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Development
of a Medicine
Dr Ciara Hughes
January 2011
DISCOVERY OF NEW
MEDICINES
Time and Money
 Discovery of new chemical entities
(NCE’s)
 Preclinical development
 Clinical development ( I-IV)
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http://www.wellcome.ac.uk/Education-resources/Teaching-and-education/BigPicture/All-issues/Drug-development/WTX042562.htm
WHAT IS A DRUG?

“Any chemical agent that affects the processes of
living”

A medicinal substance that interacts with a biological
system - and changes it

Those operating within the herbal medicine sector
need to understand and comply with the Traditional
Herbal Medicines Registration Scheme (THMRS), as
required by Directive 2004/24/EC on Traditional
Herbal Medicinal Products.
Other examples
Morphine from the Poppy plant
 Digoxin from the Foxglove
 Aspirin from apple skin
 Taxol from the Yew tree

The cost of drug development
Costs of drug development £500 million
for one drug
 Takes 15-16 year to develop a drug
 75% of this cost is attributable to failure
 90% of all drugs developed don’t make it
to the market

Allocation of funds
Allocation of time (in years)
PRECLINICAL
DEVELOPMENT
Identification of
drug targets
Identification of drug targets
Identification of drug targets
Identification of drug targets
Identification of
drug targets
Identification of drug targets
Identification of
drug targets
Identification of drug targets
Biological activity
Biological activity
Preclinical Information
Required Before A Selected
Drug Candidate Can Be
Administered To Humans
Pharmacological activity
 Pharmacokinetics and drug
metabolism
 Toxicology
 Pharmaceutics

EVIDENCE OF PRIMARY
PHARMACOLOGICAL ACTIVITY
Decision to proceed to man only after
thorough characterisation of
dose/concentration response
relationships of candidate compound in
vitro and in vivo
 This is the scientific basis for all rational
drug development today and the
essential information required before
first pharmacological studies in man

Behavioural Activity and CNS
(including dependence)
General observational studies in
animals.
 CNS evaluation.
 Psychomotor testing.

PHARMACOKINETICS
Absorption
 Distribution
 Metabolism
 Excretion

PHARMACOKINETICS AND
DRUG METABOLISM
►
PK of drug in rodents, dogs and
primates as predictor of the
human situation
►
PK in animals is an essential
part of drug selection to define
the desired kinetic profile for a
drug eg. half-life and
bioavailability
Toxicity Package Generated
Before Phase 1 Trial

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Safety pharmacology – CVS, CNS, RS
PK’s – preliminary studies on ADME
Acute toxicity – 2 species by 2 routes of
administration; evaluation of MRD
Repeat dose toxicity – rodent and non-rodent;
two 14 day studies before man
Reproductive toxicology – embryo/foetal
development studies – 2 species
Mutagenicity/chromosomal
PHARMACEUTICS
Provide pharmacist with information for
optimal formulation
 Concentrations and volumes of injections
 Strength of capsules or tablets
 Choose unit doses providing greatest
flexibility

Phase I
Initial studies to evaluate
Pk, Pd, tolerability.
 30- 50 volunteers usually
healthy.
 Starting dose.
 Single Ascending Dose
(SAD).
 Multiple Ascending Dose
(MAD).
 80% of drugs fail at phase 1
trials

OBJECTIVES OF
THE FIRST STUDY
Define success/fail criteria of the drug
before starting the study
 Study objectives based on a
combination of:
-Tolerability/ “safety”
- Kinetics
- +/- Dynamics
- +/- Quantitative dose-response,
concentration-response relationships

FACTORS TO BE
CONSIDERED IN DECIDING
THE STARTING DOSE
Maximum no effect dose/exposure in
toxicity studies using most sensitive
species (NOAEL)
 Nature & severity of toxicity seen in
animals
 Nature of PD activity in animals and
slope of dose-response curve

PK REASONS FOR
STOPPING DRUG
DEVELOPMENT
Half-life (t ½) too short or too
long
 Poor bioavailability
 Inconsistent bioavailability
with low therapeutic index
 Saturable clearance
mechanisms
 Multiple metabolites not
covered by toxicity studies

FINDINGS LIKELY TO LEAD
TO PROJECT TERMINATION
Poor tolerability at
therapeutic concentrations
 Unsatisfactory
kinetics/metabolism
 Low potency
 Absence of efficacy

Phase II
Small scale studies in patient population.
 Pharmacokinetics.
 Pharmacodynamics / surrogate endpoints
 Tolerability.
 250-500 human exposures.
 Decisions before full Phase 3.

Phase III
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Large scale efficacy trials (1000s patients).
Comparator vs placebo.
Several hundred to several thousand.
Power curves.
Ongoing PK studies special populations.
Ongoing formulation studies.
Ongoing toxicity / oncogenicity studies.
Usually 2 successful phase 3 trials required for
FDA approval
Phase IV
 Post
licensing safety evaluation
 Black triangle
► 1:
Black triangle, spontaneous reporting
► 2: Periodic drug safety reporting
 Pharmacovigilance
(PV)
 Safety Assessment of Marketed
Medicines
What is pharmacovigilance?
Pharmacovigilance is the science
of collecting, monitoring,
researching, assessing and
evaluating information from
healthcare providers and patients
on the adverse effects of
medicines, biological products,
herbals and traditional medicines
with a view to:


Identifying information about
potential new hazards
Preventing harm to patients.
Legislation 2004
Medicines for Human Use Act

The MHRA Pharmacovigilance
Inspectorate is part of the Inspections and
Standards Division of the MHRA. It
assesses pharmaceutical companies’
compliance with UK and EU legislation
relating to the monitoring of the safety of
medicines given to patients
http://www.youtube.com/watch?v=wvDvAEmq-cM