Senior Vice-President Global Head de Investigaciones Clínicas de MSD

1. Current and Future Innovation :
A perspective from the International Pharmaceutical Industry
1
Andy Lee
Senior Vice-President
Head of Global Clinical Trial Operations
Merck Research Laboratories, USA

2. 2
Our Strategy
We will follow the science to
discover, develop and bring to
market innovative human and
animal health medicines, vaccines
and solutions that address
significant unmet medical needs
and responsibly deliver patient
and customer value.
• INVENT – pursue the most
promising internal and external
science to address significant
unmet medical needs
• EXECUTE – prioritize
resources behind our key
opportunities
• ADAPT – develop our people,
culture and business model to
evolve with a dynamic landscape

3. 3

4. 2018: A Story by the Numbers
4As of year-end 2018
242
Late- and Early-Stage
Database locks
accomplished
~57,900,000
Clinical data
points processed
~430,000
Global pharmacovigilance
cases processed
~260
Late-stage development
clinical trials supported
~130
External Collaboration &
Joint Venture studies
supported
58
Protocols approved
190
Face-to-face investigator
meetings held
376
Virtual investigator
meetings conducted
~83,000
Onsite monitoring
visits conducted
47
Countries where we have
a direct presence
~45,000
Active patients supported
~11,600
Active sites supported
75
Clinical Study Reports
(CSRs) completed
~4,760
Patient narratives
completed
92
Inspections conducted
115
Filing Documents

5. Development Plan
5
DEVELOPMENT
PLAN
Top-notch Science; Patient Safety; 100% Compliance
UNMET
MEDICAL NEED
1. Burden of disease
2. Deficits of current
therapy
VALUE
PROPOSITION
1. Unambiguous
advantage vs. current
therapies
2. Regulatory path
3. Payer perspective
• Who pays, who
benefits
• Cost-effectiveness
• Affordability
• Prioritization of use
DEFINITIVE, EFFICIENT
CLINICAL PROGRAM
1. Dose, formulation
2. Efficient study designs
and statistical plans
3. Selection of countries
4. Safety database
5. Economic dossier
OBJECTIVE
MANAGEMENT
1. Real-time safety &
compliance monitoring
2. Endpoint collection
methodologies
3. Go/No Go decisions
4. Monitor landscape
5. Contingency planning

6. Our Core Clinical Trial Operations Business
6
Strategic input and
feedback into global
clinical development plan
and operational plans to
increase project value
and R&D productivity
LOCKED
DATABASE
CLINICAL TRIAL
EXECUTION
DOCUMENTATION
FOR REGULATORY
SUBMISSION
EXPERIMENTAL
CONCEPT
Our value chain
• Design, plan, implement, project-manage,
monitor, data-manage and complete protocols
conducted globally
• Adhere to the highest ethical and regulatory
standards: ICH and GCP
• Meet internal quality, dependability, speed,
flexibility, cost and value goals
Deliver and
manage data:
“data is our currency”
Program-level
planning
Trial
mgmt.
Study
start-up
Execution
and site
mgmt.
Data
processing
Safety
mgmt.
Quality
mgmt.
Protocol Clinical study
report (CSR)
Acronyms: ICH GCP – International Conference on Harmonization Good Clinical Practices

7. PDT/CST/CTT Relationship
7
Product
Development
Team (PDT)
Clinical Sub-Team
(CST)
Clinical Trial Team(s)
(CTT)
Program level conversations to
decide broad strategy for the
product and drive execution
Strategic program planning
and execution
Cross-functional, operational
oversight and execution for a
clinical trial

8. Our Planning Cascade
8
MEDICAL/CLINICAL/REGULATORY/COMMERCIAL
OPERATIONS
Protocol
Site
Recruitment
Plans
PTA
Site
Initiation
Protocol
Feasibility
Protocol
Recruitment
Plan
Site
Assessment
Therapeutic Area
Level Strategies
Study
Execution
Program Planning
Study Planning
Project Planning
Protocol
Synopsis
Development Plan
CDP/MIP
Protocol
Outlines
Program
Feasibility
Country Strategy
Country Placement Site Selection

9. Protocol Design
• The best protocols ask the (few) key scientific questions, they are
not fishing expeditions
–Simplify
–Fewer procedures
• Need to balance between burden-on-the-patient and volume of
data collected
• External validation (field testing) … ask
–“is this how medicine is practiced?”
• Feasibility in countries prior to selection and engagement
• Protocol amendments are costly and can result in added
complexity at the site level (informed consent)
9

10. What Drives Country/Site Selection
A balanced approach is applied considering:
• Regulatory environment
• Intellectual Property Protection
• How medicine is practiced
–Medical need
–Available patients
–Standard of care
• Logistics and Resources
• Geographic Flexibility Model
–Ebola, Dengue, Rare Diseases
–Epidemiology, incidence and prevalence of disease
10

11. Site Contribution by Randomized Patients
11
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
110%
0
10
20
30
40
50
60
70
80
90
100
1
182
363
544
725
906
1087
1268
1449
1630
1811
1992
2173
2354
2535
2716
2897
3078
3259
3440
3621
3802
3983
4164
4345
4526
4707
4888
5069
5250
5431
5612
5793
5974
6155
6336
6517
6698
6879
7060
7241
7422
7603
7784
7965
8146
8327
8508
8689
8870
9051
9232
9413
9594
9775
9956
10137
10318
10499
10680
10861
Cumulative%ofPatients
NumberofPatients
# Patients % of Patients
30 % of Sites (3,335 sites) provide
80% of Patients
10,984 Sites
92,956 Patients
~45 % of Sites (4,904 sites)
provide lowest 5% of Patients

12. Pembrolizumab Monotherapy Has Shown Activity in >20 Tumors
ChangeFromBaselineinTumorSize,%
1. Daud A et al. ASCO 2015; 2. Garon EB et al. ESMO 2014; 3. Seiwert T et al. ASCO 2015; 4. Plimack E et al. ASCO 2015; 5. Nanda R et al. SABCS 2014; 6. Bang YJ et al. ASCO 2015 ; 7. Moskowitz C et al. ASH 2014; 8. Zinzani PL et al. ASH 2015; 9. Alley
EA et al. AACR 2015; 10. Varga A et al. ASCO 2015; 11. Ott PA et al. 2015 ASCO; 12. Doi T et al. ASCO 2015; 13. Hsu C et al. ECC 2015; 14. Ott PA et al. ECC 2015; 15. Bang Y-J et al. ECC 2015; 16. O’Neil B et al. ECC 2015; 17. Rugo HS et al. SABCS 2015;
18. Frenel JS et al. ASCO 2016; 19. Mehnert JM et al. ASCO 2016; 20. Cohen R et al. ASCO 2016; 21. Ott PA et al. ASCO 2016; 22. Hansen AR et al. ESMO 2016; 23. Reardeon D et al. SNO 2016; 24. Diaz L et al. ASCO 2017.
-100
0
100
-100
0
100
-100
0
100
Melanoma1
-100
0
100
NSCLC2
-100
0
100
Gastric6
-100
0
100
-100
0
100
H&N3 TNBC5
-100
0
100
cHL7
-100
0
100
NHL PMBCL8Urothelial4
-100
0
100
Mesothelioma9
-100
0
100
Anal14
-100
0
100
-100
0
100
SCLC11
-100
0
100
NPC13
-100
0
100
Biliary Tract15
-100
0
100
Colorectal16
Esophageal12
-100
0
100
Ovarian10
-100
0
100
ER+/HER2– BC17 Cervical18 Thyroid19 Salivary20 Endometrial21 Prostate22 GBM23
-100
0
100
-100
0
100
-100
0
100
-100
0
100
-100
0
100
-100
0
100
MSI-H24
Updated 18-Aug-2017

13. Testing in Different Treatment Settings
Prevention
and
Diagnosis
Neo-Adjuvant
3 tumor types
3 registration studies
3 combo
Adjuvant
5 tumor types
6 registration studies
5 mono/1 combo
1st Line
12 tumor types
24 registration studies
7 mono/17 combo
2nd Line +
16 tumor types
28 registration studies
24 mono/4 combo
Clinical Development
Disease Progression
Goal: Identify the best treatment
for each group of patients
What are rational combination therapies ? What is the Standard of Care ?

14. Pembrolizumab
Pembrolizumab as
Olaparib
Lenvatinib

15. Pembrolizumab COMBINATIONS
Data-Driven Approach to Signal Finding
• With Chemotherapy in Multiple Tumor TypesStandard Therapies
• With CTLA-4 in Multiple Tumor Types
• With T-VEC in Melanoma
• With LAG-3 in Multiple Tumor Types
• With CAVATEK in Melanoma
Immuno-modulators
• With VEGF/TKI in Multiple Tumor Types
• With PARP in Multiple Tumor Types
Targeted Therapies
Diverse signal-finding effort with rational combinations leveraging internal, collaboration,
and investigator-initiated trials (>500 in total )
Rapidly progress
early promising
signals into
registration
studies

17. Pembrolizumab in combination with
targeted therapy/immunotherapy
Pembrolizumab in combination with
vaccines/viruses/bacteria
Pembrolizumab in combination
with chemotherapy
Strategic Alliances – PARP, TKI, MEK

18. 18
2018 – Translational Oncology Studies – Next Generation
Biomarker Approaches Inform Combination Strategies
Which Patients are likely to respond to which therapies ?
Tissue vs circulating markers ?

19. 19
Adaptation for the Future
• Diagnosis and treatment paradigms are changing
• Monotherapies may be limited to certain patient profiles
• Combination therapies are evolving rapidly, with increasing Sponsor collaboration
• Personalized treatments are evolving rapidly
• Clinical Trials are complex and expensive
• Interdisciplinary research teams are needed to develop new medicines (oncologist, surgeon,
radiologist, pathologist and specialty laboratories)
• Panel Discussion – Challenges facing cancer research in Chile (12.20 – 12.50)

20. Chile Studies, Sites and Subjects by Therapeutic Area
Company-Sponsored Only*
*As of 31-May-2019
Number of sites
Number of company-managed studies
Number of Ongoing Subjects
20

21. Chile Study Approval Process

22. CYCLE TIMES FOR STUDY STARTUP - CHILE
22
Days
FSR Avg (days) Study Count Avg (days) Study Count
Chile LATAM (inc. Chile)
2016 142 7 226 47
2017 127 8 234 45
2018 134 10 166 48
Final Protocol Package Received (FPPR)  First Site Ready (FSR)
White line represents median

23. Summary
• Developing innovative new medicines is high-risk,
complex and costly
• Science should drive decision making
• Exquisite planning, design and operational
execution is essential to get the correct answers
• Medicine development is a team sport –
collaboration is essential between regulators,
scientists, Sponsors and an engaged ecosystem of
skilled physicians and ancillary professionals
• Several factors make some countries more
attractive to work in than others
23

24. 24

25. Hepatitis C – Example
• How does one conduct a trial that covers
all genotypes
– (GT 1-6)?
• Development team request:
– Pangenotypic regimen
– Simple dosing (and safe)
– Shorter treatment than 12 weeks
– Cirrhotic and non-cirrhotic patients
25

26. Challenges with Developing a Pangenotypical (GT1-GT6) HCV agent
• There are many different types of
HCV, based on differences in the
genomic sequence
• Genotypes 1-3 are found worldwide;
others have more limited distribution
• Genotype is important for predicting
response to treatment
North America
Europe, Western
Europe, Central
Europe, Eastern
Asia, Central
Asia Pacific, High Income
Asia, South
Asia, Southeast
Asia, East
Australasia
Sub-Saharan Africa, West
Sub-S Africa, Southern
Sub-S Africa, Central
North Africa/Middle East
Latin America, Andean
Latin America, Southern
Latin America, Tropical
Latin America, Central
Caribbean
Prevalence (Viremic)
0.0%-0.6%
0.6%-0.8%
0.8%-1.3%
1.3%-2.9%
2.9%-7.8%
Razavi H, Gower E, Estes C, Hindman S. Global HCV Genotypes. Poster presented at: AASLD: The Liver Meeting 2013; 2013 Nov
1-5; Washington, DC, United States.
26

27. HCV Genotype Distribution by Region
27Gower, E., Estes C., Hindman, S., Razavi-Shearer, K., Razavi, H. Global epidemiology and genotype distribution of the hepatitis C
virus. Journal of Hepatology 2014.