Dr.

Stephanie Fay Cagayan

1
THER 201
Pharmacologic Basis of Therapeutics
Lecture 4: Drug Discovery and Development

Outline: • Global economy

• Interdisciplinary
I. Introduction

II. Drug Discovery

III. Pre-clinical Research and Development DRUG DISCOVERY

IV. IND
Steps in Developing a New Drug
V. Clinical Trials
1. Preclinical

Transers’ Note: This six-page trans is equivalent to five points in

the exam. Haha. Focus on phases of clinical trials and rational
• Discovery or synthesis of a new drug
drug designs. molecule and correlating it with a biological
Dr. Cagayan: “yung table (phases of clinical trials) na lang ipaaral target
mo sa kanila para hindi toxic.”
• In vitro and animal studies to assess the
safety and efficacy of drugs (as required
by law)
INTRODUCTION
Objectives:
• Describe the drug discovery process
• Define key players in drug development 2. Clinical
• Discuss cost of drug development

Drug discovery is the process of by which drugs are

discovered and/or designed • Human testing

• Discovery includes: Concept, mechanism, assay, • Safety monitoring after approval for
screening, hit identification, lead demonstration, general use
lead optimization
• Discovery also includes in vivo proof of concept in
Drug Discovery Overview
animals and concomitant demonstration of a
therapeutic index
- A drug discovery effort addresses a biological
Drug Development is the process taking a new chemical target that has been shown to play a role in the
lead through the stages necessary to allow it to be tested development of the disease or starts from a
in human clinical trials. molecule with interesting biological activities

• Development begins when the decision is made to 1. Identification of a new potential drug target
put a molecule into phase I clinical trials 2. Rational drug design
3. Modification of an existing drug/potential drug
Aims of Drug Development 4. Screening of chemical/macromolecule/ organic
chemical libraries
5. Biotechnical approaches using the human
• Provide information on the optimal use of a new
genome.
drug in treatment or prevention of a disease
6. Combinations of known drugs to obtain added or
• To document the quality of the pharmaceutical synergistic effects.
product
• Provide for an economically sound investment

Drug Development and Regulation

• The cost estimate to bring a single drug to market

range from $150 million to $900 million for
research & development; this does not include the
costs of marketing.
• Only 3 of 10 marketed drugs return their R&D
costs.
• Literally hundreds of thousands of both synthetic
and naturally occurring compounds are tested for
each successful drug discovery.
• Compounds which show potential for therapeutic
benefit usually undergo further modification to
improve efficacy, potency and/or safety prior to
formal evaluation.

Profile of Today’s Pharmaceutical Business

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THER 201
Pharmacologic Basis of Therapeutics
Lecture 4: Drug Discovery and Development
Figure 1 | Drug Discovery
Types of Targets
Figure 2 | Therapeutic target classes.
Target Discovery
1. Physiology-based Drug Discovery
• follows physiological readouts
• E.g. the amelioration of a disease
phenotype in an animal model or cell-
based assay.
- Compounds are screened and
profiled based on this readout.
- A purely physiology-based
approach would initially forgo
target identification/validation and
instead jump right into screening.
- Identification of the drug target
and the mechanism of action
would follow in later stages of the
process by deduction based on
the specific pharmacological
properties of lead compounds.
2. Target-based Drug Discovery
Everly, Edge, Julie, Ado Mon, July 5, 2010
Dr. Stephanie Fay Cagayan
1
• begins with identifying the function of a
possible therapeutic target and its role in
disease
Note: The main difference of the between the two
paradigms lies in the time at which the drug
target is actually identified.
Target Identification
1. Disease Mechanism
• understanding the disease mechanism
directs research and formulates a possible
treatment to slow or reverse the disease
process
• predicts a change of the disease pattern
and its implications
2. Disease Genes and Functional Genomics
• specific gene defects or mutations that
bring about a hereditary disorder have
been identified for a number of diseases
• functional genomics aims to determine
disease mechanisms and to identify
disease genes and disease markers
• guide the understanding of signal
transduction pathways that either lead to
disease or indicate therapeutic strategies
for the development of novel therapeutics.
3. Target Type and “Druggability”
• targets can be receptors, proteins,
enzymes, DNA, RNA or Ribosomal targets
• “druggability" of a given target is defined
either by how well a therapeutic, such as
small molecule drugs or antibodies, can
access the target, or by the efficacy a
therapeutic can actually
Lead Discovery
• identification of a compound that triggers specific
biological actions
• approaches:
1. Serendipity
- “Chance favors the prepared mind”
- 1928 Fleming studied Staph, but
contamination of plates with
airborne mold. Noticed bacteria
were lysed in the area of mold. A
mold product inhibited the growth
of bacteria: the antibiotic penicillin
2. Screening of biologic activity of a wide
array of natural products or chemical
entities
- Testing a random and large
number of different molecules for
biological activity reveals leads.
Innovations have led to the
automation of synthesis
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THER 201
Pharmacologic Basis of Therapeutics
Lecture 4: Drug Discovery and Development
(combinatorial synthesis) and
testing (high-throughput
screening).
- Example: Prontosil is derived from
a dye that exhibited antibacterial
properties.
3. Chemical modification of known molecules
- Traditional method: an analog of a
known, active compound is
synthesized with a minor
modification, that will lead to
improved biological activity.
- Advantage and Limitation: you
end up with something very similar
to what you start with
4. Rational drug design
- Establishes structural relationships
between the biological properties
and the molecular structures.
- Basis of drug-target interactions is
molecular recognition: the specific
attractions between the chemical
groups of a biological target (large
protein, usually) and a drug (small
molecule, usually).
- New molecules that can optimally
interact with a biological target can
be designed to block or trigger a
specific biological activity.
- Begins with the design of
compounds that conform to
specific requirements. The
molecules are synthesized, tested.
Then the molecule is redesigned,
synthesized, tested.
- Two Sources:
 3D structure of biological
target (receptor-based
drug design)
 Structure(s) of known active
small molecules
(pharmacophore-based
drug design)
Pharmacophore-based Drug Design
- Examine features of inactive small
molecules (ligands) and the
features of active small molecules
(ligands).
- Generate a hypothesis about what
chemical groups on the ligand are
necessary for biological function;
what chemical groups suppress
biological function.
- Generate new ligands which have
the same necessary chemical
Everly, Edge, Julie, Ado Mon, July 5, 2010
Dr. Stephanie Fay Cagayan
1
groups in the same 3D locations.
(“Mimic” the active groups)
- Advantage: Don’t need to know the
biological target structure
Receptor-based Drug Design
- Examine the 3D structure of
the biological target
- Look for specific chemical
groups that could be part of an
attractive interaction between the
target protein and the drug.
- Design a drug candidate that
will have multiple sites of
complementary interactions with the
biological target.
- Advantage: Visualization
allows direct design of molecules
Note: Typical projects are not purely receptor-
based or pharmacophore-based; they use
combination of information, hopefully
synergistically.
Example of Rational Drug Design: Cimetadine
(Tegamet)
- Starts with a validated
biological target and ends up with a
drug that optimally interacts with the
target and triggers the desired
biological action.
- Problem: histamine triggers
release of stomach acid. Want a
histamine antagonist to prevent
stomach acid release by histamine
= VALIDATED BIOLOGICAL
TARGET.
- Histamine analogs were
synthesized with systematically
varied structures (chemical
modification), and SCREENED. N-
guanyl-histamine showed some
antagonist properties = LEAD
compound.
a. Chemical modifications were
made of the lead = LEAD
OPTIMIZATION.
b. More potent and orally active,
but thiourea found to be toxic in
clinical trials.
c. Replacement of the group led
to an effective and well-tolerated
product.
d. Eventually replaced by Zantac
with an improved safety profile.
Lead optimization
• properties of the lead are tested with biological
assays; new molecules are designed and
synthesized to obtain the desired properties
PRE-CLINICAL RESEARCH AND DEVELOPMENT
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 Dr. Stephanie Fay Cagayan
1
THER 201
Pharmacologic Basis of Therapeutics
Lecture 4: Drug Discovery and Development
• The goal of preclinical studies includes identifying
potential human toxicities and designing INVESTIGATIONAL EXEMPTION FOR A NEW DRUG (IND)
mechanisms to monitor for these toxicities in
clinical trials.
• The discovery of a significant toxicity may not
preclude further development but indicate the
need for some drug modification.
• At the preclinical stage, the FDA will generally
ask, at a minimum, that sponsors:
1. develop a pharmacological profile of the
drug;
2. determine the acute toxicity of the drug
in at least two species of animals, and
3. conduct short-term toxicity studies
ranging from two weeks to three
months, depending on the proposed
duration of use of the substance in the
proposed clinical studies.
• Specific testing is determined by the proposed
therapeutic use of an agent.

Figure 3 | IND Application

• Once a drug has been judged

ready to be studied in humans
a Notice of Claimed
Investigational Exemption for a
New Drug (IND) must be filed
with the FDA; this application
must include an extensive
profile of drug including the
mechanism of action,
formulation & composition of
the drug, the proposed clinical
plans and protocols, the names
and credentials of physicians
who will conduct the trials.

• All this data is made available

Table 1 | Safety Tests to investigators and their
institutional review boards.

Limitations of Preclinical Testing • The investigational new drug

(IND) application is the result of
1. Toxicity testing is time consuming and a successful preclinical
expensive. It may require 2-6 years to acquire development program. The IND
this data prior to human testing. is also the vehicle through
2. Large numbers of animal subjects are which a sponsor advances to
needed; Molecular, cell and tissue culture the next stage of drug
methods may be substituted but their predictive development known as clinical
value is severely limited. trials (human trials)
3. The extrapolation of animal data to humans may
not be accurate for all toxicities (antiemetics • Generally, this includes data
tested in a rat, cinnamyl anthranilate). and information in three broad
areas:
4. Rare adverse effects are unlikely to be detected
(AA with chloramphenicol). 1. Animal Pharmacology and Toxicology
Studies

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 Dr. Stephanie Fay Cagayan
1
THER 201
Pharmacologic Basis of Therapeutics
Lecture 4: Drug Discovery and Development
2. Manufacturing Information
Phase 4 Clinical Trials
3. Clinical Protocols and Investigator
Information • Is the treatment safe over time?
• Phase 4 trials are less common and serve to
answer questions after the FDA has already
CLINICAL TRIALS approved a drug for general use. These can
address questions such as long-term safety of a
Human Trials drug, or other circumstances in which the drug
may be helpful.
• Less than 1/3rd of drugs tested in clinical trials
reach the market place.
• Human clinical trials are replete with oversight NEW DRUG APPLICATION (NDA)
from a number of institutions.
• Federal law requires human drug trials are
conducted in accordance with strict rules.
• Sophisticated, elegant trial design is required to
successfully identify appropriate drugs

Confounding Factors in Clinical Trials

1. The variable natural history of most diseases

2. Most diseases have a variable clinical course,
exacerbations & remissions are common and
some get better with no intervention. Study
design must account for the natural history of the
disease. (cross over design).
3. The presence of other diseases and risk factors
4. Subject and observer bias
5. Study design must account for the placebo effect;
a review of any drug trial reveals the remarkable
power of a placebo to produce a response (both
beneficial & detrimental). Single-blind and
double-blind studies seek to remove this bias.

Phase 1 Clincal Trials

• Is the treatment safe?

• After an experimental drug or treatment has been
tested in the lab and/or on animals, it enters a
phase 1 trial. These trials involve a small number
of patients to test safety in humans and
determine the correct dose of a drug. These trials
also help determine the best way to give the
drug, whether oral or intravenously.

Phase 2 Clinical Trials

Figure 4 | NDA Chart
• Does the treatment work?
• In the primary review process, reviewers attempt
• After determining that a treatment is reasonably to confirm and validate the sponsor's conclusion
safe in people, it enters phase 2 trials. These are that a drug is safe and effective for its proposed
done to test for effectiveness – does the use
treatment work? Since a larger number of people • NDAs can consist of as many as 15 different
are studied, further information is gained on sections:
safety during phase 2 trials. - Index
- Summary
Phase 3 Clinical Trials - Chemistry, Manufacturing, and Control
(CMC)
• Does the new treatment work better than the - Samples, Methods Validation Package,
standard treatment? and Labeling
• Phase 3 trials test the new drug or treatment on - Nonclinical Pharmacology and
hundreds or thousands of individuals. These Toxicology
studies are often “double-blind” trials, which • Human Pharmacokinetics and Bioavailability
mean that neither the patient nor the investigator - Microbiology (for anti-microbial
knows which treatment is being used. They are drugs only)
designed to answer the question of whether or - Clinical Data
not the new treatment works better, or has fewer - Safety Update Report (typically
side effects, than the standard treatment. submitted 120 days after the NDA's
submission)
- Statistical
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THER 201
Pharmacologic Basis of Therapeutics
Lecture 4: Drug Discovery and Development
- Case Report Tabulations
- Case Report Forms
- Patent Information
- Patent Certification
- Other Information
GUIDELINES OF DRUG DEVELOPMENT
Good Laboratory Practice (GLP)
• In vitro screening
• Animal studies
• The purpose of these Principles of Good
Laboratory Practice is to promote the
development of quality test data
• Comparable quality of test data forms
the basis for the mutual acceptance of
test data among countries
Dr. Stephanie Fay Cagayan
1
• Given the massive cost for drug development and
approval drugs the development of drugs for rare
disease would be cost prohibitive (they are drug
companies).
• Frequently these diseases involve pediatric age
patients in whom testing justifiably is severely
restricted.
• Often promising treatments would languish due to
the lack of potential return, the Orphan Drug Act
of 1983 provided incentives for the investigation
and development of drugs for rare diseases
( <200,000 patients in the US or if >200,000 the
expected return will not meet costs).
• Since 1983 the FDA has approved 268 orphan
drugs for 82 rare diseases.
ADVERSE DRUG REACTIONS

Good Clinical Practice (GCP)

• Human clinical trials
• An international ethical and scientific quality
standard for designing, conducting, recording,
and reporting trials that involve the participation
of human subjects

• To provides public assurance that the rights,

safety, and wellbeing of trial subjects are
protected and that the clinical trial data are
credible

• To provide a unified standard for the European

Union (EU), Japan, and the United States to
facilitate the mutual acceptance of clinical data by
the regulatory authorities in these jurisdictions.
The guidance was developed with consideration
of the current good clinical practices of the
European Union, Japan, and the United States,
as well as those of Australia, Canada, the Nordic
countries, and the World Health Organization
(WHO)
Good Marketing Practice
• a system for ensuring that products are
consistently produced and controlled according to
quality standards.
• An ADR is a reaction to a drug that is harmful or
an unintended response.
• ADRs are claimed to be the 4th leading cause of
death in the US (> AIDS, accidents & automobile
deaths).
• During the IND and clinical phase (1-3) all
adverse events related to use of the drug must be
reported to allow continued testing. This process
continues after market approval by the FDA but
reporting is on a voluntary basis; drug recalls due
to this phase IV reporting are not uncommon
(phen-phen, COX-2inhibitor Vioxx,).

• Designed to minimize the risks involved in any

pharmaceutical production that cannot be
eliminated through testing the final product. The
main risks are:

- unexpected contamination of products,

causing damage to health or even
death;

- incorrect labels on containers, which

could mean that patients receive the
wrong medicine;

- insufficient or too much active

ingredient, resulting in ineffective
treatment or adverse effects.

ORPHAN DRUGS AND RARE DISEASES

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 Dr. Stephanie Fay Cagayan
1
THER 201
Pharmacologic Basis of Therapeutics
Lecture 4: Drug Discovery and Development

Everly: thanks to Ed and Julie for this trans. To my researchmates, don’t ever let
go of me, please! Hello to bea and al, my beks girls anne and april. BILI KAYO NG
RSO SCRUBS AND PANTS. AVAILABLE IN GRAY, PINK AND APPLE GREEN.
Goodluck and Godbless 2014 in this yearead.
Edge: Lunchmates hello! Hi kay Jean at Default! Thanks sa pagpapainternet sakin.
Haha. Tags! Badminton ulit! Jesh, miss earth! Marcus, wag naiinggit. Jason,
musta? Haha. Ado, Aidz, Pats, train na tayo! Happy birthday Evs! Belated Sharms!
Julie: Ask me anything (about the trans). 09158507391 I love 35G Psych
Ward+Motch! Hello Psych! Hello S.Karla, S.Carla, S.Coy, S.Shayne, S.Maetrix,
S.Janna, S.Mindy and B.Ace, B.Apol, B.Karl, B.Monchi, B.Mark, B.Pangs,
B.Tonicci! Edge, magtrabaho ka naman h*y*p ka. Hi Lance! Bryan pengeng pasta!
Ikaw din, Austeon.Anna alam mo na. Pors I miss you. Hi Pito! Jean, Leeann, no.4!
Marvie JTama na gailt na si Edge.
Ado: MSSR Cereals Party. Wed, 5pm, MSU 2F. See you there!

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 Dr. Stephanie Fay Cagayan
1
THER 201
Pharmacologic Basis of Therapeutics
Lecture 4: Drug Discovery and Development

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