Non-Clinical and Clinical Investigation of Devices Used for the Treatment of Benign Prostatic Hyperplasia (BPH): Guidance for Industry and Food and Drug Administration Staff

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

Contains Nonbinding Recommendations
Non-Clinical and Clinical Investigation
of Devices Used for the Treatment of
Benign Prostatic Hyperplasia (BPH)
Guidance for Industry and
Food and Drug Administration Staff
Document issued on December 27, 2021.
The draft of this document was issued on July 14, 2020.
This document supersedes “Guidance for the Non‐Clinical and Clinical
Investigation of Devices Used for the Treatment of Benign Prostatic
Hyperplasia (BPH),” issued on August 17, 2010.
For questions about this document, contact OHT3: Office of Reproductive, Gastro-Renal,
Urological, General Hospital Device, & Human Factors/DHT3B: Division of Reproductive and
Urology Devices at (301) 796-7030.
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Devices and Radiological Health

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Preface
Public Comment
You may submit electronic comments and suggestions at any time for Agency consideration to
https://www.regulations.gov. Submit written comments to the Dockets Management Staff, Food
and Drug Administration, 5630 Fishers Lane, Room 1061, (HFA-305), Rockville, MD 20852.
Identify all comments with the docket number FDA-2020-D-1118. Comments may not be acted
upon by the Agency until the document is next revised or updated.
Additional Copies
Additional copies are available from the Internet. You may also send an email request to CDRH-
Guidance@fda.hhs.gov to receive a copy of the guidance. Please include the document number
1724 and complete title of the guidance in the request.

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Table of Contents
I. 	Introduction ............................................................................................................................. 1
II. 	Scope ....................................................................................................................................... 3
III. 	Non-Clinical Testing Recommendations ............................................................................. 4
A. 	Material Safety ................................................................................................................. 5
B. 	Electrical Safety and Electromagnetic Compatibility (EMC) .......................................... 6
C. 	Magnetic Resonance (MR) Compatibility for Passive Implants ...................................... 7
D. 	Mechanical Testing .......................................................................................................... 7
E. 	Corrosion or Degradation ................................................................................................. 8
F. 	Sterilization .......................................................................................................................... 8
G. 	Software ........................................................................................................................... 9
H. 	Repeated Use Reliability .................................................................................................. 9
I. 	In Vitro Thermal Mapping (Phantom Study)....................................................................... 9
J. 	Animal Study ..................................................................................................................... 10
(1) 	Thermotherapy............................................................................................................ 11
(2) 	Stents .......................................................................................................................... 12
IV. 	Pilot Clinical Study Recommendations ............................................................................. 13
V. 	Pivotal Clinical Study Recommendations ............................................................................ 15
A. 	Study Objective .............................................................................................................. 15
B. 	Minimizing Bias ............................................................................................................. 15
C. 	Randomization and Controls .......................................................................................... 16
D. 	Blinding (Masking) ........................................................................................................ 18
E. 	Study Endpoints ............................................................................................................. 19
(1) 	Primary Endpoints ...................................................................................................... 19
(2) 	Primary Effectiveness Endpoint ................................................................................. 19
(3) 	Primary Safety Endpoint ............................................................................................ 21
(4) 	Secondary Endpoints .................................................................................................. 21
F. 	Study Duration ................................................................................................................... 23
G. 	Statistical Hypothesis ..................................................................................................... 24
H. 	Sample Size .................................................................................................................... 24
I. 	Patient Selection Criteria ................................................................................................... 24
J. 	Pre-Treatment Evaluation Schedule .................................................................................. 27
K. 	Investigator Selection and Training ............................................................................... 28

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L. 	Treatment Information ................................................................................................... 29
M. 	Post-Treatment Evaluations ........................................................................................... 29
N. 	Statistical Analysis Recommendations .......................................................................... 30
(1) 	Statistical Analyses ..................................................................................................... 31
(2) 	Primary Endpoint Analyses ........................................................................................ 31
(3) 	Secondary Endpoint Analyses .................................................................................... 32
(4) 	Missing Data ............................................................................................................... 33
O. 	Risk Analysis.................................................................................................................. 34
P. 	Study Monitoring ............................................................................................................... 34
Q. 	Case Report Forms ......................................................................................................... 35
VI. 	Conclusions ........................................................................................................................ 36
Appendix 1. ................................................................................................................................... 37

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Non-Clinical and Clinical Investigation
of Devices Used for the Treatment of
Benign Prostatic Hyperplasia (BPH)
Guidance for Industry and
Food and Drug Administration Staff
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
or Office responsible for this guidance as listed on the title page.
I. 	Introduction
As men age, the prostate enlarges over time obstructing the prostatic urethra resulting in
anatomic and functional changes in the bladder. The resulting condition, known as benign
prostatic hyperplasia (BPH), can be associated with decreased peak urinary flow rate (Qmax ) and
increased post void residual urine (PVR). Men with BPH experience bothersome lower urinary
tract symptoms (LUTS) that affect their quality of life by disrupting sleep patterns or interfering
with daily activities. The development of LUTS is a complex process that involves the
interaction of prostatic enlargement and bladder outlet obstruction with age-related effects on the
bladder and nervous system.
Although BPH is uncommon in young men, it is remarkably common in older men.
Epidemiological studies estimate that 50% of men have histological BPH by age 60. The
prevalence increases to 90% in men over 85.1, 2 Similar to the histological evidence, the
prevalence of LUTS and other clinical indicators of BPH increases with age and is similar across
1 Berry SJ, Coffey DS, Walsh PC, Ewing LL, The development of human benign prostatic hyperplasia by age. J
Urol, 1984, 132:474-479.
2 Isaacs, JT, Coffey DS, Etiology and disease process of benign prostatic hyperplasia. Prostate, 1989, 2(Suppl):33-
50.

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various countries and ethnic groups studied.3, 4, 5, 6, 7 Therefore, BPH is considered a significant
medical condition that has, and will continue to have, considerable public health impact.
A well-designed, scientifically sound investigational plan, both non-clinical and clinical, is
essential to evaluate the safety and effectiveness of a medical device intended to treat BPH.
Prior to use in humans, it is essential to demonstrate that the device will function as intended in
its environment of use. The design of medical devices involves the development and verification
of a battery of specifications that define basic safety and performance requirements of the device.
Most design specifications are validated in non-clinical testing, which allows assessment of
device function and safety under controlled circumstances. Additionally, a comprehensive non-
clinical battery of testing provides a foundation for evaluating future changes to the device.
The ultimate goal when conducting a clinical investigation of a device to treat BPH is to design a
study using objective, unbiased outcomes to measure the safety and effectiveness of treatment.
Major challenges faced when designing a clinical study to assess the safety and effectiveness of a
BPH device include the placebo effect and spontaneous remissions that commonly occur with
BPH, the inherent variability and subjectivity of the typical outcome measures commonly used to
assess the effectiveness of treatment, and the availability of effective treatments for BPH.
This guidance identifies the key features of non-clinical and clinical investigational plans used to
support investigational device exemption (IDE) applications, premarket approval applications
(PMAs), De Novo classification requests, and some premarket notification (510(k)) submissions
for devices used in the treatment of BPH. Some recommendations in this document may not
apply to a particular device, and additional recommendations may be appropriate for novel
device types or technologies. FDA will consider alternative non-clinical and clinical testing
when the proposed alternatives are supported by an adequate scientific rationale. We encourage
you to contact DHT3B, the Division of Reproductive and Urology Devices, when designing your
clinical investigation and prior to submission of an original IDE application.
For the current edition of the FDA-recognized consensus standard(s) referenced in this
document, see the FDA Recognized Consensus Standards Database.8 For more information
regarding use of consensus standards in regulatory submissions, please refer to the FDA
3 Chute CG, Panser LA, Girman CJ, et al., The prevalence of prostatism: a population-based survey of urinary
symptoms. J Urol, 1993, 150:85-89.
4 Homma Y, Kawabe K, Tsukamoto T, et al., Epidemiological survey of lower urinary tract symptoms in Asia and
Australia using the International Prostate Symptom Score. Int Urol 1997, 4:40-46.
5 Hunter DJW, Berra-Unamuno A, Martin-Gordo A, Prevalence of urinary symptoms and other urological
conditions in Spanish men 50 years old or older. J Urol, 1996; 155:1965-1970.
6 Sagnier PP, MacFarlane G, Richard F, Botto H, Teillac P, Boyle P, Results of an epidemiological survey using a
modified American Urological Association (AUA) symptom index for benign prostatic hyperplasia in France. J
Urol, 1994, 151:1266-1270.
7 Tan HY, Choo WC, Archibald C, Esuvaranathan K, A community-based study of prostatic symptoms in
Singapore. J Urol, 1997; 157:890-893.
8 Available at https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfStandards/search.cfm.

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guidance titled “Appropriate Use of Voluntary Consensus Standards in Premarket Submissions
for Medical Devices.”9
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 Agency
guidance means that something is suggested or recommended, but not required.
II. 	Scope
This guidance document addresses the general concepts that we recommend you consider when
designing an investigational plan, both non-clinical and clinical, for a medical device indicated
for the treatment of BPH. We do not distinguish between indications for use that specifically
identify BPH as the disease being treated, and indications for use that identify surgical treatments
for BPH, e.g., prostatectomy, transurethral incision of the prostate. This guidance does not apply
to devices intended to treat other diseases of the prostate, such as prostate cancer.
These concepts are generally applicable for any type of BPH treatment device undergoing non-
clinical and clinical investigation to support a marketing submission. The device may be either
class II or class III, and the technologies may include the following:
Product
Code
Description 	Classification Regulation
(21 CFR)
OEL10 	Laser surgical instrument for use in general
and plastic surgery and in dermatology
21 CFR 878.4810
KNS,
OEK, OEJ
Endoscopic electrosurgical unit and
accessories
21 CFR 876.4300
MIK* 	Device, Ultrasonic, Thermal Ablation 	No corresponding CFR
section
MEQ* 	System, Hyperthermia, Microwave (BPH) 	No corresponding CFR
section
MER* 	Stent, Urethral Prostatic, Permanent 	No corresponding CFR
section
NZC* 	Stent, urethral, prostatic, semi-permanent 	No corresponding CFR
section
PEW 	Implantable transprostatic tissue retractor
system
21 CFR 876.5530
PZP 	Fluid jet removal system 	21 CFR 876.4350
9 Available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/appropriate-use-
voluntary-consensus-standards-premarket-submissions-medical-devices.
10 Medical lasers with specific indications for BPH cleared prior to issue of this guidance may have been assigned
GEX as a product code.

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NOY 	Agents, embolic, for treatment of benign
prostatic hyperplasia
21 CFR 876.5550
QKA11 	Temporarily-placed urethral opening system
for symptoms of benign prostatic hyperplasia
21 CFR 876.5510
* These devices are class III and require premarket approval before marketing.
The non-clinical recommendations apply to class II and class III devices. The recommendations
provide a framework for performance testing to support marketing authorization or initiation of a
clinical study in humans.
The clinical recommendations in this guidance are not intended for the review of 510(k)
submissions for class II devices that have traditionally been used in surgical interventions for
BPH, such as cutting loops or scalpels.
For some class II devices, the submission of clinical data to support an indication for the
treatment of BPH (or any equivalent term) is appropriate and may be necessary to support a
510(k) submission or De Novo request. If you plan to collect clinical performance data to
support marketing authorization of a device with new technological characteristics, a new
indication, or specific labeling and marketing claims, we recommend that submitters address the
considerations discussed in this guidance document when designing the clinical study.
If a clinical study is needed to support marketing authorization, the study must be conducted
under the Investigational Device Exemptions (IDE) regulation, 21 CFR part 812, for studies
conducted in the United States (U.S.). Generally, we believe the devices addressed by this
guidance document are significant risk devices subject to all requirements of 21 CFR part 812.
See the FDA guidance titled, “Significant Risk and Nonsignificant Risk Medical Device
Studies.”12 In addition to the requirements of 21 CFR part 812, sponsors of such trials of a
device conducted in the U.S. must comply with the regulations governing institutional review
boards (21 CFR part 56) and informed consent (21 CFR part 50).
III. 	Non-Clinical Testing Recommendations
Prior to use in humans, it is essential to demonstrate that the device will function as intended in
its environment of use. The design of medical devices involves non-clinical development and
verification of specifications that define basic safety and performance requirements of the
device. Most design specifications are validated in non-clinical testing, which allows assessment
of device function and safety under controlled circumstances. Additionally, a comprehensive,
non-clinical battery of testing provides a foundation for evaluating future changes to the device.
We recommend you provide comprehensive non-clinical testing with predefined performance
limits (i.e., specifications) to support an IDE application, PMA, 510(k) submission, or a De Novo
request for a new device intended to treat BPH.
11 This classification regulation is subject to special controls. See https://www.accessdata.fda.gov/scripts/cdrh/
cfdocs/cfpmn/denovo.cfm?ID=DEN190020 for more information.
12 https://www.fda.gov/regulatory-information/search-fda-guidance-documents/significant-risk-and-nonsignificant-
risk-medical-device-studies.

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This section describes the types of testing that generally have been adequate to support
applications for devices intended to treat BPH. Not all of the issues and testing discussed below
are applicable to every new device intended to treat BPH, and additional issues or testing not
described below may be appropriate for your device depending on its design and mechanism of
action.
When you develop the non-clinical testing plan for your device, we encourage you to explore the
use of other FDA guidance documents and consensus standards that directly or indirectly relate
to relevant aspects of your device. For example, some of the methods frequently used to test
performance characteristics of urinary catheters may be applicable to devices intended to treat
BPH, such as transurethral microwave thermotherapy (TUMT) applicators. If you use other FDA
guidance or consensus standards in developing your non-clinical test plan, we recommend you
provide a clear rationale describing how the FDA guidance or consensus standards are relevant
to your device.
For information on the recommended content and format of test reports for the testing described
in Sections III.A, III.D, III.E, III.H, and III.I, refer to FDA’s guidance, “Recommended Content
and Format of Non-Clinical Bench Performance Testing Information in Premarket
Submissions.”13
A. 	Material Safety
We recommend that you provide data or information that supports the material safety of all
patient-contacting components of your device. Because steps in processing, manufacturing and
sterilization may introduce new materials and potentially harmful agents not present in the raw
material components, it is difficult to support the material safety of a device based solely upon
the safety of either similar devices or the raw materials. Therefore, to demonstrate the material
safety of your device, we recommend that you conduct biocompatibility testing on the patient-
contacting components of your device in their final finished form, in accordance with recognized
standards and applicable FDA guidance.
For guidance on the selection of biocompatibility tests, refer to “Use of International Standard
ISO 10993-1, ‘Biological evaluation of medical devices - Part 1: Evaluation and testing within a
risk management process.’”14
To facilitate our independent assessment, we recommend you include the following for all
biocompatibility testing conducted:
• 	a summary of the results;
• 	test protocols;
• 	all raw data sheets;
• 	the acceptance criteria; and
13 https://www.fda.gov/regulatory-information/search-fda-guidance-documents/recommended-content-and-format-
non-clinical-bench-performance-testing-information-premarket.
14 https://www.fda.gov/regulatory-information/search-fda-guidance-documents/use-international-standard-iso-
10993-1-biological-evaluation-medical-devices-part-1-evaluation-and.

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• 	any other supporting data.
Frequently, the highest concentrations of potentially harmful materials or agents exist in a new
device and may gradually diminish over time. For this reason, biocompatibility testing is often
conducted on new devices with little storage time. However, for some devices, the material risks
change during long-term storage. For example, long-term storage can allow potentially harmful
agents removed from the surface during processing to resurface from the bulk of the device. We
recommend you evaluate the impact of device storage on the material safety of your device and
conduct the biocompatibility testing at time points in which the potentially harmful materials or
agents are likely to be at their highest concentration.
B. 	Electrical Safety and Electromagnetic Compatibility
(EMC)
Some BPH devices are medical electrical equipment and therefore may expose the operator and
patient to hazards associated with the use of electrical energy or may fail to operate properly in
the presence of electromagnetic disturbance.
Electrically powered BPH devices should be tested to demonstrate that they perform as
anticipated in their intended use environment. We recommend that this testing be performed as
described in the currently FDA-recognized versions of the following standards for medical
electrical equipment safety and electromagnetic compatibility:
• 	ANSI/AAMI ES60601-1: Medical electrical equipment - Part 1: General requirements
for basic safety and essential performance.
• 	ANSI/AAMI/IEC 60601-1-2: Medical electrical equipment - Part 1-2: General
requirements for basic safety and essential performance - Collateral standard:
Electromagnetic disturbances - Requirements and tests.
If submitting a declaration of conformity to the above standards, we recommend that appropriate
supplemental documentation such as an assessment of the results and how conformity was
determined, and information regarding test methods used should be provided because this series
of standards includes general methods with multiple options and, in some cases, does not include
specific acceptance criteria or address assessment of results. For additional information on
providing electromagnetic compatibility information in a premarket submission, see FDA’s
guidance, “Information to Support a Claim of Electromagnetic Compatibility (EMC) of
Electrically-Powered Medical Devices.”15
If your device contains a thermometry system, electromagnetic interference can impair the
function and accuracy of the temperature sensors. We recommend you include a discussion of
how you eliminated or avoided electromagnetic interference with the temperature sensors during
testing and treatment, especially if the thermometry system controls treatment delivery. We
recommend your discussion include:
15 https://www.fda.gov/regulatory-information/search-fda-guidance-documents/information-support-claim-
electromagnetic-compatibility-emc-electrically-powered-medical-devices.

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• 	the method used to electrically isolate the signal paths of the system's thermocouples;
• 	the thermocouple sheathing material;
• 	the filters used to decrease electromagnetic interference; and
• 	how electromagnetic interference will be minimized in the clinical environment.
C. 	Magnetic Resonance (MR) Compatibility for Passive
Implants
The MR environment includes a strong static magnetic field and its associated spatial gradient,
pulsed gradient magnetic fields, and pulsed radio frequency (RF) fields. The interactions of the
medical device with the MR environment create safety concerns including serious patient injury,
device malfunction, and poor image quality.
We recommend that you address the issues affecting safety and compatibility of your device in
the MR environment as described in the FDA guidance, “Testing and Labeling Medical Devices
for Safety in the Magnetic Resonance (MR) Environment.”16 We also recommend that you
consider the labeling recommendations given in the same guidance document. If you would like
to market various sizes and shapes of your device, then we recommend you follow our
recommendations in the FDA guidance, “Assessment of Radiofrequency-Induced Heating in the
Magnetic Resonance (MR) Environment for Multi-Configuration Passive Medical Devices.”17
D. 	Mechanical Testing
Medical devices are subject to mechanical forces during use. Damage or failure of the device due
to mechanical forces could result in poor performance or injury to the patient. Therefore, we
recommend that you conduct comprehensive mechanical testing to demonstrate that the device
and its components can withstand the mechanical stresses of its environment over its expected
lifetime. In addition, we recommend this set of tests simulate the mechanical stresses
experienced by the device during use, e.g., the forces associated with body movement, insertion,
or removal. Mechanical testing includes mechanical strength (e.g., tensile testing), cyclic
loading, and simulated use.
To facilitate our review, we recommend you provide a complete description and justification for
each mechanical test conducted, including:
• 	a description of the test article, including its size, sterilization status, age, and any
modifications that were made to allow the performance of the test;
• 	the number of samples tested;
• 	the testing environment used, e.g., synthetic urine, water, air;
• 	the load applied, including the rate, direction, and placement;
• 	the predetermined performance criteria; and
• 	other relevant parameters used in the tests.
16 https://www.fda.gov/regulatory-information/search-fda-guidance-documents/establishing-safety-and-
compatibility-passive-implants-magnetic-resonance-mr-environment.
17 https://www.fda.gov/regulatory-information/search-fda-guidance-documents/assessment-radiofrequency-induced-
heating-magnetic-resonance-mr-environment-multi-configuration.

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E. 	Corrosion or Degradation
The urological environment can degrade materials routinely used in medical devices, impacting
device performance and safety. For devices that have extended indwelling durations within the
urinary tract, we recommend you include corrosion or degradation testing that assesses the
effects of bodily fluids on your device. We recommend you:
• 	perform the testing in a natural or artificial medium that is chemically equivalent to the
environment the device will experience in vivo;
• 	select a time course relevant to the proposed clinical use;
• 	examine the device for any visible corrosion product or encrustation;
• 	test the device to determine changes in structural integrity or function; and
• 	measure the device for any change in weight or dimensions.
We recommend you provide a complete description and justification of the following:
• 	the test articles, including the size, sterilization status, age, and any modifications that
were made to allow the performance of the test;
• 	the number of samples tested;
• 	the methods used, including the environment and time course;
• 	the evaluation methods, i.e., visual evaluation, dimensional evaluation, mechanical
integrity;
• 	the predetermined performance criteria; and
• 	any other relevant parameters.
F. 	Sterilization
If any component of your device has the potential to introduce pathogens into otherwise aseptic
or sterile tissues, we recommend you provide information regarding how pathogens are
eliminated from the device, such as sterilization. For any devices or components that are
provided sterile, refer to the document “Submission and Review of Sterility Information in
Premarket Notification (510(k)) Submissions for Devices Labeled as Sterile”18 for the
recommended information to include in your 510(k) submission. Additional information (e.g.,
package integrity testing) or more detailed information (e.g., the results of sterilization cycle
validation testing) may be requested for IDE applications, De Novo requests, or PMAs.
If your device, or any of its components, is intended to be reused and has the potential to
introduce pathogens into otherwise aseptic or sterile tissues, we recommend you provide detailed
instructions on reprocessing methods and evidence that the components can be safely disinfected
or sterilized through these methods.19
18 https://www.fda.gov/regulatory-information/search-fda-guidance-documents/submission-and-review-sterility-
information-premarket-notification-510k-submissions-devices-labeled.
19 For more information, see the FDA guidance “Reprocessing Medical Devices in Health Care Settings: Validation
Methods and Labeling,” available at https://www.fda.gov/regulatory-information/search-fda-guidance-
documents/reprocessing-medical-devices-health-care-settings-validation-methods-and-labeling.

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G. 	Software
If your device includes software, we recommend you provide the information based on the risks
associated with software failure prior to mitigation, i.e., “Level of Concern.” We recommend you
submit the information for software devices described in “Guidance for the Content of Premarket
Submissions for Software Contained in Medical Devices.”20
H. 	Repeated Use Reliability
The performance and safety of devices, components, or accessories intended for use in multiple
treatments can degrade with repeated use and sterilization. If your device contains components
intended for use in multiple treatments, we recommend you provide mechanical and functional
test data that support device reliability throughout the life expectancy of the components.
I. 	In Vitro Thermal Mapping (Phantom Study)
Some devices treat BPH by generating thermal fields within the prostate (e.g., TUMT). The
magnitude and distribution of the thermal field impacts the therapeutic effect and risks associated
with the device. In vitro thermal mapping in a tissue-equivalent phantom provides important
information on the thermal field prior to use of the device in human or animal populations.
If your device is a thermal field-producing device, we recommend you map the temperature
gradient (i.e., the depth of penetration and distribution of heat), in a tissue-equivalent phantom, at
body temperature. We recommend that the design of the phantom studies provide the following
information:
• 	a spatial plot of the specific absorption rate (SAR, in W/Kg);
• 	a spatial plot of the measured temperature as a function of time;21
• 	the value, location, and time of maximum recorded temperature; and
• 	data recorded at various distances along multiple radial planes (i.e., preferential side,
opposite the preferential side, and on each of the lateral sides), including the value, radial
distance, and time of the maximum recorded temperature in each plane, if preferential
heating applies to the device.22
A variety of scientifically valid methods exists to conduct these types of phantom studies. We
recommend you provide a detailed explanation and justification of the methods used including:
• 	the test apparatus, including diagrams labeled with dimensions and the location of the
sensors;
20 https://www.fda.gov/regulatory-information/search-fda-guidance-documents/guidance-content-premarket-
submissions-software-contained-medical-devices.
21 For catheter-based applicators, a spatial plot is usually most conveniently created by measuring the temperature
along the length of the catheter and in multiple radial planes.
22 Some thermotherapy applicators are specifically designed to provide preferential heating. However, preferential
heating occurs to some extent in any applicator that is not perfectly axi-symmetric. Therefore, we recommend that
you collect data in multiple radial planes for all devices in the initial phantom testing. If the testing verifies that the
thermal fields are symmetric, you can reduce the number of planes during subsequent phantom testing.

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• 	the sensors used, including evidence that they are not affected by the field generated by
the device;
• 	the phantom, including its composition, thermal and physical constants (e.g., thermal
conductivity, density, and heat capacity) electromagnetic properties, e.g., permittivity and
electrical conductivity at the proposed frequency, and a literature reference for the
phantom, if available;
• 	the device settings and parameters used; and
• 	the technological characteristics of the power control unit and the power adjustment
method.
When you report the findings of thermal mapping for your device, we recommend that you
include a scientifically sound rationale describing how the results obtained with the tissue-
equivalent phantom relate to clinical use in humans. Specifically, we recommend the discussion
include the following:
• 	the relationship between results and the pertinent anatomy of the lower urinary tract;
• 	how the data demonstrate that your device provides therapeutic heating to the prostate
without clinically significant heating of the non-target tissues; and
• 	the impact of the heterogeneous tissue composition of the prostate and surrounding
tissues including blood flow.
J. 	Animal Study
Animal studies23 provide a valuable assessment of the device’s functional design characteristics
to evaluate the device for its intended use. The limitations of bench models can make adequate
assessment of some safety and effectiveness concerns difficult with bench testing alone. For
example, bench testing does not assess tissue necrosis and healing for thermal field-producing
devices. For most new BPH devices, animal studies provide data to evaluate such safety and
effectiveness concerns prior to use in humans.
We recommend that you assess whether animal studies are warranted in your comprehensive
non-clinical testing plan. Conducting animal studies for a new device intended to treat BPH
depends on factors that include:
• 	device design;
• 	material construction;
• 	mechanism of action;
• 	duration of clinical use;
• 	history of clinical use; and
• 	data from prior animal studies, human clinical investigations (foreign and domestic), or
other appropriate studies.
23 FDA supports the principles of the “3Rs,” to reduce, refine, and replace animal use in testing when feasible. We
encourage sponsors to consult with us if it they wish to use a non-animal testing method they believe is suitable,
adequate, validated, and feasible. We will consider if such an alternative method could be assessed for equivalency
to an animal test method.

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Animal studies intended to evaluate device safety should be conducted pursuant to 21 CFR part
58. To facilitate our evaluation of your study methods and results, we recommend that you
provide complete descriptions and justifications for the following:
• 	choice of animal model and the number of animals tested;24
• 	the test protocol, including objectives and procedures;
• 	the study results, including the investigator's comments;
• 	the study conclusions;
• 	the treatment site;
• 	all complications;
• 	all device malfunctions; and
• 	the study results relating to the human anatomy and the intended use of the device.
In addition, animal study(ies) should include gross and histological examination of the treatment
areas by a blinded, independent pathologist that includes the following:
• 	serial sectioning and staining with hematoxylin and eosin stain and/or a functional stain
to evaluate thermal injury, as appropriate;
• 	representative photomicrographs of histopathological sections; and
• 	pathologist review and histological description of tissue changes, and extent of changes
in three dimensions, in the prostate, prostatic urethra, rectal wall, bladder neck, external
sphincter, neurovascular bundle, and prostatic capsule. For technologies such as prostate
artery embolization that use embolic agents, we recommend the anatomy surrounding the
urethra (e.g., bladder, rectum) be examined for non-target embolization leading to
damage, ischemia, or necrosis.
Prior to initiating an animal study, the Agency encourages manufacturers to submit a Q-
Submission to obtain detailed feedback on any animal studies for devices intended to treat BPH.
For more information, see the FDA guidance document “Requests for Feedback and Meetings
for Medical Device Submissions: The Q-Submission Program.”25
We recommend that the following specific animal studies be conducted for new thermal field-
producing devices and stents.
(1) 	Thermotherapy
Thermal field-producing (i.e., thermotherapy) devices for the treatment of BPH by design
generate tissue damaging temperatures. Bench testing, such as in vitro thermal mapping,
provides partial evidence that a thermal field-producing device can raise the target tissue to
therapeutic temperatures without clinically significant heating of the surrounding non-target
tissues (e.g., rectum, bladder). However, these models do not capture important characteristics of
the human urological system that impact device performance and safety, such as blood flow,
tissue heterogeneity, and active tissue processes such as healing.
24 We recommend that you conduct the study using an analytically meaningful number of animals for each
experimental condition (i.e., each observation time point, each device operational setting).
25 https://www.fda.gov/regulatory-information/search-fda-guidance-documents/requests-feedback-and-meetings-
medical-device-submissions-q-submission-program.

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We believe animal studies examining the temperature distributions, histological changes, and
safety of the non-target tissues are important in assessing the tissue effects of the treatment prior
to clinical use in humans. Animal studies are important for devices in which the heating is not
localized, and the entire prostate is exposed to prolonged heating (e.g., transurethral microwave
thermotherapy (TUMT) devices), or for devices using new ways to generate the thermal field.
We recommend you conduct an in vivo animal study to provide complete thermal mapping of the
prostate and non-target tissues (i.e., transperineal interstitial thermal mapping including the
urethral, intraprostatic, periprostatic, and anterior rectal wall tissues) using intact male dogs of
sufficient age and size to mimic the human prostate anatomy. Tissue temperatures should be
recorded following treatment until they return to baseline to ensure capture of maximum
temperature and time-temperature history. Due to the differences in human and animal anatomy,
we recommend image verification of the location of the device components (e.g., treatment
applicator, temperature probes) and the temperature sensors.
We recommend you select device operating parameters for the animal study that mimic clinical
use in humans to evaluate the safety and functional characteristics of the device design, and to
validate the performance of the device for its intended use. You should evaluate the complete
range of achievable power levels and temperatures, including the maximum power and time
settings. If your device includes multiple applicator designs or variable operational settings (e.g.,
treatment time, power), we recommend you conduct complete testing for each design and setting.
For example, if your device includes both a cooled applicator and a non-cooled applicator, we
recommend you evaluate each applicator using minimum, mid-range, and maximum settings in
your animal study. If your device includes multiple treatments, the number of treatments used in
the animal study should equal or exceed your intended maximum number of treatments.
Because these devices rely on acute tissue injury, followed by necrosis and subsequent healing to
achieve their intended use, we recommend you evaluate both the early tissue effects and
subsequent early healing (e.g., 24 hours, three weeks after treatment).
As described above, we recommend you provide histological assessment of tissue changes and a
discussion of the extent of thermal effects as they relate to human anatomy. Specifically, we
recommend you compare the observed area of histological thermal effects with the relevant
anatomy, including:
• 	in-target compared with non-target tissue; and
• 	the target tissue in relation to that of surrounding critical tissues, including rectal wall,
urethra, neurovascular bundles.
(2) 	Stents
Whether we recommend conducting animal studies for prostatic stents intended to treat or relieve
BPH depends on the device design, material construction, mechanism of action, duration of use,
and any novel aspect. For example, we recommend animal data to evaluate the safety of a
permanent prostatic stent prior to clinical use in humans.

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We recommend the animal study protocol closely approximate the intended clinical methods to
evaluate the safety of the procedure, functional design characteristics, and to validate the
performance of the device for its intended use. In addition, we recommend you select follow-up
periods and sacrifice periods that provide clinically meaningful assessment of the device effects.
We recommend the animal study include:
• 	placement of a single stent as per clinical protocol;
• 	placement of the maximum number of stents proposed for use in the clinical study;
• 	repositioning the device; and
• 	removal using the manufacturer’s recommended techniques.
We recommend this animal study assess the following adverse events using imaging, gross, and
histologic evaluation as indicated based on a clinical risk assessment:
• 	stent migration;
• 	encrustation;
• 	erosion;
• 	pressure necrosis;
• 	urothelial hyperplasia/tissue ingrowth;
• 	stone formation;
• 	urethral edema;
• 	cellular atypia; and
• 	device failure or breakage.
We recommend you conduct a macroscopic and microscopic evaluation of the stent including
calcification, erosion, and epithelization.
If your stent can be explanted or removed, we recommend you conduct mechanical testing
similar to the non-clinical testing on the explanted stents in order to evaluate any changes to the
structural integrity of the device that may have occurred due to stent implantation.
If your stent is designed to resorb or degrade in situ, we recommend you evaluate the degree of
absorption or degradation at multiple time points over the course of its degradation to ensure that
tissue response to starting, intermediate, and final degradation products are fully assessed. We
also recommend the timing of your evaluations be sufficient to determine the rate of degradation
and to demonstrate that complete healing and total elimination of the stent occurs. The selection
of time points for the study may depend on the nature of the material and should relate to its
estimated degradation time.
IV. 	Pilot Clinical Study Recommendations
For BPH devices that are novel or represent a significant shift in technology or use relative to
existing products, we recommend that you stage the clinical investigation of your device in
phases to minimize the risks to investigational subjects, to ensure device functionality, to
monitor safety, and to gain experience in use of the device prior to commencing a large clinical

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study. These phases typically consist of an initial phase, commonly referred to as a “pilot” or
“feasibility” study, followed by a pivotal study.
During the pilot study phase, you can gain valuable information regarding short-term safety,
treatment technique, study conduct, and the optimal patient population. Additionally, information
obtained from exploratory analyses of the pilot study results can be used to refine pivotal study
hypothesis, identify the most suitable endpoints and estimate their response to treatment and
variance, and investigate potential indications for use. Information from a pilot study may also
allow a limited evaluation of the factors that may introduce bias (e.g., covariates).
A pilot study generally involves a limited number of subjects and sites, and close monitoring of
all adverse events. The size and duration of the pilot study can vary depending upon the type of
device being investigated. For example, a pilot study for a novel or high risk device generally
begins with a smaller sample size and follows subjects for a longer period of time. We
recommend the pilot study protocol prospectively define the minimum dataset (i.e., number of
enrolled subjects and the minimum duration of follow-up on those subjects) to be collected to
support initiation of the pivotal study. For investigations conducted under an IDE application, we
recommend you submit a detailed report of the pre-specified pilot study dataset prior to, or at the
time of, the request for pivotal study approval. Analysis of the pilot study dataset will help
determine whether it is appropriate to initiate the pivotal study.
In situations where the performance of the control group is not well characterized, or there are
logistical issues associated with randomization that require exploration, we recommend you
randomize subjects in your pilot study between study groups. This information can help you
adequately power and carry out the subsequent pivotal study.
We believe it is unlikely that pilot study data can be pooled with pivotal study data because there
are often differences in the pilot and pivotal study protocols. If you intend to pool pilot and
pivotal study results, we recommend you plan it prospectively and provide a rationale showing
that it is statistically and clinically valid to pool the data from the pilot and the pivotal studies.
For thermal field-producing devices in which heating is not localized and the entire prostate is
exposed to prolonged heating (e.g., TUMT devices), we recommend that you conduct a pilot
study that includes transperineal interstitial thermal mapping to ensure that the pivotal study
population will not be placed at unreasonable risk. We acknowledge that there are risks
associated with interstitial thermometry. However, we believe that interstitial thermal mapping
provides essential data needed to evaluate the temperatures achieved and to assess the safety of
exposure to such temperatures, which support the reliability of the treatment effect and the safety
profile of the device. We recommend you conduct interstitial thermal mapping to provide
reasonable assurance that therapeutic temperatures are reached, can be controlled, and are safe.
For interstitial thermal mapping, we recommend you acquire temperature measurements at the
time of the first treatment session on a small but analytically useful number of subjects, e.g., the
first 10 patients treated. The methods should characterize the temperature distribution in the
prostatic and periprostatic tissues, including the rectal wall and urethra, and monitor for
unexpectedly high or low temperatures being produced within affected areas. These

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measurements are usually accomplished by introducing at least two fiber optic thermal sensors
transperineally using direct imaging control by transrectal ultrasound under local anesthesia
extending into the prostatic capsule. Alternate thermosensors are acceptable if there is an
adequate demonstration that they are not affected by the energy field generated by the device.
We recommend you carefully collect and report all adverse events.
V. 	Pivotal Clinical Study Recommendations
The purpose of the pivotal clinical study is to collect the primary evidence of safety and
effectiveness to support a marketing submission or application. This phase of the clinical
investigation is conducted after sufficient evidence of device safety and function is available
from preclinical and (if needed) pilot clinical study testing to support its use in human research
subjects.
Proper pivotal study design can minimize error and bias; and facilitate an objective assessment of
the investigational device. We recommend you conduct a pivotal study of a device intended to
treat BPH at multiple clinical sites to demonstrate that the study results are repeatable among a
wide variety of investigators and patient populations, and to increase the likelihood that the study
population is representative of the general patient population.
We recommend that you address the following when designing a pivotal clinical study for a
device intended to treat BPH.
A. 	Study Objective
The study objective forms the basic framework for the study design and helps in identifying the
control, the primary endpoint, the study follow-up duration, and the primary statistical analysis.
The statistical hypothesis follows directly from the primary objective of the study. For these
reasons, you should state a clear study objective before you design your pivotal clinical trial. All
elements of your trial design should be consistent with your study objective.
B. 	Minimizing Bias
One consideration in the design of any clinical study is how to minimize known or suspected
sources of bias so the study conclusions can be clearly and objectively assessed. Bias occurs
when any characteristic of the investigator, study population, or study conduct interferes in a
systemic way with the ability to measure a variable accurately. Appendix 1 identifies common
sources of potential bias and methods that are frequently employed to mitigate them. These
sources of bias are discussed individually in Sections V.C (Randomization and Controls), V.D
(Blinding (Masking)), V.I (Patient Selection Criteria), and V.N (Statistical Analysis
Recommendations) of this guidance document.
If these sources of bias are not adequately minimized, the validity of the study’s conclusions
regarding the safety and effectiveness of the investigational device may be questionable. For all
study designs, we recommend your protocol include a section describing how the study design
intends to minimize bias.

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C. 	Randomization and Controls
Clinical investigations of devices for the treatment of BPH pose unique challenges such as a
placebo effect, spontaneous remissions, subjectivity of lower urinary tract symptoms (LUTS)
and their impact on quality of life, difficulty in securing reliable measurement of LUTS and
quality of life, and wide availability of effective treatments for BPH.
We believe these challenges are most efficiently overcome by using a randomized, controlled
trial design. The benefit of a randomized, controlled trial is its tendency to balance confounding
factors, measurable and unmeasurable, between study groups and minimize the potential for bias.
The potential advantages of a randomized, controlled trial design extend not only to the
evaluation of device effectiveness, but also to the evaluation of safety. Adverse event rates may
be affected by factors such as subject characteristics, device design, evolving procedural
methods, and operator experience, and may be much more difficult to evaluate when using
historical control data.
Randomizing subjects between study groups is a standard method to minimize selection bias and
control for confounding factors. Selection bias occurs when subjects possessing one or more
important prognostic factor appear more frequently in one study group than the other. The
randomization process assigns subjects to an intervention or control group with a known
probability and each subject has an equal chance of being selected for a group. Randomization
also protects the trial from conscious or subconscious actions on the part of study investigators
that could lead to study groups that are not comparable, e.g., selecting the most symptomatic
patients for the therapy thought by the study investigator to be the more aggressive treatment.
We recommend you:
• 	pre-specify the randomization method in the study protocol;
• 	balance the assignment of subjects within each site, e.g., stratification by site, block
randomization;
• 	preclude investigators and other study personnel from predicting or influencing the
assignment of subjects; and
• 	prevent natural patterns of patient behavior from influencing study assignment.
When designing a randomized, controlled study, we recommend you select an appropriate
control therapy. There are a variety of scientific and ethical issues that may influence the choice
of control.26 Typically, the current standard of care for the targeted patient population represents
the most clinically meaningful control. However, other factors may also influence this decision.
We recommend you address each of the following specific factors when choosing a control:
• 	standard of care;
• 	indications for use of the investigational device;
• 	any desired representations of device performance in future labeling;
26 Temple R, Ellenberg SS, Placebo-controlled trials and active-control trials in the evaluation of new treatments.
Part 1: Ethical and scientific issues. Ann Intern Med, 2000, 133(6):455-461.

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• 	risks versus benefits, i.e., to permit a clinically meaningful comparison, it is desirable for
the risk-to-benefit ratio of the control treatment to be comparable to that of the
investigational device;
• 	ability to effectively mask the investigator, subject, and evaluator;
• 	time to treatment effect; and
• 	device design characteristics.
Potential control therapies for clinical investigations for the treatment of BPH include:
• 	an accepted surgical procedure, e.g., transurethral resection of the prostate (TURP);
• 	a medical device cleared or approved for the treatment of BPH; and
• 	sham treatment.
TURP is considered the gold standard surgical treatment for BPH and there are many successful
clinical trials using TURP as a control.
A control that consists of a treatment with a legally marketed device, similar in design to the
investigational device, is often a desirable option because study design, patient enrollment, and
data analysis may be straightforward. For example, it might be both simple and appropriate to
use a randomized study to compare the safety and effectiveness of a new implantable
transprostatic tissue retractor system to a legally marketed system with similar design and
operational characteristics.
Sham effect during BPH procedures has been shown to be significant, on the order of change
seen with commonly used medications.27 Sham controlled studies represent one study design and
choice of control group which may allow for discrimination of patient outcomes caused by the
test treatment from outcomes caused by other factors such as patient or observer expectations.
This type of study design may be most appropriate for studies with subjective endpoints, such as
reduction in patient-reported symptoms. Sham surgical procedures/treatments typically involve
more risk than the placebo control arm in drug trials and these risks should be considered when
designing a clinical trial. This study design should be considered when it is methodologically
warranted, i.e., when designs that are unblinded are methodologically unacceptable (e.g., because
endpoints are subjective) and when a “no treatment” control is methodologically warranted.
Furthermore, the withholding of treatment should not lead to serious injury, such as irreversible
morbidity, or death. FDA recognizes that it may be difficult for sponsors to develop a clinical
study design with a sham control arm that investigators, institutional review boards, and patients
believe is ethical; for this reason, studies involving a sham control arm should be carefully
considered and planned.
While potentially useful to certain stakeholders, the use of an approved drug therapy as a control
is complicated because devices used to treat BPH generally have significantly dissimilar
expected risks and different mechanisms of action compared to approved drug therapies.28
Additionally, devices intended to treat BPH achieve full effectiveness quickly, while drug
27 Welliver C, Kottwitz M, Feustel P, McVary K, Clinically and Statistically Significant Changes Seen in Sham
Surgery Arms of Randomized, Controlled Benign Prostatic Hyperplasia Surgery Trials. J Urol, 2015, 194:1682-7.
28 AUA Guideline “Surgical Management of Benign Prostatic Hyperplasia/Lower Urinary Tract Symptoms (2018,
amended 2019)” (https://www.auanet.org/guidelines/benign-prostatic-hyperplasia/lower-urinary-tract-symptoms).

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therapies often take many months to reach full effectiveness. Consequently, the results of drug-
controlled studies can be difficult to interpret when assessing the safety and effectiveness of a
device.
It is often difficult to obtain adequate, dependable, and directly applicable historical information
from published literature or a prospective chart review due to variations in patient demographics,
selection criteria, and evaluation methodologies. Consequently, we believe using an historical
control complicates the demonstration of safety and effectiveness in most investigations.
You can employ several strategies to facilitate subject recruitment and retention. For example,
2:1 (or other) randomization schemes increase the likelihood that a given subject will receive the
investigational treatment. Study designs may allow sham subjects, for example, to receive
treatment with the investigational device after a pre-specified time or significant disease
progression.
We generally recommend a randomized, controlled trial to address the challenges described in
this guidance document; if you use an alternative study design, we recommend you discuss how
it is scientifically sound and will address relevant safety and effectiveness questions. While we
recognize that there is no unique “best design” for investigations of BPH treatments, we consider
the elements discussed in this document as core features of well-designed studies. As noted, we
will consider alternative study designs, but we recommend that you clearly explain the scientific
reasoning supporting your alternative design (e.g., How will bias be minimized? How does the
study address placebo effects? How does the control compare with current patient characteristics
and standards of clinical care?). Prior to initiating a clinical study with an alternative design,
FDA encourages manufacturers to submit a Q-Submission to obtain detailed feedback on such
studies. For details on Q-Submissions, refer to the guidance “Requests for Feedback and
Meetings for Medical Device Submissions: The Q-Submission Program.”29
For all study designs, we recommend you collect detailed baseline and demographic information
on all study subjects so that the study groups can be assessed for imbalances in prognostic
factors.
D. 	Blinding (Masking)
Sources of bias in a clinical trial include investigator bias, evaluator bias, and placebo or sham
effect (defined in Appendix 1). To protect the study against these sources of biases, we
recommend you incorporate blinding (masking) into the study design. Single-blind designs mask
the subject from knowing what intervention was assigned. Double-blind studies mask both the
subject and the investigator. In cases where single- and double-blind designs are impossible or
not feasible, it is usually possible to use a masked third party evaluator to evaluate certain
outcome measures, e.g., symptoms scores, quality of life, cystoscopy, adverse events.
Blinding is usually accomplished by coding the interventions and having an individual who is
not on the patient care team control the key to the code. Since bias introduced by breaches in
29 https://www.fda.gov/regulatory-information/search-fda-guidance-documents/requests-feedback-and-meetings-
medical-device-submissions-q-submission-program.

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blinding can be very difficult to assess in the analysis, we recommend you do not to break the
code until the analysis is completed. If your study incorporates blinding, the protocol should
describe the blinding methodology and prospectively define the conditions for breaking the
blinding code.
E. 	Study Endpoints
Your clinical protocol should clearly specify and support the study’s primary and secondary
endpoints. To ensure the collection of meaningful results, these endpoints should be clinically
relevant to the patient population you intend to target in the study. Additional factors to consider
when selecting the optimum endpoints for your clinical investigation are described below.
(1) 	Primary Endpoints
The primary safety and effectiveness endpoints are the clinical measures that best characterize
the safety and effectiveness of the device and are used to judge the overall success of the study.
For a BPH device study, the primary endpoint specified in the statistical hypothesis is usually an
effectiveness endpoint, which, in turn, directly impacts the indications for use. Generally, study
success is based on the ability of the study to achieve both the primary effectiveness endpoint
and the primary safety endpoint.
(2) 	Primary Effectiveness Endpoint
The primary effectiveness endpoint should be one that is clinically meaningful and should fully
characterize the effect of treatment. Due to the subjective nature of BPH symptoms, it is difficult
to find an effectiveness measure that is objective and repeatable (i.e., has low test-retest
variability), yet is also meaningful to patients and relevant to their reasons for seeking treatment.
Since its development, the most widely used primary outcome measure used in studies of
therapies for BPH has been the American Urological Association Symptom Index (AUA-SI) and
the equivalent International Prostate Symptom Score (IPSS). These measures consist of seven
questions assessing LUTS associated with BPH (i.e., incomplete emptying, frequency, hesitancy,
urgency, weak stream, straining, and nocturia). Each question is scored on a 0-5 scale and
summed to form a final score from 0-35, where higher scores reflect more severe symptoms.30
An additional disease-specific quality of life question scored separately on a 0-6 scale is included
in the IPSS. These instruments are considered reliable measures of LUTS due to BPH and have
been validated in multiple languages.31
Bothersome LUTS is usually the primary reason a patient seeks treatment for his BPH, and most
devices used to treat BPH are designed to provide symptomatic relief. In most clinical trials, the
30 Barry MJ, Fowler FJ Jr., O'Leary MP, Bruskewitz RC, Holtgrewe HL, Mebust WK, et al., The American
Urological Association symptom index for benign prostatic hyperplasia. The Measurement Committee of the
American Urological Association. J Urol, 1992, 148:1549.
31 Barry MJ, Adolfsson J, Batista JE, et al., Measuring symptoms and health impact of benign prostatic hyperplasia
and its treatments. In: Denis L, Griffiths K, Khoury S et al. (eds). Fourth international consultation on BPH.
Plymouth: Plymbridge Distributors: 1998: 265-321.

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primary effectiveness endpoint should demonstrate improvements in symptom severity.
Specifically, we recommend you base the primary effectiveness endpoint upon the improvement
in AUA-SI (or IPSS) compared to baseline.
Generally, patients are unable to discern an AUA-SI (or IPSS) score difference of less than 3
points.32 However, the minimal clinically significant difference following treatment depends on
the baseline symptom score. Investigations evaluating the minimal clinically significant
difference in AUA-SI used drug therapy for BPH. FDA is unaware of studies that identified the
minimal clinically significant difference in AUA-SI following device treatment. Furthermore,
many trials enroll subjects across more than one symptom severity classification. Therefore,
identifying an appropriate minimal clinically significant difference for the AUA-SI following
device therapy can be challenging.
One study of men with moderate to severe LUTS used a balanced Likert score to investigate the
extent to which patient satisfaction is influenced by a change in BPH symptoms.33 This study
identified a range of improvement in AUA-SI across symptom severity classifications needed to
achieve certain satisfaction levels. An improvement of at least 30% in the AUA-SI was used for
a “Satisfied” or “Very Satisfied” response. This is an appropriate level of response given the
difference in risk profiles between drug and device therapies. Based on this literature, we
recommend an improvement of ≥ 30% over baseline as the minimum clinical improvement in
AUA-SI following device therapy. Higher risk devices may warrant a more significant benefit.
We recommend a 12-month analysis of the primary effectiveness endpoint(s) for an active
control trial. For a study design that does not include an active control, we recommend
incorporating a sham control. Given the challenge in maintaining a sham control for 12 months,
we recommend a shorter timepoint for head-to-head comparison between the treatment and sham
arms. However, stability of effectiveness should still be demonstrated at 12 months for the
treatment arm in a sham-controlled trial.
Separation of the irritative and obstructive symptom questions in the AUA-SI (or IPSS) is
psychometrically valid, but at this time it is not clear that such sub-score analyses are clinically
meaningful.34
We recognize that other outcome measures may be appropriate as well due to specific device
design characteristics or desired marketing claims. For example, claims for reduction of
obstruction could be based on documented improvement in flow rate, results of “pressure/flow”
studies (cystometry), and post-void residual urine volume. If you choose an alternative outcome
measure, it is important that you provide a scientifically valid rationale that explains its
appropriateness for your device.
32 Barry MJ, Willlifred WO, Chang Y, et al., Benign prostatic hyperplasia specific health status measures in clinical
research: How much change in the American Urological Association Symptom Index and the Benign Prostatic
Hyperplasia Impact Index is perceptible to patients. J Urol, 1995, 154:1770-1774.
33 Roehrborn CG, Wilson TH, Black LK, Quantifying the Contribution of Symptom Improvement to Satisfaction of
Men with Moderate to Severe Benign Prostatic Hyperplasia: 4-Year Data from the CombAT Trial. J Urol, 2012,
187:1732-1738.
34 Barry M.J., et al., Filling and voiding symptoms in the American Urological Association symptom index: the
value of their distinction in a Veterans Affairs randomized trial of medical therapy in men with a clinical diagnosis
of benign prostatic hyperplasia. J Urol, 164:1559-1564, 2000.

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(3) 	Primary Safety Endpoint
We recommend you base the primary safety endpoint on the incidence and severity of adverse
events. However, if the device is associated with, or intended to mitigate, a specific safety
concern, then it may be appropriate to base the primary safety endpoint on the specific adverse
event(s) of interest associated with that concern, while still recording all adverse events.
To collect safety information reliably, we recommend your protocol instruct the investigators to
record all adverse events, regardless of whether you believe they are device-related or
anticipated. Regardless of study design, we recommend you follow subjects during the premarket
follow-up period for one year following treatment to monitor adverse events. We recommend
you routinely record the following events at baseline and at follow up time points, noting the
severity of each event:
• 	genitourinary events, i.e., events associated with the urinary tract and/or the surrounding
genital region, including, but not limited to, stress urinary incontinence, urge urinary
incontinence, and urinary retention (defined by any need for catheterization ≥ 7 days
post-procedure);
• 	damage to the bladder floor, trigone, sphincters, and rectum;
• 	infections;
• 	worsening or new onset erectile and/or ejaculatory dysfunction;
• 	secondary surgical interventions;
• 	all transient post-procedure events; and
• 	deaths.
Adverse events should be categorized according to their respective relatedness to the device or
procedure, and their severity (e.g., using the Clavien-Dindo classification of complications or the
latest version of the Common Terminology Criteria for Adverse Events35). This categorization
should be based on pre-defined criteria and can be accomplished by study investigators or an
independent, third-party Clinical Events Committee (CEC). Because of the difficulty of
determining the root cause of genitourinary events, we recommend you categorize events
conservatively as either device- or procedure-related unless there is clear evidence of other
causation. Additionally, we recommend that investigators document the onset and resolution
times of each adverse event, noting the method of resolution.
We recommend the safety analysis include a descriptive assessment of the types and frequency
of adverse events observed in the study, with comparison to the control therapy, as appropriate.
(4) 	Secondary Endpoints
FDA believes secondary endpoints, by themselves, are not sufficient to fully characterize
treatment benefit. However, these measures may provide additional characterization of the
treatment effect. Specifically, secondary endpoints can:
• 	supply background and understanding of the primary endpoints;
35 For more information, see https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.

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• 	be the individual components of a composite primary endpoint, if used;
• 	aid in the understanding of the treatment’s mechanism of action;
• 	be associated with relevant sub-hypotheses (separate from the major objective of the
treatment); or
• 	be used to perform exploratory analyses.
Assuming that the primary safety and effectiveness endpoints of the study are successfully met,
we recommend you analyze the secondary endpoints to provide supportive evidence concerning
the safety and effectiveness of the device, and to support device performance if you plan to make
such representations in your labeling.
Although there are many possible secondary endpoints to consider for clinical investigations of
devices intended to treat BPH, we recommend your protocol include the endpoints discussed
below:
• Prostate volume: Many devices intended to treat BPH, such as transurethral microwave
thermotherapy (TUMT), can reduce prostatic volume. Increases in prostatic volume can
also indicate the progression of BPH. Therefore, we recommend that you evaluate
prostatic volume throughout the study for those devices where the mechanism of action
depends on reduction in prostate volume.
• Uroflowmetry: Decreased peak urine flow rates are common in men with BPH. We
recommend you conduct uroflowmetry including peak and average flow rates, total void
time, and total void volume at each follow-up visit.
• Post void residual (PVR) urine volume: PVR has generally been considered to reflect the
severity of bladder outlet obstruction. We recommend you measure PVR at each follow-
up visit to monitor impairment or improvement of bladder emptying due to the treatment
or disease progression.
• Quality of life: BPH is associated with impairment of quality of life. Therefore, we
recommend you incorporate a validated quality of life measure specific to BPH into the
study. The measure most commonly used is the disease-specific quality of life question
included with the AUA-SI (or IPSS) questionnaire.
• Return to “Normal” symptom severity: There is value in knowing the percentage of
subjects whose symptoms improve to what is considered “normal” (i.e., AUA-SI < 8)
after therapy. Conversely, the proportion of subjects whose symptoms worsen after
therapy is also important to know. Therefore, we recommend you collect pre- and post-
treatment AUA-SI scores.
• Return to normal activities: The time to recovery is also important to patients. Recovery
time may be assessed by recording the days to return to normal activities or to return to
pre-operative activity level.
• Sexual function and dysfunction: Both BPH and many of its therapies adversely affect
sexual function, including erectile and ejaculatory dysfunction. Therefore, we
recommend you incorporate a validated, sex-specific measure of sexual function assessed
at each follow-up visit.

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• 	The recommended instrument to assess erectile function is the International Index
of Erectile Function, specifically the Erectile Function domain (IIEF-5).36 The
Minimal Clinically Important Difference (MCID) has been shown to be 4
points.37 However, the MCID is a function of baseline erectile function. For
example, the MCID is 2, 5, or 7 for men with mild, moderate, or severe erectile
dysfunction, respectively. If your study population is limited to men in only one
subgroup of erectile dysfunction (mild, moderate, or severe), it is appropriate to
use the specific MCID for your study group. However, if you choose to include
men across two or more ranges of erectile dysfunction (e.g., mild and moderate,
moderate and severe, or mild, moderate, and severe), then a responder analysis
using the appropriate MCID considering baseline values is more appropriate.
• 	We recommend you assess ejaculatory function using a validated instrument.
Recommendations regarding the statistical analysis of secondary endpoints are discussed in
Section V.N(3) of this guidance document.
F. 	Study Duration
You should design your clinical study to assess whether the treatment effect, assessed using the
primary and secondary effectiveness endpoints, persists for a clinically meaningful period of
time. For devices intended either as a curative treatment for BPH or for long-term management,
we recommend you follow subjects during the premarket follow-up period for 1 year following
treatment to document the stability of the treatment effect and to monitor adverse events.
However, it is possible that longer follow-up may be appropriate depending upon a variety of
device-specific factors or study design considerations. For example, for devices in which
retreatment is needed or permitted, we recommend the follow-up duration refer to the period
following final treatment. As another example, if either the device or the control is expected to
have a significant delay in the time to achieve the full treatment effect, we recommend the
duration of the study be extended accordingly.
In addition to the premarket follow-up considerations discussed above, long-term postapproval
studies may be appropriate for class III (premarket approval) devices to assess the stability of the
treatment effect and any specific long-term safety and effectiveness concerns that arise during
the premarket study. For devices for which postapproval studies are anticipated or possible, we
recommend your study continue to follow subjects annually beyond marketing approval. In the
event FDA requires a postapproval study as a condition of PMA approval,38 incorporating this
extended follow-up in the original pivotal study will allow you to convert the premarket study
into a postapproval study, eliminating the need to obtain additional informed consent from study
subjects for follow-up and recruiting new subjects.
36 Rosen RC, Riley A, Wagner G, et al., The International Index of Erectile Function (IIEF): a multidimensional
scale for assessment of erectile dysfunction. Urology, 1997,49:822–30.
37 Rosen RC, Allen KR, Ni X, Araujo AB. Minimal Clinically Important Differences in the Erectile Function
Domain of the International Index of Erectile Function Scale. Eur Urol, 2011, 60:1010-1016.
38 21 CFR 814.82(a)(2).

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G. 	Statistical Hypothesis
The statistical hypothesis follows directly from the primary objective of the study and establishes
the framework for the design of your study. The statistical hypothesis is also used to calculate the
sample size and helps determine the statistical methodology that will be used to analyze the
primary study endpoint. For these reasons, you should formulate a clear statistical hypothesis
that is consistent with the primary objective of your study when you design your pivotal clinical
trial and include it in your protocol. All other elements of your clinical study design should be
consistent with your statistical hypothesis.
For non-inferiority studies, we recommend the hypothesis incorporate a non-inferiority margin
that reflects a maximum tolerable difference that is “clinically insignificant” (i.e., “not clinically
meaningful”) in the analysis of the primary effectiveness endpoint. Larger values of the non-
inferiority margin may be selected by demonstrating significant benefits in the safety of the
investigational device.
H. 	Sample Size
We recommend your protocol include the calculation of the estimated sample size appropriate to
test the statistical hypothesis. For this calculation, we recommend using a statistical formula that
is appropriate for the proposed statistical hypothesis. We recommend you state and support all
statistical assumptions associated with the sample size calculation. For additional
recommendations, see the FDA guidance “Design Considerations for Pivotal Clinical
Investigations for Medical Devices.”39
Since patient drop-out and other forms of missing data may occur in any clinical study, we
recommend adjusting the calculated sample size upward by the anticipated loss to follow-up rate.
Additionally, upward adjustment of the sample size can minimize the likelihood of having
inadequate statistical power due to incorrect assumptions regarding the treatment and placebo
effects and their variance.
I. 	Patient Selection Criteria
Although BPH is predominantly confined to older men, age and other baseline characteristics of
the patient population can impact the effectiveness and safety of different device therapies for
BPH. Therefore, we recommend you develop inclusion and exclusion criteria for your clinical
trial that select a cohort representative of the population that will be treated clinically, while
limiting characteristics that could confound the interpretation of the data.
We recommend your protocol define inclusion criteria that identify an appropriate target
population. Specifically, your study should enroll men clinically diagnosed with BPH for which
treatment is recommended. The patient characteristics we recommend you consider in
developing the inclusion criteria for your study include the following.
39 https://www.fda.gov/regulatory-information/search-fda-guidance-documents/design-considerations-pivotal-
clinical-investigations-medical-devices.

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• 	Age: The protocol should state the age range eligible for enrollment. Because BPH is
generally confined to older men, we recommend you include men over 50.
• 	Diagnosis: Investigators should diagnose subjects as having symptomatic BPH. We
recommend the diagnosis criteria specified in the protocol be consistent with the current
standard of care.
• 	Prostate size and shape: Frequently, devices intended to treat BPH are specifically
designed to treat prostates of a specific size in terms of volume and length. We
recommend your inclusion criteria prospectively define intended prostate size within
lower and upper limits based on the parameters of the particular therapy. Prostate size
and shape should be determined according to current AUA BPH guidelines.
• 	Symptom severity: Generally, patients seek treatment for BPH due to bothersome
symptoms. We recommend your protocol prospectively define a range of AUA-SI (or
IPSS) scores consistent with the severity of symptoms your device is intended to treat.
For example, an AUA-SI > 20 is consistent with the current clinical definition of severe
BPH.40
• 	Peak urine flow rate: Reduced urinary flow rates are indicative of bladder outlet
obstruction and are suggestive of BPH. We recommend you include subjects with peak
urine flow rates that are indicative of obstruction (e.g., < 12 ml/sec).41
• 	Subject compliance and suitability: We recommend enrolling subjects who are able to
understand all study requirements and have life expectancies greater than the study
period. Further, we recommend enrolling subjects who are able to tolerate the procedure
(e.g., good surgical candidates) and agree to baseline and follow-up evaluations specified
in the protocol.
Investigational devices present some unknown risk to study subjects. For this reason, patients
with substantial comorbidities are more vulnerable and should be protected from this unknown
risk by appropriately devising exclusion criteria for a clinical trial. However, FDA recognizes
that a device intended to treat BPH could potentially offer an advantage, especially suitable for
those subjects with substantial comorbidities (e.g., shorter procedure time, local anesthesia
instead of general anesthesia, minimal bleeding risk). We recommend justifying inclusion of
such subjects with a clear explanation of the expected benefits and risks if these patients are
intended to be included in the study.
We recommend your study protocol define exclusion criteria that prevent enrollment of subjects
with characteristics that could confound the interpretation of the data or that suggest that your
device poses undue risk. The patient characteristics we recommend you consider in developing
the exclusion criteria for your study include the following.
• 	Confounding conditions: We recommend your protocol exclude men with a history of
any illness that might confound the results of the study, produces symptoms that might be
40 Barry MJ, Fowler FJ Jr., O'Leary MP, Bruskewitz RC, Holtgrewe HL, Mebust WK, et al., The American
Urological Association symptom index for benign prostatic hyperplasia. The Measurement Committee of the
American Urological Association. J Urol, 1992, 148:1549.
41 Using current techniques, an adequate minimum voided volume (i.e., 125 ml) is needed to obtain accurate
measurement of flow rates. Also, we recommend that you base the baseline flow rates on two separate
measurements.

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confused with those of BPH, or poses additional risk to the patient based on device
design. Examples include:
• 	cardiac arrhythmias, cardiac disease including congestive heart failure,
uncontrolled diabetes mellitus, significant respiratory disease, known
immunosuppression, or bleeding disorders;
• 	neurogenic bladder and/or sphincter abnormalities due to Parkinson's disease,
multiple sclerosis, cerebral vascular accident, diabetes;
• 	a post void residual (PVR) volume > 250 ml measured by ultrasound or acute
urinary retention;42
• 	compromised renal function (i.e., serum creatinine level > 1.8 mg/dl, or upper-
tract disease);
• 	confirmed or suspected bladder cancer;
• 	recent (within three months) cystolithiasis or hematuria;
• 	urethral strictures, bladder neck contracture, or other potentially confounding
bladder pathology;
• 	a history of prostatitis within the last two years; or
• 	an active urinary tract infection.
• 	Prostate cancer: We recommend your protocol exclude men with confirmed or suspected
malignancy of the prostate based on the digital rectal exam (DRE), prostate biopsy,
transrectal ultrasound (TRUS), or prostate specific antigen (PSA) level. We recommend
your protocol include testing the PSA level of all subjects. Currently clinical guidelines
indicate that a PSA level > 10 ng/ml is indicative of prostate cancer. We recommend your
protocol include a prostate biopsy prior to enrollment, if indicated, based on DRE, or if
the subject’s PSA level is > 2.5 ng/ml and ≤ 10 ng/ml and his free PSA is < 25% of total
PSA.43 Finally, we recommend you follow the aforementioned American Urological
Association (AUA) guidelines to help determine in which subjects prostate cancer
screening is appropriate based upon age, ethnicity, family history.
• 	Surgical history: We recommend your protocol exclude men with a history of any
surgery that might confound the results of the study, or that poses additional risk to the
patient based on device design. Examples include:
• 	previous rectal surgery (other than hemorrhoidectomy) or history of rectal disease
if the therapy may potentially cause injury to sites of previous rectal surgery, e.g.,
if a transrectal probe is used;
• 	previous pelvic irradiation or radical pelvic surgery;
• 	previous prostate surgery, balloon dilatation, stent implantation, laser
prostatectomy, hyperthermia, or any other invasive treatment to the prostate; or
42 Subjects with acute urinary retention should be excluded or treated as a separate cohort due to confounding
problems in this group.
43 We recognize that current thinking on best clinical practices on the use of PSA in screening for prostate cancer
and the minimum normal value for PSA is under debate in the clinical community (see Barry MJ, Prostate-specific-
antigen testing for early diagnosis of prostate cancer, N Engl J Med, 2001, 344:1373-1377; and “Early Detection of
Prostate Cancer (2018),” AUA Guideline, https://www.auanet.org/guidelines/prostate-cancer-early-detection-
guideline). We believe that it is important to exclude subjects with prostate cancer from clinical studies of devices
used to treat BPH and, therefore, recommend that you adopt the more conservative limits for PSA as described.

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• 	cardiac pacemaker or metallic implants in the pelvic/femoral area, if warranted,
based on device design (unless electromagnetic compatibility and safety with
these implants are prospectively demonstrated).
• 	Future fertility: We recommend your protocol exclude men interested in future fertility, if
your device has the potential to impact fertility.
• 	Concomitant medications: We recommend your protocol exclude men on medications
that affect BPH symptoms as these medications can confound the study results. However,
we recognize that requesting men discontinue their BPH medications to participate in the
study could put them at risk for adverse events including worsening LUTS, hematuria,
infection, or urinary retention. Furthermore, excluding men who cannot or will not
discontinue these medications eliminates men who might benefit the most from the
device from the study. Therefore, it is reasonable to include men on BPH medications if
their dose has been stable after an appropriate period and the dose is not changed
throughout the study unless medically warranted.
BPH medications include prescription and over-the-counter drugs, and dietary
supplements. If potentially confounding medications are clinically appropriate to be taken
concurrent with the study, we recommend your protocol indicate that the dosage should
not change during the study period unless medically warranted. If you intend to include
such medications in your study, subjects should be on them for at least a minimal amount
of time prior to the study (“wash-in”), and the recommended wash-in period should be
specified. The recommended wash-in and wash-out periods are the same and are
described below. If you intend to exclude specific medications from your study, we
recommend your protocol specify wash-out periods after which subjects can be enrolled
or treated.
For example, we recommend excluding men using:
• 	Antihistamines, anticonvulsants, and antispasmodics within one week of
treatment unless there is documented evidence that the patient was on the same
drug dose for at least six months with a stable voiding pattern (the drug dose
should not be altered or discontinued for entrance into or throughout the study);
• 	α blockers within four weeks of treatment;
• 	Anticholinergics within two months of treatment;
• 	Androgens, and gonadotropin-releasing hormonal analogs within two months of
treatment; and
• 	5-alpha reductase inhibitors within six months of treatment.
Your clinical study protocol should justify wash-in or wash-out periods for medications
not listed above (e.g., PDE-5 inhibitors, β3 agonists, tricyclic antidepressants).
Subjects who receive new BPH medications or an increased dose of a current BPH
medication during the course of a trial should be considered treatment failures.
J. 	Pre-Treatment Evaluation Schedule

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We recommend your protocol clearly describe all baseline tests, measurements, and
examinations you plan to conduct at the pre-treatment evaluation. To ensure consistency among
investigators and investigational sites, we recommend your protocol specify clearly defined,
well-recognized measures for all tests and measurements. The pre-treatment urological
evaluation should rule out any significant coexisting disease that might simulate BPH and
document all of the inclusion and exclusion criteria contained in the study protocol.
To accomplish this, we recommend pre-treatment evaluation include the following:
• 	a complete history and physical examination, including a focused genitourological exam
with peri-anal sensation and anal sphincter tone, and total duration of the patient's
symptoms;
• 	patient questionnaires including AUA-SI (or IPSS), quality of life assessment, and sexual
function and dysfunction assessment;
• 	uroflowmetry including voided volume with a prospectively defined minimum to ensure
meaningful analysis (e.g., > 125 ml), total time of voiding, peak flow rate, and average
flow rate, and post void residual volume (PVR);44
• 	cystometry (liquid or gas) on all patients with simultaneous assessment of intravesical
and intra-abdominal pressure for determination of detrusor pressure;45
• 	blood and urine chemistry including urinalysis, urine cultures, complete blood count
(CBC), PSA, blood urea nitrogen (BUN), creatinine, and electrolytes;
• 	prostate length and weight using DRE and TRUS;
• 	prostate biopsy with a minimum of 12 cores46, 47 if clinically indicated; 48
• 	cystoscopic examination to document bladder neck obstruction, the presence or absence
of urethral strictures or bladder pathology, the condition of the prostatic urethra, and the
anatomy of the gland (e.g., size, lobar distribution and anatomy, length from the
verumontanum to the bladder neck); and
• 	proctoscopy if the therapy may potentially cause rectal injury.
K. 	Investigator Selection and Training
We recommend you select study sites and investigators that are capable of recruiting sufficient
numbers of eligible subjects, who are representative of the target population for your particular
44 PVR can be measured by ultrasound or catheterization, but consistent methods should be used pre- and post-
treatment and across investigational sites.
45 LUTS can arise from several pathophysiological conditions besides BPH. Pressure-flow urodynamics are helpful
in establishing the mechanism of action for a device, particularly a novel treatment. We recommend that you
conduct detrusor pressure-flow studies in as many subjects as possible, preferably greater than 30% of subjects.
Additionally, in order to minimize bias we recommend that this sub-group consist of both treatment and control
subjects and that you prospectively define the means for selecting subjects for the sub-group.
46 Escew LA, Bare RL, McCollough DL, Systematic 5 region prostate biopsy is superior to sextant method for
diagnosing carcinoma of the prostate. J Urol, 1997, 157:199-203.
47 Levine MA, Ittman M, Melamed J, et al. 2 consecutive set of transrectal ultrasound guided sextant biopsies of the
prostate for the detection of prostate cancer. J Urol, 1998, 159:471-476.
48 We recommend that a prostate biopsy be performed if indicated based on DRE or if the subject’s PSA is > 2.5
ng/ml and ≤ 10 ng/ml and his free PSA is < 25% of total PSA (see Barry MJ, Prostate-specific-antigen testing for
early diagnosis of prostate cancer, N Engl J Med, 2001, 344:1373-1377).

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device. Sites that have a large proportion of protocol deviations can complicate pooling and
statistical analysis of the results, and ultimately may invalidate the study conclusions.
To ensure the safe, proper, and consistent use of the device, prospective investigators often
benefit from training, particularly if the investigational device is novel in clinical design or
application or necessitates different procedures and settings than those used for similar devices.
Therefore, we recommend the protocol describe a training program that will be used to educate
investigators on the use of the investigational device during the study. We recommend training
consist of didactic instruction covering the device functions and principles of operation and
include proctoring by an experienced physician. If the plan includes proctored training, we
recommend you prospectively identify the number of proctored subjects per investigational site
and state how these subjects will be included in the analysis. Additionally, it may be useful for
the training to highlight the important or unique aspects of the clinical study, such as screening,
obtaining informed consent, the randomization process, study blinding, the follow-up schedule,
data collection methodology, and adverse event reporting.
L. 	Treatment Information
To promote consistency across investigators and investigational sites, the study protocol should
describe the investigational and control treatments. This information should include the
following:
• 	patient preparation;
• 	need for, and details of, anesthesia;
• 	device directions for use (e.g., sizing, route of administration, technique, placement,
settings/treatment parameters);
• 	recommended instrumentation and imaging;
• 	surgical technique; and
• 	post-operative care.
Additionally, if the investigational or control therapy involves multiple or staged treatments, or if
the protocol allows the option of retreatment during the study, we recommend your protocol
describe these aspects of treatment in detail. In the case of retreatment, we recommend your
protocol specify the criteria for retreatment, the minimum and maximum time intervals between
treatments, the maximum number of treatments, and any special treatment instructions for
performing retreatment.
M. 	Post-Treatment Evaluations
We recommend the post-treatment evaluation schedule include multiple follow-up visits
spanning the entire study duration, e.g., 2 weeks (unless there is follow-up at an earlier
timepoint) and one, three, six, and 12 months post-treatment. For thermotherapy devices, we
recommend a follow-up visit shortly after treatment, (e.g., 8-10 days after removal of a post-
treatment catheter), consistent with the standard of care. For devices in which a post-market
study is possible or anticipated, we recommend the post-treatment evaluation schedule include
periodic follow-up visits, e.g., yearly for all subjects until marketing approval.

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Your protocol should clearly describe the follow-up schedule, and identify all tests,
measurements, and examinations you plan to conduct at each post-treatment evaluation. To
ensure consistency with the investigators and investigational sites, we recommend all tests and
measurements be performed using well-recognized methods clearly defined within the protocol.
To allow comparisons to the baseline data, we recommend you perform all applicable post-
treatment tests using the same methodology as the pre-treatment evaluation. Additionally, we
recommend the control population undergo evaluation identical to the investigational group.
We recommend that post-treatment evaluations include the following tests and assessments:
• 	Physical examination;
• 	Updated medical and surgical history, including medications and procedures (especially
if needed to address treatment failure or complication);
• 	AUA-SI (or IPSS);
• 	Quality of life assessment;
• 	Sexual function assessment;
• 	Adverse events;
• 	Uroflowmetry including voided volume with a prospectively defined minimum to ensure
meaningful analysis (e.g., 125 mL), total time of voiding, peak flow rate, average flow
rate, and post void residual volume;
• 	Cystometry on all patients at later visits, e.g., 6 and 12 months post-treatment, with
simultaneous assessment of intravesical and intra-abdominal pressure for determination
of detrusor pressure;49
• 	Blood and urine chemistry, e.g., urinalysis, urine cultures, CBC, PSA, BUN, creatinine,
and electrolytes;
• 	Biopsy, if clinically indicated;
• 	DRE at each follow-up, if appropriate;
• 	TRUS at 6 and 12 months post-treatment (to include measurement of prostate volume
and other relevant dimensions);
• 	Cystoscopic examination as medically or technically warranted;50 and
• 	Proctoscopy, if medically or technically warranted, to monitor any observed rectal injury.
Unless you plan to contraindicate patients interested in future fertility from treatment, we
recommend you assess the effects of your device on future fertility by evaluating semen quality
and quantity.
N. 	Statistical Analysis Recommendations
The protocol should include a comprehensive statistical analysis plan that prospectively
describes how the study results will be analyzed. All statistical analyses used in an investigation
should be appropriate for its analytical purpose and thoroughly documented. We recommend the
statistical analysis plan include the information discussed below.
49 Detrusor pressure-flow studies should be conducted in the subgroup of patients evaluated pre-treatment.
50 For some devices, it may be acceptable to conduct the cystoscopic follow-up examination in a subgroup. This
subgroup should be randomly selected to minimize bias and consist of at least 30% of the study patients.

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(1) 	Statistical Analyses
We recommend your protocol prospectively state all planned statistical analyses of the primary
and key secondary endpoints. If you plan that the study subjects and investigators (or other
evaluators) be blinded to the subject’s treatment allocation (i.e., investigational devices vs.
control therapy), your protocol should collect information to assess the effectiveness of the
blinding (e.g., by asking subjects which study group they think they are in). Your protocol
should also specify when blinding will be broken.
When reporting the findings of your clinical trial, we recommend you:
• 	compare all treatment data to the control;
• 	stratify the safety and effectiveness data by relevant covariates including pre-treatment
patient characteristics and treatment parameters;
• 	account for all patients at each follow-up period;
• 	provide graphical presentation of data and results;
• 	provide summary tables for all important parameters (including summary tables
presenting the raw data for each patient and cohort analysis);
• 	provide a justification for pooling results across investigational sites and a stratification
of the data as a function of investigational site; and
• 	consider the addition or increase in BPH medications, or treatment of BPH with
additional modalities as treatment failure.
(2) 	Primary Endpoint Analyses
The primary statistical analysis of the study generally uses the primary endpoint to assess the
study’s overall success or failure. Therefore, we recommend you describe and document the
details of this analysis in your protocol. To reduce bias, we recommend performing this primary
analysis using the intention-to-treat (ITT) population. The ITT population includes all subjects
randomized into the study regardless of whether the subjects received the treatment to which
they were randomized. Using the ITT population preserves the comparability of patients with
respect to (observed and unobserved) baseline characteristics. The ITT population is generally
regarded as the preferred method for evaluating a new therapy.51
In addition to the ITT analysis, we recommend your protocol specify other analyses of the
primary endpoint to assess the robustness of the study results. We recommend you conduct these
additional analyses to assess whether the results are consistent with the conclusion of the primary
ITT analysis and, therefore, are supportive of your study conclusions. You should assess the
plausibility of the underlying assumptions for each sensitivity analysis. We recommend these
additional analyses include at least the following:
• 	Analysis of the “per protocol” population (e.g., subjects treated and followed per the
protocol);
• 	Sensitivity analyses using a pre-specified variety of methods for imputing missing data;
• 	Longitudinal or repeated measures analysis to assess impact of “time post-treatment”
upon the results; and
51 Ellenberg JH, Intent-to-treat analysis versus as-treated analysis. Drug Inf J, 1996, 30:535-44.

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• 	Assessment of the number of subjects who are “significantly improved,” “not
significantly improved,” and “worse” at each follow-up period relative to baseline.
To investigate the potential impact of subject-related and treatment-related factors upon the
primary safety and effectiveness endpoints and to uncover any important prognostic factors, we
recommend that you consider subgroup analyses. To minimize bias associated with these
analyses, we recommend your protocol prospectively define all important factors. Important
factors may include, but are not limited to:
• 	Investigational site;
• 	Age;
• 	Weight or body mass index;
• 	Ethnicity;
• 	Duration of BPH symptoms;
• 	All baseline measures of BPH (e.g., prostate size/volume, peak and mean flow rates,
PVR, AUA-SI (or IPSS), and a BPH-specific quality of life score);
• 	Retreatments;
• 	Medication usage; and
• 	Important device-related covariates (e.g., device settings, size).52
(3) 	Secondary Endpoint Analyses
We recommend your protocol prospectively define the statistical analysis plan for important
secondary endpoints if you intend to include secondary endpoints in your labeling. If any of the
secondary endpoint analyses are intended to support the indications for use or to describe device
performance in the labeling (e.g., comparing treatment and control groups using p-values or
confidence intervals), we recommend you pre-specify this intention in your study protocol and
provide a detailed description of the statistical methods you plan to follow. We recommend that
you ensure that the overall Type I error rate is controlled when you plan such analyses. If the
secondary endpoint analyses are intended as exploratory analyses or are not intended to support
the indication for use or representations of device performance, we recommend you submit
simple descriptions of the analyses.
One of the statistical challenges in supporting the indications for use or device performance
through multiple statistical tests is the control of the overall type 1 error rate at 0.05 or below.
There are many valid multiplicity adjustment strategies available for use to maintain the type 1
error at or below p=0.05, including:
• 	Bonferroni procedure;
• 	Hierarchical closed test procedure; and
• 	Holm’s step-down procedure.
Because each of these multiplicity adjustment strategies involves balancing different potential
advantages and disadvantages, we recommend you carefully consider each of the adjustment
strategies when you design your clinical study and prospectively define the strategy that you
52 All characteristics of the treatment mode (e.g., size, power level, treatment time) should be analyzed. The data
should support the complete range of device sizes and treatment parameters that will be available.

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intend to use. We recommend your protocol prospectively state a statistical hypothesis for each
secondary endpoint for which you intend to make representations about device performance in
your labeling.
(4) 	Missing Data
Missing data can represent a significant source of potential bias. Although many statistical
methods exist for imputing missing data, excessive missing data can introduce an unacceptable
level of uncertainty in the results and invalidate the study conclusions. Therefore, we recommend
every effort be made to minimize the incidence of missing data through trial design and
conduct.53 We recommend your protocol incorporate the elements listed below:
• 	Efforts to minimize missed visits and drop-outs: We recommend that you design the
study to reduce missing data. Strategies to consider include providing incentive for
patients to remain in the study, such as randomization (e.g., 2:1) schemes or options for
control patients to switch to the investigational device after completion of follow-up or
the assessment of the primary effectiveness endpoint. We recommend you describe in the
protocol the efforts to be used during the course of the study to monitor and minimize the
incidence of patient drop-outs, such as monitoring activities, special incentives to
subjects for study compliance, methods to remind subjects of scheduled visits, and
specific efforts to contact subjects who miss their visit (e.g., telephone calls, postcards,
contact next-of-kin); and
• 	Efforts to document the reasons for missing data: We recommend you identify the steps
to document:
• 	The reason for each missed visit, e.g., complications, difficulty getting
transportation to the site;
• 	The reason for each drop-out, e.g., seeking alternate therapy, complications or
intolerance to the device, dissatisfaction with the device, moved away; and
• 	The cause of any death, e.g., autopsy report or death certificate.
To facilitate a complete and detailed accounting of all study subjects, we recommend you collect
complete information on each subject’s follow-up status during the study. Because loss to
follow-up jeopardizes the conclusions that can be made about the long-term safety and
effectiveness of a device, we recommend you limit the overall rate of loss to follow-up to less
than 20% over the course of the study.
The protocol should specify how you plan to handle missing primary effectiveness endpoint data
for the primary analysis. To conduct the ITT analysis in the presence of missing primary
endpoint data, we recommend that you use existing statistical methods for missing data, such as
multiple imputation.54 Since these methods usually involve assumptions about the missing data
mechanism, the plausibility of the assumptions should be assessed. As discussed in Section
53 National Research Council. (2010). The Prevention and Treatment of Missing Data in Clinical Trials. Panel on
Handling Missing Data in Clinical Trials. Committee on National Statistics, Division of Behavioral and Social
Sciences and Education. Washington DC: The National Academies Press.
54 National Research Council. (2010). The Prevention and Treatment of Missing Data in Clinical Trials. Panel on
Handling Missing Data in Clinical Trials. Committee on National Statistics, Division of Behavioral and Social
Sciences and Education. Washington DC: The National Academies Press.

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V.N(2), sensitivity analyses that compare results obtained under various assumptions about the
missing data mechanism should be conducted.
O. 	Risk Analysis
The protocol should contain a clinically sound risk analysis in support of the proposed
investigation. In clinical studies that require an approved IDE application,55 the risk analysis
must include the elements specified in 21 CFR 812.25(c), which are listed below:
• 	a description and analysis of all increased risks to which subjects will be exposed by the
investigation;
• 	the manner in which these risks will be minimized;
• 	a justification for the investigation; and
• 	a description of the patient population, including the number, age, sex, and condition.
We recommend the risk analysis section of your protocol include the risks of the device itself
and the risk associated with the treatment procedure. In addition, we recommend you convey
these risks to potential subjects using easily understood terminology in the informed consent
document.
P. 	Study Monitoring
We believe that proper study monitoring is critical to assure the safety of study subjects,
investigator adherence to the investigational plan and the applicable requirements of 21 CFR
parts 50 and 812, and the quality and integrity of the resulting clinical data. Therefore, we
recommend that the investigational plan incorporate a comprehensive, written monitoring plan
that investigators agree to follow during the study. In clinical studies that require an approved
IDE application, the IDE application must include written monitoring procedures in accordance
with 21 CFR 812.25(e). In addition, see the Agency’s guidance “Establishment and Operation of
Clinical Trial Data Monitoring Committees”56 on recommended approaches to monitoring
clinical investigations involving FDA-regulated products.
Written monitoring procedures help to assure that each person involved in the monitoring
process carries out their duties. In addition to the elements required by 21 CFR part 812 and 21
CFR part 50 and recommended in the FDA guidance “Establishment and Operation of Clinical
Trial Data Monitoring Committees,” we recommend you include the following elements into
your monitoring procedures:
• 	identification of a trained and qualified monitor;
• 	description of pre-investigation and periodic visits, including the timing of these visits
and the specific monitoring activities to be performed;
• 	criteria for the review of representative subject records for completeness and accuracy;
and
55 An approved IDE is required before beginning a clinical study of a significant risk device in the United States as
defined in 21 CFR 812.3(m).
56 https://www.fda.gov/regulatory-information/search-fda-guidance-documents/establishment-and-operation-
clinical-trial-data-monitoring-committees.

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• 	elements for an adequate record of on-site monitoring visits, including findings,
conclusions, and action taken to correct any deficiencies.
We recommend the study monitor overseeing the trial identify potential weaknesses during the
study that may necessitate modifying the protocol. The study monitor should also have
contingency plans available for unforeseen problems that may occur and have a means to rapidly
implement those plans. We recommend you and the monitor carefully devise any contingency
plans for the study with the goal of preserving the integrity of your study design. We also
recommend your monitor assure that study subjects are entered, interventions are assigned,
follow-up data are collected at the appropriate times, and data are completely and accurately
recorded, as specified in the protocol.
Q. 	Case Report Forms
To ensure all information collected during the course of the clinical study is documented, we
recommend your study incorporate case report forms for investigators to complete separately for
each subject. To facilitate the documentation of all subject, treatment, and study data, we
recommend you record all information described in your protocol on case report forms
including:
• 	a pre-treatment evaluation form;
• 	a treatment information form;
• 	post-treatment evaluation forms;
• 	a concomitant medication form;
• 	a protocol deviation form;
• 	an adverse events form; and
• 	a patient discontinuation information form.
We recommend the content of these forms reflect the following information:
• 	A pre-treatment evaluation form includes all relevant information from pre-treatment
evaluation, such as medical history, physical exam, baseline screening measures, and
documentation of inclusion and exclusion criteria.
• 	A treatment information form includes all relevant information regarding the treatment
procedure for both the investigational device and the control therapy, such as date, pre-
operative preparation, anesthesia usage, device directions for use (e.g., sizing, placement,
settings or treatment parameters), instrumentation and imaging usage, surgical technique,
post-operative care, protocol deviations, and complications. If retreatment is permitted
during the study, similar information should be recorded at that time.
• 	Post-treatment evaluation forms include all data collected at each follow-up visit. We
recommend a separate post-treatment evaluation form be completed at each follow-up
visit.
• 	A concomitant medication form lists all medications and dietary and herbal supplements
taken by the subject at baseline and during the study, specifying the dates of usage and
dosage.
• 	A protocol deviation form identifies and describes each protocol deviation, indicating the
date, type of deviation, and clinical justification for the deviation.

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• 	An adverse events form identifies and describes each adverse event, including the onset
date, type and description, device-relatedness, severity, method of intervention or
resolution, and resolution date.
• 	A patient discontinuation information form includes the date and reason for a patient’s
discontinuation from the study. Typical reasons for study termination include study
follow-up completed, consent withdrawn by the subject, the subject exited to receive
alternate treatment, the investigator chooses to exit the subject, death of the subject, and
the subject became lost to follow-up.
VI. 	Conclusions
Our intent of this guidance is to assist you in developing non-clinical and clinical trials for
devices to treat BPH. In addition, we encourage you to contact us to discuss any questions you
may have regarding your specific device, its intended use, clinical study design, or other
considerations. If you are proposing an alternative approach to the study design
recommendations in this guidance, we also encourage you to request a Pre-Submission meeting.

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Appendix 1.
Sources of Bias 	Common Bias Mitigation Methods
Selection Bias
occurs when patients possessing one or
more important prognostic factors appear
more frequently in one of the comparison
groups than in the others.
• 	Randomization
• 	Objective diagnostic and outcome
measures
• 	Homogeneous study population
• 	Pre-specified protocol, endpoints, and
statistical plan
Investigator Bias
occurs when an investigator consciously or
subconsciously favors one study group at
the expense of the others.
• 	Blinding
• 	Pre-specified protocol, endpoints, and
statistical plan
Evaluator Bias
is a type of investigator bias in which the
person measuring the outcome variable
intentionally or unintentionally records the
measurements in favor of one intervention
over another intervention. Studies that have
subjective endpoints (e.g., quality of life)
are particularly susceptible to this form of
bias.
• 	Blinding
• 	Objective diagnostic and outcome
measures
Placebo or Sham Effect
is a bias that occurs when a patient exposed
to an inactive therapy believes that he (or
she) is being treated with an intervention
and subsequently shows or reports
improvement.
• 	Inclusion of a sham arm
• 	Randomization
• 	Blinding
• 	Objective diagnostic and outcome
measures
Missing Data
can introduce bias when subjects who do
not report for follow-up experience a
different outcome from those who do.
• 	Option for active device for sham arm
patients after completion of follow-up
• 	Documentation and enhanced compliance
• 	Plan to conduct sensitivity analyses