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[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With Healthy Subjects; Draft Guidance for Industry; Availability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the availability of a draft guidance for industry entitled 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 This draft guidance makes recommendations on 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DATES: Submit either electronic or written comments on the draft 
guidance by February 25, 2025 to ensure that the Agency considers your 
comment on this draft guidance before it begins work on the final 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]
BILLING CODE 4164-01-P
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