Guidance for Industry and 
Food and Drug Administration Staff 
Clinical Investigations of Devices 
Indicated for the Treatment of 
Urinary Incontinence 
 
Document issued on: March 8, 2011 
The draft of this document was issued on September 19, 2008. 
 
For questions regarding this document, contact John Baxley at (301) 796-6549 or via email at 
John.Baxley@fda.hhs.gov. 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Devices and Radiological Health 
 
Office of Device Evaluation 
Division of Reproductive, Gastro-Renal, and Urological Devices 
Urology and Lithotripsy Devices Branch  Contains Nonbinding Recommendations 
 
Preface 
 
Public Comment 
You may submit written comments and suggestions at any time for Agency consideration to the 
Division of Dockets Management, Food and Drug Administration, 5630 Fishers Lane, 
rm. 1061, (HFA-305), Rockville, MD, 20852.  Submit electronic comments to 
http://www.regulations.gov.  Identify all comments with the docket number listed in the notice of 
availability that publishes in the Federal Register.  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 at: 
http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm07
0852.htm.  You may also send an e-mail request to dsmica@fda.hhs.gov to receive an electronic 
copy of the guidance or send a fax request to 301-847-8149 to receive a hard copy.  Please use the 
document number (1636) to identify the guidance you are requesting. 
 
  Contains Nonbinding Recommendations 
 
Table of Contents 
1.  INTRODUCTION...................................................................................................................1 
2.  SCOPE.....................................................................................................................................3 
3.  CLINICAL INDICATIONS...................................................................................................6 
4.  PILOT STUDY RECOMMENDATIONS............................................................................7 
5.  PIVOTAL STUDY RECOMMENDATIONS......................................................................8 
A.  STUDY OBJECTIVE.................................................................................................................8 
B.  MINIMIZING BIAS...................................................................................................................8 
C.  RANDOMIZATION AND CONTROL...........................................................................................8 
D.  BLINDING.............................................................................................................................11 
E.  STUDY ENDPOINTS...............................................................................................................11 
1.  Primary Endpoints....................................................................................................................................11 
2.  Primary Effectiveness Endpoint................................................................................................................12 
3.  Primary Safety Endpoint...........................................................................................................................16 
4.  Secondary Endpoints.................................................................................................................................17 
F.  STUDY DURATION................................................................................................................18 
G.  STATISTICAL HYPOTHESIS...................................................................................................19 
H.  SAMPLE SIZE........................................................................................................................20 
I.  PATIENT SELECTION CRITERIA............................................................................................20 
1.  Inclusion Criteria......................................................................................................................................21 
2.  Exclusion Criteria.....................................................................................................................................22 
J.  PRE-TREATMENT EVALUATION...........................................................................................24 
1.  Medical History.........................................................................................................................................24 
2.  Physical Examination................................................................................................................................25 
3.  Neurological Examination.........................................................................................................................25 
4.  Voiding Diary............................................................................................................................................25 
5.  Pad Weight Testing...................................................................................................................................26 
6.  Urodynamics Testing.................................................................................................................................26 
7.  Cystoscopy.................................................................................................................................................27 
8.  Laboratory Testing....................................................................................................................................27 
9.  Questionnaires...........................................................................................................................................28 
K.  INVESTIGATOR SELECTION AND TRAINING..........................................................................28 
L.  TREATMENT INFORMATION..................................................................................................28 
M.  POST-TREATMENT EVALUATIONS....................................................................................29 
N.  STATISTICAL ANALYSIS RECOMMENDATIONS.....................................................................30 
1.  Primary Endpoint Analyses.......................................................................................................................30 
2.  Secondary Endpoint Analyses...................................................................................................................31 
3.  Missing Data.............................................................................................................................................32 
O.  RISK ANALYSIS....................................................................................................................33 
P.  STUDY MONITORING............................................................................................................33 
Q.  CASE REPORT FORMS..........................................................................................................34 
APPENDIX 1.................................................................................................................................36 
 
  Contains Nonbinding Recommendations 
 
 
Guidance for Industry and FDA Staff 
Clinical Investigations of Devices Indicated 
for the Treatment of Urinary Incontinence 
 
This guidance represents the Food and Drug Administrations (FDA's) current thinking on 
this topic.  It does not create or confer any rights for or on any person and does not operate to 
bind FDA or the public.  You can use an alternative approach if the approach satisfies the 
requirements of the applicable statutes and regulations.  If you want to discuss an alternative 
approach, contact the FDA staff responsible for implementing this guidance.  If you cannot 
identify the appropriate FDA staff, call the appropriate number listed on the title page of this 
guidance. 
1.  Introduction 
This guidance document describes FDAs recommendations for clinical investigations of medical 
devices indicated for the treatment of urinary incontinence.  Urinary incontinence is defined as 
the involuntary loss of urine.  It is a common health problem, especially among women.  
Depending on the definition of urinary incontinence used, the prevalence ranges from 5% to 50% 
of the adult U.S. population.1  The prevalence of urinary incontinence also increases with 
advancing age,2 implying that the impact of this condition is likely to increase over the next 
several decades as the growing U.S. population ages.  Urinary incontinence is associated with 
poor self-rated health and quality of life, social isolation, and depressive symptoms,3 and is a 
significant medical condition with considerable public health impact. 
 
The ultimate goal when investigating a urinary incontinence device is to design a study using 
objective, unbiased outcomes to measure the safety and effectiveness of the device.  Conducting 
objective clinical studies to investigate the safety and effectiveness of urinary incontinence 
devices, however, is fraught with difficulties due to unique challenges posed by this condition and 
patient population.  Major challenges faced when designing a clinical study to assess the safety 
and effectiveness of a urinary incontinence device include the inherent variability and subjectivity 
                                                 
 
1 MS Litwin, CS Saigal, editors. Urologic Diseases in America. US Department of Health and 
Human Services, Public Health Service, National Institutes of Health, National Institute of 
Diabetes and Digestive and Kidney Diseases. Washington, DC: US Government Printing Office 
2007; NIH Publication No. 07-5512, pg. 161, 
http://kidney.niddk.nih.gov/statistics/uda/Urologic_Diseases_in_America.pdf. 
2 JA Fantl, DK Newman, J Colling, et al. Urinary incontinence in adults: acute and chronic 
management. Clinical Practice Guideline Number 2 (1996 Update). Rockville, MD: Agency for 
Health Care Policy and Research, 1996, AHCPR Publication No. 97-0682. 
3 JL Melville, K Delaney, K Newton, W Katon. Incontinence Severity and Major Depression in 
Incontinent Women. Obstet Gynecol, 2005, 106(3):585-592. 
1  Contains Nonbinding Recommendations 
 
 
of the typical outcome measures commonly used to assess the device effectiveness, the significant 
placebo effect associated with some of these outcome measures, and the heterogeneous nature of 
the general patient population.  These challenges are described in further detail, below. 
 
The psycho-social dimension of urinary incontinence inherently relies on the patients 
perceptions of their condition, and quality of life is the primary motivator of patients to seek 
treatment for their condition.  While quality of life is an important outcome measure, it is 
subjective and inherently difficult to measure reliably, and may be age- and symptom-dependent.4  
 
There is a strong behavioral component to urinary incontinence, and enrollment in a clinical study 
in and of itself may make subjects more aware of their voiding habits and potential risk factors.  
This phenomenon makes urinary incontinence studies susceptible to a significant placebo 
effect.5,6 
 
Patients activities of daily living (e.g., mobility, recreation, exercise) and daily habits (e.g., diet, 
fluid intake) are difficult to control, yet can directly affect the frequency and amount of urine loss.  
Thus, variability in the types and levels of activities among patients seeking treatment for urinary 
incontinence is an important issue. 
 
There can be a high degree of heterogeneity in the potential patient population, which could 
introduce bias if covariates are not carefully balanced between treatment and control arms.   
 
For these reasons, we believe sound clinical study design is essential when investigating the 
safety and effectiveness of a device for urinary incontinence.  We believe that, in general, a 
randomized, controlled trial is the least burdensome means of collecting data to demonstrate the 
safety and effectiveness of urinary incontinence devices.  Reasons supporting this view are that 
the randomized controlled trial inherently balances patient covariates between study groups, 
permits assessment of placebo effects, and may provide the most reliable method of assessing 
subjective or variable safety and effectiveness outcome measures.  In considering alternative 
study designs, using patients as their own control or using a historical control may hinder the 
ability to demonstrate safety and effectiveness in most investigations.  Statistical concerns 
underlying this recommendation include both general considerations, such as regression to the 
mean, and the disease-specific considerations listed above.  These and other study design 
recommendations are discussed in detail in section 5. Pivotal Study Recommendations.
                                                 
 
4 S. Hunskaar, A. Vinsnes.  The quality of life in women with incontinence as measured by 
Sickness Impact Profile.  J Am Geriatr Soc, 1991, 39(4):378-382. 
5 I. Yalcin, R.C. Bump,.  The effect of previous treatment experience and incontinence severity on 
the placebo response of stress urinary incontinence, Am J Obstet Gynecol, 2004, 191:194-197. 
6 J.H. Schagen van Leeuwen, R. Castro, M. Busse, B.L. Bemelmans.  The placebo effect in the 
pharmacologic treatment of patients with lower urinary tract symptoms, Eur Urol, 2006, 
50(3):440-452. 
2  Contains Nonbinding Recommendations 
 
 
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 guidances means that something is suggested or 
recommended, but not required.  
2.  Scope 
This guidance document addresses the general clinical study design concepts that you should 
consider when designing clinical investigations of medical devices indicated for the treatment of 
urinary incontinence.  This document does not address preclinical testing issues, which should, on 
a case-by-case basis, take into account the specific clinical indications and technology of the 
device. 
 
Premarket notifications (510(k)s) for class II devices, as well as class I devices with new 
indications or technology that exceed the limitations of exemption, may sometimes include 
clinical data that support the performance specifications of the device.  In accordance with the 
Federal Food, Drug, and Cosmetic Act (the Act), the agency will rely upon well-designed bench 
and/or animal testing rather than requiring clinical studies for new class I and II urinary 
incontinence devices, unless there is a need for clinical information to support a determination of 
substantial equivalence.  (See sec. 513(i)(1) of the Act (21 U.S.C. 360(i)(1)). While, in general, 
clinical studies may not be needed for most class I and II urinary incontinence devices, FDA may 
recommend that you collect clinical data for a class I and II urinary incontinence device with any 
one of the following:  
  indications for use dissimilar from a legally marketed device of the same type;  
  designs dissimilar from designs previously cleared under a premarket notification; or  
  new technology, i.e., technology different from that used in legally marketed devices 
of the same type.  
 
FDA may consider alternatives to clinical testing when the proposed alternatives are supported by 
an adequate scientific rationale.  
 
A premarket approval application (PMA) for a class III device requires valid scientific evidence 
in the form of clinical data to demonstrate a reasonable assurance of safety and effectiveness for 
its conditions of use (21 CFR 860.7). 
 
This document is intended to cover any type of urinary incontinence device undergoing clinical 
investigation to support a marketing submission or application.  The device technologies may 
include, but are not limited to, the device types shown in the tables below. 
 
3  Contains Nonbinding Recommendations 
 
 
The following table lists class III (premarket approval) urinary incontinence devices. 
 
Classification (21 CFR)  Class  Product  Description 
Code 
 
GASTROENTEROLOGY-UROLOGY DEVICES 
876.5270  III  EZT  Pacemaker, bladder 
Implanted electrical urinary  III  EZW  Stimulator, electrical, implantable, 
continence device  for incontinence 
876.5280  III  EZY  Device, incontinence, 
Implanted mechanical/hydraulic  mechanical/hydraulic 
urinary continence device 
  III  LNM  Agent, bulking, injectable for 
gastro-urology use 
  III  OCK  Transurethral occlusion insert, 
urinary incontinence-control, female 
Requires premarket approval application before marketing (see section 513(a) of the Federal 
Food, Drug, and Cosmetic Act (21 U.S.C. 360c(a))). 
 
4  Contains Nonbinding Recommendations 
 
 
The following table lists class I and II urinary incontinence devices. 
 
Classification (21 CFR)  Class  Product  Description 
Code 
 
GASTROENTEROLOGY-UROLOGY DEVICES 
876.5160  I  FHA  Clamp, penile 
Urological clamp for males  510(k) 
Exempt 
I  MNG  External urethral occluder, urinary 
incontinence-control, female 
876.5310  II  NAM  Stimulator, peripheral nerve, non-
Nonimplanted, peripheral  implanted, for pelvic floor 
electrical continence device  dysfunction 
876.5320  II  KPI  Stimulator, electrical, non-
Nonimplanted electrical  implanted, for incontinence 
continence device 
876.5920  I  EYQ  Garment, protective, for 
Protective garment for  510(k)  incontinence 
incontinence  Exempt 
 
GENERAL AND PLASTIC SURGERY DEVICES 
 
878.3300  II  FTM  Mesh, surgical 
Surgical mesh  II  FTL  Mesh, surgical, polymeric 
878.4400  II  MUK  Electrosurgical radiofrequency 
Electrosurgical cutting and  system, stress urinary incontinence, 
coagulation device and  female, transvaginal or laparoscopic, 
accessories  pelvic tissue 
II  NVJ  Applicator, transurethral, radio 
frequency, for stress urinary 
incontinence in women 
 
OBSTETRICAL AND GYNECOLOGICAL DEVICES 
884.1425  II  HIR  Perineometer 
Perineometer 
884.1720  II  OCQ  Laparoscopic bladder-neck 
Gynecologic laparoscope and  suspension instrument, stress urinary 
accessories  incontinence 
884.3575  II  HHW  Pessary, vaginal 
Vaginal pessary 
 
If a clinical study is needed to support PMA approval or 510(k) clearance, the study must be 
conducted under the Investigational Device Exemptions (IDE) regulation, 21 CFR Part 812.  
Most of the devices addressed by this guidance document are significant risk devices as defined 
5  Contains Nonbinding Recommendations 
 
 
in 21 CFR 812.3(m).7  In addition to the requirement of having a FDA-approved IDE, sponsors of 
such trials must comply with the regulations governing institutional review boards (21 CFR Part 
56) and informed consent (21 CFR Part 50).8  
3.  Clinical Indications 
The condition of urinary incontinence can be divided into several categories, depending upon the 
physiologic mechanism triggering urine loss.9  These categories are listed and defined below. 
 
Stress Incontinence is urinary incontinence during physical activities that increase intra-
abdominal pressure, such as coughing, sneezing, or lifting.  It occurs whenever the intra-
abdominal pressure exerted on the bladder exceeds the closing pressure of the bladder neck.  
Stress incontinence can be further divided into two subcategories, hypermobility and intrinsic 
sphincter deficiency, which are defined below. 
 
Hypermobility is stress incontinence caused by the abnormal descent of the bladder neck 
below the zone of abdominal pressure.  When intra-abdominal pressure rises, pressure to the 
bladder increases but the zone of pressure does not include the bladder neck. 
 
Intrinsic Sphincter Deficiency (ISD) is stress incontinence caused by weakness of the 
urinary sphincter. 
 
Note:  Hypermobility and ISD are not mutually exclusive.  In cases where the two 
subcategories of stress incontinence co-exist, the patients diagnosis is typically 
based on the predominant mechanism of urine loss.  As detailed later under section 
I. Patient Selection Criteria, your study should properly define and document the 
criteria for study entry to verify that subjects with co-existing categories or 
subcategories of incontinence are appropriate candidates for the investigational 
treatment and will not confound the studys conclusions. 
 
Urge Incontinence is urinary incontinence secondary to a sudden, strong desire to void 
(urgency).  This type of incontinence is generally caused by either an involuntary detrusor 
contraction or neurological impairment.  
 
Mixed Incontinence is a combination of stress and urge incontinence. 
 
                                                 
 
7 See Significant Risk and Nonsignificant Risk Medical Device Studies, 
http://www.fda.gov/downloads/ScienceResearch/SpecialTopics/RunningClinicalTrials/Guidances
InformationSheetsandNotices/UCM118082.pdf . 
8 For devices that are not significant risk, sponsors of clinical investigations still must comply 
with the regulations governing institutional review boards (21 CFR Part 56) and informed consent 
(21 CFR Part 50). 
9 G.D. Webster, M.L.Guralnick,. in Campbells Urology, edited by PC Walsh, AB Retik, V.E. 
Darracott Jr., et al., Philadelphia:  Saunders, 2002, 8th edition, vol. 2, pp. 901. 
6  Contains Nonbinding Recommendations 
 
 
Overflow Incontinence is urinary incontinence where the leakage of urine is due to the urine 
volume exceeding the normal capacity of the bladder.  This type of incontinence occurs 
secondary to poor bladder emptying caused by either impaired detrusor contractility or 
outflow obstruction. 
 
Functional Incontinence is urinary incontinence that occurs when physical or mental 
disabilities prevent a person from getting to a bathroom before they urinate.  Disabilities that 
often lead to functional incontinence are problems with walking and dementia. 
 
Continuous Incontinence is urinary incontinence where the leakage of urine is due to either 
a urinary tract fistula or ectopic ureter that allows urine to bypass the urethral sphincter. 
 
A wide range of underlying mechanisms may cause or contribute to urinary incontinence, and 
patients outcomes after device therapy generally depend on the underlying physiological 
mechanism of urine loss.  Therefore, we recommend you tailor the indication of your device to 
the specific categories of urinary incontinence relevant to the devices mechanism of action and 
targeted for treatment in your study. 
4.  Pilot Study Recommendations 
We recommend you separate your urinary incontinence device investigation into phases to 
minimize the risks to investigational subjects and to gain clinical experience in using your 
device prior to initiating a large-scale clinical study.  These phases typically involve an initial 
study, 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 may be used to refine 
the 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 that 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) that 
will be collected to support initiating 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 
7  Contains Nonbinding Recommendations 
 
 
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 the pilot study data can be pooled with pivotal study data, since 
there are often differences in the pilot and pivotal study protocols.  If you intend to pool pilot 
and pivotal study results, we recommend you provide a rationale showing that it is statistically 
and clinically valid to pool the data from the pilot and the pivotal studies. 
5.  Pivotal 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.  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 urinary incontinence device at multiple clinical sites 
to assess the consistency of the study results among a wide variety of investigators and patients, 
and to increase the likelihood that the study population is representative of the general patient 
population. 
 
Your study design should address the factors described below. 
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 the C. Randomization and Control,  
D. Blinding, I. Patient Selection Criteria, and N. Statistical Analysis Recommendations 
sections of this guidance document.   
 
If sources of bias are not adequately minimized, the validity of the studys conclusions may be 
questionable.  For all study designs, we recommend your protocol include a section describing 
how the study design intends to minimize bias. 
C.  Randomization and Control 
Clinical investigations of urinary incontinence devices pose unique challenges, such as the 
influence of subjects perceptions on outcome (placebo effect), the inherent variability and 
subjectivity of the available effectiveness endpoints, and heterogeneity within the patient 
8  Contains Nonbinding Recommendations 
 
 
population.  For most urinary incontinence devices, we believe that these challenges are most 
efficiently overcome by using randomized, controlled trial designs.  The benefit of a 
randomized, controlled trial is its tendency to balance confounding factors between study 
groups and minimize the potential for bias. 
 
The potential advantages of conducting a randomized, controlled trial 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 are often much more difficult to evaluate when using 
historical control data. 
 
Randomizing subjects between study groups is a standard method for minimizing selection 
bias and controlling for confounding factors.  Selection bias occurs when subjects possessing 
one or more important prognostic factors appear more frequently in one study group than the 
other.  The randomization process assigns subjects to an intervention or control group such 
that each subject has a prospectively defined chance of being selected for each group.  
Randomization also protects the trial from conscious or subconscious actions on the part of 
the study investigators that could lead to study groups that are not comparable, e.g., selecting 
the most incontinent patients for the therapy thought by the study investigator to be the more 
aggressive treatment.  We recommend you prospectively define the randomization method in 
your study protocol.  The randomization method should balance the assignment of subjects 
within each site (e.g., by 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.10  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 that you address each of the following factors when choosing a 
control: 
  standard of care; 
  desired indications for use of the investigational device;  
  patient population being targeted; 
  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 blind the subject and evaluator; 
  time to treatment effect; and 
  device design. 
                                                 
 
10 R. Temple, S.S. Ellenberg. 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. 
9  Contains Nonbinding Recommendations 
 
 
 
Potential control therapies include: 
  use of an accepted surgical procedure; 
  treatment with a legally marketed medical device; 
  treatment with an approved drug; 
  behavioral therapy; and 
  sham treatment. 
 
A control that consists of treatment with a legally marketed urinary incontinence device that is 
similar in design to the investigational device is often a desirable option because study design, 
subject 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 
an investigational injectable bulking agent to those of a legally marketed injectable bulking 
agent. 
 
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 should be used in limited circumstances.  This study 
design should only be considered when it is methodologically necessary, i.e., when designs 
that are unblinded are methodologically unacceptable (e.g., because endpoints are subjective) 
and when a no treatment control is methodologically required.  Furthermore, the 
withholding of treatment should not lead to serious harm, such as death or irreversible 
morbidity.  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.  Additionally, if a sham procedure/treatment is being considered in a 
clinical investigation involving children, the requirements of 21 CFR Part 50 Subpart D also 
apply. 
 
You can employ several strategies to facilitate patient recruitment and retention in 
concurrently controlled studies, such as through randomization ratios other than 1:1 and 
crossover study designs that would allow either sham or medically managed control patients 
to receive treatment with the investigational device and after a pre-specified time offer 
potential subjects increased availability to the investigational treatment. 
 
Generally, we recommend a randomized, controlled trial to address the challenges described 
in this guidance document.  However, if you use an alternative study design, we recommend 
that you show that it is scientifically sound and addresses the relevant safety and effectiveness 
questions.  While we recognize that there is no unique best design for urinary incontinence 
investigations, 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 arguments supporting the use of your alternative design 
10  Contains Nonbinding Recommendations 
 
 
(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?).   
 
For all study designs, we recommend that 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 
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 bias, we 
recommend you incorporate blinding into your 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 not feasible, 
it is usually possible to use a blinded third-party evaluator for the evaluation of certain 
outcome measures (e.g., pad weight testing, evaluation of voiding diary information, quality 
of life, cystoscopy, adverse events). 
 
Blinding is usually accomplished by coding the interventions and having an individual who is 
not a member of the patient care team control the key to the code.  Since bias introduced by 
breaches in blinding can be very difficult to assess in the analysis, we recommend that you do 
not break the code until the analysis is complete.   
 
If study subjects and investigators (or other evaluators) are going to be blinded to the 
subjects treatment allocation (i.e., investigational device 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 describe the blinding 
methodology and specify when blinding will be broken. 
E.  Study Endpoints 
Your clinical protocol should clearly specify and support the studys primary and secondary 
endpoints.  To ensure the collection of meaningful results, these endpoints should be clinically 
relevant to the specific condition and patient population you intend to target in the study.  
Listed below are additional factors to consider when selecting the optimum endpoints for 
clinical investigations of urinary incontinence devices. 
1.  Primary Endpoints 
The primary safety and effectiveness endpoints should be 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 urinary incontinence device study, the primary endpoint 
specified in the statistical hypothesis is usually an effectiveness endpoint, which, in turn, 
directly affects the indications for use.   
11  Contains Nonbinding Recommendations 
 
 
2.  Primary Effectiveness Endpoint 
The selection of the primary effectiveness endpoint can be one of the major challenges in 
designing an investigation of a urinary incontinence device.  The primary effectiveness 
endpoint should be clinically meaningful, and, ideally, should fully characterize the effect 
of treatment.  However, due of the nature of urinary incontinence, 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.  For 
this reason, defining the optimum primary effectiveness endpoint can be a challenge. 
 
The following table lists commonly used effectiveness endpoints for urinary incontinence 
therapies, along with their potential advantages and disadvantages. 
 
Endpoint  Potential Advantages   Potential Disadvantages 
 
  Objective    Outcomes other than 
1-Hour Pad Weight Test 
dryness may not be 
  Standardized 
 
meaningful to patients 
(Amount of urine leakage    Assesses severity of 
  Not correlated with 
experienced by the subject in  urine leakage 
patients daily activities 
1 hour during a standardized 
series of activities or exercises    Poor to moderate 
in the investigators office)11  sensitivity12 
  Subject to variability  
  Not meaningful for 
urinary incontinence 
categories other than 
stress incontinence 
 
  Objective    Outcomes other than 
24-Hour Pad Weight Test 
dryness may not be 
  Correlated with 
 
meaningful to patients 
patients daily 
(Amount of urine leakage 
activities    Less standardized 
experienced by the subject at 
  High sensitivity14    Subject to variability 
                                                 
 
11 P. Abrams, J.G. Blaivas, S.L. Stanton, J.T. Anderson.  The standardization of terminology of 
lower urinary tract function.  Scand J Urol Nephrol Suppl, 1988, 114:5-19. 
12 A. Tubaro, W. Artibani, C. Bartram, et al., Imaging and other investigations, in Incontinence: 
Basics and Evaluation, edited by P. Abrams, L. Cardozo, S. Khoury, and A. Wein A., vol. 1, 
Paris:  Health Publication Ltd., 2005, pp. 775. 
13 L. Jrgensen, G. Lose, P. Thunedborg.  Diagnosis of mild stress incontinence in females:  24-
hour home pad weight testing versus the 1-hour ward test.  Neurourol Urodyn, 1987, 6:165-166. 
12  Contains Nonbinding Recommendations 
 
 
Endpoint  Potential Advantages   Potential Disadvantages 
home during a 24-hour period; 
  Assesses severity of    Requires patient 
all pads used during the test 
urine leakage   compliance 
period are weighed before and 
 
after use)13 
 
  Objective    May not directly 
Number of Incontinence 
correlate with the 
  Meaningful to 
Episodes/Day 
severity of urine leakage 
patients 
 
  Less standardized 
(Obtained using a voiding    Correlated with 
diary)  patients daily    Subject to variability 
activities 
  Requires patient 
compliance 
    Objective    May not directly 
Number of Pads Used/Day  correlate with the 
  Meaningful to 
  severity of urine leakage 
patients 
(Obtained using a voiding    Less standardized 
  Correlated with 
diary)    Subject to variability 
patients daily 
  Requires patient 
activities 
compliance 
    Meaningful to    Significant placebo 
Quality of Life   patients15  effect16 
    Standardized    Subjective 
(Assessed using a validated    Patients daily    Subject to variability 
questionnaire)  activities taken into    Not correlated with the 
account  severity of urine leakage 
    Objective    Not meaningful to 
Urodynamics Measure    Standardized  patients 
    Less subject to    Not correlated with 
(Measurement such as leak  variability  patients daily activities 
point pressure, cystometric    Invasive; patients may be 
outcome, etc.)  unwilling to comply 
  Specific to particular 
categories (per Section 3 
                                                                                                                                                               
 
14 A. Tubaro, W. Artibani, C. Bartram, et al., Imaging and other investigations, in Incontinence: 
Basics and Evaluation, edited by P. Abrams, L. Cardozo, S. Khoury, and A. Wein., vol. 1, Paris:  
Health Publication Ltd., 2005, pp. 777. 
15 K.S. Kinchen, K. Brugio, A.C. Diokno, N.H. Fultz, et al., Factors associated with womens 
decisions to seek treatment for urinary incontinence.  J Womens Health (Larchmt), 2003, 
12(7):687698. 
16 J.H. Schagen van Leeuwen, R. Castro, M, Busse, B.L. Bemelmans.  The placebo effect in the 
pharmacologic treatment of patients with lower urinary tract symptoms, Eur Urol, 2006, 
50(3):440-452. 
13  Contains Nonbinding Recommendations 
 
 
Endpoint  Potential Advantages   Potential Disadvantages 
above) of incontinence 
 
 
In light of these potential advantages and disadvantages, we recommend that a urinary 
incontinence device investigation use one or both of the following measures as the 
primary effectiveness endpoint.  Our recommendation is derived from a detailed 
comparison of the relative benefits and limitations of the various endpoints, which is 
consistent with a consensus effort sponsored by the World Health Organization.17   
 
Reduction in urine leakage, as assessed by pad weight, at the follow-up visit 
(relative to baseline) 
We recommend that investigators conduct pad weight testing (i.e., 1-hour pad weight 
test, 24-hour pad weight test, or both) using standardized techniques. 
 
The most meaningful measure of success for any urinary incontinence treatment is 
dryness, which is the outcome that patients ultimately seek.  Therefore, your protocol 
should prospectively define dryness with respect to pad weight as pad weight increase 
during the test of less than X grams (where the variable X denotes a negligible 
increase in weight due to measurement uncertainty, subject perspiration, or other 
source).  For the 1-hour pad weight test, we recommend defining dryness as pad 
weight increase of less than 1 gram.18  For the 24-hour pad weight test, we recommend 
defining dryness as pad weight increase of less than 1.3 grams.19 
 
Although dryness is the ultimate goal of treatment, we recognize that many patients 
are satisfied if they only experience a reduction in urine leakage.  Based on our 
experience reviewing urinary incontinence studies, we recommend defining the 
clinically meaningful level of improvement in pad weight as greater than 50% 
reduction from baseline.   
 
Reduction in the number of incontinence episodes per day at the follow-up visit 
(relative to baseline) 
                                                 
 
17 C. Payne, P. Van Kerrebroeck, J. Blaivas, et al., Research Methodology in Urinary 
Incontinence in Incontinence, edited by Abrams P, Cardozo L, Khoury S, and Wein A, Paris: 
Health Publication Ltd., 2002, pp.10581061. 
18 A. Tubaro, W. Artibani, C. Bartram, et al., Imaging and other investigations, in Incontinence: 
Basics and Evaluation, edited by P. Abrams, L. Cardozo, S. Khoury, and A. Wein A., vol. 1, 
Paris:  Health Publication Ltd., 2005, pp. 779. 
19 A. Tubaro, W. Artibani, C. Bartram, et al., Imaging and other investigations, in Incontinence: 
Basics and Evaluation, edited by P. Abrams, L. Cardozo, S. Khoury, and A. Wein A, vol. 1, Paris:  
Health Publication Ltd., 2005, pp. 779. 
14  Contains Nonbinding Recommendations 
 
 
We recommend that investigators assess this endpoint using a standardized voiding 
diary that documents the daily chronological record of fluid intake, incontinence 
episodes with associated activity and perceived level of urgency, severity of each 
incontinence episode (i.e., estimated volume of leakage), pad usage, and normal 
voiding episodes with measured volume.  To reduce within-patient variability, we 
recommend collecting this voiding diary information over 7 consecutive days and 
reporting the average number of incontinence episodes per day. 
 
We recommend your protocol define dryness with respect to number of incontinence 
episodes as zero (0) episodes per day.  Additionally, we recommend your protocol 
specify the clinically meaningful level of improvement in the number of incontinence 
episodes per day as greater than 50% reduction from baseline.  
 
We recommend that you evaluate these primary endpoint measures, pad weight and 
number of incontinence episodes, with respect to the definitions of both dryness and 
improvement.  However, the choice of which success criterion to use for the primary 
effectiveness endpoint is up to you.  We recommend that the definition of success not 
chosen for the primary endpoint be evaluated as a secondary endpoint. 
 
To combine the strengths of the 1-hour pad weight test (i.e., highly standardized) and the 
24-hour pad weight test (i.e., correlated with patients daily activities, high sensitivity), we 
recommend that you incorporate both pad weight tests in a composite primary 
effectiveness endpoint.  A composite endpoint incorporates two or more effectiveness 
endpoints into a single, unified endpoint using a clearly stated decision rule, and can 
overcome the disadvantages of using a single measure as the primary endpoint for a 
urinary incontinence device study.  Examples of composite endpoints constructed from 
pad weight testing measures are listed below: 
 
  reduction in 1-hour pad weight and reduction in 24-hour pad weight; or 
 
  dryness in 1-hour pad weight and reduction in 24-hour pad weight. 
 
Likewise, composite endpoints can also combine the strengths of pad weight testing with 
those of other effectiveness measures, and we recommend that such approaches be 
considered.  Examples of such composite endpoints are listed below: 
 
  reduction in 24-hour pad weight and reduction in number of incontinence 
episodes; or  
 
  reduction in 1-hour pad weight and reduction in number of incontinence episodes 
and improvement in quality of life. 
 
If you select only one of these outcome measures, reduction in 1-hour pad weight, 
reduction in 24-hour pad weight, or reduction in number of incontinence episodes, as the 
primary effectiveness endpoint, we recommend your protocol include the others as 
15  Contains Nonbinding Recommendations 
 
 
secondary endpoints.  Alternatively, if you select a composite endpoint in the primary 
assessment of device effectiveness, we recommend your protocol include the individual 
components of the composite endpoint as secondary endpoints. 
 
3.  Primary Safety Endpoint 
We generally recommend you base the primary safety endpoint on the incidence and 
severity of adverse events.  However, if your 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 events associated with that concern, while still recording 
all adverse events. 
 
To collect safety information reliably, we recommend your protocol instruct investigators 
to record all adverse events, regardless of whether you believe they are device-related or 
anticipated.  Events you should routinely record include, but are not limited to: 
  genitourinary events (i.e., events associated with the urinary tract or the 
surrounding genital region); 
  infections; 
  pain and discomfort; 
  foreign body reactions; 
  secondary or unplanned 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.  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 that 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. 
16  Contains Nonbinding Recommendations 
 
 
4.  Secondary Endpoints 
FDA believes secondary endpoint measures, by themselves, are not sufficient to 
characterize fully the treatment benefit.  However, these measures may provide additional 
characterization of the treatment effect.20  Specifically, secondary endpoints can: 
  supply background and understanding of the primary endpoints, in terms of overall 
direction and strength of the treatment effect; 
  be the individual components of a composite primary endpoint, if used; 
  include variables for which the study is underpowered to definitively assess; 
  aid in the understanding of the treatments 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, as well as to support descriptions of 
device performance in the labeling.  To minimize bias, your protocol should prospectively 
identify all secondary endpoints, indicating how the data will be analyzed and what 
success criteria will be applied. 
 
Although there are many possible secondary endpoints to consider for clinical 
investigations of urinary incontinence devices, we recommend your protocol include the 
endpoints discussed below. 
 
Quality of Life 
Urinary incontinence is strongly associated with impairment of quality of life, which 
typically leads patients to seek treatment.21  Therefore, we recommend your protocol 
instruct investigators to assess the quality of life of study subjects using a validated 
measure specific to urinary incontinence.22  For example, the Incontinence Quality of 
Life (I-QOL) questionnaire is an instrument for which validity, reliability, and 
                                                 
 
20 R.B. DAgostino, Sr., Controlling alpha in a clinical trial: the case for secondary endpoints. 
Statist Med, 2000, 19(6):763-766. 
21 K.S. Kinchen, K. Brugio, A.C. Diokno, N.H. Fultz, et al., Factors associated with womens 
decisions to seek treatment for urinary incontinence.  J Womens Health (Larchmt), 2003, 
12(7):687-698. 
22 There are numerous incontinence-specific quality of life measures.  These measures differ in 
the populations and settings in which they were developed and validated, and in their potential 
applicability to other patient groups.  The 3rd International Consultation on Incontinence 
discusses many of these measures and states current international consensus on incontinence-
specific quality of life questionnaires.  [J. Donovon, R. Bosch, M. Gotoh, S. Jackson, et al., 
Symptom and quality of life assessment in Incontinence: Basics and Evaluation, edited by P. 
Abrams, L. Cardozo, S. Khoury, and A. Wein, vol. 1, Paris:  Health Publication Ltd., 2005.] 
17  Contains Nonbinding Recommendations 
 
 
responsiveness have been demonstrated.23,24  To analyze improvement in quality of 
life, we recommend your protocol specify a clinically meaningful difference.  For 
instance, a 2.5-point change in the I-QOL has been determined to be the minimum 
clinically meaningful difference for women with stress urinary incontinence.25 
 
Sexual Function 
Given the proximity of urinary incontinence devices to the genitalia, we recommend 
your protocol assess the impact of the device upon sexual function using a validated, 
gender-specific measure of sexual function. 
 
Leak Point Pressure 
We recommend your protocol specify this urodynamic parameter as a secondary 
endpoint when the device is indicated for the treatment of stress urinary incontinence 
secondary to intrinsic sphincter deficiency (ISD), or when the device has the potential 
to negatively affect the anatomy surrounding the external urinary sphincter. 
 
Post-void Residual (PVR) Urine Volume 
We recommend your protocol include PVR as a secondary endpoint if the device has 
the potential to impact bladder emptying.  
 
Patient Satisfaction 
We recommend your protocol include a standardized patient satisfaction survey as a 
secondary endpoint to rate subject satisfaction with each aspect and dimension of 
treatment (e.g., rating of improvement, discomfort, ease of use, confidence in social 
situations, confidence in active situations, overall satisfaction). 
 
Recommendations regarding the statistical analysis of secondary endpoints are discussed 
below in N. Statistical Analysis Recommendations. 
F.  Study Duration 
You should design your study to assess whether the treatment effect of your urinary 
incontinence device, as measured using the primary and secondary effectiveness endpoints, 
persists for a clinically meaningful period of time.  Additionally, longer follow-up duration 
                                                 
 
23 T.H. Wagner, D.L. Patrick, T.G. Bavendum, M.L. Martin, et al., Quality of life of persons with 
urinary incontinence:  development of a new measure.  Urology, 1996, 47(1):67-72. 
24 D.L. Patrick, M.L. Martin, D.M. Bushnell, I. Yalcin, et al., Quality of life of women with 
urinary incontinence:  further development of the incontinence quality of life instrument (I-QOL).  
Urology, 1997, 53(1):71-76. 
25 I. Yalcin, D.L. Patrick , K. Summers, K. Kinchen, et al.  Minimal clinically important 
differences in incontinence quality-of-life scores in stress urinary incontinence, Urology, 2006, 
67(6):1304-1308. 
18  Contains Nonbinding Recommendations 
 
 
may diminish placebo effects.26  For urinary incontinence devices that are intended either as a 
curative treatment or for long-term management, we recommend your study follow subjects 
during the premarket follow-up period for 1 year following treatment to document the 
stability of the treatment effect.  It is possible, however, that longer term follow-up may be 
appropriate, depending upon a variety of device-specific factors.  Examples of such factors 
include, but are not limited to, unique device material properties, retreatment or repeated use 
requirements, and delay in the time to achieve the full treatment effect.  In studies where 
device retreatment is permitted, we recommend the follow-up duration refer to the period 
following final treatment. 
 
In addition to the premarket follow-up considerations discussed above, long-term postmarket 
studies may be appropriate for class III (premarket approval) devices or certain class II 
(510(k)) 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 
postmarket studies are anticipated or possible, we recommend your study continue to follow 
subjects annually beyond marketing approval or clearance.  In the event that FDA requires a 
postapproval study as a condition of PMA approval for a Class III device or postmarket 
surveillance (also known as a section 522 study) in accordance with its statutory authority for 
either a Class II or III device, 27 incorporating this extended follow-up in the original pivotal 
study will allow you to convert the premarket study into a postmarket study, avoiding the 
problems of obtaining new informed consent from study subjects for additional follow-up and 
recruiting new subjects. 
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.  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 delta 
level that reflects a maximum tolerable difference that is clinically insignificant (i.e., not 
clinically meaningful) in the analysis of the primary endpoint.  Larger values of the non-
inferiority delta level are usually supported by demonstrating significant benefits in the safety 
of the investigational device.  For superiority studies, we recommend the hypothesis state a 
clinically meaningful level of improvement (i.e., a superiority delta) by which the 
investigational device should exceed the control with regard to the analysis of the primary 
endpoint.  If the investigational device offers a clinically significant improvement in safety, 
                                                 
 
26 J.H. Schagen van Leeuwen, R. Castro, M. Busse, B.L. Bemelmans.  The placebo effect in the 
pharmacologic treatment of patients with lower urinary tract symptoms, Eur Urol, 2006, 
50(3):440-452. 
27 See sec.522(a)(1) of the Act (21 U.S.C.360l(a)(1); 21 CFR 814.82(a)(2). 
19  Contains Nonbinding Recommendations 
 
 
however, a superiority delta level of zero in the evaluation of the effectiveness endpoint may 
be appropriate. 
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 
method that is consistent with the proposed statistical hypothesis.  You should state and 
support all statistical assumptions associated with the sample size calculation.  For additional 
recommendations, see Statistical Guidance for Clinical Trials of Non-Diagnostic Medical 
Devices28 and Guidance for the Use of Bayesian Statistics in Medical Device Clinical 
Trials.29  
 
Since patient dropout 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 may reduce the chance of having 
inadequate statistical power due to incorrect assumptions regarding the treatment and placebo 
effects and their variance. 
I.  Patient Selection Criteria 
We recommend your protocol clearly define and support the patient population proposed for 
study enrollment.  Important considerations include, but are not limited to: 
  the category of incontinence (e.g., stress urinary incontinence due to hypermobility, 
stress urinary incontinence due to ISD, urge incontinence); 
  prior incontinence history (e.g., duration and severity of incontinence, prior treatments 
or surgery for incontinence); 
  general medical history (e.g., comorbidities, confounding conditions); 
  gender (i.e., female only, male only, both females and males); and 
  age range. 
 
An important consideration is whether to define the eligible patient population broadly or 
narrowly.  There is no universal approach to this issue, as each has potential advantages and 
disadvantages that you should carefully weigh.  Designing the study to enroll a broad patient 
population potentially increases the enrollment rate and the device use may be studied over a 
wide range of subjects.  However, a broadly defined patient population can result in the 
enrollment of patients with a wide variety of confounding factors, which can add significant 
variability and negatively affect the data analysis.   
 
                                                 
 
28 http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm
106757.htm    
29 http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm
071072.htm  
20  Contains Nonbinding Recommendations 
 
 
For example, while many devices are designed for either the male or female anatomy, some 
devices implanted near the bladder (e.g., injectable bulking agents, artificial urinary sphincter, 
electrical stimulators) may be used for treating both male and female incontinence.  If a 
device is designed for or studied in only one gender, its indication will be limited to that 
population.  However, if a device can be used for treating both male and female incontinence 
and is studied in both sexes, a single study may become difficult to analyze and interpret due 
to the potential confounding effect of gender, related, for example, to different mechanisms 
and severity of incontinence and differences in surrounding anatomy.  In investigations of 
urinary incontinence devices, we believe permitting the enrollment of both genders in the 
same study (instead of enrollment of men in one study, women in another) could confound 
interpretation of study outcomes by reducing the overall observed safety and effectiveness of 
the device and obscuring the specific subpopulation that actually benefits from device use.  
Post-hoc subgroup analyses of broadly defined patient populations are typically more subject 
to bias than prospectively defined analyses of narrower patient populations.  
 
Alternatively, defining the patient population narrowly may result in a homogeneous 
population that may be straightforward to analyze.  A homogeneous population may also lead 
to a small sample size, since the variability in the responses to treatment will likely be 
reduced.  Lastly, a patient population that is recruited with more stringent entry criteria may 
minimize placebo effect.30  However, studying a narrow patient population could slow the 
rate of enrollment and restrict the devices indications for use.   
 
Therefore, we recommend your study design address the potential impact of the choice of 
patient population.  The recommendations below are intended to help you adequately describe 
the target patient population and ensure the study subjects accurately reflect your description. 
 
1.  Inclusion Criteria 
Diagnosis 
Investigators should diagnose subjects as having the specific category (or one of the 
categories) of urinary incontinence for which the device is indicated.  The diagnostic 
criteria specified in the protocol should be consistent with the current standard of care. 
 
Severity 
We recommend your protocol specify an objectively measured severity of 
incontinence that reflects the targeted patient population (e.g., minimum baseline pad 
weight as measured by a 1-hour pad weight test, three 24-hour pad weight tests, 
minimum average number of baseline incontinence episodes per day as determined on 
a 7-day voiding diary).  When multiple assessments of incontinence severity are 
obtained at baseline (e.g., multiple 24-hour pad weight tests), we recommend your 
                                                 
 
30 J.H. Schagen van Leeuwen, R. Castro, M. Busse, B.L. Bemelmans.  The placebo effect in the 
pharmacologic treatment of patients with lower urinary tract symptoms, Eur Urol, 2006, 
50(3):440-452. 
21  Contains Nonbinding Recommendations 
 
 
protocol specify that the subject meet the pre-defined severity level for study inclusion 
on each assessment. 
 
Age 
The protocol should state the age range eligible for enrollment.  We recommend you 
consider the following factors in determining this range:  the typical age range 
associated with the particular category of urinary incontinence being studied, whether 
investigation of the device is appropriate for pediatric patients, and the minimum life 
expectancy to ensure study completion. 
 
Prior Treatment   
We recommend your protocol specify that subjects have failed or are refractory to 
more conservative therapies over a clinically meaningful period of time prior to study 
enrollment.  Generally, the type and duration of prior failed therapies depend upon the 
risks and benefits of study participation.  That is, studies for more aggressive 
investigational devices should specify longer trial periods of conservative therapies 
(e.g., 6-12 months of failed therapy prior to enrollment) than studies for lower risk 
devices.  This practice helps control the overall risks associated with the investigation 
by excluding subjects who may benefit from more conservative treatment options. 
 
Subject Compliance and Suitability   
In addition to giving informed consent in accordance with the requirements of 21 CFR 
Part 50, subjects should understand all the studys procedures, restrictions, and follow 
up duration, have life expectancies greater than the study period, be capable of 
tolerating the procedure (e.g., good surgical candidate, where appropriate), and agree 
to the baseline and follow-up evaluations specified in the protocol. 
 
2.  Exclusion Criteria 
Confounding Conditions 
Your protocol should exclude subjects who have a history of any condition, illness, or 
surgery that might confound the results of the study.  Confounding conditions include, 
but are not limited to, the following examples:   
  categories of urinary incontinence other than the categories being investigated; 
  prominent (i.e., greater than stage II as defined by the International Continence 
Society31) pelvic organ prolapse32,33 (e.g., cystocele, rectocele); 
                                                 
 
31 B.L. Shull, G. Hurt, J. Laycock, et al., Physical Examination, in Incontinence, Edited by P. 
Abrams, L. Cardozo, S. Khoury, and A. Wew , Paris: Health Publication Ltd., 2002, pg. 377 
32 S. Hunskaar, K. Burgio, A. Clark, et al., Epidemiology of urinary and faecal incontinence and 
pelvic organ prolapse, in Incontinence: Basics and Evaluation, edited by P. Abrams , L. 
Cardozo, S. Khoury, and A. Wein, vol. 1, Paris:  Health Publication Ltd., 2005, pp. 290-297. 
33 R.M. Ellerkmann, G.W. Cundiff, C.F. Melick, et al., Correlation of symptoms with location and 
severity of pelvic organ prolapse, Am J Obst Gynecol, 2001, 185(6):1332-1338. 
22  Contains Nonbinding Recommendations 
 
 
  neurological disorders (e.g., multiple sclerosis, Parkinsons disease);  
  abnormal bladder capacity (i.e., greater than 300 cc);  
  abnormal post void residual (i.e., greater than 50 cc); 
  urethral stricture and bladder neck contracture; 
  spastic bladder; 
  urinary tract infection (UTI); 
  vesicoureteral reflux 
  bladder stones; 
  bladder tumors; and  
  morbid obesity.  
 
Conditions Posing Additional Risks 
Depending upon the particular urinary incontinence device being studied, certain 
underlying conditions may pose unreasonable risks to the subject and should be 
excluded.  Examples include, but are not limited to:  concurrent infection (e.g., UTI, 
cystitis, urethritis), coagulation abnormalities, abnormal kidney function, and 
uncontrolled diabetes. 
 
Concurrent Medication 
Subjects who are taking medication that affects urination should either be excluded or 
adequately supported (e.g., medically necessary, stable dosage).  Such medication may 
include prescription drugs, over-the-counter drugs, or dietary supplements (including 
herbal supplements and those taken as teas).  If potentially confounding medications 
are clinically appropriate to take concurrently with the study, the protocol should 
request that the dosage not change during the study period unless medically necessary. 
 
Pregnancy 
The enrollment of pregnant women, women who might become pregnant, and 
lactating women presents two distinct challenges.  First, since pregnancy and delivery 
contribute to urinary incontinence and impact the measures used to evaluate this 
condition, the enrollment of pregnant and recently pregnant women has the potential 
to confound study interpretation.  Second, many of the devices covered by this 
guidance, such as those that are implanted, may present a risk to pregnant women, 
their fetuses, or their nursing offspring.  We recommend a detailed, case-by-case 
consideration of the merits of including such women in the study.  When risks to 
pregnant or nursing women, or fetuses or nursing offspring, are identified, we 
recommend that women who are pregnant or nursing at the screening exam be 
excluded from study enrollment.  If risk to the woman or fetus is an issue, we 
recommend that study participants who are of child-bearing potential consider using a 
form of contraception to limit the possible risks of the device.  If the risk to the 
nursing offspring is an issue, we recommend that women be warned of the risk and 
advised not to nurse while enrolled in the study.  
 
23  Contains Nonbinding Recommendations 
 
 
Prior Treatment 
Depending upon the particular urinary incontinence device being studied, certain prior 
incontinence treatments may confound the study results and, therefore, should be 
excluded.  For example, subjects treated previously with a device type similar to the 
one under investigation (e.g., injectable bulking agent) may be at greater risk of 
experiencing adverse events or have less potential for benefit. 
 
Contraindications and Warnings Related to the Control Therapy 
Subjects who would be excluded from treatment with the control therapy due to its 
labeled or known contraindications and warnings (e.g., hypersensitivity to the control 
injectable bulking agent) should be excluded.  
J.  Pre-Treatment Evaluation 
We recommend your protocol clearly describe all baseline tests, measurements, and 
examinations you plan to conduct at the pre-treatment evaluation.  To ensure consistency 
across the investigators and investigational sites, your protocol should specify clearly defined, 
well-recognized measures for all tests and measurements.  The pre-treatment evaluation 
should document all of the inclusion and exclusion criteria contained in the study protocol, 
such as (1) confirming the diagnosis of the category of urinary incontinence under study, and 
(2) ruling out any significant coexisting disease or condition that might put the subject at 
increased risk or confound the data analysis. 
 
In cases where clinically valid pre-treatment data already exists in the subjects medical 
records, these data may be used to document baseline status and avoid the need to repeat a test 
or measurement.  To ensure consistency, we recommend that the protocol clearly specify the 
conditions under which existing pre-treatment data may be used. 
 
We recommend your protocol specify the collection of the following information at the pre-
treatment evaluation. 
1.  Medical History  
We recommend your protocol instruct investigators to perform a thorough medical 
history, focused on the subjects urinary incontinence.  The purpose of the medical history 
is to evaluate the subjects eligibility for the study and to rule out confounding factors.  To 
permit future analyses of the contribution of various patient factors to the study results, 
investigators should record detailed medical history information in the case report forms.  
We recommend that the medical history include, but not be limited to: 
  dates and types of prior surgeries for problems other than urinary incontinence; 
  information regarding prior or ongoing therapies for urinary incontinence (e.g., 
surgeries, medications, device treatments, pelvic floor exercise therapy, 
biofeedback, electrostimulation therapy), such as:  treatment type, dates of therapy, 
duration, outcome, and side effects experienced; 
  dates of past bladder or kidney infections; 
24  Contains Nonbinding Recommendations 
 
 
  a detailed record of all medication (over-the-counter and prescription) and 
dietary/herbal supplements taken over the previous 6 months, indicating those 
currently being taken and their dosages; 
  description of the method currently being used by the subject to manage urinary 
incontinence; 
  vaginal parity, if applicable; 
  menopausal status, if applicable; 
  history of allergies; 
  history of current or past malignancy; and 
  documentation of other conditions that could be affected by treatment (e.g., 
autoimmune diseases for devices that use materials of animal origin) or that could 
affect or confound treatment outcome. 
 
Those potential study subjects found to have urinary incontinence based on the medical 
history described above should undergo the evaluations listed below to confirm the 
diagnosis of the specific urinary incontinence category being investigated and to exclude 
pelvic organ prolapse or neurologic disorders as the predominant factors causing urinary 
incontinence. 
2.  Physical Examination  
We recommend your protocol instruct investigators to perform a physical examination, 
including a detailed urological history, to assess urinary symptoms and symptoms of 
bowel function, sexual function, and, in females, pelvic organ prolapse. 
3.  Neurological Examination  
We recommend investigators perform a simple neurological examination on all patients, 
including assessment of anal sphincter tone, evaluation of voluntary anal contractions, and 
evaluation for intact perineal sensation.  If abnormalities are noted which would confound 
the study results, the investigator should exclude the subject from study participation. 
4.  Voiding Diary  
To document the frequency and severity of urinary incontinence and the circumstances 
under which urine leakage occurs, we recommend that subjects complete voiding diaries.  
Voiding diaries should document the daily chronological record of fluid intake, 
incontinence episodes with associated activity and perceived level of urgency, severity of 
each incontinence episode (i.e., estimated volume of leakage), pad usage, and normal 
voiding episodes with measured volume.  To maximize the quality of the collected 
information, we recommend that investigators provide subjects with adequate instructions 
on completing the voiding diary and train them on how to collect this information. 
 
Due to the high within-patient variability associated with urinary incontinence, acquiring a 
stable baseline measure is difficult using a voiding diary that is assessed over a limited 
duration of time.  Therefore, we recommend the use of a 7-day voiding diary during the 
pre-treatment evaluation. 
25  Contains Nonbinding Recommendations 
 
 
5.  Pad Weight Testing  
We recommend your study include pad weight testing to document quantitatively the 
severity of urine leakage at baseline.  Two commonly used methods of measuring urine 
leakage using pad weight are: 
  the 1-hour in-clinic provocative pad weight test; and 
  the 24-hour in-home pad weight test. 
 
The subject generally performs the 1-hour provocative pad weight test in the doctors 
office under prescribed exercises, whereas the subject performs the 24-hour pad weight 
test at home, by going about his or her normal daily activities (all pads used during the 24-
hour period are collected and weighed).  Although a 1-hour provocative pad weight test is 
inherently more standardized than the 24-hour pad weight test, it does not incorporate 
activities of daily living, which affect the patients quality of life.  However, the 1-hour 
provocative pad weight test specifically targets stress urinary incontinence and can be 
used to aid in making a differential diagnosis, whereas the 24-hour pad weight test is 
generally applicable to all categories of urinary incontinence.  Therefore, we recommend 
performing both types of pad weight tests.  To ensure consistency within and between 
subjects, we recommend your protocol standardize both types of pad weight tests to the 
extent possible.  Female subjects should not undergo pad weight testing during menses. 
 
Due to the high within-patient variability associated with urinary incontinence, acquiring a 
stable baseline measure is difficult using a single 24-hour pad weight test.  Therefore, we 
recommend performing three 24-hour pad weight tests during the pre-treatment 
evaluation. 
6.  Urodynamics Testing  
We recommend you perform the following baseline urodynamics tests at the pre-treatment 
evaluation to confirm the diagnosis of the specific urinary incontinence categories being 
investigated and to rule out abnormal bladder function. 
 
Uroflowmetry 
Uroflowmetry should include a measure of voided volume above a predefined 
minimum amount (e.g., 125 cc),34,35 total time of voiding, peak urine flow rate, 
average urine flow rate, and post-void residual urine volume (PVR).  Either ultrasound 
or catheterization is appropriate to measure PVR, but you should use the same method 
pre- and post-treatment. 
 
                                                 
 
34 P. Abrams, Bladder outlet obstruction index, bladder contractility index and bladder voiding 
efficiency: three simple indices to define bladder voiding function, BJU Int, 1999, 84:14-15. 
35 J.G. Blaivas and A. Groutz, Campbells Urology, edited by P.C. Walsh, A.B. Retik, E. 
Darracott Vaughan Jr., et al., Philadelphia:  Saunders, 2002, 8th edition, vol. 2, pp. 1039. 
26  Contains Nonbinding Recommendations 
 
 
Leak Point Pressure 
Leak point pressure (LPP) is the minimum intravesical pressure at which urine leaks 
around a small, pressure-sensing urethral catheter.  LPP is determined by inserting a 
catheter into the bladder and filling the bladder with 200-250 cc of water, and should 
be used as part of the subjects work-up to identify the presence or absence of stress 
urinary incontinence.36,37  LPP is usually low (less than 50-60 cm H O) for patients 
2
whose stress urinary incontinence is predominantly due to ISD.  Therefore, for studies 
targeting stress urinary incontinence due to ISD, we recommend your protocols 
inclusion criteria specify a maximum LPP for study entry. 
 
Cystometry 
Liquid cystometry (using saline) should include a measure of bladder capacity, 
sensation of fullness (compliance), and urgency (volume at which involuntary leakage 
occurs).  In addition to being a useful test for documenting normal bladder function, 
you should also include cystometry as part of the subjects work-up to identify the 
presence or absence of urge incontinence. 
7.  Cystoscopy  
Your protocol should instruct investigators to perform cystoscopic examination at the pre-
treatment evaluation to document the absence of bladder neck obstruction, presence or 
absence of urethral strictures, and other bladder pathology. 
8.  Laboratory Testing  
Your protocol should instruct investigators to perform the following laboratory tests to 
screen the subject for study entry. 
 
Urinalysis with Urine Culture 
Investigators should perform urinalysis with urine culture to exclude patients with 
active UTI. 
 
Blood Chemistry 
We recommend your protocol specify the collection of routine blood chemistry 
information, including complete blood count (CBC) and blood urea nitrogen (BUN). 
 
Pregnancy Test 
To screen subjects for pregnancy, investigators should administer a pregnancy test to 
women of child-bearing potential. 
                                                 
 
36 R. A. Appell, Injectables for urethral incompetence, World J Urol, 1990, 8(4):208-211. 
37 E.J. McGuire, C.C. Fitzpatrick, J. Wan, et al., Clinical assessment of urethral sphincter 
function, J Urol, 1993, 150(5 Pt 1):1452-1454. 
27  Contains Nonbinding Recommendations 
 
 
9.  Questionnaires  
Your protocol should instruct investigators to administer the following questionnaires to 
study subjects. 
 
Quality of Life 
Subjects should complete a validated, incontinence-specific quality of life assessment.  
The purpose of this questionnaire is to assess subject perceptions of the impact of 
treatment upon various aspects of their lives. 
 
Sexual Function 
Subjects should complete a validated, gender-specific sexual function questionnaire 
prior to treatment, to enable assessment of whether device use impacts sexual function. 
 
Patient Satisfaction 
Subjects should complete a standardized survey to record their satisfaction with 
specific aspects and dimensions of their lives that may be impacted by urinary 
incontinence.  We recommend you compare these baseline results to the results of the 
post-treatment satisfaction survey. 
K.  Investigator Selection and Training 
We recommend you select study sites and investigators that are capable of recruiting 
sufficient numbers of eligible subjects representative of the target population for your 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.   
 
Many investigational devices for urinary incontinence are novel in design or clinical 
application, or involve different techniques than used for existing devices.  To help ensure the 
safe, proper, and consistent use of the investigational device, and to enhance the ability to 
pool the data across study sites, we recommend your protocol describe a training program to 
educate investigators on the use of your device.  This training should consist of didactic 
instruction, covering the device functions and principles of operation, and may also involve 
proctoring by an experienced physician.  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, blinding, the follow-up schedule, data 
collection methodology, and adverse event reporting. 
L.  Treatment Information 
To promote consistency across investigators and investigational sites, we recommend your 
study protocol thoroughly describe the investigational and control treatments.  This 
information should include, but is not limited to: 
  pre-operative patient education and preparation; 
  anesthesia requirements; 
28  Contains Nonbinding Recommendations 
 
 
  device directions for use (e.g., sizing, route of administration, technique, placement, 
amount implanted, settings or treatment parameters); 
  recommended instrumentation or 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, your protocol should 
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, and any special treatment instructions for performing retreatment. 
M.  Post-Treatment Evaluations 
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.  The 
follow-up schedule should include early examinations to assess any post-operative healing 
period and the initial use of the device, in addition to regular visits throughout the follow-up 
period to collect outcome information to allow assessment of the primary and secondary 
endpoints.  To ensure consistency during the study and across investigational sites, we 
recommend your protocol instruct investigators to perform post-treatment tests using the same 
methodology as used during the pre-treatment evaluation. 
 
We recommend that the post-treatment evaluations include, but not be limited to, the 
following tests and assessments: 
  physical examination; 
  voiding diary; 
  pad weight testing; and 
  questionnaires. 
 
In addition, we recommend your protocol specify the following tests and assessments during 
the post-treatment evaluation period. 
 
Urodynamics Testing 
For a device that has the potential to impact bladder emptying, we recommend assessing 
PVR at each post-treatment exam.  For an indication of stress urinary incontinence, we 
recommend assessing LPP at 6 and 12 months post-treatment.  For an indication of urge 
incontinence, we recommend performing cystometry at 12 months post-treatment. 
 
Cystoscopy   
For an intravesical or intraurethral device, we recommend cystoscopic examination at 
12 months post-treatment; for other device designs, we recommend that cystoscopic 
examinations be scheduled at appropriate times post-treatment to assess the potential 
impact of the device upon the bladder and urethra. 
29  Contains Nonbinding Recommendations 
 
 
 
Laboratory Testing 
To assess for UTI, we recommend performing urinalysis at each follow-up visit, with 
urine culture if indicated.  Additionally, we recommend collecting blood chemistry 
information at 12 months post-treatment, including CBC and BUN. 
N.  Statistical Analysis Recommendations 
Your 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 to the analytical purpose and thoroughly documented.  We 
recommend your statistical analysis plan include the information described below.  However, 
depending on the design or indications of your device, or the nature of the data you have 
collected, FDA may recommend additional or different analysis techniques. 
1.  Primary Endpoint Analyses  
The primary statistical analysis of the study is generally the statistical analysis used to 
assess the overall success or failure of the study.  Therefore, we recommend describing 
and documenting the details of this analysis in your protocol.  As stated under F. Study 
Duration, we recommend conducting the primary analysis of study success using 12-
month follow-up data.  To reduce bias, we recommend performing this primary analysis 
using the intent-to-treat (ITT) population.  The ITT population includes all subjects 
randomized into the study, regardless of whether or not the subjects received the treatment 
to which they were randomized. 
 
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.  Every effort should be made to assess the plausibility of the underlying 
assumptions for each of these sensitivity analyses.  We recommend these additional 
analyses include the following, among others: 
  analysis of the per protocol population (e.g., subjects treated and followed per the 
protocol); 
  sensitivity analyses, using a variety of pre-specified methods for imputing missing 
data; 
  longitudinal or repeated measures analysis, to assess impact of time post-
treatment upon the results; and 
  assessment of the number of subjects who are dry, 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 the protocol describe comprehensive covariate analyses.  To 
30  Contains Nonbinding Recommendations 
 
 
minimize bias associated with these analyses, we recommend your protocol prospectively 
define all important covariates.  Important covariates include, but are not limited to: 
  investigational site; 
  gender; 
  age; 
  weight or body mass index; 
  ethnicity; 
  smoking status; 
  alcohol use status; 
  occupation; 
  duration of incontinence; 
  all baseline measures of incontinence, including incontinence-specific quality of 
life score; 
  vaginal parity, if applicable; 
  menopausal status, if applicable; 
  prior hysterectomy, if applicable; 
  prior surgery for incontinence; 
  retreatments; 
  medication usage; and 
  device-related covariates (e.g., device settings). 
2.  Secondary Endpoint Analyses  
We recommend your protocol prospectively define the statistical plan for performing 
secondary endpoint analyses in the event that the primary endpoint analysis has been 
successfully met.  If the secondary endpoint analyses are intended purely as exploratory 
analyses, or are not intended to support the indication for use or device performance, we 
recommend you submit only simple descriptions of the analyses.  If, on the other hand, 
any of the secondary endpoint analyses are intended to support the indication for use or 
the performance of your device 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 describe in detail the statistical methods you plan to 
follow. 
 
The primary statistical challenge in supporting the indication for use or device 
performance in the labeling is in making multiple assessments of the secondary endpoint 
data without increasing the type 1 error rate above an acceptable level (typically 5%). 
There are many valid multiplicity adjustment strategies available for use to maintain the 
type 1 error rate at or below the specified level, three of which are listed below: 
  Bonferroni procedure; 
  Hierarchical closed test procedure; and 
31  Contains Nonbinding Recommendations 
 
 
  Holms step-down procedure. 
 
Because each of these multiplicity adjustment strategies involves balancing different 
potential advantages and disadvantages, we recommend you prospectively state the 
strategy that you intend to use.  We recommend your protocol prospectively state a 
statistical hypothesis for each secondary endpoint related to the indication for use or 
device performance.   
3.  Missing Data 
Missing data can represent a significant source of potential bias.  Although a variety of 
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.38  To this end, we recommend your protocol incorporate the elements listed below. 
 
Efforts to minimize missed visits and drop-outs 
We recommend you describe the special efforts to monitor and minimize the incidence 
of missing data and patient drop-outs during the study, such as monitoring activities, 
instruction and training on voiding diary data collection, special incentives to subjects 
for study compliance, methods to remind subjects of scheduled visits, and specific 
efforts to contact subjects who miss their visits (e.g., telephone calls, post cards, 
contact next-of-kin). 
 
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, death certificate). 
 
To permit a complete and detailed accounting of all study subjects, we recommend you 
collect complete information 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, you 
should attempt to minimize the overall rate of loss to follow-up over the course of the 
study. 
 
The protocol should specify how you plan to address missing data in the statistical 
analysis.  A common approach is ITT analysis.  Other approaches include the as-treated or 
per protocol analyses.  The ITT approach preserves the comparability of patients with 
                                                 
 
38 R.H. Woolhard, K. Carty, P. Wirtz, R. Longabaugh, et al., Research fundamentals:  follow-up 
of subjects in clinical trials:  addressing subject attrition, Acad Emerg Med, 2004, 11(8):859-866. 
32  Contains Nonbinding Recommendations 
 
 
respect to (observed and unobserved) baseline characteristics and is generally regarded as 
the preferred method for evaluating a new therapy.39  As discussed above (in 1. Primary 
Endpoint Analyses), 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,40 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 
(e.g., unintended electrical shock from an implantable stimulator, or tissue burns occurring 
during the use of an electrosurgical heating device), and the risks associated with the 
treatment procedure (e.g., the surgical risks associated with the placement of an implant, the 
risks of cystoscopy associated with the use of an injectable bulking agent, or anesthesia risks).  
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 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, please see 
the Agencys guidance entitled Guideline for the Monitoring of Clinical Investigations41 
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 his or her duties.  In addition to the elements required by 21 CFR Part 812 
and 21 CFR Part 50 and the recommendations of the Guideline for the Monitoring of 
                                                 
 
39 J.H. Ellenberg, Intent-to-treat analysis versus as-treated analysis, Drug Inf J, 1996, 30:535-544. 
40 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). 
41 http://www.fda.gov/RegulatoryInformation/Guidances/ucm126400.htm  
33  Contains Nonbinding Recommendations 
 
 
Clinical Investigations, we recommend you incorporate the following elements into your 
monitoring procedures, including, but not limited to: 
  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 
  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 and a means to rapidly implement those 
plans.  You and the monitor should carefully devise 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 assigned, follow-up data collected at the 
appropriate times, and data are completely and accurately recorded, as specified in the 
protocol. 
Q.  Case Report Forms 
To assure 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 format these forms to instruct investigators to record all information 
described in your protocol.  The case report forms should include, but not necessarily be 
limited to: 
  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.  
 
FDAs recommendations for the content of each form are discussed below.   
 
A pre-treatment evaluation form should include all relevant information from the pre-
treatment evaluation, such as medical history, physical exam, baseline screening 
measures, and documentation of inclusion and exclusion criteria. 
 
A treatment information form should include 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, 
34  Contains Nonbinding Recommendations 
 
 
route of administration, technique, placement, amount implanted, 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 should include all data collected at each follow-up visit.  
Generally, a separate post-treatment evaluation form should be completed at each follow-
up visit. 
 
A concomitant medication form should list all medications and dietary supplements taken 
by the subject at baseline and during the study, and specifies the dates of usage and 
dosage. 
 
A protocol deviation form should identify and describe each protocol deviation, indicating 
the date, type of deviation, and clinical justification for the deviation. 
 
An adverse events form should identify and describe 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 should include the date and reason for patient 
discontinuation from the study.  Typical reasons for study termination include study 
follow-up completed, consent withdrawn by subject, exited to receive alternate treatment, 
exited by investigator, death, and lost to follow-up. 
 
 
35  Contains Nonbinding Recommendations 
 
 
Appendix 1 
 
Sources of Bias  Common Mitigation Methods 
Selection Bias 
  Randomization 
occurs when patients 
possessing one or more    Objective diagnostic and outcome measures 
important prognostic factors 
  Homogeneous study population 
appear more frequently in one 
  Pre-specified protocol, endpoints, and 
of the comparison groups than 
statistical plan 
in the others. 
Investigator Bias 
occurs when an investigator    Blinding 
consciously or subconsciously 
  Pre-specified protocol, endpoints, and 
favors one study group at the 
statistical plan 
expense of the others. 
Evaluator Bias 
is a type of investigator bias in 
which the person measuring 
the outcome variable 
intentionally or unintentionally 
  Blinding 
records the measurements in 
favor of one intervention over    Objective diagnostic and outcome measures 
another.  Studies that have 
subjective endpoints (e.g., 
quality of life) are particularly 
susceptible to this form of bias.
Placebo or Sham Effect 
is a bias that occurs when a 
patient exposed to an inactive    Randomization 
therapy believes that he (or    Blinding 
she) is being treated with an 
  Objective diagnostic and outcome measures 
intervention and subsequently 
shows or reports improvement. 
Missing Data 
can introduce bias when 
  Documentation and enhanced compliance 
subjects who do not report for 
  Plan to conduct sensitivity analyses 
follow-up experience a 
different outcome from those   
who do. 
 
36