Contains Nonbinding Recommendations 
Clinical Investigations for Prostate 
Tissue Ablation Devices 
Guidance for Industry and 
Food and Drug Administration Staff 
Document issued on July 15, 2020. 
The draft of this document was issued on June 29, 2019. 
For questions about this document, contact OHT3: Office of Gastro-Renal, ObGyn, General 
Hospital, and Urology Devices/DHT3B: Division of Reproductive, Gynecology, 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  Contains Nonbinding Recommendations 
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-2019-D-2223. 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 e-mail request to CDRH-
Guidance@fda.hhs.gov to receive a copy of the guidance. Please include the document number 
16011 and complete title of the guidance in the request. Contains Nonbinding Recommendations 
Clinical Investigations for Prostate 
Tissue Ablation Devices 
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 
 
This guidance document provides recommendations for (1) complying with the clinical testing 
special control under 21 CFR 876.4340(b)(8) for premarket notifications (510(k)s) for high 
intensity ultrasound systems for prostate tissue ablation, and (2) collecting clinical data to 
support marketing submissions for new types of prostatic tissue ablation devices. High intensity 
ultrasound systems for prostate tissue ablation transmit high intensity therapeutic ultrasound 
energy into the prostate to thermally ablate a defined, targeted volume of tissue. Other prostate 
ablation devices achieve the same clinical effect of ablating targeted tissue volumes using 
different sources of energy. Regardless of the energy type used for ablation, these devices may 
receive marketing authorization for a general indication for ablation of prostatic tissue. This 
guidance does not address intended uses for the treatment of a specific disease (e.g., prostate 
cancer or benign prostatic hyperplasia). 
FDAs guidance documents, including this guidance, do not establish legally enforceable 
responsibilities. Instead, guidances describe the Agencys current thinking on a topic and should 
be viewed only as recommendations, unless specific regulatory or statutory requirements are 
cited. The use of the word should in Agency guidance means that something is suggested or 
recommended, but not required. 
II. Background 
In 2015, the Agency granted a De Novo request for a high intensity ultrasound system for 
prostate tissue ablation.1 The special control under 21 CFR 876.4340(b)(8) includes a 
requirement for clinical testing to document the adverse event profile, provide evidence of 
                                                
1 The DEN150011 transparency summary and final classification order are available at 
https://www.accessdata.fda.gov/cdrh_docs/reviews/DEN150011.pdf and 82 FR 45725. 
1  Contains Nonbinding Recommendations 
prostatic ablation, and demonstrate that the device performs as intended under anticipated 
conditions of use. The purpose of this guidance document is to provide clinical testing 
recommendations for submitters seeking a general indication for ablation of prostate tissue (i.e., 
not intended for the treatment of any specific prostate disease), whether by high intensity 
ultrasound to ensure compliance with the clinical testing special control or alternative 
technologies. 
Prior to initiating a clinical investigation, the Agency encourages manufacturers to submit a Pre-
Submission to obtain detailed feedback on the clinical investigation of prostate tissue ablation 
devices. For details on Pre-Submissions, refer to the guidance Requests for Feedback and 
Meetings for Medical Device Submissions: The Q-Submission Program.2
III. Scope 
The scope of this guidance document is limited to the clinical investigations to support marketing 
authorization for general indications of prostate tissue ablation systems, including devices that 
are regulated under the product code PLP. This guidance does not address the clinical 
investigations of devices that are intended to treat specific prostatic diseases (e.g., prostate cancer 
or benign prostatic hyperplasia). Additionally, this document does not address recommendations 
or other requirements for non-clinical testing, training, or labeling of prostate tissue ablation 
systems. 
IV. Clinical Investigation Recommendations 
We recommend that you conduct a clinical study to (1) comply with the clinical testing special 
control under 21 CFR 876.4340(b)(8) for new high intensity ultrasound systems for prostate 
tissue ablation and systems with changes to the ablation energy output characteristics relative to 
the 510(k)-cleared versions, or (2) to support marketing submissions for prostate tissue ablation 
devices outside the scope of 21 CFR 876.4340. 
Generally, we believe prostate tissue ablation devices addressed by this guidance document are 
significant risk devices subject to all requirements of the Investigational Device Exemptions 
(IDE) regulation, 21 CFR 812, for studies conducted in the United States (US). See the FDA 
guidance titled, Significant Risk and Nonsignificant Risk Medical Device Studies.3 In addition 
to the requirements of 21 CFR 812, sponsors of such trials of a device conducted in the US must 
comply with the regulations governing institutional review boards (21 CFR 56) and informed 
consent (21 CFR 50). 
                                                
2 https://www.fda.gov/regulatory-information/search-fda-guidance-documents/requests-feedback-and-meetings-
medical-device-submissions-q-submission-program.
3 https://www.fda.gov/regulatory-information/search-fda-guidance-documents/significant-risk-and-nonsignificant-
risk-medical-device-studies. 
2 Contains Nonbinding Recommendations 
When data from clinical investigations conducted outside the United States are submitted to 
FDA for prostate tissue ablation devices, the requirements of 21 CFR 812.28 may apply.4 21 
CFR 812.28 outlines the conditions for FDA acceptance of clinical data from investigations 
conducted outside the US when submitted to support premarket submissions. For more 
information, see the FDA guidance Acceptance of Clinical Data to Support Medical Device 
Applications and Submissions: Frequently Asked Questions.5
In some cases, real-world data (RWD) may be used to support changes to the ablation energy 
output characteristics for a device for which 510(k) clearance has already been obtained. 
Whether the collection of RWD for a legally-marketed device requires an IDE depends on the 
particular facts of the situation. Specifically, if a cleared device is being used in the normal 
course of medical practice, an IDE would likely not be required. For additional information 
regarding this topic, please refer to the FDA guidance entitled Use of Real-World Evidence to 
Support Regulatory Decision-Making for Medical Devices.6
The results of the clinical investigation should be presented in a complete test report, formatted 
to include the following elements: 
  Executive summary/overview; 
  Site/investigator identification; 
  Patient demographics and baseline characteristics; 
  Treatment data; 
  Protocol deviations; 
  Safety and effectiveness endpoints analysis (analyzed and raw line data formats); 
  Conclusions; and 
  Study protocol. 
Specific clinical study recommendations for prostate tissue ablation devices are summarized 
below. The clinical study recommendations reflect CDRHs current thinking regarding study 
design for prostate tissue ablation devices. However, consistent with least burdensome 
principles,7 we recognize that, for any regulatory decision, there exists some degree of 
uncertainty around benefits and risks. It is important to acknowledge and appropriately mitigate 
uncertainty in benefit-risk determinations supporting FDA premarket decisions.8 As such, the 
                                                
4 This applies to data from clinical investigations that began on or after February 21, 2019 and are submitted to 
support a premarket submission, including IDEs, premarket approval applications (PMAs), and 510(k)s. 
5 https://www.fda.gov/regulatory-information/search-fda-guidance-documents/acceptance-clinical-data-support-
medical-device-applications-and-submissions-frequently-asked. 
6 https://www.fda.gov/regulatory-information/search-fda-guidance-documents/use-real-world-evidence-support-
regulatory-decision-making-medical-devices. 
7 Please see FDAs guidance Least Burdensome Provisions: Concept and Principles 
(https://www.fda.gov/regulatory-information/search-fda-guidance-documents/least-burdensome-provisions-concept-
and-principles) for more information on this topic. 
8 Please see FDAs guidances on this topic: Factors to Consider When Making Benefit-Risk Determinations for 
Medical Device Investigational Device Exemptions (https://www.fda.gov/regulatory-information/search-fda-
guidance-documents/factors-consider-when-making-benefit-risk-determinations-medical-device-investigational-
device), Factors to Consider When Making Benefit-Risk Determinations in Medical Device Premarket Approval 
and De Novo Classifications (https://www.fda.gov/regulatory-information/search-fda-guidance-documents/factors-
 
3 Contains Nonbinding Recommendations 
acceptable level of uncertainty in benefit-risk determinations to support premarket decisions is 
flexible in some cases, and is tailored to the type and intended use of the device and the type of 
decision we are making. Therefore, FDA will consider alternatives to the study design when the 
proposed alternatives are supported by an adequate scientific rationale. 
A. Purpose/Objective 
The objective of the clinical investigation is to demonstrate the safety and effectiveness of the 
device for its intended use  as a general surgical tool for the ablation of prostate tissue. FDA 
notes that the endpoints in this clinical investigation should address safety by determining 
whether the device does not ablate or damage tissue outside of the targeted volume as reflected 
in the adverse event profile, and effectiveness by determining whether the device ablates tissue 
within the targeted volume. 
B. Study Design and Sample Size 
FDA recommends that the clinical evidence to support a marketing submission consist of either 
an internally- or externally-controlled trial. While a benefit of an internally-controlled trial is the 
collection of robust data on the subject and comparator devices from the same patient population 
that was followed in the same manner, a benefit of an externally-controlled trial is the reduced 
burden of enrolling and following only a single patient cohort (study arm) to be compared to the 
clinical results of an existing prostate tissue ablation device. 
To adequately estimate the adverse event profile with clinically meaningful precision, including 
the incidence of infrequent device- or procedure-related complications, FDA recommends that 
the dataset include a minimum of 100 patients treated with the subject device and who were 
clinically followed as recommended below in Sections IV.C, G, and H, respectively.
Indirect measures of ablation effectiveness, such as prostate biopsy, prostate-specific antigen 
(PSA) levels, and prostate volume, should be analyzed in the same patient population of at least 
100 patients that was followed for safety. Alternatively, if ablation effectiveness is instead 
supported by treat and resect data (i.e., whole-mount histopathology analysis of the extent and 
position of ablation, obtained from patients undergoing prostate tissue ablation prior to scheduled 
radical prostatectomy) collected from a separate study cohort, the sample size of this 
effectiveness population should be scientifically justified. While studies with separate safety and 
treat and resect cohorts will, by design, enroll a greater total number of subjects than studies in 
which both safety and indirect measures of ablation effectiveness are evaluated in the same 
                                                
consider-when-making-benefit-risk-determinations-medical-device-premarket-approval-and-de), Benefit-Risk 
Factors to Consider When Determining Substantial Equivalence in Premarket Notifications (510(k)) with Different
Technological Characteristics(https://www.fda.gov/regulatory-information/search-fda-guidance-
documents/benefit-risk-factors-consider-when-determining-substantial-equivalence-premarket-notifications-510k), 
and Consideration of Uncertainty in Making Benefit-Risk Determinations in Medical Device Premarket Approvals, 
De Novo Classifications, and Humanitarian Device Exemptions (https://www.fda.gov/regulatory-
information/search-fda-guidance-documents/consideration-uncertainty-making-benefit-risk-determinations-medical-
device-premarket-approvals-de).
4 Contains Nonbinding Recommendations 
cohort, a benefit of the former approach is avoiding the burden of collecting post-ablation biopsy 
data, PSA levels, and imaging. 
C. Study Duration and Follow-up Schedule 
FDA recommends that the minimum duration of scheduled follow-up for studies to support a 
marketing submission is one year. This recommended minimum follow-up duration is based on 
the delayed onset or presentation of known probable adverse events (e.g., urethral stricture, rectal 
fistula, and osteomyelitis pubis), as well as the time course for potential resolution of other 
anticipated complications (e.g., erectile dysfunction, urinary incontinence). The protocol should 
prospectively specify collection of adverse event information at regular intervals, with specific 
assessment of known probable device- and procedure-related adverse events. 
Effectiveness measures should be collected post-ablation at time frames that are scientifically 
justified for the specific endpoint measure(s) being collected. For example, prostate biopsy, PSA 
levels, and prostate volume should be analyzed one year post-ablation, while treat and resect 
data may be collected and analyzed less than one month post-ablation. The study duration and 
timing of follow-up for all endpoints should be clinically justified, and the timing of assessments 
should be uniform within the study. 
D. Inclusion/Exclusion Criteria 
The study should enroll men for whom prostate tissue ablation is clinically warranted. To 
minimize confounding in the review of the clinical data, patient and treatment characteristics 
should be uniform with respect to: 
  The underlying clinical condition for the prostate ablation (i.e., benign versus malignant 
disease); 
  The prostate treatment history prior to the ablation procedure (e.g., treatment naive, 
post-external beam radiotherapy, post-brachytherapy, post-cryotherapy); 
  The prescribed extent of ablation (e.g., whole gland ablation, hemiablation, focal 
ablation); 
  Anatomical limitations associated with the specific technological characteristics of the 
ablation device (e.g., excluding subjects with prostate volumes above a certain size); and 
  General clinical safety precautions (e.g., excluding subjects with uncontrolled bleeding 
disorders or active urinary tract infection). 
E. Patient Demographics 
Patient demographic information should be reported using descriptive statistics. Refer to the 
FDA guidance Evaluation and Reporting of Age-, Race-, and Ethnicity-Specific Data in 
Medical Device Clinical Studies9 for details on reporting this demographic information. This 
information should include, but is not limited to, the following: 
                                                
9 https://www.fda.gov/regulatory-information/search-fda-guidance-documents/evaluation-and-reporting-age-race-
and-ethnicity-specific-data-medical-device-clinical-studies. 
5 Contains Nonbinding Recommendations 
  Patient age and race/ethnicity; 
  Body mass index (BMI); 
  Prostate volume; 
  Prostate disease characteristics (as appropriate for the enrolled population), for example: 
  PSA level; 
  Clinical cancer stage; 
  Gleason scores and sum; and 
  Prior therapies (including surgeries, radiation, and hormone therapy). 
  Imaging findings (e.g., suspicious regions on multi-parametric MRI); and 
  Related medical history and physical exam details (including baseline erectile function 
and urinary continence status). 
F. Treatment Parameters/Protocol (including post-operative 
regimen) 
The protocol for the clinical study should pre-specify, and the complete test report should 
describe, the following treatment parameters and related information: 
  Extent of ablation (e.g., whole gland ablation, hemiablation, focal ablation); 
  Prostate tissue volume targeted for ablation; 
  Concurrent interventions (e.g., transurethral resection of the prostate, bladder neck 
incision); 
  Ablation time and parameters; 
  Malfunctions or interruptions; 
  Anesthesia or sedation used; 
  Hospitalizations; and 
  Catheterizations. 
G. Safety Endpoints and Data Analysis 
To support a general indication for ablation of prostate tissue (i.e., not intended for the treatment 
of any specific prostate disease), a clinical investigation should address safety by demonstrating 
that the device does not ablate or damage tissue outside of the targeted volume. Safety endpoints 
should consist of prospectively collected adverse events, with emphasis on key safety issues that 
may reflect damage to the surrounding, non-target tissues. These key safety issues include, but 
are not limited to, erectile dysfunction, urinary incontinence, voiding symptoms or dysfunction, 
urethral stricture, rectal fistula, and osteomyelitis pubis. 
To ensure robust collection of safety information, adverse events should be: 
  Prospectively collected without regard to device-relatedness; 
  Defined using pre-specified, standardized criteria (such as when reporting erectile 
dysfunction); 
6 Contains Nonbinding Recommendations 
  Graded for severity according to a standard adverse event grading system (e.g., Common 
Terminology Criteria for Adverse Events10); 
  Categorized according to whether they meet the established serious adverse event 
definitions;11
  Assessed for resolution status; and 
  Adjudicated by an independent clinical events committee.12
H. Effectiveness Endpoints and Data Analysis 
To support a general indication for ablation of prostate tissue (i.e., not intended for the treatment 
of any specific prostate disease), a clinical investigation should address effectiveness by 
demonstrating that the device ablates tissue within the targeted volume. Effectiveness endpoints 
may be either direct measurements of the extent of ablation (e.g., histopathology data from a 
treat and resect study cohort), or alternatively, indirect measurements using a composite of the 
following surrogate measures of prostate tissue ablation: 
  Histological findings from prostate biopsies consisting of 12-core systematic transrectal 
biopsy of the entire gland, with heightened sampling in the region that was targeted for 
ablation (using image-guided targeting to direct the biopsy); 
  Ultrasound or MRI follow-up of prostate volume or non-perfused volume; and 
  PSA levels. 
FDA believes that either effectiveness endpoint (i.e., the single treat and resect histopathology 
endpoint, or the three-part composite endpoint of histological findings from prostate biopsies, 
prostate volumes from imaging, and PSA levels) is equally valid. Regardless of the endpoint 
used, the data should collectively provide evidence of the extent to which the intended region of 
tissue is ablated to support marketing authorization. 
FDA recommends that you report the applicable effectiveness endpoints of your study as 
follows: 
  Biopsy results: Report the percentage of patients who had a negative biopsy post-
ablation. For this endpoint, only biopsy cores taken within the region targeted for ablation 
should be included in the negative biopsy rate analysis, and patients with missing biopsy 
information post-ablation should be imputed as positive; 
o  The following biopsy information should be reported in the raw line data listing: 
date of biopsy, total number of cores taken, location of each core with respect to 
the region targeted for ablation (i.e., within or outside the targeted region), 
number of positive cores, and the Gleason scores and sum of each positive core; 
  Prostate volume results: 
                                                
10 For more information, see https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
11 For the purposes of this guidance, the term serious adverse event is used consistent with the FDA guidance 
Factors to Consider When Making Benefit-Risk Determinations for Medical Device Investigational Device 
Exemptions, available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/factors-
consider-when-making-benefit-risk-determinations-medical-device-investigational-device. 
12 For more information, see Establishment and Operation of Clinical Trial Data Monitoring Committees, 
available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/establishment-and-
operation-clinical-trial-data-monitoring-committees. 
7 Contains Nonbinding Recommendations 
o  Report the percent decrease in total prostate volume (from baseline), as 
determined by pre- and post-ablation imaging (e.g., ultrasound, MRI). For this 
endpoint, men without both pre- and post-ablation measurements should be 
imputed as having a zero change in volume; or 
o  Compare the volume of non-perfused prostate tissue, as determined by post-
ablation imaging (e.g., ultrasound, MRI), to the volume targeted for ablation. For 
this endpoint, missing non-perfused volume measurements should be imputed 
conservatively using statistically valid methods; 
  PSA levels: Report the overall percent reduction in PSA levels from baseline. 
Additionally, studies involving whole-gland ablation should report the percentage of 
patients achieving a pre-specified post-ablation PSA nadir (i.e., the lowest PSA level 
measured post-ablation). For this endpoint, missing PSA data should be imputed 
conservatively using statistically valid methods; and 
  Treat and resect histopathology results: Report the extent/percent volume of viable 
tissue within the targeted region. 
If effectiveness is assessed in a treat and resect study, it is impossible to determine whether 
subsequent adverse events in these patients are due to the ablation procedure or the subsequent 
radical prostatectomy. For this reason, safety should be assessed in a separate cohort of patients 
who are similarly treated with the ablation device and prospectively followed for one year post-
ablation. The safety assessment in this cohort should follow the recommendations in Sections 
IV.B, C, and G above. In this scenario, you should demonstrate that the treat and resect and 
safety cohorts are similar with respect to patient demographics, disease characteristics, prostate 
treatment history, and extent of ablation (e.g., whole gland ablation, hemiablation, focal 
ablation). 
I. Statistical Analysis Considerations 
The safety and effectiveness endpoints should be analyzed using an intent-to-treat (ITT) 
approach. The extent of missing data should be reported and justified. 
For each effectiveness endpoint, means and 95% confidence intervals should be reported in your 
complete test report. The safety and effectiveness endpoints should be descriptively compared to 
those reported for an existing prostate ablation device (either an internal or external control), 
with the goal of clinically demonstrating that the subject prostate ablation device has an 
equivalent or better benefit-risk profile. 
8