1. 1
Seminar 6-11-2012 Agenda
1. Drug Development – General Overview
2. Biopharmaceutics
 Definitions
 Types of products
 Development
 Production
 Quality Assurance
 Market and future developments
3. Biosimilars
 Definitions
 Products
 Regulatory aspects
 Challenges
 Market and Future Developments

2. 2
Jacques Schipper
- 1974 Master Chemistry and Molecular Pharmacology
- 1979 PhD Neuropharmacology
- 1983 Scientist University of Amsterdam
- 1992 Discovery Project Manager Antidepressants
Solvay Pharma
- 1999 International Development Manager Solvay Pharma
- 2007 Senior Project Director Organon
- 2009 Senior Project Director Schering Plough
- 2012 Senior Project Director MSD
- Senior expert PUM

3. Drug Development
General Overview
From Molecule to Market
Jacques Schipper, PUM
Lima, 6 November 2012

4. 4
From Molecule to Market (small molecules)
Knowledge & Medical need
Idea for New Therapy
Chemical Synthesis and Biological Testing
Selection of Development Candidate
Preclinical Safety Evaluation
Phase I - Clinical trials (Safety & Tolerance)
Phase II - Clinical Trials (Efficacy)
Phase III - Large Scale Clinical Trials
First Registration Submission
Approval and launched to market
Discovery
Development
Product
time
estimate
in years
>4
>8
> 1

5. 5
Drug Discovery Phase 1
Clinical Trials
Phase 2
Clinical Trials
Phase 3
Clinical Trials
Priority Substance
50%40%
60%
70%
Drug Candidate Survival Rates
Product Registration
Overall only 8% Survive
Probability of success in each phase
F
F
F
N
O
O
N
. maleate

6. 6
Global R&D expenditure has grown significantly
Confidential Slide No. 12
CMR International 2006/2007 Pharmaceutical R&D Factbook
PerspectiveInsightOpinion
Global pharmaceutical R&D expenditure 1996–2009p
0
10
20
30
40
50
60
70
80
1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006p 2007p 2008p 2009p
GlobalR&Dexpenditure(US$bn).
Year
P - Projected figures have been calculated based on an average annual growth in R&D expenditure between 2000 and 2005.

7. 7
Yet, the number of new approved drugs tend to decrease
Confidential Slide No. 54
CMR International 2006/2007 Pharmaceutical R&D Factbook
PerspectiveInsightOpinion
Number of new molecular entities and new active substances first
launched onto the world market 1996-2005
0
5
10
15
20
25
30
35
40
45
50
1996 1997 1998 1999 2000 2001 2002 2003 2004 2005
Year of first launch
NumberofNMEs/NASs
Number of NMEs first launched onto the world market
Number of NASs first launched onto the World Market

8. 8
Development time is long and has not decreased (in spite of
efforts)
Confidential Slide No. 55
CMR International 2006/2007 Pharmaceutical R&D Factbook
PerspectiveInsightOpinion
Development time for medicines first launched onto the world market
1998-2005
4
6
8
10
12
14
16
18
1998 1999 2000 2001 2002 2003 2004 2005*
Year of first launch
Developmenttime(3yearmovingaverage/years).
All Companies Major Companies
* The development time data point for 2005 includes data from 2004 and 2005 only
Major companies are defined as those spending =US$ 1.8 billion in 2005 on ethical pharmaceutical R&D.

9. 9
Research Strategy: How to select R&D projects
Medical need
Commercial
Opportunity
Scientific
Feasibility Viable Projects

10. 10
Lead-Finding
Teams
LO Teams ED Teams
Life Cycle
Teams
Project
Teams
Project Teams to facilitate development process
Target-focus
Disease-focus
Target selection
for LF
Target Engagement POC Lite POC
Push
from Target to
Clinical Disease
Pull
to Clinical Disease
from Target
LO nomination Approval

11. 11
If you leave it to the departments, this happens in projects

12. 12
Preclinical Development
safety pharmacology
acute toxicology
subacute toxicology
(2-4 weeks)
genotoxicity
Clinical
Candidate
Start clinical
pharmacology
Kg -production (GMP)
early dose form
Clinical Development Plan
Biomarker strategy
Proof of Concept Strategy
Development
Candidate

13. 13
Phase 1 : Bridging from animals into humans: translational
medicine and question based drug development
• Translational approach: alignment between animal and
clinical pharmacology
• Use of biomarkers
• Use of human models for disease state
• Proof of Concept definition and study design
• Question based drug development
– Presence / absence of the compound in the target organ
– Presence or absence of pharmacodynamic activity at well tolerated doses
– Appropriate or inappropriate pharmacodynamic characteristics according to the
therapeutic indication
Go/no-go decision
into PoC / Phase 2
Combined with safety and first clinical data

14. 14
Early Development
Team
Research and Early Development
PoC
Study
results
Full Development
in-house
Develop with
a Partner
Out-licence
Stop
Key decision points after Proof of Concept study

15. 15
Full Development Clinical Program
• Pivotal studies for proof of efficacy
• Pivotal studies for proof of safety
• Long term safety data (>100 patients for 1 year, >300 for 6months)
• Long term efficacy data (EU)
• Special populations
• Drug – drug interactions
• Etc
Typically takes more than 3 years at the expense of >200 M$ and
>3000 patients are included in clinical studies

16. Confidential
Summary