Medtronic, Inc.
7000 Central Avenue, RCW-235
Minneapolis, MN 55432-3576
www.medtronic.com
tel 763.526.6753
fax 763.526.6246
December 18, 2008
Food and Drug Administration
Division of Dockets Management (HFA-305)
5630 Fishers Lane, Room 1061
Rockville, MD 20852
RE: Docket No. FDA-2008-D-0285: Draft Guidance for Industry and Food and Drug
Administration Staff; Clinical Investigations of Devices Indicated for the Treatment of
Urinary Incontinence
Medtronic appreciates the opportunity to provide input to the Draft Guidance for Industry
and Food and Drug Administration Staff; Clinical Investigations of Devices Indicated for
the Treatment of Urinary Incontinence. Medtronic’s comments are provided in the
attached document.
Medtronic understands the scope of the Guidance is specific to devices with urinary
incontinence indications. Medtronic’s InterStim Therapy for Urinary Control is indicated
for the treatment of urinary retention and the symptoms of overactive bladder, including
urinary urge incontinence and significant symptoms of urgency-frequency alone or in
combination, in patients who have failed or could not tolerate more conservative
treatments, so this Guidance does not represent all of our indications. We look forward
to discussing with FDA the implication of this Guidance for studies that include
endpoints other than urinary incontinence.
We would appreciate the opportunity to review future drafts of this Guidance. Please
contact me if you have specific questions.
Sincerely,
Daniel Ritter
Medtronic Neuromodulation
Rice Creek West
7000 Central Ave., N.E.
Minneapolis, MN 55432-3576
Phone: 763-526-6753
Fax: 763-526-6246
Medtronic, Inc.
7000 Central Avenue, RCW-235
Minneapolis, MN 55432-3576
www.medtronic.com
tel 763.526.6753
fax 763.526.6246
1. Introduction
Medtronic has identified concerns with the Guidance document. All of our comments are
outlined below but we would like to suggest the following changes be made to the
Guidance:
1) Voiding diaries should be the primary source of data collection
2) Pad weights should be used as a secondary endpoint
3) Urodynamics testing should not be a required protocol measurement or diagnostic
Throughout the comments below, Medtronic will reference InterStim systems.
Medtronic InterStim Systems are designed to deliver therapeutic nerve stimulation
through the following system components: a neurostimulator, a lead with four
programmable electrodes, and a lead extension (Model 3023 Neurostimulator only). The
system works by conducting electrical pulses, which are produced by the
neurostimulator, through the lead system.
2. Endpoints
2.1
Recommendation of pad weight as an endpoint
The Guidance document recommends 1-hour and 24-hour pad weight as a primary
effectiveness endpoint (page 14). Medtronic is concerned about this recommendation for
reasons addressed below and therefore recommends that pad weight is not considered as
a primary endpoint measure.
 It appears that recently approved medications for the treatment of urinary
incontinence used voiding diary data, not pad weight, as the primary outcome
measure.1,2,3 We failed to find literature that supported the use of pad weight as a
primary efficacy endpoint.
 The literature suggests that the reliability of pad weight is poor.4,5 Simons5
concluded that the poor repeatability in 1-hour pad weight tests suggest that it is
not an optimal measure of post-treatment change. Jorgensen4 reported no
relationship between 1-hour and 24-hour pad weight tests and showed a
significant variation in repeated 24-hour pad tests.
 Medtronic had the opportunity to survey 8 physicians who have conducted several
urinary incontinence safety and effectiveness studies. Their experience was that
study subjects have a difficult time collecting and storing pads between study
visits; often, the liquid in the pad evaporates by the time the pads are collected.
 Although the Guidance recommends the use of both 1-hour and 24-hour pad
weight tests, the Guidance also states that 1-hour pad weight “…specifically
targets stress urinary incontinence…” (p. 25). Medtronic agrees that 1-hour pad
weight is related to stress incontinence and believes that using 1-hour pad weight
as a primary endpoint seems to be an undue burden for a device that does not treat
stress incontinence.
Medtronic, Inc.
7000 Central Avenue, RCW-235
Minneapolis, MN 55432-3576
www.medtronic.com
tel 763.526.6753
fax 763.526.6246
2.2
Use of a composite endpoint
The Guidance discusses the use of a composite endpoint that would include both the
1-hour and 24-hour pad weight tests (page 15). But then the Guidance gives, as an
example of a composite endpoint, the use of pad weight and incontinence episodes. We
were not able to find literature to support the use of a composite endpoint for any of the
examples in the Guidance. Medtronic suggests that the use of a composite endpoint is
removed as a recommendation.
2.3
Use of secondary endpoints
The Guidance then states on page 15, “If you select only one of these outcome measures,
reduction in pad weight or reduction in number of incontinence episodes, as the primary
effectiveness endpoint, we recommend your protocol include the other as a secondary
endpoint.” If a sponsor chooses this strategy, it is not clear if the study needs to be
powered to detect a difference in the secondary outcome and if the sponsor needs to pass
the secondary endpoint for product approval. Medtronic recommends that the study need
only be powered for a primary endpoint.
2.4
Dryness definition
For both pad weight and incontinence episodes/day (pages 14-15), FDA recommends a
definition of dry and clinically meaningful.
Pad weight:
 Dry: increase of less than 1 gram (for 1-hour pad weight test) and less than 1.3
grams for 24-hour pad weight.
 Clinically meaningful level of improvement: >50% reduction from baseline.
Incontinent episodes/day:
 Dry: 0 incontinent episodes/day.
 Clinically meaningful level of improvement: >50% reduction from baseline
Should the study design incorporate both of these definitions as endpoints? That is, do
both dry and clinically meaningful level of improvement definitions need to be met to
pass endpoints?
Medtronic, Inc.
7000 Central Avenue, RCW-235
Minneapolis, MN 55432-3576
www.medtronic.com
tel 763.526.6753
fax 763.526.6246
3. Use of Urodynamics
The Guidance recommends the measure of post-void residual (PVR) as a secondary
endpoint if the device has the potential to impact bladder emptying (page 18). PVR is a
common diagnostic used with retention patients. Enforcing the measurement of PVR in a
study that is assessing urinary incontinence may be an undue diagnostic burden for our
study subjects. Medtronic requests removal of this requirement or more clarification of
why this measurement should be used for urinary incontinence studies.
The Guidance recommends the use of 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 (page 26). Medtronic’s InterStim
device is indicated for patients who have failed more conservative medical therapy for
urinary incontinence such as OAB medications, behavioral modifications, and
biofeedback. By the time InterStim is considered as a therapy option, the patient’s
diagnosis of urinary incontinence is well-known. While urodynamics testing is used as a
confirmatory diagnostic tool, it is an extra burden for this patient population prior to
study enrollment. In addition, urodynamics testing is difficult to standardize across study
centers. We understand the need to ensure the subjects who enter a study meet
standardized inclusion criteria but the variability in urodynamics testing may not help this
cause. Medtronic requests removal of this requirement from the guidance to minimize
the burden on the patient.
Medtronic, Inc.
7000 Central Avenue, RCW-235
Minneapolis, MN 55432-3576
www.medtronic.com
tel 763.526.6753
fax 763.526.6246
4. Primary Safety Endpoint
Medtronic agrees with the Guidance that the primary safety endpoint should be based on
the incidence and severity of adverse events. However, we would like further information
regarding the recommendation on page 16 which states:
“Because of the difficulty determining the root cause of genitourinary events, we
recommend you categorize all genitourinary events conservatively as either
device- or procedure-related.”
Medtronic feels this conservative approach may produce a misleading safety assessment
of a new therapy. Our therapies are used in patients who commonly have genitourinary
events, such as urinary tract infections (UTIs). We feel categorizing these as device- or
procedure-related would not be representative of the therapy. We take the following
steps to determine root cause of all adverse events:
1) We approach highly qualified research physicians who are knowledgeable
about the therapy being investigated and the disease being treated. These
physicians accept the responsibility to assess the relationship and severity of
all adverse events to the device or procedure.
2) We instruct study physicians and their staff to report all adverse events
regardless of relatedness to the device or procedure.
3) The use of an independent Clinical Events Committee (CEC) is required on all
studies to review all adverse events that occur throughout the study. The CEC
adjudicates the relatedness to the device or procedure and the severity of the
event. If the CEC has further questions about an event or requests an event
categorization be changed, the physician will be queried.
4) The MedDRA coding system is used to code all adverse events allowing
trending analyses to be done throughout the study.
We do agree that if the root cause can not be determined, it is prudent to go with the
conservative assessment of categorizing as device- or procedure-related. However, we
would like to maintain the option of categorizing a genitourinary event as subject related
if, through the above processes, the event is determined not to be related to the device or
procedure.
Medtronic, Inc.
7000 Central Avenue, RCW-235
Minneapolis, MN 55432-3576
www.medtronic.com
tel 763.526.6753
fax 763.526.6246
5. Three 3-day diary
The Guidance recommends an objectively measured severity of incontinence that reflects
the targeted patient population (… minimum average number of baseline incontinence
episodes per day as determined on three 3-day voiding diaries) (page 21). Can FDA
provide the rationale and support for this measure? Medtronic has the following
concerns with the diary recommendation in this guidance:
1) The literature supports the use of diary periods ranging from 3-7 days6,7,8 as being
acceptable in assessing patients’ symptoms. Increasing diary duration is
associated with decreased patient compliance.
2) As stated above, patients are indicated for Medtronic’s Interstim after failing other
conservative therapies and their diagnosis and severity of urinary incontinence is
understood. Three 3-day voiding diaries would be burdensome to this patient
population.
3) In addition, it is unclear how these diaries would be collected and analyzed. For
example, is a 9 consecutive day diary equivalent to three 3-day diaries?
6. Control Groups
The Guidance has an exhaustive list of control groups that would aid in the assessment of
safety and effectiveness (page 10). FDA lists potential control therapies and recommends
the current standard of care as the most clinically meaningful control.
The document states on page 11 that "…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." Medtronic looks forward to speaking to FDA in the future
(through the pre-IDE process) about the study design, including the appropriate control
group, needed for future studies.
Medtronic, Inc.
7000 Central Avenue, RCW-235
Minneapolis, MN 55432-3576
www.medtronic.com
tel 763.526.6753
fax 763.526.6246
References
1. Basra R, Kelleher Con. A review of solifenacin in the treatment of urinary
incontinence. Nat Clin Pract Urol. 2008;4:117-128.
2. Sahai A, Mallina R, Dowson C, Larner T, Khan MS. Evolution of transdermal
oxybutynin in the treatment of overactive bladder. Int J Clin Pract. 2008;62:167-170.
3. Steers WD, Herschorn S, Kreder KJ et al. Duloxetine compared with placebo for
treating women with symptoms of overactive bladder. JSteers, 2007
4. Jorgensen L, Lose G, Thunedborg P. Diagnosis of mild stress incontinenence in
females. Neurourol Urodyn. 1987;6:165-166.
5. Simons AM, Yoong WC, Buckland S, Moore KH. Inadequate repeatability of the
one-hour pad test: the need for a new incontinence outcome measure. BJOG.
2003;108;315-319.
6. Brown, J; McNaughton, K; Wyman, J; Burgio, K, et al. Measurement characteristics
of voiding diary for use by men and women with overactive bladder. Urology; 2003, vol.
61. n4. pp. 802-809.
7. Nygaard, I; Holcomb, R. Reproducibility of the seven-day voiding diary in women
with stress incontinence. Intern. Urogyn Journal. Vol 11, number 1/January, 2000; pgs
15-17.
8. Groutz, A; Blavas, D; Chaikin, N; Resnick, K; et al. Noninvasive outcome measures
of urinary incontinence and lower urinary tract symptoms: a multicenter study of
micturition diary and pad tests. Journal of Urology, Vol. 164, issue 3, pgs 698-701.