Establishing Effectiveness for 
Drugs Intended to Treat Male 
Hypogonadotropic 
Hypogonadism Attributed to 
Nonstructural Disorders 
Guidance for Industry 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
May 2018 
Clinical/Medical 
   
Establishing Effectiveness for 
Drugs Intended to Treat Male 
Hypogonadotropic 
Hypogonadism Attributed to 
Nonstructural Disorders 
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/GuidanceComplianceRegulatoryInformation/Guidances/default.htm 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
May 2018 
Clinical/Medical 
   
TABLE OF CONTENTS 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 2 
III.  CLINICAL TRIAL DESIGN FEATURES  KEY CONSIDERATIONS ................ 2 
A.  Enrollment Criteria ....................................................................................................................... 2 
B.  Efficacy Endpoints ......................................................................................................................... 3 
 
  Contains Nonbinding Recommendations 
Establishing Effectiveness for Drugs Intended  
to Treat Male Hypogonadotropic Hypogonadism  
Attributed to Nonstructural Disorders 
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 office responsible for this guidance as listed on the 
title page.   
 
 
 
 
I.  INTRODUCTION 
 
This guidance provides recommendations for establishing clinical effectiveness for drugs 
intended to treat male hypogonadotropic hypogonadism associated with obesity and other 
conditions that do not cause structural disorders of the hypothalamus or pituitary gland.  These 
drugs should both increase serum testosterone concentrations and improve how patients feel, 
function, or survive.  This guidance incorporates advice the FDA received at a December 2014 
advisory committee meeting on the appropriate indicated population for testosterone therapy2 
and a December 2016 advisory committee meeting on hypogonadotropic hypogonadism.3 
 
This guidance does not address the development programs for testosterones or testosterone esters 
seeking the traditional indication of replacement therapy in adult males for conditions associated 
with a deficiency or absence of endogenous testosterone.  This guidance also does not address 
the development of drugs to treat specific conditions associated with male hypogonadotropic 
hypogonadism (e.g., weight management in patients with obesity).  
 
                                                 
1 This guidance has been prepared by the Division of Bone, Reproductive and Urologic Products in the Center for 
Drug Evaluation and Research at the Food and Drug Administration.  
 
2 See the FDAs archived 2014 Meeting Materials, Drug Safety and Risk Management Advisory Committee web 
page at https://wayback.archive-
it.org/7993/20170403223847/https://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Drug
SafetyandRiskManagementAdvisoryCommittee/ucm380883.htm.  
 
3 See Meeting Materials on the FDAs December 6, 2016: Meeting of the Bone, Reproductive, and Urologic Drugs 
Advisory Committee web page at https://www.fda.gov/AdvisoryCommittees/Calendar/ucm522253.htm.  
  1  Contains Nonbinding Recommendations 
In general, FDAs guidance documents do not establish legally enforceable responsibilities.  
Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
as recommendations, unless specific regulatory or statutory requirements are cited.  The use of 
the word should in Agency guidances means that something is suggested or recommended, but 
not required. 
 
II.  BACKGROUND 
 
Male hypogonadism is characterized by serum testosterone concentrations below the lower limit 
of the normal range for young, healthy men accompanied by associated symptoms (e.g., reduced 
libido) or signs (e.g., loss of muscle mass with reduced muscle strength).  Hypogonadism is 
classified as hypogonadotropic when serum gonadotropin concentrations are normal or low 
despite low serum testosterone concentrations. 
 
Men with classic hypogonadotropic hypogonadism have low serum testosterone because of 
intrinsic damage to the hypothalamus or pituitary gland caused by well-recognized conditions, 
including congenital disorders that affect sexual development or puberty (e.g., Kallmann 
syndrome) or following pituitary resection.  These men are clearly testosterone deficient; 
testosterone replacement therapy is the standard of care for these men when they have no desire 
for near-term fertility.  A sponsor can establish effectiveness of a testosterone drug for use in 
these patients by showing the drug reliably increases serum testosterone concentrations to within 
the normal range for young, healthy men.  The design features of such trials are well established 
and not covered in this guidance. 
 
Some men who have had normal puberty and sexual development are subsequently diagnosed 
with hypogonadotropic hypogonadism associated with obesity or other acquired conditions in the 
absence of intrinsic damage to the hypothalamus or pituitary.  Although these men have serum 
testosterone concentrations below the lower limit of the normal range for young, healthy men, 
the associated symptoms often experienced in this population (e.g., low energy, depressed mood) 
are nonspecific and cannot definitively be attributed to the low testosterone concentrations.  In 
addition, it is unclear whether these testosterone concentrationsin the absence of intrinsic 
damage to the hypothalamus and pituitary glandare inappropriately low and whether 
increasing testosterone concentrations in these men confers clinical benefit.  For these reasons, 
serum testosterone is not a validated surrogate endpoint for establishing efficacy in these 
patients, and sponsors should show that an increase in serum testosterone translates into 
improvement in how patients feel, function, or survive.  The key design features of such trials are 
discussed below. 
 
 
III.  CLINICAL TRIAL DESIGN FEATURES  KEY CONSIDERATIONS 
 
A.  Enrollment Criteria 
 
  The trial population should have clinical and laboratory evidence of hypogonadotropic 
hypogonadism, including the following:  
 
  2  Contains Nonbinding Recommendations 
  Low serum total testosterone concentrations in the morning on at least two occasions 

separated by at least 3 days, assessed using a validated assay  
 
  Low free testosterone concentrations in the morning on at least two occasions 

separated by at least 3 days using a validated assay (if there are sex hormone binding 
globulin abnormalities)  
 
  Serum gonadotropins (follicle-stimulating hormone and luteinizing hormone) that do 

not exceed the upper limit of the reference range   
 
  Symptoms or signs that the drug is intended to target 

 
  Normal serum prolactin concentration 

 
  Normal thyroid function tests (with or without thyroid hormone supplementation) 

 
  The patients enrolled in the trial should have no intrinsic damage to their hypothalamus, 
pituitary glands, and testes, but the trial population should be well defined with regard to 
the underlying associated condition, symptoms, and signs. 
 
B.  Efficacy Endpoints 
 
  Randomized, double-blind, placebo-controlled trials should show that the drug increases 
serum testosterone and provides clinically meaningful improvement in at least one 
symptom or sign of hypogonadism.  
 
  For example, a responder would be a patient who has normalized testosterone 

concentrations (based on pharmacokinetic sampling) and also has clinically 
meaningful improvement in the specified symptoms or signs. 
 
  Patient-reported outcome (PRO) instruments may play a central role in establishing 
efficacy because they provide direct evidence of how patients feel or function.  
 
  Sponsors should use well-defined and reliable instruments that take into account the 

recommendations in the guidance for industry Patient-Reported Outcome Measures: 
Use in Medical Product Development to Support Labeling Claims.4  
 
  Currently, the FDA is not aware of PRO instruments shown to be adequate for 

regulatory use to assess improvement in hypogonadal symptoms or signs.  We are 
open to evaluating existing or modified PRO instruments assessing the important 
disease-related symptoms or signs in men with hypogonadism.   
 
  The FDA encourages development of a publicly available, fit-for-purpose PRO 

instrument that can be used across multiple drug development programs.5 
                                                 
4 We update guidances periodically.  To make sure you have the most recent version of a guidance, check the FDA 
guidance web page at https://www.fda.gov/RegulatoryInformation/Guidances/default.htm.  
  3  Contains Nonbinding Recommendations 
 
  The FDA does not consider improvement in biomarkers (e.g., changes in muscle mass) 
that are not established surrogate endpoints6 for how patients feel, function or survive to 
be sufficient for establishing evidence of clinical benefit.  
 
  Depending on the mechanism of action, the drug could worsen or improve or have no 
effect on spermatogenesis.  
 
  For drugs that improve spermatogenesis, sponsors could establish efficacy by 

showing improved fertility outcomes (e.g., pregnancy in the partner).  Changes in 
semen parameters (e.g., sperm count) alone are not sufficient for establishing efficacy 
because of the following:  
 
  The intent of the drug is to improve fertility in these men  
 
  Sperm count is only one measure of normal spermatogenesis  
 
  Improvement in semen parameters does not ensure fertility 
 
  For drugs that do not show an effect on spermatogenesis (or that show an adverse 

effect on spermatogenesis), sponsors could establish efficacy by showing 
improvement in other hypogonadal symptoms or signs.  
 
                                                                                                                                                             
5 See the guidance for industry and FDA staff Qualification Process for Drug Development Tools. 
 
6 Established surrogate endpoints can be used to support marketing approval of a drug in a defined context without 
the need for additional studies to demonstrate the clinical benefit directly. 
  4