Transcript Introduction to the Pharmaceutical Industry

The Pharmaceutical Industry and The Process of
Drug Discovery

What is a Drug?

Types of Pharmaceutical Products

What are the Important Disease Targets?

How the Industry Has Evolved

Drug Discovery and The Process of Getting
a Drug to Market - an overview
What is a drug?
“A Chemical Substance that Interacts with a Living
System and Produces a Biological Response”
What is a drug?
“A Chemical Substance that Interacts with a Living
System and Produces a Biological Response”
What is a drug?
“A Chemical Substance that Interacts with a Living
System and Produces a Biological Response”

Good and Bad Drugs?

Safe Drugs?
What is a drug?
“A Chemical Substance that Interacts with a Living
System and Produces a Biological Response”

Good and Bad Drugs?

Safe Drugs?
Morphine (bad?) vs. penicillin (good?)
Curare vs. paracetamol
Classification of Drug Types
 Ethical drugs
 Generic drugs (no longer under patent)
 “Prescription Only” vs “Over the Counter”
 “Off Label” applications
 Orphan drugs
 Biotechnology products
 Counterfeit drugs
 Street drugs!
What criteria MUST new drugs meet?
 Drugs must address a new need or
provide a significant “added benefit” over
an existing medicine
 Drugs must also meet five criteria:
 Must be safe, effective, of high quality
 …cost effective (1980s)
 ……….affordable (1990s)
 ……………REALLY affordable (2000+)
Major Therapeutic Targets
 Infectious disease – anti-infectives
 Anti-bacterial, anti-viral, anti-parasitic drugs
 Metabolic disease
 cancer, cardiovascular, diabetes,
inflammation, high blood pressure,
neurological disease, pain
 Other aspects of health care
 Hormonal treatments, contraception,
vaccines, immunosuppresents, anaesthetics,
nutraceuticals, “life style” drugs
A History of the Pharmaceutical Industry
 The early days - Egyptians, Greeks, Arabs, China, India
 Plant-derived medicines
 morphine (1805), quinine (1819), colchicine (1820), pilocarpine (1875)
 Hormones

insulin (1921), estradiol (1929), testosterone (1931), “the pill” (1960)
 Antibiotics, Psychoactive drugs (post-1945 to 1960’s)

penicillin (1944), streptomycin (1944), valium (1963)
 Treatment of metabolic disorders (1960’s to current day)

Ventolin (1969), Lipitor (1997), Viagra (1998), Avandia (1999), Vioxx
(1999), Gleevec (2001)

Search for gene therapies (1990), stem cell-based therapies

Stem-cell replacement of a trachea (2008)
Some Important Events

American Civil War

Legislation – UK Cruelty to Animals Act (1876); US Federal Food
and Drug Act (1906)

World War 1 - Development of UK regulatory rules

World War 2 – antibiotics

Vaccines – Smallpox: Jenner (1796) – eradicated in 1977

Thalidomide (1960) – report adverse drug reactions

AIDS (1980s) – fast track approval, “buyer power”

Viagra (1998)

Tamiflu – H1N1 (swine flu) pandemic (2009)

NICE (1999) – the affordability factor

Vioxx – anti-inflammatory – 1999-2004 due to litigation

Avandia – Type 2 (non-insulin dependent) diabetes - 1999-2010
also due to litigation
How do drugs work?
 The Biological Target - enzyme or receptor
 Where is the target - part of “us” or elsewhere
 Paul Ehrlich, Nobel Prize 1908, salvarsan;
 blood-brain barrier; “Lock and Key”
hypothesis; chemotherapy and “magic bullet”
The Lock - Active Site of
Enzyme/Receptor
The Key - the Drug
The “Lock and Key” analogy
Key
Lock
Binding
 Here the KEY is the natural substrate
 Binding of the KEY to the LOCK (an enzyme
or a receptor) then causes a response – a
shape change in the protein/receptor
The “Lock and Key” analogy
Key
Lock
Binding
Biological
Response
 Here the KEY is the natural substrate
 Binding of the KEY to the LOCK (an enzyme
or a receptor) then causes a response – a
shape change in the protein/receptor
But when an effective drug is present
Biological response
is altered OR shut down
vs.
Binding of Drug
is preferred
 Drug may bind preferentially to the “active site”
 Antagonist – binds and BLOCKS
 Agonist – binds and ACTIVATES
 Partial agonist – induces a partial response
Who discovers drugs? Doctors?
 Identify biological target - biology
 Prioritise/ validate target – pharmacology and
chemistry
 Identify and optimise lead molecules –
chemistry/pharmacology
 Preclinical studies – chemistry/pharmacology/
toxicology
 Formulation - pharmaceutical sciences
 Clinical evaluation – medicine
 Manufacture - chemical engineering
Getting a drug to market
 Disease target - possible drug candidates
 Pre-clinical testing; R&D (1-3 yrs)
 Toxicology, “ADME”
 Clinical R&D (2-10 yrs; Av. 5yrs)
 Phase 1 – healthy volunteers
 Phase 2 – small patient group
 Phase 3 – larger patient group
 Regulatory approval (2-10(!) yrs)
 Market
 Phase 4 – long term monitoring
The Gamble - wastage and timescale
 For EACH DRUG approved, an average of 7500
compounds will have been made
 Of this 7500, an average of 21 will be tested for
subacute toxicology, 6.5 will be tested in humans and
2.5 will reach Phase 3 – 1 then gets to market………
 Entire process takes on average 12 years
 Costs $138M (1975); $800M (2000); $1.6Bn (2008)
 Development costs do NOT include pre-launch
marketing which can DOUBLE costs
The “Pay Off”……to the companies
 Typical R&D budget: 33% R and 67%D
 R&D = 15 to 25 % of sales turnover
 Patent protection – 20 years from filing
 On average, 11yrs. of productive market life
 Losec – $2.7Bn in 1998; Nexium (single
enantiomer) $7.7Bn in 2008
 Lipitor - $1Bn in 1998; $13.8Bn in 2008
The “Pay Off”…….to us
 Massive contributions to health, quality of life,
reduced child mortality, life expectancy
 Vaccines have eradicated major disease –
smallpox; vaccines for malaria and pneumonia
soon……..?
 But costs and accessibility to healthcare are
becoming major social and geopolitical issues
 And, is there something seedy about making
money out of illness?
 What will happen into the future?
The Companies in 2010
Total Sales $billions
1
2
3
4
5
6
7
8
9
10
Johnson & Johnson
Pfizer
Roche
GSK
Novartis
Sanofi-Aventis
AstraZeneca
Abbott
Merck
Bayer
61.9
50.0
47.4
45.8
44.3
42.0
32.8
30.8
27.4
22.3
Major Therapeutic Targets
CNS
Metabolic
Cardiovascular
Anti-infectives
Respiratory
Gentio-urinary
Musculoskeletal
Oncology
Top 10 Therapies - sales in 2008 (US$Bn)
2008 sales
% share
Oncology agents
45.8
6.4
Lipid regulators
34.2
4.8
Respiratory agents
30.7
4.3
Acid pump inhibitors
26.7
3.8
Antidiabetics
26.0
3.7
Antipsychotics
22.4
3.1
Angiotensin antagonists
21.6
3.0
Antidepressants
20.4
2.9
US$227.8Bn
32.1%
What makes a good drug?
Lipinski's rules (Chris Lipinski – 1997)
In general, an orally active drug will meet most of the
following:
•
Not more than 5 hydrogen bond donors (nitrogen or
oxygen atoms with one or more hydrogen atoms)
•
Not more than 10 hydrogen bond acceptors (nitrogen or
oxygen atoms)
•
A molecular weight under 500 daltons
•
An octanol-water partition coefficient log P of less than 5
•
http://www.molinspiration.com/cgi-bin/properties
Case Study
Cimetidine (Tagamet)
1979
 H2 blocker; anti-ulcer/heartburn
US
1976
UK
 1983 First drug to reach $1Bn
1974
 Cleared for OTC in 1995
1972
1970
1968
1966
1964
Programme
starts
Into volunteers
Cimetidine
Burimamide
First lead
What is a drug?
“A Chemical Substance that Interacts with a Living
System and Produces a Biological Response”