Establishing Effectiveness for Drugs Intended to Treat Male Hypogonadotropic Hypogonadism Attributed to Nonstructural Disorders Guidance for Industry

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

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
1
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 FDA’s 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 FDA’s December 6, 2016: Meeting of the Bone, Reproductive, and Urologic Drugs
Advisory Committee web page at https://www.fda.gov/AdvisoryCommittees/Calendar/ucm522253.htm.

Contains Nonbinding Recommendations
2
In general, FDA’s guidance documents do not establish legally enforceable responsibilities.
Instead, guidances describe the Agency’s 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 concentrations—in the absence of intrinsic
damage to the hypothalamus and pituitary gland—are 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:

Contains Nonbinding Recommendations
3
— 	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.

Contains Nonbinding Recommendations
4
• 	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.