Guidance Agenda: Guidance Documents CBER is Planning to Publish During Calendar Year 2024

(Updated January 2024)

This is the list of guidance topics CBER is considering for development during Calendar Year 2024. The list includes topics that currently have no guidance associated with them, topics where updated guidance may be helpful, and topics for which CBER has already issued Level 1 draft guidances that may be finalized following review of public comments. We currently intend to develop guidance documents on these topics; however, the Center is neither bound by this list of topics, nor required to issue every guidance document on this list. We are not precluded from developing guidance documents on topics not on this list.

For further information regarding specific topics or guidances, please contact the Office of Communication, Outreach and Development, Center for Biologics Evaluation and Research,

Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 71, Rm. 3128, Silver Spring, MD 20993-0002, 1-800-835-4709 or 240-402-8010, ocod@fda.hhs.gov.

Guidance Documents CBER is Planning to Issue in 2024:

CATEGORY – Blood and Blood Components:

• Recommendations for Investigational and Licensed COVID-19 Convalescent Plasma; Guidance for Industry
• Considerations for the Development of Blood Collection, Processing, and Storage Systems for the Manufacture of Blood Components Using the Buffy Coat Method; Draft Guidance for Industry
• Collection of Platelets by Automated Methods; Draft Guidance for Industry
• Blood Pressure and Pulse Donor Eligibility Requirements; Compliance Policy; Guidance for
  Industry
• Recommendations for Testing Blood Donations for Hepatitis B Surface Antigen; Draft Guidance for Industry
  CATEGORY – Therapeutic Products:
• Human Gene Therapy Products Incorporating Human Genome Editing; Guidance for Industry
• Considerations for the Development of Chimeric Antigen Receptor T Cell Products; Guidance for Industry
• Frequently Asked Questions — Cell and Gene Therapy Products; Draft Guidance for Industry
• Considerations for the Use of Human- and Animal- Derived Materials and Components in the Manufacture of Cell and Gene Therapy and Tissue-Engineered Medical Products; Draft Guidance for Industry
• Safety Testing of Human Allogeneic Cells Expanded for Use in Cell-Based Medical Products; Draft Guidance for Industry
• Recommendations for Determining Eligibility of Donors of Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps); Draft Guidance for Industry
• Manufacturing Changes and Comparability for Human Cellular and Gene Therapy Products; Guidance for Industry
• Potency Assurance for Cellular and Gene Therapy Products, Guidance for Industry
• Recommendations to Reduce the Risk of Transmission of Mycobacterium tuberculosis by Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps), Guidance for Industry
• Recommendations to Reduce the Risk of Transmission of Disease Agents Associated with Sepsis for Donors of Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps), Guidance for Industry
  CATEGORY – Other:
• Standardized Format for Electronic Submission for Marketing Applications Content for the Planning of Bioresearch Monitoring (BIMO) Inspections for Center for Biologics Evaluation and Research Submissions

Human Gene Therapy Products Incorporating Human Genome Editing

Guidance for Industry

This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on this topic. It does not establish any rights for any person and is not binding on FDA or the public. You can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations. To discuss an alternative approach, contact the FDA staff responsible for this guidance as listed on the title page.

I. INTRODUCTION
In this guidance, we, FDA, are providing recommendations to sponsors developing human gene therapy1 products incorporating genome editing (GE) of human somatic cells. Specifically, this guidance provides recommendations regarding information that should be provided in an Investigational New Drug (IND) application in order to assess the safety and quality of the investigational GE product, as required in Title 21 of the Code of Federal Regulations 312.23 (21 CFR 312.23). This includes information on product design, product manufacturing and testing, nonclinical safety assessment, and clinical trial design.

In general, FDA’s guidance documents, including this guidance, do not establish legally enforceable responsibilities. Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in Agency guidance means that something is suggested or recommended, but not required.

II. BACKGROUND
The level of interest in human GE as a scientific technology used in the treatment of human disease has increased substantially, and there has been rapid development of gene therapy products incorporating GE. While the potential of such products for the treatment of human
1 Human gene therapy seeks to modify or manipulate the expression of a gene or to alter the biological properties of living cells for therapeutic use. FDA generally considers human gene therapy products to include all products that mediate their effects by transcription or translation of transferred genetic material, or by specifically altering host (human) genetic sequences. Some examples of gene therapy products include nucleic acids, genetically modified microorganisms (e.g., viruses, bacteria, fungi), engineered site-specific nucleases used for human genome editing, and ex vivo genetically modified human cells.

Gene therapy products meet the definition of “biological product” in section 351(i) of the Public Health Service (PHS) Act (42 U.S.C. 262(i)) when such products are applicable to the prevention, treatment, or cure of a disease or condition of human beings.

(See Federal Register Notice: Application of Current Statutory Authorities to Human Somatic Cell Therapy Products and Gene Therapy Products (58 FR 53248, October 14, 1993), https://www.fda.gov/media/76647/download)

Contains Nonbinding Recommendations

disease is clear, the potential risks are not as well understood. To assist in the translation of these products from the bench to clinical trials, this guidance includes recommendations for how to assess the safety and quality of these products and address the potential risks of these products.
For the purpose of this guidance, human GE is a process by which DNA sequences are added, deleted, altered or replaced at specified location(s) in the genome of human somatic cells, ex vivo or in vivo, using nuclease-dependent or nuclease-independent GE technologies. Human gene therapy products incorporating GE are referred to as human GE products throughout this guidance.
FDA evaluates human GE products using a science-based approach weighing the benefits and risks of each product. The benefit-risk profile for each product depends on the proposed indication and patient population, the extent and duration of therapeutic benefit achieved, and the availability of alternative therapeutic options. Some of the specific risks associated with GE approaches include off-target editing, unintended consequences of on-target editing, and the unknown long term effects of on- and off-target editing.

Human GE is a rapidly evolving field and this guidance encompasses FDA’s current thinking regarding the development of human GE products for clinical studies and licensure. As the field evolves, product design advances, and we gain information on the safety of human GE products, we may revise our recommendations to take into account such changes.

III. CONSIDERATIONS FOR PRODUCT DEVELOPMENT

A. General Considerations

A GE technology may be composed of a single or multiple GE component(s). For the purpose of this guidance, a GE component is considered any material that is essential for the intended genomic modification, including those that may not appear in the final drug product. GE components may include, but are not limited to, the editor, DNA targeting elements (i.e., elements used to dictate the target DNA sequence, such as guide RNA) and a donor DNA template (i.e., DNA sequence provided to repair the target sequence), if applicable. When developing a human GE product, we recommend that sponsors consider: 1) the method by which the DNA sequence change will be achieved; 2) the type of genomic modification needed for the desired therapeutic effect; and 3) the delivery method of the human GE components.

1. Genome Editing methods
   GE can be achieved by either nuclease-dependent or nuclease-independent methods. Nuclease-dependent GE technologies introduce site-specific breaks in the DNA, which may result in modification of the DNA sequence at the editing site. Some examples of nuclease-dependent GE technologies include, but are not limited to, zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), modified-homing endonucleases (meganucleases), and q(CRISPR)-associated (Cas) nucleases. Nuclease-independent GE technologies can change a DNA sequence without cleaving the DNA. Examples of nuclease-independent GE technologies include, but are not limited to, some forms of base editing and synthetic triplex-forming peptide nucleic acids. When choosing a specific GE technology, consideration should be given to the nature of the desired editing outcome (e.g., gene inactivation, restoration, or introduction), the ability to specifically target the desired DNA sequence, and the ability to optimize the GE components to improve safety, efficiency, specificity, or stability.