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NEW DRUG DISCOVERY

Final Examination Requirement

Submitted by : Ariel Nico A. Villariaza


Master of Science in Pharmacy student

Submitted to : Dr. Jennilyn Corvera


Professor
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I. Explain the chemical synthesis and formulation as to method development,


validation and transfer.

Answer:

Chemical synthesis is a purposeful execution


of chemical reactions to obtain a desired
product, or several products. It is concerned
with the formation/creation of complex chemical
compounds from a simple lead compound
that was discovered. A synthesis usually is
undertaken to meet an industrial demand for a
product and to obtain a compound of specific structure that does not occur
naturally and has not previously been made. It also examines the properties of the
compound and thereby test theories of chemical structure and reactivity.
Therefore, chemical synthesis and formulation is done in order to reproduce a
specific chemical compound that is already enhanced by laboratory procedures
and experiments. This chemical compound is free from unwanted effects,
impurities and was already altered structurally for better pharmacokinetic and
pharmacodynamics properties.

CHEMICAL SYNTHESIS METHOD


AND FORMULATION DEVELOPMENT

METHOD METHOD
TRANSFER VALIDATION

Fig.1.0

The synthesized chemical compound (Fig.1.0) will then undergo method


development. Being decisive element for the quality of active pharmaceutical
ingredients and formulations it is very important to develop efficient and
accurately validated methods for pharmaceutical analysis as per guidelines.
Effective method development ensures that laboratory resources are optimized,
while methods meet the objectives required at each stage of drug development.
Method development is intended to establish the identity, purity, physical
characteristics and potency of the drugs that we use. The methods may focus on
API behavior. They should be suitable to support preclinical safety evaluations,
pre-formulation studies, and prototype product stability studies.

After developing a robust method for the chemical compound, method


validation is required by regulatory agencies at certain stages of the drug
approval process. It simply means that method validation is the process of
demonstrating that analytical procedures are suitable for their intended use. It
also demonstrates that an analytical method measures the correct substance, in
the correct amount, and in the appropriate range for the intended samples.
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Lastly, to assess the sustainability of methods being conducted or used, it will


undergo method transfer wherein it will be tested using other laboratories.

2. In designing a medicine, what are the primary factors to consider. Give their
importance.

Answer:

Formulated and synthesized chemical compounds after being studied,


modified, improved and tested will have to undergo series of development for it to
become a drug that is useful to every individual experiencing disease or infimity.
Any chemical entities having therapeutic effect cannot be taken in its purest form,
so it is formulated into a suitable dosage forms for their safe and compatible
administration into the body.

DRUG FACTORS:
BIOPHARMACEUTICAL THERAPEUTIC PREFORMULATION
ASPECTS CONSIDERATION
• Organoleptic
• Route of • Nature of clinical
properties
indication
Administration • Bulk
• The way disease or
• Pharmacokinetic characteristics
illness is treated
parameters • Solubility
analysis
• Stability analysis
Fig. 1.1

Following qualities of features are required in drug and dosages form design:
1. Drug would produce specifically desired (therapeutic) effect.
2. Be administered by most desired route at minimal dose and dosing frequency
3. Drugs have short onset and optimum duration of activity, without any side
effect.
4. Would be completely eliminated from the body efficiently without any residual
effect.
5. Pharmaceutically dosage forms should be elegant, physically, and chemically
stable at various conditions of use and storage.
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Biopharmaceutical aspects, therapeutic consideration, drug factors (pre-


formulation) are to be considered primary factors for achieving the above goal
(Fig. 1.1).

BIOPHARMACEUTICAL ASPECTS
A route of administration varies with pharmacokinetic parameters of drug, such
as, absorption, distribution, metabolism, and elimination (ADME). Drug is
administered into body by various routes such as oral, topical, parenteral,
respiratory (inhalation), rectal, nasal, ear, and eye. According to drug candidate
pharmacokinetic profile (ADME) and type of illness (disease condition), route of
administration is preferred.

THERAPEUTIC CONSIDERATION
Nature of clinical indication, disease/illness for that drug is intended is an
important factor for selection of dosages form and route of administration. In case
of emergency sublingual, an injection is given. In infants: Liquid drops, children’s:
Liquid dosage forms (e.g., syrup), in geriatric and patients suffering from
swallowing difficulties chewing tablets is preferred.

DRUG FACTORS : PREFORMULATION


For the achieving goals of drug and dosage forms, pre-formulation testing is a
first step in the development of dosage forms before the formulation. Pre-
formulation is defined as an investigation of physical and chemical properties of
a drug substance alone and along with excipients before the formulation. The
main objective of pre-formulation testing is to generate information useful to the
formulator in developing stable and bioavailable dosage forms before formulation
development. Pre-formulation investigations are designed to deliver all
necessary data, especially physicochemical, physico-mechanical, and
biopharmaceutical properties of drug substances, excipients, and packaging
materials.

PREFORMULATION PARAMETERS

Physicochemical characterization
I. Organoleptic properties

II. Bulk characteristics


a. Assay development
b. Melting point
c. Solid state characteristics: Particle size, surface
area
d. Flow properties
e. Densities
f. Compressibility
g. Crystalline and amorphous
h. Polymorphism
i. Hygroscopicity.
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III. Solubility analysis
a. Ionization constant (pKa)
b. Partition coefficient
c. Dissolution
d. Solubilization
e. Thermal effect
f. Common ion effect (Ksp).

IV. Stability analysis


a. Solid-state stability
b. Solution-state stability
c. Drug-excipients compatibility

3. Make a brief explanation / discussion of the following steps in product


development and discovery.

DISCOVERY : RESEARCH

LEAD COMPOUND DISCOVERY: HIGH-THROUGHPUT SCREENING


There are many ways to discover a lead compound. These includes medicinal
screening, folklore medicines, out of serendipity and high-throughput screening.
HIGH-THROUGHPUT screening (HTS) is the process by which large numbers of
compounds can be tested, in an automated fashion, for activity as inhibitors
(antagonists) or activators (agonists) of a particular biological target, such as a
cell-surface receptor or a metabolic enzyme. The primary goal is to identify high-
quality 'hits' or 'leads' (compounds that affect the target in the desired manner)
that are active at a fairly low concentration and that have a new structure. The
lower the concentration at which the compound acts, the more likely that it will
exhibit specificity and, as a corollary, the less likely that it will have undesired side
effects. If different chemotypes can be identified using the same screen then
medicinal chemists will have a broader range of options for modifying the lead.
The greater the number and diversity of compounds that are run through a
screen, the more successful it is likely to be, a fact that further propels rapid
developments in HTS.

DRUG METABOLISM AND PHARMACOKINETICS

1. Pre-Clinical
During pre-clinical testing, lead compound was synthesized and modification
in their structure was done to improve its pharmacokinetic properties.
Absorption, distribution, metabolism and elimination aspects were enhanced to
established safety and efficacy. The lead compound must undergo also series of
assays and experiments to improve its specificity and selectivity. These assays
and tests were done using animal test samples since it is still in preclinical phase.

2. Clinical
The central role of Drug Metabolism and Pharmacokinetics in drug discovery
is to contribute to the optimization of compounds for man by balancing the
properties associated with drug gastrointestinal absorption (for orally delivered
therapies), distribution, clearance, elimination and DDI potential as rapidly and
cost effectively as possible. This can be achieved from a consideration of
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physicochemical properties and data obtained from in vitro assays with human-
derived material.

MANUFACTURING : QC OF API AND DOSAGE FORMS

1. IN-PROCESS
In a manufacturing plant, In-process control methods for the manufacture of API
and dosage forms are key components of quality control. These methods ensure
that a production reaction step conducted by trained operators within the entire
validated process will produce a quality chemical entity in the expected yields.

2. INTERMEDIATES
Pharmaceutical intermediates are the chemical compounds that serve as
building blocks used in the production of active pharmaceutical ingredients.
During the manufacturing or synthesis of the API, pharmaceutical intermediates
are produced. The produced pharmaceutical intermediates will then under
changes in their molecular level and several processing before they will become
an active pharmaceutical ingredients.

3. IMPURITIES
In drug manufacturing especially the in manufacturing API, impurities must be
controlled. Impurities are the unwanted qualities of a drug which offer no
therapeutic effects. These impurities sometimes are potentially toxic.

4. CLEANING
Cleaning is also important in drug manufacturing. Before the production
proper, the trained personnel must see to it that all raw materials are clean or
have undergone cleaning before entering the production. Cleaning also is vitally
applicable to the equipment, premises, and personnel. The goal of cleaning is to
avoid contamination during the production.

5. FINAL API
After intermediates were produced during the making of API, these will be used
since intermediates are the building blocks in API production. The final API will
then undergo several tests and process to remove impurities, improve stability
and quality. Therefore final API are those chemical compounds ready for drug
designing which includes the making of dosage forms, etc.

6. STABILITY
In the manufacturing API and dosage forms, stability is one of the factor to be
considered. The purpose of stability testing in drug development is to provide
evidence on how the quality of an active substance or pharmaceutical product
varies with time under the influence of a variety of environmental factors such as
temperature, humidity, and light.

7. DISSOLUTION
Dissolution testing is a requirement for all solid oral dosage forms and is used
throughout the development life-cycle for product release and stability testing. It
is a pivotal analytical test used for detecting physical changes in an active
pharmaceutical ingredient and formulated product. At the early stages of the
drug development process, in-vitro dissolution testing underpins the optimization
of drug-release from a given formulation. The effectiveness of an oral dosage
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form depends upon the intrinsic ability of the drug to dissolve in the fluids of the
gastrointestinal tract prior to being absorbed into the circulation. Therefore, the
rate of dissolution of the tablet or capsule is pivotal to this process.

8. EXCIPIENTS
Excipients are crucial to drug delivery within the body. Generally, an excipient
has no medicinal properties. Its standard purpose is to streamline the
manufacture of the drug product and ultimately facilitate physiological absorption
of the drug. Excipients might aid in lubricity, flowability, disintegration, taste and
may confer some form of antimicrobial function. Selecting the appropriate
excipient to support the design of your pharmaceutical formulation is an
important step in the drug manufacturing process.

9. UNIFORMITY
Drug-substance uniformity is an important consideration for the final step in
the manufacture of drug substance/active pharmaceutical ingredient. Uniformity
studies are necessary to ensure that the entire contents of the batch are
homogenous and that the drug substance specification sample is representative
of the batch.

10. LEACHABLES
A chemical species that has migrated from packaging or other components
into the dosage form under normal conditions of use or during stability studies.
Leachables are substances identified in a defined laboratory regimen by
simulating use conditions.

11. PACKAGING
Packaging is an important component in the development of various drugs, as
it can greatly affect drug stability and safety. Packaging material is chosen on the
basis of its efficacy and other characteristics that enable it to preserve the
quality, potency, and safety of the pharmaceutical products.

12. ASSAY
Assay is a procedure for the examination or determination of quality or
strength of a substance. An assay procedure is generally employed to evaluate
an intensive property of the measured entity, called "analyte". It is expressed in a
relevant measurement unit like density, molarity, etc.
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5. Make a hypothetical product (drug) development following the fifteen steps or


process from discovery of compounds to the value of marketing research.

PRODUCT DEVELOPMENT FOR ANTIANGIOGNESIS DRUG AS CANCER


TREATMENT
STEPS EXPLANATION PROCESSES AND RESULTS
I. DISCOVERY OF In medicine, a chemical compound The results of phytochemical
LEAD COMPOUND that shows promise as a treatment for investigation of Ixora javanica
a disease and may lead to the in ethyl acetate extract shown
development of a new drug. the presence of flavonoids,
Thousands of compounds are tested in triterpenoids and
the laboratory to find a lead (“leading”) carbohydrates, while ethanolic
compound that may act on specific extract (70%) indicated the
genes or proteins involved in a presence of steroids,
disease. Once a lead compound has triterpenoids, flavonoids,
been found, the chemical structure is alkaloids and glycosides
used as a starting point to make a drug (Dontha et al., 2015).
that has the most benefits and the least
harms. Finding a lead compound is the
first step in making a new drug to treat
a disease.

In this phase, I will conduct lead


compound screening to my sample
which is Ixora javanica Linn. (Santan)
Leaf Extract using High Throughput
Screening. The reason why I chose
this plant because of its availability
and abundance.
Ixora javanica plant which was identified by a
botanist.

The plant then undergo extraction


process using ethanol. After the
extraction, screening was done to
identify the metabolites present in the
extract.
I. LEAD COMPOUND After the discovery of the lead The result of lead compound
OPTIMIZATION/ compound from the plant sample optimization were favored to
PRIORITIZATION above, it will then undergo the metabolite flavonoid and
optimization and prioritization. alkaloid. During the chemical
Structure of the compounds were used synthesis, SAR were studied
as starting point for chemical for optimization of each
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modification to improve potency, compounds. It was found out


selectivity and pharmacokinetic that they are more safe,
parameters. It gives better quality ofeffective, and selective. These
the lead molecules. two class of metabolites were
then prioritized by the
There were almost a thousand researcher.
metabolites present. Chemical
structure of the compounds present
were obtained for chemical synthesis.

The following structure below are


the representation of the compounds
after screening.

Quercetin

Bioflavanoids present in the extract that are also present in other


plants

Alkaloids present in the extract


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Carbohydrates present in the extract

Glycosides present in the extract

II. CHOOSING A One of the crucial steps in drug The chosen lead compound
CANDIDATE FOR development is the selection of the was Flavanoid which is
DRUG most optimal candidate (ex. lead specifically quercetin. This is
DEVELOPMENT compound with the best chance of due to the ADMET properties.
clinical success). In vitro and in vivo Below are the results
studies was conducted to permit concerning the properties of
further selection of lead compound quercetin.
candidates with desired ADMET
(absorption, distribution, metabolism, Quercetin is a polyphenolic
excretion, toxicology) properties as secondary metabolite that
well as pharmacology and efficacy to belongs to the flavonol class of
assist in the prediction of clinical flavonoids. It is characterized
‘drug-like’ properties. Completion of by a benzo-(γ)-pyrone skeletal
the drug candidate selection studies structure with C6-C3-C6
will provide the data to support the carbon framework, consisting
nomination to ‘clinical candidate’ of of two benzene rings, A and B,
the best compound within a list of linked by a three-carbon
potential candidates. It is key to pyrone ring C. Quercetin is
eliminate potential drug candidates referred to as
that are likely to fail in clinical trials as pentahydroxyflavonol due to
early as possible in their development the presence of five hydroxyl
(‘Fail fast and cheap’). groups on its flavonol skeletal
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framework at 3, 3′, 4′, 5, and 7


carbons. The wide range of
biochemical and
pharmacological activities of
quercetin and its metabolites is
due to the relative substitution
of various functional groups on
the flavonol molecule.
Phytochemical investigations
of various plant extracts have
revealed that quercetin can
exist in a free state as an
aglycone, or as its derivative by
conjugating with: (1)
carbohydrates as quercetin
glycosides, (2) lipids as
prenylated quercetin, (3)
alcohols as quercetin ethers,
and (4) a sulfate group as
quercetin sulfate.

Quercetin glycosides are


formed through the O-
glycosidic bond between a
sugar and the hydroxyl group
of quercetin molecule, and the
general glycosylation site on
the quercetin molecule is at the
3-hydroxyl position. However,
glycosylation of other hydroxyl
groups has also been reported.
The sugar moieties can be
monosaccharides,
disaccharides, or
polysaccharides, and the most
common carbohydrate
substituents are glucose,
galactose, rhamnose, and
xylose. Isoquercetin,
hyperoside, quercitrin, and
rutin are a few of the most
abundant and well-studied
quercetin glycosides.

Quercetin methyl ethers are


one of the most widely studied
natural pigments, and they are
formed through the
conjugation of the quercetin
hydroxyl group with alcohol,
generally methanol. Quercetin
ethers can exist in various
configurations, from mono-
ethers to penta-ethers, with
substitution on all the hydroxyl
groups of quercetin molecule.
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Rhamnetin, isorhamnetin, and


rhamnazin are a few
representatives of quercetin
ether analogs.

Prenylflavonols are an
important group of molecules
belonging to the flavonol
subclass. They are well-known
for their wide range of
biological activities, such as
antioxidant, antibacterial, anti-
inflammatory, and anticancer
properties. Structurally, in C-
prenylflavonols, prenyl groups
are attached to the carbon
atom of the flavonol skeleton.
In the past few years,
prenylated quercetin analogs,
such as solophenol D and
uralenol, have gained a lot of
attention due to their
antibacterial properties. It has
been reported that prenylation
may enhance the biological
functions of quercetin by
increasing its hydrophobicity
and bioavailability.

In addition to the sugar, lipid,


and alcohol derivatives,
quercetin also exists as sulfate
conjugate in nature. Quercetin
3,7,3′,4′-tetrasulfate, isolated
from the leaves Flaveria
bidentis, has shown
remarkable anticoagulant
properties. The
multisubstituted derivatives,
such as icaritin, isorhamnetin
3-O-glucoside, quercetin-3,4′-
di-O-glucoside, and
dorsmannin, can form from the
combination of same or
different functional groups.
The number and nature of
these functional group
substitutions have profound
effects on the physicochemical
properties and biological
effects of quercetin analogs.

The best described


biochemical property of
quercetin is its ability to act as
an antioxidant. The antioxidant
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activity and free radical


scavenging properties of
quercetin are attributed to its
chemical structure. There are
three important structural
features: (1) catechol
functionality (ortho-dihydroxyl)
on B ring, (2) a Δ2 double bond
adjacent to a 4-oxo group in
pyrone C ring, and (3) hydroxyl
groups at C-3 and C-5 carbons
in the benzopyrone AC ring.
The structural variables—such
as configuration, substitution,
and number of hydroxyl
groups—greatly influence the
mechanisms involved in
antioxidant activity, like their
ability to scavenge radical
species and their ability to
chelate metals.

Quercetin also inhibits the lipid


peroxidation process, a
common consequence of
oxidative stress, and
consequently protects against
lipid membrane damage. Due
to its lower redox potential,
quercetin is able to reduce
highly oxidizing free radicals,
such as superoxide and
peroxide radicals. Because of
its ability to chelate metal ions,
quercetin can inhibit the
generation of free radicals.

Bioavailability and Metabolism


of Quercetin
In order to estimate the
efficacy of quercetin in terms of
its anticarcinogenic effect, it is
important to understand the
bioavailability of quercetin as
well as its intestinal absorption
and metabolism conversion
rate. When quercetin was
administered intravenously to
rodents, it immediately
disappeared from the plasma.
It was evident from this
experiment that quercetin was
rapidly metabolized and
eliminated from the body
through urine and no evidence
was observed regarding the
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storage of quercetin inside the


tissues and body fluids.
Previously, there was a
common belief about the
excretion of quercetin into
feces without being absorbed
by the intestine, but it is evident
from recent studies that an
excessive amount of quercetin
found in foods is likely to be
absorbed from the intestine
and subsequently converted to
its respective metabolites. In
the transportation of the
metabolites of quercetin, the
body’s lymphatic system is also
involved. Repeated intake of
onion resulted in accumulation
of quercetin metabolites in
various tissues and blood,
which reached a total plasma
concentration of 0.6 µM after 1
week. Hence, it is important to
keep the plasma quercetin
metabolite concentration at an
acceptable and significant
level.

It is evident from studies


conducted recently that the
metabolites of quercetin were
rapidly distributed among
various organs at low levels
after intake of dietary
quercetin for a long time. It is
also evident that regular
consumption of dietary
quercetin results in the storage
of metabolites throughout the
body. Generally, the
conversion of quercetin to its
metabolic derivatives
decreases its free radical
scavenging activity, but there
are some metabolic derivatives
of quercetin, which are
capable of removing the
reactive species from the body.
Moreover, during the process
of inflammation, quercetin-3-
glucuronide is metabolized,
resulting in the accumulation of
quercetin aglycone. Recent
studies showed that
glucuronide, a more active
form of aglycone metabolite of
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quercetin, was used for the


incorporation into
macrophages. This study
showed those actions of
quercetin metabolites which
are mostly site-specific in
nature and are recommended
for inflammatory conditions.
The modified forms of
quercetin are present in human
blood and stored in inactive
forms, which are further
converted into active residues
and ultimately converted into
the active constituents to exert
their actions at specific target
sites.

Protective Effects of Quercetin


Quercetin and its metabolites
are crucial due to their
physiological functions as well
as their role in the elimination
of cancerous cells. Therefore,
it is important to further
investigate this specialized
aspect of quercetin in terms of
protection against cancer and
other degenerative disorders,
as these ailments are the
leading causes of death
throughout the world.

It was investigated recently


that by influencing the pentose
phosphate pathway with the
production of CYP450, the
preventive environment for
cytochrome c-mediated
apoptosis can be maintained.
This cytochrome is an
important part of the electron
transport chain and is released
from mitochondria during the
apoptosis process. Therefore,
the cancerous cells keep
constant control over cell
death through the release of
cytochrome C. These
metabolic changes are
important for the survival of
cells for a longer time and also
for the spreading of cancer
cells. Various studies have
been performed to evaluate the
pharmacological actions of
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quercetin in biological systems


in order to investigate the
precise mode of action of
quercetin. Therefore, it is
evident from these studies that
quercetin and its metabolites,
which are present in various
plants, play crucial roles in the
protection against cancer and
oxidative stress. When PC-12
cells were treated with nerve
growth factor (NGF), the cells
ceased to multiply and began
to extend branching varicose
processes similar to those
produced by sympathetic
neurons in primary cell culture.
Quercetin exhibited NGF-like
action when it came in contact
with PC-12 cells. Quercetin
also causes cell differentiation
similar to that caused by NGF .
Although the exact mechanism
is still unclear, the well-
characterized NGF-inducing
capacity is more likely related
to the differentiation-inducing
effects of quercetin. The
protective effects of quercetin
have also been observed in
primary cultures. Quercetin
increased the rate of survival of
cells when it was administered
24 h before the oxidative
stress. In a cell culture model,
it was reported that quercetin
internalization into neurons
happened rapidly, and a
neuroprotective pathway
involved Nrf2-dependent
variation of the GSH redox
system was observed.

When the aqueous quercetin


was administered in
experimental animals, there
was a significant reduction in
brain ischemic lesions.
Quercetin has been used in a
variety of studies to evaluate its
protective effects. In one
study, the anticancer effects of
quercetin were studied in
animal models. The
investigators examined the
physiological changes after
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they administered colchicine


by intracerebroventricular
route.

In a similar study, quercetin


was administered to mice for a
period of seven days through
intraperitoneal (i.p.) route.
After administration of
quercetin, memory
improvement was observed in
mice . In this study the
developmental changes were
linked with the inhibition of
cyclooxygenase 2 enzyme. It
was observed that there was a
noteworthy improvement in the
learning ability of mice in
comparison with the control
group of mice. Quercetin also
increased the activity of
superoxide dismutase (SOD)
and lowered the level of
malondialdehyde. Quercetin
and other flavonoids acted as
prodrugs and were
metabolized into active
hydroxyphenyl acetic acid
metabolites by microflora in
the intestine. The protective
effects of quercetin were
observed in rats with known
evidence of cerebral ischemia.
By administering two
consecutive doses of
quercetin, the memory
problem in rats—which was
induced by repeated cerebral
ischemia—was improved and
the level of cell death was
reduced in the region I of
hippocampus proper area
(CA1). In another study, when
quercetin was administered
through i.p. route to rats with
spinal cord injuries for a period
of 10 days, half of the rats
started walking.

In a study evaluating the


penetration of quercetin
across the blood–brain barrier,
it was observed that quercetin
induced various changes
within different brain regions
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based on an in situ brain


perfusion model in rats.

Molecular Mechanisms of
Quercetin
Quercetin is used for
therapeutic purposes in
various disorders due to its
antioxidant capability The
reactive oxygen species (ROS)
scavenging activity is
attributed to a change in OH−
ions, which has a relation to
electron exchange. Catechol
oxidative agents, such as
semiquinones and quinones
formed due to quercetin, alter
redox homeostasis and inhibit
primary positive effects. In
vitro study predicted that due
to this special feature
quercetin has a protective role
in the nervous system. In the
current scenario, the
neuroprotective activity of
quercetin cannot be ignored
and additional in vivo studies
should be investigated with
different humanized animal
models to translate the
efficacy. Quercetin exerts its
antioxidant activity by
competitively inhibiting the
xanthine oxidase enzyme and
noncompetitively blocking the
xanthine dehydrogenase
enzyme. The inhibitory
capabilities are due to its
flavonoid structure rather than
to its antioxidant potential.

III. DRUG TARGETS The term "biological target" is HMGB1 Signaling Pathway
AND TOOLS DURING frequently used in pharmaceutical High-mobility group box
PRECLINICAL research to describe the native protein 1 (HMGB1) is a nuclear
DEVELOPMENT protein in the body whose activity is protein which is highly
modified by a drug resulting in a preserved. It is secreted by the
specific effect, which may be a action of macrophages
desirable therapeutic effect or an previously activated and it
unwanted adverse effect. In this works as a crucial “late”
context, the biological target is often facilitator of fatal endotoxemia
referred to as a drug target. The most and sepsis formation. The
common drug targets of currently HMGB1 protein, which is
marketed drugs include: present outside the cell, can
motivate the release of tumor
1. PROTEINS necrosis factor-α (TNF-α),
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G protein-coupled receptors (target of interleukin-1β (IL-1β), and


50% of drugs)[7] other inflammatory mediators
enzymes (especially protein kinases, from monocytes. Quercetin
proteases, esterases, and stimulates the inhibition of
phosphatases) HMGB1-induced TNF-α and IL-
• ion channels 1β mRNA expression, which
• ligand-gated ion channels suggests that quercetin
• voltage-gated ion channels modulates cell signaling that in
• nuclear hormone receptors turn regulates the action of
• structural proteins such as proinflammatory cytokines.
tubulin The activation of mitogen-
• membrane transport proteins activated protein kinase
2. NUCLEIC ACIDS (MAPK) signaling pathway is a
significant step in the HMGB1-
Identifying the biological origin of a induced gene expression
disease, and the potential targets for process, which causes the
intervention, is the first step in the release of inflammatory
discovery of a medicine using the cytokines—such as TNF-α, and
reverse pharmacology approach. IL-1β—inside macrophages,
Potential drug targets are not neutrophils, and endothelial
necessarily disease causing but must cells. HMGB1-induced
by definition be disease modifying.[8] cytokine release partially
An alternative means of identifying interferes with MAPK
new drug targets is forward pathways. HMGB1 or
pharmacology based on phenotypic lipopolysaccharides (LPS)
screening to identify "orphan" time-dependently induce
ligands[9] whose targets are phosphorylation of p38, c-Jun
subsequently identified through target N–terminal kinase, and
deconvolution. extracellular signal-regulated
kinase in macrophages.
Databases containing biological Quercetin considerably
targets information: inhibits HMGB1- or LPS-
induced phosphorylation of
• Therapeutic Targets Database each kinase. Apart from MAPK
(TTD) activation, the nuclear factor-
• DrugBank κB (NF-κB) signal transduction
• Binding DB pathway is also involved in
HMGB1-induced cellular
activation, and NF-κB-
dependent transcriptional
activity is very important for
cytokine expression. In cells,
NF-κB subunits (p50 and p65)
exist as inactive trimers in the
cytosol through the interaction
with IκBα, which is the most
important member of the IκB
family. Quercetin significantly
inhibits IκBα degradation and
nuclear translocation of NF-κB
p65. Therefore, after
stimulation with HMGB1 or
LPS, p65, the key activator of
NF-κB-regulated transcription,
becomes available to NF-κB-
regulated genes in the nucleus
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and nuclear localization is most


effectively inhibited by
quercetin.

Thymic Stromal Lymphopoietin


(TSLP) Activation

The level of TSLP, which is an


epithelial-derived cytokine with
a role in T helper (Th) cells’
Type-2 immunity, is
considerably increased in
human skin as well as blood.
The TSLP signaling process is
initiated through proteins,
including 1L-7 chain of
receptor, which has potential
to enhance the B lymphocyte
activation and dendritic cells.
Primary skin keratinocytes are
mostly responsible for
expressing the TSLP in smooth
muscle and lung connective
tissues. TSLP contributes its
main biological role by
influencing various cells. It is
evident that TSLP has the
potential to activate both CD4+
T and CD8+ cells along with
other B lymphocytes’
differentiation, which in turn
promotes the release and
activation of chemokines.
Additionally, it can enhance the
secretory mechanism of the
Th2 cytokines from mast cells.
During the binding of TSLP with
respective receptors, various
signaling pathways are
activated. It has been reported
in a recent study that due to the
activation of these receptors,
there is a marked promotion in
the phosphorylation process of
Janus kinase-signal
transducers and activators of
transcription (JAK-STAT)
signaling, which further causes
skin inflammation. Thus,
targeting the above signaling
pathway is a viable approach to
design a treatment plan for
various inflammatory diseases,
including cancer.

JAK-STAT Signaling Pathway


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JAK-STAT signaling pathway is


a typical signal transduction
pathway for various types of
inflammatory cytokines and
growth regulatory factors. The
binding of ligands to their
respective receptors leads to
the activation of JAK, which
further increases the
phosphorylation process and
hence leads to the activation of
STAT. The STATs, which are
already activated, enter the
nucleus, where they start the
regulation of gene expression.
Studies have shown that the
activated mast cells stimulate
the formation of the Th2
cytokines and decrease the
secretory mechanism of Th1
cytokines. JAK-STAT signaling
is activated by mast cells,
which in turn activate the IL-13
production in the Th2 cell line.

Quercetin has the ability to


actively inhibit the JAK-STAT
signaling pathway in various
inflammatory disorders.
Furthermore, treatment of
activated T cells with quercetin
in vitro inhibited the
interleukin-12 (IL-12)-induced
phosphorylation of JAK2,
tyrosine kinase-2 (TYK2),
STAT3, and STAT4, which
result in decreased levels of T
cell propagation and Th1
variation. Therefore, these
anti-inflammatory and
antiapoptotic properties of
quercetin have a key role in the
reduction of cancer by
controlling the toll-like
receptor-2 (TLR2) and
JAK2/STAT3 pathway and
causing the inhibition of STAT3
tyrosine phosphorylation
within inflammatory cells [68].
Pretreatment of
cholangiocarcinoma cells with
quercetin inhibited the
cytokine-mediated
upregulation of inducible nitric
oxide synthase (iNOS) and
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expression of intercellular
adhesion molecule-1 (ICAM-1)
in the JAK/STAT cascade
pathway. Also, quercetin
blocked the activation of
inflammatory cytokine
interleukin-6 and interferon-γ.
It was reported that LPS-
induced STAT1 activation was
inhibited by quercetin in
combination with its profound
inhibitory effects on iNOS and
NF-κB expression, which are
persistently involved in
activation of interleukin-2 (IL-2)

IV. ROLE OF Drug discovery is a lengthy and highly The development of


GENOMICS AND expensive process that uses a variety proteomics will require
PROTEOMICS IN of tools the simultaneous advancement
DRUG DISCOVERY from diverse fields. To facilitate the of a number of techniques,
process, several biotechnologies, because the challenges that
including genomics, face proteomics technologies
proteomics, cellular and organismic are far reaching. Both two-
methodologies have been developed. dimensional gel
The present review aims electrophoresis and Mass
to provide a basic understanding of Spectrometry play a major role
proteomics research by discussing in proteomics; however, they
the methods used to study are not the only technologies
large numbers of proteins and by available and necessary. Some
reviewing the application of commonly used technologies
proteomics methods to identify are shown in the Figure 1:
biomarkers, to identify drug target and
to conduct drug’s mode of action and
toxicology studies. It
is expected that this will lead to
important new insights into disease
mechanisms and improved
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drug discovery strategies to produce


novel therapeutics.

‘Proteomics’ is the study of the


proteome and involves the technology
used to identify
and quantify the various proteins,
protein-protein and protein-nucleic
acid interactions within the
proteome, as well as the post-
translational modifications that affect
protein activity (Hewick et al.,
2003). Proteomic technologies with
computational methods have been
advanced recently over
many other complementary
techniques. This enables scientists to
screen large numbers of proteins
within clinically distinct samples that
helps to discover disease biomarkers,
identify and validate
drug targets, design more effective
drugs, assessment of drug efficacy
and patient response, i.e., to
interfere with almost every steps in
modern drug discovery process (Ahn
et al., 2008). Proteomic
approach of drug discovery includes
finding an unstable protein that is
causing an undesirable
affect and then usage of a molecule to
modify its effect (Veenstra, 2006).
Proteomics combines
aspects of biology, chemistry,
engineering and information science
and apply them to all areas of
drug discovery. Introduction of safer,
more effective and more cost-effective
drugs will be the
ultimate outcome of improvement of
this technology (Burbaum et al., 2002).

V. COMPOUND A drug candidate suitable for clinical EFFECT OF QUERCETIN


SELECTION AND testing is expected to bind selectively TREATMENT ON TUMOR
PRECLINICAL to the receptor site on the target, to VOLUME:
STUDIES elicit the desired functional response In continuation, we
of the target molecule, and to have evaluated the in vivo effect of
adequate bioavailability and quercetin on CT-26 and MCF-7
biodistribution to elicit the desired tumors; these cells lines
responses in animals and humans; it exhibited a relatively lower
must also pass formal toxicity sensitivity to quercetin in in
evaluation in animals. The path from vitro experiments. Therefore,
lead to clinical drug candidate mice bearing CT-26 and MCF-7
represents the most idiosyncratic tumors were treated with
segment of drug discovery and various concentrations of
development. Each program is unique quercetin (50, 100 and 200
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and setbacks are common, making it mg/kg; i.p.) This approach


difficult to predict accurately the revealed that the
duration or costs of this segment. administration of quercetin
Because of incidents of unpredicted significantly reduced the tumor
human toxicity seen in recent years, volume at all 3 utilized doses on
the regulatory agencies and public day 18 post-treatment for CT26
demands for safety of new drug tumors and on day 20 post-
candidates have become very strict, treatment for MCF-7 tumors.
and safety issues are dominant when
identifying a clinical drug candidate. ANIMAL SURVIVAL RATE
Modern drug discovery and In vivo experiments
development efforts typically emerge demonstrated that the survival
from basic research and then rate for mice bearing CT-26
gradually move on to specific and MCF-7 tumors that were
sequential tasks, which – if successful treated with the two higher
– culminate in a new drug for the concentrations of quercetin
treatment of a human disease. The (100 and 200 mg/kg) was
overall pathway is structured by well- significantly higher compared
delineated milestones, which include to the control group (P<0.05
selection of the drug target, and P<0.01, respectively). No
identification of a lead compound, its significant difference in the
modification to a compound suitable survival rate was evident
for toxicity testing in animals, and between the group treated with
selection as drug candidate for clinical quercetin at 50 mg/kg and the
testing. Although the road is well control group.
mapped out, it is by no means easy or
guaranteed to end in success. Even TUNEL ASSAY
before the onset of human studies, a At the end of the experiment
drug candidate suitable for clinical (36 days following treatment),
testing is expected to satisfy specific all surviving animals were
and demanding criteria. It must bind sacrificed, and tumors from all
selectively to the receptor site on the animals were dissected and
target and elicit the desired functional the poly-D-lysine-coated
response from the target molecule. It coverslips for TUNEL assay
must have sufficient bioavailability and were positioned. An increase in
distribution within the body to reach the percentage of apoptotic
the receptor site, and it must elicit the cells in the treated as
desired responses in vivo, in animal compared to the control
models of the human disease. Most groups was observed;
importantly, a drug candidate suitable however, it did not reach
for testing in humans must pass a statistical significance.
formal toxicity evaluation in animals, to
demonstrate that humans
participating in the clinical studies are
exposed to minimal risks only.
VI. IMPACT OF The label “translational research” New medical knowledge
TRANSLATIONAL (TR) has become ever more popular in and technologies are important
RESEARACH IN the biomedical domain in recent years. building blocks to enhance
DRUG DISCOVERY It is usually presented as an attempt to health and quality of life in the
bridge a supposed gap between society. TR in cancer has led to
knowledge produced at the laboratory improvements in molecular
bench and its use at the clinical diagnosis, tumor
bedside. This is claimed to help society heterogeneity, and newer
harvest the benefits of its investments systematic therapies. This has
in scientific research. The past decade brought challenges to the clinic
has witnessed a remarkable in terms of patient education,
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acceleration in the pace of toxicity management,


translational cancer medicine – workflow, and prognostication
genome sequencing of various human for PC. The process of
cancers has been broadly deployed in “translation” is a nexus of many
drug discovery programs, diagnostic ideas involved in the design of
tests have been developed to predict scientific work, which needs
molecularly targeted anticancer anticipation and coordination
agents, advent of cancer with the requirements for
immunotherapies, an enhanced applicability in the future. Thus,
appreciation of the complex collaboration between
interactions that exist between tumor researchers and stakeholders
cells and their microenvironment have is vital to ensure the success of
revolutionized the management of TR and benefits to science and
cancers. society.

Recent decades have yielded


unprecedented advances in
understanding the biological
mechanisms underlying cancer
development, progression, and
symptomatology. Translation of this
knowledge to the clinic promises new
treatments tailored to exploit the
molecular intricacies of a patient's
tumor. In the cancer field, this is what
is generally understood by
translational cancer research.
Translational research (TR) has been
described in various ways such as –
“taking research from bench-to-
bedside;” “bridging basic research
and medical innovation;” “translating
research into medical practice (…);”
“translating science into better
healthcare.”
VII. CLINICAL Over the past decade, the The use of cytotoxicity as
DEVELOPMENT: emphasis in anticancer drug the end point for random
STRATEGY AND discovery has shifted from an screening assays evolved from
DESIGN empirical approach, characterized by the concept that the cure for
random screening of a variety of cancer could be achieved by
natural and synthetic compounds eradicating all cancer cells in
using high throughput cell-based the body, analogous to the
cytotoxicity assays, to a more rational successful treatment of
and mechanistic, target-based bacterial infections with
approach. The goal of this new target- antibiotics. The cytotoxic
based approach is to improve the anticancer drugs discovered
efficacy and selectivity of cancer through random screening
treatment by developing agents that have diverse mechanisms of
specifically block the pathogenic action, but most target or
mechanisms that account for damage DNA. As a result, the
malignant transformation. This new pharmacologic effects of most
approach reflects our rapidly of these drugs are nonselective
expanding knowledge of the and, unlike classical drug-
pathogenesis of a variety of forms of receptor interactions, their
cancer at the molecular level, pharmacologic effects, which
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providing new targets for drug lead to cytotoxicity, are


discovery. irreversible.
The clinical development
and subsequent clinical use of
cytotoxic anticancer drugs
also reflect the goal of cure
(eradicating all cancer cells) as
the treatment end point. The
optimal dose is usually defined
as the maximum tolerated dose
in phase I trials, and the activity
of a new drug is determined by
whether it produces tumor
shrinkage (response) in
patients with advanced
disease in phase II trials. In
many front-line treatment
regimens, conventional
cytotoxic drugs are
administered parenterally at
their maximum tolerated dose
in a pulsed fashion, which
results in substantial toxicity in
many patients and
necessitates reiterative
interruption of cycles of
treatment to allow for recovery
of normal tissues, usually bone
marrow.
Target-based drug
discovery selects agents for
development based on their
mechanisms of action.
Validated targets are usually
proteins that play a direct role
in malignant transformation,
such as the products of
mutated genes that result in a
gain of function (e.g., ras, bcr-
abl), or normal receptors and
signaling proteins in pathways
that regulate apoptosis or the
cell cycle and that are
dysregulated by a mutation
that results in the loss of
protein function. For example,
mutations or hypermethylation
of the von Hippel-Lindau gene
result in the loss of functional
pVHL (protein product of the
VHL gene), which acts as the
substrate recognition
component for the
ubiquitination and degradation
of hypoxia-inducible factors
(HIFs) in the presence of
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oxygen. The constitutive


activation of HIF
transcriptional activity in the
absence of pVHL leads to an
increased production of the
proangiogenic factor, vascular
endothelial growth factor
(VEGF), and a subsequent
increase in microvessel
density. Many of the current
molecular targets are proteins
with enzymatic activity.
Potential drugs to block these
molecular targets may be
designed and synthesized
based on the three-
dimensional structure of the
target or identified by
screening compound libraries
for their ability to inhibit the
target (target-based
screening).
Unlike cytotoxic drugs, the
interaction of molecularly
targeted drugs with their target
(receptor) can be described by
classical drug-receptor theory.
Their immediate
pharmacological effects do not
induce acute cellular damage,
and therefore, are likely to be
cytostatic rather than
cytotoxic, although some
agents can induce apoptosis.
Cytostatic agents are more
likely to be effective when they
are administered continuously
rather than in pulses, and oral
formulations are preferred for
continuous dosing schedules.
Ideally, molecularly targeted
drugs will interact with
proteins that are specific to
tumor cells or that are
upregulated during malignant
transformation. Under these
conditions, target-based
therapies hold the promise of
being more selective and less
toxic to normal tissues. As
target-based therapies are
developed, the common
toxicities of cytotoxic therapy,
such as bone marrow
suppression and mucositis,
may be replaced by unique and
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agent-specific toxicities, such


as pseudotumor cerebri in
children who are treated with
retinoids, arthralgia
associated with the matrix
metalloproteinase inhibitors,
and the cardiac toxicity of
herceptin.

8. ROLE OF THE Current Federal law requires that a The IND application was
FOOD AND DRUG drug be the subject of an approved approved by the FDA and is
ADMINISTRATION marketing application before it is ready for product formulation
AND OVERVIEW OF transported or distributed across and clinical trails.
THE state lines. Because a sponsor will
INVESTIGATIONAL probably want to ship the
NEW DRUG(IND) investigational drug to clinical
PROCESS investigators in many states, it must
seek an exemption from that legal
requirement. The IND is the means
through which the sponsor technically
obtains this exemption from the FDA.
During a new drug's early preclinical
development, the sponsor's primary
goal is to determine if the product is
reasonably safe for initial use in
humans, and if the compound exhibits
pharmacological activity that justifies
commercial development. When a
product is identified 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 specific
requirements of the drug regulatory
system.
There are three IND types:
• An Investigator IND is submitted
by a physician who both initiates
and conducts an investigation,
and under whose immediate
direction the investigational
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drug is administered or
dispensed. A physician might
submit a research IND to
propose studying an
unapproved drug, or an
approved product for a new
indication or in a new patient
population.
• Emergency Use IND allows the
FDA to authorize use of an
experimental drug in an
emergency situation that does
not allow time for submission of
an IND in accordance
with 21CFR , Sec. 312.23 or
Sec. 312.20. 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.
• Treatment IND is submitted for
experimental drugs showing
promise in clinical testing for
serious or immediately life-
threatening conditions while the
final clinical work is conducted,
and the FDA review takes place.
There are two IND categories:
• Commercial
• Research (non-commercial)
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. Also
included are any previous
experience with the drug in
humans (often foreign use).
• 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
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whether the initial-phase trials


will expose subjects to
unnecessary risks. Also,
information on the qualifications
of clinical investigators--
professionals (generally
physicians) who oversee the
administration of the
experimental compound--to
assess whether they are
qualified to fulfill their clinical
trial duties. Finally,
commitments to obtain informed
consent from the research
subjects, to obtain review of the
study by an institutional review
board (IRB), and to adhere to the
investigational new drug
regulations.
Once the IND is submitted, the sponsor
must wait 30 calendar days before
initiating any clinical trials. During this
time, FDA has an opportunity to review
the IND for safety to assure that
research subjects will not be
subjected to unreasonable risk.

The IND application may be divided


into the following categories:
1. Preclinical Testing consists of
animal pharmacology and
toxicology studies to assess
whether the drug is safe for
testing in humans. Also included
are any previous experience
with the drug in humans (often
foreign use).
2. Manufacturing
Information includes
composition, manufacturer, and
stability of, and the controls
used for, manufacturing the
drug. Used to ensure that the
company can adequately
produce and supply consistent
batches of the drug.
3. Investigator Information on the
qualifications of clinical
investigators, that is, the
professionals (generally
physicians) who oversee the
administration of the
experimental drug to the study
subjects. Used to assess
whether the investigators are
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qualified to fulfill their clinical


trial duties.
4. Clinical Trial Protocols are the
centerpiece of the IND. Detailed
protocols for proposed clinical
studies to assess whether the
initial-phase trials will expose
the subjects to unnecessary
risks.
5. Other Commitments are
commitments to obtain informed
consent from the research
subjects, to obtain review of the
study by an institutional review
board (IRB), and to adhere to
the investigational new drug
regulations.
An IND must also include
an Investigator's Brochure intended to
educate the trial investigators of the
significant facts about the trial drug
they need to know to conduct their
clinical trial with the least hazard to the
subjects or patients.
Once an IND is submitted, the FDA has
30 days to object to the IND or it
automatically becomes effective
and clinical trials may begin. If the FDA
detects a problem, it may place a
clinical hold on the IND, prohibiting the
start of the clinical studies until the
problem is resolved.
Experimental drugs under an IND must
be labeled "Caution: New Drug –
Limited by Federal (or United States)
law to investigational use."
IX. FORMULATION Cancer is one of the major fatal Nanoparticles take the
DEVELOPMENT AND diseases in the world and causes advantages of small size in
MANUFACTURING abnormal growth of cells spreading to terms of both
surrounding tissues in the body. It is pharmacodynamic and
known that there is an insufficient pharmacokinetic profiles, e.g.,
breakthrough in clinical treatment of release profiles,
cancer despite the progress in biodistribution, absorption rate
chemotherapy for years. There are still and cellular uptake. Therefore,
some limitations that restrain the the particle size should be in an
efficacy and safety of cancer optimum range which enables
chemotherapy. The most important particles to diffuse and
drawback is the poor aqueous permeate through the
solubility due to the hydrophobicity of biological membranes, but also
most anticancer drugs. Most of the should provide the maximum
anticancer drugs are formulated with ability for encapsulation of
co-solubilizers via intravenous drugs and sustained release.
administration; however, these co- The influence of CD
solubilizers lead to severe side effects concentration, concentration
restricting both the patient’s quality of of oil phase and organic to
life and efficacy of the therapy. aqueous phase volume ratio
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Another major factor is that anticancer have been studied to optimize


drugs have a wide distribution the nanocapsule formulation
capacity in the body and owing to non- The effect of the
selective cytotoxicity of these drugs concentration of 6OCAPRO on
not only the cancer cells, but also particle size and PDI. It is
healthy cells are killed. Due to low clearly seen that the particle
therapeutic indices of anticancer size increases linearly with
drugs, a rapid increase and polymer concentration which is
subsequent decay of drug attributed to higher organic
concentration in blood is also one of solution viscosity with increase
the limitations of cancer therapy. in polymer concentration.
Thus, the increase of drug
concentration in blood during the In this work CPT-loaded
chemotherapy falls into a decline in amphiphilic CD nanocapsules
the cooling period which makes were developed and in vitro
therapeutic effect repetition limited evaluated for oral
and therefore contributes to cancer chemotherapy for the first
cell growth. time. The results obtained from
Although in cancer therapy, the this work suggest that CD
intravenous route is more common nanocapsules offer a new
than the others, it is thought that with strategy for the development of
recent advances oral chemotherapy a safe and effective oral
will be the breakthrough step in future chemotherapy. CD
chemotherapy. From the patient’s nanocapsules might be an
viewpoint, the oral route allows for interesting strategy to improve
painless self-medication and thus it is the stability and bioavailability
considered the most convenient route. of the anticancer drug CPT. In
Besides, it reduces reimbursement a second step, interaction with
load in the health budget also, since it mucus and the GI uptake of
does not require therapy in medical nanocapsules will be evaluated
centres. By means of oral using artificial mucus model
administration, it is possible to prevent and in vivo animal studies.
the initial rapid increase and the
subsequent decay of drug
concentration in blood that occurs via
the intravenous route. However most
anticancer drugs are not good
candidates for oral delivery owing to
their low absorption in the
gastrointestinal tract (GI) and as a
result exhibit low oral bioavailability. In
order to develop an effective oral
chemotherapy, the bioavailability of
anticancer drugs should be improved.
Nanoparticulate drug delivery
systems are promising in this field.
Nanoparticles are defined as
submicron colloidal systems that
include both nanospheres and
nanocapsules. Nanospheres are
defined as matrix systems whereas
nanocapsules are core-shell
structures consisting of an inner liquid
core (which can be either aqueous or
oily depending on the core material)
surrounded by a polymeric wall.
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Nanocapsules present many


advantages, such as improving poor
water solubility, maintaining drug
stability by protecting the molecule
from the environment, providing
controlled release and improving the
desired pharmacokinetic profile.
Considering the advantages of the
nanocapsules depending on the
structure, the oily core enables an
improvement in the solubility of
hydrophobic drugs and the polymeric
wall surrounding it provides
protection of the molecules against the
harsh environment.
In cancer therapy, a common
problem is drug ineffectiveness
because of physicochemical and
biopharmaceutical problems of drugs
and CPT is cited as a prime example.
CPT is a very effective anticancer
agent against a wide spectrum of
cancers such as colon, breast,
ovarian, lung cancers in in vitro cell
culture studies. However, its poor
aqueous solubility and the pH-
dependent stability problem results in
the diminishing of clinical efficacy for
the drug. CPT is in active lactone form
under pH 5 but is rapidly hydrolysed
into the inactive carboxylate form in
physiological or alkaline pH causing
the effectiveness of chemotherapy to
be reduced or even inhibited. In
addition to its stability problem, CPT
has a very poor water solubility which
is less than 1 µg/mL and is only soluble
in dimethyl sulfoxide (DMSO) and
mixtures of methanol with either
dichloromethane or chloroform at a
ratio 1:1 and 1:4 in volumes,
respectively. Therefore, formulation
approaches should be evaluated to
improve the aqueous solubility and to
protect this drug from hydrolysis at pH
7.4 in order to obtain an effective in
vivo administration of CPT for cancer
therapy. CDs can be a means of
overcoming these problems for the in
vivo behaviour of CPT upon
intravenous or oral administration.
CDs are natural polymers which are
produced from enzymatic degradation
of starch. They are cyclic
oligosaccharides and consist of at
least 6 D-(+)-glucopyranose units
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linked by α-(1,4) glucosidic bonds. The


most common advantages of CDs in
the pharmaceutical field are to
enhance the stability, solubility, and
bioavailability of drug molecules.
Amphiphilic CDs are derivatives of
natural CDs which are chemically
obtained and modified on the primary
and/or secondary face. It is very
common to use CDs as complexing
agents with the intention of increasing
poor water solubility, maintaining
stability, improving permeability and
ultimately bioavailability . Furthermore
inclusion complexation with CDs can
reduce or prevent GI irritation. It is
known that complexation of drugs with
CDs provide an improvement in its
dissolution rate and consequently in
oral absorption. Besides, CDs serve as
a permeability enhancer upon oral
administration which plays an
important role for drugs having low
intestinal permeability.
Taking into consideration of the
disadvantages that limit the
effectiveness of oral chemotherapy
and the advantages of nanoparticular
drug delivery systems, developing a
strategy with nanoparticles and even
nanocapsules might be very promising
for oral delivery of anticancer agents.
Nanocapsules are especially
beneficial for oral administration of
anticancer drugs, e.g., CPT, suffering
from poor solubility, instability, low
permeability and ultimately poor oral
bioavailability. Nanocapsules can i)
enhance the poor solubility of
hydrophobic drugs owing to the oily
liquid cores, ii) improve the stability of
drugs and prolong residence time in
the GI tract due to the polymeric wall,
and iii) enhance permeability of drugs
by taking the advantages of both small
size of nanoparticles and
mucoadhesive properties of polymers
as coating materials. The main goal of
this study therefore in a first step, to
design and evaluate nanocapsules for
the oral delivery of the anticancer
agent CPT, which has a limited clinical
usage by maintaining its stability and
improving its eventual bioavailability.
For this reason, amphiphilic CD,
6OCAPRO (heptakis(6-O-
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hexanoyl)cyclomaltoheptose) was
used as core polymer for
nanocapsules. These nanocapsules
were then coated with the cationic
polymer chitosan to improve the
cellular uptake and interaction with
biological membranes and penetration
through intestinal mucosa for
absorption of CPT and reaching the
circulation. Nanocapsules were
characterized for their in vitro
properties followed by cell culture
studies evaluating anticancer efficacy
and permeability in comparison to CPT
in solution form.

X. CLINICAL STUDY Clinical trials are biomedical or


START-UP health-related research studies using
ACTIVITIES human subjects that investigate how
well new medical approaches work in
people. Each study answers specific
scientific questions and attempts to
discover better ways to prevent,
diagnose or treat a disease. Clinical
trials are extremely important to the
pharmaceutical industry for the
development of new drugs or
therapies. Every clinical trial has a
protocol or action plan, for conducting
the trial. The plan describes what will
be done in the study, how it will be
conducted and why each part of the
study is necessary. The study start up
phase of clinical trials is a very crucial
and time consuming component of the
clinical study process. A key challenge
in conducting the clinical trials is that
it spans so many different parties,
including study sponsors, contract
research organizations (CROs), site
management organizations (SMOs),
patient recruiters, investigators and
patients. It is critical that sponsors,
CROs and SMOs bring the right
resources, tools and techniques to the
clinical trial start up process to meet
study start up timelines. It is important
to streamline the start up from the
beginning because it sets the pace for
the study. Study start up activities
includes assessment of site feasibility,
negotiation of contract and budgets,
planning for patient recruitment, legal
reviews and approvals by Institutional
Review Board (IRB) and/or ethics
committee. The pharmaceutical
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industry is bestowed with an


impressive history of blockbuster
drugs, lifesaving medicines and new
therapies that have enhanced our
lives. But today pharmaceutical
companies are facing intense financial
pressure due to patent expiration on
blockbuster drugs. 2 This has lead the
drug development costs and timelines
to increase at alarming rates . As a
point of comparison, a new drug in
1960 could be developed in 8.1 years
versus 15 years in 1990’s. Over the
past 40 years, the cost of developing
one drug development has escalated
from a mere $4 million in 1962 to an
astounding $800 million or more in
today’s market. Drug industry is facing
challenges which include satisfying
ever increasing consumer demands,
following stringent rules and
regulations in drug development and
conducting clinical trials. These
challenges are contributing to the
delay in the process of bringing the
drug to the market. On an industry-
wide basis, clinical trials often fall
behind their timelines due to delay in
study start up. Thus, there is greater
opportunity for an investigative sites
and sponsors to evaluate better ways
to optimize productivity by expediting
the clinical trial start up process. The
internship practicum site, Advanced
Care Research Center (ACRC) Trials,
is a Site Management Organization
(SMO) which provides services to the
Contract Research Organization
(CROs) and pharmaceutical
companies in conducting successful
phase II, III and IV drug trials. ACRC
Trials has its own Standard Operating
Procedures (SOPs) and checklists to
expedite the study start up process.
The general study start up activities at
ACRC Trials include maintaining
regulatory documentation, obtaining
IRB approval for the study, negotiating
budget and contract and preparing for
the first patient first visit. The study
start up activities also includes
recruitment task like chart review of
in-house patients, creation of
recruitment materials like
advertisements for local newspaper
and radio, pocket inclusion and
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exclusion cards for PIs, study


synopsis, phone screen synopsis, etc.
It is challenging on part of the
investigative sites to meet the
timelines of the study start up process
because of the following factors: 3 •
Communicating with sponsors,
principal investigators (PIs),
Institutional Review Boards (IRBs), •
Obtaining IRB approval, • Maintaining
regulatory documentation, • Patient
recruitment. Each investigative site
has its own SOPs for study start up.
These SOPs ensures that the conduct
of clinical trials is in compliance with
Good Clinical Practice (GCP) and
helps in adhering to the timelines of the
study start up process. Hence, the aim
of the internship practicum was to
comprehend, describe and analyze
the crucial study start up activities at
the practicum site (ACRC Trials).
XI. CLINICAL TRAILS : Phase I (Dose-Finding) Trials The results of molecular
PHASE 1,2,3,4 Phase I trials are small dose-finding biological studies of cancer are
studies designed to rapidly identify the changing the way we diagnose
optimal dose of a new agent, which is and treat cancer. Tremendous
administered on one or more dosing strides continue to be made in
schedules that were shown to be understanding the pathways
effective in preclinical models of and networks that control cell
human cancer. For conventional signaling, proliferation,
cytotoxic anticancer drugs, the metastasis, and cell death. We
optimal dose has usually been defined are developing agents and
as the maximum tolerated dose (MTD) treating patients with drugs
rather than the dose that produces a that act at individual points in
quantifiable therapeutic effect. these networks. As our
Cohorts of three to six patients are understanding of these
treated at gradually increasing doses, pathways and the complexity of
and the MTD is defined as the dose their interaction develops, we
level below the dose at which must learn how and when to
unacceptable or dose-limiting toxicity use agents to target specific
occurs in two or more of the three to steps in malignant
six patients who were treated at that transformation and
dose. This toxicity-based dosing proliferation, and we must
approach is founded on the adapt clinical trial designs to
assumption that the therapeutic test the clinical utility of this
anticancer effect and toxic effects of promising new class of
the drug increase in parallel as the anticancer drugs
dose is escalated. This assumption is
sound if the mechanisms of action of
the toxic and therapeutic effects are
the same, as is often the case with
cytotoxic agents.

Phase II (Activity) Trials


The primary objective of phase II
trials is to define the spectrum of
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antitumor activity for a new agent


administered at the optimal dose and
schedule from phase I trials. These
trials are restricted to patients with
specific histologic types of cancer,
which are selected based on activity of
the drug in preclinical cancer models,
the mechanism of action of the drug,
and activity observed in phase I trials.
For conventional cytotoxic drugs, the
end point in a phase II trial is response,
which is measured as the percent
decrease in size of tumor nodules
compared with the pretreatment
tumor size. Therefore, patients
enrolled in conventional phase II trials
must have measurable tumors
(advanced disease) that are refractory
to standard therapy.
Until recently, individual tumor
nodules were measured in two
dimensions (the longest diameter and
then the longest diameter
perpendicular to the initial
measurement), and the products of
these two measurements for each
measurable tumor were then summed.
An objective response was defined as
a ≥50% reduction in the sum of the
products of the two longest
perpendicular diameters. More
recently, the Response Evaluation
Criteria in Solid Tumors (RECIST)
guidelines were established and
validated in an attempt to simplify and
standardize the evaluation of
response to treatment in solid tumors
in clinical trials. With RECIST, the sum
of the longest single diameter of
measurable lesions is used to estimate
overall tumor burden. An object
response in RECIST is a ≥30%
decrease in the sum of the longest
diameters from all target measurable
lesions.

Phase III (Efficacy) Trials


Phase III trials are designed to
determine efficacy or clinical benefit.
They are typically large cooperative
group trials that randomize patients to
new regimens versus standard
therapy. Patients and medical staff
may be blinded to the treatment arm to
reduce bias. The end points are time to
progression or survival. With target-
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based therapy alone or in combination


with cytotoxic agents, traditional
phase III trial designs should remain
relatively unchanged. The eligibility
criteria should include only patients
that demonstrate the target, and end
points could be expanded to include
quality-of-life measures.

XII. Biologics are important treatments


PHARMACOECONOMI for a number of cancers, but they are
CS IN DRUG also significant drivers of globally
DEVELOPMENT escalating
healthcare costs. Biosimilars have
the potential to offer cost-savings with
comparable efficacy and safety to
innovator products. They are being
used in the European Union, Canada,
Japan, and Australia and may help
with improving health outcomes while
minimizing costs to patients and global
healthcare systems. The overall value
of a biosimilar is not determined solely
by its pricing. Efficacy and safety
relative to the reference
biologic drug and competitive agents
as well as development and
manufacturing costs, treatment
administration costs, and results from
long-term safety monitoring are
considered. Optimizing economic
efficiency is one part of an ongoing
healthcare decision-making process
with all therapeutics that aims to attain
high levels of quality-of-care and
safety given available resources.
Some analytic tools stakeholders use
to determine the pharmacoeconomic
value of a therapy that are highlighted
in this review article are opportunity
cost, cost-effectiveness, and cost-
minimization analyses. These
methodologies can provide
information to physicians, patients,
and payers that may help reaffirm the
value of a given biosimilar compared
with its reference product throughout
its life cycle.

Pharmacoeconomic analyses may


help to inform healthcare
professionals
regarding therapeutic options that
represent potentially beneficial and
economical alternatives for patients
and healthcare systems.
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With biosimilars, pharmacoeconomic


analyses findings are impacted
by development and
manufacturing costs, monitoring and
acquisition costs, as well as the
determination of potential benefits to
patients in terms of offsetting
healthcare expenses. For patients, a
broader role for effectiveness
research in formulary and drug benefit
design may be advantageous,
because decisions may be driven by
overall value as opposed to solely by
economics. As biosimilars emerge and
potentially become more widespread
in clinical practice, additional
pharmacoeconomic analyses may be
performed and yield additional data on
the effects of biosimilars on reducing
cancer treatment costs, shedding
greater light on the potential
pharmacoeconomic benefits of these
agents. Ultimately, the question may
not be “Will biosimilars provide cost-
savings?” Instead, it may be “Will they
be cost-effective compared with their
branded equivalents?”
As was the case in the EU,
the adoption of biosimilars in the
United States will not be driven solely
by monetary concerns, but by safety
and efficacy data.9, 17Savings from
biosimilars also have the potential
to enable use of biologicdrugs (in the
form of biosimilars) to patients who
may not have had access to biologic
therapies previously, leading to
potentially improved patient outcomes
which, in turn, may have a positive
effect on cost-effectiveness models.
Finally, the balance between the need
for increased access and innovative
therapies is a consideration that may
be achieved through the additional
competition and potential cost-savings
associated with biosimilars.

XIII. NEW DRUG The Food and Drug


APPLICATION (NDA) Administration's New Drug
FILING AND Application (NDA) is the vehicle in the
PRODUCT LABELING United States through which drug
sponsors formally propose that the
FDA approve a new pharmaceutical
for sale and marketing. Some 30% or
less of initial drug candidates proceed
through the entire multi-year process
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of drug development, concluding with


an approved NDA, if successful.
The goals of the NDA are to provide
enough information to permit FDA
reviewers to establish the complete
history of the candidate drug. Among
facts needed for the application are:
• Patent and manufacturing
information
• Drug safety and specific
effectiveness for its proposed
use(s) when used as directed
• Reports on the design,
compliance, and conclusions of
completed clinical trials by
the Institutional Review Board
• Drug susceptibility to abuse
• Proposed labeling (package
insert) and directions for use

The legal requirement for approval


is "substantial" evidence of
effectiveness demonstrated through
controlled clinical trials. This standard
lies at the heart of the regulatory
program for drugs. Data for the
submission must come from rigorous
clinical trials.]
The trials are typically conducted in
three phases:
• Phase 1: The drug is tested in 20
to 100 healthy volunteers to
determine its safety at low
doses. About 70% of candidate
drugs advance to Phase 2.
• Phase 2: The drug is tested for
both efficacy and safety in up to
several hundred people with the
targeted disease. Some two-
thirds of candidate drugs fail in
Phase 2 clinical trials due to the
drug not being as effective as
anticipated.
• Phase 3: The drug is typically
tested in several hundred to
several thousand people with
the targeted disease in double-
blind, placebo controlled trials
to demonstrate its specific
efficacy. Under 30% of drug
candidates succeed through
Phase 3.
• Phase 4: These
are postmarketing
surveillance trials in several
thousand people taking the drug
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for its intended purpose to


monitor efficacy and safety of
the approved marketed drug.
The legal requirements for safety and
effectiveness have been interpreted
as requiring scientific evidence that
the benefits of a drug outweigh the
risks and that adequate instructions
exist for use, since many drugs
have adverse side effects.
Many approved medications for
serious illnesses (e.g., cancer) have
severe and even life-threatening side
effects. Even relatively safe and well
understood OTC drugs such
as aspirin can be dangerous if used
incorrectly.

The results of the testing program


are codified in an FDA-approved
public document that is called
the product label, package insert or
Full Prescribing Information. The
prescribing information is widely
available on the web, from the
FDA, drug manufacturers, and
frequently inserted into drug
packages. The main purpose of a drug
label is to provide healthcare
providers with adequate information
and directions for the safe use of the
drug.
The documentation required in an NDA
is supposed to tell the drug’s whole
story, including what happened during
clinical tests, what the ingredients of
the drug formulation are, results of
animal studies, how the drug behaves
in the body, and how the company
manufactures, processes and
packages it. Currently, the FDA
decision process lacks transparency,
however, efforts are underway to
standardize the benefit-risk
assessment of new medicines. Once
approval of an NDA is obtained, the
new drug can be legally marketed
starting that day in the U.S.
Of original NDAs submitted in 2009, 94
out of 131 (72%) were in eCTD format.
Once the application is submitted, the
FDA has 60 days to conduct a
preliminary review, which assesses
whether the NDA is "sufficiently
complete to permit a substantive
review." If the FDA finds the NDA
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insufficiently complete (reasons can


vary from a simple administrative
mistake in the application to a
requirement to re-conduct testing),
then the FDA rejects the application by
sending the applicant a Refuse to
File letter, which explains where the
application failed to meet
requirements.
Assuming the FDA finds everything
acceptable, they decide if the NDA
needs a standard or accelerated
review, and communicates
acceptance of the application and
their review choice in another
communication, known as the 74-day
letter. A Standard Review implies an
FDA decision within about 10 months
while a Priority Review should
complete within 6 months.[13] The
decision comes in a Complete
Response Letter.

Biologics, such as vaccines and


many recombinant proteins used in
medical treatments are generally
approved by FDA via a Biologic
License Application (BLA), rather than
an NDA. The manufacture of biologics
is considered to differ fundamentally
from that of less complex chemicals,
requiring a somewhat different
approval process.
Generic drugs that have already been
approved via an NDA submitted by
another maker are approved via
an Abbreviated New Drug
Application (ANDA), which does not
require all of the clinical trials normally
required for a new drug in an
NDA. Most biological drugs, including
a majority of recombinant proteins are
considered ineligible for an ANDA
under current US law. However, a
handful of biologic medicines,
including biosynthetic insulin, growth
hormone, glucagon, calcitonin,
and hyaluronidase are grandfathered
under governance of the Federal Food
Drug and Cosmetics Act, because
these products were already
approved when legislation to regulate
biotechnology medicines later passed
as part of the Public Health Services
Act.
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XIV. DRUG A growing number of innovative


COMMERCIALIZATIO therapies are making their way
N STRATEGIES through the drug development
pipeline, ranging from CAR T-cell
therapies that show promise in
treating certain cancers, to novel
therapies that offer new hope to
patients struggling with neurologic
diseases such as Alzheimer’s,
epilepsy and multiple sclerosis. As
these products move through the
pipeline, there is significant focus on
whether the clinical data will be
compelling enough to achieve
regulatory approval. However, there
has been considerably less discussion
about how these therapies will be
adopted by patients, payers and the
broader healthcare industry once they
are approved.
According to a 2014 McKinsey
report, approximately two-thirds of
new drugs fail to meet prelaunch sales
expectations in Year One, and those
that fall short typically continue to
under-deliver for the next two years.
As an increasing number of these
often high-cost products come to
market, worldwide efforts to contain
healthcare spending are also gaining
traction, as are efforts to drive patient
adherence and reduce adverse
events. In this environment, drug
manufacturers who want their drug
launches to meet or exceed sales
expectations must develop robust
commercialization plans that manage
challenges related to market
conditioning, provider education,
reimbursement, patient access and
support.

COMMERCIALIZATION STRATEGIES

The complete patient experience


Because many of the innovative
therapies in development target
smaller patient populations, often at
various phases in disease
progression, it’s never been more
important for manufacturers to
understand the unique journey their
patients are traveling.

Market conditioning and education


Budgeting and planning for
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thorough, multifaceted market


conditioning and provider education
are also increasingly important.
If a product is first-to-market in a
disease category where there have
been no breakthroughs for a number
of years, nuanced and targeted patient
and provider education will likely be
necessary. Consider, for example, if a
patient population is accustomed to
being treated with inexpensive
medications, such as steroids to
control the symptoms of a medical
issue, is presented with a new product
that will pinpoint and resolve that same
medical issue—at a much higher cost.
The manufacturer needs to allocate
adequate resources for educating the
physician, payer and patient about the
true value of the therapy.

Targeted stakeholders
Today, pharmaceutical companies
that are launching new products have
less opportunity to ‘test, learn from
and refine’ messages due to the rapid
pace at which new therapies are
entering the market. Even when the
science and clinical results are in a
product’s favor, getting a product’s
messaging and services right—the
first time—can make or break the
success of its commercial launch.

Tell the broader story


In today’s value-based care world,
perhaps the most important element of
any commercialization plan is an
effective payer reimbursement
strategy. It starts with collecting the
clinical evidence and health
economics outcomes data that clearly
prove efficacy. It also means
developing effective messages that
communicate the broader value the
product delivers, and being strategic
about the people, tactics and channels
used to communicate with patients
and payers alike.

Overcoming access hurdles


As medications grow more
targeted and therefore more costly,
patient access is also growing
exponentially more complicated. Prior
authorization is often mandated;
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prescribing physicians are often


required to provide specific patient
information (which usually varies by
payer, further complicating the
process) before writing the
prescription; and payers are
increasingly requiring evidence that
less expensive medications have failed
before authorizing a patient to receive
more costly and targeted ones. Many
of these prescriptions are initially
denied, leading the provider to file an
appeal, resulting in more
administrative work for the practice.

Wrap-around services
Manufacturers need to connect
patients with wrap-around services
that will help drive utilization and
support compliance, particularly when
medications are targeted toward small
patient populations. And, because
many of these treatments are
approved with a Risk Evaluation and
Mitigation Strategy (REMS),
manufacturers are required to
maintain patient registries, collect
data on patients who experience
adverse events, and report that data
back to FDA. These requirements vary
by therapy—in some cases
manufacturers may need to collect
patient data for as long as 10 years
after treatment. Successful
commercialization plans support
patients in improving compliance and
managing side effects, while also
collecting the related REMS data.
XV. THE VALUE OF Anticancer Drugs Market research
MARKETING report gives an expert, knowledgeable
RESEARCH and in-depth study of the major
Anticancer Drugs Market leading
players along with the company
profiles and strategies adopted by
them. this enables the buyer to gain a
telescopic view of the competitive
landscape and design the strategies
accordingly. A separate section with
Anticancer Drugs industry key players
is included within the report, which
provides a comprehensive analysis of
CAGR, value, cost, gross, revenue,
product picture, specifications,
company profile, and contact info.

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