This webinar presentation discusses operationalizing advanced therapy clinical trials using lessons learned from past experiences. The webinar covers regulatory considerations, operational challenges, and case studies. Regulatory agencies require strategic engagement, assessment of regulatory readiness, and oversight of country requirements. Investigative sites face additional committee reviews and license applications. Manufacturing complex cell and gene therapies poses challenges around process transfer, scaling, and product availability. Aligning supply chain readiness, site capabilities, and an investigational product tracking process is key to avoiding delays. Developing a global strategy requires addressing requirements for manufacturing, stability data, labeling, and supply logistics early.

1. AVOIDING COMMON PITFALLS IN
CELL AND GENE THERAPY TRIALS
OPERATIONALIZING ADVANCED THERAPY CLINICAL TRIALS USING
HARD-WON LESSONS LEARNED

2. M A K I N G T H E C O M P L E X S E A M L E S S
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WEBINAR PRESENTERS
Jan Ohotski, PhD
Regulatory Submissions Manager
• 10 years experience in developing pharmaceuticals
• Global regulatory experience in developing advanced therapy
medicinal products across varying therapeutic indications –
Europe, North America, Latin America and Asia Pacific regions
• Subject matter expert in regulatory CMC surrounding the
development of ATMPs and complex protocol designs
Elizabeth Shepherd, PhD
Clinical Trial Manager
• 8 years experience in clinical research
• Global Phase I-III clinical trial management experience with
emphasis on operational execution of advanced therapeutics
• Subject matter expert in operational development of cell tracking
systems and processes

3. M A K I N G T H E C O M P L E X S E A M L E S S
WEBINAR OUTLINE
Cell and gene therapy background
Regulatory considerations
Operational considerations
Hurdles for cell therapies at the intersection of regulatory and operations
Case studies & best practices

4. M A K I N G T H E C O M P L E X S E A M L E S S
CELL AND GENE THERAPY BACKGROUND
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Advanced Therapy
Medicinal Products
(ATMP) or Cell and
Gene Therapies (CGT)
are an innovative group
of medicines based on
recombinant nucleic
acids (genes) or
engineered cells
and tissues offering
groundbreaking new
opportunities for the
treatment, prevention
and diagnosis of disease.
Novelty, complexity and
technical specificity of
ATMPs and CGTs pose
specific regulatory and
operational challenges to
the conduct of clinical
trials.
Regulations and
guidelines surrounding
ATMPs and CGTs vary
greatly between
countries posing
regulatory and
operational challenges
for companies
conducting global clinical
trials.

5. IT IS CRUCIAL TO ALIGN THE OVERALL
PRODUCT DEVELOPMENT STRATEGY WITH
REGULATORY, CLINICAL OPERATIONS,
MANUFACTURING AND SUPPLY CHAIN
REQUIREMENTS TO FACILITATE THE CLINICAL
DEVELOPMENT OF ATMPS AND CGTS.

6. M A K I N G T H E C O M P L E X S E A M L E S S
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MEDPACE EXPERIENCE WITH ATMP/CGT TRIALS
ATMP
expertise
Medical Directors
Leaders in the field
Advanced Clinical
Practitioners
Experience at clinical level
Investigational
product experience
Allogeneic and
Autologous
cellular products
Ex vivo and in vivo
gene transfer
Gene-editing
• CRISPR/Cas9
• TALEN
• Zinc finger
nucleases
ATMP trial
management
>7,000
enrolled subjects
28 countries
US, Europe, APAC
>1,570 sites
US and global ATMP
trial experience that spans
>70 trials
Clinical Trial Managers
Site and regulatory expertise
First in human
Highlights
Founded 1992
~3,600 employees
Global reach
Therapeutic focus
Integrated efficiency
Organic growth – stability

7. M A K I N G T H E C O M P L E X S E A M L E S S
TYPES OF ADVANCED THERAPY MEDICINAL PRODUCTS
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• United States
‒ Gene therapy product
‒ Human somatic cell therapy
product
‒ Combination product
• European Union
‒ Gene therapy medicinal products
‒ Somatic cell therapy medicinal
products
‒ Tissue engineered
medicinal products
‒ Combined advanced therapy
medicinal products
Cell
therapy
Gene
therapy
Genetically
modified
cell therapy

8. M A K I N G T H E C O M P L E X S E A M L E S S
REGULATORY CONSIDERATIONS FOR ATMP/CGT

9. M A K I N G T H E C O M P L E X S E A M L E S S
REGULATORY CONSIDERATIONS
COMMON PITFALLS IN GLOBAL TRIALS
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The most common pitfalls in advanced therapy trials are lack of:
These factors lead to delays in site activation, recruitment and timely
completion of the study.
Strategic
engagement
with the
authorities
Assessment
of regulatory
readiness
Regulatory
oversight in
operational
planning
Oversight of
country
requirements

10. M A K I N G T H E C O M P L E X S E A M L E S S
Strategic
Engagement
Scientific Advice
Pre-CTA submission
consultation
Pre-submission
consultation with
GMO* Authorities
Gap Analyses
Characteristics of the IP
Regulatory readiness
Documents required for
RA and EC submissions
Documents required
for GMO
submissions
IP Labelling &
Logistics
Compliance with
country regulations
Import, export and
transport licenses
Local depot
requirements
Regulatory
submissions
Additional review
bodies – site specific
Additional review
bodies – country
specific
Extended RA and
IRB/EC review
timelines
Cell and tissue
license
Manufacturing
license
GLOBAL REGULATORY CONSIDERATIONS
REGULATORY AND OPERATIONAL EXPERIENCE APPLIED
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*Genetically Modified Organisms

11. M A K I N G T H E C O M P L E X S E A M L E S S
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KEY CONSIDERATIONS
REGULATORY AND OPERATIONAL EXPERIENCE APPLIED
STRATEGIC
ENGAGEMENT
Scientific advice
• FDA and EMA scientific advice are often used to design the trial
and determine quality requirements.
• Depending on the country list, scientific advice should be obtained
from other regulatory authorities (e.g. China, Germany and Japan).
Pre-CTA submission
consultation
• Pre-CTA submission consultation is recommended to facilitate
site start-up (e.g. Argentina, Brazil and South Korea).
For Genetically Modified
Cell Therapies (GMCTs):
Pre-submission
consultation with GMO*
authorities
• Authorities responsible for reviewing the use of Genetically Modified
Organisms (GMO) should be contacted (e.g. Belgium, Norway and
Finland).

12. M A K I N G T H E C O M P L E X S E A M L E S S
KEY CONSIDERATIONS
REGULATORY AND OPERATIONAL EXPERIENCE APPLIED
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GAP ANALYSES
Characteristics of
the product
• Gene therapy – in vivo, ex vivo, route of delivery
• Cell therapy – autologous, allogeneic, type(s) of substantial modification(s)
Regulatory
readiness
• IMP dossier – manufacturing methods, starting materials, cell and tissue
testing requirements, formulation, product characterization, specifications,
stability/in-use stability.
• Investigator’s Brochure - proven mode of action, non-clinical safety studies.
• Protocol – long-term safety and efficacy follow-up and IP dose.
• Site specific cell and tissue licenses – handling, import, export and
manufacturing.
Documents required
for RA and
EC submissions
• Surgery/Apheresis manual, Cell therapy Manual, Tissue Handling Manual.
*Genetically Modified Organisms
For GMCTs:
Documents required
for GMO submissions
• Environmental Risk Assessment, Common application form, Summary form,
country-specific application forms (e.g. Australia, Brazil, Canada, Japan).
• Material Safety Data Sheet – biosafety level determined for safe handling of
the product.

13. M A K I N G T H E C O M P L E X S E A M L E S S
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KEY CONSIDERATIONS
REGULATORY AND OPERATIONAL EXPERIENCE APPLIED
Compliance with country
regulations
• Label design and strategy should be compliant with local
regulations – ATMPs are not exempt from the regulations of IP
labelling.
• Precaution language for handling, dosing and disposing
instructions is often mandatory (e.g. ”The package contains human
tissues or cells”). For GMCTs: “Contains genetically modified
organisms”.
• Auxiliary labels are required for syringes and IV bags used for
injection or infusion at the clinical sites.
Import, export and
transport licenses
• Country specific import, export and transport licenses issued by
the regulators should be obtained prior to site activation (e.g.
Australia, Brazil, China, Hong Kong, South Korea, Turkey).
Local depot requirements
IP LABELLING
AND
LOGISTICS
• It is advisable to set up a depot in countries with multiple clinical
sites. This requirement is assessed during country feasibility.

14. M A K I N G T H E C O M P L E X S E A M L E S S
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KEY CONSIDERATIONS
REGULATORY AND OPERATIONAL EXPERIENCE APPLIED
Extended RA and IRB/EC
review timelines
• RA and IRB/ECs often seek expert opinion which extends the
review timelines.
Additional review
bodies - site specific
Additional review
bodies – country specific
REGULATORY
SUBMISSIONS
Manufacturing license
Cell and tissue license
• Additional site specific review bodies are required to approve the
study (e.g. Institutional Biosafety Committee, Stem cell research
committee, Advance therapy advisory committee).
• For GMCT: Additional country review bodies are required to
approve the study (e.g. Australia, Brazil, Canada, France and
Spain).
• License to procure, use, import and export cells and tissues is
required for clinical sites, infusion sites and pharmacies handling
the product (e.g. Germany, France, United Kingdom).
• Manufacturing license is required for activities classified as
manufacturing at the sites (e.g. All EU countries).

15. OPERATIONAL
CONSIDERATIONS

16. M A K I N G T H E C O M P L E X S E A M L E S S
• 21 CFR Part 1271.290 requires establishment and maintenance of a tracking
system that enables the tracking of HCT/P* from donor to consignee and the
return of the HCT/P (vein-to-vein).
• At or before the time of HCT/P distribution to a consignee, you must inform the
consignee in writing of the established tracking requirements and the tracking
system.
• The tracking system must include:
‒ Labeling designed to facilitate effective tracking that uses a distinct identification code
relating the HCT/P to the donor and to all records pertaining to the HCT/P
‒ A method for recording the distinct identification code and type of each HCT/P to
enable tracking
‒ A method for documenting the disposition of each of your HCT/Ps to enable tracking
• Global regulatory requirements are equivalent to FDA requirements
OPERATIONAL CONSIDERATIONS
REGULATORY REQUIREMENTS FOR CELL TRACKING
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*HCT/P: human cells, tissues, and cellular and tissue-based products

17. M A K I N G T H E C O M P L E X S E A M L E S S
OPERATIONAL CONSIDERATIONS
TRACKING THROUGH COMPLEX LOGISTICS
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18. M A K I N G T H E C O M P L E X S E A M L E S S
OPERATIONAL CONSIDERATIONS
MANUFACTURING
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Scalability and transfer of
complex process
Availability of starting
material
Location of manufacturing
vs location of sites and IP
stability
Site Operations
• FACT and JAICE accreditation
• Manipulation of starting material

19. M A K I N G T H E C O M P L E X S E A M L E S S
Regulatory Agencies
• Requirement for
strategic engagement,
assessment of
regulatory readiness,
regulatory oversight of
operational planning,
oversight of country
requirements
Investigative Site
Submissions
• Additional committee
reviews (e.g. feasibility,
biosafety)
• License applications
• Requirement for
additional documents –
cell therapy manual
Manufacturing
• Complex processes to
transfer, scale, and
validate
• HCT product availability
Patient Identification
& Eligibility
• Specific subpopulations
within an indication
AVOIDING COMMON PITFALLS IN CLINICAL TRIALS

20. M A K I N G T H E C O M P L E X S E A M L E S S
CASE STUDY 1: SUPPLY CHAIN AND OPERATIONS
HURDLE: ALIGNING SUPPLY CHAIN AND CLINICAL OPERATIONS READINESS
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Hurdle Considerations Impact
Supply chain readiness for enrollment
• Limited starting materials e.g. donor cells
• Complex manufacturing
methods/challenges
• Limited understanding of product stability Timeline delay to enrollment
Investigative site readiness for enrollment
• Limited site capacity and capabilities for
complex trials
• Lengthy site start-up procedures
Development and validation of the
investigational product tracking process
• Complex logistics with many stakeholders
and a customized process
• Requirement to maintain Chain of Custody
and Identity
• Insufficient documentation and
oversight
• Addition of stakeholders
• Unsuccessful validation attempts

21. M A K I N G T H E C O M P L E X S E A M L E S S
CASE STUDY 1: SUPPLY CHAIN AND OPERATIONS
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Initiate development of the
tracking process early with
involvement from all
stakeholders
Evaluate site capabilities
and clinical flow in the
context of product specific
handling requirements
Consider investigational
product handling in a
clinical setting early and
include in product design
and manufacturing plans
Best practices for aligning supply chain and
clinical operations readiness

22. M A K I N G T H E C O M P L E X S E A M L E S S
CASE STUDY 2: GLOBAL STRATEGY
HURDLE: TAKING A CELL THERAPY TRIAL GLOBAL
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Hurdle Considerations Impact
Chemistry, Manufacturing,
and Controls data
• Well-defined product development strategy
• Country specific requirements
• Timeline delay for submissions
• Additional submissions
• Country feasibility
Investigational product labeling • Country labeling requirements
• Add labeling documentation
• Update labeling / relabel
• Country-specific labeling
Supply chain logistics
• Human material import / export requirements
• Transport timelines and IP stability
• Vendor and site capabilities globally
• Additional / change in vendors
• Additional product stability testing
• Changes to tracking process

23. M A K I N G T H E C O M P L E X S E A M L E S S
CASE STUDY 2: GLOBAL STRATEGY
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Identify and confirm feasibility by
addressing local requirements and
regulations for investigational product
manufacturing and stability data and
labeling early and in the context of the
study timeline
Assess feasibility of investigational
product supply in the context of site and
vendor capabilities prior to selection of
sites and vendors
Best practices for developing a global strategy

24. M A K I N G T H E C O M P L E X S E A M L E S S
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RESOURCES &
INFRASTRUCTURE
• Operational & Administrative
Response Teams
• OnDemand Regulatory
Intelligence
• References Libraries
MEDICAL & OPERATIONAL
EXPERTISE
• Protocol Risk Assessment
& Mitigation
• Protocol Deviation Handling
& Oversight
• Consenting Guidelines
• IP/Supply Management Strategies
• Safety Monitoring
• Statistical Impact Assessment
• Comprehensive CSR
ADAPTIVE
MONITORING
• Risk Based Monitoring
• Virtual Monitoring Visits
• Remote access to medical
records
• Centralized Data Review
• Site Quality Indicators
SITE & PATIENT
SERVICES
• Heightened Site Support
• Preferred Home Health
Care Providers
• Patient Concierge Services
• Patient Recruitment &
Education Services
• Direct to Patient IP/Supply
Management
INTEGRATED TECHNOLOGY
Telemedicine eConsent
Virtual Source Data
Verification
Analytical Data
Visualizations

25. M A K I N G T H E C O M P L E X S E A M L E S S
OVERALL BEST PRACTICES
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Product development
strategy should include
global considerations
Ensure communication
and alignment between
regulatory submissions,
clinical operations, and
manufacturing and supply
chain
Strategically engage
regulatory authorities with
consideration for variation
in local regulations
Avoid timeline delays and increased costs

26. QUESTIONS
THANK YOU

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