Notice2025-08960
Dihydropyrimidine Dehydrogenase Deficiency and the Use of Fluoropyrimidine Chemotherapy Drugs; Establishment of a Public Docket; Request for Comments
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Published
May 20, 2025
Issuing agencies
Health and Human Services DepartmentFood and Drug Administration
Abstract
The Food and Drug Administration (FDA or Agency) is announcing the establishment of a docket to solicit public comment for information on dihydropyrimidine dehydrogenase (DPD) deficiency and the use of fluorouracil and capecitabine (both fluoropyrimidine chemotherapy drugs). The purposes of the docket establishment are to foster Agency transparency and to solicit input on the currently available information on DPD deficiency and the use of fluorouracil and capecitabine.
Full Text
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<title>Federal Register, Volume 90 Issue 96 (Tuesday, May 20, 2025)</title>
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[Federal Register Volume 90, Number 96 (Tuesday, May 20, 2025)]
[Notices]
[Pages 21483-21485]
From the Federal Register Online via the Government Publishing Office [<a href="http://www.gpo.gov">www.gpo.gov</a>]
[FR Doc No: 2025-08960]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. FDA-2025-N-1110]
Dihydropyrimidine Dehydrogenase Deficiency and the Use of
Fluoropyrimidine Chemotherapy Drugs; Establishment of a Public Docket;
Request for Comments
AGENCY: Food and Drug Administration, HHS.
ACTION: Notice; establishment of a public docket; request for comments.
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SUMMARY: The Food and Drug Administration (FDA or Agency) is announcing
the establishment of a docket to solicit public comment for information
on dihydropyrimidine dehydrogenase (DPD) deficiency and the use of
fluorouracil and capecitabine (both fluoropyrimidine chemotherapy
drugs). The purposes of the docket establishment are to foster Agency
transparency and to solicit input on the currently available
information on DPD deficiency and the use of fluorouracil and
capecitabine.
DATES: Submit either electronic or written comments by June 20, 2025.
ADDRESSES: You may submit comments as follows. Please note that late,
untimely filed comments will not be considered. Electronic comments
must be submitted on or before June 20, 2025. The <a href="https://www.regulations.gov">https://www.regulations.gov</a> electronic filing system will accept comments until
11:59 p.m. Eastern Time at the end of June 20, 2025. Comments received
by mail/hand delivery/courier (for written/paper submissions) will be
considered timely if they are postmarked or the delivery service
acceptance receipt is on or before that date.
You may submit comments as follows:
Electronic Submissions
Submit electronic comments in the following way:
<bullet> Federal eRulemaking Portal: <a href="https://www.regulations.gov">https://www.regulations.gov</a>.
Follow the instructions for submitting comments. Comments submitted
electronically, including attachments, to <a href="https://www.regulations.gov">https://www.regulations.gov</a>
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 <a href="https://www.regulations.gov">https://www.regulations.gov</a>.
<bullet> 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:
<bullet> 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.
<bullet> 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-2025-N-1110 for ``Dihydropyrimidine Dehydrogenase Deficiency and
the Use of Fluoropyrimidine Chemotherapy Drugs; Establishment of a
Public Docket; Request for Comments.'' 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 <a href="https://www.regulations.gov">https://www.regulations.gov</a> or at the Dockets Management
Staff between 9 a.m. and 4 p.m., Monday through Friday, 240-402-7500.
<bullet> 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.'' FDA 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 <a href="https://www.regulations.gov">https://www.regulations.gov</a>. Submit both
copies to the Dockets Management Staff. If you do not wish your name
and contact information be made publicly available, you can provide
this information on the cover sheet and not
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in the body of your comments and you must identify the 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: <a href="https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf">https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf</a>.
Docket: For access to the docket to read background documents or
the electronic and written/paper comments received, go to <a href="https://www.regulations.gov">https://www.regulations.gov</a> 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: Clara Lee, Oncology Center of
Excellence, Food and Drug Administration, 10903 New Hampshire Ave.,
Bldg. 32, Rm. 3138, Silver Spring, MD 20993, 240-402-4809, or Marianela
Perez-Torres, Center for Devices and Radiological Health, Food and Drug
Administration, 10903 New Hampshire Ave., Bldg. 66, Rm. 3554, Silver
Spring, MD 20993, 301-796-1489.
SUPPLEMENTARY INFORMATION:
I. Background
Fluorouracil and capecitabine are fluoropyrimidine chemotherapy
drugs used to treat patients with various solid tumor malignancies.
Fluorouracil injection was initially approved in the United States in
1962 and capecitabine tablets were approved in 1998. These drug
products (and their generic equivalents) are currently approved for
multiple oncology indications and are components of standard of care
treatment regimens in a variety of cancers and treatment settings.
Fluorouracil and capecitabine (a prodrug of fluorouracil) are
metabolized in the body by the dihydropyrimidine dehydrogenase (DPD)
enzyme to nontoxic metabolites that are excreted in the urine. The DPD
enzyme is encoded by the DPYD gene.\i\ Patients with certain homozygous
or compound heterozygous variants in the DPYD gene known to result in
complete or near complete absence of DPD activity (complete DPD
deficiency) will have higher amounts of fluorouracil in the blood and
are at increased risk for acute early-onset toxicity and serious,
including fatal, adverse reactions (e.g., mucositis, diarrhea,
neutropenia, and neurotoxicity). Patients with DPYD variants resulting
in partial DPD activity (partial DPD deficiency) may also have an
increased risk of serious, including fatal, adverse reactions.
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\i\ van Kuilenburg AB. Dihydropyrimidine dehydrogenase and the
efficacy and toxicity of 5[hyphen]fluorouracil. Eur J Cancer
2004;40:939-950.
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Available evidence estimates that complete DPD deficiency is
present in approximately 0.2% of the White population, and partial DPD
deficiency is seen in approximately 3-5% of the White
population.<SUP>ii</SUP> <SUP>iii</SUP> The rates of complete and
partial DPD deficiency are not well-established in other populations,
and variants may differ based on ancestry.\iv\
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\ii\ Dean L, Kane M. Fluorouracil therapy and DPYD genotype. In:
Pratt VM, Scott SA, Pirmohamed M, et al., editors. Medical Genetics
Summaries. Bethesda, MD: National Center for Biotechnology
Information (US); 2012.
\iii\ Innocenti F, Mills SC, Sanoff H, Ciccolini J, Lenz HJ,
Milano G. All You Need to Know About DPYD Genetic Testing for
Patients Treated With Fluorouracil and Capecitabine: A Practitioner-
Friendly Guide. JCO Oncol Pract 2020;16(12):793-798.
\iv\ See endnote ii.
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On January 16, 2025, the FDA Oncology Center of Excellence, in
collaboration with the American Association for Cancer Research, held a
public workshop \v\ to hear from the oncology community and other
interested parties on considerations for DPD deficiency testing for
patients receiving fluoropyrimidine drugs as part of their cancer
treatment regimen. During the workshop, the benefits and challenges of
pretreatment DPD deficiency testing were discussed, and perspectives
from patient advocates, practicing oncologists, pharmacists,
pharmacogenomics experts, molecular geneticists, and clinical guideline
development representatives were heard. The workshop presentations
highlighted revisions in recent years to the FDA-approved labeling for
fluorouracil and capecitabine products, the clinical use of genotypic
and phenotypic test methods, the clinical data regarding efficacy and
safety of fluoropyrimidine drugs in patients with different DPYD
genotypes, the challenges related to the dosing of fluorouracil and
capecitabine in the setting of potential partial DPD deficiency,
current clinical and pharmacogenomic guideline recommendations, and
patient perspectives on shared decision-making. Workshop speakers
expressed the view that patients scheduled to begin treatment with
fluorouracil or capecitabine should be informed of the potential risk
of severe adverse reactions in the setting of DPD deficiency and the
role of pretreatment testing, as is recommended in the Patient
Counseling Information section of current FDA-approved labeling.
Workshop speakers also expressed the view that the currently available
data supporting avoidance of fluoropyrimidine use in the setting of
complete DPD deficiency are relatively robust, but that dosage
modification recommendations for consideration for use in the setting
of partial DPD deficiency would need to address the varying contexts in
which fluoropyrimidines are used (e.g., with curative intent).
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\v\ <a href="https://www.fda.gov/news-events/fda-meetings-conferences-and-workshops/fda-aacr-workshop-test-or-not-test-question-dpd-deficiency-and-weighing-potential-harms-01162025#event-materials">https://www.fda.gov/news-events/fda-meetings-conferences-and-workshops/fda-aacr-workshop-test-or-not-test-question-dpd-deficiency-and-weighing-potential-harms-01162025#event-materials</a>
[verbar] FDA; accessed January 30, 2025.
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There is no FDA-authorized test intended to identify DPD deficiency
or identify patients at risk for fluoropyrimidine-related toxicity at
this time, and available tests intended to identify DPYD variants may
vary in accuracy, reliability and design (e.g., which DPYD variant(s)
they are intended to identify). FDA encourages in vitro diagnostic
(IVD) device sponsors to discuss with FDA any potential or planned IVD
devices intended for the identification of DPD deficiency through the
Agency's Q-Submission Program.\vi\
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\vi\ See the draft guidance for industry and FDA staff: Requests
for Feedback and Meetings for Medical Device Submissions: The Q-
Submission Program (March 2024). When final, this guidance will
represent FDA's current thinking on this topic. For the most recent
version of a guidance, check the FDA guidance web page at <a href="https://www.fda.gov/regulatory-information/search-fda-guidance-documents">https://www.fda.gov/regulatory-information/search-fda-guidance-documents</a>.
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II. Request for Public Input on Information on DPD Deficiency and the
Use of Fluorouracil and Capecitabine
FDA is seeking public input on information about DPD deficiency and
the use of fluorouracil and capecitabine based on the following
considerations:
<bullet> as reflected in current FDA-approved labeling, available
data suggest that patients with complete DPD deficiency are at
increased risk of life-threatening or fatal adverse reactions when
treated with fluorouracil or capecitabine at the dosages recommended in
the currently approved labeling; and
<bullet> some participants in the January 16, 2025, workshop
advocated for FDA to consider undertaking efforts to revise
fluoropyrimidine drug product labeling to recommend that all patients
be tested for DPYD variants before treatment with fluorouracil or
capecitabine due to the risks of life-threatening or fatal adverse
reactions, most notably in patients with complete DPD deficiency,
despite
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uncertainties about the strength of the available evidence on the
clinical management (e.g., dosage modifications, monitoring
recommendations) of patients whose test results purport to identify
partial DPD deficiency.
FDA is interested in obtaining public input on the above
considerations and any other related aspects on which interested
parties would like to comment. Specifically, FDA is interested in
information on the following topics:
1. What, if any, challenges have healthcare providers and patients
encountered based on the current recommendation to consider testing for
genetic variants of DPYD prior to initiating treatment with
fluorouracil or capecitabine to reduce the risk of serious adverse
reactions if the patient's clinical status permits and based on
clinical judgment?
2. What factors are considered by healthcare providers when
deciding whether or not to test patients for DPD deficiency prior to
initiating treatment with fluorouracil or capecitabine? Which, if any,
of these factors may result in a healthcare provider's decision to
initiate treatment with fluorouracil or capecitabine without prior
testing for DPD deficiency?
3. What factors are considered by healthcare providers in deciding
whether or not to use a fluorouracil or capecitabine product in a
patient with a complete DPD deficiency (e.g., using a markedly reduced
dosage regimen) based on currently available data and information?
4. What factors are considered by healthcare providers for
determining dosing and monitoring approaches when using a fluorouracil
or capecitabine product in patients with purported partial DPD
deficiency based on currently available data and information?
FDA will consider all suggestions, recommendations, and comments;
however, the Agency will not respond directly to the person or
organization making the suggestion, recommendation, or comment.
Dated: May 13, 2025.
Grace R. Graham,
Deputy Commissioner for Policy, Legislation, and International Affairs.
[FR Doc. 2025-08960 Filed 5-19-25; 8:45 am]
BILLING CODE 4164-01-P
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</html>Indexed from Federal Register on May 20, 2025.
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