human use
Continuous monitoring and evaluation of potential safety issues in relation to
reported adverse reactions
 CHAPTER 1: New Drug Development Decision making process, based on a broader knowledge of the adverse
INTRODUCTION TO DRUG DEVELOPMENT reaction pro le of medicinal products especially in the frame of risk
management.
 REGULATORY APPROVALS FOR PHARMACOVIGILANCE IN THE UNITED STATES OF AMERICA
MedWatch is the reporting system for adverse events in the USA. This system
Of Biologics
provides important and timely clinical information about safety issues involving
 CHAPTER 3: Clinical Development Of New medical products, including prescription and over-the-counter drugs, biologics,
Drugs medical and radiation-emitting devices, and special nutritional products.
Development MedWatch allows healthcare professionals and consumers to report serious
problems that they suspect are associated with the drugs and medical devices
they prescribe, dispense, or use. Reporting can be done on line, by phone, or by
 submitting the MedWatch 3500 form by mail or fax.
The FDA Form 3500 are used by healthcare professionals and consumers
for voluntary reporting of adverse events noted spontaneously in the course of
clinical care, not events that occur during IND clinical trials or other clinical
studies. Those mandatory reports are submitted to FDA. 93

PHARMACOVIGILANCE SOFTWARE
The fast and reliable reporting of ADR (adverse drug reaction) data is an
important task for pharmaceutical companies. In order to comply with
regulations, good information management systems are essential. Many of the
systems available are client speci c.
Drug safety software applications should be simple, easy to use with

functionality to comply with ADR reporting requirements, web based to enhance
cross-divisional and cross a liate work ows as well as being able to scale up
with increasing demands, company growth and mergers.
Features of good ADR management tool (drug safety software):
ICH compliance by design including E2B reporting

Collect and report data to meet all common international regulations including
FDA, CIOMS (Council for International Organizations of Medical Sciences),
EMEA (European Medicines Agency), and MHRA (Medicines and Healthcare
Products Regulatory Agency)
Code against standard dictionaries including current MedDRA
Data validation, cross- eld validation checks and use of pick lists
FDA 21 CFR part 11 compliance
Duplicate check
Built-in query tool
Data export function
Integrated spell-checker
Full audit trail
Mandatory elds
Letter generation using Microsoft Word

Open database for use of third-party query and reporting tools
Use of reference dictionaries, e.g. contacts, lab tests.
Drug Discovery
and Clinical
Research
SK Gupta VIGIBASE
From the start of the international movement for drug safety it was recognized
that pooling data in a central database in order to detect signals early was
essential. The creation of the WHO Collaborating Centre for International Drug
Monitoring, collecting case information in an internationally agreed format has
 DRUG DISCOVERY PROCESS led to a high-quality, accessible data store for use by researchers from National
 PRECLINICAL DRUG DEVELOPMENT Centres connected to the WHO Drug Monitoring Program.
Over the years, many technical modi cations have been made to the ways in
 REGULATORY APPROVALS FOR which data held in the WHO database were processed and retrieved. In the mid
REGISTRATION OF DRUGS 1990s, the UMC decided to start work on a new database system for the
management of WHO Program case report information. This led to the
Of Biologics
development of a new web-based database search program called Vigibase
 CHAPTER 3: Clinical Development Of New which makes use of XML (international computer language understandable in
Drugs different computer programs). XML makes searching easier and also improves
data handling, as data elds and their contents are kept together as part of the
Development
structured document. 94
Remote access to information in the WHO database takes place through

 internet-based interfaces, a main advantage of this is that the user does not
have to install the application interface software on local computers, but can run
the program from an internet browser. As new search modules are added or
other improvements made, these become instantly accessible for all users,
without the need for reinstallation of software.
Vigibase is updated every night, so all correct reports will be entered within
24 hours of receipt by the UMC. Another feature is that technically incomplete
reports will be stored as a searchable subset of the database in the same
structure as the correct ones. The report handling system has built-in features to
speed up corrections, keeping the same high quality standard. For acceptance
into the ADR (adverse drug reaction) database, a report has to pass an extensive,
error-checking procedure while in a buffer data folder, involving the following:
Syntax check
Inter- eld coherence check
Check for duplication
Check of drug names and adverse reaction terms.
Vigibase includes new features of the WHO Drug Dictionary, for entering
more detailed information about each drug name. However, since ICH has
declared it mandatory to use MedDRA terms, Vigibase is also compatible with
the MedDRA software.
The WHO database, Vigibase, has these main tables:
Report: Case identi cation, dates, classi cation

Patient: Identi cation, age, gender, outcome, causality
Background: Patient's previous illnesses/predisposing conditions
Death: Cause of death, causality, and postmortem information.

TOTAL SAFETY—A COMMERCIALLY AVAILABLE

PHARMACOVIGILANCE SOFTWARE SYSTEM
In order to ful ll the regulatory requirements it is essential for companies to have

proactive pharmacovigilance programs that include comprehensive risk
management plans and signal detection/analysis throughout a product's life

cycle.
Drug Discovery To address these needs, Aris Global has developed software known as total
and Clinical safety. Total Safety is an integrated software solution that enables companies to
Research implement effective domestic and global pharmacovigilance, clinical safety and
SK Gupta risk management programs.
The Total Safety site comprises of the following industry-leading solutions
ARISg™ – The world's leading pharmacovigilance and clinical safety system

ARISj™ – Japanese pharmacovigilance system 95
INTRODUCTION TO DRUG DEVELOPMENT agXchange ESM™ – Modular gateway for extended electronic exchange
agXchange IRT™ – Inbound receipt and triage of adverse event information
 CLINICAL DEVELOPMENT agConnect™ – Clinical safety reconciliation system
 PHARMACOVIGILANCE agComposer™ – Comprehensive periodic and aggregate reporting system
REGISTRATION OF DRUGS agSignals™ – Advanced signal detection and data mining system.
Of these solutions agComposer is a comprehensive periodic and aggregate
Of Biologics reporting system that schedules, creates and tracks a full range of submission-
 CHAPTER 3: Clinical Development Of New ready, ICH-approved periodic reports, including PSURs, bridging reports and
Drugs
other annual reports such as the ASR.
Development
agComposer automatically sets deadlines and reminders to ensure
reporting obligations are met on time. As a periodic or aggregate report is due, it
can only be generated in cooperation with other departments. agComposer fully
 integrates the required departments and processes—clinical trial, regulatory and
medical information—to ensure deadlines are met and reports meet the various
regulatory agency requirements.

REGULATORY APPROVALS FOR REGISTRATION OF DRUGS
DRUG REGULATION SCENARIO
Drug regulation has developed over the past 50 years in response to crises in
relation to pharmaceutical products. The initial regulatory standards were
primarily related to ensuring the pharmaceutical quality of medicinal products
and subsequent developments in the early 1960s led to the development of
standards for testing e cacy and safety of new medicines as well.
Despite the existence of standards for drug regulation since 50 years, there
are still many problems with the safety and quality of medicines. The primary
aim of drug regulation is protection of public health. Medicines are not normal
‘commodities’; they should meet health needs, and access to essential
medicines is a fundamental human right. Thus, medicines have additional social
value. Appropriate use of medicines requires a ‘learned intermediary’ to
prescribe them and a trained person to dispense them appropriately before the
consumer takes them.
The market for pharmaceuticals is therefore not a usual market in economic

terms, there are major informational asymmetries and monopoly behaviors by
suppliers that include patent rights and ‘data exclusivity’ clauses that further
strengthen monopolies. In addition to the quality, safety and e cacy
requirements, therefore, these are the arguments for regulating the
pharmaceutical industry more generally and controlling what it supplies.
Over the past 10 to 15 years, the balance between controlling

pharmaceuticals in the interests of ensuring public health and encouraging the
development of the pharmaceutical industry has shifted in favor of the
innovative industry. Regulation has been seen as an ‘impediment’ to pro ts and 96
industry development. The resulting pressure on regulators has been to approve

new medicines quickly—sometimes on the basis of what can only be described
as preliminary data—to remove regulatory ‘bottlenecks’, to carry out reviews and
Drug Discovery evaluations of data in the shortest possible time. There has also been pressure
and Clinical from patient groups to speed up access to new, ‘breakthrough’ medicines, for
Research
example in the eld of HIV/AIDS.
SK Gupta

CHALLENGES FACED BY THE PHARMACEUTICAL INDUSTRY
The drug development process is known to be complex, costly and time-

INTRODUCTION TO DRUG DEVELOPMENT consuming. The process is also risky in that most compounds that undergo
 DRUG DISCOVERY PROCESS clinical testing are abandoned without obtaining marketing approval. The cost of
 PRECLINICAL DRUG DEVELOPMENT new drug development is also critically dependent on the proportion of drugs
 CLINICAL DEVELOPMENT that fail in clinical testing. Given the length and cost of the drug development
process, careful consideration of all factors that have a signi cant impact on the
REGISTRATION OF DRUGS process is needed to appropriately allocate research and development
 CLINICAL DATA MANAGEMENT resources.
Of Biologics The pharmaceutical industry is faced with the challenge of surviving and
 CHAPTER 3: Clinical Development Of New succeeding in an environment that has become more complicated and
Drugs
uncertain, and one that is characterized by rapid developments in science and
Development technology, and organizational change. From the standpoint of the
 CHAPTER 5: Bioethics In Clinical Research pharmaceutical industry, the drive for change is the result of a combination of
political, economic, technological and social factors; all of which have helped
rede ne the dynamics of this particular industry. If product is to be marketed

globally, pharmaceutical industry is burdened with different requirements for
registration of product.
Issues and challenges faced by pharmaceutical industry are not restricted

during drug development process alone but well beyond this which includes
registration of their product and placing their product in highly competitive
environment. Following topics discusse few of the issues.

BARRIERS DURING DRUG DEVELOPMENT PROCESS
Most of the tools used by pharmaceutical company for toxicology and human
safety testing may fail to predict the speci c safety problem that ultimately halts
development or that requires post-authorization withdrawal. More generally,
there are too few analytic tools (e.g. analytical devices, assay systems, surrogate
markers and cell culture methods) to assist in providing medicine safety and
effectiveness studies more quickly, with more certainty, and at lower cost. Key
enabling technologies involving the use of animals and the use of human tissue
in biomedical research are subject to complex regulations which impede drug
development.
Regulatory authorities are becoming more risk-averse. This lack of exibility

only entrenches the existing regulatory requirements and perceptions, and often
results in the need for expanded studies to quantify potential adverse events.
Industry experts feel that alternative approach to traditional randomized 97
controlled trial should be evaluated that does not compromise safety and
e cacy. Such alternative approaches have been successfully used for high risk
diseases such as cancer or AIDS where accepting results from limited size
studies combined with post-authorization monitoring have allowed products to
come to market far more quickly than by conventional approaches.
Poor communication between the industry, physicians and regulators during

medicines development results in requests for additional data and regulatory
questions following submission, and in turn these requests lead to increasing
unpredictability of outcomes and delays in the marketing authorization process.

CHALLENGES RELATED TO COST FACTOR
Drug Discovery Over the past few years, the growth of the worldwide pharmaceutical industry
and Clinical has been slower than the increases in research and development (R & D) costs,
Research and this has led to a cost-earnings differential that cannot be sustained
SK Gupta
inde nitely. Firms have found it increasingly di cult to sustain historical levels
of growth principally because of two converging factors. First, the earnings of
the pharmaceutical industry are being increasingly squeezed between pricing
constraints due to government policies and generic competition; and second,
 CHAPTER 1: New Drug Development through the rising costs of R & D due to increasing legislative requirements and
INTRODUCTION TO DRUG DEVELOPMENT growing technological sophistication.
 PRECLINICAL DRUG DEVELOPMENT As a consequence of these pressures on pharmaceutical earnings,
 CLINICAL DEVELOPMENT combined with that of rising R & D costs, pharmaceutical rms have been forced
 PHARMACOVIGILANCE to adopt a number of cost containment measures in addition to those pertaining
to the safety and e cacy of drugs. The need to demonstrate ‘value’ to the
consumer has now become imperative.
Of Biologics Traditionally, the pricing methods adopted in the former producer-driven
 CHAPTER 3: Clinical Development Of New environment for pharmaceuticals was essentially based on what was considered
Drugs
to be ‘fair returns’ for the high costs and risks associated with innovation. Today,
Development
however, much of that has changed. The deregulation of generic products has
 CHAPTER 5: Bioethics In Clinical Research helped to bring about a much greater acceptance of product substitution, which
in turn has led to changes in consumer choice— an event that has acted as a
catalyst for change within the marketplace. Therefore, rather than being
 producer-driven, the market for pharmaceuticals today is essentially customer-
led.
Price has become the key indicator of how the marketplace truly values the
products that are discovered, marketed and sold. Consequently, the price that a
company charges for a product is the culmination of every decision made along
the chain of discovery to marketing. Therefore, in order to be able to survive this
challenging environment, pharmaceutical companies can no longer permit their
internal processes to determine price levels, as this has now become the
privilege of the customer. 98
The demand for innovation in an increasingly complex, global business

environment has necessitated new approaches to organization because the
requirements for success in the marketplace have changed in a number of
profound ways. In addition to demands for e ciency, quality and exibility,
pharmaceutical companies are also required to simultaneously cut costs,
improve standards of quality, shorten product development times, and introduce
innovative products that customers value. As a result, companies have been
forced to re-examine every aspect of how their businesses are implemented and
conducted, and this has given rise to a number of important issues that question
the long-held and accepted ways of managing pharmaceuticals.
The discovery, development and marketing of new pharmaceutical products

are the essence of the research-based pharmaceutical industry. As a result of
the transformation toward a customer-led marketplace, important issues have
been raised which present a number of challenges to many pharmaceutical
companies. Of greater signi cance is the issue of cost.
The total cost of bringing a new product to market from discovery through to
launch, including the cost of capital with a risk premium and the cost associated
with failures, is estimated to be approximately $800 million, over a 10 to 12 years
period. Of this total, around 30 percent of the costs are concentrated in
exploratory research while the remaining 70 percent are invested in subsequent
development phases. At the same time, the percentage of money spent on
innovation has been increasing steadily from around 6 percent in the 1960s to
approximately 20 percent by the late 1990s.
Both the increased cost together with the growing quantity of resources
being invested in pharmaceutical innovation are due to a combination of factors
other than in ation. Traditionally, the rate of growth of the rm has been linked to
Drug Discovery new product introductions, as it was believed that increased investment in
and Clinical innovation generally guaranteed more novel products. Furthermore, the shift
Research
from acute to chronic therapy has increased the complexity of research as well
SK Gupta
as the regulatory approval process. Demands for regulatory data have almost
doubled since the mid-1980s thus increasing the time it takes to get a product to
market. In addition, companies with low levels of new product innovation have
spent vast amounts of capital in an effort to secure future sources of revenue.
INTRODUCTION TO DRUG DEVELOPMENT Owing to the culmination of these factors pharmaceutical companies face
 DRUG DISCOVERY PROCESS the immediate prospect of lower margins and almost no price exibility for
 PRECLINICAL DRUG DEVELOPMENT existing products in the world's largest markets. Therefore, the fundamental
 CLINICAL DEVELOPMENT question that arises is whether pharmaceutical companies can afford to keep
 PHARMACOVIGILANCE spending on innovation at current industry levels?
CHALLENGES TO IMPROVE INPUT/OUTPUT RATIO
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 CHAPTER 3: Clinical Development Of New Regarding the level of research productivity within pharmaceutical rms, two
Drugs
important features have emerged. First, companies have discovered that as 99
Development research moves up the technology curve it not only becomes more complex and
 CHAPTER 5: Bioethics In Clinical Research costly, but that the level of output begins to decline as well. Second, as size and
complexity increase, so do organizational ine ciencies. This combination of
technological complexity, increase in cost, the effect of diminishing returns, as

well as greater bureaucracy have consequently led to growing levels of
ine ciency within the innovation process. The implication of this long-term
decline in innovative productivity within the pharmaceutical industry suggests
that companies are not as successful as they used to be at innovation.
It is universally acknowledged that in customer-led markets the customer's

perception of value is paramount. It is for this reason that the products that do
not meet the requirements and satisfaction of the customer base will not be able
to recoup the investments made. Therefore, this is another challenge faced by
pharmaceutical companies to improve the input/output ratio by customizing
innovative output to match more closely the needs of sophisticated, cost-
conscious and value-driven customer base.

CHALLENGES IN PRODUCING UNIQUE PRODUCT RAPIDLY
Historically, the largest pharmaceutical companies have achieved the majority of

their sales by developing so-called annuity drugs that treat long-term chronic
diseases within the largest number of patients. Because of this, the real strength
of all of the pharmaceutical majors is contained in the various therapeutic
classes they serve. However, most of these categories are now mature and
already have relatively well satis ed patients. With mature products going off
patent and with no new major therapies on the immediate horizon, there is the
potential for a price ceiling to be placed for large-volume categories
experiencing the move to generic status for many of the leading products.
Consequently, the move toward organized generic, class and therapeutic
substitution is a signal that imitative R & D will be less rewarding in the future.
Economic venture into large number of ‘me-too’ drugs might be a futile.
One of the most important issues facing most pharmaceutical companies at

present is the question of whether they have the capacity to convince their
customers to pay premium prices to cover production costs, as well as to
provide satisfactory returns for the future development of additional
undifferentiated drugs. Many of the currently untreatable diseases such as AIDS,
cancer, migraine and multiple sclerosis are those that provide the most lucrative
business opportunities. At the same time, healthcare providers and insurers
within the industrialized nations continue to debate the sensitive issue of

whether society can afford the costs of maintaining and extending the quality of
life. As a result, an inherent paradox exists.
Drug Discovery
and Clinical The challenges pharmaceutical companies are facing is to rapidly produce
Research unique products that are truly successful in treating unconquered diseases,
SK Gupta while at the same time obtaining high prices that are required to pay for cutting-
edge research. 100

CHALLENGES IN ESTABLISHING “VALUE-FOR-MONEY”

One of the most signi cant developments in the move toward customer-led
change is the accelerated search for mechanisms to establish a sense of ‘value-
 CLINICAL DEVELOPMENT for-money’. This has led to the creation of pharmacoeconomics, which
 PHARMACOVIGILANCE encompasses a set of potentially useful approaches for making more rational
 REGULATORY APPROVALS FOR decisions for selecting drugs. Such approaches include analysis of cost versus
bene t ratio, cost effectiveness, cost minimization, cost utility, the quality of
adjusted life years and eventual outcomes. Pharmacoeconomics will enable the
Of Biologics pharmaceutical companies to demonstrate value in order to support the
 CHAPTER 3: Clinical Development Of New marketing of products. It could also be used when selecting projects for R & D
Drugs
purposes.
Development
In most instances, however, there are con icting forces at work. On one
hand, healthcare payers as well as providers demand the lowest-cost solution to
their healthcare problems while remaining partial to acquisition costs.
 Conversely, pharmaceutical companies wish to avoid the downward pressure on
prices by focusing on product value rather than on the cost of acquisition.
Further escalating the value-cost con ict is the fact that there are no global
standards for pharamacoeconomic techniques, coupled with a severe lack of
conformity on how customers interpret output. When these factors are
combined, the use of a particular set of approaches that are based on single
cost structures becomes problematic.

CHALLENGES IN CONVINCING CUSTOMERS TO ACCEPT THE

PRODUCT
In order for pharmaceutical companies to be able to reverse the decline of their

pro t margins, it is important that an atmosphere of acceptance be created
among customers concerning the value of drugs rather than of their costs. If
customers are not convinced that healthcare costs can only be reduced through
integrated approaches and not by ingredient cost management, then this effort
will surely fail. Conversely, unless research-based rms can discover a
mechanism through which future returns for a successful product can be
secured, thereby justifying the signi cant investment required for high risk,
cutting-edge research, there will be a general decline in the number of products
offering genuine solutions to healthcare problems.
Another challenge faced by research-based pharmaceutical companies is

the need to convince their increasingly cost-conscious customers to look beyond
the management of acquisition costs, and to appreciate instead the overall value
of a drug in terms of its total savings in overall healthcare costs.
Furthermore, many of the development pipelines are currently saturated with

chemical class variations, which will only serve to provide low-grade
improvements in e cacy or safety. Such substances only have a limited
potential to create meaningful differentiation over existing brands, or cheaper
generic or therapeutic substitutes. In addition, the degree of patent protection
available no longer provides a safety net over gross pro t margins. Thus, the key 101
issue centers on the extent to which a customer perceives how much a product
is worth.
Inevitably, many pharmaceutical companies will have to implement an in-

depth review regarding the potential marketability of their product pipelines.
Therefore, pharmaceutical companies, need to decide whether they should
Drug Discovery continue to develop products for which customers are unlikely to pay enough in
and Clinical order that rms may recoup their development costs, or should such projects be
Research
abandoned in the rst instance?
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CHALLENGES DUE TO CHANGING MARKET ENVIRONMENT
In the past, it was widely accepted that the more money and effort were put into
INTRODUCTION TO DRUG DEVELOPMENT innovation the greater was the chance of discovering new products.
 DRUG DISCOVERY PROCESS Corresponding to this stream of thought, it was also believed that the greater the
 PRECLINICAL DRUG DEVELOPMENT number of new products introduced to the market, the greater the prospect of
 CLINICAL DEVELOPMENT achieving considerable market success and hence competitive advantage.
Although somewhat correct, this is no longer the case due to the changes that
REGISTRATION OF DRUGS have occurred in the marketplace. Since much of today's management practice
 CLINICAL DATA MANAGEMENT and operating culture in large industrial research laboratories was established
 CHAPTER 2: Drug Discovery And Developmen prior to 1970, many of the institutions and instincts developed in this early period
Of Biologics
are now at odds with current realities. A new set of rules has emerged which
Drugs now governs the market for pharmaceuticals, and as a result, requires re-
 CHAPTER 4: Phase 0 Trials In Cancer Drug examination of the assumptions upon which traditional pharmaceutical
Development management is based.
In today's customer-driven market the degree of innovation success is a
function of how well a product is perceived to offer new or better solutions to a

customer's clinical problems. Companies are forced to make decisions based on
resource allocation. They must favor new and better products, select from those
considered marginal that will establish clinical and cost value from the
customer's perspective, and abandon all products deemed mediocre. Success in
the pharmaceutical industry is no longer determined by product innovation
alone, but through a combination of value generating factors.
For many years the role of the physician was deemed crucial to ensuring
product success. This was most common in instances where physicians had
complete freedom of choice with regard to prescribing, or where there was
relatively little concern for cost containment measures. However, since the end
of the 1980s a rapid change has occurred as both public and private payers have
come to realize that a policy of cost containment could only become truly
effective if industry-focused supply side controls are effectively linked with
physician and patient focused demand side controls. This has resulted in the
development of a wide array of containment measures ranging from formularies
to prescribing guidelines, mandatory substitution of cheaper products, as well as
practice protocols. Therefore, while the physician remains an important
constituent in the marketplace, the upstream consolidation of buyers together 102
with tighter cost control measures has irreversibly changed the balance of
power.
In summary, pharmaceutical manufactures should meet the needs of a

modern and aggressive market and satisfy the healthcare need of cost-
conscious customers rather than just sell pharmaceuticals. Companies need to
look beyond “me-too” products and move towards developing innovative
targeted therapies that address the underlying molecular mechanisms of
disease. Ultimately, keeping both biology and clinical practice in mind throughout
the entire drug discovery and development continuum can increase the
likelihood that compounds reaching the development-candidate stage will have
the safety and tolerability pro les and pharmaceutical characteristics necessary
for successful clinical development.

CLINICAL DATA MANAGEMENT
INTRODUCTION
Drug Discovery
and Clinical All clinical trials are performed to answer certain questions about the e cacy
Research and safety of a drug or device. The answers solely depend upon the quality of
SK Gupta data, which are collected during the trial and submitted after the trial. The study
data are the immense asset for the pharmaceutical and biotech companies.
Probability of getting a marketing approval for a drug or device increases if the
study data are accurate. Hence, data management plays a crucial role in
ensuring the success of a trial. Adopting proper methods to manage the trial
INTRODUCTION TO DRUG DEVELOPMENT data helps in increasing the quality of data. Learning, practicing and improving
 DRUG DISCOVERY PROCESS upon these methods has led to the creation of clinical data management as a
 PRECLINICAL DRUG DEVELOPMENT specialty.
 PHARMACOVIGILANCE Drug development encompasses stages such as formulation, toxicology and
 REGULATORY APPROVALS FOR clinical trials. Clinical trial or a study in turn has various stages as depicted in
Figure 1.23. However these may overlap. A study starts with an objective, which
gets translated to a protocol, proceeds with identi cation of sites and
Of Biologics management of the trial.
Drugs
Development
Fig. 1.23: Overview of clinical trial processes 103
Actual process of data management is initiated with the collection of data.

HISTORY OF CLINICAL DATA MANAGEMENT
Clinical data management (CDM) has evolved from a data entry process into a
diverse process to “provide clean data in a useable format in a timely manner”,
“provide a database t for use” or “ensure data are clean and database is ready
to lock”.
Though clinical data management had to be done with whatever data was
collected for clinical trials from its earliest days, the processes were given a
major focus in the early 1970s, when the Public Health Service recognized the
need for good practices in clinical data management. With the advent of
electronically transmitted clinical trial data, standardized practices and
procedures developed further. Regulatory requirements have advanced the
necessity of clinical data management as a science.
Quality of the trial data is much more critical as pharmaceutical companies

invest vast amounts of money in drug research. It is also vital for regulatory
submission and approval. Hence, CDM has grown from a mere data entry
process to a technology based science.

ORACLE CLINICAL (OC)
It is a vendor developed data management system and also known as a

Relational Database Management System. It is used for managing database
design and data acquisition for clinical study.
The global library contained in OC is a central repository for the objects that
compose data collection de nitions for clinical studies. This allows for objects
to be re-used for multiple studies, saves time in study set-up and ensures that
Drug Discovery there is standardization and consistency of data collection and reporting. OC
and Clinical can be customized to contain “Views” that allow the data to be browsed. System
Research
generated error messages are programmed to conduct Data validation. They are
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called—
Validations: Programmatic procedure which checks for illogical or incorrect data,

e.g. check AE Start Date is after the Stop Date.
 CHAPTER 1: New Drug Development Derivations: Programmatic procedure which calculate data based on data that
are stored in the database, e.g. Derive Age from Birth date.
 PRECLINICAL DRUG DEVELOPMENT The Oracle clinical applications allow electronic data to be created, modi ed,
maintained and transmitted. Therefore, in accordance with 21 CFR Part 11,
procedures and controls are established to ensure the authenticity, integrity and
REGISTRATION OF DRUGS when appropriate the con dentiality of electronic records. Such procedures and
 CLINICAL DATA MANAGEMENT controls include:
Of Biologics Audit trials: The use of secure, computer-generated, time-stamped audit trials
 CHAPTER 3: Clinical Development Of New to independently record the date and time of entries and actions that create,
Drugs 104
modify or delete electronic records
Development Electronic signature certi cation: Individuals must be trained to use applicable
 CHAPTER 5: Bioethics In Clinical Research systems/programs and that training must be documented
Electronic signature controls: Ensure uniqueness
 Two distinct ID components (non-biometric).
All individuals receive a unique sign-on and password that is considered the
electronic signature. Every sign-on ID has assigned security to allow or
prevent software access as well as software functionality
The user sign-on is the legally binding equivalent of the individual's
handwritten signature
System and data security: Limits system access to authorized individuals.

OVERVIEW OF CLINICAL DATA MANAGEMENT
Clinical data management refers to the management of data capture and data
ow processes in conduct of a clinical research. It begins with design of data
capture instrument and data collection, continues with data quality control
procedures and ends with database nalization. The locked database undergoes
a statistical analysis after which it is ready to be submitted to the regulatory
authority for approval. Processes used to support the clinical data must be
clearly de ned and documented. Documents supporting CDM activities include
protocol and standard operating procedures (SOPs).

DATA MANAGEMENT PLAN
Before starting with the data management processes, a data management plan
(DMP) must be put in place. DMP helps to proactively assess and plan for the
study-speci c data management processes. The DMP serves as the backbone
of overall quality system of data management (DM) and outlines:
How and when each step of the CDM process must be carried out
What documents are to be created and nalized
De nes the data management tasks, responsibilities, deliverables and
timelines
Which SOPs or guidelines will apply to the various processes
What document or output to collect or produce
What level of quality must be achieved.
Preparation, review and nalization of the DMP involves participation from

sponsor, lead data managers, project managers, biostatisticians, database
programmers, lead clinical research associates (CRAs), project directors,
Drug Discovery medical monitors and clinical scientists.
and Clinical
Research Some of the key elements included in a typical DMP include (Fig. 1.24):
SK Gupta
Trial work ow
Study set-up/design
Computing environment
Database development and testing
INTRODUCTION TO DRUG DEVELOPMENT CRF management, including CRF ow and tracking 105
Of Biologics
Drugs
Development Fig. 1.24: An outline of the development and review process of a DMP
Data capture, data entry and study speci c guidelines
Serious adverse event reconciliation

Data validation procedures
Coding procedures
Lab data management
Data transfer procedures
Discrepancy management
Reporting processes
Study lock
Quality audit.
DATA CAPTURE AND COLLECTION
Data capture is a key concept in data management. This refers to procedures for
gathering and recording data from or related to subjects in the study. It could
either be paper-based or through electronic data capture (EDC). Promise of
enhanced e ciency has led to increasing movement towards implementation of
the electronic medical record and to computerized automation in general.

PAPER CRF BASED STUDY
Trial data are written on paper CRF(s) at the investigator sites. The study
coordinator refers to “the source” (patient, patient's chart or other medical
records, source document, etc.) and transcribes the data onto the paper CRF.
This is just the rst of many ‘transcription’ processes in clinical data
management. These CRF(s) are periodically reviewed by CRAs to ensure that the
data is valid and complete. A copy of the CRF is retained at the site and
additional copies are sent to the sponsor and the data management team where
the data is entered into a database. Data can be transferred from the paper CRF
to the customized database in different ways.
One way is to scan the CRF. The scanned images of the CRF(s) are
electronically transferred to the database. Data entry is then performed as per
the scanned images of CRF(s) into the database 106
Image recognition technology includes optical character recognition (OCR)

and optical mark recognition (OMR). Here the data is captured from
handwritten printed copies. Then the handwritten information is translated
Drug Discovery into electronic text documents. The image recognition software converts the
and Clinical scanned image to machine-readable and editable text.
Research
SK Gupta Data editors then review the data in the database and identify any
discrepancies in the data. These are resolved using a Data clari cation form
(DCF), which is sent to the investigator at the site. After all the discrepancies are
resolved, the data in the database is declared as “clean”, at which point the
database is locked. These paper CRF(s) have to be retained for up to 15 years at
INTRODUCTION TO DRUG DEVELOPMENT the sponsor and investigator sites.
Paper based trials have their own disadvantages. The cost of printing and
distributing CRF(s) is high. Enormous amount of time is spent in resolving
 PHARMACOVIGILANCE simple data entry errors. Study performance information is not available to
 REGULATORY APPROVALS FOR project managers in time for smooth conduct of trials. Repetition of tasks by
different departments in regard to serious adverse event recording and reporting
is common.
Of Biologics

Drugs EDC BASED STUDY
Development
EDC is the capability to collect data electronically, without using paper CRF(s). It
could consist of both online and off-line technologies. EDC is de ned by the
Clinical Data Interchange Standards Consortium (CDISC) as follows:

“Collecting or acquiring data as a permanent electronic record with or
without a human interface (e.g., using data collection systems or applications
that are modem-based, web-based, optical mark/character recognition, or
involve audio text, interactive voice response, graphical interfaces, clinical
laboratory interfaces, or touch screens). Note: ‘Permanent’ in the context of
these de nitions implies that any changes made to the electronic data are
recorded via an audit trial.”
Interactive voice response system (IVRS) consists of interactive speech or

touch-pad menu-driven systems that take the caller through a series of prompts.
Responses are entered through a telephonic keypad. This technology is typically
used in areas such as patient randomization, adverse event reporting, trial
supply management, patient visit tracking, assisting with study startup or
collecting subject diary information.
The database designed electronic CRF, (eCRF) is a true replica of the paper
CRF in order to store the subject data when viewed on-screen. These eCRF (s)
will have built-in real-time data validation checks. The data is entered directly
into the interface of the central/global clinical database and immediately
available for review to authorized study staff. This technology is also referred to
as remote data entry (RDE) or remote data capture (RDC). eCRF(s) have certain
advantages over paper CRF(s). They are:
Facilitates faster and more active management of the data gathering and
processing work ow, thereby accelerating the transmission time of data to
the sponsor 107
Automated data edit checks alert the site to possible errors in data entry
Ensures faster correction of issues and immediate site education, hence is
cost saving
Ensures immediate viewing and review of the data by the sponsor and data
management, hence online feedback is provided to the site immediately.
EDC has its own demerits. Primarily the reluctance of the investigators to
use technology is a concern. As use of technology not only involves newer
processes but also integration of other systems and groups, it requires higher
planning and investment.
DATA PRIVACY
Drug Discovery
and Clinical The ICH Guideline for Good Clinical Practice (GCP) states, “The con dentiality of
Research records that could identify subjects should be protected, respecting the privacy
SK Gupta and con dentiality rules in accordance with applicable regulatory
requirement(s).”
Adherence to sponsor's privacy policies is essential for maintenance of

subject con dentiality. Security of all paper and electronic data has to be
 CHAPTER 1: New Drug Development maintained. Paper CRF(s) are preferably stored in reproof vaults with restricted
access and all electronic data are protected with a password and rewall.
Regulatory issues associated with patient data collection include nalization of
 CLINICAL DEVELOPMENT error correction rules for CRF(s) using GCP, ensuring computer systems are 21
 PHARMACOVIGILANCE CFR Part 11 compliant and ensuring that all SOPs related to data management
 REGULATORY APPROVALS FOR are in place and adhered to.
 CLINICAL DATA MANAGEMENT Investigator's training helps to generate better quality data thereby avoiding
 CHAPTER 2: Drug Discovery And Developmen the generation of frequent queries. Detection of training issues by study
Of Biologics
monitors for common problems associated with CRF(s) and looking for
Drugs recurring types of queries adds to improve the quality of the data.
Development
CRF DESIGN
 CRF(s) are instruments used to collect data from the clinical trials. They are
designed to collect all data points speci ed in the protocol. CRF(s) standardize
the collection of study data and also help in meeting the needs of medical,
statistical, regulatory and data management personnel. The CRF(s) are lled in
by the investigator and then forwarded to the data management unit for entry
and review.
In terms of design a well-designed CRF(s) should have the following

features:
Consistency across patients and sites

Clear, concise and easy to ll questions
Support data management activities
Well-designed headers
Aid computerization of data
Reliable and clean data for analysis 108
Grouping of similar type of data together

Collect raw data rather than calculated data
Avoidance of long elds of free text
Easy access of header information
Legible font style and size
Su cient margins for binding and punching purposes.
Some of the CRF essentials include study name/identi er, unique subject
identi er, form name, page number, signature of person completing the form,
date of form completion, instructions (when to complete, where to send) and
numbering of items for easy reference.
While designing a CRF, there are typically three types of question responses
that can be incorporated:
Open response: This typically involves free text, for example, adverse event
(AE) text, medication text, medical history details, date/time, numeric lab
values
Closed response: This typically consists of check boxes, multiple choice, etc
Combination response: This consists of a combination of both open and

closed type responses. For example, on the medical history record, a question
asking for specifying if any abnormality present, requires an answer yes or no
Drug Discovery (closed). If the answer is yes, then one is asked to specify details of the
and Clinical abnormality (open).
Research
SK Gupta Before design nalization, a pilot is carried out with few ‘dummy’ CRF(s) to
identify potential troublesome elds; accordingly training sessions are
conducted for investigators and CRAs during study initiation. The CRF design
review and nalization involves participation from the project data managers,
statisticians, regulatory managers, medical monitors, lead CRAs and clinical
INTRODUCTION TO DRUG DEVELOPMENT scientists.
A set of CRF completion guidelines are nalized and documented in the
DMP. This serves as a guideline to the investigators while lling in the CRF(s)
 PHARMACOVIGILANCE and would typically consist of the following instructions:
Read and follow all instructions carefully
 CLINICAL DATA MANAGEMENT Write legibly on the form
Of Biologics
Use permanent ink on the forms
 CHAPTER 3: Clinical Development Of New Ensure all questions are answered and complete
Drugs
Write answers inside the space provided
Development Submit original forms when necessary
Use appropriate mechanisms for making corrections on the CRF(s)
Check the forms before submission to the data management unit

Ensure that patient ID information is correct
Follow correct schedule/visits for forms submission
Follow procedures for visits/examinations/tests that are not done and for
unscheduled visits 109
List abbreviations, if applicable

Instructions for early terminators/study discontinuation
Instructions for SAE reporting.

CLINICAL DATABASE/DATA MANAGEMENT TECHNOLOGY
A comprehensive system is required to manage clinical trial data including

database creation and automated data entry screen design, e cient support for
double data entry, terminology encoding, data validation, query management,
data review and reporting, exible database import and export.
Such systems are evolved out of the deep rooted knowledge and experience
of professionals, the system can then represent an unparalleled level of maturity
and a rich understanding of the day-to-day requirements for e cient and
effective clinical data management work ow processes — from database set-up,
to data quality controls and nal export. The system has to be complete,
intelligent, easy to learn and use and powerful.
A clinical data management system (CDMS) enhances the e ciency of the

clinical trial process. Implementation of the CDMS involves planning and
interaction of various teams. Design of CRF data ow into the system either
manually or electronically is the rst step. Subsequent steps are creating the
global database, validation/derivation procedures, data extraction programs and
reporting. One can also integrate dictionaries, AE (Adverse Event) reporting
systems, EDC/RDC (Electronic Data Capture/Remote Data Capture) and CTMS
(Clinical Trial Management System) with CDMS. It is essential to ensure that
data is automatically transformed from a collection format to the reporting
formats as needed by the sponsor and the regulatory authorities.
The main objective of database design is to capture and store clinical data
accurately. The essential features of good design are ease of data capture,
e cient creation of analysis data sets and accommodation of source data
Drug Discovery transfer formats.
and Clinical
Research
SK Gupta CRF LOGIN AND INVENTORY
The paper CRF(s) from site must be e ciently transmitted to the data
management unit for entry and processing. Typical methods include faxing,
mailing, scanning and in some cases hand delivered by the site monitor. Once
INTRODUCTION TO DRUG DEVELOPMENT the CRF(s) are received at the data management unit, each CRF page must be
 DRUG DISCOVERY PROCESS logged into the CDMS and each page gets inventoried into the CDMS. Tracking
 PRECLINICAL DRUG DEVELOPMENT inventories are set-up to detect missing pages and duplicate pages. When the
 CLINICAL DEVELOPMENT CRF(s) are received as faxes or scanned images, some of the CDMS(s) can
automatically store the images in a CRF image database. When paper CRF(s) are
REGISTRATION OF DRUGS manually received, one can scan the CRF pages and store the images in CDMS.
 CLINICAL DATA MANAGEMENT Subsequent processing steps may utilize images rather than paper. 110
Of Biologics
 CHAPTER 3: Clinical Development Of New AUDIT TRIAL
Drugs
Development 21 CFR Part 11 compliance requires that all persons accessing the clinical data
 CHAPTER 5: Bioethics In Clinical Research management system must have electronic signatures of their own. All CDM
personnel who access the database must have their unique electronic
 signature/user IDs. Any modi cation, change, updation or deletion made in the
database will be captured in the ‘audit trial’. A well-designed audit trial captures
details of the date and time of change, user ID of person making the change,
original entry on database, nal entry on database (changed value) and the
reason for change.

DATA ENTRY
Data entry refers to the process of transferring data from the paper CRF to the
database. This is also referred to as transcribing the data. Data entry results in
creation of electronic data, which corresponds to the CRF data. Once data is
entered into the database, it is reviewed and validated by the data editor.
Emphasis for data entry is on typing speed and typing skills, since this activity
requires large amounts of data to be keyed into the database. Data entry
consists of both double entry and single entry.

DOUBLE ENTRY
This involves entry of the same CRF page by two independent data entry
personnel. The rst data entry personnel keys in the data into the database.
Later, a second independent data entry personnel keys in the same data. In case
of a difference or discrepancy between the rst and second entry, a ‘pop up’ box
throws up, alerting the second data entry personnel to either key in what they
see or to accept what the rst data entry personnel has entered. Another option
is to have a ‘third’ personnel review the differences/ discrepancies and resolve
them. Thus double data entry serves as a quality check on the data that is
entered into the database.

SINGLE ENTRY
This involves entry by single data entry personnel. This process is used when
there are su cient and extensive checks built into the database that would
detect certain errors that might be missed out by the data entry personnel.
Single data entry is extensively used in EDC and RDC systems, where the
investigator and site personnel directly key in the data. This eliminates having
data entry personnel within the data management unit. Once the data is keyed in
directly at site, it is ready to be reviewed, edited and validated by the data editors.
Drug Discovery
and Clinical Data entry could be of two types:
Research
Data entry is done locally at the site database and then transmitted
SK Gupta
periodically to the central database via internet or using a dialup line. 111

Of Biologics Fig. 1.25: Types of data inconsistencies
Drugs
Sometimes the data is also sent using other electronic media such as a CD,
 CHAPTER 4: Phase 0 Trials In Cancer Drug oppy or as a mail attachment
Development
Data entry is done online directly into the central database via internet. Usually
these systems are web-based and the data are available in real time for
review.

DATA REVIEW AND VALIDATION
Once data entry is complete, the data is ready to be reviewed by the data editor.
The data editor ensures that all discrepancies are addressed and resolved and
that the database is nally clean and ready to be locked. Discrepancies are any
inconsistencies found in the clinical trial data that need to be addressed.
Discrepancies include incomplete data, illogical data, incorrect data and illegible
data (Fig. 1.25).
Discrepancies could be checked either manually or through computer-

generated checks (validations and edit checks) that are programmed into the
database. System-programmed validations are designed before start of the data
management activities and these serve as checks or alerts to the data editor.
The data editor ensures that all discrepancies and validations are addressed and
resolved before locking the study.
Data cleaning or validation refers to a collection of activities by data

management, used to assure validity and accuracy of the clinical data. It
comprises of both logical and statistical checks to detect impossible values due
to data entry errors, coding and inconsistent data. The DMP and SOPs clearly
de nes the tasks, roles and responsibilities involved in cleaning a database.
There are various types of checks that must be performed and various types
of data points and discrepancies that must be addressed during the process of
review and cleaning (accordingly validations could be programmed for these
discrepancies). 112

POINT-BY-POINT CHECKS
This refers to cross checking between the CRF and the database for every data
point. If the data editor performs this check, it serves as a second quality check
apart from double data entry. Incorrect entries or entries missed out by data
entry are corrected during this check. Special emphasis is given to dates,
numerical values and header information, where there are likely to be more data
entry misses.

Drug Discovery
and Clinical MISSING DATA OR BLANK FIELD CHECKS
Research
SK Gupta Missing data and blank elds must be queried for, unless indicated by the
investigator as ‘not done’, ‘not applicable’ or ‘not available’. It is better to program
validations for missing data elds rather than review them manually. Examples
of missing data include missing AE/medication term, missing start/stop dates,
completely blank CRF(s) where none of the question responses are provided.
 PRECLINICAL DRUG DEVELOPMENT DATA CONSISTENCY CHECKS
 PHARMACOVIGILANCE Checks are designed to identify potential data errors by checking corresponding
 REGULATORY APPROVALS FOR events, sequence of dates, missing data (indicated as existing elsewhere) etc.
Checks include cross checking between data points both across different CRF(s)
and also within the same CRF.
Of Biologics
Consider an example of inconsistent data across different CRF records: On
Drugs the AE record, an AE is reported with action ‘concomitant medication’; however
 CHAPTER 4: Phase 0 Trials In Cancer Drug on the Concomitant Medication record, there is no appropriate medication
Development
administered within the timeframe.
Consider the AE record where fever is reported with action ‘concomitant

 medication’:
Event Start Date Stop Date Action Outcome
Fever 13-Jun-2005 20-Jun-2005 Concomitant Medication Resolved
Now consider the concomitant medication record where paracetamol is

reported as follows:
Medication Start Date Stop date Outcome
Paracetamol 21-Jun-2005 21-Jun-2005 Stopped
Here, paracetamol has not been given in the appropriate timeframe and
hence this data is considered inconsistent.
Examples of inconsistent data across different elds, but within the same
CRF include (a) an AE reported with a ‘start date’ but the outcome is reported as
‘continuing/persisting’ (b) stop date of a medication is greater than the visit
date. 113
Consider another example of an antibiotics record versus a trial medication

record. Data consistency checks are to be reviewed both within a particular CRF
and across different CRFs. Note the two sections/modules in the antibiotics
record. The rst section is designed to “report doses of antibiotics taken before
intake of rst dose of trial drug”. The second section is designed to “report
doses of antibiotics taken after intake of rst dose of trial drug”.
The rst section of the antibiotics record is reported with the following
details:
Antibiotic Dose Route Start date Stop date
Amoxicillin 6 mg Oral 11-May-2001 14-May-2001
The second section of the antibiotics record is reported with the following
details:
Antibiotic Dose Route Start date Stop date
Streptomycin 7 mg IV 16-May-2001 17-May-2001
The trial medication record where the rst dose of trial drug is reported with
the following details:
Trial medication Dosage Route Dosing dates

Drug Discovery
and Clinical XX 50 mg IV 15-May-2001
Research
SK Gupta In this example, a crosscheck of data between the two sections of the same
antibiotic record and also between the antibiotic record and trial medication
record shows that the data reported is logical and consistent.

 CHAPTER 1: New Drug Development LABORATORY DATA AND RANGE CHECKS

Laboratory data has to be treated in a special manner, as they are different from
all other CRF data. The data have to be interpreted with the help of reference
 PHARMACOVIGILANCE ranges and must be expressed in the speci ed units for proper interpretation.
 REGULATORY APPROVALS FOR This is much more important when data are combined from multiple studies. If
the units are different they have to be converted to one common unit before
interpretation. Hence, the data have to be stored along with the original units in
Of Biologics which they were captured. Linking the data with proper normal ranges is critical.
 CHAPTER 3: Clinical Development Of New Reference ranges may have to be taken from the study speci c ranges or
Drugs
standard books when ranges are not available with the data.
Development
Range validations are designed to identify statistical outliners, values that
are outside normal variation of population under study and values that are
physiologically impossible. An example of an ‘out-of range’ discrepancy is the 114
 reporting of hemoglobin value as 90 g/L, where the normal speci ed range as
per the protocol is 110 to 160 g/L. While carrying out range checks, data editors
need to ensure that appropriate range values and range units are applied for the
particular test performed. For example, ranges for WBC types could be applied in
units of either ‘percentage’ or ‘absolute’. A granulocyte value could be reported in
the unit of percentage, whereas the corresponding range could be applied in the
absolute unit, hence the granulocyte value would most de nitely be out of range.
Consider the following cross-check between the hematology record and AE

record:
Hematology record:
Hematology test Date Result Normal range
WBC 05-Jan-2006 13,710 cells/cu mm 4,300–10,800 cells/cu mm
AE record:
Event Start date Stop date Outcome
Streptococcal infection 04-Jan-2006 07-Jan-2006 Resolved
In this case, a validation should ideally be programmed to ag a WBC ‘out of

range’ discrepancy. The study guidelines may instruct the data editor to either
query the site to con rm the correct value or to accept the discrepancy since an
increase in WBC count is justi ed by streptococcal infection in the same time
frame.

DISCRETE VALUE GROUP (DVG) DISCREPANCY CHECKS
DVG is a question where there is a xed or expected set of responses. DVG(s)

are built into the database in the form of drop-down options. An example of a
DVG is the set of responses for the severity of an AE – ‘mild’, ‘moderate’, ‘severe’
and ‘life-threatening’. However, if the severity is reported as ‘not known’, which is
not part of this DVG, it constitutes a DVG discrepancy.
Another type of DVG discrepancy is a ‘length’ discrepancy. When the

database is designed, each free text eld is assigned a maximum number of
characters that it will be allowed to accept when the data is keyed in. If the text
reported exceeds the maximum number of characters, a length discrepancy is
created, which needs to be addressed by the data editor.
Drug Discovery
and Clinical
Research HEADER INCONSISTENCY CHECKS
SK Gupta
Examples of discrepancies with the header information include (a) an incorrect

visit date like 30-Feb-2005 (b) an incomplete visit date like 12-Jan, whereas the
date is expected to be reported in the DD-MM-YYYY format (c) incomplete
patient initials. 115
 PRECLINICAL DRUG DEVELOPMENT MISSING PAGES CHECKS AND CRF TRACKING
 PHARMACOVIGILANCE Details of transmittals and receipt processes of CRF(s) and DCF(s) are
 REGULATORY APPROVALS FOR documented and maintained during all stages of the data management process.
Missing and expected pages tracking systems are also planned and setup in the
DMP. Tracking reports of missing pages have to be maintained to identify CRF(s)
Of Biologics misrouted in-house as well as CRF(s) not sent from the site.
Drugs
Development
PROTOCOL VIOLATION CHECKS
Protocol adherence ought to be reviewed at all stages of data management.
Violations found have to be queried. Special emphasis is given for reviewing
 primary safety and e cacy endpoints, adherence to inclusion and exclusion
criteria, adherence to trial drug dosing regimen, study or drug termination
speci cations, etc.

DATES OUT OF SEQUENCE CHECKS
Dates out of sequence, refers to dates either in the header or the body of the CRF
being inconsistent and out of sequence. Sequence of visits are reviewed and if
found to be out of sequence, will be either queried or corrected. Examples
include (a) a record belonging to visit 4 has a visit date belonging to that of visit
2 (b) one of the records within a particular visit has a visit date that is out of
sequence with the visit date of the other records of the same visit (c) the trial
medication is to be taken on a ‘daily’ basis as per the protocol, however, the
dosing details on one of the dates has not been reported in the trial medication
record.
Example where one of the screening records is reported with an incorrect

‘year’, hence there is a screening visit date out of sequence:
Record Name Visit Date
Demography 20-Feb-2006
Med. history 20-Feb-2005
Inclusion criteria 20-Feb-2006
AE 20-Feb-2006
CONTINUITY OF DATA CHECKS
These are checks performed for ensuring continuity of events (AE(s),

medications, treatments/procedures etc.) across the study and across visits.
Overlapping start/stop dates are checked across visits.
For example, consider a scenario where the protocol states that AE(s) are to
be reported in visits 1, 2 and 3. “Headache” is reported as follows: 116
Start Date Stop Date Outcome
1 01-Jan-2004 12-Jan-2004 Continues
2 01-Jan-2004 12-Jan-2004 Resolved

Drug Discovery
and Clinical 3 20-Jan-2004 20-Jan-2004 Resolved
Research
SK Gupta There is an issue in visit 1 reporting, where the ‘stop date’ has been reported
and the outcome is reported as ‘continues’. There is also the issue of
overlapping start/stop dates in visits 1 and 2. All such issues are queried and
clari ed with the investigators.

CODING CHECKS
All the data such as concomitant medications, adverse events, medical history
 PHARMACOVIGILANCE and diseases have to be substituted with a standard reference terminology. This
 REGULATORY APPROVALS FOR is known as ‘coding’. The reference terminology may come from sponsor
speci c dictionaries or other published dictionaries. The coding of data helps in
grouping them under speci c systems. Such groupings are required for
Of Biologics summary analysis of these data. Coding is done before the database lock.
Drugs As an example, consider medications ‘paracetamol’ (generic name) and
 CHAPTER 4: Phase 0 Trials In Cancer Drug ‘Crocin’ (trade name) reported on the CRF. Both medications have the same
Development
active ingredient ‘paracetamol’ and hence must be considered as the ‘same
entity’ for analysis purpose. Hence, both terms must be coded to ‘paracetamol’,
so that the safety and e cacy analysis during statistical analysis is not affected.

There are certain terms that cannot be directly coded without further
clari cation from site. For example, the adverse event “ulcers” requires a
‘location’ (gastric, duodenal, mouth, foot, etc.) in order to be coded. Hence, this
must be queried to the site in order to obtain the location of the ulcer.
Standard global dictionaries having their unique coding structures are used
for coding terms collected in clinical trials. Different dictionaries follow different
structures and different hierarchies based on the classi cation levels. However,
there are many similarities among the dictionaries. There is a term or text (AE,
medication, disease) that is often referred to as the “preferred term” and the
related “code”. In addition to terms and codes, dictionaries generally have
auxiliary tables. For example, AE dictionaries have information on effected body
systems and drug dictionaries may have additional information on the key
ingredients.
Some of the common standard dictionaries used are:
MedDRA—Medical Dictionary for Regulatory Activities

COSTART—Coding Symbols for a Thesaurus of Adverse Reaction Terms
WHO-DRL—World Health Organization Drug Reference List
WHO-ART—World Health Organization Adverse Reactions Terminology 117
ICD-9-CM—International Classi cation of Diseases, Ninth Revision, Clinical

Modi cation.
Auto-encoding: Most modern and advanced coding dictionaries heavily depend

on auto-encoders rather than manual coding. Once data from the case report
form has been entered and veri ed, the process of auto-encoding begins, where
the text of the investigator term in the clinical trial database is compared to the
text strings stored in the dictionary database. When an exact match occurs, the
code from the term in the dictionary database is automatically entered into the
clinical trial database and the term is considered auto-encoded.
Auto-encoders help in handling synonyms, misspellings, word variations,

etc. Auto-encoders may be built-in with CDMS or as stand-alone systems. Auto-
encoders have numerous advantages over manual coding such as the ability to
handle large numbers of terms and the ability to facilitate consistent coding,
without having to rely on the manual re-evaluation of previously coded terms.

Drug Discovery
and Clinical EXTERNAL DATA CHECKS
Research
SK Gupta During the conduct of a clinical trial, some data external to the CRF(s), such as
laboratory data, PK/PD data and device data (ECG, images, owmetry, vital
signs) are also collected.
Central labs are used to maintain ‘uniformity’ across the study and across
 CHAPTER 1: New Drug Development the sites. External data from all the study sites is directly sent to a central lab,
from where the vendors provide electronic transfer of computerized data into the
sponsor's database. Electronic transfer of data helps in avoiding the
 CLINICAL DEVELOPMENT transcription errors. At the time of data transfer one has to take care that all the
 PHARMACOVIGILANCE variables are included and are loaded onto the proper study/visit without
 REGULATORY APPROVALS FOR affecting the blinding.
 CLINICAL DATA MANAGEMENT Data management tracks loading of incorrect subject number, incorrect visit
 CHAPTER 2: Drug Discovery And Developmen number, incorrect study number, incorrect date/time of sample collection,
Of Biologics
incorrect date/time of examination, etc. Missing data such as missing collection
Drugs date/time of blood sample, missing date/time of ECG, missing location of chest
 CHAPTER 4: Phase 0 Trials In Cancer Drug radiograph, missing systolic/diastolic blood pressure, missing microbiological
Development
culture transmittal ID, etc. are also tracked by data management. Incorrect and
incomplete loading details are communicated to the centralized vendors so that
the appropriate data can be subsequently ‘reloaded’.

DUPLICATE DATA CHECKS
This refers to duplicate data entries of a particular data value within a single CRF
or across similar CRF(s). Duplicate entries and duplicate records are generally
deleted as per guideline speci cations. Examples of duplicate data include:
Treatment ‘physiotherapy’ on ‘30-Aug-2001’ reported twice on either the same

treatment record or across two different treatment records 118
Both visit 4 and visit 10-blood chemistry CRF(s) (with different collection
dates) are updated with same values for all tests performed. In this case,
either the collection date on one of the CRF(s) is incorrect or the reported
blood chemistry values in one of the CRF(s) are incorrect
Both ‘primary’ and ‘additional’ medical history CRF(s) at screening are
reported with same details of abnormalities.
TEXTUAL DATA CHECKS
All textual data are to be proof read and checked for spelling errors. Common
examples of textual data include pre-existing conditions in medical history
record, adverse events, medications/antibiotics, physical examination ndings,
etc.

SAE RECONCILIATION CHECKS
An adverse event is any undesirable experience associated with the use of a

medicinal product in a patient. The event is considered as a serious adverse
event (SAE) if it results in any of the following outcomes:
Death
Life-threatening illness
Inpatient hospitalization or prolongation of existing hospitalization
Persistent or signi cant disability/incapacity
Congenital anomaly/birth defect.
Expedited reports are required by the regulatory agencies for certain SAE(s).
Drug Discovery Accordingly the investigator submits the SAE report to the sponsor and the SAE
and Clinical details are subsequently maintained in the SAE database. The SAE details from
Research the clinical trials are also reported on the CRF(s) which are sent to data
SK Gupta management. Before close of study, the data management staff must compare
and reconcile the SAE data in the SAE database with that in the clinical trial
database, to ensure that all SAE(s) were collected and reported properly (Fig.
1.26).

Of Biologics
Fig. 1.26: Diagrammatic representation of SAE reconciliation 119
Drugs

Development
 CHAPTER 5: Bioethics In Clinical Research DISCREPANCY MANAGEMENT
A discrepancy is initially in an open or un-reviewed status. The data editor


addresses the discrepancy and resolves it, based on the project-speci c
guidelines or standard guidelines. There are various actions that can be taken to
address a discrepancy:
Closing discrepancy per internal correction: The data editor can ‘internally’
resolve and close out the issue without sending a query to the site. This action is
applicable when the resolution is fairly ‘obvious’. For example,
A lab value 0.6 is out of range and an ‘out of range’ validation is generated.
The data editor refers to the CRF and notices that the value is actually 6.6 and
not 0.6 and that the value was incorrectly entered by data entry. In this case,
the data editor could change the value in the database to 6.6
A medication is reported as ‘paracetamol’. This will not code and hence would
throw up a coding validation. Since this seems to be very obviously a
misspelling, the guidelines may allow the data editor to correct the spelling to
‘paracetamol’.
Closing discrepancy per clinical team: A discrepancy can sometimes be closed

out directly based on instructions from the clinical scientist. Based on an
ongoing review, the clinical scientist can instruct the data editor to either create
a query to the investigator or provide a resolution for a discrepancy.
Generating a query to the investigator: The study guidelines can include

instructions to the data editor to query a discrepancy in case it cannot be
resolved by internal correction. Queries are generated on data clari cation forms
[DCF(s)], which are in turn sent to the respective sites. DCF(s) are also referred to
as query forms, correction forms or discrepancy forms. DCF drafts can be auto-
generated from a discrepancy management system and contain the query text
templates.
The process of query management can be broadly classi ed into ve steps.
Creating queries: Queries for discrepancies are entered onto the DCF manually
based on reports from the discrepancy management system or the system
may create them automatically. A DCF should ideally contain queries
belonging to the same patient and to the same site.
A DCF would typically consist of the following entities:
Study number/ID
Site number
Patient number
Drug Discovery
and Clinical Investigator name
Research Date of generation
SK Gupta
Unique DCF ID
Query text
Space for the query resolution (to be lled by investigator)
Date and signature of investigator 120
Of Biologics
Drugs
Development
 Fig. 1.27: Process of discrepancy management
In the case of Remote Data Capture (RDC) systems, queries are entered
directly into the database. The investigator answers the queries online and the
responses are then available to the data editor
Sending queries: DCF(s) are delivered to site via fax, paper mail, in person or
by e-mail. In the case of RDC systems, the queries are immediately accessible
to the investigator who can view the queries and provide resolutions online
Tracking queries: The data editor tracks the ow of queries between self and
the site. Following up on delayed responses and misrouted DCF(s) is
important
Resolving queries: Once the DCF is received from a site, the responses are
integrated into the database. Common types of resolutions include retaining
the queried value as the correct value, replacing the incorrect value with the
correct one provided by the investigator, updating a missing response
provided by the investigator
Re-querying: Re-queries are needed when the investigators do not provide a
response or provide an incorrect/inconsistent/incomplete response or provide
the same response to a query (Fig. 1.27).

QUERY WRITING
Good query writing is extremely important so that the investigator can fully
understand the query and hence would in turn provide the correct response. This
helps in avoiding re-queries and reduces the turn-around time for query
integration into the database.
General tips for query writing include having a thorough understanding of

the guidelines and protocol, stating the problem in a simple way, being precise
and to the point while wording the query text, using proper punctuation and
grammatically correct sentences and avoiding repetition of words in the query
text. 121
Drug Discovery
and Clinical
Research
SK Gupta
Fig. 1.28: Diagrammatic representation of database lock

 DRUG DISCOVERY PROCESS DATABASE CLOSURE
 CLINICAL DEVELOPMENT Database closure is done to prevent unauthorized or inadvertent changes to the
 PHARMACOVIGILANCE database once the nal analysis of the data has begun. This process is referred
 REGULATORY APPROVALS FOR to as ‘soft-locking’ the database. This is done after completion of last patient
last visit (LPLV).
Of Biologics
Database lock is critical in randomized trials to ensure the integrity of the
 CHAPTER 3: Clinical Development Of New randomization process (as the blind has been broken). Database closure is done
Drugs when all the discrepancies and validations are resolved, all edit checks are
 CHAPTER 4: Phase 0 Trials In Cancer Drug completed, all missing data/external data are in-house, all terms are coded, all
Development
lab ranges are applied and SAE(s) reconciled. In other words it is done once the
database is cleaned completely (Fig. 1.28).
 In order to safeguard the integrity of the data well-de ned procedures for the
database closure have to be documented and followed. A database can be
unlocked with special user access in case there is a necessity of making further
updates or modi cations to the database. In such cases, the change control
procedures must be clearly de ned and documented. Change control
procedures include notifying the study team, clearly de ning the changes being
made, specifying the reasons for the changes and documenting the dates when
the changes are made. Database closure is followed by nal analyses, which
lead to conclusions on the trial and for the regulatory submissions.

QUALITY ASSURANCE AND QUALITY CONTROL (QA/QC)
QA/QC audits are done periodically—on an ongoing basis as well as at or after

the end of the study. QA audits are systematic and independent examinations of
trial-related activities and documents to ensure that the CDM related activities
and processes were conducted and completed and that the data were accurately
recorded, analyzed, documented and reported according to the protocol, SOPs,
GCP and applicable regulatory requirements.
Errors or ndings are mismatches found between the CRF and the database
during a review. They could be due to incorrect transcriptions, incorrect data
processing (at the level of data entry or data validation) and incorrect query 122
integration. The error rate or quality index (QI) is calculated as number of
ndings against the number of elds in the database. The acceptable error rate
is pre-determined by the sponsor and is documented early on in the DMP. For
example, a sponsor may require a quality index of 99.9 percent, whereas another
sponsor may require a quality index of 99.5 percent.
The sample size for audit should be statistically appropriate and could vary
from sponsor to sponsor. For example, some audits could use a 10 percent
random sample where the system can randomly auto generate 10 percent of the
total enrollment for analysis. Some other audits could involve a 100 percent
sampling of all safety and e cacy end points.
Interim analysis may be done at regular time intervals for an ongoing study,
if speci ed in the protocol. The analysis may be done monthly, quarterly,
biannually, annually, etc. depending on the study duration. The analysis could
also be done either on speci ed modules in the study like safety modules or
e cacy modules, or on all modules. Findings from the analysis give a clear
Drug Discovery picture if the study is on track. Decisions are taken on the proceedings of the
and Clinical trial and if needed, amendments to the protocol are made in order to ensure
Research
successful completion of the trial. If major deviations are found against the
SK Gupta
protocol or the expected results, the data is assessed as a whole to evaluate the
quality of the study and decide if the study should proceed as planned. Analyzing
ndings on a periodic basis helps in making appropriate recti cations to the
database early on in the study. Accordingly training is provided to the data
 CHAPTER 1: New Drug Development management staff so that the ndings and errors are not repeated for the rest of
INTRODUCTION TO DRUG DEVELOPMENT the incoming data.
 PRECLINICAL DRUG DEVELOPMENT Final analysis is done after completion of LPLV. This analysis collates the
 CLINICAL DEVELOPMENT data from all the interim analyses as well as the data analyzed after the last
 PHARMACOVIGILANCE interim and gives a combined result of all the data modules. The nal analysis
gives a collective conclusion about the safety and e cacy of the trial drug,
 CLINICAL DATA MANAGEMENT which would be part of regulatory submissions (Fig. 1.29).
Of Biologics
Drugs
Development
Fig. 1.29: Overview of processes in clinical data management

123

DATA STORAGE AND ARCHIVAL
All trial related paper documents including CRF(s) and/or electronic les must
be stored in a secure and controlled place. It is good to scan all paper
documents so that they can be archived in an electronic form. Open formats
such as Operational Data Model (ODM) offered by CDISC or PDF are
recommended for storage.
Information regarding all clinical data, database design speci cations,

external data, structural metadata, coding dictionaries, lab ranges, audit trial,
listings for edit checks and derived data, discrepancy management logs, queries,
program codes, PDF formats of CRF(s), data management plan, validation
documentation, regulatory documentation, documentation/memos of deviations
from SOPs and other working procedures, are stored in a central document
library and should be included in a clinical data archive.

CLINICAL DATA MANAGEMENT SOFTWARES
Listed below are different software systems categorized as clinical data

management systems (designed to capture clinical trial data), drug safety
system (designed to capture adverse events), remote data systems (RDC-
designed to capture clinical trial data directly into the interface/software
application) and data exchange solutions (applications which connect/integrate
two different kinds of software applications being used to capture clinical trial
data) (Fig. 1.30).
Drug Discovery
and Clinical
Research
SK Gupta

Fig. 1.30: Summarized process ow of clinical data management 124
Clinical Data Management Systems
Of Biologics
Oracle Clinical – Provided by Oracle, it is a simple and full-featured
Drugs interface; investigators, monitors and site coordinators can enter and
 CHAPTER 4: Phase 0 Trials In Cancer Drug clean clinical data, monitor trial progress and track source-document
Development
veri cation.
Clintrial-phase Forward has provided a clinical data management
 solution which streamlines data entry and lab loading, discrepancy

management, patient and site reporting, data exporting, coding and
system administration.
STARLIMS – LIMS has provided a web-based laboratory information

management system.
SAS/SHARE – Application, in which all data are entered, stored,

managed, and analyzed as the database server, SAS tables for physical
storage, and Microsoft Windows® as the operating system on both the
server and desktop.
WebVDME – Phase forward has provided a signal detection solution for

post-marketing data.
CTSD – Phase forward has provided a signal detection solution for data
from clinical trials.
WebSDM – Phase forward has provided a system for validating and

reviewing clinical trial data represented in formats meeting industry
standards.
Drug Safety Systems
Clintrace – phase Forward has provided a solution for monitoring drug

safety and reporting adverse events that occur during and after
conclusion of the clinical trial process.
Total safety – Aris Global has developed a comprehensive suite of

integrated software solutions that enable organizations, regardless of
status or size, to implement effective domestic and global
pharmacovigilance, clinical safety and risk management programs.
ERT eSafety Net – this system is designed by eResearch Technology to

provide a safety data system which utilizes physician front-end support
to enable the effective management of global adverse reactions
occurring anywhere in the clinical trial process.
RDC Systems
Rave – Developed by Medidata; is the industry-leading system for

Drug Discovery capturing, managing and reporting clinical research data, designed to
and Clinical help life science companies optimize their research investments by
Research e ciently streamlining the clinical trial process. It is a single platform
SK Gupta
supporting both electronic data capture (EDC) and clinical data
management systems (CDMS) functionality. Medidata Rave has the
exible design to support the breadth of any organization's clinical
processes, as well as the unique aspects of individual clinical trials.

Inform ITM – Phase Forward has provided an internet-based electronic
data capture solution for collection and transmission of patient
 PRECLINICAL DRUG DEVELOPMENT information in clinical trials.

MACRO- It is InferMed's electronic data collection solution for clinical
 REGULATORY APPROVALS FOR trials. MACRO's intitutive drag-and-drop tools for eCRF creation reduce
REGISTRATION OF DRUGS study design time and provide complete control over eCRF layout,
 CLINICAL DATA MANAGEMENT ensuring that eCRFs are comparable to paper equivalents. 125
Of Biologics
TrialMax – CRF Health – TrialMax is the world leader in electronic
Drugs patient reported outcomes (e-PRO) and wireless data collection solution
 CHAPTER 4: Phase 0 Trials In Cancer Drug for the biopharmaceutical industry.

Development
 CHAPTER 5: Bioethics In Clinical Research ERT eData Management – eDE designed by eResearchTechnology, Inc.
meets the needs of study investigators and monitors. Speci cally, eDE
offers a task-and-work ow-driven EDC solution that helps smooth

process management by providing organized access to study data. eDE
supports sophisticated on-screen validations. eDE's edit check
mechanisms include eld level validations, which can identify errors at
the time of data entry based on values from derived elds or provide
conditional navigation throughout a page in addition to consistency
checks. eDE allows clients to develop, deploy, manage – and reuse –
standards that are drawn from a library that can be maintained at any or
all of these levels. Furthermore, eDE is designed so that multiple eDE
studies are supported in a single environment. This capability helps
clients maintain compliance with internal standards, which provides a
method to achieve rapid and consistent study set up every time. It also
ensures immediate availability for interim or nal analysis.
Data Exchange Solutions
Connect by ClinPhone – An automated data exchange solution to

facilitate seamless sharing of information between independent
systems and software. It allows pharmaceutical sponsors to integrate
clinical data without having to modify applications on connected
systems. Built on revolutionary middleware technology to support two-
way, real-time data interchange, Connect enables diverse electronic
clinical trial solutions such as IVR (Interactive Voice Response), EDC
(Electronic Data Capture), CTMS (Clinical Trial Management System),
and DSM (drug supply management) to work together synergistically.
ClinPhone Combined EDC-IVR – The combined EDC-IVR solution

provides EDC, CDMS, randomization, trial supply management and
ePRO, integrated through an innovative Connect software and platform.
DataLabs by ClinPhone – Industry's rst single data management

system that uni es the functionality of paper data entry (PDE) with the
exibility of electronic data capture (EDC) into one, easy-to-use
electronic clinical data management platform.

RECENT ADVANCES IN CDM
Drug Discovery Clinical trial systems to conduct clinical trials electronically have become a
and Clinical necessity today to increase the time to market as well as decrease the cost of
Research trials. The various technologies utilized include EDC systems, adverse event
SK Gupta
reporting systems (AERS), OCR, OMR, IVRS, etc. These and many other
technologies are providing number of bene ts in the conduct of the clinical trial.
Technology enables advances in trial design, faster data entry, more e cient
communications between participants, and improved process management,
 CHAPTER 1: New Drug Development collection of clinical endpoint data directly from the patients. Technology can
INTRODUCTION TO DRUG DEVELOPMENT also help in the design of a clinical trial especially in the randomization process.
 DRUG DISCOVERY PROCESS It is possible to design a trial that is automatically modi ed as it progresses 126
through an adaptive trial design. Continuous monitoring of a critical variable
from EDC data can automatically adjust the sample size of a trial for the power
that is desired.
EDC decreases paper handling, improves data clari cation process, provides
 CHAPTER 2: Drug Discovery And Developmen validations at the time of data entry, provides realtime access to data, allows for
Of Biologics remote monitoring, speeds up regulatory agency submissions and lessens the
number of CDM resources required to process the data. EDC data can be
Drugs
integrated by loading of SAS datasets or transport les into a data repository
Development that becomes the source for study analysis and reporting. EDC systems can also
 CHAPTER 5: Bioethics In Clinical Research be integrated with IVR systems, electronic patient diaries, labs, EKGs and AERS.
With lab integration investigators can also look at lab data on-line.
 Smart pens are available which enable patients ll out a form, and then use
the pen itself to transmit the recorded data via a cradle to the database.
Discrepancies in the data are shown to the site, which can correct them against
the paper copy. The pen also creates an exact copy of the CRF to be saved
online.
Electronic devices such as personal digital assistants [PDA(s)], palm pilots

are very e cient in capturing data from subjects. These typically work in an
o ine mode and are slowly replacing paper-based subject diaries. These
devices can also display metrics or tracking status to monitor patient schedules
and compliance with alerts to record the data as per the protocol. Some can
even help collection of various parameters such as measurement of pain, etc.
Biometric devices provide another way of data collection. Electronic

spirometers can record the time, date and measurements of home-administered
pulmonary function tests. Some devices can simultaneously record numerous
physiological variables.
Data are stored in the memory of the clinical data systems or on paper,
micro che, computer tape, computer disk, optical laser disk or smart cards. Data
may be transmitted through hard-wired direct connections, disks, audiotape or
videotape broadcast, microwave beroptic links. Retrieval of data can be done
by automated prompts, query, and search programs. The output may be in a
typed format, an audio format or a visual format (e.g. pictures, graphs and
tables).
A number of technologies are available to help better communication

between sites and sponsors who can help achieve higher quality data in a
shorter period of time. Trial portals are available where start-up and other
documents can be downloaded, completed and can be shared with the sponsor.
In addition, these portals can be used for live investigator training, site personnel
training and for investigator meetings. Monitors can send edit checks and
protocol changes to the trial sites via the portal. Monitors can conduct protocol-
compliance checks by examining the data being collected and fully manage trial
processes from their home or o ce via these web portals. They can also query 127
sites and generate data-correction forms in realtime. Sites can be graphically
shown their recruitment, time from query to response, queries per page, and
many other metrics. These reports will allow the site to understand areas that
need improvement, or areas in which they excel. Over all, much less efforts are
spent reviewing and managing queries which helps to increase study capacities
Drug Discovery and smooth conduct of multicenter studies.
and Clinical
Research Desktop productivity tools have been integrated with ERP systems to enable
SK Gupta process functions and data to be available through familiar desktop
applications. They provide access to tasks such as time management, budget
monitoring and organization management from a desktop. Globalization
management systems are available to accelerate capturing, authoring, managing
and distributing content across multiple formats and languages. To avoid the
INTRODUCTION TO DRUG DEVELOPMENT problem of clinical trials generating mountains of paperwork, FDA is promoting
 DRUG DISCOVERY PROCESS eSourcing. This involves capturing clinical data electronically at the source
 PRECLINICAL DRUG DEVELOPMENT meaning in the patient diaries and eCRFs. FDA is also encouraging completely
 CLINICAL DEVELOPMENT paperless submissions of clinical trial results. As a method of eSourcing
 PHARMACOVIGILANCE investigators can record all trial data in their laptops and the same can be
synchronized daily with central servers.
Integrated data capture and management systems with lab data integration,
Of Biologics integrated dictionary coding and translation tools provide for better reporting.
 CHAPTER 3: Clinical Development Of New Some systems can help generate the extracts for analysis in analytical tools and
Drugs
also help in generating submission les exactly as requested by FDA. Web-based
Development
tools for safety research with search engine, querying, access to information
 CHAPTER 5: Bioethics In Clinical Research sources—including FDA and WHO datasets, help manage and analyze data
e ciently. FDA has collaborated with private vendors for electronic review tools,
which provide quicker access to key information.

DATA STANDARDS
Data standards are being developed to overcome the problems of data

integration from different systems. Data structure (variable names, variable
types and labels), screen layout/paper CRF module, completion instructions,
monitoring guidelines, standard reports, tables, listings, laboratory data, global
libraries are all being standardized. Clinical data interchange standards
consortium (CDISC) is at present leading the way. There are currently over 60
companies that are members of CDISC, and many companies are starting to
adopt the CDISC models, even down to the variable name.
Apart from data management personnel, the senior management, clinicians,

statisticians, medical writers, auditors, regulatory affairs, IT support and central
labs contribute to these data standards development. Standards have become
the necessity of the day because of the rapidly increasing number of drugs in
development and global submissions. 128

CRF IMAGING SYSTEM
Document imaging and work ow systems streamline document handling by

eliminating duplication services, reducing hand-offs, simplifying storage,
automating process tracking, and speeding distribution. Character recognition
software automates data processing so that the staff can focus on data quality
instead of data entry.
Case report form (CRF) imaging and work ow application are also sold by
Integic by the name “CRF WorkManager” and by ISI as ‘CRFTrack”.

SCAN, FAX OR IMPORT CRFS
Software applications are available to scan locally or remotely and import CRFs
quickly and easily. Powerful imaging tools and the ability to fax-in CRFs also help
improve the quality and accessibility of documents (Fig. 1.31).
Quick and easy scanning: CRFs can be organized into a batch that share
common attributes, and assigned keywords to clinical and process information
for convenient access. In addition, users can scan documents remotely into a
Drug Discovery centralized database through remote scan.
and Clinical
Research Fax-in capabilities: Users in remote locations can now be connected in more
SK Gupta ways than ever. Regardless of where the user is, CRFs can be faxed into the
same database. The process is fast and secure, allowing the user to focus on
gathering CRFs for submission.
Import les: CRFs in TIFF format can be imported into the application used and
 CHAPTER 1: New Drug Development included in an existing or new batch. Files can also be replaced or revised,
allowing for easy movement and management of pages and versions as they
change.
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Drugs
Development
Fig. 1.31: CRF import and export system

129
Powerful imaging tools: A palette of imaging tools helps the readability and
presentation of scanned CRFs with options to detect and set page orientation
automatically, set rotation of pages by reformatting pages or changing the
display, and clean pages by removing unwanted holes and scanner marks. In
addition, user can set lters to de-skew text, ignore holes, clean edges, remove
horizontal and vertical lines and more.

INDEX BY OCR OR BARCODE
Assign attributes and numbering information to CRFs through a number of

different methods: by page template, OCR, barcode or manually. Also, create
virtual CRFs for specialized separation.
Index manually, by OCR or barcode: There are several options for indexing
scanned pages into proper CRFs. If manual indexing is required, helpful page
templates can be created to de ne a page structure for a CRF, so that certain
pages that share a common format can be easily identi ed and indexed (Fig.
1.32).
OCR indexing is a convenient and automatic way of indexing page numbers

through speci ed keywords and “zones” on CRFs. OCR Indexing can also be run
in batch mode, allowing multiple batches of scanned les to be indexed at once.
Barcode indexing allows user to gather attribute information automatically

and accurately through barcode recognition of protocol, investigator and patient
information.
Drug Discovery
and Clinical
Research
SK Gupta

Fig. 1.32: OCR indexed scan page
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Create virtual CRFs for specialized separation: Create a virtual CRF that
 CHAPTER 3: Clinical Development Of New condenses pages from multiple patients into a single document based on
Drugs speci ed criteria. For example, with Virtual CRFs the user can copy Adverse
 CHAPTER 4: Phase 0 Trials In Cancer Drug Event pages from patients in a protocol for review, and then convert the Virtual
Development
CRF to PDF. The PDF can then be distributed to internal reviewers (Fig. 1.33). 130
Fig. 1.33: Virtual CRF

ADD NAVIGATION, ENSURE QUALITY AND MORE
Bookmarks, hyperlinks, annotations and comments can all be added to images

and eventual PDFs effortlessly. In addition, QA tools ensure the quality and
integrity of pages with a number of options – through searching le size, setting
statuses and checking page settings. And with the ability to route pages to be
reworked, managing the work ow is easier than ever.
Create bookmarks and hyperlinks: Bookmarks and hyperlinks are created easily
to ensure submission compliance. In addition, create TOCs that add a structural
hierarchy to PDFs that enhance document navigation, and export them as a CSV
le for later reference.
Annotate and comment: Through a variety of annotations, user can add notes
and highlights to CRFs, most of which can also be preserved in PDF. Whether it
is notes for clari cation or noti cation, hyperlinks that navigate to predetermined
pages, or highlights within CRFs, there are multiple options to choose from.
Additional options to lock show and search annotations make it easy to manage
comments for team-wide collaboration.
Perform QA: Through specialized work ows and QA tools; the application helps
ensure the validity and integrity of documents. Search for speci ed protocols
and investigators by le size, as well as for blank pages or speci c types of
pages, such as DCFs and cover pages. In addition, de ne the status of a page as
“Passed”, “Rejected”, or “None” during a work ow and then route pages to the
appropriate destination. User will be able to ensure quality as the work ow is

happening (Fig. 1.34).
Drug Discovery
and Clinical
Research
SK Gupta

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Drugs
Development
Fig. 1.34: QA tools 131


REVIEW AND MANAGE GLOBALLY
Everything the user needs to manage CRFs better – with an easy-to-view

workspace, remote global access, collaborative capabilities and convenient
EDMS integration – are conveniently at your ngertips today with the existing
software applications.
Automatic PDF conversion: With speeds up to 72,000 pages per hour, converting
paper CRFs to electronic format has never been quicker and easier. CRFs
converted to PDF are ready for submission and can contain bookmarks grouped
by Domain and Visit with the proper hyperlinks between DCF and CRF pages.
Additional features that prepare CRFs for PDF conversion allow users to create
and manage annotations (Fig. 1.35).
Drug Discovery
and Clinical
Research
SK Gupta

Of Biologics
Drugs
Development
Fig. 1.35: Automatic PDF conversion
Create work ows and route jobs: Administrators can also create work ows and
 route jobs to appropriate departments and keep track of the work ow as it
happens. It is easy for administrators to view remaining pages for each job, as
well as assign, reject or con rm completion of jobs.
Remote global access: CRA's, clinical trial monitors, investigators, and other key
team members can fax and view CRFs from remote investigator sites and
access the information they need through the CRF web portal.
A collaborative environment is created among clinical trial team members

through a secure web interface. Members can download patient PDFs for o ine
review, assign and restrict access to CRFs for secure document access and
ensure the integrity of CRF documents.
Convenient integration: Integration with oracle clinical and clintrial allows for
faster work ow task processing. To streamline clinical operations as much as
possible, split-screen data entry integration allows for greater speed and quality
during rst and second pass data entry.

TRACK AND REPORT
Accurate CRF tracking and reporting: In dealing with an overwhelming amount of

information, software applications simplify the tedious process of reviewing and
verifying CRF collection (Fig. 1.36).
Drug Discovery
and Clinical
Research
SK Gupta

Of Biologics
Drugs
Development
Fig. 1.36: Accurate CRF tracking and reporting 132
A simpler, more accurate way to track CRFs: Maintaining complicated

spreadsheets that track CRF information is no more required since a simpler and
powerful method is available in the software applications. Users can perform
vital QA functions through a host of automated search methods. Users can
perform searches to determine missing and contained pages, advanced
searches by keyword, drug, investigator, patient and workplace.
Detailed reporting: In addition to searching across patients and by keyword, user

can also view more detailed tracking, such as page history, user history and audit
trail mapping. Print reports for streamlined QC on CRF documents and
submission requirements.

DIRECT ACCESS SOLUTIONS
The means by which a direct connection into sponsors’ clinical data

management systems can be made. This access ensures that processes and
standards are followed, while the sponsor maintains control over data. This is a
permission provided to examine, analyze, verify, and reproduce any records and
reports that are important to evaluation of a clinical trial. Any party (e.g.,
domestic and foreign regulatory authorities, sponsor's monitors and auditors)
with direct access should take all reasonable precautions within the constraints
of the applicable regulatory requirement(s) to maintain the con dentiality of
subjects’ identities and sponsor's proprietary information.

EDIARIES
A patient diary is a tool used during a clinical trial or a disease treatment to

measure treatment compliance. An electronic patient diary registers the diary in
a storage device and allows for monitoring the time the medication was taken,
and symptoms or quality of life data were recorded.
Patient diaries are way to nd out if a patient takes the medication

according to the treatment schedule, which is an important problem during
clinical trials and the treatment of degenerative diseases with relatively few
Drug Discovery symptoms.
and Clinical
Research
SK Gupta CLINICAL TRIAL PORTALS
Clinical trial portal has been designed as a single entry or a ‘one-stop-shop’

allowing you to search for comprehensive information on the on-going clinical
trials (registry) or results of completed trials (database) conducted by the
INTRODUCTION TO DRUG DEVELOPMENT innovative pharmaceutical industry worldwide.
WHO International Clinical Trials Registry Platform is one of the most
 CLINICAL DEVELOPMENT valuable sources of evidence about safety and e cacy of health interventions.
 PHARMACOVIGILANCE Extensive media coverage is also done on several cases selective reporting of
 REGULATORY APPROVALS FOR results. Such trial registration and full reporting of trial results would help ensure
a full and unbiased public record on safety and effectiveness public record on
safety and effectiveness. 133
Of Biologics
Many journals in addition to International Committee of Medical Journal
Drugs Editors (ICMJE) now accept only registered trials for potential publication. It is a
 CHAPTER 4: Phase 0 Trials In Cancer Drug global, neutral, independent body with convening capacity (i.e. World Health
Development
Assembly resolutions). It is authoritative and has an important role in setting
norms and standards in research, policy and practice {Good Clinical Practice,
Ethics guidelines, Classi cation standards (e.g., ICD)}. WHO contributes to
 capacity building (i.e. in developing countries) and has a political legitimacy,
accountable to 192 member States. WHO shows commitment to achieving
equity in health and has been de ned a coordinated global “platform” for trial
registration.
The goal is to strengthen public trust in clinical research by promoting

transparency and accountability. The objectives are to ensure that all trials
worldwide are registered and thus publicly declared and identi able and
ensuring that a minimum set of results are publicly reported for all registered
trials and support use of trial registration information for recruitment, research
planning, etc.
Some important portals complying with requirements set out by the World
Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP)
and the International Committee of Medical Journal Editors (ICMJE) guidelines,
and the WHO 20-item Trial Registration Data Set are—
1. International Clinical Trials Registry Platform (ICTRP).

2. Australian New Zealand Clinical Trials Registry (ANZCTR)
3. ClinicalTrials.Gov
4. International Standard Randomized Controlled Trial Number Register
(ISRCTN).
5. University hospital Medical Information Network-Clinical Trials Registry
(UMIN-CTR).
6. Netherland's Trial Register (NTR).
BIBLIOGRAPHY
1. Abbreviated New Drug Application (ANDA) Process for Generic Drugs
Http://Www.Fda.Gov/Cder/Regulatory/Applications/ANDA.Htm. (Accessed on 20/07/2008).
2. Bianca Piachand. 2002. Challenges facing the pharmaceutical industry. Http://Findarticles.Com/
3. CDER Manual of Policies and Procedures (MaPP). Http://Www.Fda.Gov/Cder/Mapp.Htm.
(Accessed on 23/07/2008).
4. Code of Federal Regulations (CFR). Http://Www.Gpoaccess.Gov/Cfr/Index.Html. (Accessed on
22/07/2008).
5. Decoster G, Buye M. Clinical research after drug approval. What is needed and what is not. Drug
Drug Discovery
Information Journal 33(1999)2:627–634.
and Clinical
Research 6. Dimasi JA. Risks in new drug development: approval success rates for investigational drugs. Clin
SK Gupta Pharmacol Ther 2001;69:297–307.
7. EMEA. Eudravigilance data analysis system. 2006. Www.Eudravigilance.Emea.Europa.Eu
8. EMEA. Transitional measures for submission of PSURs for centrally authorized medicinal 134
products for human and veterinary use. 2005. Www.Emea.Europa.
 DRUG DISCOVERY PROCESS 9. FDA. Reporting adverse experience to FDA. 2007. Www.Fda.Gov/Medwatch/How/Htm
 CLINICAL DEVELOPMENT 10. Giersiefen H, Hilgenfeld R, Hillisch A. Modern methods of drug discovery: an introduction. In
 PHARMACOVIGILANCE Hilgenfeld R, Hillisch A (Eds): Modern Methods of Drug Discovery Eds: 2004;1–18.

REGISTRATION OF DRUGS 11. ICH Guidance for Industry, S7A Safety Pharmacology Studies for Human Pharmaceuticals.
 CLINICAL DATA MANAGEMENT Available on Http://Www.Fda.Gov/Cber/Gdlns/Ichs7a071201.Htm (Accessed on 30/07/2008).

12. IND Forms and Instructions
Of Biologics
 CHAPTER 3: Clinical Development Of New Http://Www.Fda.Gov/Cder/Regulatory/Applications/Ind_page_1.Htm#IND%20Forms.
Drugs (Accessed on 20/07/2008).
Development 13. Investigational New Drug (IND) Application Process,
 CHAPTER 5: Bioethics In Clinical Research Http://Www.Fda.Gov/Cder/Regulatory/Applications/Ind_page_1.Htm. (Accessed on
23/07/2008).
 14. Jens Eckstein. ISOA/ARF Drug Development Tutorial. Available on
Http://Www.Alzforum.Org/Drg/Tut/ISOATutorial.Pdf (Accessed on 30/07/2008).
15. Lindquist M. Data quality management in pharmacovigilance. In Rosie Stather (Ed.) Drug Safety,
2005.
16. Mant T. Early phase studies, pharmacokinetics and adverse drug reactions. In Giovanna I D,
Hayes G (Eds): Principles of Clinical Research. 2001;117–60.
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.
Www.Jipmer.Edu
19. Mishra SK. Drug development and discovery. In Gupta SK (Ed): Basic Principles of Clinical
Research and Methodology. 2007.
20. Naidu MUR, Usharani P. Drug development and discovery In SK Gupta (Ed): Basic Principles of
Clinical Research and Methodology 2007.
21. New Drug Application (NDA) Process.
Http://Www.Fda.Gov/Cder/Regulatory/Applications/Nda.Htm. (Accessed on 23/07/2008).
22. Posner J. Exploratory development. In The Textbook of Pharmaceutical Medicine. (Ed.) Gri nJ
P, O'Grady J 2005;170–213.
23. Ratti E, Trist D. Continuing evolution of the drug discovery process in the pharmaceutical
industry. Pure Appl Chem 2001;73(1):67–75.
24. Rolan P. Clinical pharmacokinetics. In: The Textbook of Pharmaceutical Medicine. Edited by
Gri n J P, O'Grady J 2005:214–46.
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://Cdsco.Nic.In/Html/Schedule-Y%20(Amended%20Version-2005)%20original.Htm.
(Accessed on 23/07/2008).
27. Schedule Y (Amended Version)-CDSCO, Appendix IV of Schedule Y, Animal Pharmacology.
Available on Http://Cdsco.Nic.In/Html/Schedule-Y%20(Amended%20Version-
2005)%20original.Htm. Accessed on 27/07/2008).
28. Spilker B. Classi cation and Description of phases I, II, III Designs. In Williams L, Wilkins (Eds):
Guide to Clinical Trials 1991;27–43.
Drug Discovery
29. Spilker B. Classi cation and Description of phases IV Post marketing Study Designs. In: Guide 135
and Clinical
to Clinical Trials. Williams L and Wilkins 1991:44–58.
Research
SK Gupta 30. The process of Drug Development. Available on
Http://Www.Netsci.Org/Courseware/Drugs/Intro.Html (Accessed on 25/07/2008).
31. Tweats D J, Scales M D C. Toxicity testing. In Gri n J P, O'Grady (Eds): The Textbook of
Pharmaceutical Medicine. J 2005;128–69.

32. Work ow driven Pharmacovigilance software. Http://Www.Assured.Co.Uk/Pv-Workdetail.Htm.
Downloaded on 20th August 2008.
CDM
33. Clinical Data Management System, Http://Www.Exploreconsulting.Com (accessed on
20/07/2008)
 CHAPTER 2: Drug Discovery And Developmen 34. Clinical Trials Portal, Http://Clinicaltrialsportal.Co.Uk/ (accessed on 20/07/2008)
Of Biologics
 CHAPTER 3: Clinical Development Of New 35. ClinPhone Inc., Http://Www.Zoominfo.Com/Industries, (accessed on 05/07/2008)
Drugs
 CHAPTER 4: Phase 0 Trials In Cancer Drug 36. Colleen M Cox. Planning the data management process for a clinical trial, Technology and Data
Development
Management. Monitor 2005.
37. Get your CRF's on the Right Track, Http://Www.Imagesolutions.Com, (accessed on 05/07/2008)
 38. Guidance for industry, Computerized systems used in clinical trials,
Http://Www.Fda.Gov/Ora/Compliance_ref/Bimo/F nalcct.Htm#_Toc444571269 (accessed on
05/07/2008)
39. Laboratory Information Management System, Http://Www.Starlims.Com/Solutions/ (accessed
on 03/07/2008)
40. Louis Pozzo, Glen de Vries. Applied Clinical Trials, 2005.
41. Medidata Solutions Inc., Http://Www.Zoominfo.Com/Industries, (accessed on 05/07/2008)
42. paul bliecher. Applied Clinical Trials 2005.
43. Phase forward Inc, Http://Www.Zoominfo.Com/Industries, (accessed on 05/07/2008)
44. Product Datasheet, Http://Www.Symetric.Ca/Product_datasheet.Html (accessed on
03/07/2008)
45. Rebecca Daniels Kush. eClinical Trials – Planning and Implementation, Thomson Center Watch
2003.
46. Rondel R, Varley S, Webb C. Clinical Data Management. John Wiley and Sons LTD New York,
NY: 2000.
47. SAS, Http://Www.Zoominfo.Com/Industries, (accessed on 05/07/2008)
48. Society for Clinical Data Management. Good Clinical Data Management Practices Version 3.
September 2003.
49. Spilker B, Schoenfelder J. Data Collection Forms in Clinical Trials. Raven Press. New York, NY:
1991.
50. Susanne Prokscha. Practical Guide to Clinical Data Management, CRC Press LLC 1999.
51. The Rough Guide to Electronic Data Capture, ENGAGE. i3 Pharma Resourcing. Issue 7, Oct 05.
52. WHO International Clinical Trial Registry Platform, Http://Www.Who.Int/Ictrp (accessed on
05/07/2008)

New Drug Development

Uploaded by

New Drug Development

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4/10/2020 JaypeeDigital | eBook Reader

New Drug Development CHAPTER 1

After target identi cation and validation, a lead compound needs to be

The decision to develop a new drug by a pharmaceutical company depends

Table 1.1 Cost and time involved in drug discovery

Drug Discovery 2.5 years ↓ 4%

1.0 year ↓ 10%

 DRUG DISCOVERY PROCESS

 The drug discovery and development process is designed to ensure that

DRUG DISCOVERY PROCESS

OVERVIEW OF DRUG DISCOVERY PROCESS

Before the existence of pharmaceutical industry, medicines were discovered by

In 1950s and 1960s, pharmaceutical industries’ success in drug discovery

STEPS IN DRUG DISCOVERY

The disease mechanism de nes the possible cause or causes of a

Fig. 1.1: Steps in new drug development

It also predicts a change of the disease pattern and its implications.

Disease mechanisms can be broadly classi ed into the following groups:

Defects in distinct genes—genetic disorders

Drug Discovery Infection by bacteria, fungi, viruses, protozoa or worms

 CHAPTER 1: New Drug Development

The newer methods like genomics and proteomics along with

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

The validation of a molecular target in vitro (in an arti cial environment)

Targets are validated with:

In vivo models: In vivo testing involves testing in whole animals. It assesses

The success of screening depends on the availability of compounds, as well

There are several sources for compounds:

A primary screen is designed to rapidly identify hits from compound

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

Drug Discovery Establishing a dose-response relationship is an important step in hit

High-throughput screening (HTS) aims to rapidly assess the activity of a large

X-ray crystallography: Uses X-rays to determine the structure and functioning

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

Pharmacodynamic properties, e.g. e cacy, potency and selectivity in vitro and

 CHAPTER 1: New Drug Development LEAD OPTIMIZATION

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

Pharmacokinetics (PK)/pharmacodynamics (PD)/absorption, distribution,

The recent innovation and progress in mass spectroscopy (whole-body) imaging,

increased the quantity and quality of data generated in PK/PD experiments.

Formulation development: It is the process of turning an active compound into a

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

STAKEHOLDERS IN NEW DRUG DEVELOPMENT

Research and development: This department is responsible for nding new

NEED FOR SYSTEMATIC APPROACH IN NEW DRUG DISCOVERY

The advent of the human genome's publication now offers a great

 Developability: A large proportion of molecules fail due to of lack of

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

Screening automation and combinatorial chemistry have greatly reduced the

PRECLINICAL DRUG DEVELOPMENT

INTRODUCTION TO PRECLINICAL DRUG DEVELOPMENT

Preclinical research includes synthesis, puri cation and animal testing

The main goals of preclinical studies are to determine a drug's

 The need for nonclinical information including toxicology, pharmacology and

TYPES OF PRECLINICAL STUDIES

Few examples of in vitro studies include:

laboratory animals as models of humans or some other target species to

Purpose of models: A speci c model is chosen because it is believed to be

Greater similarity to human studies when compared to in vitro screening

Some of the examples of in vivo studies are:

Noninvasive method—rat tail cuff method

GENERAL REQUIREMENTS FOR CONDUCTING PRECLINICAL

 ANIMAL PHARMACOLOGY STUDIES

Safety pharmacology studies are studies that investigate potential undesirable

Based on the individual properties and intended uses of an investigational

In addition to the essential safety pharmacological studies, additional

Speci c and essential pharmacological studies should be conducted to

The following factors are to be considered when speci c tests are to be

Safety pharmacology studies are usually not required when:

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

 ANIMAL TOXICITY STUDIES

Toxicokinetic studies should be conducted to assess the systemic exposure

To relate the toxicological ndings to clinical safety

SYSTEMIC TOXICITY STUDIES

Repeated-dose systemic toxicity studies: The primary goal of repeated dose

The decision whether a developmental toxicity study needs to be performed