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Drug Development and Assessment in Man Pharmaceutical Medicine

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Drug Development and Assessment in Man Pharmaceutical Medicine
Drug Development and
Assessment in Man
Pharmaceutical Medicine
Thursday 11th October 2007
Dr John Stinson
An expert is somebody who
is more than 50 miles from
home, has no responsibility
for implementing the advice
he gives, and shows slides.
Edwin Meese
What do Doctors Do?
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Diagnose and treat
Cost of diagnosing
What do we cure?
What do we alleviate?
How do we achieve these effects?
Who makes medicines?
Future threats?
Antibiotic Resistance
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1937
1944
1947
1947
1947
1952
1953
1956
1960
Sulphonamides
Penicillin
Cephalosporins
Chloramphenicol
Aminoglycosides
Macrolides
Tetracyclines
Glycopeptides
Flucloxacillin
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1961 Rifampicin
1962 Fusidic Acid
1970 Trimethoprim
1975 Carbipenems
1982 Fluoroquinolones
• A new class of
antibiotic every 3 years
• 18 year gap to 2000
Introduction
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1935
<1950
1950s
1960s
1970s
1980s
1990s
Few effective Medicines
No antihypertensive agents
Diuretics
B2 Receptor antagonists
Calcium Channel antagonists
ACE Inhibitors
Angiotensin II receptor antagonist
• BNF 2004 > 100 antihypertensives
• Before 1960
Random screening and empirical drug
design
i.e. LUCK!
• 1960s
Medicinal Chemistry
Better organic Biochemistry
Mass spectroscopy
NMR developments
• 1970s Receptor Science
Agonists/Antagonists
• 1980s Protein Chemistry
Enzyme Chemistry
Inhibitors of Enzymes
• 1990s Molecular Biology
Gene Therapy
Biopharmacuticals
Receptor Science Discovered Medicines
Receptor
Agonist/Antagonist
Disease
Benzodiazepine
Diazepam
Opiate
B2
B1 & B2
Morphine
Salbutamol
Propanolol
Epilepsy, Anxiety
Sedation
Analgesia
Asthma
Hypertension
H2
Dopamine
5HT
AII
Cimetidine
Levodopa
Ondansetron
Losartan
Peptic Ulceration
Parkinsonism
Emesis
Hypertension
Non Peptide Enzyme Inhibitors
Enzyme
Inhibitor
Therapy
ACE
HMG CoA
DHFR
b-lactamase
14 a lactamase
Captopril
Simvastatin
Trimethoprim
Clavulinic acid
Ketoconazole
Hypertension
Hi Cholesterol
Antibacterial
Antibiotic Adjunc
Antifungal
Molecules Registered in Libraries
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Screened in biological systems
>100,000 molecules screened
Automated systems
Intelligent screening using 3-D structures
Molecule Receptor Binding
Appropriate shaped molecule tried
Potential Drug Candidate
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More intensely assessed for activity
As it passes more hurdles
Proceed into toxicology testing
Now considered a New Chemical Entity
NCE
New Chemical Entity
• What route of administration?
Parenteral
Oral
Transcutaneous
Subcutaneous
Inhalation
Rectal
Eye
Buccal
NCE Formulation
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Tablet
Suspension
Solution
Capsule
Enteric coated
Cream
Ointment
Pro-drug?
Route of Synthesis?
• Economics (platinum)
• Which Salt?
Hydrocortisone = mild steroid
Hydrocortisone butyrate = potent
• Solubility
• Physicochemical properties
• Stability
• Compatibility with excipients
Clinical Pharmacology
• The Scientific basis of drug therapy,
includes:
Pharmacokinetics
Pharmacodynamics
Pharmaceutical development
Pharmacovigilance
Pharmacoeconomics
Pharmacoepidemiology
Pharmaceutical Process
• Is the drug getting into the patient?
Route?
Formulation?
Dissolution?
Absorption?
Pharmacokinetic Process
• Is the drug getting to its site of action?
Absorption?
Distribution?
Metabolism?
Excretion?
Pharmacodynamic & Therapeutic
Process
Is the drug producing the required
pharmacological effect?
Is the pharmacological effect being translated
into a therapeutic effect?
Phase 1 Trials
• Initial studies in man to determine
tolerance and the safe dosage range and
to give indication of metabolic handling.
These studies are usually undertaken with
healthy volunteers but may be extended to
include patients. Pharmacokinetic (ADME)
and pharmacodynamic activities are
measured if possible.
• N= 30-80
Phase II Trials
• Early controlled trials in a limited number
of patients (with the disease) under closely
monitored conditions to show efficacy and
short term safety.
• Humans exposed 250-500
Phase III Trials
• Extended large-scale trials to obtain
additional evidence of efficacy and safety,
and definition of most common adverse
effects. Longer term trials possible
• Humans exposed 300 - 10,000+
Phase IV Trials
• These are performed after the medicine
has been licensed and marketed. Postmarketing surveillance occurs after the
clinical trials programme is complete. It is
used to collect adverse event data from a
large patient population.
• Humans exposed 10,000+
When Phase I to III Complete
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Apply for Product Licence or authorisation
From FDA
From EMEA
From National authority (IMB etc)
Decision based on
Safety Data
Efficacy Data
Pharmaceutical Quality
Pharmacovigilance
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Sulfanilamide one of first antibiotics
Effective against streptococcal infections
Not under patent protection (1908)
Many manufacturers marketed it
A small company decided to produce a
liquid formulation
• Found that diethylene glycol was a
suitable solvent
Pharmacovigilance
• Raspberry tasting elixir of sulfanilamide
• 72% diethylene glycol, 16% water, 10%
sulfanilamide
• “Control laboratory” found it suitable with
regards to appearance, flavour and
flagrance.
• There was no toxicity testing of the
ingredients
Pharmacovigilance
• 105 patients died (out of 353 treated)
• A mass poisoning
• The only rule broken by the manufacturer,
the Massengill Company, was that it called
the product an elixir although it did not
contain ethanol!
• The FDA changed the law:
• Manufacturers had to prove safety before
marketing a medicine.
Toxicology Testing
• Thalidomide 1956 Germany Antiemetic in
pregnancy
• 1961 Reports of Phocomelia
no cases in 1949-1959
477 cases in 1961 alone
400-500 cases in UK 1959-61
• 1963 CSM in UK
• 1968 Medicines Act UK
Regulatory Control
Pharmacovigilance
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Thalidomide was not approved in US
However studies were undertaken in US
624 Pregnant women received thalidomide
10 cases of Phocomelia occurred
FDA tightened rules to all stages of drug
development
• This required extensive testing in animals
first
Before NCE tested in Man
• Safety Pharmacology in Animals Dog&Rat
CNS Activity
CVS Activity
Respiratory Activity
• Pharmacokinetics
Dog & Rat usually
Absorption
Distribution
Metabolism
Excretion
Before NCE tested in Man
• Acute Toxicity single dose
2 Species of animlas by 2 routes
Usually IV and Oral (or proposed route)
Maximum well tolerated dose
• Repeat dose toxicity
Rodent and non-rodent
Using route proposed for man
Duration depends on proposed
duration in man
Before NCE tested in Man
• Genotoxicity
Ames Test- bacteria gene mutation
S.Typhi, E.Coli
Mouse Lymphoma Cell line –
mammalian gene mutation
Chinese Hamster Ovary –
chromosomal damage
Micronucleus Test
mammalian in vitro chromosome damage
Assay of DNA synthesis in rat liver
• Reproductive toxicity
only if women of child bearing potential
Adverse Drug Reaction Reporting
Pharmacovigilance
• When a new medicine gets a licence
• On average about 4,000 humans have
received it in trials
• Many have only received it for a short time
• If an adverse event only occurs in 1: 5,000
• No chance to detect it
• Especially if it occurs rarely in background
• Pharmacovigilance only starts with licence
VIOXX –Rofecoxib
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MSD – COX 2 inhibitor
In theory less risk of GI bleeds
Approved by FDA in 1999
$ 2,500,000,000 per year
VIGOR study
RR 5 x of AMI compared to naproxen
• FDA estimate 27,000 excess AMI/deaths
between 1999-2003
VIOXX
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APPROVe study
Study in preventing colonic polyps
Showed increased CV deaths
September 30th 2004 product withdrawn
Cost will probably be $9 billion in sales &
$5 billion in law suits
Bayer statin
• Statin withdrawn due to rhabdomyolisis
• Dose response curve not properly
explored
• Could have been avoided?
• Pharmacovigilance does not stop at
licensing, indeed it really only starts then
Pharmacovigilance Methods
• Spontaneous Reporting
• Cohort Studies
Defined size group of patients
Followed for defined period of time
10,000 pts recruited from 2500 GPs
Non-promotional, only if going to be Rx
Doctor reports and ADEs
Can come up with new ADEs
“Hypotheses generating”
Pharmacovigilance Methods
• Case Control studies
Hypothesis testing, not generating
Select cohort with suspected
disease/ADE
Select larger cohort without ADE
Look for differences in exposure to
drug
Pharmacovigilance Methods
• Computerised databases
Prescriptions/Patients Linked
To medical adverse events/disease
Getting better as I.T. improves
Depends on quality of data entered
The interface between the medical
profession and the pharmaceutical
industry
• Research State funded = €30 million/year
• Research Funded by Pharma = €50 million
• Approx 160 doctors, nurses and scientists
are funded by pharma industry
• Used to be area of growth --now ?
• Fraud rare but does occur
Medicine Promotion
• Advertisements
Strict Guidelines
safe, best, most etc.
reminder vs full advertisement
Code of practice
Complaints procedure
Medicine Promotion
• Representatives
Educational
Informative
Promotional
Not paid by commission
Rising standards
Must have data sheet
Must report ADEs
Must not mislead
Medicine Promotion
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safety
tolerability
efficacy
price
Medicine Promotion
• Samples
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must be in response to signed dated
request
No more than 6 samples per year
Smallest pack available
Marked “not for resale/free medical
sample”
Medicine Promotion
• Sponsorship
IPHA code of practice (new 6th edition)
Doctors should not ask for a fee for apt
Sponsorship should be appropriate &
not out of proportion
Sponsored meetings must have major
educational component
No sponsorship for non-medical people
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