FDA issues draft guidance on development considerations for CAR-T cell therapy

On March 15, 2022, the U.

The release of the guidance has been on the FDA's Center for Biologics Review and Research (CBER) list of guidance plans since 2020, but it was delayed until this year

CAR-T cell products are human gene therapy products in which T cells are specifically genetically modified to recognize the target antigen required for therapeutic purposes

While the draft guideline specifically focuses on CAR-T cell products, much of the information and recommendations provided in the guideline also apply to other genetically modified lymphocyte products, such as CAR natural killer (NK) cells or T cell receptor (TCR) modified T cells.

The FDA states that careful design and proper testing of CAR transgenes and delivery vehicles are critical to the safety, specificity, and function of the product

Preclinical evaluation of CAR-T cells is necessary to support the conclusion that the product is reasonably safe to use in clinical studies

Well-designed early-stage clinical studies are critical to determine: product safety, response to risk-mitigating measures, dose-response relationships, optimal dose differences based on indication differences, and preliminary evidence of efficacy and manufacturing feasibility

The draft guideline table of contents is translated as follows:

I.

IV.

1.

2.

3.

D.
MANAGING MANUFACTURING CHANGES AND ASSESSING COMPATIBILITY IN THE CAR-T CELL PRODUCT LIFE CYCLE

1.
Change Management

2.
Comparable study design

E.
Single or multi-site production

1.
Single point production

2.
Multi-site production

3.
Multi-point detection

V.
Preclinical Recommendations A.
General Preclinical Considerations for Cell and Gene Therapy B.
Preclinical Considerations for CAR-T Cell Carrier Components C.
Preclinical Considerations for CAR-T Cell Components D.
In Vivo Testing of CAR-T Cells E.
CAR-T cells with additional modifications

VI.
Clinical Recommendations

A.
Study population

1.
Late-stage versus early-stage disease

2.
Organization agnostic approach

3.
Target identification

4.
Pediatric Subjects

B.
Treatment Plan

1.
Dose Selection, Initial Dose, and Dose Escalation

2.
Repeated dosing

3.
Staggered

4.
Consideration of production delays or nonconformities

5.
Bridging therapy

C.
Clinical Pharmacological Considerations

1.
Pharmacokinetics

2.
Pharmacodynamics

3.
Immunogenicity

D.
SAFETY ASSESSMENT AND MONITORING

1.
Clinical Monitoring

2.
Toxicity classification

3.
Toxicity Limiting Dose (DLT), Discontinuation Rules, and Attribution

E.
Persistence and long-term follow-up of CAR-T cells F.
Allogeneic CAR-T cells

VII.
References

Original link: https://

Original link: https://

Original link: https://