[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]
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