May 30, 2024

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FDA issued guidance document for human gene-editing therapies

FDA issued guidance document for human gene-editing therapies



FDA issued guidance document for human gene-editing therapies with at least 15 years of clinical follow-up to monitor potential risks.


Since the birth of CRISPR gene editing technology in 2012, in just ten years, CRISPR gene editing technology has been rapidly developed and widely used. A number of CRISPR gene editing therapies have entered clinical trials and have shown good therapeutic effects.


The potential of CRISPR gene-editing technology for the treatment of human disease is clear, but its potential risks remain unclear . To help these CRISPR gene editing studies move from the laboratory to the clinic, a guidance document on how to assess the safety and quality of human genome editing products and address potential risks is urgently needed.


On March 15, 2022, the U.S. Food and Drug Administration (FDA) issued a draft guidance document for human gene therapy products involving human genome editing . On the same day, the FDA also released a draft guidance document on CAR-T , CAR-NK and TCR-T cell therapies.


FDA issued guidance document for human gene-editing therapies



In the draft, the FDA provides guidance to research teams developing human gene therapy products involving human somatic genome editing.

Specifically, the draft recommends information that should be provided in an investigational new drug (IND) application , which includes product design, manufacture, testing, preclinical safety assessment, and clinical trial design to facilitate the assessment of the safety and quality of these investigational gene therapy products.


The human genome editing referred to in the draft includes the use of nuclease-dependent or nuclease-independent processes to add , delete , alter or replace DNA sequences at specific positions in the human somatic genome , including in vitro editing (ex vivo) and editing in vivo .

That is, as long as DNA is modified (whether it is Cas9 or base editing, or other gene editing tools) , it is human genome editing , but editing RNA is not.


The FDA uses a science-based approach to evaluate human genome editing products, weighing the benefits and risks of each product.

The benefit-risk profile of each product depends on the indication and patient population, the therapeutic benefit achieved and duration, and the availability of alternative treatment options.

Some of the specific risks associated with human genome editing methods include off-target editing, unintended consequences of off-target editing, and unknown long-term effects of off-target editing.



For gene editing in vivo

For gene editing performed in vivo, if delivered by plasmid or viral vector, a full description of plasmid or viral vector fabrication and testing should be provided.

If delivered by a nanoparticle carrier, a detailed description of the nanoparticle formulation, a detailed description of each nanoparticle composition, testing, and fabrication should be provided, as well as a determination of the efficiency with which the gene editing components are packaged into the nanoparticle.




For in vitro gene editing

For gene editing performed in vitro, provide and justify acceptance criteria for critical steps that may have a significant impact on editing efficiency or specificity , such as the RNP formation step in CRISPR-mediated gene editing .

The following evaluation data are also required:

• Target editing efficiency, including the characterization of editing events occurring at the target site;
• frequency of off-target editing;
• Chromosomal rearrangement;
• Residual genome editing components;
• Total number of genome edited cells.


In addition, if the in vitro edited allogeneic human cell product (eg, next-generation universal cell therapy) is to be used to treat multiple patients in one batch, additional testing and establishment of acceptance criteria are required.



Preclinical proof of concept and risk assessment

Preclinical in vitro and in vivo proof-of- concept studies are recommended to determine the feasibility of human genome editing in clinical trials.

In vitro models should be considered to study gene editing efficiency in target cell types, and when selecting an animal model for in vivo research, it should be demonstrated that the model has an alternative biological response to an investigational human genome editing product.

Given the differences in genome sequences between humans and animals, bioactivity analysis can be performed in the context of a specific species.


It is recommended that preclinical safety studies be designed to identify potential risks associated with the administration of human genome editing products.

Potential risks may be related to the delivery method of the genome editing components, the expression of the components, the modification of the genome structure and/or the expression of the gene product.

The safety assessment should include the identification and characterization of off-target activities, chromosomal rearrangements and their possible biological consequences.


For preclinical safety studies of in vivo gene editing , elements of the planned clinical trial (including dose range, ROA, delivery system, dosing regimen, assessment endpoints) should be incorporated to the extent feasible .

Study designs should be comprehensive enough to identify, characterize, and quantify potential local and systemic toxicity, possible onset and resolution of toxicity, and the effect of dose on these conditions.

In addition, the FDA recommends characterization of the in vivo distribution , persistence, and clearance of gene editing components to provide additional information on editing activity on target and off-target.


In addition, the FDA specifically mentioned the need to evaluate human genome editing products for the possibility of unintended editing of human germ cells.



Considerations in Clinical Trials

The FDA recommends that clinical development programs for human genome editing products address both the risks associated with the gene therapy product itself and other risks associated with genome editing, including the unintended consequences of on-target and off-target editing.

Clinical trial designs should include appropriate patient selection, effective and safe methods of product administration (including data-based dosing, dosing regimens, and treatment plans) , adequate safety monitoring, and appropriate endpoint selection.


In addition, FDA recommends long-term follow-up of clinical trial subjects receiving human genome-edited products to assess clinical safety.

In general, the IND application should describe in detail the overall study design, assessment of adverse events, and plans for subject follow-up.


Long-term follow-up

For human genome editing, the intended and unintended editing and long-term effects of on-target and off-target loci are largely unknown.

Therefore, the FDA recommends long-term follow-up of patients for at least 15 years after gene editing therapy . To observe, monitor and identify various potential risks that may arise in patients.






FDA issued guidance document for human gene-editing therapies

(source:internet, reference only)

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Important Note: The information provided is for informational purposes only and should not be considered as medical advice.