Introduction to the Pharmaceutical Industry

crunchkingofprussiaBiotechnology

Dec 6, 2012 (4 years and 11 months ago)

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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”


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?


What is a drug?



A Chemical Substance that Interacts with a Living
System and Produces a Biological Response”

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 (
1980
s)


……….affordable (
1990
s)


……………
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 (
1980
s)


fast track approval, “buyer power”


Viagra (
1998
)


Tamiflu



H
1
N
1
(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

Lock

Key

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

Lock

Key

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

Binding of Drug

is preferred

vs.

Biological response

is altered
OR shut down


But when
an effective drug is present


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.
5
yrs)


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 $
138
M (
1975
); $
800
M (
2000
);
$
1.6
Bn (
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,
11
yrs. of
productive

market life


Losec



$
2.7
Bn in
1998
;
Nexium

(single
enantiomer
)
$
7.7
Bn in
2008


Lipitor

-

$
1
Bn in
1998
;
$
13.8
Bn 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

Johnson & Johnson

61.9

2

Pfizer

50
.0

3

Roche


47.4

4

GSK


45.8

5

Novartis

44.3

6

Sanofi
-
Aventis


42.0

7

AstraZeneca

32.8

8

Abbott

30.8

9

Merck

27.4

10

Bayer

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$
227.8
Bn

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)

1964

1966

1968

1970

1972

1974

1976

1979

First lead

Burimamide

Cimetidine

Into volunteers


UK


US


Programme
starts


H
2

blocker; anti
-
ulcer/heartburn


1983
First drug to reach $
1
Bn


Cleared for OTC in
1995

What is a drug?



A Chemical Substance that Interacts with a Living
System and Produces a Biological Response”