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, 

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-othersubmissions/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 60- 

day 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: 

TABLE 1—ESTIMATED ANNUAL REPORTING BURDEN 1

Activity/21 CFR section; or FDA form No. Number of 

respondents 

Number of 

responses per 

respondent 

Total annual 

responses 

Average 

burden per 

response 

Total hours 

Total 

operating 

and 

maintenance 

costs 

Submission of Petitions: Color Additive 

Including Labeling—70.25 and 71.1 .... 2 1 2 1,337 2,674 $5,600 

Submission of Petitions: Food Additive 

Including Labeling—171.1 .................... 3 1 3 7,093 21,279 0 

Form FDA 3503 2 ..................................... 5 1 5 1 5 0 

Total .................................................. ........................ ........................ ........................ ........................ 23,958 5,600 

1There are no capital costs associated with this collection of information. 

2Form 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 

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 

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. 

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 


ddrumheller on DSK120RN23PROD with NOTICES1
Federal Register / Vol. 88, No. 182 / Thursday, September 21, 2023 / Notices 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 


ddrumheller on DSK120RN23PROD with NOTICES1
65176 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. 

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 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 

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 


ddrumheller on DSK120RN23PROD with NOTICES1
Federal Register / Vol. 88, No. 182 / Thursday, September 21, 2023 / Notices 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-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://

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 

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. 

ACTION: Notice of availability. 

SUMMARY: 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 

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 


ddrumheller on DSK120RN23PROD with NOTICES1