Document Headings

                    Document headings vary by document type but may contain                    the following:                  
                -                       the agency or agencies that issued and signed a document                    
                -                       the number of the CFR title and the number of each part                      the document amends, proposes to amend, or is directly                      related to                    
                -                       the agency docket number / agency internal file number                    
                -                       the RIN which identifies each regulatory action listed in                      the Unified Agenda of Federal Regulatory and Deregulatory                      Actions                    

                    See the                                          Document Drafting Handbook                                        for more details.                  

###### Department of Health and Human Services

###### Food and Drug Administration

          - [Docket No. FDA-2023-N-3742]

# AGENCY:

Food and Drug Administration, HHS.

# ACTION:

Notice; request for information and comments.

# SUMMARY:

                        The Food and Drug Administration (FDA or Agency), Center for Biologics Evaluation and Research (CBER) is requesting information from stakeholders regarding critical scientific                               ( print page 65175)                            challenges and opportunities to advance the development of individualized cellular and gene therapies (CGTs). FDA intends to gather information and comments submitted in response to this request for information (RFI) to inform potential planning of future town halls, workshops, or discussion papers which could ultimately facilitate the development of additional regulatory science tools, standards, or guidance.                    

# DATES:

Either electronic or written comments on the notice must be submitted by November 20, 2023.

# ADDRESSES:

                        You may submit comments as follows. Please note that late, untimely filed comments will not be considered. The                         *https://www.regulations.gov*                         electronic filing system will accept comments until 11:59 p.m. Eastern Time at the end of November 20, 2023. Comments received by mail/hand delivery/courier (for written/paper submissions) will be considered timely if they are received on or before that date.                    

### Electronic Submissions

Submit electronic comments in the following way:
      -  Federal eRulemaking Portal: https://www.regulations.gov.                      Follow the instructions for submitting comments. Comments submitted electronically, including attachments, to                      https://www.regulations.gov                      will be posted to the docket unchanged. Because your comment will be made public, you are solely responsible for ensuring that your comment does not include any confidential information that you or a third party may not wish to be posted, such as medical information, your or anyone else's Social Security number, or confidential business information, such as a manufacturing process. Please note that if you include your name, contact information, or other information that identifies you in the body of your comments, that information will be posted on                      https://www.regulations.gov. 
      - If you want to submit a comment with confidential information that you do not wish to be made available to the public, submit the comment as a written/paper submission and in the manner detailed (see “Written/Paper Submissions” and “Instructions”).

### Written/Paper Submissions

Submit written/paper submissions as follows:
      -  Mail/Hand Delivery/Courier (for written/paper submissions):                      Dockets Management Staff (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.                
      - For written/paper comments submitted to the Dockets Management Staff, FDA will post your comment, as well as any attachments, except for information submitted, marked, and identified, as confidential, if submitted as detailed in “Instructions.”

*Instructions:*                     All submissions received must include the Docket No. FDA-2023-N-3742 for “Scientific Challenges and Opportunities To Advance the Development of Individualized Cellular and Gene Therapies.” Received comments, those filed in a timely manner (see                     **ADDRESSES**                    ), will be placed in the docket and, except for those submitted as “Confidential Submissions,” publicly viewable at                     *https://www.regulations.gov*                     or at the Dockets Management Staff between 9 a.m. and 4 p.m., Monday through Friday, 240-402-7500.                
      - Confidential Submissions—To submit a comment with confidential information that you do not wish to be made publicly available, submit your comments only as a written/paper submission. You should submit two copies total. One copy will include the information you claim to be confidential with a heading or cover note that states “THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.” The Agency will review this copy, including the claimed confidential information, in its consideration of comments. The second copy, which will have the claimed confidential information redacted/blacked out, will be available for public viewing and posted on https://www.regulations.gov.                      Submit both copies to the Dockets Management Staff. If you do not wish your name and contact information to be made publicly available, you can provide this information on the cover sheet and not in the body of your comments and you must identify this information as “confidential.” Any information marked as “confidential” will not be disclosed except in accordance with  21 CFR 10.20  and other applicable disclosure law. For more information about FDA's posting of comments to public dockets, see  80 FR 56469 , September 18, 2015, or access the information at:                      https://www.govinfo.gov/​content/​pkg/​FR-2015-09-18/​pdf/​2015-23389.pdf. 

*Docket:*                     For access to the docket to read background documents or the electronic and written/paper comments received, go to                     *https://www.regulations.gov*                     and insert the docket number, found in brackets in the heading of this document, into the “Search” box and follow the prompts and/or go to the Dockets Management Staff, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852, 240-402-7500.                

# FOR FURTHER INFORMATION CONTACT:

Karen Fikes, Center for Biologics Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 71, Rm. 7301, Silver Spring, MD 20993-0002, 240-402-7911.

# SUPPLEMENTARY INFORMATION:

## I. Background

Personalized medicine has often been described as the use of individual characteristics, such as genetic markers or other measurable traits, to guide disease prevention or treatment among existing products (Ref. 1). An improved understanding of the molecular basis of disease along with the availability of sensitive diagnostic tools has led to the increasing opportunity to create individualized products based upon such genetic markers or measurable traits. These individualized therapies can now be developed for a single patient (or a very small number of patients) based on designing or engineering a product that specifically targets the mechanism underlying a patient's (or small number of patients') illness (Ref. 2). The opportunities and challenges associated with individualized therapies span the entire development pathway; from robust and consistent manufacturing with assurance of product quality, to nonclinical models and tools to characterize safety and activity, to the generation, collection, and assessment of clinical evidence from an individual patient (or a very small number of patients) (Refs. 3 and 4). For the purposes of this RFI, these types of products will be referred to as individualized CGTs. Examples of these emerging areas of research include:
    - Products designed for the same indication with the same mode of action. For instance, a personalized vaccine for pancreatic cancer that consists of autologous dendritic cells pulsed with patient-specific neoantigen peptides (Ref. 5).
    - Products designed for different indications with different modes of action. For instance, two gene therapy vector products for separate rare genetic neurological diseases, where both products utilize the same vector backbone but contain different transgene inserts.

                    This RFI is specifically seeking input on the scientific challenges and opportunities for individualized CGTs. The outcomes of this RFI are meant to complement other ongoing and planned CBER town halls, workshops, and discussion papers designed to educate and seek feedback on a broad range of considerations for the development of                           ( print page 65176)                        CGTs (Ref. 6). The purpose of this RFI is limited to planning purposes only and should not be construed as a policy, a solicitation for applications, or an obligation on the part of the government to provide support for any ideas identified in response to it.                

## II. Request for Information and Comments

                    FDA is requesting information regarding major scientific challenges and opportunities to advance the development of individualized CGTs, with a specific focus on the areas outlined below, including manufacturing (                    *e.g.,*                     product quality), nonclinical development (                    *e.g.,*                     toxicology, proof of concept, biodistribution), clinical development (                    *e.g.,*                     assessing safety and efficacy), and additional questions to consider (                    *e.g.,*                     additional scientific needs, best practices, opportunities for collaborations).                

### A. Manufacturing

All CGTs, including individualized CGTs, need to be manufactured with sufficient quality, purity, and potency to ensure that each batch of the product has adequate safety and full potential to achieve the intended therapeutic outcome. In the case of CGTs for rare diseases, where a single batch of product may be sufficient to treat a small number of patients diagnosed with the rare disease, it can be challenging to develop a consistent manufacturing process and robust control strategy for future batches of the product for additional patients diagnosed with the same rare disease.

Additionally, the manufacturing of some individualized CGTs may need to be tailored to each patient, leading to high variability among each batch of the individualized product. For example, autologous CAR-T cell products are derived from a patient's own cells, and variability in this starting material leads to variability in the drug product. It can be challenging to understand and control the impact of this variability on the safety and efficacy of the product. As additional examples, a tumor neoantigen vaccine may be based on the genetic sequence of the individual patient's tumor, and some genome editing products may be customized to treat the individual patient's genetic mutation. The tailored manufacturing processes needed for these types of products can be difficult to standardize and can also result in significant variability among batches.
    - Given the challenges to develop consistent manufacturing strategies for CGTs designed for a very small number of patients or an individual patient, how can manufacturers leverage their prior experience manufacturing one CGT to support subsequent development and approval of another related, but distinct CGT (potential areas for leveraging may include manufacturing process validation, control strategy, assay validation, and drug product stability studies)?
    - When the batch size of a CGT is very small, what are some challenges and solutions regarding the volume of product (or number of vials) needed for batch release testing, stability testing, retention of reserve samples, and comparability studies?
    - What are some challenges and solutions for individualized CGTs that need to be tested and released rapidly, either because the product has a very short shelf life or because the patient's clinical status may be rapidly declining and treatment is urgently needed?
    - For many individualized CGT products, each batch is tailored to an individual patient ( e.g.,                      autologous CAR-T cells, tumor neoantigen vaccines, certain genome editing products). For such products, what are some challenges and solutions for assuring that each batch has adequate potency to achieve the intended therapeutic effect?                
    - What are some challenges and solutions for individualized genome editing products that aim to treat monogenic diseases for which the target gene has different mutations in different patients?

### B. Nonclinical Development

There are several challenges in translating nonclinical data to humans for individualized CGTs. Because the final investigational product is unique to an individual or a small number of subjects, it often is not possible to evaluate the final clinical product in nonclinical studies. Additionally, many individualized CGTs target antigens that are human-specific and thus lack relevant animal models to inform safety and activity. An example includes T-Cell receptor-engineered T cells that target a patient-specific neoantigen, or a shared target in the context of an HLA allele specific to a small group of human subjects. There are also opportunities and challenges to utilizing prior knowledge from nonclinical studies of other approved or investigational individualized CGTs that may be leveraged for a related product under development for different populations or indications. An example includes two or more gene therapy vector products for different rare genetic diseases that utilize the same vector backbone while containing different transgene inserts.

With continued scientific advances in the CGT field, it is also important to consider the use of computational approaches to support nonclinical evaluation of individualized CGTs. Computational approaches may present an opportunity to quickly and efficiently screen product safety or activity, but may pose additional challenges in their consistent use and validation.
    - What nonclinical studies could be leveraged in support of a related product using similar technologies? What nonclinical studies are important to conduct with each final clinical product?
    - What nonclinical development approaches could be considered when there are no relevant animal models or animal models are unable to replicate each individual disease/condition?
    - For patient-specific products where evaluating each individual product is infeasible or impractical, what is the role for nonclinical studies conducted with representative product(s)?
    - What are the opportunities and challenges with using computational approaches to support nonclinical development?

### C. Clinical Development

Assessing efficacy can be a particular challenge in clinical studies of individualized CGTs, particularly for rare diseases with heterogeneous presentations. Randomized controlled designs are desired for interpretability of results, but may be unfeasible or unethical for various reasons in rare disease clinical trials. However, natural history data may be limited and/or lack suitability to support outcome assessments. Additional specific challenges in individuals or small groups include development and interpretation of novel endpoints, limitations in statistical analyses to understand treatment effects, and determining appropriate study design and duration to assess clinically meaningful benefit. An example may be a newly identified specific genetic mutation associated with a unique phenotypic presentation of disease, where only a few individuals with the specific mutation have been identified, and the natural history of disease is poorly understood. Adaptive, Bayesian, and other trial designs may provide different opportunities or challenges, and the approach will likely need to be considered on a case-by-case basis.

                    Understanding clinical safety of individualized CGTs may also be difficult and may depend on relevant                           ( print page 65177)                        available data for similar products or other treatments for the disorder or similar disorders.                
    - What are challenges and strategies/opportunities with interpreting efficacy data from individual patients (including expanded access) and small groups of patients? What opportunities are there in leveraging prior and/or collective experiences?
    - What strategies can be utilized to accumulate and interpret safety data in personalized/individualized CGTs?
    - For genetic disorders with clear genotype-phenotype associations for disease manifestations or severity, what opportunities are there for tailoring treatments and study design to specific genotypes/phenotypes?

### D. Additional Questions To Consider

    - What additional major scientific challenges to advance the development of individualized CGTs should be considered?
    - What existing best practices or scientific approaches should be leveraged to address any of these challenges? Are there specific opportunities for collaborations to advance the development of individualized CGTs?
    - Are there specific areas where flexibility in regulatory approaches would improve the feasibility of developing and commercializing individualized CGTs?

## III. References

                    The following references are on display in the Dockets Management Staff (see                     **ADDRESSES**                    ) and are available for viewing by interested persons between 9 a.m. and 4 p.m., Monday through Friday; they are also available electronically at                     *https://www.regulations.gov.*                     FDA has verified the website addresses, as of the date this document publishes in the                     **Federal Register**                    , but websites are subject to change over time.                

1. President's Council of Advisors on Science and Technology, “Priorities for Personalized Medicine,” September 2008.

                        2. FDA, “Focus Area: Individualized Therapeutics and Precision Medicine,” 2022. Available at                         *https://www.fda.gov/​science-research/​focus-areas-regulatory-science-report/​focus-area-individualized-therapeutics-and-precision-medicine.*

                        3. Marks, P. and C. Witten, “Toward a New Framework for the Development of Individualized Therapies,”                         *Gene Therapy,*                         28:615-617, 2021.                    

                        4. FDA, “Facilitating End-to-End Development of Individualized Therapeutics” (Public Workshop) (March 3, 2020). Available at                         *https://fda.yorkcast.com/​webcast/​Catalog/​Mobile/​FolderPresentation/​6d6af3ca61754c3c869f7f556bbede9e21/​4174764f-a52d-4503-893d-0b8bc35e1da7/​b9c6ac08f3d040eba768ef43befb498f1d/​.*

                        5. Fritah, H., R. Rovelli, C.L. Chiang, and C.L. Kandalaft, “The Current Clinical Landscape of Personalized Cancer Vaccines,”                         *Cancer Treatment Reviews,*                         106:102383, 2022.                    

                        6. FDA, “OTP Events, Meetings, and Workshop,” (2023). Available at                         *https://www.fda.gov/​news-events/​otp-events-meetings-and-workshops.*

Dated: September 18, 2023.

Lauren K. Roth,

Associate Commissioner for Policy.

[FR Doc. 2023-20452 Filed 9-20-23; 8:45 am]

BILLING CODE 4164-01-P