Escolar Documentos
Profissional Documentos
Cultura Documentos
INTRODUCTION ON NEW
DRUG DEVELOPMENT
Prof. JanHasker G. Jonkman,
Ph.D., F.C.P., F.R.Q.A., R.Ph.,
Clinical Pharmacologist
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Country
Sales
(billion US $)
% of worldwide
sales
North America
342
39.1
Europe
Asia (excluding Japan),
Africa and Australia
Japan
Latin America
TOTAL
250
28.6
129
99
53
875
14.8
11.3
6.2
100.0
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Therapeutic Class
Sales
(billion US $)
Cytostatics
Cholesterol &
Triglyceride reducers
Respiratory agents
Antidiabetics
Anti-ulcerants
Angiotensin-II inhibitors
Antipsychotics
Autoimmune agents
Antidepressants
HIV Antivirals
% of worldwide
sales
% of growth
(vs 2009)
56.0
6.4
+ 6.7
36.4
35.9
34.4
28.0
26.6
25.4
20.7
20.2
15.4
4.2
4.1
3.9
3.2
3.0
2.9
2.4
2.3
1.8
+ 2.0
+ 7.0
+ 12.2
- 6.5
+ 4.5
+ 9.0
+ 14.7
+ 3.4
+ 13.2
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4.
5.
Product
Lipitor
(atorvastatin; antilipidic agent)
Plavix
(clopidogrel; antithrombic agent)
Seretide
(salmeterol/fluticasone;
asthma/COPD)
Nexium
(esomeprazol; antiulcer)
Seroquel
(quetiapine; antipsychotic agent)
Sales
(billion US $)
12.7
Company
Pfizer
8.8
Sanofi-Aventis
8.5
GSK
8.4
Astra Zeneca
6.8
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Product
Sales
(billion US $)
Crestor
(rosuvastatine; antilipidic agent)
Enbrel
(etanercept; antirheumatic agent)
Remicade
(infliximab; antirheumatic agent)
Humira
(adalimulab; antirheumatic agent)
Zyprexa
(olanzapine; antipsychotic agent)
Company
6.8
Astra Zeneca
7.3
Wyeth
6.0
6.0
Schering-Plough
(Merck&Co)
Abbott
5.7
Eli Lilly
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Company
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
Pfizer (US)
Sanofi-Aventis (F/Ger)
Merck & Co (US)
Novartis (Swi)
GlaxoSmithKline (UK)
Roche (Swi)
AstraZeneca (Swe/UK)
Johnson & Johnson (US)
Eli Lilly & Co (US)
Abbott (US)
Pharma sales
(billion US $)
58.2
40.3
39.8
39.1
36.1
35.6
33.3
22.4
21.1
19.9
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Rank
Company
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
Merck & Co
Pfizer
Roche
Novartis
GlaxoSmithKline
Sanofi-Aventis
AstraZeneca
Eli Lilly
Johnson & Johnson
Abbott
R&D spend
(US $ billion)
11.0
9.4
8.7
7.7
5.9
5.8
5.3
4.9
4.4
3.7
R&D as
%of sales
27.6
16.2
24.4
19.7
16.3
14.4
13.2
22.7
19.6
18.6
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36
27
26
25
24
22
21
18
17
2000
2001
2002
21
21
20
2003
2004
2005
2006
2007
2008
2009
2010
2011
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50
42
39
39
34
32
24
24
2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
22
21
2010
2011
(Source: EMEA)
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Studies in animals
Studies in patients
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SYNTHESIS (1)
(the development of a new therapeutic effective
molecule = drug / medicine)
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SYNTHESIS (2)
2005
2010
12%
18%
88%
Biotechnology
82%
Organic Chemistry
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SYNTHESIS (3)
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Studies in animals
2 - 4 years
Studies in humans
4 - 5 years
Registration procedure :
2 - 3 years
TOTAL
8 - 12 years
average
10 years
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802
467
335
318
214
104
84
138
54
Preclinical
Clinical
Total
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17 - 20 years
(depending on country)
Thereafter:
many generic versions of the drug
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- cats
- dogs
- pigs (!)
- monkeys
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BIOANALYTICAL
LABORATORY
BIOMETRICS
(STATISTICS)
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BIOANALYTICAL
LABORATORY
BIOMETRICS
(STATISTICS)
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Phase II
(= therapeutic exploration)
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Protocol
Participants
Phase I
Phase II
Phase III
Phase IV
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BIOANALYTICAL
LABORATORY
BIOMETRICS
(STATISTICS)
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1% (pro cent)
10 g/kg
10 mg/g
1 (pro mille)
1 g/kg
1 mg/g
0,6 litre
1 milligram
= 10-3 g
6 litres
= 0.001 g
1 mg/kg
1 g/g
1 microgram
= 10-6 g
6.000 litres
1 lump
of sugar (6 g)
dissolved in:
= 0.000 001 g
1 g/kg
1 ng/g
1 nanogram
= 10-9 g
6 million litres
1 ng/kg
1 pg/g
1 picrogram
= 10-12 g
6 milliard litres
1 pg/kg
1 fg/g
1 femtogram
= 10-15 g
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BIOANALYTICAL
LABORATORY
BIOMETRICS
(STATISTICS)
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PHASE I - STUDIES
(non-therapeutic studies; safety) (1)
Aim
to gather fundamental scientific information,
enabling the determination of the correct dosage
for use in larger clinical studies
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PHASE I - STUDIES
(non-therapeutic studies; safety) (2)
Required by authorities
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PHASE I - STUDIES
(non-therapeutic studies; safety) (3)
Questions:
Adverse events (= side effects;
dosage)
Pharmacokinetics
how long does the drug stay in the body?
(
dosing frequency)
how is the drug metabolized in the body?
single and multiple dose (up to 4 weeks)
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PHASE I - STUDIES
(non-therapeutic studies; safety) (4)
Mass balance studies (14C)
Biopharmaceutics (optimal dosage form)
Result: dosing schedule (dose + frequency)
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PHASE I - STUDIES
(non-therapeutic studies; safety) (5)
Characteristics of Phase I studies:
work accurately
very detailed protocol ( 50 pages)
very detailed procedures (300 SOPs)
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PHASE I - STUDIES
(non-therapeutic studies; safety) (6)
Important aspects of Phase I studies:
fully equipped modern in-house clinical research centre
fully equipped modern bioanalytical laboratory
biometrics (data management, pharmacokinetics, statistics)
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PHASE II - STUDIES
(therapeutic studies; efficacy; therapeutic exploration)
Patients in university hospitals ( 250)
Pharmacodynamics (measurements of effects)
single dose (Proof of Concept; Proof of Principle)
(multiple dose)
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EMA
(European Medicines
Agency, London, UK)
(In the past: EMEA: European
Medicines Evaluation Agency)
USA:
FDA
(Food and Drug Administration)
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Definition:
Process of reviewing and assessing the dossier to
support a medicinal product in view of its marketing,
finalized by granting of the product license to sell it
(also called: registration, approval or licensing)
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Application is called:
USA: New Drug Application (NDA)
EU: Marketing Authorization Application (MAA)
or (in general): registration dossier
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Module 1
1.0
2.1
2.2
2.4
2.5
2.3
Module 3
Quality
2.
6
Module 4
Nonclinical
Study Reports
(Source: L. Vromans)
2.7
Module 5
Clinical
Study Reports
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(Source: L. Vromans)
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(Source: L. Vromans)
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(Source: L. Vromans)
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(Source: L. Vromans)
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USA
Top-down approach in
evaluation
Expert evaluations
Raw data only analysed if
grounds for doubt are
found
Some interaction before
submission (increasing)
Limited company
interaction with experts
during procedure
Accelerated assessment
for high medical need
products
(Source: L. Vromans)
Bottom-up approach in
evaluation
ISS / ISE, integrated
summaries of safety &
efficacy
FDA always analyses raw
data
Many meetings before
submission
Advisory Committee
involvement
Accelerated development
and priority review for high
medical need products
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USA
Withdrawal if a negative
opinion is expected
Labelling can not contain
detailed study results
(Source: L. Vromans)
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Maintenance (1)
Marketing authorization is valid for 5 years
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Maintenance (2)
Marketing authorization need maintenance:
Variations
quality variations to improve production method
new indications, new formulations, new route of administration
results of pharmacovigilance, new safety information
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Pharmacovigilance (1)
purpose: to provide accurate, complete and timely
information about the benefit-risk profile of a medical
product throughout its life cycle
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Pharmacovigilance (2)
each pharmaceutical company need to maintain a system
that ensures:
- an active, systematic and continuous monitoring
of pharmacovigilance cases reviewed
- early detection of safety signals
- that appropriate actions are taken to minimize risks
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PHASE IV - STUDIES
(efficacy/safety; therapeutic use)
Patients (ambulant GPs; 25,000)
Performed after marketing authorization was
obtained
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CONCLUSIONS