UNIT I: INTRODUCTION TO DRUG DISCOVERY AND DEVELOPMENT

LEARNING OBJECTIVES:
At the end of the lesson, the student will be able to:
a. Understand the background and development of product research.
b. Demonstrate knowledge in understanding basic biology of diseases.
INTRODUCTION

Drug Discovery and Development (DDD) is a significant approach to the overall advancement of the
healthcare community. Yet, it is broad and complex. From the pre-discovery phase up to the Post Marketing
Surveillance involves a lot of procedures and protocols that must be followed throughout the process and may
even take more than 10 years. In this unit, we will discuss the overview of DDD, ethnopharmacological
characteristics of natural product research and understanding the biology of disease.

Overview of Drug Discovery and Development

Medical and pharmaceutical research provides a basis for the development of new therapeutic
approaches to human and animal disease. This process of drug discovery research can be Basic (seeking
an understanding of biological phenomena that are unknown) or applied (using principles that are
‘Anown to produce a desired new product or effect). In either case, drug discovery research results from
an unmet clinical need, a recognized deficit in treatment options. Drug discovery is the process by which drugs
are discovered or designed. In the past most drugs were discovered either by identification of the active
ingredient from traditional remedies or by serendipitous discovery. Today we know how disease and infection
are controlled at the molecular and physiological level. Drug discovery involves the identification of candidates,
synthesis, characterization, screening, and assays for therapeutic efficacy. Drug discovery is stil! a lengthy,
expensive, difficult, and inefficient process with a low rate of new therapeutic discovery. The outcome of a
successful drug discovery program is the generation of a therapeutic entity where none previously existed or
the replacement of established therapies in favor of a newer modality that is safer and more efficacious.

The main function of the phanmaceutical industry is to create products (i.e., drugs that have an impact on health
care). Drug development is the process of bringing a new drug to the market once a lead compound has been
identified through drug discovery. Drug development includes preclinical research (microorganisms/animal) and
clinical trials (human). Products of this type can be foreseen to some extent through knowledge and study and
thus are amenable to planned research and development (R&D). For example, if the cause of a disease has
been identified as an infection by a microorganism, a search can be undertaken for an agent that will prevent
or cure the infection. However, in some instances, the etiology of a disease is unknown despite intensive
investigation. In this situation, the pathway to a satisfactory cure or method of prevention cannot be foreseen
or forecast. In such cases, products may only be developed after application of careful investigations, from a
revolutionary new approach, or perhaps from a serendipitous finding.

The major objective of research in the pharmaceutical industry is to produce safe drugs that
prevent, cure, or ameliorate disease. Interim research
goals that Jjead to this major objective are
fo:
1. Understand the molecular basis of biological mechanisms in health and disease.
2. Develop new biological testing procedures relevantto human and veterinary medicine.
3. Develop a quantitative understanding of the interaction of drugs with key biological systems, leading to
the more rational design of drugs.
4, Understand the absorption, transport, and mode of action of drugs.
Develop drugs of low toxicity, reproducible delivery, and high specificity for a given pathological state
or target organ.
 It is the mission of pharmaceutical research companies to take the path from understandinga disease to
bringing a safe and effective new treatment to patients. Scientists work to piece together the basic causes of
disease at the level of genes, proteins and cells. Out of this understanding emerge “targets,” which potential
new drugs might be able to affect. Putting everything into perspective takes about an average of 10-15 years
just to develop one new medicine from the earliest stages of discovery to the time it is available for treating
patients.

Researcherswork to:
A. validate these targets,
B. discover the right molecule (potential drug) to interact with the target chosen,
Cc. test the new compound in the lab and clinic for safety and efficacy and
D. gain approval and get the new drug into the hands of doctors and patients.

For the first time in history, scientists are beginning to understand the inner workings of human disease at
the molecular level. Recent advances in genomics, proteomics and computational power present new ways to
understand illness. The task of discovering and developing safe and effective drugs is even more promising as
our knowledge of disease increases. As scientists work to harness this knowledge, it is becoming
an increasingly
challenging undertaking.

The average cost to research and develop each successful drug is estimated to be $800 million
fo $1 Billion. This number includes the cost of the thousands of failures: For every 5,000- 10,000 compounds
that enter the research and development (R&D) pipeline, ultimately
only one receives approval.

These numbers defy imagination, buta deeper understanding

of the R&D process can explain why so
many compounds don’t make it and why it takes such a /Jarge, fengthy effort to get one medicine to
patients. Success requires immense resources — the best scientific minds, highly sophisticated
technology and complex project management. It also takes persistence and, sometimes, fuck.
Ultimately, though, the process of drug discovery brings hope and relief to millions
of patients.

SURVEELLANCE
ST-MAR KETING

The discovery process includes all early research to identify a new drug candidate and testing it in the lab.
The process takes approximately 3-6 years. By the end, researchers hope to have a promising candidate drug
to test in people.

Modern drug discovery is the product of cooperation. Many sectors contribute, particularly in building
the basic science foundations. Both public and private organizations play unique but increasingly interdependent
roles in translating basic research into medicine. Major biopharmaceutical companies are the primary source of
R&D funding for new medicines, both for projects in their own laboratories as well as for research licensed from
other sectors. Smaller companies also drive innovation, conducting basic research, drug discovery, preclinical
experiments and, in some cases, Clinical trials. The National Institutes of Health (NIH) provides leadership and
funding support to universities, medical schools, research centers and other nonprofit institutions, and
stimulates basic research and early- stage development of technologies that enable further targeted drug
discovery and development.

Typically, researchers discover new drugs through:

 « New insights into a disease process that allow researchers to design a product to stop or reverse the
effects of the disease.
« Many tests of molecular compounds to find possible beneficial effects against any of a large number
of diseases.
e Existing treatments that have unanticipated effects.
« New technologies, such as those that provide new ways to target medical products to specific sites
within the body or to manipulate genetic material.

Ethnopharmacology

Drug discovery from Ethnopharmacology and Ethnomedicine literally begins with an ethnopharmacologist
or plant botanist. This approach is based on botany, chemistry and pharmacology and other various disciplines.
Based on these considerations, Ethnopharmacology is defined as ‘the Jinterdisciplinary scientific
exploration of Biologically active agents traditionally employed or observed by man’
Ethnophanmacology is the cross-cultural study of how people derive medicines from plants, animals, fungi,
or other naturally occurring resources. Up to now, the field has focused mostly on developing drugs based on
the medicinal use of plants by indigenous people. The discipline researches human interactions with biologically
active plants (and other living things) as medicines, poisons, and intoxicants with a primary focus on indigenous
and non-Western cultures. Ethnopharmacology seeks to document plants and animals used by various cultures,
and describe their use and preparation. These plants and their preparations are then studied to identify, isolate,
and characterize the active compounds responsible for the plant actions on people.

Due to the potential for profit, some drug companies have teamed up with botanists, anthropologists,
biochemists, conservation organizations, and governments of less-developed countries to protect biologically
diverse areas and search for new drugs and this has renewed the interest of younger indigenous people in
preserving their culture, and led to grass-roots, indigenous-based, entrepreneurial businesses targeting
altemative medicine markets.

An example of ethnopharmacological study is the discovery of reserpine from a traditional medicinal plant
(Rauvolfia serpentina). This plant which is called Chota-chand in Hindi, has been used by local people of
Himalayan Mountains for snakebite. A local legend claims that in ancient times mongooses were observed to
feed on the plant before engaging in combat with cobra. Copying the reputed activity of the mongoose, local
people found that the shrub could serve as a potent antidote to snakebite. In Bihar Province of India people
use the plant to treat insanity, epilepsy and insomnia. Reserpine isolated from Aauvolfa is a potent drug for
hypertension. Interestingly, there is a similar legend among Turkmens of Iran concerning a different plant,
Verbascum, called Segher-ghureg in Turkmeni. Verbascurm species are also used to treat snakebites. Despite
the Aauvolfia which finally captured the attention of scientists, Verbascurn sp. are still waiting for scientists to
have a closer and detailed look on them.

Ethnophar-macology as a science bridges the gap between natural sciences and anthropology, should look at
symbolic and cognitive aspects. People may select plants because of their specific pharmacological properties,
but also because of the symbolic power they may believe is in a plant. Understanding these aspects requires
cognitive and symbolic analysis of field data

Natural Product Research

Natural products are the sources of pharmacologically active agents and recent progress in discovering NCEs
has resulted in new drugs that are useful in treating cancer, viral, bacterial and immunosuppressive diseases
(Butler, 2005). Discovering new chemical entities (NCEs) from plant sources has been the first mind stuck for
the plant chemists in both academics and industry. Compounds of natural origin still play a major role in
development of new drugs. About 40% of the world’s best selling drugs are derived directly or indirectly from
compounds of plant origin. Paclitaxel, world’s largest selling anticancer drug is the synthetic derivative of Taxol,
isolated from Taxus brevifolia (Newman & Cragg, 2007).
Opportunities in the field of natural product research:
1. Vast literature in the field of plant studies were reported in the traditional Ayurvedic medical scriptures
like Rig veda, Charaka sambhita etc. but these literature was not used by natural chemists in this modern
era. Now there is a need to use these reference data to understand pharmacology and hence describing
the phytochemistry behind the pharmacological aspects of plant materials.
2. Inthe Ayurvedic system of medicine, traditional people used plants in their surroundings for preventing
them from various diseases. In short, the Ayurvedic system is the only system of medicine which claims
direct health benefits of plant material on human beings.
3. Lack of standardization report on medicinal plants.
4. Lack of Chemical fingerprints of medicinal plants.

Challenges in the field of natural product research:

1. Lack
of funds and interest
by the government of the developing countries for discovery of natural
products.
2. It is very difficult
to isolate and identify new compounds from the plant extracts and also it is very time
consuming.
3. Multi Component Analysis (MCA) of plant extracts.

Testing and identifying biologically active compounds from plant extracts should be accomplished with
defining the structure of that particular compound which is performed by using modern phytochemical and
analytical techniques. Liquid Chromatography (LC) and Gas Chromatography (GC), Mass Spectroscopy (MS) and
Nuclear Magnetic Resonance (NMR) are methods that are very helpful in Multi Component Analysis (MCA) in
the herbal extracts. These techniques are sensitive, selective and fast where simultaneous separations as well
as identification of separated components in a mixture are possible. Globally, there is an increasing trend
towards natural product research due to large number of opportunities, modernization of analytical tools and
availability of validated methods of High Performance Liquid Chromatography (HPLC), GC, GC/MS, LC/MS,
LC/MS/NMR, LC/MS/MS. These analytical tools are the important milestones in the natural product
characterization, identification and quantification.
Ever increasing cost and increasing failure at the end of discovery make medicine unaffordable to the
developing countries. The natural products are the new approaches which are more attractive and also with
advancement in the analytical methodologies make the research more innovative for drug discovery. It is known
to all of us that the drug discovery pipeline in modern drug discovery is getting dry and this modern world is
looking again towards natural products with great expectations.
Understanding the Disease
Before any potential new medicine can be discovered, scientists work to understand the disease to be treated
as well as possible, and to unravel the underlying cause of the condition. They try to understand how the genes
are altered, how that affects the proteins they encode and how thase proteins interact with each other in living
cells, how those affected cells change the specific tissue they are in and finally how the disease affects the
entire patient. This Knowledge
is the basis for treating the problem. Researchers from government, academia and industry all contribute to
this knowledge base. However, even with new tools and insights, this research takes many years of work and,
too often, leads to frustrating dead ends. And even if the research is successful, it will take many more years
of work to turn this basic understanding of what causes a disease intoa néw treatment.

Recent advances in molecular medicine and powerful tools to enhance computational capacity are enabling
researchers to better understand the inner workings of human disease at the molecular level. As our knowledge
of disease increases, so does the potential of discovering and developing innovative medicines.
Biopharmaceutical companies perform basic research independently and in partnership with researchers and
others from across the biomedical research ecosystem, including disease foundations and patient groups,
venture capital, and pre-competitive consortia.

Models for Studying Diseases

The following tools help researchers gain insights into how disease develops.

1. Cell cultures: By growing both diseased and healthy cells in cell cultures, researchers can study
differences in cellular processes and protein expression.
2. Cross-species studies: Genes and proteins found in humans may also be found in other species. The
functions of many human genes have been revealed by studying parallel genes in other organisms.
3. Bioinformatics: The scientific community generates huge volumes of biological data daily.
Bioinformatics helps organize that data to form a clearer picture of the activity of normal and diseased
cells.
4. Biomarkers: These are substances, often proteins, that can be used for measuring a biological
function, identifying a disease process, or determining responses to a therapy. They also can be used
for diagnosis, for prognosis, and for guiding treatment.
5. Proteomics: Proteomics is the study of protein activity within a given cell, tissue or organism. Changes
in protein activity can shed light on the disease process and the impact of medicines under study.
 UNIT II: DRUG DISCOVERY AND DEVELOPMENT AS A PROCESS
LEARNING OBJECTIVES:
a. To demonstrate knowledge on discovery of lead compounds.
b. To understand the significance of early safety tests and technology in developing lead compounds.
c. To identify the different characteristics to consider in conducting preformulation studies.
INTRODUCTION

This chapter tackles on the different processes and principles that are involved in Drug Discovery and
Development specifically the discovery, optimization, validation, early safety test of the lead compound and
preformulation studies for the lead compound.

Target Identification and Validation

Anmed with an idea, researchers work to identify biological targets for a potential medicine. A drug target is a
malecular structure in the body that, when it interacts with a potential drug compound, produces a clinical effect
(treatment or prevention of a disease, for example). Once they have enough understanding of the underlying
cause of a disease, pharmaceutical researchers select a “target” for a potential new medicine. A target is
generally a single molecule, such as a gene or protein, which is involved in a particular disease. Even at this
early stage in drug discovery it is critical that researchers pick a target that is “druggable,” i-e., one that can
potentially interact with and be affected by a drug molecule. The investigators conduct studies in cells, tissues
and animal models to determine whether the target can be influenced by a medicine.

After choosing a potential target, scientists must show that it actually is involved in the disease and can be
acted upon by a drug. Researchers demonstrate that a particular target is relevant to the disease being studied
through complicated experiments in both living cells and in animal models of disease. Target validation is crucial
to help scientists identify the most promising approaches before going into the laboratory to develop potential
drug candidates, increasing the efficiency and effectiveness of the R&D process. Once identified, the target then
needs to be fully prosecuted. Validation techniques range from 4 vitro tools through the use of whole animal
models, to modulation of a desired target in disease patents. While each approach is valid in its own right,
confidence in the observed outcome is significantly increased by a multi-validation approach.

(Spectrum of target validation techniques.)

Lead Identification
Armed with their understanding of the disease, scientists are ready to begin looking for a drug. They search
for a molecule, or “lead compound,” that may act on their target to alter the disease course. If successful
over long odds and years of testing, the lead compound can ultimately becomea new medicine.

These are a few ways to find a lead compound:

1. Nature: Until recently, scientists usually tunned to nature to find interesting compounds for fighting
disease. Bacteria found in soil and moldy plants both led to important new treatments, for example.
Nature still offers many useful substances, but now there are other ways to approach drug discovery.

2. De novo: The word De novo means “scratch”. It does mean that scientists start from the beginning.
They can use sophisticated computer modeling to predict what type of molecule may work. It is done
by utilizing the 3D structure of the receptorto come up with new molecules that can bind or suit the
receptor and involves structural determination of the lead target complexes using molecular modeling
‘tools.
 Protien structure Build model of ac os 6Out@e eases
binding site

ses
’

‘
(Principle of De novo Drug Design)

3. High-throughput Screening(HTS): This process is the most common way that leads are usually
found. Advances in robotics and computational power allow researchers to test hundreds of thousands
of compounds against the target to identify any that might be promising. Based on the results, several
lead compounds are usually selected for further study. This is a key process used in drug discovery to
identify hits from compound libraries that may become leads for medicinal chemistry optimization.

High-Throughput Screening
Speeding Up CF Drug Discovery
Sermereng Aassy

>10,000 Primary assayscay

SAR based
Mectcnal
Cheesy

Coneteny of ewer aren ees CFTR Moctator Drug

(Principle of HTS being used in Cystic Fibrosis Transmembrane Conductance Regulator (CFTR)
modulator drug discovery by Vertex Pharmaceuticals)

4. Biotechnology: Scientists can also genetically engineer living systems to produce disease-fighting
biological molecules. Biotechnological methods have become an important tool in pharmaceutical drug
research and development. Today approximately 15 % of drug revenues are derived from
biopharmaceuticals. The most relevant indications are oncology and metabolic disorders.

Early Safety Test for the Lead Compound

Lead compounds go through a series of tests to provide an early assessment of the safety of the lead
compound. Scientists
test Absorption, Distribution, Metabolism, Excretion and Toxicological
(ADME/Tox) properties, or “pharmacokinetics,”
of each bead.

Successful drugs must be:

A. Absorbed into the bloodstream

B. Distributed to the proper site of action in the body
C. Metabolized efficiently and effectively
D. Successfully excreted from the body
E. Demonstrated to be not toxic.

These studies help researchers prioritize lead compounds early in the discovery process. ADME/Toxicity studies
are performed in living cells, in animals and via computational models.

Lead Optimization:
Alter the structure of lead candidates
to improve properties

Lead compounds that survive the initial screening are then “optimized,” or altered to make them more effective
and safer. By changing the structure of a compound, scientists can give it different properties. They can also
modify the therapeutic index of the drug in order for it to be eligible for clinical trials.

For example, they can make it less likely to interact with other chemical pathways in the body, thus reducing
the potential
for side effects. Hundreds of different variations or “analogues” of the initial leads are made and
tested. Teams of biologists and chemists work together closely: The biologists test the effects of analoques on
 biological systems while the chemists take this information to make additional alterations that are then retested
by the biologists. The resulting compound is the candidate drug.

Even at this early stage, researchers begin to think about how the drug will be made, considering formulation
(the recipe for making a drug, including inactive ingredients used to hold it together and allow it to dissolve at
the right time), delivery mechanism (the way the drug is taken by mouth, injection, inhaler) and large-scale
manufacturing (how you make the drug in large quantities).

Computer-aided Drug Design (CADD)

Drug Design is the inventive process of finding néw medications based on the Knowledge of a biological target.
It involves the design of molecules that are complementary in shape and charge to the biomolecular target with
which they interact and therefore will bind to it. Drug design frequently but not necessarily relies on computer
modeling techniques. This type of modeling is sometimes referred to as Computer-Aided Drug Design. When
the disease process is understood at the molecular level and the target molecule(s) are defined, drugs can be
designed specifically to interact with the target molecule in such a way as to disrupt the disease.

New techniques have revolutionized the ability of researchers to optimize potential drug molecules. Thanks to
technologies such as magnetic resonance imaging and X-ray crystallography, along with powerful computer
modeling capabilities, chemists can actually “see” the target in three dimensions and design potential drugs to
more powerfully bind to the parts of the target where they can be most effective. In addition, new chemistry
techniques help scientists to synthesize the new compounds quickly.
Computer aided drug design (CADD) is an evolving cascade of research areas encompassing many facets.
Computer-aided drug design (CADD) is an exciting and diverse discipline where various aspects of applied and
basic research merge and stimulate each other. The theoretical basis of CADD involves quantum mechanics and
molecular modeling studies like structure based drug design; ligand-based drug design; database searching and
binding affinity based on the knowledge of a biological target.
(CADD represents computational methods and resources that are used to facilitate the design and discovery of
new tHheraneutic solutions.

Drug design with the help of computers may be used at any of the following stages of drug
discovery:

A. Hit identification using virtual screening (structure- or ligand-based design)

B. Hit-to-lead optimization of affinity and selectivity (structure-based design, QSAR, etc.)
Cc. Lead optimization: optimization of other pharmaceutical properties while maintaining affinity.

=<
cata ==} =
/
(Basic CADD workflow in drug discovery. Wet-lab, SBDD and LBDD CADD techniques are outlined in solid
lines, dashed lines or dotted lines, respectively. Double headed arrows indicate the two techniques can be
used interactively in several iterative rounds of ligand design.)

Goals of CADD:
1. To shift from:
a. Random screening against disease assays
b. Natural products, synthetic chemicals
2. To:
a. Rational drug design and testing
b. Speed-up screening process
 c. Efficient screening (focused, target directed)
d. De novo design (target directed)
e. Integration of testing into design process
f. Fail drugs fast (remove hopeless ones as early as possible)

Toward the design of new drugs, computer-aided drug design (CADD) can be combined with wet-lab techniques
to elucidate the mechanism of drug resistance, to search for new antibiotic targets and to design novel
antibiotics for both known and new targets. Notably CADD methods can produce an atomic level structure-
activity relationship (SAR) used to facilitate the drug design process thereby minimizing time and costs.

Two Types
of Drug Design
1. Structure-based
a. relies on knowledge of the three dimensional structure of the biological target obtained through

i. X-ray crystallography
ii. Nuclear Magnetic Resonance (NMR) spectroscopy.
b. If an experimental structure of a target is not available, it may be possible to create a homology
model of the target based on the experimental structure of a related protein. Homology
modeling, also known as comparative modeling of protein, refers to constructing an atomic
resolution model of the "target" and an experimental three-dimensional structure of a related
homologous protein (the "template".
c. Using the structure of the biological target, candidate drugs that are predicted to bind with high
affinity and selectivity to the target may be designed using:
i. Interactive graphics Intelligence of a medicinal chemist.
ii. Various automated computational procedures may be used to suggest new drug
candidates.

2. Ligand-based
@ Relies on knowledge of other molecules that bind to the biological target of interest. used ta
derive a pharmacophore model that defines the minimum necessary structural characteristics
a molecule must possess in order to bind to the target.
b. JA model of the biological target may be built based on the knowledge of what binds to it, and
this. model in turn may be Used to design new molecular entities that interact with the target.
c Alternatively, a quantitatwe sbtructure-actvity relationship (QSAR), in which a correlation
between calculated properties of molecules and their expenmentally determined biological
activity, may be derived. These OSAR. relationships in turn may be used to predict the activity
of new analogs.

Pre-formulation Studies

Prefornmulation studies were evolved in 1950 & earhy 1960. Preformulation testing is the first step in the rational
development of dosage forms of a drug substance. [t can be defined as an investigation of physical and chemical
Properties of a drug substance alone and when combined with excipients. The overall objective of
preformulaton testing is to qenerate information useful to the formulator in developing stable and bioavailable
dosage forms that can be mass produced. Preformulation investigations are designed to deliver all mecessary
data especially physicochemical, physico- mechanical and bio pharmaceutical properties of drug substances,
excipients
and packaging materials.

Prefornmulation studies help in assessing the “drugability’ of a molecule. Preformulation can thus be considered
25 a ontical decdsion-making tool during both — drug discovery and development phase. A comprehensive
understanding of physicochemical properties and its effect on biological performance, allows selection of
potential lead molecules and in identification of drug delivery challenges.

Objectives and Goals of Preformulation

Studies
I. Objectives
A. To develop the elegant dosage forms (stable, effective & safe).
B. It if important to have an understanding of the physical description of 4 drug substance
before dosage form development.
Cc. It is the 1st step in rational development of a dosage form of a drug subt before dosage form
development.
. Goals
A. To establish
the physico-chemical parameters of new drug substamces.
 To establish the physical characteristics

mong
To establish the kinetic rate profile.
To establish the compatibility with the common excipient.
To choose the correct form of a drug substance.

PREFORMULATION PARAMETERS
1. Physical Characteristics
Organoleptic properties
Bulk characterstics
Solid state characteristics.
Flow properties
Densities
Compressibility
Crystalline
Polymorphism
Hygroscopicity
Solubility analysis
Tonization constant{Pka)
Partition coefficient

Thermal effect
Common bon effect (Ksp)
Dissolution
Stability analysis
Solution-state stability
Solid-state stability
i

Drug-excipients compatibility
2. Chemical Characteristics
Hydrolysis
~"pangoo

UNIT III: PRECLINICAL PHASE

Objectives:
a. To identify the steps involved in the preclinical phase of drug discovery and development.
b. To demonstrate a complete understanding on the importance of toxicity screening in DDD.
c. To demonstrate proper ethical protocols and principles in conducting human and animal testing.
INTRODUCTION

In this chapter, the concept of preclinical phase will be discussed. This includes the biologic activity test,
chemical synthesis, formulation studies, stability testing and safety test on animal and human subjects.
 LEARNING CONTENT
Preclinical Phase
Many of the lead compound's critical properties. This team might continue to work with the compound
throughout the entire development process or the development responsibilities might be transferred to another
group of scientists during the clinical testing phase.

Preclinical testing includes:

I. Discovery testing to ensure biological activity in vivo
2. Chemical synthesis and scale-up to ensure adequate quantities of high purity can be made
3. Formulation development and stability testing to characterize various chemical properties,
developthe initial drug delivery system, and determine the stabilityof the compound
4, Animal safety testing to ensure limited toxicities of the lead agent.

At this stage of the development process, good laboratory practices (GLPs) are followed and Qualifications of
personnel and requirements for standard operating procedures are specified. During discovery testing, the
specifics of the compound's properties, such as the mechanism of action in. animal models, compound specificity,
duration of action, and structure-activity relationships, are determined. Adequate quantities
of the new chemical
compound must be produced at a high level of purity. Impurities present at concentrations greater than 0.1%
must be characterized and tested for toxicity. The physicochemical properties of the active compound are
determined, and development of the drug delivery system to be used in human testing begins. Animal testing
provides initial data regarding the absorption, distribution, metabolism, and excretion (ADME) in a living system.
Possible side effects and toxicities are noted. Toxicity studies of at least the same duration as the proposed
human testing and a minimum of two weeks must be completed. Active and inactive metabolites must be
characterized. Often, the most appropriate animal model to predict human response is not known, thus toxicity
studies are conducted in at least 2 animal species, one rodent and one nonrodent, to obtain a comprehensive
view of the potential toxicity. Early absorption, distribution, metabolism, and excretion or toxicity problems may
be corrected by slight modifications in the chemical structure of the new entity.

Animals should be given the new drug product by the same route intended for humans. Certain dosage forms,
such as aerosol, nasal, or buccal delivery systems, might be difficult to administer to animals. In these
circumstances, alternative drug delivery routes may be used, and the selected route of administration should
ensure sufficient exposure to the new chemical entity. During animal safety testing, dosing studies are
conducted, and the highest no-effect dose is determined. In addition to dose, plasma concentrations of the
drug are followed, and noted toxicities are correlated to dose and/or plasma concentration. Generally, once
discovery testing shows therapeutic promise, the chemical synthesis, formulation development, and animal
safety testing occur concurrently (see Figure below). Although resources may be wasted on earlier failures,
successful candidates will be ready for human testing more quickly. The administration of drugs in humans at
the earliest time possible ultimately saves valuable resources, as highly toxic compounds can be eliminated and
alternative lead compounds can be developed. Additional preclinical studies may be conducted during clinical
testing to support larger trials and, eventually, the marketing of the drug product. Formulation development
continues throughout the process, and the data gained from both animal and human testing allow for
optimization of the drug delivery system. It is imperative to identify and resolve formulation problems early in
the development process, as unresolved problems will surely reemerge later, costing the company both time
and money as clinical testing is delayed. More chronic animal exposure experiments are conducted to support
further clinical testing,
 ‘Clinical
Chemical | Hold
Synthesis and
Scale-Up Tasting

Drug Decovery i _" y oniulation

and ‘ peeioeeert A IND
Lead Compound esl and Stability Application Filing
Selection
Safety Testing in
Aun Ss

Ind
Approval

Phase | Phase ll Phase ill

‘Clinical Trials Clinical Trials Clinical Triaks
(20-20 healthy (100-300 patient (1000-3000 patient
volunteers) wun eer volunteers)

NDA
Filimg
|
J ! 1
FOoA FO Ganditional FoOA,
Disapproval Approval Approval

Lesecencsas +] Market
Post-Approval Safety
Reports to FDA |. ____]

Drug Safety Evaluation

With one or more optimized compounds in hand, researchers turn their attention to testing them extensively to
determine if they should moveon to testing in humans. Scientists carry out in vitro and in vivo tests. In vitro
tests are experiments conducted in the lab, usually carriéd out in test tubesand beakers (“vitro” is “glass” in
Latin) and in vivo studies are those in living cell cultures and animal models (“vivo"
is “life” in Latin). Scientists
try to understand how the drug works and what its safety profile looks like.

The U.S. Food and Drug Administration (FDA) requires extremely thorough testing before the candidate drug
can be studied in humans. During this stage researchers also must work out how to make large enough
quantities
of the drug for clinical trials. Techniques
for making a drug in the lab on a small scale do not translate
easily
to larger production. This is the first scale up. The drug will need to be scaled up even more
if it is
approved for use in the general patient population. At the end of several years of intensive work, the discovery
phase concludes. After starting with approximately 5,000 to 10,000 compounds, scientists now have winnowed
the group down to between one and five molecules, “candidate drugs,” which will be studied in clinical trials.

Toxicity testing or studies of new compounds is essential for the drug development process. The
preclinical toxicity testing on various biological systems reveals the species-, organ- and dose- specific toxic
effects of an investigational product. The toxicity of substances can be observed by (a) studying the accidental
exposures
to a substance (®@) Jn witro studies using celfs/ cell lines (c) in vive exposure
on
experimental animals. The preclinical toxicity testing helps to calculate “No Observed Adverse Effect Level”
which
is needed to initiate
the clinical evaluation
of investigational products. Usually toxicants are classified
based on their chemical nature, mode of action, or dass (exposure class and use class). The exposure class
classifies toxicants as occurring in food, air, water, or soil. The use class classifies drugs as drugs of abuse,
therapeutic drugs, agriculture chemicals, food additives, pesticides, plant toxins (phytotoxins), and cosmetics.
Usually toxicants are classified based on their chemical nature, mode of action, or class (exposure class and use
class). The exposure class classifies toxicants as occurring in food, air, water, or soil. The use class classifies
drugs as drugs
of abuse, therapeutic drugs, agriculture chemicals, food additives, pesticides, plant toxins
(phytotosins),
and onsmeetics.

In vivo methods.

47 wire toxicity testing should build upon test models that are relevant for the species to be protected. Proper
test development requires well defined test compounds
with high quality
47 wre data (gold standard) and cell
systems that mimic Ja wit the key ewents that are known to ocour én vive. This type of screening is carried out
in the laboratory ware in the absence of living animals.

In vitro methods
The animal widely used for this method are rodents (mice, rats, rabbits, hamsters), nvost
of which are raised
commernrcdally to offer the pharmacologists uniformity of genetic, nutritional, sex and health standards.

Toxicity Studies:

I. Acute toxicity testing

A. Acute toxicity testing is carried out to determine the effect of a single dose on a particular
animal species. In general, it is recommended
that acute toxicity testing be carried
out with
two different animal species (one rodent and one monrodent). In acute toxicological testing,
the investigational product is administered at different dose levels, and the effect is observed
for 14 days. All mortalities caused by the investigational product during the experimental period
are recorded and morphological, biochemical, pathological, and histological changes iin the dead
animals
are investigated.
It. Acube toxicity testing for inhalation
A. Acute inhalation toxicity testing is performed for aerosol-like preparations. Rats are the most
preferred animal species. The animals are acclimatized to laboratory conditions (temperature
preferably 22°C
+ 25C). They are maintained in an air flow of 12—15 air changes per hour with
adequate oxygen (19%/h). The animal is exposed to the test substance for a minimum of 4h,
and then it is monitored
for 14 days. Food
is withheld during the exposure period, and water
may be withheld under certain conditions. During the observation pernod, the animal is observed
for tremors, convulsions, salivation, diarrhea, lethargy, sleep, and coma. Mortality during the
exposure and observation period & noted. Dead animals are examined for histological and
Pathological changes.
At the end of the study, the animak are sacrificed, and pathological
changes
are evaluated

Itt. Acube toxicity testing for topical preparations

A. The eye irritation test and skin imitation test are very important for topical preparations. Dermal
and ophthalmic preparations can be tested using Draize tests. The Draize eye initancy test and
the Draize skin irritancy test are used to measure the harmfulness of chemicals and
pharmaceutical substances in rabbits and guinea pigs. In the eye irritation test, 0.5 ml of a test
substance is. administered to an animal's eyes, and the animal is restrained for 4h. Redness,
swelling, discharge, ulceration, hemorrhage,
and blindness are assessed and monitored
for 14
days.
B. In the skin invitation test, 0.5 9g of a test substance is applied to the surface of an animal's skin.
During the observation period (14 days), signs such as erythema and edema are assessed.
Some alternative fv eiro testing methods are available that can be used in place of the Draie
eye initamcy
test. At the end of the study, the animak are sacrificed
and pathological changes
are evaluated.
Iv. Skin sensitization tests
A. Skin sensitization tests are carried out using the guinea pig as a model. Skin sensitization is
assessed using the Draize test, open epicutaneous test, optimization test, split adjuvant test,
guinea pig maximization test (GPMT}), Buehler test, and murine bocal hymiph mode assay (LLNA).
The LLNA method is used as an alternative to the guinea pig Draize test, and it is widely
accepted that this method meets regulatory requirements. In the LLNA test, the test substance
is applied on the surface of the ears of a mouse for three consecutive days, and the proliferation
of lymphocytes in the draining lymph node is measured at the end.
W. Mutagenicity testing
A. Mutagenicity testing & used to assess submicroscopic changes in the base sequence of DNA,
chromosomal aberrations, and structural aberrations in DNA imcluding duplications, insertions,
inversions, and translocations. Certain types of mutations result in carcinogenesis (alteration im
 proto-oncogenes of tumor suppressor gene mutation), and so the determination of the
mutagenicity is essential in the drug development process. Jin wine testing is carried out in two
or three different bacteria and mammalian cells to cover the end points of gene mutations,
clastogenicity, and aneuploidy. The test generally includesa bacterial reverse mutation assay.
The choice of an additional test depends on the chemical structure/class of the substance. Ji
Mwive mutagenicity which is dose dependent is used to determine the case-by-case basis risk
assessment of the test substances. Mutagenicity studies with transgenic animals are more
appropriate assay techniques to determine the toxicity of a test substance.
WI. Carcinogenicity testing
A. Both rodents and mon rodent animal species may be used in carcinogenicity testing. The tests
are carried out ower the greater portion of an animal's lifespan. During and after exposure
to
test substances, the experimental animals are observed for signs of toxicity and development
of tumors. If these are mot found, a test may be terminated after 18 months in the case of mice
and hamsters and after 24 months with rats. If the animals are healthy, hematological analysis
is performed after the 12 months and the 18 months, respectively, and the study is terminated.
The animak& are sacrificed, and gross pathological changes are moted and histopathological
studies are carned out on all the tissues.

Ethical Considerations in Human and Animal Experimentation

Before using animak, it is mandatory for researchers to clearly clarify their scientific purpose. There should be
@ reasonable expectation that the research will result in increasing scientific knowledge in different aspect: of
biomedidme
and also will increase understanding of the species under study or provide results that coulkd
improwe
the quality of health or welfare
of humans or other animals.
The scientific purpose
of the reseanch
should be of sufficient potential significance to justify the use of animalk. The species chosen for study should
be the best suited to answer the question(s) posed. Moreover, it is noteworthy that good experimental design
helps reduce the number of animak used in research since they allow scientists
to collect data using the
minimum number of animals required. However, a sufficient number must be used
to enable precise statistical
analysis and results, prewenting the repetition of experiments and the consequent
need to use more animals.

All procedures on animals are to be reviewed by a local animal care committee to ensure that the procedures
are appropriate and humane. In the event that it is mot possible to constitute an appropriate local animal care
committee, scientists are encouraged to seek advice from a corresponding committee of a cooperative
institution. Responsibilites. for the conditions under which animak are kept, both within and outside of the
context
of active experimentation or teaching, rests with the researcher under the supervision of the animal
care committee and with individuals appointed by the institution to oversee animal care.

Ethical Requirements For Human Testing

“When people are invited to participate

in research, there is a strong belief that it should be their choice
based on their understanding of what the study is about, and what the risks and benefits of the study are,”
said Dr. Christine Grady, chief of the NIH Clinical Center Department of Bioethics, to Clinical Center Radio in a
podcast.

Clinical research advances the understanding of science and promotes human health. However, it is important
to remember the individuals who volunteer to participate in research. There are precautions researchers can
take = in the planning, implementation and follow-up of studies — to protect these participants in research.
Ethical guidelines are established for clinical research to protect patient volunteers and to preserve the
integrity of the science.

The National Ethical Guidelines is a distinct manifestation of the country's commitment to the protection of the
rights, welfare, and well-being of human participants in research, and to research integrity. Ethical
assessment of health and health-related research requires a framework that may consist of principles, values,
Guidelines for Ethical Conduct in the Care of Human subjects (Clinical Phase) in Drug Testing
Social Value

The participation of human beings in research can only be justified if the study has social value. Social
value refers
to the relevance of the study to an existing social or health problem such that the results
are expected to bring about a better understanding of related issues, or contribute to the pramotion
of well-being of individuals, their families, and communities.
The significance of the study shall be clearly described in a separate section of the protocol with an
accurate and updated description of the status of the social or health problem, and how the study will
help arrive at a solution.
The study design, methodology, and data collection, overall, should be able to generate information
supportive
of the objectives of the study. Social value can only be realized if the study is scientifically
valid.
4. A dissemination plan for the study results shall be included in the protocol. Dissemination is essential
to achieving social value.
5. The REC shall determine the appropriateness and the practicability of the dissemination plan, as well
as the suitability of the recipient(s) of the information.

Informed Consent

Informed consent is a decision of a competent potential participant to be involved in research after

receiving and understanding relevant information, without having been subjected to coercion, undue
influence, or inducement.
Obtaining informed consent is a process that is begun when initial contact is made with a potential
participant and continues throughout the course of the study. By informing the potential participants,
by repetition and explanation, by answering their questions as they arise, by ensuring that they
understand each procedure, and by obtaining agreement from them, researchers elicit their informed
consent, and in so doing manifest respect for their dignity and autonomy.
For all research involving humans, the researcher shall obtain the voluntary informed consent of the
prospective research participant. In the case of an individual who is incapableof giving or who has
diminished capacity to give informed consent, the researcher must exert effort to obtain his or her
assent and the consent of a legally authorized representative (LAR), in accordance with applicable
laws.
In obtaining informed consent, sponsors and researchers shall have the duty to avoid deception,
undue influence, or intimidation.
10. Informing the potential participant shall not be simply a ritual recitation of the contents of a written
document. Rather, the researcher shall convey the information, whether orally, in writing, or other
modes of communication, in a language and manner that suit the individual's capacity and level of
understanding.
11. The researcher shall ensure that the prospective participant has adequately understood the
information. The researcher shall give each one the full opportunity to ask questions, and should
answer them honestly, promptly, and completely.
Essential information
for participants

12. The researcher shall provide the following information to the potential research participant, whether
orally or in writing, in a language that suits the participant's level of understanding:
12.1. That the individual is invited to participate in the research which is being undertaken by the
researcher (name of researcher) from the institution (name of institution);
12.2. The reasons for considering the individual suitable for the study, and that participation is
voluntary;
12.6. Any foreseeable risks, pain or discomfort, or inconvenience to the individual (or others)
associated with participation in the research (in both the control and experimental group),
including risks to the health or well-being of the individual’s spouse or partner;
12.7. The direct benefits, if any, expected to manifest to individuals from participating in the research;
12.8. Whether money or other forms of material goods will be provided in return for the individual's
participation and, if so, the kind and amount;
12.9. The expected benefits of the research to the community or to society at large, or contribution
to scientific knowledge;
12.10. Whether, when, and how, any intervention proven by the research to be safe and beneficial
will be made available to the individuals after they have completed their participation in the
research, and whether they will be expected to pay for them;
12.11. The provisions to ensure respect for the privacy of research participants and the confidentiality
of records in which they are identified, including documentation through taking of pictures and
recording of the interview and that these might be displayed in publications and conferences
or fora;
12.12. Legal or other limits to the researcher's ability to safeguard confidentiality, and the possible
consequences of breaches of confidentiality;
12.13. The participants are free to withdraw from the research at any time without having to give any
reason, and without penalty or loss of benefits to which he or she is entithed;
12.14. The sponsors or funders of the research, the institutional affiliation
of the researchers, and the
nature and sources of funding for the research;
12.15. The possible research uses, direct or secondary, of the individual's medical or health records,
and the possible future use and final disposition of biological specimens;
12.16. If the specimens collected will not be destroyed, then where, how, and for how long they are
going to be stored;
12.17. That the research participants have the right to decide about future use, continued storage, or
destruction of collected specimens and/or personal information;
12.18. Whether commercial products may be developed from biological specimens, and whether the
research participant shall receive monetary or other benefits from the development of such
products;

12.19. The extent of the researcher's responsibility to ensure needed services to the research
participant;
That treatment and rehabilitation will be provided free of charge for specified types of research-
related injury or for complications associated with the research, the nature and duration of such
care, the name of the medical service or organization that will provide the treatment and
whether there is any uncertainty regarding funding of such treatment;
12.21. That a PHREB-accredited REC has approved or cleared the research protocol;
The contact information of persons designated to respond to the following:
137..32.1. Queries on the details of the protocol;
12.23.23. Issues relating to the human rights of participants;
12.22.53. Related concerns and grievances; and
12.22.4. Management of research-related injuries.

Documentation
of consent

13. As a general rule, documentation of informed consent includes an actual signature or thumb mark of
the prospective participant on the informed consent form.
14. When the use of an informed consent form is not feasibleor unacceptable to the prospective participant,
a descriptionof the process, attested by a witness, may be an alternative that meeds prior approval of
the REC.
Waiver of the informed consent

15. Waiver of individual informed consent is to be regarded as exceptional, and must be approved by an
REC.
16. The informed consent process may be waived in specific research contexts, such as:
16.1. Archival research involving publicly available documents;
16.2. Research that uses the method of naturalistic observation (often described as “covert” method)
in data collection provided that all of following requirements are complied with: Thorough
justification for the use of naturalistic observation;
16.3. Plan tor how the data collected will be used;
16.4. Assurance that risks to participants are unlikely; and
16.5. Mechanism to ensure confidentiality and anonymity of observed individuals and their data (e.g.,
observations are recorded in such a way that the individuals involved are not identifiable).
17. Some or all of the elements in the informed consent may be waived or altered (with prior approval of
the REC) if all these conditions are met:
17.1. The research presents no more than minimal risk;
17.2. The waiver or alteration will not adversely affect the rights and welfare of the participants;
17.3. The research cannot be practicably carried out without the waiver or alteration;
17.4. The participants will be provided with additional pertinent information after their participation
(whenever appropriate).

Renewing consent

18. The informed consent of each research participant shall be renewed under the following conditions:
18.1. If there are any significant changes in the circumstances or procedures of the research;
18.2. If new information becomes available that could affect the willingness of research participants
bo continue to participate; or
18.3. In long-term studies at predetermined intervals even if there are mo changes in the design or
objectives of the research.

Vulnerability of Research Participants

19. Vulnerable participants shall require special protection because of certain characteristics or situations
that render them as such. Vulnerable participants are those who are relatively or absolutely incapable
of deciding for themselves whether or not to participate in a study for reasons such as physical and
mental disabilities, poverty, asymmetric power relations, and marginalization, among others and who
are at greater risk for some harms.
Vulnerable groups shall not be included in research unless such research:
20.1.1. Is necessary to promote the welfare of the population represented;
20.1.2. Cannot be performed on non-vulnerable persons or groups.
21. Researchers, sponsors, or RECs shall not arbitrarily exdude women of reproductive age from biomedical
research. The potential for becoming pregnant during a study shall not, in itself, be used as a reason
for precluding or limiting women’s participation in research.
Competent advice and assistance shall be provided to participants who, by virtue of social, economic,
political or medical disadvantages, are liable to give consent under duress or without the benefit of
adequate information. Caution shall be exercised in obtaining informed consent for a research project
if the research participant is in a dependent relationship with the researcher (¢.9., as a research
participant) to ensure that the consent is not given under duress or undue influence.
Risks, Benefits,
and Safety

Research is justified if there is a reasonable likelihood that the population from which the participants
are derived stand to benefit from the research.
All research involving human participants shall be preceded by a careful assessment of predictable risks,
burdens, and foreseeable benefits to the research participant or to others.
Every precaution shall be taken to minimize the negative impact of the study on the research
Participant's wellbeing.
Research shall be conducted only if there is an acceptable positive benefit-risk ratio.
The researcher/funder/sponsor shall endeavor to ensure the reasonable availability and accessibility of
favorable research outcomes to the community.
When there is ethical and scientific justification to conduct research with individuals capable of giving
informed consent, the risk fram reseanch interventions that do not hold out the prospectof direct benefit
for the individual participant shall be no more likely and no greater than the risk attached to routine
medical or psychological examination of such persons. Slight or minor increases above such risk may
be permitted when there is an overriding scientific or medical rationale for such increases and when
the REC has approved them.

Privacy and Confidentiality

of Information

29. Researchers shall adhere to the principles of transparency, legitimate purpose, and proportionality in
the collection, retention, and processing of personal information (Data Privacy Act of 270127).

30. Researchers must respect participants’ right to privacy. Unless required by law, the confidentiality of
information shall at all times be observed. Records that link individuals to specific information shall not
be released. This requirement shall be included in the informed consent form.
31. Researchers shall refrain from identifying individuals or groups when release of information about them
can expose them to possible harm or social stigma unless required by law.
32. Where there is some likelihood or opportunity for the researcher to observe the occurrence of illegal or
harmful behaviors (e.g., child abuse, substance use, self-harm, or suicide ideation), the researcher
shall:
32.1. Explicitly indicate the limits of confidentiality in the informed consent process, such as when
the researcher is ethically and legally obligated to disclose the identity of the respondent to
forestall imminent harm to self or others;
32.2. Emphasize the right of the respondent to withdraw from the study or withdraw his or her data,
and to refuse to answer any question; and
32.3. Prepare a concrete and realistic protocol for reporting and referral in the event that imminent
harm and/or a criminal act is disclosed or discowered in the process of data collection.
33. Researchers shall recognize that collecting data using group methods (e.g., FGDs) has implications for
the privacy and confidentiality of individuals. As it might not be possible for researchers to ensure the
confidentiality of information or the anonymity of research participants, the researcher shall ensure that
the nature of the study and the questions would cause minimal harm should confidentiality or anomymity
be breached.
The researcher shall describe his or her data protection plan in the protocol, including the steps to be
taken so that all who have access to the data and the identities of the respondents can safeguard
privacy and confidentiality. For example, the researcher shall provide adequate and clear instructions
to research assistants, transcribers of audio recordings, or translators of transcriptions.

fas tioe

In research invwohding human participants the principle of justice refers primarily

to distributive justice,
which requires the equitable distribution of both the burdems and the benefits of participation in
research. That is, it should mot be the case that one growp in society bears the costsof research while
@mothheer group reaps its benefits. Research should not worsen existing health and social inequities.
35.1. There shall be fair seftection in the choice of popalation, sampling, and assignments.
35.2. There shall be provision of appropriate care to research participants regardless of their
economic status, gender, race, of creed.
35.3. There shall be just compensation for harms browght about by participation in the research.
35.4. Research perticipants shall be reimbursed for bost earnings, travel costs, and other expenses.
imourred when taking Part in a study. Where there i mo prospec of direct benefit, participants
may be given a reasonable and appropriate incentivefor imoonvenience. The payments shall
mot be so large as to induce prospective Participants to comsent to participate in the research
against their better judgment (urtdue imducenment).
Individuak and communities shall hawe access to benefitc related to participation im the stidy.
Transparency
Ethical research shall be characterized by transparency. It is imperative for all parties to be transparent
S38

about matbhers relating to their involwement. Transparency is mot diametrically opposed to privacy. On
the contrary, transparencyis an Gement of ethical research that promotes comfidence im the research
enterprise, ewenm when privacy and anonymity need to be preserved about sensitive matters. The need
for transparency also entails disclosure of research results.
Researchers mast be transparent about aspects of =a shidy that may hawe an impect on the rights,
8

health, and safety of participants, or in respect to information that may hawe a bearing on the decision
of participantsto give or withhold their informed comsent.
Disclosureof research results to research participants shall occur only when all of the following apply:
é

So.1. The findings are scientifically walid and comfirmed;

3o.2. Tihe findings hawe significant implicatioms
for the participant's well-being; and
Sso.3. The course of action to ameliorate these comcerns is readily available when research results are

financial interests, or other loyalties that may affect their objectivity and the integrity of their research
soot.
Ack the same time, transparemcy imposes responsibilities on research Participants to be truthtul in
declaring their health comditions, and to be candid in e=pressing their conmocerns about their invohwrement
im resea
 The protocal is the definitive document of the research or study. It provides quidance for those who will
conduct the research, reference for evaluators and rewiewers, template for validation, substantiation for
intellectual property claims, and legacy of the proponent. As such, it should be rigorously conceptualized,
carefully crafted, and elegantly formulated.

1. The research protocol shall be sufficiently detailed to serve as documentation of the study. Further, it
shall:
1.1. Justify the meed for the study, that is, why the study shall be conducted given the cumrent
state of knowledge;
1.2. Establish the appropriateness of the proposed methods for investigating the research
problem;
1.3. Provide evidence for the feasibility of doing the study as proposed, that is, that the study can
be completed successfully in the specified time and with the available resources;
14. Describe the recruitment process (where, who, how); amd
1.5. Describe the dissemination plan for research results and oubocomes.
The purpose of the study, the design, the population, the methods of data collection,
and the planned
analyses shall be dearly described.
3. All procedures, whether invasive or not, shall be satisfactorily described in detail.
4. The research protocol shall adequately address the elements of research ethics as part of the Ethical

5S. The protocol shall prowide infommation on how the safety and welfare of research participants shall be
protected.

UNIT IV: CLINDICAL TRIALS

LEARNING OBJECTIVES:

At the end of the lesson, the student will be able to:

a@. define clinical triak
b. describe the design and types of clinical trials.
c. discuss the importance of conducting clinical trials in drug discovery

Acoording to WHO, Clinical trials are a type of research that studies new tests and treatments and
evaluates their effects on human health outcomes. People wolunteer to take part in clinical trials to test
medical interventions inchuding drugs, cells and other biclogical products, surgical procedures, radiological
procedures, devices, behavioural treatments and preventive care.
Clinical trials are carefully designed, reviewed and completed, and meed to be approwed before they
can start. People of all ages can take part in clinical trials, including children.

What is clinical research?

Clinical tials are conducted to collect data regarding the safety and efficacy of mew drug and dewice
There are seweral steps and stages of approval in the clinical trials process before a drug or
device can be sold in the comsumer market, if ewer.
Drug and device testing begins with extemsive laboratory research which can involwe years oF
ex pernbents
in animals and hunnan cells. If the initial laboratory research is successful, researches send the
data to the Food and Orwg Administration (FDA) for approval to continue research and testing in humans.
Once approved. human testing of experimental drugs and devices can begin and is typically
comdiucted im four phases. Each phase i comsidered a separate trial and, after completion
of a phase,
investigators are required to submit their data for approwal from the FDA before comtinuing to the ne=t
phase.

What are the Clinical Trial Phases?

Whike preclinical research answers basic questions about a drug’s safety, it & mot a substitute for
studies
of ways the drug will interact with the human bod, “Clinical research”
refers to studies, or tiak,
that
are done in people. As the Gdewelopers design the clinical study, they
will comsider what they want ta
@ooompmlish for each of the different Clinical Research Phases and begin the Investigational New Drug
Process (IND), a process
they mart go through before clinical research begins.

Designing Clinical Trials

Researchers design clinical trials to answer specific research questions related to a medical product.
These trials follow a specific study plam, called a protocol that is developed by the researcher or

(Heo home Chee study wall last

Wihretiner there will be a comtrol group and other ways to limit research bias
How the drug will be given to patents and at what dosage
What assessnvents
will be conmducted, when, and what data wall be collected
Hew the data will be rewiewed and analyzed
Clinical tisk follow a typical series from earty, small-scale, Phase 1 studies to late-stage, large
Phase
3 studies.
t
5

Tyres:
 1. Controlled clinical trial
- Subjects are divided into the treatment group (those given the investigational drug) and a control
ro
- Depending on the purpase of the trial, patients in the contro! group get no treatment, a placebo
(an inactive product resembling the investigational drug), another drug known to be effective or a
different dose of the drug under study
> Treatment and control group must have the disease
> Treatment and control should also be similar in age, weight, general health

2. Randomization
- Subjects are randomly assigned to treatment or control

3. Blinding
- In Single blind study, patients do not Know whether they are receiving the investigational drug or
placebo
In double blind study, patients, investigators and data analysts do not know which patients received
the investigational drug. Only when the assignment code is broken, usually at the end of the trial,
is it possible to identify treatment and control patients.

Preparing a promising new drug to start a clinical trial is a significant stage in the drug development
process. There has been a significant investment in identifying an active pharmacologic compound ,
developing a stable formulation and performing pharmacologic and toxicological tests. Safety in animal
models has been established to a degree that the pharmaceutical firm feels that there are sufficient data to
being testing in humans.

Links:
Clinical Trials — What you need to know
2G WW. tch?v=6B553-nTdD4

Clinical Trial Players

httos://www. youtube.com, watch?v=0uPdjoONjDq