A Rare International Dialogue (Saturday May 11, 2019) Drivers of Drug Development – Regulatory Collaboration Medical Product Development for Rare Diseases: FDA perspective CDER Larissa Lapteva, US Food and Drug Administration, CBER Medical Product Development For Rare Diseases Part 2: Regenerative Medicine Therapies FDA Regulatory Perspective

1. Medical Product Development For Rare Diseases
Part 2: Regenerative Medicine Therapies
FDA Regulatory Perspective
Rare International Dialogue: Drivers of Drug Development
Canadian Organization for Rare Disorders
May 10-12, 2019
Larissa Lapteva, MD, MHS, MBA
Associate Director
Division of Clinical Evaluation and Pharmacology/Toxicology
Office of Tissues and Advanced Therapies
Center for Biologics Evaluation and Research
US Food and Drug Administration

2. 2
Efficient Development
Regulatory Programs
• Fast Track
• Breakthrough Therapy
• Regenerative Medicine Advanced Therapy
• Qualified Infectious Disease Product
• Orphan* Product
• Priority review
• priority review voucher program
• Accelerated approval
• Grant programs, user fee waivers, and other
incentives
Product Development
• INTERACT**
• Innovative study designs
• Effective use of “reduce, refine, replace”
principle and modeling in preclinical
programs
• Enrichment strategies
• Adaptive and complex innovative
designs****
• Product development tools including
biomarkers and clinical outcomes assessments
• Patient Engagement***
to support
*Designating an Orphan Product: Drugs and Biological Products
https://www.fda.gov/ForIndustry/DevelopingProductsforRareDiseasesConditions/HowtoapplyforOrphanProductDesignation/default.htm
**INTERACT https://www.fda.gov/BiologicsBloodVaccines/ResourcesforYou/Industry/ucm611501.htm
***Patient-Focused Drug Development https://www.fda.gov/drugs/developmentapprovalprocess/ucm610279.htm
****Complex Innovative Design Pilot Program https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/ucm617212.htm

3. 3
Fast Track (FT) Breakthrough
Therapy (BT)
Regenerative Medicine Advanced
Therapy (RMAT)
Criteria -Serious condition
AND
-Nonclinical or clinical
data demonstrate the
potential to address
unmet medical need
Note: Information to
demonstrate potential
depends upon stage of
development at which FT
is requested
-Serious condition
AND
-Preliminary clinical
evidence indicates that the
product may demonstrate
substantial improvement
over available therapy on
one or more clinically
significant endpoints
-Serious condition
AND
-Preliminary clinical evidence indicates that
the product has the potential to address
unmet medical need
Note: RMT include cell therapies, therapeutic tissue
engineering products, human cell and tissue
products, and combination products using such
therapies or products (human gene therapies,
including genetically modified cells, that lead to a
sustained effect on cells or tissues, xenogeneic cell
products)
Expedited Programs for Product Development
Guidance for Industry: Expedited Programs for Serious Conditions – Drugs and Biologics
https://www.fda.gov/downloads/Drugs/Guidances/UCM358301.pdf
Guidance for Industry: Expedited Programs for RMAT for Serious Conditions
https://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/CellularandGeneTherapy/UCM585414.pdf

4. 4
Expedited Programs for Product Development
Fast Track (FT) Breakthrough
Therapy (BT)
Regenerative Medicine
Advanced Therapy (RMAT)
Features
Frequent meetings
Frequent written
communication
Eligibility for *:
ü Accelerated approval
ü Priority review
Rolling Review
*if relevant criteria are met
All of FT Features +
ü Intensive guidance on an
efficient drug development
program, beginning as early
as Phase 1
ü Organizational commitment
All of BT Features +
ü Early interactions to discuss
any potential surrogate or
intermediate endpoints
ü Statute addresses potential
ways to support accelerated
approval and satisfy post-
approval requirements
Guidance for Industry: Evaluation of Devices Used with RMATs
https://www.fda.gov/downloads/biologicsbloodvaccines/guidancecomplianceregulatoryinformation/guidances/cellularandgenetherapy/ucm585417.pdf

5. 5www.fda.gov
Requested and Granted BT and RMAT Designations
(through April 1, 2019)
BT Requested
BT Granted
RMAT Requested
RMAT Granted

6. 6
Draft Guidance Documents To Facilitate
Gene Therapies for Rare Diseases: July 2018
• Human Gene Therapy for Rare Diseases
• Human Gene Therapy for Hemophilia
• Human Gene Therapy for Retinal Disorders
• Chemistry, Manufacturing, and Control (CMC) Information for Human Gene
Therapy Investigational New Drug Applications (INDs)
• Long-Term Follow-up After Administration of Human Gene Therapy Products
• Testing of Retroviral Vector-Based Human Gene Therapy Products for
Replication Competent Retrovirus During Product Manufacture and Patient
Follow-up
https://www.fda.gov/BiologicsBloodVaccines/
GuidanceComplianceRegulatoryInformation/Guidances/CellularandGeneTherapy/
default.htm

7. 7
Medical Product Development Tools
• Methods, materials, and measures that can potentially facilitate medical
product development
• May be developed, qualified, and/or used within individual product programs
OR outside any specific product development in the pre-competitive space
through the existing regulatory qualification programs
• Animal Model Qualification Program
• Biomarker Qualification Program
• Clinical Outcome Assessment Qualification Program
FDA Qualification Programs Contacts
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DrugDevelopmentToolsQualificationProgram/ucm284396.htm
FDA’s COA Qualification Program
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DrugDevelopmentToolsQualificationProgram/ucm284077.htm

8. 8
Complex Innovative Design (CID) Pilot Program
• Highly innovative trial designs which may require simulations to determine
clinical trial operating characteristics (type I error rate and power)
• Sponsors:
• submit meeting requests to discuss proposed CIDs (CBER and CDER will
select up to 2 requests per quarter)
• have the opportunity to engage with FDA regulatory staff on designs via
2 extra meetings with statistical reviewers
• Need an active IND or Pre-IND number
• FDA: uses the design as a case study for continuing education and
information sharing
For more information, visit:
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/ucm617212.htm

9. 9
Patient Engagement and
Patient-Focused Drug Development
• FDA Patient Representative Program
• Patient-Focused Drug Development meetings (FDA and stakeholders)
• Formation of FDA Patient Affairs Staff group in 2017
• FDA Listening Sessions (patient experiences with specific conditions)
• Science of Patient Input: series of guidance documents on methodological
approaches to incorporating patient voice in medical product development and
regulatory decision-making
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/ucm610279.htm
• Inclusion of Patient Experience Data in marketing applications and reviews
The 21st Century Cures Act (2016) and the FDA Reauthorization Act (2017): Plan for Issuance of Patient-Focused Drug Development Guidance
https://www.fda.gov/downloads/ForIndustry/UserFees/PrescriptionDrugUserFee/UCM563618.pdf

10. 10
Contact Information
§ Larissa.Lapteva@fda.hhs.gov
§ Regulatory Questions:
OTAT Main Line – 240 402 8190
Email: OTATRPMS@fda.hhs.gov and
Lori.Tull@fda.hhs.gov
§ OTAT Learn Webinar Series:
http://www.fda.gov/BiologicsBloodVaccines/NewsEvents/ucm232821.htm
§ CBER website: www.fda.gov/BiologicsBloodVaccines/default.htm
§ Phone: 1-800-835-4709 or 240-402-8010
§ Consumer Affairs Branch: ocod@fda.hhs.gov
§ Manufacturers Assistance and Technical Training Branch: industry.biologics@fda.hhs.gov
§ Follow us on Twitter: https://www.twitter.com/fdacber