
[Federal Register Volume 88, Number 182 (Thursday, September 21, 2023)]
[Notices]
[Pages 65174-65177]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2023-20452]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

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


Scientific Challenges and Opportunities To Advance the 
Development of Individualized Cellular and Gene Therapies; Request for 
Information

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice; request for information and comments.

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SUMMARY: The Food and Drug Administration (FDA or Agency), Center for 
Biologics Evaluation and Research (CBER) is requesting information from 
stakeholders regarding critical scientific

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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

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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

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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


