Scientific Challenges and Opportunities To Advance the Development of Individualized Cellular and Gene Therapies; Request for Information, 65174-65177 [2023-20452]
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65174
Federal Register / Vol. 88, No. 182 / Thursday, September 21, 2023 / Notices
Respondents may transmit FAP or
CAP regulatory submissions in
electronic format or paper format to the
Office of Food Additive Safety in the
Center for Food Safety and Applied
Nutrition (CFSAN) using Form FDA
3503. Form FDA 3503 helps the
respondent organize their submission to
focus on the information needed for
FDA’s safety review. Form FDA 3503
can also be used to organize information
within a master file submitted in
support of petitions according to the
items listed on the form. Master files
can be used as repositories for
information that can be referenced in
multiple submissions to the Agency,
submissions/cfsan-online-submissionmodule-cosm.
Description of respondents:
Respondents are businesses engaged in
the manufacture or sale of food, food
ingredients, color additives, or
substances used in materials that come
into contact with food.
In the Federal Register of February 1,
2023 (88 FR 6757), FDA published a 60day notice requesting public comment
on the proposed collection of
information. Although one comment
was received, it was not responsive to
the four collection of information topics
solicited.
We estimate the burden of this
collection of information as follows:
thus minimizing paperwork burden for
food and color additive approvals.
We improved the information
collection by using the CFSAN Online
Submission Module (COSM). COSM
provides a real-time user interface
process that assists respondents in
preparing and making submissions to
CFSAN. COSM is a web-based tool that
supports electronic submissions,
thereby eliminating the need for
printing and mailing of paper
submissions. COSM is available 24
hours a day and 7 days a week. Further
information about COSM, including
user instruction, is available on the
internet at: https://www.fda.gov/food/
registration-food-facilities-and-other-
TABLE 1—ESTIMATED ANNUAL REPORTING BURDEN 1
Activity/21 CFR section; or FDA form No.
Number of
responses per
respondent
Number of
respondents
Average
burden per
response
Total annual
responses
Total hours
Total
operating
and
maintenance
costs
Submission of Petitions: Color Additive
Including Labeling—70.25 and 71.1 ....
Submission of Petitions: Food Additive
Including Labeling—171.1 ....................
Form FDA 3503 2 .....................................
2
1
2
1,337
2,674
$5,600
3
5
1
1
3
5
7,093
1
21,279
5
0
0
Total ..................................................
........................
........................
........................
........................
23,958
5,600
1 There
ddrumheller on DSK120RN23PROD with NOTICES1
are no capital costs associated with this collection of information.
2 Form FDA 3503 is used for both CAPs and FAPs.
We have adjusted our burden
estimate, which has resulted in a
decrease to the currently approved
burden by 1 hour. Our estimate of
burden attributable to FAPs or CAPs is
based on our experience with the
information collection, which has not
changed since our last review, and
reflects the average number of petitions
we have received annually over a period
of 10 years. The attendant burden we
estimate also reflects an industry
average, although burden associated
with individual petitions may vary
depending on the complexity of the
petition, and the amount and type of
data needed for scientific analysis.
CAPs are subject to fees. The listing
fee for a CAP ranges from $1,600 to
$3,000, depending on the intended use
of the color additive and the scope of
the requested amendment. A complete
schedule of fees is set forth in 21 CFR
70.19. An average of one Category A and
one Category B CAP is expected per
year. The maximum CAP fee for a
Category A petition is $2,600, and the
maximum CAP fee for a Category B
petition is $3,000. Because an average of
two CAPs are expected per calendar
year, the estimated total annual cost
burden to petitioners for this startup
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cost would be less than or equal to
$5,600 ((1 × $2,600) + (1 × $3,000)
listing fees). There are no capital costs
associated with CAPs.
The labeling requirements for food
and color additives were designed to
specify the minimum information
needed for labeling in order that food
and color manufacturers may comply
with all applicable provisions of the
FD&C Act and other specific labeling
Acts administered by FDA. Label
information does not require any
additional information gathering beyond
what is already required to assure
conformance with all specifications and
limitations in any given food or color
additive regulation. Label information
does not have any specific
recordkeeping requirements unique to
preparing the label. Therefore, because
labeling requirements under § 70.25 for
a particular color additive involve
information required as part of the CAP
safety review process, the estimate for
number of respondents is the same for
§§ 70.25 and 71.1, and the burden hours
for labeling are included in the estimate
for § 71.1. Also, because labeling
requirements under parts 172, 173, 179,
and 180 for particular food additives
involve information required as part of
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the FAP safety review process under
§ 171.1, the burden hours for labeling
are included in the estimate for § 171.1.
Dated: September 18, 2023.
Lauren K. Roth,
Associate Commissioner for Policy.
[FR Doc. 2023–20451 Filed 9–20–23; 8:45 am]
BILLING CODE 4164–01–P
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.
Notice; request for information
and comments.
ACTION:
The Food and Drug
Administration (FDA or Agency), Center
for Biologics Evaluation and Research
(CBER) is requesting information from
stakeholders regarding critical scientific
SUMMARY:
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Federal Register / Vol. 88, No. 182 / Thursday, September 21, 2023 / Notices
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.
ddrumheller on DSK120RN23PROD with NOTICES1
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
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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-201509-18/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.
PO 00000
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65175
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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Federal Register / Vol. 88, No. 182 / Thursday, September 21, 2023 / Notices
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.
ddrumheller on DSK120RN23PROD with NOTICES1
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
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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 TCell 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
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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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Federal Register / Vol. 88, No. 182 / Thursday, September 21, 2023 / Notices
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?
fda.yorkcast.com/webcast/Catalog/
Mobile/FolderPresentation/
6d6af3ca61754c3c869f7f556bbede9e21/
4174764f-a52d-4503-893d0b8bc35e1da7/b9c6ac08f3d040eba
768ef43befb498f1d/.
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-eventsmeetings-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
D. Additional Questions To Consider
ddrumheller on DSK120RN23PROD with NOTICES1
• 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?
DEPARTMENT OF HEALTH AND
HUMAN SERVICES
Food and Drug Administration
[Docket No. FDA–2023–D–3550]
Considerations for the Conduct of
Clinical Trials of Medical Products
During Major Disruptions Due to
Disasters and Public Health
Emergencies; Guidance for Industry,
Investigators, and Institutional Review
Boards; Availability
AGENCY:
Food and Drug Administration,
HHS.
Notice of availability.
III. References
ACTION:
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.
SUMMARY:
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-regulatoryscience-report/focus-areaindividualized-therapeutics-andprecision-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://
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The Food and Drug
Administration (FDA or Agency) is
announcing the availability of a final
guidance for industry entitled
‘‘Considerations for the Conduct of
Clinical Trials of Medical Products
During Major Disruptions Due to
Disasters and Public Health
Emergencies.’’ This guidance
recommends approaches that sponsors
of clinical trials of medical products can
consider when there is a major
disruption to clinical trial conduct and
operations due to disasters or public
health emergencies, which can include
but are not limited to hurricanes,
earthquakes, military conflicts,
infectious disease outbreaks, or
bioterrorist attacks. The appendix to this
guidance further explains those
approaches by providing answers to
questions that the Agency has received
about conducting clinical trials during
major disruptions.
DATES: The announcement of the
guidance is published in the Federal
Register on September 21, 2023.
ADDRESSES: You may submit either
electronic or written comments on
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65177
Agency guidances at any time as
follows:
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–D–3550 for ‘‘Considerations for
the Conduct of Clinical Trials of
Medical Products During Major
Disruptions Due to Disasters and Public
Health Emergencies.’’ Received
comments 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
E:\FR\FM\21SEN1.SGM
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]]>Agencies
[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]
-----------------------------------------------------------------------
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.
-----------------------------------------------------------------------
SUMMARY: The Food and Drug Administration (FDA or Agency), Center for
Biologics Evaluation and Research (CBER) is requesting information from
stakeholders regarding critical scientific
[[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
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Submit written/paper submissions as follows:
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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
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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
[[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
[[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
