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Drug Development
Marilyn Lockyer, RN, BSc, CCRP
Senior Clinical Research Coordinator
King Faisal Heart Institute
What is a drug?
• Any chemical compound
• Anything which produces a change in the
body
• Defined by characteristics:
• use or potential use in diagnosis, prevention
or treatment of disease
• selective in its actions
Why are new drugs/devices
needed?
• Unmet medical need: treat old and new diseases that
•
•
•
•
have no or ineffective treatments
Desire for drugs with less side effects that present
treatments (e.g. drugs used in oncology, steroids)
Less expensive treatments than presently used ones
Decrease costs to individual/country
Sustain industrial activity: pharmaceutical industry
employs thousands and makes a massive contribution
to overseas earnings
How are potential new
drugs identified?
• Alteration of a Known Compound to act on a
selected target
• Computer aided molecular design
• Plant extracts
• Screening large collections of chemical
compounds and natural compounds for
desired activity
Drug discovery and development
• During the 1800s drugs were natural sources;
therefore there were limited possibilities; prepared
by individuals; small scale; not purified; limited
administration; no controls; no idea of mechanism
of action.
• In the 1990s types of drugs expanded to include
synthetic sources, resulting in unlimited possibilities;
prepared by companies; massive scale; highly
purified, standardized and tested; world-wide
administration; tight legislative control; mechanism
of action partly understood.
Sources of drugs
Animal
insulin (pig, cow)
Plant
digitalis (digitalis purpurea foxglove) morphine (papaver
somniferum)
Inorganic
arsenic, mercury, lithium, platinum
Synthetic
chemical (propranolol)
Drug development process
discovery; refinement; chemical & biological
characterization
safety & toxicity in animals; formulation
development
volunteer studies; patient studies
post marketing
regulatory process
marketing
Discovery = find new active structure & develop/refine it = convert it to a useful drug
The Regulatory process
• Differs from country to country (Medicine
Control Agency (MCA) in UK, European
Medicine Evaluation Agency (EMEA) a
central body in Europe, or the Food and
Drugs Administration [FDA] in USA)
• Demands safety and quality of product
• Grants clinical trials certificate if volunteer
and animal data acceptable
• Approves protocols and examines data
Pre-clinical testing in animals
• Done in at least two species of animals
• One rodent & one non-rodent species
• Potential safety & toxic effects measured
• Mutagenicity / Genotoxicity, Teratogenicity
• Carcinogenicty
• LD50 (Lethal Dose) determined
• The dose which kills 50% of animals tested
Animal testing (cont.)
• ADME (Absorption, Distribution, Metabolism
and Excretion)
• Absorption includes route of administration,
dosage form, effects of food, % of absorption,
and effect of the first pass through the liver.
• Distribution includes peak and trough tissue
concentrations and accumulation in serum, CSF,
urine and bile.
• Metabolism refers to organs and percentages of
toxicity and teratogenicity of metabolites.
• Excretion pertains to quantities and routes.
Pre-clinical testing
• By the end of pre-clinical testing many drugs
that seemed promising are abandoned.
• Research on a compound may be stopped
due to problems with poor absorption, toxicity
or simply because it doesn’t work.
Pre-clinical testing
• Lasts 3 to 5 years
• Only 1 out of 1000 compounds that enter preclinical testing continue to human testing.
• Before testing in humans can begin a licence will be
required from the regulating authorities; each
country will have its own body such as:
• FDA (USA)
• MCA (UK)
• EMEA (EU)
Pre-clinical testing
• The regulating bodies (e.g. FDA) will have a
team of scientists and doctors who will review all
the pre-clinical data
• Drug companies will need to address these
agencies’ guidelines and deliver the kind of
results that they require if they want to gain the
go ahead for testing in humans
Pre-clinical testing
• A licence for testing in humans should be
granted, only when the regulators are entirely
satisfied that the drug has not shown any
potential adverse effects in pre-clinical testing.
• In the USA, after pre-clinical testing the
pharmaceutical company applies to the FDA for
an Investigational New Drug (IND) application.
“Pre-clinical” to “clinical” trials
First consideration is the
protection of the rights, safety
and well-being of the study
subject
Clinical trials
Drug action depends on:
• Medical condition being treated
• Pharmacodynamics
• Pharmacokinetics and dose regimen
• Drug interactions
• Receptor sensitivity of patient
• Mood/personality of patient & doctor
• Patients expectations and past experience
• Social environment of patient
• Clinical state of patient
Clinical trials account for or control these variables and examine
the effect of the drug being tested.
Clinical trials
• Phase I (usually healthy volunteers)
• Phase II (patients or person with the
condition)
• Phase III (large scale multi-centre)
• Phase IV (post marketing)
New Drug Application (NDA) USA
• Filed with the FDA after Phase I thru Phase
III trials are completed
• Contains all scientific information the
company has gathered
• May run thousands of pages or more in
length
• Average FDA review time is 29.9 months
Cost of Developing New Drugs
Breakdown of Total Costs by Clinical
Development Phase
5%
8%
15%
Preclinical
Phase I
Phase II
72%
Phase III
Cost of Developing New Drugs
• Top 14 pharmaceutical companies spent over almost $29 billion
(65% of their total research and development expenditure of
$44.5 billion) but obtained FDA approval for only 26% of their
new compounds. (2005)
• On average, it costs a company $359 million to develop one
new medicine from the laboratory to the pharmacist's shelf
(according to figures filed by the pharmaceutical companies to
the US Internal Revenue Service)
• On average, it takes 12 -13 years for drug discovery to drug
aproval.
• Only one in 1,000 compounds that enter pre-clinical testing
make it to human testing.
Drug Sales Curve
Unit sales
serious side effects
adverse reactions
wonder drug
no side effects
not always
effective
balanced view of
advantages &
problems
appreciate where best
used and risks
0
Time
New Devices
• New devices are divided into class: (USA)
Class 1: Minimal potential for harm. May not be lifesustaining or life-supporting or play a substantial role
in preventing impairment of health (eg hospital bed)
Class 2: More direct impact on patient care (eg IV
infusion pump)
Class 3: Usually devices that support or sustain
human life, are of substantial importance in
preventing impairment of human health, or which
present a potential, unreasonable risk of illness or
injury (eg pacemaker, ventilators, perfusion pumps)
In Canada devices are divided into 4 classes.
Phases of Clinical Research:
Drugs Versus Devices
• Drugs generally have 4 phases in clinical research
(I, II, III, IV)
• Devices generally have 2 clinical phases:
 feasibility study (pilot) – small number of patients
to confirm device design, operating specifications,
and initial safety.
 pivotal studies – larger number of patients; refines
any issues identified in pilot study; safety and
effectiveness confirmed.
Conclusion
Developing new drugs and devices:
• is a long and costly process,
• requires extensive testing before being
tested in human subjects,
• must pass through phases of testing in
sequence (eg 1 and 2 before 3, or pilot
before feasibility)
• Requires the experience, knowledge,
and cooperation of healthcare providers
to be safely tested in patients.