Regulatory Framework for Gene Therapies 

Incorporating Human Genome Editing 

A CBER Perspective 

Anna Kwilas, Ph.D.

CMC Reviewer, Gene Therapy Branch

Division of Cellular and Gene Therapies

Office of Tissues and Advanced Therapies

Center for Biologics Evaluation and Research

Food and Drug Administration

NIST-FDA Genome Editing Workshop

April 23, 2018
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Gene Therapy & Genome Editing

• Gene therapy products mediate their effects by 

transcription or translation of transferred genetic 

material, or by specifically altering host genetic 

sequences.

• Human genome editing is a process by which DNA 

is inserted, deleted, or replaced in the human 

genome using engineered site-specific nucleases 

and is therefore regulated as a gene therapy

www.fda.gov
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Regulation of Genome Editing Products

• CBER received the first submissions for genome editing 

products in 2008

– 14 INDs 

– 8 Pre-INDs 

– 8 Pre-pre-INDs

• Science-based approach

• Benefit-Risk analyses

– Potential to correct or remove defective genes 

– Risk of off-target genome modification, genome instability

– Unknown long term effects of on- or off-target genome editing

www.fda.gov
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Considerations for Developing Human 

Genome Editing Products

• Type & degree of modification needed

• Nuclease design

• Optimization of targeting elements

• Delivery method

– Viral vectors, plasmid DNA, mRNA, protein (RNP)

• Direct administration

• Modification of cells ex vivo

www.fda.gov

PNA
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Considerations for Developing Human 

Genome Editing Products

• Safety and efficacy

– Optimization of genome editing component 

expression

– Target validation studies

– Preclinical studies

• What models are available/appropriate?

• What will you monitor – sequence, expression, function?

– Clinical trial design, patient monitoring, long-term 

follow-up

www.fda.gov
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Human Genome Editing Safety Concerns

• Off-target genome editing

– Sensitivity of off-target screening methods

• Unintended biological consequences of on-target editing

– Mutagenesis as a result of imprecise DNA repair following ontarget editing

• Additional adverse effects due to genomic DNA cleavage 

at on- and off-target sites

– Chromosomal translocations, inversions, etc.

• Immunogenicity

• Adverse impact of the delivery system

• In the case of in vivo genome editing, off-target 

cell/tissue editing

www.fda.gov
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Challenges to Addressing Human 

Genome Editing Safety Concerns 

• Multiple methods for predicting and identifying 

intra-chromosomal off-target and interchromosomal genomic modifications

• Accounting for genomic variation between 

individual human subjects

• Not all off-target genomic modifications will 

necessarily lead to adverse biological consequences

• Possible limitations of animal models for evaluation 

of safety and activity

www.fda.gov
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Methods for Identifying IntraChromosomal Off-Target Modifications

• In silico methods

– Computational methods identifying areas of homology to 

targeting sequence (e.g. BowTie2, BFAST, Cas-Off-Finder)

– Platforms are based on different algorithms and often give 

different results

• Cellular methods

– PCR amplification of tagged sequences allows identification 

of edited sites (e.g. Guide Seq, BLESS/BLISS, IDLV Capture)

– Off-target editing events may be cell type specific

• Biochemical Methods

– Sequencing of edited, fragmented DNA (e.g. SELEX, Circle 

Seq, DiGenome Seq)

– May give rise to many false positive hits

www.fda.gov
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• In silico modeling

• Cellular approaches

– Unidirectional sequencing (e.g. HTGTS, AMP-seq, 

UDiTaS)

– Imaging based genome analysis (e.g. BioNano, FISH, 

karyotyping)

• Whole genome sequencing

www.fda.gov

Methods for Identifying InterChromosomal Modifications
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Assessing the Safety of Human 

Genome Editing Products

• How are genome editing components produced 

and tested?

• How is on-target editing activity being 

evaluated?

• What are the kinetics of editing activity?

• Has there been thorough evaluation of potential 

off-target sites?

– Types & frequency

– Downstream consequences

– Ratio of cleavage at on- versus off-target sites

www.fda.gov
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Assessing the Safety of Human 

Genome Editing Products

• What models have been used to assess safety and 

activity?

– Have in vitro and in vivo studies been performed?

– Are genome editing components active in the models?

– Are models informative for effects of on- and off-target 

editing?

– Has safety of delivery vector been assessed?

– In the case of in vivo genome editing, have off-target 

cells/tissues been characterized?

– Has data been generated to inform the design of long 

term follow-up of potential study subjects?

www.fda.gov
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Clinical Monitoring Considerations

• Clinical safety monitoring should be guided by:

– Findings from preclinical studies 

– Features of the underlying disease

– Anticipated disease-product interactions 

• Safety reporting requirements (21 CFR 312)

– Systematic observations of patients should be 

performed 

• Clinical, Radiological (if appropriate), Laboratory

– Defined timed intervals for observations 

• Long term follow-up studies 

www.fda.gov
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Early Communication with CBER/OTAT

• Pre-pre-IND interactions 

– Non-binding, informal scientific discussions between CBER/OTAT 

nonclinical review disciplines (P/T & CMC) and the sponsor

– Initial targeted discussion of specific issues

– Primary contact: Mercedes Serabian mercedes.serabian@fda.hhs.gov

• Pre-IND meetings

– Non-binding, but formal meeting between FDA and sponsor (with 

minutes generated)

– Meeting package should include summary data and sound scientific 

principles to support use of a specific product in a specific patient 

population

– Draft Guidance for Industry: Formal Meetings Between the FDA and 

Sponsors or Applicants of PDUFA Products (December 2017) 

https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryI

nformation/Guidances/UCM590547.pdf

www.fda.gov
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Summary

• Gene therapies based on genome editing technologies are 

regulated using a science based approach, with 

consideration of the benefits and risks of each product

– Comprehensive product characterization is key to understanding 

product risk

• On-target editing efficiency

• Off-target editing effects

• Delivery method

• Immunogenicity

– Preclinical evaluation should be adapted to the specific product 

and level of perceived risk 

• Appropriate and informative models

• Multiple orthogonal methods

www.fda.gov
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CBER Contact Information

• Anna Kwilas

Gene Therapy Branch, 

Division of Cellular & Gene Therapies

OTAT/CBER/FDA

WO Bldg. 71 Room 4266

10903 New Hampshire Ave.

Silver Spring, MD 20993

Tel: 240-402-6000

anna.kwilas@fda.hhs.gov

• Regulatory Questions: 

Contact the Regulatory Management Staff in OTAT at CBEROCTGTRMS@fda.hhs.gov

or Lori.Tull@fda.hhs.gov

• References for the regulatory process for OTAT

http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/OtherRecom

mendationsforManufacturers/ucm094338.htm

• OTAT Learn Webinar Series: 

http://www.fda.gov/BiologicsBloodVaccines/NewsEvents/ucm232821.htm

www.fda.gov