[Federal Register Volume 89, Number 229 (Wednesday, November 27, 2024)]
[Notices]
[Pages 93610-93611]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2024-27796]
[[Page 93610]]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. FDA-2024-D-4540]
Recommended Followup Testing for an Ames-Positive Drug (Active
Ingredient) or Metabolite To Support First-in-Human Clinical Trials
With Healthy Subjects; Draft Guidance for Industry; Availability
AGENCY: Food and Drug Administration, HHS.
ACTION: Notice of availability.
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SUMMARY: The Food and Drug Administration (FDA or Agency) is announcing
the availability of a draft guidance for industry entitled
``Recommended Followup Testing for an Ames-Positive Drug (Active
Ingredient) or Metabolite To Support First-in-Human Clinical Trials
With Healthy Subjects.'' This draft guidance makes recommendations on
followup testing for Ames-positive active ingredients in circumstances
when a sponsor decides to continue development. The guidance recommends
a consistent process of followup testing and evaluation that first
should be conducted for an Ames-positive active ingredient before
proceeding with first-in-human (FIH) trials in healthy human subjects.
These recommendations are intended to potentially help address and
lower safety concerns before proceeding with FIH trials in healthy
human subjects.
DATES: Submit either electronic or written comments on the draft
guidance by February 25, 2025 to ensure that the Agency considers your
comment on this draft guidance before it begins work on the final
version of the guidance.
ADDRESSES: You may submit comments on any guidance 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-2024-D-4540 for ``Recommended Followup Testing for an Ames-Positive
Drug (Active Ingredient) or Metabolite To Support First-in-Human
Clinical Trials With Healthy Subjects.'' 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 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.
You may submit comments on any guidance at any time (see 21 CFR
10.115(g)(5)).
Submit written requests for single copies of this draft guidance to
the Division of Drug Information, Center for Drug Evaluation and
Research, Food and Drug Administration, 10001 New Hampshire Ave.,
Hillandale Building, 4th Floor, Silver Spring, MD 20993-0002. Send one
self-addressed adhesive label to assist that office in processing your
requests. See the SUPPLEMENTARY INFORMATION section for information on
electronic access to the draft guidance document.
FOR FURTHER INFORMATION CONTACT: Timothy W. Robison, Center for Drug
Evaluation and Research, Food and Drug Administration, 10903 New
Hampshire Ave., Bldg. 22, Rm. 3328, Silver Spring, MD 20993, 301-796-
1283.
SUPPLEMENTARY INFORMATION:
I. Background
FDA is announcing the availability of a draft guidance for industry
entitled ``Recommended Followup Testing for an Ames-Positive Drug
(Active Ingredient) or Metabolite To Support First-in-Human Clinical
Trials With Healthy Subjects.'' Positive results in the Ames test
suggest potential DNA reactivity, indicating that followup testing and
evaluation of an Ames-positive active ingredient are necessary to
assess its in vivo mutagenic and carcinogenic potential.\1\ Positive
results in the Ames test are correlated with carcinogenic potential in
rodents; however, this correlation is not perfect because mutations are
only one of many
[[Page 93611]]
stages in tumor development. In addition, the mutagenic response may be
due to exceeding a detoxification threshold or the induction of
oxidative damage to which bacterial cells may be more sensitive than
mammalian cells in vitro or tissues in vivo.
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\1\ See the International Council for Harmonisation guidance for
industry ``S2(R1) Genotoxicity Testing and Data Interpretation for
Pharmaceuticals Intended for Human Use,'' available at https://www.fda.gov/media/170461/download.
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This guidance makes recommendations on followup testing for Ames-
positive active ingredients in those rare circumstances when a sponsor
decides to continue development for potential approval by FDA. These
recommendations are intended to potentially address and lower certain
safety concerns before proceeding with FIH trials in healthy human
subjects. Followup testing cannot entirely mitigate the concerns raised
by an Ames-positive finding, and some residual risk remains in the
absence of an adequate carcinogenicity assessment. Thus, Ames-positive
active ingredients that are further developed should be those targeting
serious or life-threatening diseases with unmet medical needs.
Consideration might be given to the administration of an
investigational new drug containing an Ames-positive active ingredient
to healthy human subjects only if the results of extensive followup
testing conducted before clinical administration lowered the concern
for cancer based on a weight-of-evidence (WoE) approach evaluating the
potential for mutagenicity. A WoE evaluation, for instance, might find
that followup testing in an in vitro mammalian cell mutation assay and
in vivo mutation assay are both negative and that other considerations
do not raise any other safety concerns. Positive findings in either the
in vitro mammalian cell mutation assay or in vivo mutation assay would
preclude testing in healthy human subjects. The sponsor also should
provide a thoroughly considered rationale for why FIH trials should
enroll healthy subjects in lieu of patients with the disease or
condition the investigational drug product with the Ames-positive
active ingredient is intended to treat. Alternatively, consideration
should be given to enrolling patients with the disease or condition of
interest and designing the trial in a manner that may offer a treatment
benefit in addition to the usual aims of a phase 1 trial (e.g.,
pharmacokinetics, tolerability, etc.).
The guidance recommends that a consistent process of followup
testing and evaluation should first be conducted for an Ames-positive
active ingredient before FIH trials are commenced in healthy subjects.
An Ames-positive metabolite observed at low levels (e.g., at the
threshold of toxicological concern) would generally pose minimal safety
concerns and may be managed differently. The recommendations explained
in the guidance for followup testing are intended to inform both review
staff and industry.
This draft guidance is being issued consistent with FDA's good
guidance practices regulation (21 CFR 10.115). The draft guidance, when
finalized, will represent the current thinking of FDA on ``Recommended
Followup Testing for an Ames-Positive Drug (Active Ingredient) or
Metabolite To Support First-in-Human Clinical Trials With Healthy
Subjects.'' It does not establish any rights for any person and is not
binding on FDA or the public. You can use an alternative approach if it
satisfies the requirements of the applicable statutes and regulations.
II. Paperwork Reduction Act of 1995
While this guidance contains no collection of information, it does
refer to previously approved FDA collections of information. The
previously approved collections of information are subject to review by
the Office of Management and Budget (OMB) under the Paperwork Reduction
Act of 1995 (PRA) (44 U.S.C. 3501-3521). The collections of information
in 21 CFR part 312 for investigational new drug applications have been
approved under OMB control number 0910-0014. The collections of
information found in 21 CFR parts 50 and 56 pertaining to protection of
human subjects have been approved under OMB control number 0910-0130.
III. Electronic Access
Persons with access to the internet may obtain the draft guidance
at https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs, https://www.fda.gov/regulatory-information/search-fda-guidance-documents, or https://www.regulations.gov.
Dated: November 21, 2024.
P. Ritu Nalubola,
Associate Commissioner for Policy.
[FR Doc. 2024-27796 Filed 11-26-24; 8:45 am]
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