93610 Federal Register / Vol. 89, No. 229 / Wednesday, November 27, 2024 / Notices 

1See 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. 

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Healthy Subjects; Draft Guidance for 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. 

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 This draft guidance 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 Amespositive 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written comments on the draft guidance 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draft guidance before it begins work on 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 Amespositive 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 


ddrumheller on DSK120RN23PROD with NOTICES1
Federal Register / Vol. 89, No. 229 / Wednesday, November 27, 2024 / Notices 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. 

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 lifethreatening 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/guidancecompliance-regulatory-information/ 

guidances-drugs, https://www.fda.gov/ 

regulatory-information/search-fdaguidance-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 

DEPARTMENT OF HEALTH AND 

HUMAN SERVICES 

Food and Drug Administration 

[Docket No. FDA–2024–D–4643] 

Assessment of Ovarian Toxicity in 

Premenopausal Adults During Drug 

Development for Oncologic Products; 

Draft Guidance for Industry; 

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 draft 

guidance for industry entitled 

‘‘Assessment of Ovarian Toxicity in 

Premenopausal Adults During Drug 

Development for Oncologic Products.’’ 

This draft guidance provides 

recommendations to sponsors regarding 

the measurement of ovarian toxicity 

using clinical measures and biomarkers 

of ovarian function in relevant cancer 

clinical trials that enroll premenopausal 

adults with ovaries. Assessment of 

ovarian toxicity in cancer trials helps 

ensure that patients and clinicians have 

information about the possible longterm impacts of treatment on ovarian 

function and thus facilitate informed 

decision-making regarding anti-cancer 

agents. 

DATES: Submit either electronic or 

written comments on the draft guidance 

by January 27, 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 


ddrumheller on DSK120RN23PROD with NOTICES1