Premenopausal Women with Breast Cancer: Developing Drugs for Treatment: Guidance for Industry

Administrative guidance, not enacted legislation. This captured publisher edition preserves the listed document and attachments; later developments are not independently consolidated.

Premenopausal Women
with Breast Cancer:
Developing Drugs for
Treatment
Guidance for Industry
U.S. Department of Health and Human Services
Food and Drug Administration
Oncology Center of Excellence (OCE)
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
June 2021
Clinical/Medical

Premenopausal Women
with Breast Cancer:
Developing Drugs for
Treatment
Guidance for Industry
Additional copies are available from:
Office of Communications, Division of Drug Information
Center for Drug Evaluation and Research
Food and Drug Administration
10001 New Hampshire Ave., Hillandale Bldg., 4th Floor
Silver Spring, MD 20993-0002
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353; Email: druginfo@fda.hhs.gov
https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs
and/or
Office of Communication, Outreach, and Development
Center for Biologics Evaluation and Research
Food and Drug Administration
10903 New Hampshire Ave., Bldg. 71, rm. 3128
Silver Spring, MD 20993-0002
Phone: 800-835-4709 or 240-402-8010; Email: ocod@fda.hhs.gov
https://www.fda.gov/vaccines-blood-biologics/guidance-compliance-regulatory-information-biologics/biologics-
guidances
U.S. Department of Health and Human Services
Food and Drug Administration
Oncology Center of Excellence (OCE)
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
June 2021
Clinical/Medical

Contains Nonbinding Recommendations
TABLE OF CONTENTS
I. 	INTRODUCTION............................................................................................................. 1
II. 	BACKGROUND ............................................................................................................... 1
III. 	RECOMMENDATIONS.................................................................................................. 2

Contains Nonbinding Recommendations
1
Premenopausal Women with Breast Cancer: Developing Drugs for
Treatment
Guidance for Industry1
This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on
this topic. 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.
To discuss an alternative approach, contact the FDA staff responsible for this guidance as listed on the
title page.
I. 	INTRODUCTION
This guidance provides recommendations to sponsors developing drugs or biological products2
regulated by CDER and CBER for the treatment of breast cancer. Specifically, this guidance
includes recommendations regarding the inclusion of premenopausal women, as defined by
serum hormonal levels (including but not limited to follicle-stimulating hormone and estradiol),
in breast cancer clinical trials. The issues of fertility and fertility preservation when treating
premenopausal women with breast cancer are outside the scope of this guidance and are not
addressed.
The contents of this document do not have the force and effect of law and are not meant to bind
the public in any way, unless specifically incorporated into a contract. This document is intended
only to provide clarity to the public regarding existing requirements under the law. FDA
guidance documents, including this guidance, should be viewed only as recommendations, unless
specific regulatory or statutory requirements are cited. The use of the word should in FDA
guidances means that something is suggested or recommended, but not required.
II. 	BACKGROUND
Historically, premenopausal women have been excluded from some trials that have investigated
the efficacy of certain drugs that rely upon manipulation of the hormonal axis for the treatment
of hormone receptor (HR)-positive breast cancer. In some cases, separate studies have been
conducted to confirm the benefit in this patient population, which has resulted in delays in the
availability of these therapies for premenopausal women with HR-positive breast cancer.
1 This guidance has been prepared by the Oncology Center of Excellence, Center for Drug Evaluation and Research
(CDER), and Center for Biologics Evaluation and Research (CBER) at the Food and Drug Administration.
2 For the purposes of this guidance, references to drugs include drugs approved under section 505 of the Federal
Food, Drug, and Cosmetic Act (21 U.S.C. 355) and biological products licensed under section 351 of the Public
Health Service Act (42 U.S.C. 262).

Contains Nonbinding Recommendations
2
Certain groups of drugs such as chemotherapy, immunotherapy, and targeted therapy (which act
independent of the hormonal axis) have similar efficacy in pre- and post-menopausal women
with breast cancer.
In patients with HR-positive breast cancer, where drugs are targeting or being combined with
drugs targeting the hormonal axis, FDA believes hormonal drugs administered to premenopausal
women with adequate estrogen suppression are likely to have generally the same efficacy and
safety profile as in postmenopausal women, based on a review of the nonclinical, clinical
pharmacology, and clinical literature. The inclusion of premenopausal women in breast cancer
oncology product development programs will result in more complete clinical information to
inform clinical decision making and bring safe and effective therapies in a timely manner to this
patient population.
III. 	RECOMMENDATIONS
Consideration should be given to including premenopausal women in breast cancer drug
development programs.3 FDA encourages sponsors to discuss their breast cancer drug
development plan with CDER and CBER, as applicable, early in development. FDA
recommends:
• 	Menopausal status should not be the basis of exclusion from breast cancer clinical trials.
• 	Premenopausal women4 with adequate estrogen suppression5 and postmenopausal
women should be equally eligible and included in clinical trials for drugs or combinations
manipulating the hormonal axis.
• 	Stratification of randomization based on menopausal status at study entry may be
appropriate if there are efficacy and/or safety concerns.
3 See the guidance for industry: Male Breast Cancer: Developing Drugs for Treatment (August 2020) for FDA’s
recommendations regarding including another patient population (i.e., males) in breast cancer clinical trials. We
update guidances periodically. For the most recent version of a guidance, check the FDA guidance web page at
https://www.fda.gov/regulatory-information/search-fda-guidance-documents.
4 See the draft guidance for industry: Estrogen and Estrogen/Progestin Drug Products to Treat Vasomotor
Symptoms and Vulvar and Vaginal Atrophy Symptoms – Recommendations for Clinical Evaluation (January 2003).
When final, this guidance will represent the FDA’s current thinking on this topic.
5 We acknowledge challenges with defining a cut-off level for estrogen suppression given differences in assays,
patient demographics such as weight, medical comorbidities (e.g., polycystic ovarian syndrome), etc.

Contains Nonbinding Recommendations
3
• 	An assessment of the weight of evidence that includes published literature and existing
nonclinical data for reproductive toxicity should be provided to allow FDA to determine
if reproductive toxicity studies may be necessary for an indication that will include
premenopausal women.6
• 	Information on clinical effects (e.g., bone health, cardiac health) of breast cancer drugs in
all patients should be collected as part of the clinical development plan and analyzed
overall and by stratification (if applicable) based on menopausal status at study entry. As
warranted under applicable law or regulation, FDA may require, or seek agreement from
the sponsor to conduct post-marketing studies to analyze additional long-term clinical
effects.7
• 	Clinical studies evaluating drugs in premenopausal women with breast cancer should
reflect the racial and ethnic diversity of this patient population to support the assessment
of short- and long-term effects of these therapies across clinically relevant subgroups of
patients.
• 	Where patient experience data are collected (e.g., to better inform tolerability of a
therapy), refer to FDA guidance for methods and approaches for collecting data
throughout the development program.8
• 	While the issues of fertility and fertility preservation are outside the scope of this
guidance, a gynecologist should be consulted during trial planning and monitoring, as
needed.
6 For recommendations regarding nonclinical data needed to support clinical trial design and marketing applications,
refer to ICH guidance for industry S9 Nonclinical Evaluation for Anticancer Pharmaceuticals (March 2010), ICH
guidance for industry S9 Nonclinical Evaluation for Anticancer Pharmaceuticals Questions and Answers (June
2018), and guidance for industry Oncology Pharmaceuticals: Reproductive Toxicity Testing and Labeling
Recommendations (May 2019).
7 See 21 USC 355(o)(3); 21 CFR 312.85.
8 See the guidance for industry, Food and Drug Administration staff, and other stakeholders: Patient-Focused Drug
Development: Collecting Comprehensive and Representative Input (June 2020).