The document discusses effective pathways for late-stage biosimilar clinical trials. It outlines strategies for optimizing patient recruitment and retention, leveraging data-driven monitoring, and enhancing operational efficiencies. Specific considerations include understanding regulatory environments, selecting appropriate reference products and clinical endpoints, identifying qualified investigator sites, and employing risk-based monitoring approaches using data surveillance technologies. The presentation emphasizes that innovative trial designs and leveraging data-driven approaches will be important to efficiently reach biosimilar approval in the intensifying race to launch new products.

1. © 2017 PAREXEL INTERNATIONAL CORP.
EFFECTIVE LATE
STAGE PATHWAYS
FOR BIOSIMILAR
PRODUCTS
Dr. JingPing Yeo
Corporate Vice President, Clinical Research
Services, PAREXEL International
February 17th, 2017
PAREXEL India Symposium 2017

2. © 2017 PAREXEL INTERNATIONAL CORP. / 2
AGENDA
EFFECTIVE LATE STAGE
PATHWAYS FOR
BIOSIMILAR PRODUCTS
• Enhancing operational efficiencies of
Late Phase Biosimilar trials
• Optimizing patient recruitment and
retention strategies
• Investigator interest
• Acquiring the reference product and changes in
the reference product
• Leveraging data driven monitoring for
data surveillance in Biosimilar studies

3. © 2017 PAREXEL INTERNATIONAL CORP. / 3
SEAMLESS OPERATIONAL INTEGRATION
Strategic Development Clinical Trials Marketing Approval
Consulting
Development Plan
Commercialization
Plan
Early Phase
Phase I
Global Clinical
Research Services
Phase III
Consulting
Regulatory
Filings
 Create aggressive defensible
development
plans and gain
Agency buy-in
 Maximize ROI
through a compelling value
proposition
• Overcome local regulatory and operational hurdles
• Optimise patient access – “global reach”
• Optimize operational efficiencies and risk
management via integrated technologies
• Direct experience in the preparation
and submission
of Biosimilar CTDs that resulted in
approval
• Negotiation of Phase IV
commitments (risk management)
• Implement risk sharing program that drives speed & efficiency
• Implement dedicated leadership & expertise model

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BIOSIMILAR COMPOUND GLOBALIZATION ROADMAP
Phase III in US, Europe & Asia (>500 subjects)
• Therapeutic equivalence (safety and immunogenicity)
• 2 arms
• Investigational product – xx subjects
• Reference product (EU sourced) – xx subjects
Global market access
• Leverage the Phase I and Phase III study to apply Asia & EU MAA
• Leverage EU MAA to apply for most emerging market MAA without or limited
additional studies (local patients required in India, Russia, Mexico, Japan, Korea)
Phase I & Phase Ib PK in a particular country
• PK Equivalence in specific patient population
• 2 arms
• Investigational product – xx subjects
• Reference product (EU sourced) – xx subjects

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ACCELERATING THE PHASE III STUDY
• Conservative Plan (Long overall timeline, Low risk if true no similarity)
• Aggressive Plan (Short overall timeline, High risk if true no similarity)
• Relative aggressive and Control the risk
• Aggressive Plan and minimized the overall sample size
Phase Ia
Phase Ib PK
Phase III
Phase Ia
Phase Ib PK
Phase III
Phase Ia
Phase Ib PK
Phase III
Phase Ia
Phase Ib PK/ Phase III

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OPERATIONAL CONSIDERATIONS
 Understanding the regulatory environment
• Early engagement of regulators (open to negotiation)
• Manage the specific requirements of IRB/EC
– Work closely with sites, lab to collect required documentation
• Identify phase III sites in parallel with preclinical/Phase I work
– RA and IRB/IEC submissions made in parallel
– Consider early Phase III submissions
• Appropriate patient population and sample size
– Required designs not set in stone; early health authority input is critical
– Limited relevance of original innovator’s basis of approval
– Safety as a factor for sample size
 Knowing the “right” sites and engaging the investigators

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OPERATIONAL CONSIDERATIONS (2)
 Ensuring quality data and compliance
• Contingency plan in monitoring plan for missing data
• Clear guidelines on SD requirement, CRF completion and protocol deviation management
• Leverage data driven monitoring technology & data surveillance tools
• Comprehensive/continuous training, tools and lessons learned to sites
 Identifying the right clinical endpoints
• Include biomarkers or other surrogates predictive of clinical efficacy
 Selecting the reference products
• Obtain from a combination of sources
• May need to demonstrate in-vitro comparability to multiple sources

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KEY SUCCESS FACTORS IN PATIENT ENROLMENT
Proactive engagement with sites
 Accelerate site start-up and site activation
• Weekly Prescreening log
• Offer site support – e.g., via SMOs
• Study level documentation in English, localized in each country
 Investigator relationship and retention is key
• Bi-weekly enrollment status letter to all PIs, and Weekly booster call by CRA
• Engage the sites at identification and qualification phase
• Emphasize the study benefits including the extension study
 Patient and health care provider confidence
• Perception that biosimilars have less rigid pre and post market data requirements
• As a new category of drug products, need to educate on safety and efficacy
Make effective use of Asian countries
 Leverage on established footprint and infrastructure

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IDEAL SITE CRITERIA
Key Factors
• Does the site have this patient population?
• Is the site correctly aligned to the protocol
criteria?
• Investigators with affiliation to country
therapeutic groups/disease networks
• The number of studies that PI conduct in
parallel?
The “Right” Sites
• Sites that routinely treat specific indication patients
with biologic agents
• Sites that PAREXEL has a working relationship with,
or has pre-identified, including good-performing sites
from the previous biosimilar studies
• Investigators with affiliation with strong network of
indication working groups
• Centers that have an adequate facility to conduct
clinical trials for patients (e.g. chest x-ray, ESR
measurement etc.)
PATIENT EXPERIENECE & TECHNOLOGY PATIENTS MAKE INFO MORE TRANSPARENT,
ACCESSIBLE, PATIENT FRIENDLY
• Improve participation
& experience
• Reduce patient
burden
• Innovate data capture
Difficult to:
• Identify sites
• Engage in a
meaningful
conversation

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PATIENT ENROLLMENT/RETENTION STRATEGY
Newsletters Referrals
Patient Materials /
Others
Resource /
Compensation
Booster Actions
• Give a heads-up in
advance to
investigators to
assign sufficient
Sub-Is/ SCs
• Increased
investigator fee for
high enrollers
considering the
workload of site staff
• Assign more CRA
hours for high
recruiting sites to
provide more site
support.
• Compensations to
patients for
transportation fee
• Recommend
‘Meetings within
hospital’ to create
awareness amongst
colleagues on regular
basis.
• Laminated charts for
trial design and trial
flow chart for easy
reference
• Dear Doctor letter to
other doctors within
the country explaining
Study
• Prepare and distribute
newsletters on a
regular basis with up
to date study updates
• Highlight enrollment
• Newsletters to
address enrollment
issues and major
changes/ updates to
the study procedures
• Targets - high
enrollers –
Appreciation and
Recognition!!
• Patient retention
status update
• Close contact with
the sites weekly
during start-up to
keep continued site
engagement
• PL/COL/sponsor
visits sites, discuss
with PI to motivate
• Interim SC or local
investigator meeting
(experience sharing
from high recruiters
or good performance
sites)
• To share with PI the
publication policy
during SIV, if
applicable
• Patients facing tools:
poster, study
brochure, etc.
• Identify Back-up sites
at the beginning and
get those initiated if
applicable
• Patient retention
materials;
appointment
reminder card, etc.

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LEVERAGING DATA DRIVEN MONITORING
(Off site &
centralized monitoring)

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Improved data quality and patient safety
RISK-BASED OPERATIONAL STRATEGY
Design
• Protocol Optimization (Design)
• Data Driven Site Placement
• Data Driven Patient Recruitment
Risk
Avoidance
Execution
• Mitigation & Contingency Planning
• Adaptive Monitoring & Data Surveillance
• Ongoing Risk Measurement
Risk
Monitoring
Delivery Outcomes
• Risk at Acceptable Levels
• Mitigation & Triggered Contingency Deployment
• Data Driven Operational Interventions
Risk
Mitigation
DATA-DRIVEN OPERATIONAL STRATEGY
CONTINUOUS FOCUS ON RISK MANAGEMENT
Risk
Assessment
Assessment
• Identification of Risk
• Analysis of Risk
• Evaluation of Risk
DataSurveillanceTeam
Project Lead
Global Clinical Operations
Lead
Data Management Lead
Medical Monitor(s)
Biostatistics Lead
Primary Statistical
Programmer

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RISK CATEGORIES
Data Quality
Data timeliness
Milestone delay
Protocol Adherence
Site Management Quality
Site Visit compliance
Subject Safety
DDM APPLICATION RISK CATEGORIES

14. © 2017 PAREXEL INTERNATIONAL CORP. / 14
EXAMPLES OF RISKS IDENTIFIED – FROM DDM
High risk sites
0.00
0.50
1.00
1.50
2.00
2.50
3.00
3.50
4.00
4.50
5.00
Total
Data Quality
0.58
Data Timeliness
0.54
Protocol
Adherence
0.07
Site visit compliance
0.81
Subject safety
0.24
Site
management
Quality 0.98
Delay milestone
3.07
Risk Categories
Riskscore

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DATA SURVEILLANCE – COUPLING WITH TECHNOLOGY
• Standard library includes
+60 visualizations focused
on safety parameters
across 17 SDTM domains
• Visualizations align with the
Data Surveillance Plan
• Output can be accessed by
sponsor on continuous
basis

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RISKS IDENTIFIED – FROM DATA SURVEILLANCE
Inclusion/Exclusion Criteria Not Met - overall trends
INC 4. ECOG performance status of
0-1 at Screening.
INC 6. At least one measurable
lesion according to RECIST v1.1.
EXC18. Any of the following events
within 6 months prior to Screening
EXC 20. Serologically confirmed
active or chronic disease
Action: re-train investigator (as anticancer
agents are prohibited within the study
treatment). Only anticancer agents should be
reported with correspondent indication.
Supportive treatment agents should not be
reported as “anticancer”
Con Meds Distribution by Country

17. © 2017 PAREXEL INTERNATIONAL CORP. / 17
GAME CHANGER
• Race to launch biosimilar products will intensify
• Careful strategic planning and understanding of operational challenges
are critical
• Innovative trial designs needed – to reach biosimilar endpoints sooner
• Leverage on innovative platforms (Data Driven Monitoring) to optimise
study execution and deliver results of high scientific and statistical
integrity

18. © 2017 PAREXEL INTERNATIONAL CORP. / 18© 2016 PAREXEL INTERNATIONAL CORP. /
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