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 
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). 
  1  Contains Nonbinding Recommendations 
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 FDAs 
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 FDAs 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.   
  2  Contains Nonbinding Recommendations 
  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). 
 
 
  3