Presented by: Mridula Shukla Regulatory Affairs Global Lead Author: RAPS study-guide for Global RAC “International Regulatory Affairs (Chapter on Orphan Drugs)”

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Overview of Global Regulatory Affairs
for Gene Therapy
Presented by:
Mridula Shukla
Regulatory Affairs Global Lead
Author: RAPS study-guide for Global RAC
“International Regulatory Affairs (Chapter on Orphan Drugs)”

2. Confidential
● Significant Regulatory Incentives - US (FDA’s Fast Track &
RMAT) and Europe (EMA’s PRIME & ATMP) provide regulatory
pathways for gene therapy development
● North America continues to have the maximum number of
clinical trials in the gene therapy segment
● Focus therapeutic areas: Oncology and Rare Diseases
● Pharma largecaps continue to participate in Gene Therapy
through M&A, partnerships and investments
● 10+ approved products across global markets
● Various gene-based therapies include: Gene Replacement
Therapy, Gene Editing and CAR-T Cell Therapy
Overview of Gene Therapy
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Gene Therapy Trends Gene Therapy Pipeline Continues to Increase(1)
Viral Vector delivery is most prominent in Gene Therapy(2) Select Gene Therapy Companies and Acquisitions
Select Gene Therapy Companies
● Adverum Biotherapuetics
● Audentes Therapeutics
● Betalin Therapeutics
● BlueBird Bio
● CRISPR Therapeutics
● Editas Medicine
● Moderna Therapeutics
● Orchard Therapeutics
● REGENXBIO
● Rocket Pharmaceuticals
● Sangamo Therapeutics
● UniQure
Select Gene Therapy M&A
● Spark / Roche ($4.8Bn)
● Kite / Gilead ($373M)
● AveXis / Novartis ($8.7Bn)
● Myonexus / Sarepta ($165M)
● Annapurna / Avalanche ($106M)
Source: Pharma intelligence (Informa), Pharmaprojects®, public filing and sources.
https://pharmaintelligence.informa.com/~/media/informa-shop-window/pharma/whitepapers/dmhc-gene-therapy-whitepaper.pdf
(1) Annual volume snapshots are captured in May of each year
(2) Other category contains gene therapies with unspecified viral vector types
(3) Source: Review of current pipeline by Informa, November 2018.
Whether in vivo or ex vivo, gene therapies require a vector for delivery - 59% of
gene therapy candidates use a viral vector (3)

3. Confidential
Gene Therapy Development and Regulatory Guidance
➔ Offer possibility of as actual cure instead of chronic
treatment - rare diseases, hereditary diseases,
neurodegenerative diseases, cancer etc.
➔ Frequently the treatment is a one-time only treatment
➔ Gene therapies are technologically-based, hence cost
may drop with new methods and advancements
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Gene Therapy Pros and Cons
Regulatory guidance for Gene Therapy
Source: Public source.
FDA issues draft guidance for Industry - Human Gene Therapy for Rare Diseases (July 2018)
European Medicines Agency - Scientific and regulatory considerations for adeno-associated viral
vector (AAV)-based gene therapy
Report of the International Regulatory Forum of Human Cell Therapy and Gene Therapy Products
➔ High price of therapy and reimbursement issues
➔ Delivering enough product into target tissues
➔ Unique manufacturing and supply chain challenges
➔ Current limited understanding of disease pathology
and progression
➔ Ethics!

4. Confidential
FDA Draft Guidance for Human Gene Therapy (July 2018)
Brief Summary
Introduction ▪ Intended for stakeholders developing human gene therapy (GT) product intended to treat a rare disease
▪ Guidance addresses information required all phases of clinical development including study population
size and potential feasibility and safety issues etc.
Background ▪ Highlights why gene therapy could be an effective treatment option for rare diseases
▪ Importance of rare disease highlighted by that fact that about 25 million Americans affected by rare
disease and 80% of the rare diseases are caused by single-gene defect
▪ Most have no effective treatment options
Considerations for
Product Development
▪ Standard CMC considerations for Rare Gene Therapy products continue to remain applicable, but certain
innovative strategies can be applicable for specific scenarios
▪ Early discussion with FDA is encouraged and emphasis remains on demonstrating process controls for
the manufacturing processes, predefined Critical Quality Attributes (CQA)
▪ Fewer manufacturing runs may make it difficult to establish critical process parameters (CPP), however,
demonstrating process control is required for licensure and regulatory requirements
▪ Establish and qualify a potency test prior to conducting clinical trials
Considerations for
Preclinical Studies
▪ The overall objectives of a preclinical program for a GT product include:
○ Identification of a biologically active dose range
○ Recommendations for an initial clinical dose level, dose-escalation schedule, and dosing regimen
○ Establishment of feasibility and reasonable safety of the proposed clinical route of administration
(ROA)
○ Support of patient eligibility criteria
○ Identification of potential toxicities and physiologic parameters that help guide clinical monitoring for a
particular investigational product
Source: www.fda.gov
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5. Confidential
FDA Draft Guidance for Human Gene Therapy (continued)
Brief Summary
Considerations for
Preclinical Studies
(continued)
▪ Appropriate studies are recommended where applicable - preclinical in vitro proof-of-concept studies,
biodistribution studies, toxicology studies, and additional non-clinical studies as necessary
Considerations for
Clinical Trials
▪ In the majority of these rare disorders, clinical manifestations appear early in life and there are ethical
and regulatory considerations regarding the enrollment of children in clinical trials
▪ Key elements for consideration include study population, study design, dose selection, safety
considerations, efficacy endpoints, patient experience etc.
Expedited Programs ▪ Programs available for expediting development and review of therapies include:
○ Regenerative Medicine Advanced Therapy (RMAT) Designation
○ Breakthrough Therapy Designation
○ Fast Track Designation
○ Accelerated Approval
○ Priority Review
Communication with FDA ▪ FDA recommends communication with OTAT early in product development, before submission of an IND
▪ Includes pre-IND meetings and, earlier in development, INitial Targeted Engagement for Regulatory
Advice on CBER products (INTERACT) meetings
▪ INTERACT meeting can also be used to discuss product specific issues
Source: www.fda.gov
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6. Confidential
Regulatory Affairs – Overview of Expedited Pathways
Source: www.fed.gov. Public source.
Fast Track similar
designation is PRIME in
Europe
*BTD/RMAT similar
designation is ATMP in
Europe and Sakigake in
Japan
Note: ATMP is a combination
of RMAT (in terms of that its
applicable to regenerative
medicines and early frequent
interactions with regulatory
agency) and ODD (in terms
of tax incentives)
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7. Confidential
Regulatory Affairs – Overview of Expedited Pathways (continued)
Source: Public source.
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8. THANK YOU
Contact: Mridula Shukla
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