DRUG DISCOVERY AND

DEVELOPMENT
 Drug discovery
• Drug discovery is the process by which new candidate medications are discovered.
• 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
• 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
• At this stage in the process, thousands of compounds may be potential
candidates for development as a medical treatment.
• After early testing, however, only a small number of compounds look promising and call
for further study.
Step 1: Discovery and Development
 i: Target Identification
• Drug Target = specific macromolecule, or biological system, which the
drug will interact with.

• Sometimes this can happen through incidental observation.

 ii: Identification of a lead compound
• This involves identifying those hits ( molecules with activity against a
target(s)) that have properties (other than just activity against the target) that
would indicate that they have potential for being developed as drugs.

• At this stage, validated hits would be tested to determine factors such as:
• Selectivity versus a panel of other receptors (targets)
• Physicochemical characteristics
• Drug-like properties
• Metabolic properties (half life etc.)
• Those molecules with acceptable potency, physical and ADME properties can be advanced
through lead optimisation
Finding the Lead

Screening Natural Products

• Plants, microbes, the marine world, and animals,
all provide a rich source of structurally complex
natural products.
Finding the Lead (cont.)

Screening synthetic banks

• Pharmaceutical companies have prepared
thousands of compounds
• These are stored (in the freezer!), cataloged and
screened on new targets as these new targets are
identified
Finding the Lead (cont.)

Using Someone Else’s Lead

• Design structure which is similar to existing lead, but
different enough to avoid patent restrictions.
• Sometimes this can lead to dramatic improvements in
biological activity and pharmacokinetic profile. (e.g.
modern penicillins are much better drugs than original
discovery).
 Finding the Lead (cont.)
Enhancing a side effect

O
H2N S NH2
O
sulphanilamide
(an antibacterial with the side effect of
lowering glucose levels in the blood and also
diuretic activity)

Cl N
O
O S O
O NH
NH S S
H2N O
NH O O
tolbutamide Chlorothiazide
(a compound which has been optimized to only (a compound which has been optimized to only display diuretic
lower blood glucose levels. Useful in the treatment activity.)
of Type II diabetes.)
 Using structural similarity to a natural ligand

NH2 N(CH3)2

H
HO N
H3C S
O O
N N
H H

5-Hydroxytryptamine (5-HT) Sumatriptan (Imitrex)

Serotonin (a natural neurotransmitter Used to treat migrain headaches
synthesized in certain neurons in the CNS) known to be a 5-HT1 agonist
 Computer-Assisted Drug Design
• If one knows the precise molecular structure of the target
(enzyme or receptor), then one can use a computer to
design a perfectly-fitting ligand.
• Drawbacks: Most commercially available programs do
not allow conformational movement in the target (as the
ligand is being designed and/or docked into the active
site). Thus, most programs are somewhat inaccurate
representations of reality.
 Serendipity: a chance occurrence
• Must be accompanied by an experimentalist who
understands the “big picture” (and is not solely focused
on his/her immediate research goal), who has an open
mind toward unexpected results, and who has the ability
to use deductive logic in the explanation of such results.
• Example: Penicillin discovery, development of sildenafil
(Viagra®) to treat erectile dysfunction
 Finding a Lead (cont.)

Sildenafil (compound UK-92,480) was synthesized by a group of

pharmaceutical chemists working at Pfizer's Sandwich, Kent
research facility in England.

It was initially studied for use in hypertension and angina

pectoris .

Phase I clinical trials under the direction of Ian Osterloh

suggested that the drug had little effect on angina, but that it
could induce marked penile erections.
Pfizer therefore decided to market it for erectile dysfunction, rather than for angina.

The drug was patented in 1996, approved for use in erectile dysfunction by the Food and Drug
Administration on March 27, 1998, becoming the first pill approved to treat erectile dysfunction in the
United States, and offered for sale in the United States later that year.

It soon became a great success: annual sales of Viagra in the period 1999–2001 exceeded $1 billion.
iv: Lead optimisation
• Lead optimization is a stage of the drug discovery process in which
the molecules fulfilling the lead identification criteria are modified
to:
• Improve target selectivity,
• pharmacodynamic, pharmacokinetic, and toxicological properties

• The modified molecules are advanced to animal models and

preliminary toxicology to produce a preclinical drug
candidates.
Step 2: Preclinical studies
• Determine toxicity and efficacy in animal models.
 Preclinical testing

• Before a new drug is administered to humans, its

pharmacologic effects are thoroughly investigated in studies
involving animals

• These studies are called preclinical testing

• The value of the preclinical studies is based on the proven

correlation between drug toxicity in animals and humans
 Objectives of preclinical testing
• The studies are designed to:
• Ascertain whether the new drug has any harmful or beneficial
effects on vital organ function, including cardiovascular, renal, and
respiratory function;

• Elucidate the drug's mechanisms and therapeutic effects on target

organs;

• Determine the drug's pharmacokinetic properties, thereby

providing some indication of how the drug would be handled by
the human body.
 Types of toxicity studies in animals
• The studies involve short-term and long-term administration of the drug and are
designed to:
• Determine the risk of acute, subacute, and chronic toxicity,

• The risk of teratogenesis, mutagenesis,and carcinogenesis.

• After animals are treated with the new drug, their behavior is assessed and their
blood samples are analyzed for indications of tissue damage, metabolic
abnormalities, and immunologic effects.

• Tissues are removed and examined for gross and microscopic pathologic changes.

• Offspring are also studied for adverse effects.

TYPE OF STUDY METHOD OBSERVATIONS
Acute toxicity Administer a single dose of the drug in two species Behavioral changes, LD 50, and
via two routes. mortality.

Subacute Administer the drug for 90 days in two species via Behavioral and physiologic
toxicity
a route intended for humans. changes, blood chemistry levels,
and pathologic findings in tissue
samples.

Chronic toxicity Administer the drug for 6-24 months, depending Behavioral and physiologic
on the type of drug. changes, blood chemistry levels,
and pathologic findings in tissue
samples.

Teratogenesis Administer the drug to pregnant rats and rabbits Anatomic defects and behavioral
during organogenesis. changes in offspring.

Mutagenesis Perform the Ames test in bacteria. Examine Evidence of chromosome breaks,
cultured mammalian cells for chromosomal gene mutations, chromatid
defects. exchange, trisomy, or other
defects.

Carcinogenesis Administer the drug to rats and mice for their Higher than normal rate of
entire lifetime. malignant neoplasms.
Extrapolation of animal findings to
humans
• Studies in animals may not reveal all of the adverse effects
that will be found in human subjects,

• This may be due to:

• The low incidence of particular effects
• Differences in susceptibility among species.
• Therefore some adverse reactions may not be detected until
the drug is administered to humans.

• However, because studies of chronic toxicity of new drugs in

animals may require years for completion, it is usually possible
to begin human studies while animal studies are being
completed if the acute and subacute toxicity studies have not
revealed any abnormalities in animals.
The Investigational New Drug (IND)
Application
• The Food and Drug Administration (FDA) must approve an application
for an Investigational New Drug (IND) before the drug can be
distributed for the purpose of conducting studies in human subjects.
Components of IND application
• The IND application includes:
• A complete description of the drug,

• The results of all preclinical studies completed to date,

• A description of the design

• Methods of the proposed clinical studies

• The qualifications of the investigators.

Step 3: Clinical Research
• The clinical development of new drugs usually takes place in steps or
phases described as:

• Clinical pharmacology (phase I),

• Clinical investigation (phase II),

• Clinical trials (phase III)

• Post -marketing studies (phase IV).

 Designing clinical trials
• Researchers design clinical trials to answer specific research questions
related to a medical product.

• These trials follow a specific study plan, called a protocol, that is

developed by the researcher or manufacturer.
 Designing clinical trials
• Before a clinical trial begins, researchers review prior information about the drug
to develop research questions and objectives.
• Then, they decide:
• Who qualifies to participate (selection criteria)
• How many people will be part of the study
• How long the study will last
• Whether there will be a control group and other ways to limit research bias
• How the drug will be given to patients and at what dosage
• What assessments will be conducted, when, and what data will be collected
• How the data will be reviewed and analyzed
 Phase I studies
• Phase I clinical trials involve 20 to 100 healthy volunteers or people with the
disease/condition.

• Length of Study: Several months

• Phase I clinical trials seek to determine the pharmacokinetic properties and

safety of an IND in healthy human subjects.
• In the past, most of the subjects were men.

• Today, women are included in Phase I studies to determine if

gender has any influence on the properties of the IND.
Phase I studies
• The subjects typically undergo a complete history and
physical examination, diagnostic imaging studies, and
chemical and pharmacokinetic analyses of samples of
blood and other bodily fluids.

• The pharmacokinetic analyses provide a basis for estimating

doses to be employed in the next phase of trials,

• The other examinations seek to determine if the drug is safe for

use in humans.

• Percentage of drugs that move to the next phase 70%

Phase II studies
• Phase II clinical trials are the first studies to be performed
in human subjects who have the particular disease the
IND is targeting.

• These studies involve several hundreds people with the

disease/condition.

• Length of Study: Several months to 2 years

Phase II studies
• The purpose of phase II studies is to obtain a preliminary
assessment of the drug's efficacy and side effects in
diseased individuals.

• They also help to establish a dosage range for further

clinical studies.

• Percentage of drugs that move to the next phase: 33%.

Phase III studies
• Phase III clinical trials are conducted to compare the
safety and efficacy of the IND with that of another
substance or treatment approach.

• Phase III studies employ a larger group of subjects (300 to

3,000 volunteers who have the disease or condition) and
involve multiple clinical sites and investigators.

• Length of Study: 1 to 4 years

• Percentage of drugs that move to the next phase: 25-30%

Types of Phase III studies
• Phase III clinical trials are rigorously designed to prevent investigator
bias.

• They include:
• Double-blind clinical trials

• Placebo-control procedures.
Double-blind phase III studies

• In a double-blind study, neither the investigator nor the patient

knows if the patient is receiving the new drug or another substance.
Placebo-control designs
• Placebo-control design includes a group receiving an
identical formulation but with no active ingredients.

• With some diseases, it is unethical to administer a placebo

because of the proven benefits of standard drug therapy.

• In such cases the new drug is compared with the standard drug
for treatment of that disease.

• Phase III trials often involve crossover studies, in which the

patients receive one medication or placebo for a period of
time and then are switched, after a washout period, to the
other medication or placebo.
Data analysis and utilization in clinical trials
• In many cases the data are analyzed statistically at various
points to determine whether the IND is sufficiently
effective or toxic to justify terminating a clinical trial.

• For example, if a statistically significant greater therapeutic

effect can be demonstrated after 6 months in the group of
patients who are receiving the new drug, it is unethical to
continue giving a placebo or a standard drug to the control
group, the members of which could also benefit from receiving
the new drug.

• A clinical trial is also stopped if the new drug causes a

significant increase in rate of mortality or serious toxicity.
Step 4: Review by a regulatory body
• If a drug developer has evidence from its early tests and preclinical
and clinical research that a drug is safe and effective for its intended
use, the company can file an application to market the drug.

• The FDA review team thoroughly examines all submitted data on the
drug and makes a decision to approve or not to approve it.
The new drug application (NDA)
• After Phase III clinical trials have been completed and analyzed, the
drug developer may submit a new drug application (NDA) to the FDA
to request approval to market the drug.
 Components of NDA
• A drug developer must include everything about a drug—from preclinical data
to Phase 3 trial data—in an NDA.

• Developers must include reports on all studies, data, and analyses.

• Along with clinical results, developers must include:

• Proposed labelling
• Safety updates
• Drug abuse information
• Patent information
• Any data from studies that may have been conducted outside the United States
• Institutional review board compliance information
• Directions for use
Review of NDA
• The FDA often requires a number of months to review the NDA
before deciding whether to permit the drug to be marketed.

• Approved drugs are labelled for specific indications based on the

data submitted to the FDA.
 “Off-label” uses of drugs
• Some drugs are found to have other clinical uses after the drug has been
introduced to the market.

• These indications are known as unlabeled or “off-label” uses.

• For example, gabapentin (NEURONTIN) was initially approved for treating partial seizures
but was used “off label” for preventing migraine headaches and treating chronic pain.

• In some cases, manufacturers will seek revised labeling for an approved drug for
another indication and establish a new trade name.

• This was done for the antidepressant bupropion, the exact same drug marketed as
WELLBUTRIN for treating depression and ZYBAN for use in smoking cessation.
 Phase IV studies: Post-marketing surveillance
• Even though clinical trials provide important information on a drug’s efficacy
and safety, it is impossible to have complete information about the safety of a
drug at the time of approval.

• Despite the rigorous steps in the process of drug development, limitations exist.

• Therefore, the true picture of a product’s safety actually evolves over the
months and even years that make up a product’s lifetime in the marketplace.

• FDA reviews reports of problems with prescription and over-the-counter drugs,

and can decide to add cautions to the dosage or usage information, as well as
other measures for more serious issues.
 Example: the development of antidepressant drugs
• Initially it was observed that modulation of biogenic amine levels were implicated
in the development of depression

• The hypothesis was that pharmacological modulation of biogenic amines could

be a process useful in the treatment of depression

• How could this be achieved?

• By increasing the synthesis of transmitter

• By preventing its breakdown

• By producing agonists capable of stimulating post synaptic receptors

• By preventing the reuptake of neurotransmitter from the synaptic cleft

42
Which hypothesis was adopted?
• Actually, all of those hypotheses have been used in the past, some to
greater effect than others
• The final hypothesis:
• Preventing the reuptake of neurotransmitter from the synaptic cleft will have
an effect on their synaptic concentration

• Increasing the levels of biogenic amine will produce an antidepressant effect

• Such increases could be achieved by inhibiting the appropriate

neurotransmitter transporter

43
How would we go about developing a drug based upon this
hypothesis?
• We have now identified our target – the serotonin reuptake transporter

• The next part of the process involved validating the target

• Target validation involved a number of approaches:
• Collecting all available information in the public domain that support the hypothesis

• Developing in vitro and in vivo systems that can be used to support the hypothesis

• Entering into agreements with external experts who can help with verifying the hypothesis

• Assuming the hypothesis is sufficiently well validated, the team can move to the next phase
which is hit identification.

44
Can you tell what it is yet?*

*Attr. Harris, Rolf

45
Fluoxetine

46
This process doesn’t take long – right?
• It takes 3-5 years to get to candidate selection
• From candidate selection to launch it can take around
9 years
• Overall time from beginning to end of the process
averages out at about 9-16 years*

*John La Mattina (2008) Drug Truths. Dispelling the myths about Pharma R&D. Wiley
47
Myth 1: Drugs are overpriced

48
Just how much does it cost?
• This is quite a hard question to answer, but a
study by Joe DiMasi* estimated that it cost on
average $800,000,000 to develop a new drug

• Although not confirmed, estimates for

development of a new drug are now in the
order of $0.5 - 2 billion**

*DiMasi JA, Hansen RW, Grabowski HG. J Health Econ. 2003 22(2):151-85
**Adams C, Brantner V (2006). Health Aff (Millwood) 25 (2): 420–8
49
Myth 3: We can do all of this by computer (revisited)
• Predicting just how a molecule will behave in a mammal is a
particularly difficult task
• No matter how powerful the computer is, it is limited by the
knowledge of those performing the test – it would require that
we know pretty much everything about every biological system,
which, obviously, we don’t
• Even if we did understand all the biological systems, we would
have to predict how such a molecule would interact with the
various components of the system, which we can’t
• The point here would be – would you be more confident of the
prediction of safety of a molecule based purely on computer
simulations, or one that had been tested in animals?
• Moreover, this approach is just as likely to miss rare events,
based on individual genetic traits

50
Just how much does it cost?
• Broken down, the cost broadly works
out at
• Around $335 million in the preclinical
phases
• Around $467 million in the clinical
trial phases
• Around $100 million in Post approval
costs

51
Don’t forget, it also costs to develop the ones that fail

• Although these figures are a little out of date* (they are probably
worse now with the introduction of HTS), it gives an idea of how
wasteful the process is:
• For every 30,000 compounds synthesized
• 2000 (6.7%) enter preclinical development
• 200 (0.67%) enter phase 1 trials
• 40 (0.13%) enter phase 2 clinical trials
• 12 (0.04%) enter phase 3 clinical trials
• 8 (0.027%) are approved
• 1 (0.003%) makes a satisfactory ROI
*Christine A. Shillingford and Colin W. Vose Effective decision-making: progressing
compounds through clinical development DDT Vol. 6, No. 18 September 2001
52
Don’t forget, it also costs to develop the ones that fail

• Attrition at late clinical trial phase is very expensive and can be

disastrous for smaller companies.

• It is important to point out that in the last few years, some

compounds have been pulled out late because it was thought that
they would not make a return on investment (ROI).

• Clearly just getting a drug on the market is not a case of the goose
laying the golden egg

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Choosing a
Disease

• Pharmaceutical companies are commercial

enterprises.
• Pharmaceutical companies will, therefore, tend to
avoid products with a small market (i.e. a disease
which only affects a small subset of the
population)
 Choosing a
Disease

• Pharmaceutical companies will

also avoid products that would
be consumed by individuals of
lower economic status (i.e. a
disease which only affects third
world countries)
Choosing a Disease (cont.)
• Most research is carried
out on diseases which
afflict “first world”
countries: (e.g. cancer,
cardiovascular diseases,
depression, diabetes, flu,
migraine, obesity).
 The Orphan Drug Act

• The Orphan Drug Act of 1983 was passed to encourage pharmaceutical companies
to develop drugs to treat diseases which affect fewer than 200,000 people in the
US.
• Under this law, companies who develop such a drug are entitled to market it without
competition (exclusivity) for seven years.

• This is considered a significant benefit, since the standards for patent protection are
much more stringent.